The main directions of general practice family medicine with the family, prevention of congenital and hereditary diseases. Clinical supervision of children with abnormal urinary and endocrine systems in family practice doctor.

 

  Differential diagnosis of urinary tract infections include urethritis, vaginitis, trauma, hypercalciuria (dysuria), detrusor/sphincter dysfunction, neurogenic urinary bladder, different anatomical abnormalities.

 

 

 

 

  Congenital anomalies.

 

Renal agenesis – unilateral renal agenesis incidence of 1 in 450 to 1,000 births.

Ø   In true agenesis, the ureter and the ipsilateral bladder hemitrigone are absent;

Ø   The contralateral kidney undergoes compensatory hypertrophy, to some degree prenatally but primarily after birth;

Ø    Approximately 15% of these children have contralateral vesicoureteral reflux

Aplasia – nonfunctioning tissue and normal or abnormal ureter.

Ø   If there is a normal contralateral kidney, renal function should remaiormal over time.

Bilateral renal agenesis – incompatible with extrauterine life and is termed Potter syndrome.

Ø   Death occurs shortly after birth from pulmonary hypoplasia. The newborn has a characteristic facial appearance, termed Potter facies.

Familial renal adysplasia describes disease in which renal agenesis, renal dysplasia, multicystic kidney (dysplasia), or a combination, occurs in a single family.

Ø   This disorder has an autosomal dominant inheritance pattern with a penetrance of 50–90% and variable expression.

 

Renal dysgenesis refers to maldevelopment of the kidney that affects its size, shape, or structure. The 3 principal types of dysgenesis are:

Ø   Dysplastic

Ø   Hypoplastic

Ø   Cystic.

 

A multicystic kidney: a congenital condition in which the kidney is replaced by cysts and does not function, and may result from ureteral atresia.

Ø   Renal size is highly variable.

Ø   The incidence is approximately 1 in 2,000.

Ø   An inherited disorder that may be autosomal recessive or autosomal dominant and affects both kidneys

Ø   Multicystic kidney usually is unilateral and is not inherited. Bilateral multicystic kidneys are incompatible with life.

Ø   Multicystic dysplastic kidney is the most common cause of an abdominal mass in the newborn.

Ø   In most cases it is discovered incidentally during prenatal sonography.

Ø   Contralateral hydronephrosis is present in 5–10% of patients.

Renal hypoplasia: a small nondysplastic kidney that has fewer than the normal number of calyces and nephrons.

Ø   If the condition is unilateral, the diagnosis usually is made incidentally

Ø   Bilateral hypoplasia usually presents with the manifestations of chronic renal failure and is a leading cause of end-stage renal disease during the first decade of life.

Ø   A history of polyuria and polydipsia is common.

Ø   Urinalysis results may be normal.

The Ask-Upmark kidney, also termed segmental hypoplasia:

Ø   Small kidneys, usually weighing not more than 35 g, with one or more deep grooves on the lateral convexity, underneath which the parenchyma consists of tubules resembling those in the thyroid gland.

Ø   It is unclear whether the lesion is congenital or acquired.

Ø   Most patients are 10 yr or older at diagnosis and have severe hypertension.

Ø   Nephrectomy usually controls the hypertension.

 

  Urinary tract infection.

Etiology.

·                                     Escherichia coli is the most common cause of bacterial UTI.

Other organisms:

·                                     Klebsiella spp, Enterococcus, Staphylococcus saprophyticus, Proteus mirabilis;

·                                     Pseudomonas, Streptococcus, Candida albicans (usually associated with complicated UTIs or chronic antibiotic treatment).

Risk factors in all children include:

·                                     Indwelling catheters

·                                     Urologic tract anomalies

·                                     Neurogenic bladders

Risk factors specific to girls include:

·                                     Chemical irritants

·                                     Sexual activity

·                                     Sexual abuse

·                                     Constipation

·                                     Pinworms

Risk factors specific to boys include:

·                                     Phymosis       

Uncircumcised boys have an incidence of infection 10 times that of circumcised boys.

Epidemiology.

·                         Bacteriuria is present in 1%– 2% of prepubertal children.

·                         In the first year of life, the risk of infection is equal among boys and girls

·                         The risk in girls is considerably higher in toddlers and older children.

·                         The incidence of UTI is 3.0% in febrile infants younger than 12 mo of age without an obvious cause for fever

·                         Vesicoureteral reflux is present in 18%– 50% of children with UTI

Symptoms.

·                        In infants, vomiting, poor feeding, and irritability.

·                        Older children develop dysuria, urgency, frequency, incontinence, hesitancy, and retention; fever, chills, back pain are symptoms that suggest an upper tract infection (pyelonephritis).

Signs.

·             Fever

·             Jaundice (may be seen ieonates).

·             Suprapubic or costovertebral angle tenderness

·             Abdominal or flank mass: suggestive of obstructive uropathy.

·             Sacral dimple, hairy patch over the sacrum, abnormal gluteal cleft, decreased rectal tone, lipoma: suggest spinal cord anomalies.

·             Labial adhesion, trauma, and irritation: may increase the risk of infection.

Investigations.

·             Urine culture: considered positive if any organisms are present on a suprapubic collection; > 10⁴ colony forming units (CFU)/mL of a urinary pathogen from a catheterized specimen; > 10⁵ CFU/mL of a urinary pathogen from a clean catch.

·             Urinalysis with dipstick: demonstrating positive leukocyte esterase and nitrite test with microscopic examination demonstrating more than five leukocytes per hpf, bacteria is highly suggestive of a urinary tract infection (UTI); this is not reliable in infants in whom the urine is dilute; 10% may have a negative urinalysis result despite a positive culture.

·             Radiographic imaging: indicated in every boy with an infection and girls with pyelonephritis; girls with recurrent lower tract infections or those who are younger than 5 years of age with their first infection should be studied as well.

·             Renal and bladder ultrasound: a noninvasive aid to look for hydroureteronephrosis, duplex kidneys, and ureteroceles, which may be a sign of obstruction.

·             Voiding cystourethrography: might demonstrate vesicoureteral reflux and is especially important in the male to exclude posterior urethral valves.

·             99m Tc-DMSA scan: controversial; it is an excellent study to identify pyelonephritis as the cause of fever when the source is not known; it is the most sensitive study to determine the presence of scars; however, it may not ultimately change the course of treatment.

Complications.

·                        Septicemia: more likely to be present ieonates or in children with abnormal urinary tracts.

·                        Renal scarring: can develop years after infections that occurred in infancy or early childhood; it is associated with hypertension, toxemia, and the risk ofchronic renal failure leading to end-stage renal disease.

·                        Staghorn calculi: can form in the presence of repeated infections.

Treatments

·             Increased water intake offers several benefits; it dilutes urine, increases voiding frequency, and reduces constipation. Stool softeners should be considered if the latter problem persists.

·             Irritants, particularly soap, should be avoided near the perineum in prepubertal girls.

·             Sexually active women may benefit from postcoital voiding.

Pharmacologic treatment.

Complicated febrile urinary tract infections.

Complicated infections are defined as those seen in infants younger than 6 months of age and any child who is clinically ill, persistently vomiting, moderately dehydrated, or poorly compliant; these cases warrant intravenous antibiotics and hospitalization.

Standard dosage.

·             Ampicillin, 50– 100 mg/kg/d in four divided doses.

·             Gentamicin, 2– 2.5 mg/kg/dose every 8 h.

·             Ceftriaxone, 75 mg/kg/dose every 12 h (does not cover Enterococcus, which is more frequently encountered in children with recurrent infection and should be avoided ieonates).

Special points An oral agent can be used after the child improves clinically (>24 h afebrile) pending the results of the culture and sensitivities; total treatment should last 14 d or longer if there is a renal abscess or an abnormal urinary tract.

Uncomplicated febrile urinary tract infections.

These children do not appear clinically ill, can take oral antibiotics, and are only mildly dehydrated (if at all) and compliant. Treatment can start with one dose of a parenteral agent (ceftriaxone, 75 mg/kg i.v. or i.m.; gentamicin, 2.5 mg/kg i.v. or i.m.) followed by oral therapy or with oral therapy alone. Good follow-up is essential to ensure the child has responded appropriately, with treatment lasting 10– 14 d.

Standard dosage.

·             Cotrimoxazole, 6– 12 mg/kg/d trimethoprim divided twice daily.

·             Amoxicillin, 20– 40 mg/kg/d divided 3 times daily (many strains of E. coli are resistant to amoxicillin).

·             Cephalexin, 25– 50 mg/kg/d divided 4 times daily.

·             Cefprozil, 15– 30 mg/kg/d divided 2 times daily.

Afebrile urinary tract infections (acute cystitis).

Oral therapy with the agents listed above for a total of 5– 7 d assuming clinical improvement is seen; in addition, nitrofurantoin 5– 7 mg/kg/d divided 4 times daily can be considered; the liquid form of nitrofurantoin is not well tolerated.

Covert (asymptomatic) bacteriuria.

·             The treatment of this subgroup is controversial even in the presence of reflux; treatment may lead to the emergence of resistant organisms.

Prophylaxis.

Standard dosage.

·             Cotrimoxazole: 1– 2 mg/kg trimethoprim daily.

·             Nitrofurantoin, 1– 2 mg/kg/d.

Both of the above medications should be avoided in infants younger than

6 months of age.

·             Amoxicillin (10 mg/kg/d) or cephalexin (10 mg/kg/d) can be used instead.

Other treatments.

·             Infection in the presence of obstruction requires effective drainage of the urinary tract (eg, nephrostomy, bladder catheterization) in addition to antibiotic therapy.

·             Surgical correction of vesicoureteral reflux in indicated when the reflux is massive, when breakthrough infections develop, or when poor compliance is suspected.

Prognosis.

Rick for renal damage includes

· infant and young children with febrile infections in whom treatment is delayed

· Children with massive vesicoureteral reflux, and those with anatomic or neuropathic urinary tract obstruction.

Follow-up and management

· Follow-up cultures should be obtained in children with febrile UTIs to assure an appropriate response.

· Infants and young children with documented vesicoureteral reflux should remain on antibiotic prophylaxis until the reflux resolves

· Some children with recurrent infections benefit from a short course of prophylactic therapy even when reflux is not present.

 

 

Diabetes mellitus (DM) in children.

The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both (Fig. 1). The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long–term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease. Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and proteinmetabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.

Fig. 1. Pathogenesis of DM type 1.

Diagnosis and diagnostic criteria.

If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully established since theconsequences for the individual are considerable and lifelong. The requirements for diagnostic confirmation for a person presenting with severe symptoms and gross hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to be just above the diagnostic cut–off value. Severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value. For the asymptomatic person, at least one additional plasma/blood glucose test result with a value in the diabetic range is essential, either fasting, from a random (casual) sample, or from the oral glucose tolerance test (OGTT). If such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance with periodic re–testing until the diagnostic situation becomes clear. In these circumstances, the clinician should take into consideration such additional factors as ethnicity, family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action. An alternative to blood glucose estimation or the OGTT has long been sought to simplify the diagnosis of diabetes. Glycated haemoglobin, reflecting average glycaemia over a period of weeks, was thought to provide such a test. Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement, it is not available in many parts of the world and is not well enough standardized for its use to be recommended at this time.

 

 

Diabetes in children

Diabetes in children usually presents with severe symptoms, very high blood glucose levels, marked glycosuria, and ketonuria. In most children the diagnosis is confirmed without delay by blood glucose measurements, and treatment (including insulin injection) is initiated immediately, often as a life–saving measure. An OGTT is neither necessary nor appropriate for diagnosis in such circumstances. A small proportion of children and adolescents, however, present with less severe symptoms and may require fasting blood glucose measurement and/or an OGTT for diagnosis.

Diagnostic criteria

The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma; high levels of glycosuria are usually present. A single blood glucose estimation in excess of the diagnostic values indicated in Figure 2 (black zone) establishes the diagnosis in such cases.Figure 2 also defines levels of blood glucose below which a diagnosis of diabetes is unlikely ion–pregnant individuals. These criteria are as in the WHO 1985 report. For clinical purposes, an OGTT to establish diagnostic status need only be considered if casual blood glucose values lie in the uncertain range (i.e. between the levels that establish or exclude diabetes) and fasting bloodglucose levels are below those which establish the diagnosis of diabetes. If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 hours after a 75 g oral glucose load (Annexe 1). For children the oral glucose load is related to body weight: 1.75 g per kg. The diagnostic criteria in children are the same as for adults. Diagnostic interpretations of the fasting and 2–h post–load concentrations ion–pregnant subjects are shown in Table 1.

 

Classification (Tables 2, Table 3).

It is recommended that the terms “insulin–dependent diabetes mellitus” and “non–insulin–dependent diabetes mellitus” andtheir acronyms “IDDM” and “NIDDM” no longer be used. These terms have been confusing and frequently resulted in patients being classified on the basis of treatment rather than pathogenesis.

–     The terms Type 1 and Type 2 should be reintroduced. The aetiological type named Type 1 encompasses the majority of cases which are primarily due to pancreatic islet beta–cell destruction and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those with beta– cell destruction and who are prone to ketoacidosis for which neither an aetiology nor a pathogenesis is known (idiopathic). It does not include those forms ofbeta–cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects, etc.). Some subjects with this type can be identified at earlier clinical stages than “diabetes mellitus”.

–     The type named Type 2 includes the common major form of diabetes which results from defect(s) in insulin secretion, almost always with a major contribution from insulin resistance. It has been argued that a lean phenotype of Type 2 diabetes mellitus in adults found in the Indian sub–continent may be very distinct from the more characteristic form of Type 2 found in Caucasians. Not enough information is available, however, to characterize such subjects separately.

–     A recent international workshop reviewed the evidence for, and characteristics of, diabetes mellitus seen inundernourished populations. Whilst it appears that malnutrition may influence the expression of several types of diabetes, the evidence that diabetes can be caused by malnutrition or protein deficiency per se is not convincing. Therefore, it is recommended that the class “Malnutrition–related diabetes” (MRDM) be deleted. The former subtype of MRDM, Protein– deficient Pancreatic Diabetes (PDPD or PDDM), may be considered as a malnutrition modulated or modified form of diabetes mellitus for which more studies are needed. The other former subtype of MRDM,Fibrocalculous Pancreatic Diabetes (FCPD), is now classified as a disease of the exocrine pancreas, fibrocalculous pancreatopathy, which may lead to diabetes mellitus.

–     The class “Impaired Glucose Tolerance” is now classified as a stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder, and is itself not diabetes.

–     A clinical stage of Impaired Fasting Glycaemia has been introduced to classify individuals who have fasting glucose values above the normal range, but below those diagnostic of diabetes.

–     Gestational Diabetes is retained but now encompasses the groups formerly classified as Gestational Impaired Glucose Tolerance (GIGT) and Gestational Diabetes Mellitus (GDM).

Table 2. Aetiological Classification of Disorders of

Glycaemia

––––––––––––––––––––––––––––––––––––––––––––––––

Type 1 (beta-cell destruction, usually leading to absolute

insulin deficiency)

Autoimmune

Idiopathic

Type 2 (may range from predominantly insulin resistance

with relative insulin deficiency to a predominantly

secretory defect with or without insulin resistance)

Other specific types

Genetic defects of beta-cell function

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug- or chemical-induced

Infections

Uncommon forms of immune-mediated diabetes

Other genetic syndromes sometimes associated with

diabetes

Gestational diabetes

 

Table 3 Other Specific Types of Diabetes

––––––––––––––––––––––––––––––––––––––––––––––––

Genetic defects of beta-cell function

Chromosome 20, HNF4a (MODY1)

Chromosome 7, glucokinase (MODY2)

Chromosome 12, HNF1a (MODY3)

Chromosome 13, IPF-1 (MODY4)

Mitochondrial DNA 3243 mutation

Others

Genetic defects in insulin action

Type A insulin resistance

Leprechaunism

Rabson-Mendenhall syndrome

Lipoatrophic diabetes

Others

Diseases of the exocrine pancreas

Fibrocalculous pancreatopathy

Pancreatitis

Trauma / pancreatectomy

Neoplasia

Cystic fibrosis

Haemochromatosis

Others

Endocrinopathies

Cushing’s syndrome

Acromegaly

Phaeochromocytoma

Glucagonoma

Hyperthyroidism

Somatostatinoma

Others

Drug- or chemical-induced

Infections

Congenital rubella

Cytomegalovirus

Others

Uncommon forms of immune-mediated diabetes

Insulin autoimmune syndrome (antibodies to insulin)

Anti-insulin receptor antibodies

“Stiff Man” syndrome

Others

Other genetic syndromes

––––––––––––––––––––––––––––––––––––––––––––––––

Laboratory methods of examination in DM.

Measurement of glucose in blood Reductiometric methods (the Somogyi–Nelson, the ferricyanide and neocuprine autoanalyser methods) are still in use for blood glucose measurement. The o–toluidine method also remains in use but enzyme–based methods are widely available, for both laboratory and near–patient use. Highly accurate and rapid (1–2 min) devices are now available based on immobilized glucose oxidase electrodes. Hexokinase and glucose dehydrogenase methods are used for reference. Whole blood samples preserved with fluoride show an initial rapid fall in glucose of up to 10 % at room temperature, but subsequent decline is slow; centrifugation prevents the initial fall. Whole blood glucose values are 15 % lower than corresponding plasma values in patients with a normal haematocrit reading, and arterial values are about 7 % higher than corresponding venous values. The use of reagent–strip glucose oxidase methods has made bedside estimation of blood glucose very popular. However, the cost of the reagent–strips remains high. Some methods still require punctilious technique, accurate timing, and storage of strips in airtight containers. Reasonably quantitative results can be obtained even with visual colour–matching techniques. Electrochemical andreflectance meters can give coefficients of variation of well under 5 %. Reagent–strip methods have been validated under tropicalconditions, but are sensitive to extreme climatic conditions. Diabetes may be strongly suspected from the results of reagent– strip glucose estimation, but the diagnosis cannot be confidently excluded by the use of this method. Confirmation of diagnosis requires estimation by laboratory methods. Patients can easily collect small blood samples themselves (either in specially prepared plastic or glass capillary tubes or on filter–paper), and self–monitoring using glucose reagent–strips with direct colour–matching or meters is now widely practised. Patients should be properly trained in the appropriate techniques to avoid inaccurate or misleading results. The insulin–treated patient is commonly requested to build up a “glycaemic profile” by self–measurement of blood glucose at specific times of the day (and night). A “7–point profile” is useful, with samples taken before and 90 min after breakfast, before and 90 min after lunch, before and 90 min after an evening meal, and just before going to bed. Occasionally patients may arrange to wake at 0300 h to collect and measure a nocturnal sample. The complete profile rarely needs to be collected within a single 24–hour period, and it may be compiled from samples collected at different times over several days. Measurement of glucose in urine Insulin–treated patients who do not have access to facilities for self–measurement of blood glucose should test urine samples passed after rising, before main meals, and before going to bed. Non–insulin–dependent patients do not need to monitor their urine so frequently. Urine tests are of somewhat limited value, however, because of the great variation in urine glucose concentration for given levels of blood glucose. The correlation between blood and urine glucose may be improved a little by collecting short–term fractions (15–30 min) of the urine output. Benedict’s quantitative solution or self–boiling, caustic soda/copper sulphate tablets may be used or the moreconvenient, but costly, semi–quantitative enzyme–based test– strips. Ketone bodies in urine and blood The appearance of persistent ketonuria associated with hyperglycaemia or high levels of glycosuria in the diabetic patient points to an unacceptably severe level of metabolic disturbance and indicates an urgent need for corrective action. The patient should be advised to test for ketone bodies (acetone and aceto–acetic acid) when tests for glucose are repeatedly positive, or when there issubstantial disturbance of health, particularly with infections. Rothera’s sodium nitroprusside test may be used or, alternatively, reagent–strips that are sensitive to ketones. In emergency situations such as diabetic ketoacidosis, a greatly raised concentration of plasma ketones can be detected with a reagent–strip and roughly quantified by serial 1 in 2 dilution of plasma with water.

Annex 1

The Oral Glucose Tolerance Test

The oral glucose tolerance test (OGTT) is principally used for diagnosis when blood glucose levels are equivocal, during pregnancy, or in epidemiological studies. The OGTT should be administered in the morning after at least three days of unrestricted diet (greater than 150 g of carbohydrate daily) and usual physical activity. Recent evidence suggests that a reasonable (30–50g) carbohydrate containing meal should be consumed on the evening before the test. The test should be preceded by an overnight fast of 8–14 hours, during which water may be drunk. Smoking is not permitted during the test. The presence of factors that influence interpretation of the results of the test must be recorded (e.g. medications, inactivity, infection, etc.). After collection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose or 82.5 g of glucose monohydrate (or partial hydrolysates of starch of the equivalent carbohydrate content) in 250–300 ml of water over the course of 5 minutes. For children, the test load should be 1.75 g of glucose per kg body weight up to a total of 75 g of glucose. Timing of the test is from the beginning of the drink. Blood samples must be collected 2 hours after the test load. Unless the glucose concentration can be determined immediately, the blood sample should be collected in a tube containing sodium fluoride (6 mg per ml whole blood) and immediately centrifuged to separate the plasma; the plasma should be frozen until the glucose concentration can be estimated. For interpretation of results, refer to Table 1.

Age

Insulin dose (Units/kg)

Infants (< 1 year)

0,1 – 0,125

Toddlers (1-3 years)

0,15 – 0,17

3-9 years

0,2 – 0,5

9-12 years

0,5 – 0,8

> 12 years

1,0 and more

Insulin has 3 basic formulations:

– short-acting (regular, soluble, lispro)

-medium- or intermediate-acting (isophane, lente)

– and long-acting (ultralente).

Periods of action of different types of insulin you can see on Fig. 3.

Fig. 3. Periods of action of different types of insulin.

 

Complications of DM.

Nephropathy:

Microangiopathy:

·  capillary basement membrane is thickened – this affects:

o          retina

o          renal glomerulus

o          nerve sheaths

Macroangiopathy:

·  atherosclerosis occurs at an accelerated rate

·  thus diabetics are more at risk of:

o          strokes

o          MI

o          gangrene leading to amputation

Retinopathy:

 

 

Nonretinal visual problems:

·  lens affected by changes in osmolality – leads to cataracts

·  new vessel formation in the iris

·  ocular palsies eg. of sixth cranial nerve

Frequent infections:

·  with poor diabetic control

·  white blood cells are impaired with high blood glucose levels

·  important as infections then lead to poor control of diabetes

Differential diagnosis among the various obesity forms in children.

Definition. Obesity is defined as weight/height greater than 120% of standards for age and sex. Although BMI is widly used for obesity diagnostic.

Etiology and pathogenesis. Several factors may contribute to the development of obesity (Tabl.4). Exogenous-constitutive, the most common reason for obesity, typically is viewed as the consequence of increased caloric intake and genetic predisposition.

–     Genetic predisposition is suggested by twin studies. Individuals with a propensity toward obesity may require fewer calories to maintain a normal weight.

–     Increased caloric intake may be secondary to a variety of psychosocial causes, such as anxiety and family modeling.

–     Genetic disorders. For example, Prader-Willi syndrome and Laurence-Moon-Biedl syndrome are associated with obesity.

–     Neuroendocrine, cerebral and endocrine obesity are appearing because of compromised perinatal life, old severe viral (bacterial) infections or hormonal abnormalities.

 

Table 4. Classification of obesity.

 

Diagnosis.

–     History. Essential elements include: 1) family history (parental obesity is a strong predictor of childhood obesity); 2) history of the child’s weight height gain over time; 3) a dietary diary to document eating patterns and caloric intake.

–     Physical examination. 1) normal stature, sexual development and intelligence rule out most genetic disorders associated with obesity and strongly suggest exogenous obesity; 2) triceps skin fold thickness measurement may be helpful; 3) blood pressure should be obtained.

Laboratory studies. Total cholesterol, triglycerides and high density lipoprotein should be measured.

Therapy. A reduced calorie diet should be devised, nutritionist often is helpful. Anorectic drugs are useful sometimes. A formal exercise program should be encouraged. Specific weight goals should be determined. Treatment of the base disease in a case of secondary obesity.

 

Practice Essentials

Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Most pediatric patients with diabetes have type 1 and a lifetime dependence on exogenous insulin.

Essential update: Disordered eating common in pediatric patients with type 1 diabetes

In a survey of 770 Norwegian children and adolescents with type 1 diabetes, nearly 1 in 5 (and 1 in 4 females) was found to have disturbed eating behavior (DEB). Mean age of the subjects was 14.6 years, and mean diabetes duration was 5.3 years. Most respondents used insulin pumps (56%) or took at least 4 insulin shots per day.

Using a predetermined cutoff of 20 or higher on the newly developed 16-item Diabetes Eating Problem Survey-Revised (DEPS-R), DEB was identified in 18.3% of the entire group, 27.7% of the females, and 8.6% of the males.

The proportions were dramatically higher among the older group of 153 patients aged 17 to 19 years, in whom DEB was identified in 32.7% overall and in 49.4% of the females and 14.5% of the males. In contrast, all of those rates were less than 10% among the 11- to 13-year-olds.

Signs and symptoms

Signs and symptoms of type 1 diabetes in children include the following:

–                                 Hyperglycemia

–                                 Glycosuria

–                                 Polydipsia

–                                 Unexplained weight loss

–                                 Nonspecific malaise

–                                 Symptoms of ketoacidosis

See Clinical Presentation for more detail.

Diagnosis

Blood glucose

Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Diagnostic criteria by the American Diabetes Association (ADA) include the following :

–                                 A fasting plasma glucose (FPG) level ≥126 mg/dL (7.0 mmol/L), or

–                                 A 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or

–                                 A random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

Glycated hemoglobin

Measurement of HbA1c levels is the best method for medium-term to long-term diabetic control monitoring. An international expert committee composed of appointed representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others recommended HbA1c assay for diagnosing diabetes mellitus.

See Workup for more detail.

Management

Glycemic control

The ADA recommends using patient age as one consideration in the establishment of glycemic goals, with different targets for preprandial, bedtime/overnight, and hemoglobin A_1c (HbA_1c) levels in patients aged 0-6, 6-12, and 13-19 years. Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality.

Insulin therapy

All children with type 1 diabetes mellitus require insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, or glulisine) or short-acting (regular).

Diet and activity

The aim of dietary management is to balance the child’s food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia.

The following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patient’s culture):

–                                 Carbohydrates – Should provide 50-55% of daily energy intake; no more than 10% of carbohydrates should be from sucrose or other refined carbohydrates

–                                 Fat – Should provide 30-35% of daily energy intake

–                                 Protein – Should provide 10-15% of daily energy intake

Exercise is also an important aspect of diabetes management. It has real benefits for a child with diabetes. Patients should be encouraged to exercise regularly.

Possible mechanism for development of type 1 diabetes.

 

Background

Most pediatric patients with diabetes have type 1 diabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin. Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). A possible mechanism for the development of type 1 diabetes is shown in the image below.

Type 2 diabetes mellitus (non–insulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with type 2 diabetes mellitus have insulin resistance, and their beta cells lack the ability to overcome this resistance. Although this form of diabetes was previously uncommon in children, in some countries, 20% or more of new patients with diabetes in childhood and adolescence have type 2 diabetes mellitus, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release, leading to maturity onset diabetes of the young (MODY) or congenital diabetes. This topic addresses only type 1 diabetes mellitus. (See Etiology and Epidemiology.)

Hypoglycemia

Hypoglycemia is probably the most disliked and feared complication of diabetes, from the point of view of the child and the family. Children hate the symptoms of a hypoglycemic episode and the loss of personal control it may cause. (See Pathophysiology and Clinical.)

Manage mild hypoglycemia by giving rapidly absorbed oral carbohydrate or glucose; for a comatose patient, administer an intramuscular injection of the hormone glucagon, which stimulates the release of liver glycogen and releases glucose into the circulation. Where appropriate, an alternative therapy is intravenous glucose (preferably no more than a 10% glucose solution). All treatments for hypoglycemia provide recovery in approximately 10 minutes. (See Treatment.)

Occasionally, a child with hypoglycemic coma may not recover within 10 minutes, despite appropriate therapy. Under no circumstances should further treatment be given, especially intravenous glucose, until the blood glucose level is checked and still found to be subnormal. Overtreatment of hypoglycemia can lead to cerebral edema and death. If coma persists, seek other causes.

Hypoglycemia was a particular concern in children younger than 4 years because the condition was thought to lead to possible intellectual impairment later in life. Persistent hyperglycemia is now believed to be more damaging.

Hyperglycemia

In an otherwise healthy individual, blood glucose levels usually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood sugar levels rise if insulin is insufficient for a given glucose load. The renal threshold for glucose reabsorption is exceeded when blood glucose levels exceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of polyuria and polydipsia. (See Pathophysiology, Clinical, and Treatment.)

All children with diabetes experience episodes of hyperglycemia, but persistent hyperglycemia in very young children (age < 4 y) may lead to later intellectual impairment.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is much less common than hypoglycemia but is potentially far more serious, creating a life-threatening medical emergency. Ketosis usually does not occur when insulin is present. In the absence of insulin, however, severe hyperglycemia, dehydration, and ketone production contribute to the development of DKA. The most serious complication of DKA is the development of cerebral edema, which increases the risk of death and long-term morbidity. Very young children at the time of first diagnosis are most likely to develop cerebral edema.

DKA usually follows increasing hyperglycemia and symptoms of osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of subcutaneous insulin, may present with ketosis and more normal blood glucose levels. They are more likely to present with nausea, vomiting, and abdominal pain, symptoms similar to food poisoning. DKA may manifest as respiratory distress.

Injection-site hypertrophy

If children persistently inject their insulin into the same area, subcutaneous tissue swelling may develop, causing unsightly lumps and adversely affecting insulin absorption. Rotating the injection sites resolves the condition.

Fat atrophy can also occur, possibly in association with insulin antibodies. This condition is much less common but is more disfiguring.

Diabetic retinopathy

The most common cause of acquired blindness in many developed nations, diabetic retinopathy is rare in the prepubertal child or within 5 years of onset of diabetes. The prevalence and severity of retinopathy increase with age and are greatest in patients whose diabetic control is poor. Prevalence rates seem to be declining, yet an estimated 80% of people with type 1 diabetes mellitus develop retinopathy.

Diabetic nephropathy and hypertension

The exact mechanism of diabetic nephropathy is unknown. Peak incidence is in postadolescents, 10-15 years after diagnosis, and it may occur in as many as 30% of people with type 1 diabetes mellitus.

In a patient with nephropathy, the albumin excretion rate (AER) increases until frank proteinuria develops, and this may progress to renal failure. Blood pressure rises with increased AER, and hypertension accelerates the progression to renal failure. Having diabetic nephropathy also increases the risk of significant diabetic retinopathy.

Progression may be delayed or halted by improved diabetes control, administration of angiotensin-converting enzyme inhibitors (ACE inhibitors), and aggressive blood pressure control. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.

A child younger than 15 years with persistent proteinuria may have a nondiabetic cause and should be referred to a pediatric nephrologist for further assessment.

Peripheral and autonomic neuropathy

The peripheral and autonomic nerves are affected in type 1 diabetes mellitus. Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms.

Autonomic changes involving cardiovascular control (eg, heart rate, postural responses) have been described in as many as 40% of children with diabetes. Cardiovascular control changes become more likely with increasing duration and worsening control.^[16] In adults, peripheral neuropathy usually occurs as a distal sensory loss.

Gastroparesis is another complication, and it which may be caused by autonomic dysfunction. Gastric emptying is significantly delayed, leading to problems of bloating and unpredictable excursions of blood glucose levels.

Macrovascular disease

Although this complication is not seen in pediatric patients, it is a significant cause of morbidity and premature mortality in adults with diabetes. People with type 1 diabetes mellitus have twice the risk of fatal myocardial infarction (MI) and stroke that people unaffected with diabetes do; in women, the MI risk is 4 times greater. People with type 1 diabetes mellitus also have 4 times greater risk for atherosclerosis.

The combination of peripheral vascular disease and peripheral neuropathy can cause serious foot pathology. Smoking, hypertension, hyperlipidemia, and poor diabetic control greatly increase the risk of vascular disease. Smoking, in particular, may increase the risk of myocardial infarction by a factor of 10.

Autoimmune diseases

Hypothyroidism affects 2-5% of children with diabetes. Hyperthyroidism affects 1% of children with diabetes; the condition is usually discovered at the time of diabetes diagnosis.

Although Addison disease is uncommon, affecting less than 1% of children with diabetes, it is a life-threatening condition that is easily missed. Addison disease may reduce the insulin requirement and increase the frequency of hypoglycemia. (These effects may also be the result of unrecognized hypothyroidism.)

Celiac disease, associated with an abnormal sensitivity to gluten in wheat products, is probably a form of autoimmune disease and may occur in as many as 5% of children with type 1 diabetes mellitus.

Necrobiosis lipoidica is probably another form of autoimmune disease. This condition is usually, but not exclusively, found in patients with type 1 diabetes. Necrobiosis lipoidica affects 1-2% of children and may be more common in children with poor diabetic control.

Limited joint mobility

Limited joint mobility (primarily affecting the hands and feet) is believed to be associated with poor diabetic control.

Originally described in approximately 30% of patients with type 1 diabetes mellitus, limited joint mobility occurs in 50% of patients older than age 10 years who have had diabetes for longer than 5 years. The condition restricts joint extension, making it difficult to press the hands flat against each other. The skin of patients with severe joint involvement has a thickened and waxy appearance.

Limited joint mobility is associated with increased risks for diabetic retinopathy and nephropathy. Improved diabetes control over the past several years appears to have reduced the frequency of these additional complications by a factor of approximately 4. Patients have also markedly fewer severe joint mobility limitations.

Pathophysiology

Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in the liver and kidneys.

Hyperglycemia

Hyperglycemia (ie, random blood glucose concentration of more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to DKA. The effects of insulin deficiency are shown in the image below.

The effects of insulin deficiency

 

Hypoglycemia

Insulin inhibits glucogenesis and glycogenolysis, while stimulating glucose uptake. Iondiabetic individuals, insulin production by the pancreatic islet cells is suppressed when blood glucose levels fall below 83 mg/dL (4.6 mmol/L). If insulin is injected into a treated child with diabetes who has not eaten adequate amounts of carbohydrates, blood glucose levels progressively fall.

The brain depends on glucose as a fuel. As glucose levels drop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, cortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms include sweatiness, shaking, confusion, behavioral changes, and, eventually, coma when blood glucose levels fall below 30-40 mg/dL.

The glucose level at which symptoms develop varies greatly from individual to individual (and from time to time in the same individual), depending in part on the duration of diabetes, the frequency of hypoglycemic episodes, the rate of fall of glycemia, and overall control. (Glucose is also the sole energy source for erythrocytes and the kidney medulla.)

Etiology

Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

Genetic issues

Clear evidence suggests a genetic component in type 1 diabetes mellitus. Monozygotic twins have a 60% lifetime concordance for developing type 1 diabetes mellitus, although only 30% do so within 10 years after the first twin is diagnosed. In contrast, dizygotic twins have only an 8% risk of concordance, which is similar to the risk among other siblings.

The frequency of diabetes development in children with a mother who has diabetes is 2-3%; this figure increases to 5-6% for children with a father who has type 1 diabetes mellitus. The risk to children rises to almost 30% if both parents are diabetic.

Human leukocyte antigen (HLA) class II molecules DR3 and DR4 are associated strongly with type 1 diabetes mellitus. More than 90% of whites with type 1 diabetes mellitus express 1 or both of these molecules, compared with 50-60% of the general population.

Patients expressing DR3 are also at risk for developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function.

Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies. The expression of both DR3 and DR4 carries the greatest risk of type 1 diabetes mellitus; these patients have characteristics of both the DR3 and DR4 groups.

Neonatal diabetes, including diagnosis in infants younger than age 6 months, is most likely due to an inherited defect of the iKir6.2 subunit potassium channel of the islet beta cells, and genetic screening is indicated. This is particularly important, because these children respond well to sulphonylurea therapy.

Environmental factors

Environmental factors are important, because even identical twins have only a 30-60% concordance for type 1 diabetes mellitus and because incidence rates vary in genetically similar populations under different living conditions. No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates.

Viral infections may be the most important environmental factor in the development of type 1 diabetes mellitus, probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella. One survey suggests enteroviral infection during pregnancy carries an increased risk of type 1 diabetes mellitus in the offspring. Paradoxically, type 1 diabetes mellitus incidence is higher in areas where the overall burden of infectious disease is lower.

Dietary factors are also relevant. Breastfed infants have a lower risk for type 1 diabetes, and a direct relationship is observed between per capita cow’s milk consumption and the incidence of diabetes. Some cow’s milk proteins (eg, bovine serum albumin) have antigenic similarities to an islet cell antigen.

Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause type 1 diabetes mellitus in animal models; however, no definite link has been made with humans.

The known association of increasing incidence of type 1 diabetes mellitus with distance from the equator may now have an explanation. Reduced exposure to ultraviolet (UV) light and lower vitamin D levels, both of which are more likely found in the higher latitudes, are associated with an increased risk of type 1 diabetes mellitus.

Chemical causes

Streptozotocin and RH-787, a rat poison, selectively damages islet cells and can cause type 1 diabetes mellitus.

Other causes

Additional factors in the development of type 1 diabetes mellitus include the following:

–    Congenital absence of the pancreas or islet cells

–   Pancreatectomy

–    Pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic-uremic syndrome)

–   Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness [DIDMOAD])

–  Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (the risk is said to be around 1% in Down and Turner syndromes)

Epidemiology

Occurrence in the United States

The overall annual incidence of diabetes mellitus is about 24.3 cases per 100,000 person-years. Although most new diabetes cases are type 1 (approximately 15,000 annually), increasing numbers of older children are being diagnosed with type 2 diabetes mellitus, especially among minority groups (3700 annually).

International occurrence

Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 population in China to 41.4 cases per 100,000 population in Finland. Substantial variations are observed betweeearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations, such as those in Iceland and Norway.

A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.

Even more striking are the differences in incidence between mainland Italy (8.4 cases per 100,000 population) and the Island of Sardinia (36.9 cases per 100,000 population). These variations strongly support the importance of environmental factors in the development of type 1 diabetes mellitus. Most countries report that incidence rates have at least doubled in the last 20 years. Incidence appears to increase with distance from the equator.

Race-related demographics

Different environmental effects on type 1 diabetes mellitus development complicate the influence of race, but racial differences are evident. Whites have the highest reported incidence, whereas Chinese individuals have the lowest. Type 1 diabetes mellitus is 1.5 times more likely to develop in American whites than in American blacks or Hispanics. Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their rates of type 1 diabetes mellitus tend to increase toward the higher level.

Sex-related demographics

The influence of sex varies with the overall incidence rates. Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation. Females appear to be at a greater risk in low-incidence regions.

Age-related demographics

Type 1 diabetes mellitus can occur at any age, but incidence rates generally increase with age until midpuberty and then decline. Onset in the first year of life, although unusual, can occur, so type 1 diabetes mellitus must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. (Because diabetes is easily missed in an infant or preschool-aged child, if in doubt, check the urine for glucose.) Symptoms in infants and toddlers may include the following:

– Severe monilial diaper/napkin rash

–  Unexplained malaise

–   Poor weight gain or weight loss

–    Increased thirst

–    Vomiting and dehydration, with a constantly wet napkin/diaper

In areas with high prevalence rates, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, ages 4-6 y) and a second, much greater peak of incidence during early puberty (ie, ages 10-14 y).

Prognosis

Apart from severe DKA or hypoglycemia, type 1 diabetes mellitus has little immediate morbidity. The risk of complications relates to diabetic control. With good management, patients can expect to lead full, normal, and healthy lives. Nevertheless, the average life expectancy of a child diagnosed with type 1 diabetes mellitus has been variously suggested to be reduced by 13-19 years, compared with their nondiabetic peers.

Morbidity and mortality

Information on mortality rates for type 1 diabetes mellitus is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population. Children aged 1-4 years are particularly at risk and may die due to DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur and appears more likely to affect young males.

A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.

The complications of type 1 diabetes mellitus can be divided into 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases.

Acute complications, which include hypoglycemia, hyperglycemia, and DKA, reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise.

Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. Although long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life. The likelihood of developing complications appears to depend on the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender. Long-term complications include the following:

–         Retinopathy

–         Cataracts

–         Gastroparesis

–         Hypertension

–         Progressive renal failure

–         Early coronary artery disease

–         Peripheral vascular disease

–         Peripheral and autonomic neuropathy

–         Increased risk of infection

Associated autoimmune diseases are common in type 1 diabetes mellitus, particularly in children who have HLA-DR3. Some conditions may precede the development of diabetes, and others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Patient Education

Education is a continuing process involving the child, family, and all members of the diabetes team. (See the videos below.) The following strategies may be used:

–         Formal education sessions in a clinic setting

–         Opportunistic teaching at clinics or at home in response to crises or difficulties such as acute illness

–         Therapeutic camping or other organized events

–         Patient-organized meetings

 

Diabetes-related organizations and patient groups include the following:

–         Children with Diabetes – This “online community for kids, families, and adults with diabetes” is an excellent resource with good links

–         International Society for Pediatric and Adolescent Diabetes

–         International Diabetes Federation

–         Diabetes UK

–         American Diabetes Association

–         Juvenile Diabetes Research Foundation International

–         Runsweet – This is a Web site devoted to giving advice on exercise management and diabetes

History

The most easily recognized symptoms of type 1 diabetes mellitus (T1DM) are secondary to hyperglycemia, glycosuria, and DKA.

Hyperglycemia

Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. Children may also appear irritable and become ill-tempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria.

Glycosuria

This condition leads to increased urinary frequency and volume (eg, polyuria), which is particularly troublesome at night (eg, nocturia) and often leads to enuresis in a previously continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use.

Polydipsia

Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration.

Weight loss

Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, although the child’s appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia.

Nonspecific malaise

Although this condition may be present before symptoms of hyperglycemia or as a separate symptom of hyperglycemia, it is often only retrospectively recognized.

Symptoms of ketoacidosis

These symptoms include the following:

–         Severe dehydration

–         Smell of ketones

–         Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress

–         Abdominal pain

–         Vomiting

–         Drowsiness and coma

Additional symptoms

Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract. Candidiasis may develop, especially in the groin and in flexural areas.

Physical Examination

Apart from wasting and mild dehydration, children with early diabetes have no specific clinical findings. A physical examination may reveal findings associated with other autoimmune endocrinopathies, which have a higher incidence in children with type 1 diabetes mellitus (eg, thyroid disease with symptoms of overactivity or underactivity and possibly a palpable goiter).

Cataracts are rarely presenting problems ; they typically occur in girls with a long prodrome of mild hyperglycemia.

Necrobiosis lipoidica usually, but not exclusively, occurs in people with diabetes. Necrobiosis most often develops on the front of the lower leg as a well-demarcated, red, atrophic area. The condition is associated with injury to dermal collagen, granulomatous inflammation, and ulceration. The cause of necrobiosis is unknown, and the condition is difficult to manage. It is also associated with poor metabolic control and a greater risk of developing other diabetes-related complications.

Diabetic retinopathy

The first symptoms of diabetic retinopathy are dilated retinal venules and the appearance of capillary microaneurysms, a condition known as background retinopathy. These changes may be reversible or their progression may be halted with improved diabetic control, although in some patients the condition initially worsens.

Subsequent changes in background retinopathy are characterized by increased vessel permeability and leaking plasma that forms hard exudates, followed by capillary occlusion and flame-shaped hemorrhages. The patient may not notice these changes unless the macula is involved. Laser therapy may be required at this stage to prevent further vision loss.

Proliferative retinopathy follows, with further vascular occlusion, retinal ischemia, and proliferation of new retinal blood vessels and fibrous tissue; the condition then progresses to hemorrhage, scarring, retinal detachment, and blindness. Prompt retinal laser therapy may prevent blindness in the later stages, so regular screening is vital.

Diagnostic Considerations

Children with MODY may present as having type 1 diabetes. As they may respond better to oral hypoglycemic agents, recognizing MODY as a possibility is important. Always consider the diagnosis of MODY in the following circumstances:

–         A strong family history of diabetes across 2 or more generations – The age of diagnosis usually falls with each successive generation

–         Persistently low insulin requirements, particularly with good blood glucose control

–         Development of diabetes from birth or within the first 9 months of life

Conditions to consider in the differential diagnosis of type 1 diabetes include the following:

–         Type 2 diabetes mellitus

–         MODY

–         Psychogenic polydipsia

–         Nephrogenic diabetes insipidus

–         High-output renal failure

–         Transient hyperglycemia with illness and other stress

–         Steroid therapy

–         Factitious illness (Münchhausen syndrome by proxy)

Differential Diagnoses

–         Diabetes Insipidus

–         Hyperthyroidism

–         Pheochromocytoma

–         Renal Glucosuria

–         Toxicity, Salicylate

Approach Considerations

The need for and extent of laboratory studies vary, depending on the general state of the child’s health. For most children, only urine testing for glucose and blood glucose measurement are required for a diagnosis of diabetes. Other conditions associated with diabetes require several tests at diagnosis and at later review.

Urine glucose

A positive urine glucose test suggests, but is not diagnostic for, type 1 diabetes mellitus (T1DM). Diagnosis must be confirmed by test results showing elevated blood glucose levels. Test urine of ambulatory patients for ketones at the time of diagnosis.

Urine ketones

Ketones in the urine confirm lipolysis and gluconeogenesis, which are normal during periods of starvation. With hyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency and potential DKA.

Islet cell antibodies

Islet cell antibodies may be present at diagnosis but are not needed to diagnose type 1 diabetes mellitus. Islet cell antibodies are nonspecific markers of autoimmune disease of the pancreas and have been found in as many as 5% of unaffected children. Other autoantibody markers of type 1 diabetes are known, including insulin antibodies. Additional antibodies against islet cells are recognized (eg, those against glutamate decarboxylase [GAD antibodies]), but these may not be available for routine testing.

Thyroid function tests and antithyroid antibodies

Because early hypothyroidism has few easily identifiable clinical signs in children, children with type 1 diabetes mellitus may have undiagnosed thyroid disease. Untreated thyroid disease may interfere with diabetes management. Typically, hypothyroid children present with reduced insulin requirements and increased episodes of hypoglycemia; hyperthyroid children have increased insulieeds and a tendency toward hyperglycemia. Caution, therefore, is needed when initiating treatment as insulin requirements can change quite quickly. Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present). Antithyroid antibody tests indicate the risk of present or potential thyroid disease.

Antigliadin antibodies

Some children with type 1 diabetes mellitus may have or may develop celiac disease. Positive antigliadin antibodies, especially specific antibodies (eg, antiendomysial, antitransglutaminase) are important risk markers. If antibody tests are positive, a jejunal biopsy is required to confirm or refute a diagnosis of celiac disease. Once celiac disease is confirmed, the individual should remain on a gluten-free diet for life.

Lipid profile

Lipid profiles are usually abnormal at diagnosis because of increased circulating triglycerides caused by gluconeogenesis. Apart from hypertriglyceridemia, primary lipid disorders rarely result in diabetes. Hyperlipidemia with poor metabolic control is common but returns to normal as metabolic control improves.

Urinary albumin

Beginning at age 12 years, perform an annual urinalysis to test for a slightly increased AER, referred to as microalbuminuria, which is an indicator of risk for diabetic nephropathy.

Renal function tests

If the child is otherwise healthy, renal function tests are typically not required.

Blood Glucose

Apart from transient illness-induced or stress-induced hyperglycemia, a random whole-blood glucose concentration of more than 200 mg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood glucose concentration that exceeds 120 mg/dL (7 mmol/L). In the absence of symptoms, the physician must confirm these results on a different day. Most children with diabetes detected because of symptoms have a blood glucose level of at least 250 mg/dL (14 mmol/L).

Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Glycated Hemoglobin

Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) are the result of a nonenzymatic reaction between glucose and hemoglobin. A strong correlation exists between average blood glucose concentrations over an 8- to 10-week period and the proportion of glycated hemoglobin. The percentage of HbA1c is more commonly measured. (Measurement of HbA1c levels is the best method for medium-term to long-term diabetic control monitoring.)

An international expert committee composed of appointed representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others recommended HbA1c assay for diagnosing diabetes mellitus. The committee recommended that an HbA1c level of 6.5% or higher be considered indicative of diabetes, with diagnostic confirmation being provided through repeat testing (unless clinical symptoms are present and the glucose level is >200 mg/dL). Glucose measurement should remain the choice for diagnosing pregnant women or be used if HbA1c assay is unavailable. The committee cited the following advantages of HbA1c testing over glucose measurement:

–                                 Captures long-term glucose exposure

–                                 Has less biologic variability

–                                 Does not require fasting or timed samples

–                                 Is currently used to guide management decisions

The Diabetes Control and Complications Trial (DCCT) found that patients with HbA1c levels of around 7% had the best outcomes relative to long-term complications. Most clinicians aim for HbA1c values of 7-9%. Values of less than 7% are associated with an increased risk of severe hypoglycemia; values of more than 9% carry an increased risk of long-term complications. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends a target level of 7.5% (58 mmol/mol) or less for all children.

Normal HbA1c values vary according to the laboratory method used, but nondiabetic children generally have values in the low-normal range. At diagnosis, diabetic children unmistakably have results above the upper limit of the reference range. Check HbA1c levels every 3 months.

Many different methods of measuring HbA1c are available, and the variations between the different assays can be considerable and unpredictable.

A working group was established in 1995 by the International Federation of Clinical Chemists (IFCC) to find a better method of standardizing the various assays. This resulted in a global standard that is gradually being implemented. As a result, HbA1c will be reported as millimole per mole (mmol/mol) instead of as a percentage. The current target range of 7-9% is set to be replaced with values of 53-75 mmol/mol.

Microalbuminuria

Microalbuminuria is the first evidence of nephropathy. The exact definition varies slightly between nations, but an increased AER is commonly defined as a ratio of first morning-void urinary albumin levels to creatinine levels that exceeds 10 mg/mmol, or as a timed, overnight AER of more than 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. Glomerular hyperfiltration occurs, as do abnormalities of the glomerular basement membrane and glomeruli. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.

Oral Glucose Tolerance Test

Although unnecessary in the diagnosis of type 1 diabetes mellitus, an oral glucose tolerance test (OGTT) can exclude the diagnosis of diabetes when hyperglycemia or glycosuria are recognized in the absence of typical causes (eg, intercurrent illness, steroid therapy) or when the patient’s condition includes renal glucosuria.

Obtain a fasting blood sugar level, then administer an oral glucose load (2 g/kg for children aged < 3 y, 1.75 g/kg for children aged 3-10 y [max 50 g], or 75 g for children aged >10 y). Check the blood glucose concentration again after 2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) or a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. However, mild elevations may not indicate diabetes when the patient has no symptoms and no diabetes-related antibodies.

A modified OGTT can also be used to identify cases of MODY (which often present as type 1 diabetes) if, in addition to blood glucose levels, insulin or c-peptide (insulin precursor) levels are measured at fasting, 30 minutes, and 2 hours. Individuals with type 1 diabetes mellitus cannot produce more than tiny amounts of insulin. People with MODY or type 2 diabetes mellitus show variable and substantial insulin production in the presence of hyperglycemia.

Approach Considerations

All children with type 1 diabetes mellitus require insulin therapy. The following are also required in treatment:

–         Blood glucose testing strips

–         Urine ketone testing tablets or strips

–         Blood ketone testing strips

Strategies to help patients and their parents achieve the best possible glycemic management are crucial. A 2-year randomized clinical trial found that a practical, low-intensity behavioral intervention delivered during routine care improved glycemic outcomes.

A well-organized diabetes care team can provide all necessary instruction and support in an outpatient setting. The only immediate requirement is to train the child or family to check blood glucose levels, to administer insulin injections, and to recognize and treat hypoglycemia. The patient and/or family should have 24-hour access to advice and know how to contact the team. Children should wear some form of medical identification, such as a medic alert bracelet or necklace.

Awareness of hypoglycemia becomes impaired over time, and severe hypoglycemia can occur without warning. Hypoglycemia is more likely to affect people who maintain low blood sugar levels and who already suffer frequent hypoglycemic attacks. Overzealous or inadequate treatment of hypoglycemia can lead to serious consequences.

Failure to regularly examine for diabetic complications in patients with type 1 diabetes mellitus, especially renal and ophthalmic ones, can be detrimental.

Inpatient care

Where a diabetes care team is available, admission is usually required only for children with DKA. In addition, children with significant dehydration, persistent vomiting, metabolic derangement, or serious intercurrent illness require inpatient management and intravenous rehydration.

Diabetes in pregnancy

Pregnancies should be planned and carefully managed to achieve healthy outcomes for mother and infant. Preconceptual normalization of blood sugars and folic acid supplements (at least 5 mg/d) reduce the otherwise increased risk of congenital heart disease and neural tube defects. Blood sugar control during pregnancy must be strict to avoid hypoglycemia, which may damage the fetus, and persistent hyperglycemia, which leads to fetal gigantism, premature delivery, and increased infant morbidity and mortality. DKA during pregnancy may result in fetal death.

Diet

Dietary management is an essential component of diabetes care. Diabetes is an energy metabolism disorder, and consequently, before insulin was discovered, children with diabetes were kept alive by a diet severely restricted in carbohydrate and energy intake. These measures led to a long tradition of strict carbohydrate control and unbalanced diets. Current dietary management of diabetes emphasizes a healthy, balanced diet that is high in carbohydrates and fiber and low in fat.

The following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patient’s culture):

–         Carbohydrates – Should provide 50-55% of daily energy intake; no more than 10% of carbohydrates should be from sucrose or other refined carbohydrates

–         Fat – Should provide 30-35% of daily energy intake

–         Protein – Should provide 10-15% of daily energy intake

The aim of dietary management is to balance the child’s food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia.

The ability to estimate the carbohydrate content of food (carbohydrate counting) is particularly useful for children who receive fast-acting insulin at mealtimes either by injection or insulin pump, as it allows for a more precise matching of food and insulin. Adequate intake of complex carbohydrates (eg, cereals) is important before bedtime to avoid nocturnal hypoglycemia, especially for children getting twice-daily injections of mixed insulin.

The dietitian should develop a diet plan for each child to suit individual needs and circumstances. Regularly review and adjust the plan to accommodate the patient’s growth and lifestyle changes.

Low-carbohydrate diets as a management option for diabetes control have regained popularity. Logic dictates that the lower the carbohydrate intake, the less insulin is required. No trials of low-carbohydrate diets in children with type 1 diabetes mellitus have been reported, and such diets cannot be recommended at the present.

Activity

Type 1 diabetes mellitus requires no restrictions on activity; exercise has real benefits for a child with diabetes. Current guidelines are increasingly sophisticated and allow children to compete at the highest levels in sports. Moreover, most children can adjust their insulin dosage and diet to cope with all forms of exercise.

Children and their caretakers must be able to recognize and treat symptoms of hypoglycemia. Hypoglycemia following exercise is most likely after prolonged exercise involving the legs, such as walking, running or cycling. It may occur many hours after exercise has finished and even affect insulin requirements the following day. A large, presleep snack is advisable following intensive exercise.

Long-Term Monitoring

Regular outpatient review with a specialized diabetes team improves short- and long-term outcomes. Most teams have a nurse specialist or educator, a dietitian, and a pediatrician with training in diabetes care. Other members can include a psychologist, a social worker, and an exercise specialist. Involvement with the team is intense over the first few weeks after diagnosis while family members learn about diabetes management.

Conduct a structured examination and review at least once annually to examine the patient for possible complications. Examination and review should include the following:

–         Growth assessment

–         Injection site examination

–         Examination of the hands, feet, and peripheral pulses for signs of limited joint mobility, peripheral neuropathy, and vascular disease

–         Evaluation for signs of associated autoimmune disease

–         Blood pressure

In individuals aged 11 years or older, further examination should include the following:

–                                 Retinoscopy or other retinal screening, such as photography

–                                 Urine examination for microalbuminuria

Medication Summary

Insulin is always required to treat type 1 diabetes mellitus. Originally, all insulin was derived from the highly purified pancreatic extracts of pigs and cattle, and this form of insulin is still available. Human insulin was later manufactured using recombinant deoxyribonucleic acid (DNA) technology. “Designer” insulins are also now being produced; they are based on the human molecule and are tailored to meet specific pharmacologic targets, particularly duration of action. Insulin must be given parenterally, and this effectively means subcutaneous injection.

Alternatives to injecting insulin have been constantly sought, including an inhaled form of insulin. Several products were in development, and one (Exubera) was licensed for use but failed to generate sufficient market penetration to justify continued production. The search for alternatives continues, including oral sprays, sublingual lozenges, and delayed-absorption capsules.

Insulin has 4 basic formulations: ultra ̶ short-acting (eg, lispro, aspart, glulisine), traditional short-acting (eg, regular, soluble), medium- or intermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, ultralente, glargine).

Regular or soluble insulin is bound to either protamine (eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duration of action. Combinations of isophane and regular, lispro, or aspart insulins are also available in a limited number of concentrations that vary around the world, ranging from 25:75 mixtures (ie, 25% lispro, 90% isophane) to 50:50 mixtures. The following image illustrates the activity profile of various insulins.

The development of insulin analogues has attempted to address some of the shortcomings of traditional insulin. Insulins lispro, glulisine, and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia. (See the graph below.) They are also more suitable for use with insulin pumps. An intermediate-acting insulin (detemir) has a similar profile of action to isophane but is more pharmacologically predictable and is less likely to cause weight gain, whereas glargine has a relatively flat profile of action, lasting some 18-26 hours. Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates.

Representation of activity profile of some available insulins.

The FDA issued an early communication to health care practitioners regarding 4 published observational studies that described the possible association of insulin glargine (Lantus) with an increased risk of cancer.Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that which is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raised further questions about the actual risk and, therefore, further evaluation is warranted.

The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

With so many various insulins and mixtures available, a wide range of possible injection regimens exist. These can be broadly categorized into 4 types, as follows:

–         Twice-daily combinations of short- and intermediate-acting insulin.

–         Multiple injection regimens using once-daily or twice-daily injections of long-acting or intermediate-acting insulin and short-acting insulins given at each meal

–         A combination of the above 2 regimens, with a morning injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection of intermediate- or long-acting insulin

–         Continuous subcutaneous insulin infusion (CSII) using an insulin pump

Although controlled clinical trials suggest improved short-term metabolic control in children using multiple injections or CSII, international comparisons do not support any particular insulin regimen, and all have their advantages and disadvantages.

A wide variety of insulin-injection devices are available, including a simple syringe and needle, semiautomatic pen injector devices, and needle-free jet injectors. Increasing numbers of young people use insulin pumps to deliver continuous subcutaneous insulin, with bolus doses at meal times.

When prescribing, tailor the insulin dose to the individual child’s needs. For instance, if using a twice-daily regimen, then, as a rule of thumb, prepubertal children require between 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and 30-40% in the evening. Insulin resistance is a feature of puberty, and some adolescents may require as much as 2 U/kg/d. About one third of the administered insulin is a short-acting formulation and the remainder is a medium- to long-acting formulation. Basal bolus regimens have a higher proportion of short-acting insulin. Typically, 50% of the total daily dose is given as long- or intermediate-acting insulin. CSII uses only short-acting insulins, most often the analogues lispro or aspart. Typically, they also have around 50% of the insulin given at a basal rate; the remainder is given as food-related boluses.

ntidiabetic Agents

Class Summary

These agents are used for the treatment of type 1 diabetes mellitus, as well as for type 2 diabetes mellitus that is unresponsive to treatment with diet and/or oral hypoglycemics.

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Insulin detemir (Levemir)

 

This agent is indicated for daily or twice-daily subcutaneous administration for adults and pediatric patients with type 1 diabetes mellitus; it is also indicated for adults with type 2 diabetes mellitus who require long-acting basal insulin for hyperglycemic control. The duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). Prolonged action is a result of the slow systemic absorption of detemir molecules from the injection site.

Insulin detemir’s primary activity is regulation of glucose metabolism. It binds to insulin receptors and lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat. The drug also inhibits glucose output from the liver. It inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

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Insulin lispro (Humalog)

Onset of action for insulin lispro is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 2-4 hours.

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Regular insulin (Humulin R, Novolin R)

Onset of action is 0.25-1 hours, peak activity is 1.5-4 hours, and duration of action is 5-9 hours.

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Insulin NPH (Humulin N, Novolin N)

The main directions of general practice family medicine with the family, prevention of congenital and hereditary diseases. Clinical supervision of children with abnormal urinary and endocrine systems in family practice doctor.

 

  Differential diagnosis of urinary tract infections include urethritis, vaginitis, trauma, hypercalciuria (dysuria), detrusor/sphincter dysfunction, neurogenic urinary bladder, different anatomical abnormalities.

 

 

 

 

  Congenital anomalies.

 

Renal agenesis – unilateral renal agenesis incidence of 1 in 450 to 1,000 births.

Ø   In true agenesis, the ureter and the ipsilateral bladder hemitrigone are absent;

Ø   The contralateral kidney undergoes compensatory hypertrophy, to some degree prenatally but primarily after birth;

Ø    Approximately 15% of these children have contralateral vesicoureteral reflux

Aplasia – nonfunctioning tissue and normal or abnormal ureter.

Ø   If there is a normal contralateral kidney, renal function should remaiormal over time.

Bilateral renal agenesis – incompatible with extrauterine life and is termed Potter syndrome.

Ø   Death occurs shortly after birth from pulmonary hypoplasia. The newborn has a characteristic facial appearance, termed Potter facies.

Familial renal adysplasia describes disease in which renal agenesis, renal dysplasia, multicystic kidney (dysplasia), or a combination, occurs in a single family.

Ø   This disorder has an autosomal dominant inheritance pattern with a penetrance of 50–90% and variable expression.

 

Renal dysgenesis refers to maldevelopment of the kidney that affects its size, shape, or structure. The 3 principal types of dysgenesis are:

Ø   Dysplastic

Ø   Hypoplastic

Ø   Cystic.

 

A multicystic kidney: a congenital condition in which the kidney is replaced by cysts and does not function, and may result from ureteral atresia.

Ø   Renal size is highly variable.

Ø   The incidence is approximately 1 in 2,000.

Ø   An inherited disorder that may be autosomal recessive or autosomal dominant and affects both kidneys

Ø   Multicystic kidney usually is unilateral and is not inherited. Bilateral multicystic kidneys are incompatible with life.

Ø   Multicystic dysplastic kidney is the most common cause of an abdominal mass in the newborn.

Ø   In most cases it is discovered incidentally during prenatal sonography.

Ø   Contralateral hydronephrosis is present in 5–10% of patients.

Renal hypoplasia: a small nondysplastic kidney that has fewer than the normal number of calyces and nephrons.

Ø   If the condition is unilateral, the diagnosis usually is made incidentally

Ø   Bilateral hypoplasia usually presents with the manifestations of chronic renal failure and is a leading cause of end-stage renal disease during the first decade of life.

Ø   A history of polyuria and polydipsia is common.

Ø   Urinalysis results may be normal.

The Ask-Upmark kidney, also termed segmental hypoplasia:

Ø   Small kidneys, usually weighing not more than 35 g, with one or more deep grooves on the lateral convexity, underneath which the parenchyma consists of tubules resembling those in the thyroid gland.

Ø   It is unclear whether the lesion is congenital or acquired.

Ø   Most patients are 10 yr or older at diagnosis and have severe hypertension.

Ø   Nephrectomy usually controls the hypertension.

 

  Urinary tract infection.

Etiology.

·                                     Escherichia coli is the most common cause of bacterial UTI.

Other organisms:

·                                     Klebsiella spp, Enterococcus, Staphylococcus saprophyticus, Proteus mirabilis;

·                                     Pseudomonas, Streptococcus, Candida albicans (usually associated with complicated UTIs or chronic antibiotic treatment).

Risk factors in all children include:

·                                     Indwelling catheters

·                                     Urologic tract anomalies

·                                     Neurogenic bladders

Risk factors specific to girls include:

·                                     Chemical irritants

·                                     Sexual activity

·                                     Sexual abuse

·                                     Constipation

·                                     Pinworms

Risk factors specific to boys include:

·                                     Phymosis       

Uncircumcised boys have an incidence of infection 10 times that of circumcised boys.

Epidemiology.

·                         Bacteriuria is present in 1%– 2% of prepubertal children.

·                         In the first year of life, the risk of infection is equal among boys and girls

·                         The risk in girls is considerably higher in toddlers and older children.

·                         The incidence of UTI is 3.0% in febrile infants younger than 12 mo of age without an obvious cause for fever

·                         Vesicoureteral reflux is present in 18%– 50% of children with UTI

Symptoms.

·                        In infants, vomiting, poor feeding, and irritability.

·                        Older children develop dysuria, urgency, frequency, incontinence, hesitancy, and retention; fever, chills, back pain are symptoms that suggest an upper tract infection (pyelonephritis).

Signs.

·             Fever

·             Jaundice (may be seen ieonates).

·             Suprapubic or costovertebral angle tenderness

·             Abdominal or flank mass: suggestive of obstructive uropathy.

·             Sacral dimple, hairy patch over the sacrum, abnormal gluteal cleft, decreased rectal tone, lipoma: suggest spinal cord anomalies.

·             Labial adhesion, trauma, and irritation: may increase the risk of infection.

Investigations.

·             Urine culture: considered positive if any organisms are present on a suprapubic collection; > 10⁴ colony forming units (CFU)/mL of a urinary pathogen from a catheterized specimen; > 10⁵ CFU/mL of a urinary pathogen from a clean catch.

·             Urinalysis with dipstick: demonstrating positive leukocyte esterase and nitrite test with microscopic examination demonstrating more than five leukocytes per hpf, bacteria is highly suggestive of a urinary tract infection (UTI); this is not reliable in infants in whom the urine is dilute; 10% may have a negative urinalysis result despite a positive culture.

·             Radiographic imaging: indicated in every boy with an infection and girls with pyelonephritis; girls with recurrent lower tract infections or those who are younger than 5 years of age with their first infection should be studied as well.

·             Renal and bladder ultrasound: a noninvasive aid to look for hydroureteronephrosis, duplex kidneys, and ureteroceles, which may be a sign of obstruction.

·             Voiding cystourethrography: might demonstrate vesicoureteral reflux and is especially important in the male to exclude posterior urethral valves.

·             99m Tc-DMSA scan: controversial; it is an excellent study to identify pyelonephritis as the cause of fever when the source is not known; it is the most sensitive study to determine the presence of scars; however, it may not ultimately change the course of treatment.

Complications.

·                        Septicemia: more likely to be present ieonates or in children with abnormal urinary tracts.

·                        Renal scarring: can develop years after infections that occurred in infancy or early childhood; it is associated with hypertension, toxemia, and the risk ofchronic renal failure leading to end-stage renal disease.

·                        Staghorn calculi: can form in the presence of repeated infections.

Treatments

·             Increased water intake offers several benefits; it dilutes urine, increases voiding frequency, and reduces constipation. Stool softeners should be considered if the latter problem persists.

·             Irritants, particularly soap, should be avoided near the perineum in prepubertal girls.

·             Sexually active women may benefit from postcoital voiding.

Pharmacologic treatment.

Complicated febrile urinary tract infections.

Complicated infections are defined as those seen in infants younger than 6 months of age and any child who is clinically ill, persistently vomiting, moderately dehydrated, or poorly compliant; these cases warrant intravenous antibiotics and hospitalization.

Standard dosage.

·             Ampicillin, 50– 100 mg/kg/d in four divided doses.

·             Gentamicin, 2– 2.5 mg/kg/dose every 8 h.

·             Ceftriaxone, 75 mg/kg/dose every 12 h (does not cover Enterococcus, which is more frequently encountered in children with recurrent infection and should be avoided ieonates).

Special points An oral agent can be used after the child improves clinically (>24 h afebrile) pending the results of the culture and sensitivities; total treatment should last 14 d or longer if there is a renal abscess or an abnormal urinary tract.

Uncomplicated febrile urinary tract infections.

These children do not appear clinically ill, can take oral antibiotics, and are only mildly dehydrated (if at all) and compliant. Treatment can start with one dose of a parenteral agent (ceftriaxone, 75 mg/kg i.v. or i.m.; gentamicin, 2.5 mg/kg i.v. or i.m.) followed by oral therapy or with oral therapy alone. Good follow-up is essential to ensure the child has responded appropriately, with treatment lasting 10– 14 d.

Standard dosage.

·             Cotrimoxazole, 6– 12 mg/kg/d trimethoprim divided twice daily.

·             Amoxicillin, 20– 40 mg/kg/d divided 3 times daily (many strains of E. coli are resistant to amoxicillin).

·             Cephalexin, 25– 50 mg/kg/d divided 4 times daily.

·             Cefprozil, 15– 30 mg/kg/d divided 2 times daily.

Afebrile urinary tract infections (acute cystitis).

Oral therapy with the agents listed above for a total of 5– 7 d assuming clinical improvement is seen; in addition, nitrofurantoin 5– 7 mg/kg/d divided 4 times daily can be considered; the liquid form of nitrofurantoin is not well tolerated.

Covert (asymptomatic) bacteriuria.

·             The treatment of this subgroup is controversial even in the presence of reflux; treatment may lead to the emergence of resistant organisms.

Prophylaxis.

Standard dosage.

·             Cotrimoxazole: 1– 2 mg/kg trimethoprim daily.

·             Nitrofurantoin, 1– 2 mg/kg/d.

Both of the above medications should be avoided in infants younger than

6 months of age.

·             Amoxicillin (10 mg/kg/d) or cephalexin (10 mg/kg/d) can be used instead.

Other treatments.

·             Infection in the presence of obstruction requires effective drainage of the urinary tract (eg, nephrostomy, bladder catheterization) in addition to antibiotic therapy.

·             Surgical correction of vesicoureteral reflux in indicated when the reflux is massive, when breakthrough infections develop, or when poor compliance is suspected.

Prognosis.

Rick for renal damage includes

· infant and young children with febrile infections in whom treatment is delayed

· Children with massive vesicoureteral reflux, and those with anatomic or neuropathic urinary tract obstruction.

Follow-up and management

· Follow-up cultures should be obtained in children with febrile UTIs to assure an appropriate response.

· Infants and young children with documented vesicoureteral reflux should remain on antibiotic prophylaxis until the reflux resolves

· Some children with recurrent infections benefit from a short course of prophylactic therapy even when reflux is not present.

 

 

Diabetes mellitus (DM) in children.

The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both (Fig. 1). The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long–term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease. Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and proteinmetabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.

Fig. 1. Pathogenesis of DM type 1.

Diagnosis and diagnostic criteria.

If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully established since theconsequences for the individual are considerable and lifelong. The requirements for diagnostic confirmation for a person presenting with severe symptoms and gross hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to be just above the diagnostic cut–off value. Severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value. For the asymptomatic person, at least one additional plasma/blood glucose test result with a value in the diabetic range is essential, either fasting, from a random (casual) sample, or from the oral glucose tolerance test (OGTT). If such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance with periodic re–testing until the diagnostic situation becomes clear. In these circumstances, the clinician should take into consideration such additional factors as ethnicity, family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action. An alternative to blood glucose estimation or the OGTT has long been sought to simplify the diagnosis of diabetes. Glycated haemoglobin, reflecting average glycaemia over a period of weeks, was thought to provide such a test. Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement, it is not available in many parts of the world and is not well enough standardized for its use to be recommended at this time.

 

 

Diabetes in children

Diabetes in children usually presents with severe symptoms, very high blood glucose levels, marked glycosuria, and ketonuria. In most children the diagnosis is confirmed without delay by blood glucose measurements, and treatment (including insulin injection) is initiated immediately, often as a life–saving measure. An OGTT is neither necessary nor appropriate for diagnosis in such circumstances. A small proportion of children and adolescents, however, present with less severe symptoms and may require fasting blood glucose measurement and/or an OGTT for diagnosis.

Diagnostic criteria

The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma; high levels of glycosuria are usually present. A single blood glucose estimation in excess of the diagnostic values indicated in Figure 2 (black zone) establishes the diagnosis in such cases.Figure 2 also defines levels of blood glucose below which a diagnosis of diabetes is unlikely ion–pregnant individuals. These criteria are as in the WHO 1985 report. For clinical purposes, an OGTT to establish diagnostic status need only be considered if casual blood glucose values lie in the uncertain range (i.e. between the levels that establish or exclude diabetes) and fasting bloodglucose levels are below those which establish the diagnosis of diabetes. If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 hours after a 75 g oral glucose load (Annexe 1). For children the oral glucose load is related to body weight: 1.75 g per kg. The diagnostic criteria in children are the same as for adults. Diagnostic interpretations of the fasting and 2–h post–load concentrations ion–pregnant subjects are shown in Table 1.

 

Classification (Tables 2, Table 3).

It is recommended that the terms “insulin–dependent diabetes mellitus” and “non–insulin–dependent diabetes mellitus” andtheir acronyms “IDDM” and “NIDDM” no longer be used. These terms have been confusing and frequently resulted in patients being classified on the basis of treatment rather than pathogenesis.

–     The terms Type 1 and Type 2 should be reintroduced. The aetiological type named Type 1 encompasses the majority of cases which are primarily due to pancreatic islet beta–cell destruction and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those with beta– cell destruction and who are prone to ketoacidosis for which neither an aetiology nor a pathogenesis is known (idiopathic). It does not include those forms ofbeta–cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects, etc.). Some subjects with this type can be identified at earlier clinical stages than “diabetes mellitus”.

–     The type named Type 2 includes the common major form of diabetes which results from defect(s) in insulin secretion, almost always with a major contribution from insulin resistance. It has been argued that a lean phenotype of Type 2 diabetes mellitus in adults found in the Indian sub–continent may be very distinct from the more characteristic form of Type 2 found in Caucasians. Not enough information is available, however, to characterize such subjects separately.

–     A recent international workshop reviewed the evidence for, and characteristics of, diabetes mellitus seen inundernourished populations. Whilst it appears that malnutrition may influence the expression of several types of diabetes, the evidence that diabetes can be caused by malnutrition or protein deficiency per se is not convincing. Therefore, it is recommended that the class “Malnutrition–related diabetes” (MRDM) be deleted. The former subtype of MRDM, Protein– deficient Pancreatic Diabetes (PDPD or PDDM), may be considered as a malnutrition modulated or modified form of diabetes mellitus for which more studies are needed. The other former subtype of MRDM,Fibrocalculous Pancreatic Diabetes (FCPD), is now classified as a disease of the exocrine pancreas, fibrocalculous pancreatopathy, which may lead to diabetes mellitus.

–     The class “Impaired Glucose Tolerance” is now classified as a stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder, and is itself not diabetes.

–     A clinical stage of Impaired Fasting Glycaemia has been introduced to classify individuals who have fasting glucose values above the normal range, but below those diagnostic of diabetes.

–     Gestational Diabetes is retained but now encompasses the groups formerly classified as Gestational Impaired Glucose Tolerance (GIGT) and Gestational Diabetes Mellitus (GDM).

Table 2. Aetiological Classification of Disorders of

Glycaemia

––––––––––––––––––––––––––––––––––––––––––––––––

Type 1 (beta-cell destruction, usually leading to absolute

insulin deficiency)

Autoimmune

Idiopathic

Type 2 (may range from predominantly insulin resistance

with relative insulin deficiency to a predominantly

secretory defect with or without insulin resistance)

Other specific types

Genetic defects of beta-cell function

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug- or chemical-induced

Infections

Uncommon forms of immune-mediated diabetes

Other genetic syndromes sometimes associated with

diabetes

Gestational diabetes

 

Table 3 Other Specific Types of Diabetes

––––––––––––––––––––––––––––––––––––––––––––––––

Genetic defects of beta-cell function

Chromosome 20, HNF4a (MODY1)

Chromosome 7, glucokinase (MODY2)

Chromosome 12, HNF1a (MODY3)

Chromosome 13, IPF-1 (MODY4)

Mitochondrial DNA 3243 mutation

Others

Genetic defects in insulin action

Type A insulin resistance

Leprechaunism

Rabson-Mendenhall syndrome

Lipoatrophic diabetes

Others

Diseases of the exocrine pancreas

Fibrocalculous pancreatopathy

Pancreatitis

Trauma / pancreatectomy

Neoplasia

Cystic fibrosis

Haemochromatosis

Others

Endocrinopathies

Cushing’s syndrome

Acromegaly

Phaeochromocytoma

Glucagonoma

Hyperthyroidism

Somatostatinoma

Others

Drug- or chemical-induced

Infections

Congenital rubella

Cytomegalovirus

Others

Uncommon forms of immune-mediated diabetes

Insulin autoimmune syndrome (antibodies to insulin)

Anti-insulin receptor antibodies

“Stiff Man” syndrome

Others

Other genetic syndromes

––––––––––––––––––––––––––––––––––––––––––––––––

Laboratory methods of examination in DM.

Measurement of glucose in blood Reductiometric methods (the Somogyi–Nelson, the ferricyanide and neocuprine autoanalyser methods) are still in use for blood glucose measurement. The o–toluidine method also remains in use but enzyme–based methods are widely available, for both laboratory and near–patient use. Highly accurate and rapid (1–2 min) devices are now available based on immobilized glucose oxidase electrodes. Hexokinase and glucose dehydrogenase methods are used for reference. Whole blood samples preserved with fluoride show an initial rapid fall in glucose of up to 10 % at room temperature, but subsequent decline is slow; centrifugation prevents the initial fall. Whole blood glucose values are 15 % lower than corresponding plasma values in patients with a normal haematocrit reading, and arterial values are about 7 % higher than corresponding venous values. The use of reagent–strip glucose oxidase methods has made bedside estimation of blood glucose very popular. However, the cost of the reagent–strips remains high. Some methods still require punctilious technique, accurate timing, and storage of strips in airtight containers. Reasonably quantitative results can be obtained even with visual colour–matching techniques. Electrochemical andreflectance meters can give coefficients of variation of well under 5 %. Reagent–strip methods have been validated under tropicalconditions, but are sensitive to extreme climatic conditions. Diabetes may be strongly suspected from the results of reagent– strip glucose estimation, but the diagnosis cannot be confidently excluded by the use of this method. Confirmation of diagnosis requires estimation by laboratory methods. Patients can easily collect small blood samples themselves (either in specially prepared plastic or glass capillary tubes or on filter–paper), and self–monitoring using glucose reagent–strips with direct colour–matching or meters is now widely practised. Patients should be properly trained in the appropriate techniques to avoid inaccurate or misleading results. The insulin–treated patient is commonly requested to build up a “glycaemic profile” by self–measurement of blood glucose at specific times of the day (and night). A “7–point profile” is useful, with samples taken before and 90 min after breakfast, before and 90 min after lunch, before and 90 min after an evening meal, and just before going to bed. Occasionally patients may arrange to wake at 0300 h to collect and measure a nocturnal sample. The complete profile rarely needs to be collected within a single 24–hour period, and it may be compiled from samples collected at different times over several days. Measurement of glucose in urine Insulin–treated patients who do not have access to facilities for self–measurement of blood glucose should test urine samples passed after rising, before main meals, and before going to bed. Non–insulin–dependent patients do not need to monitor their urine so frequently. Urine tests are of somewhat limited value, however, because of the great variation in urine glucose concentration for given levels of blood glucose. The correlation between blood and urine glucose may be improved a little by collecting short–term fractions (15–30 min) of the urine output. Benedict’s quantitative solution or self–boiling, caustic soda/copper sulphate tablets may be used or the moreconvenient, but costly, semi–quantitative enzyme–based test– strips. Ketone bodies in urine and blood The appearance of persistent ketonuria associated with hyperglycaemia or high levels of glycosuria in the diabetic patient points to an unacceptably severe level of metabolic disturbance and indicates an urgent need for corrective action. The patient should be advised to test for ketone bodies (acetone and aceto–acetic acid) when tests for glucose are repeatedly positive, or when there issubstantial disturbance of health, particularly with infections. Rothera’s sodium nitroprusside test may be used or, alternatively, reagent–strips that are sensitive to ketones. In emergency situations such as diabetic ketoacidosis, a greatly raised concentration of plasma ketones can be detected with a reagent–strip and roughly quantified by serial 1 in 2 dilution of plasma with water.

Annex 1

The Oral Glucose Tolerance Test

The oral glucose tolerance test (OGTT) is principally used for diagnosis when blood glucose levels are equivocal, during pregnancy, or in epidemiological studies. The OGTT should be administered in the morning after at least three days of unrestricted diet (greater than 150 g of carbohydrate daily) and usual physical activity. Recent evidence suggests that a reasonable (30–50g) carbohydrate containing meal should be consumed on the evening before the test. The test should be preceded by an overnight fast of 8–14 hours, during which water may be drunk. Smoking is not permitted during the test. The presence of factors that influence interpretation of the results of the test must be recorded (e.g. medications, inactivity, infection, etc.). After collection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose or 82.5 g of glucose monohydrate (or partial hydrolysates of starch of the equivalent carbohydrate content) in 250–300 ml of water over the course of 5 minutes. For children, the test load should be 1.75 g of glucose per kg body weight up to a total of 75 g of glucose. Timing of the test is from the beginning of the drink. Blood samples must be collected 2 hours after the test load. Unless the glucose concentration can be determined immediately, the blood sample should be collected in a tube containing sodium fluoride (6 mg per ml whole blood) and immediately centrifuged to separate the plasma; the plasma should be frozen until the glucose concentration can be estimated. For interpretation of results, refer to Table 1.

Age

Insulin dose (Units/kg)

Infants (< 1 year)

0,1 – 0,125

Toddlers (1-3 years)

0,15 – 0,17

3-9 years

0,2 – 0,5

9-12 years

0,5 – 0,8

> 12 years

1,0 and more

Insulin has 3 basic formulations:

– short-acting (regular, soluble, lispro)

-medium- or intermediate-acting (isophane, lente)

– and long-acting (ultralente).

Periods of action of different types of insulin you can see on Fig. 3.

Fig. 3. Periods of action of different types of insulin.

 

Complications of DM.

Nephropathy:

Microangiopathy:

·  capillary basement membrane is thickened – this affects:

o          retina

o          renal glomerulus

o          nerve sheaths

Macroangiopathy:

·  atherosclerosis occurs at an accelerated rate

·  thus diabetics are more at risk of:

o          strokes

o          MI

o          gangrene leading to amputation

Retinopathy:

 

 

Nonretinal visual problems:

·  lens affected by changes in osmolality – leads to cataracts

·  new vessel formation in the iris

·  ocular palsies eg. of sixth cranial nerve

Frequent infections:

·  with poor diabetic control

·  white blood cells are impaired with high blood glucose levels

·  important as infections then lead to poor control of diabetes

Differential diagnosis among the various obesity forms in children.

Definition. Obesity is defined as weight/height greater than 120% of standards for age and sex. Although BMI is widly used for obesity diagnostic.

Etiology and pathogenesis. Several factors may contribute to the development of obesity (Tabl.4). Exogenous-constitutive, the most common reason for obesity, typically is viewed as the consequence of increased caloric intake and genetic predisposition.

–     Genetic predisposition is suggested by twin studies. Individuals with a propensity toward obesity may require fewer calories to maintain a normal weight.

–     Increased caloric intake may be secondary to a variety of psychosocial causes, such as anxiety and family modeling.

–     Genetic disorders. For example, Prader-Willi syndrome and Laurence-Moon-Biedl syndrome are associated with obesity.

–     Neuroendocrine, cerebral and endocrine obesity are appearing because of compromised perinatal life, old severe viral (bacterial) infections or hormonal abnormalities.

 

Table 4. Classification of obesity.

 

Diagnosis.

–     History. Essential elements include: 1) family history (parental obesity is a strong predictor of childhood obesity); 2) history of the child’s weight height gain over time; 3) a dietary diary to document eating patterns and caloric intake.

–     Physical examination. 1) normal stature, sexual development and intelligence rule out most genetic disorders associated with obesity and strongly suggest exogenous obesity; 2) triceps skin fold thickness measurement may be helpful; 3) blood pressure should be obtained.

Laboratory studies. Total cholesterol, triglycerides and high density lipoprotein should be measured.

Therapy. A reduced calorie diet should be devised, nutritionist often is helpful. Anorectic drugs are useful sometimes. A formal exercise program should be encouraged. Specific weight goals should be determined. Treatment of the base disease in a case of secondary obesity.

 

Practice Essentials

Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Most pediatric patients with diabetes have type 1 and a lifetime dependence on exogenous insulin.

Essential update: Disordered eating common in pediatric patients with type 1 diabetes

In a survey of 770 Norwegian children and adolescents with type 1 diabetes, nearly 1 in 5 (and 1 in 4 females) was found to have disturbed eating behavior (DEB). Mean age of the subjects was 14.6 years, and mean diabetes duration was 5.3 years. Most respondents used insulin pumps (56%) or took at least 4 insulin shots per day.

Using a predetermined cutoff of 20 or higher on the newly developed 16-item Diabetes Eating Problem Survey-Revised (DEPS-R), DEB was identified in 18.3% of the entire group, 27.7% of the females, and 8.6% of the males.

The proportions were dramatically higher among the older group of 153 patients aged 17 to 19 years, in whom DEB was identified in 32.7% overall and in 49.4% of the females and 14.5% of the males. In contrast, all of those rates were less than 10% among the 11- to 13-year-olds.

Signs and symptoms

Signs and symptoms of type 1 diabetes in children include the following:

–                                 Hyperglycemia

–                                 Glycosuria

–                                 Polydipsia

–                                 Unexplained weight loss

–                                 Nonspecific malaise

–                                 Symptoms of ketoacidosis

See Clinical Presentation for more detail.

Diagnosis

Blood glucose

Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Diagnostic criteria by the American Diabetes Association (ADA) include the following :

–                                 A fasting plasma glucose (FPG) level ≥126 mg/dL (7.0 mmol/L), or

–                                 A 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or

–                                 A random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

Glycated hemoglobin

Measurement of HbA1c levels is the best method for medium-term to long-term diabetic control monitoring. An international expert committee composed of appointed representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others recommended HbA1c assay for diagnosing diabetes mellitus.

See Workup for more detail.

Management

Glycemic control

The ADA recommends using patient age as one consideration in the establishment of glycemic goals, with different targets for preprandial, bedtime/overnight, and hemoglobin A_1c (HbA_1c) levels in patients aged 0-6, 6-12, and 13-19 years. Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality.

Insulin therapy

All children with type 1 diabetes mellitus require insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, or glulisine) or short-acting (regular).

Diet and activity

The aim of dietary management is to balance the child’s food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia.

The following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patient’s culture):

–                                 Carbohydrates – Should provide 50-55% of daily energy intake; no more than 10% of carbohydrates should be from sucrose or other refined carbohydrates

–                                 Fat – Should provide 30-35% of daily energy intake

–                                 Protein – Should provide 10-15% of daily energy intake

Exercise is also an important aspect of diabetes management. It has real benefits for a child with diabetes. Patients should be encouraged to exercise regularly.

Possible mechanism for development of type 1 diabetes.

 

Background

Most pediatric patients with diabetes have type 1 diabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin. Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). A possible mechanism for the development of type 1 diabetes is shown in the image below.

Type 2 diabetes mellitus (non–insulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with type 2 diabetes mellitus have insulin resistance, and their beta cells lack the ability to overcome this resistance. Although this form of diabetes was previously uncommon in children, in some countries, 20% or more of new patients with diabetes in childhood and adolescence have type 2 diabetes mellitus, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release, leading to maturity onset diabetes of the young (MODY) or congenital diabetes. This topic addresses only type 1 diabetes mellitus. (See Etiology and Epidemiology.)

Hypoglycemia

Hypoglycemia is probably the most disliked and feared complication of diabetes, from the point of view of the child and the family. Children hate the symptoms of a hypoglycemic episode and the loss of personal control it may cause. (See Pathophysiology and Clinical.)

Manage mild hypoglycemia by giving rapidly absorbed oral carbohydrate or glucose; for a comatose patient, administer an intramuscular injection of the hormone glucagon, which stimulates the release of liver glycogen and releases glucose into the circulation. Where appropriate, an alternative therapy is intravenous glucose (preferably no more than a 10% glucose solution). All treatments for hypoglycemia provide recovery in approximately 10 minutes. (See Treatment.)

Occasionally, a child with hypoglycemic coma may not recover within 10 minutes, despite appropriate therapy. Under no circumstances should further treatment be given, especially intravenous glucose, until the blood glucose level is checked and still found to be subnormal. Overtreatment of hypoglycemia can lead to cerebral edema and death. If coma persists, seek other causes.

Hypoglycemia was a particular concern in children younger than 4 years because the condition was thought to lead to possible intellectual impairment later in life. Persistent hyperglycemia is now believed to be more damaging.

Hyperglycemia

In an otherwise healthy individual, blood glucose levels usually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood sugar levels rise if insulin is insufficient for a given glucose load. The renal threshold for glucose reabsorption is exceeded when blood glucose levels exceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of polyuria and polydipsia. (See Pathophysiology, Clinical, and Treatment.)

All children with diabetes experience episodes of hyperglycemia, but persistent hyperglycemia in very young children (age < 4 y) may lead to later intellectual impairment.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is much less common than hypoglycemia but is potentially far more serious, creating a life-threatening medical emergency. Ketosis usually does not occur when insulin is present. In the absence of insulin, however, severe hyperglycemia, dehydration, and ketone production contribute to the development of DKA. The most serious complication of DKA is the development of cerebral edema, which increases the risk of death and long-term morbidity. Very young children at the time of first diagnosis are most likely to develop cerebral edema.

DKA usually follows increasing hyperglycemia and symptoms of osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of subcutaneous insulin, may present with ketosis and more normal blood glucose levels. They are more likely to present with nausea, vomiting, and abdominal pain, symptoms similar to food poisoning. DKA may manifest as respiratory distress.

Injection-site hypertrophy

If children persistently inject their insulin into the same area, subcutaneous tissue swelling may develop, causing unsightly lumps and adversely affecting insulin absorption. Rotating the injection sites resolves the condition.

Fat atrophy can also occur, possibly in association with insulin antibodies. This condition is much less common but is more disfiguring.

Diabetic retinopathy

The most common cause of acquired blindness in many developed nations, diabetic retinopathy is rare in the prepubertal child or within 5 years of onset of diabetes. The prevalence and severity of retinopathy increase with age and are greatest in patients whose diabetic control is poor. Prevalence rates seem to be declining, yet an estimated 80% of people with type 1 diabetes mellitus develop retinopathy.

Diabetic nephropathy and hypertension

The exact mechanism of diabetic nephropathy is unknown. Peak incidence is in postadolescents, 10-15 years after diagnosis, and it may occur in as many as 30% of people with type 1 diabetes mellitus.

In a patient with nephropathy, the albumin excretion rate (AER) increases until frank proteinuria develops, and this may progress to renal failure. Blood pressure rises with increased AER, and hypertension accelerates the progression to renal failure. Having diabetic nephropathy also increases the risk of significant diabetic retinopathy.

Progression may be delayed or halted by improved diabetes control, administration of angiotensin-converting enzyme inhibitors (ACE inhibitors), and aggressive blood pressure control. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.

A child younger than 15 years with persistent proteinuria may have a nondiabetic cause and should be referred to a pediatric nephrologist for further assessment.

Peripheral and autonomic neuropathy

The peripheral and autonomic nerves are affected in type 1 diabetes mellitus. Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms.

Autonomic changes involving cardiovascular control (eg, heart rate, postural responses) have been described in as many as 40% of children with diabetes. Cardiovascular control changes become more likely with increasing duration and worsening control.^[16] In adults, peripheral neuropathy usually occurs as a distal sensory loss.

Gastroparesis is another complication, and it which may be caused by autonomic dysfunction. Gastric emptying is significantly delayed, leading to problems of bloating and unpredictable excursions of blood glucose levels.

Macrovascular disease

Although this complication is not seen in pediatric patients, it is a significant cause of morbidity and premature mortality in adults with diabetes. People with type 1 diabetes mellitus have twice the risk of fatal myocardial infarction (MI) and stroke that people unaffected with diabetes do; in women, the MI risk is 4 times greater. People with type 1 diabetes mellitus also have 4 times greater risk for atherosclerosis.

The combination of peripheral vascular disease and peripheral neuropathy can cause serious foot pathology. Smoking, hypertension, hyperlipidemia, and poor diabetic control greatly increase the risk of vascular disease. Smoking, in particular, may increase the risk of myocardial infarction by a factor of 10.

Autoimmune diseases

Hypothyroidism affects 2-5% of children with diabetes. Hyperthyroidism affects 1% of children with diabetes; the condition is usually discovered at the time of diabetes diagnosis.

Although Addison disease is uncommon, affecting less than 1% of children with diabetes, it is a life-threatening condition that is easily missed. Addison disease may reduce the insulin requirement and increase the frequency of hypoglycemia. (These effects may also be the result of unrecognized hypothyroidism.)

Celiac disease, associated with an abnormal sensitivity to gluten in wheat products, is probably a form of autoimmune disease and may occur in as many as 5% of children with type 1 diabetes mellitus.

Necrobiosis lipoidica is probably another form of autoimmune disease. This condition is usually, but not exclusively, found in patients with type 1 diabetes. Necrobiosis lipoidica affects 1-2% of children and may be more common in children with poor diabetic control.

Limited joint mobility

Limited joint mobility (primarily affecting the hands and feet) is believed to be associated with poor diabetic control.

Originally described in approximately 30% of patients with type 1 diabetes mellitus, limited joint mobility occurs in 50% of patients older than age 10 years who have had diabetes for longer than 5 years. The condition restricts joint extension, making it difficult to press the hands flat against each other. The skin of patients with severe joint involvement has a thickened and waxy appearance.

Limited joint mobility is associated with increased risks for diabetic retinopathy and nephropathy. Improved diabetes control over the past several years appears to have reduced the frequency of these additional complications by a factor of approximately 4. Patients have also markedly fewer severe joint mobility limitations.

Pathophysiology

Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in the liver and kidneys.

Hyperglycemia

Hyperglycemia (ie, random blood glucose concentration of more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to DKA. The effects of insulin deficiency are shown in the image below.

The effects of insulin deficiency

 

Hypoglycemia

Insulin inhibits glucogenesis and glycogenolysis, while stimulating glucose uptake. Iondiabetic individuals, insulin production by the pancreatic islet cells is suppressed when blood glucose levels fall below 83 mg/dL (4.6 mmol/L). If insulin is injected into a treated child with diabetes who has not eaten adequate amounts of carbohydrates, blood glucose levels progressively fall.

The brain depends on glucose as a fuel. As glucose levels drop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, cortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms include sweatiness, shaking, confusion, behavioral changes, and, eventually, coma when blood glucose levels fall below 30-40 mg/dL.

The glucose level at which symptoms develop varies greatly from individual to individual (and from time to time in the same individual), depending in part on the duration of diabetes, the frequency of hypoglycemic episodes, the rate of fall of glycemia, and overall control. (Glucose is also the sole energy source for erythrocytes and the kidney medulla.)

Etiology

Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

Genetic issues

Clear evidence suggests a genetic component in type 1 diabetes mellitus. Monozygotic twins have a 60% lifetime concordance for developing type 1 diabetes mellitus, although only 30% do so within 10 years after the first twin is diagnosed. In contrast, dizygotic twins have only an 8% risk of concordance, which is similar to the risk among other siblings.

The frequency of diabetes development in children with a mother who has diabetes is 2-3%; this figure increases to 5-6% for children with a father who has type 1 diabetes mellitus. The risk to children rises to almost 30% if both parents are diabetic.

Human leukocyte antigen (HLA) class II molecules DR3 and DR4 are associated strongly with type 1 diabetes mellitus. More than 90% of whites with type 1 diabetes mellitus express 1 or both of these molecules, compared with 50-60% of the general population.

Patients expressing DR3 are also at risk for developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function.

Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies. The expression of both DR3 and DR4 carries the greatest risk of type 1 diabetes mellitus; these patients have characteristics of both the DR3 and DR4 groups.

Neonatal diabetes, including diagnosis in infants younger than age 6 months, is most likely due to an inherited defect of the iKir6.2 subunit potassium channel of the islet beta cells, and genetic screening is indicated. This is particularly important, because these children respond well to sulphonylurea therapy.

Environmental factors

Environmental factors are important, because even identical twins have only a 30-60% concordance for type 1 diabetes mellitus and because incidence rates vary in genetically similar populations under different living conditions. No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates.

Viral infections may be the most important environmental factor in the development of type 1 diabetes mellitus, probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella. One survey suggests enteroviral infection during pregnancy carries an increased risk of type 1 diabetes mellitus in the offspring. Paradoxically, type 1 diabetes mellitus incidence is higher in areas where the overall burden of infectious disease is lower.

Dietary factors are also relevant. Breastfed infants have a lower risk for type 1 diabetes, and a direct relationship is observed between per capita cow’s milk consumption and the incidence of diabetes. Some cow’s milk proteins (eg, bovine serum albumin) have antigenic similarities to an islet cell antigen.

Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause type 1 diabetes mellitus in animal models; however, no definite link has been made with humans.

The known association of increasing incidence of type 1 diabetes mellitus with distance from the equator may now have an explanation. Reduced exposure to ultraviolet (UV) light and lower vitamin D levels, both of which are more likely found in the higher latitudes, are associated with an increased risk of type 1 diabetes mellitus.

Chemical causes

Streptozotocin and RH-787, a rat poison, selectively damages islet cells and can cause type 1 diabetes mellitus.

Other causes

Additional factors in the development of type 1 diabetes mellitus include the following:

–    Congenital absence of the pancreas or islet cells

–   Pancreatectomy

–    Pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic-uremic syndrome)

–   Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness [DIDMOAD])

–  Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (the risk is said to be around 1% in Down and Turner syndromes)

Epidemiology

Occurrence in the United States

The overall annual incidence of diabetes mellitus is about 24.3 cases per 100,000 person-years. Although most new diabetes cases are type 1 (approximately 15,000 annually), increasing numbers of older children are being diagnosed with type 2 diabetes mellitus, especially among minority groups (3700 annually).

International occurrence

Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 population in China to 41.4 cases per 100,000 population in Finland. Substantial variations are observed betweeearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations, such as those in Iceland and Norway.

A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.

Even more striking are the differences in incidence between mainland Italy (8.4 cases per 100,000 population) and the Island of Sardinia (36.9 cases per 100,000 population). These variations strongly support the importance of environmental factors in the development of type 1 diabetes mellitus. Most countries report that incidence rates have at least doubled in the last 20 years. Incidence appears to increase with distance from the equator.

Race-related demographics

Different environmental effects on type 1 diabetes mellitus development complicate the influence of race, but racial differences are evident. Whites have the highest reported incidence, whereas Chinese individuals have the lowest. Type 1 diabetes mellitus is 1.5 times more likely to develop in American whites than in American blacks or Hispanics. Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their rates of type 1 diabetes mellitus tend to increase toward the higher level.

Sex-related demographics

The influence of sex varies with the overall incidence rates. Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation. Females appear to be at a greater risk in low-incidence regions.

Age-related demographics

Type 1 diabetes mellitus can occur at any age, but incidence rates generally increase with age until midpuberty and then decline. Onset in the first year of life, although unusual, can occur, so type 1 diabetes mellitus must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. (Because diabetes is easily missed in an infant or preschool-aged child, if in doubt, check the urine for glucose.) Symptoms in infants and toddlers may include the following:

– Severe monilial diaper/napkin rash

–  Unexplained malaise

–   Poor weight gain or weight loss

–    Increased thirst

–    Vomiting and dehydration, with a constantly wet napkin/diaper

In areas with high prevalence rates, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, ages 4-6 y) and a second, much greater peak of incidence during early puberty (ie, ages 10-14 y).

Prognosis

Apart from severe DKA or hypoglycemia, type 1 diabetes mellitus has little immediate morbidity. The risk of complications relates to diabetic control. With good management, patients can expect to lead full, normal, and healthy lives. Nevertheless, the average life expectancy of a child diagnosed with type 1 diabetes mellitus has been variously suggested to be reduced by 13-19 years, compared with their nondiabetic peers.

Morbidity and mortality

Information on mortality rates for type 1 diabetes mellitus is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population. Children aged 1-4 years are particularly at risk and may die due to DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur and appears more likely to affect young males.

A population-based, nationwide cohort study in Finland examined the short -and long-term time trends in mortality among patients with early-onset and late-onset type 1 diabetes. The results suggest that in those with early-onset type 1 diabetes (age 0-14 y), survival has improved over time. Survival of those with late-onset type 1 diabetes (15-29 y) has deteriorated since the 1980s, and the ratio of deaths caused by acute complications has increased in this group. Overall, alcohol was noted as an important cause of death in patients with type 1 diabetes; women had higher standardized mortality ratios than did men in both groups.

The complications of type 1 diabetes mellitus can be divided into 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases.

Acute complications, which include hypoglycemia, hyperglycemia, and DKA, reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise.

Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. Although long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life. The likelihood of developing complications appears to depend on the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender. Long-term complications include the following:

–         Retinopathy

–         Cataracts

–         Gastroparesis

–         Hypertension

–         Progressive renal failure

–         Early coronary artery disease

–         Peripheral vascular disease

–         Peripheral and autonomic neuropathy

–         Increased risk of infection

Associated autoimmune diseases are common in type 1 diabetes mellitus, particularly in children who have HLA-DR3. Some conditions may precede the development of diabetes, and others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Patient Education

Education is a continuing process involving the child, family, and all members of the diabetes team. (See the videos below.) The following strategies may be used:

–         Formal education sessions in a clinic setting

–         Opportunistic teaching at clinics or at home in response to crises or difficulties such as acute illness

–         Therapeutic camping or other organized events

–         Patient-organized meetings

 

Diabetes-related organizations and patient groups include the following:

–         Children with Diabetes – This “online community for kids, families, and adults with diabetes” is an excellent resource with good links

–         International Society for Pediatric and Adolescent Diabetes

–         International Diabetes Federation

–         Diabetes UK

–         American Diabetes Association

–         Juvenile Diabetes Research Foundation International

–         Runsweet – This is a Web site devoted to giving advice on exercise management and diabetes

History

The most easily recognized symptoms of type 1 diabetes mellitus (T1DM) are secondary to hyperglycemia, glycosuria, and DKA.

Hyperglycemia

Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. Children may also appear irritable and become ill-tempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria.

Glycosuria

This condition leads to increased urinary frequency and volume (eg, polyuria), which is particularly troublesome at night (eg, nocturia) and often leads to enuresis in a previously continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use.

Polydipsia

Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration.

Weight loss

Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, although the child’s appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia.

Nonspecific malaise

Although this condition may be present before symptoms of hyperglycemia or as a separate symptom of hyperglycemia, it is often only retrospectively recognized.

Symptoms of ketoacidosis

These symptoms include the following:

–         Severe dehydration

–         Smell of ketones

–         Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress

–         Abdominal pain

–         Vomiting

–         Drowsiness and coma

Additional symptoms

Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract. Candidiasis may develop, especially in the groin and in flexural areas.

Physical Examination

Apart from wasting and mild dehydration, children with early diabetes have no specific clinical findings. A physical examination may reveal findings associated with other autoimmune endocrinopathies, which have a higher incidence in children with type 1 diabetes mellitus (eg, thyroid disease with symptoms of overactivity or underactivity and possibly a palpable goiter).

Cataracts are rarely presenting problems ; they typically occur in girls with a long prodrome of mild hyperglycemia.

Necrobiosis lipoidica usually, but not exclusively, occurs in people with diabetes. Necrobiosis most often develops on the front of the lower leg as a well-demarcated, red, atrophic area. The condition is associated with injury to dermal collagen, granulomatous inflammation, and ulceration. The cause of necrobiosis is unknown, and the condition is difficult to manage. It is also associated with poor metabolic control and a greater risk of developing other diabetes-related complications.

Diabetic retinopathy

The first symptoms of diabetic retinopathy are dilated retinal venules and the appearance of capillary microaneurysms, a condition known as background retinopathy. These changes may be reversible or their progression may be halted with improved diabetic control, although in some patients the condition initially worsens.

Subsequent changes in background retinopathy are characterized by increased vessel permeability and leaking plasma that forms hard exudates, followed by capillary occlusion and flame-shaped hemorrhages. The patient may not notice these changes unless the macula is involved. Laser therapy may be required at this stage to prevent further vision loss.

Proliferative retinopathy follows, with further vascular occlusion, retinal ischemia, and proliferation of new retinal blood vessels and fibrous tissue; the condition then progresses to hemorrhage, scarring, retinal detachment, and blindness. Prompt retinal laser therapy may prevent blindness in the later stages, so regular screening is vital.

Diagnostic Considerations

Children with MODY may present as having type 1 diabetes. As they may respond better to oral hypoglycemic agents, recognizing MODY as a possibility is important. Always consider the diagnosis of MODY in the following circumstances:

–         A strong family history of diabetes across 2 or more generations – The age of diagnosis usually falls with each successive generation

–         Persistently low insulin requirements, particularly with good blood glucose control

–         Development of diabetes from birth or within the first 9 months of life

Conditions to consider in the differential diagnosis of type 1 diabetes include the following:

–         Type 2 diabetes mellitus

–         MODY

–         Psychogenic polydipsia

–         Nephrogenic diabetes insipidus

–         High-output renal failure

–         Transient hyperglycemia with illness and other stress

–         Steroid therapy

–         Factitious illness (Münchhausen syndrome by proxy)

Differential Diagnoses

–         Diabetes Insipidus

–         Hyperthyroidism

–         Pheochromocytoma

–         Renal Glucosuria

–         Toxicity, Salicylate

Approach Considerations

The need for and extent of laboratory studies vary, depending on the general state of the child’s health. For most children, only urine testing for glucose and blood glucose measurement are required for a diagnosis of diabetes. Other conditions associated with diabetes require several tests at diagnosis and at later review.

Urine glucose

A positive urine glucose test suggests, but is not diagnostic for, type 1 diabetes mellitus (T1DM). Diagnosis must be confirmed by test results showing elevated blood glucose levels. Test urine of ambulatory patients for ketones at the time of diagnosis.

Urine ketones

Ketones in the urine confirm lipolysis and gluconeogenesis, which are normal during periods of starvation. With hyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency and potential DKA.

Islet cell antibodies

Islet cell antibodies may be present at diagnosis but are not needed to diagnose type 1 diabetes mellitus. Islet cell antibodies are nonspecific markers of autoimmune disease of the pancreas and have been found in as many as 5% of unaffected children. Other autoantibody markers of type 1 diabetes are known, including insulin antibodies. Additional antibodies against islet cells are recognized (eg, those against glutamate decarboxylase [GAD antibodies]), but these may not be available for routine testing.

Thyroid function tests and antithyroid antibodies

Because early hypothyroidism has few easily identifiable clinical signs in children, children with type 1 diabetes mellitus may have undiagnosed thyroid disease. Untreated thyroid disease may interfere with diabetes management. Typically, hypothyroid children present with reduced insulin requirements and increased episodes of hypoglycemia; hyperthyroid children have increased insulieeds and a tendency toward hyperglycemia. Caution, therefore, is needed when initiating treatment as insulin requirements can change quite quickly. Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present). Antithyroid antibody tests indicate the risk of present or potential thyroid disease.

Antigliadin antibodies

Some children with type 1 diabetes mellitus may have or may develop celiac disease. Positive antigliadin antibodies, especially specific antibodies (eg, antiendomysial, antitransglutaminase) are important risk markers. If antibody tests are positive, a jejunal biopsy is required to confirm or refute a diagnosis of celiac disease. Once celiac disease is confirmed, the individual should remain on a gluten-free diet for life.

Lipid profile

Lipid profiles are usually abnormal at diagnosis because of increased circulating triglycerides caused by gluconeogenesis. Apart from hypertriglyceridemia, primary lipid disorders rarely result in diabetes. Hyperlipidemia with poor metabolic control is common but returns to normal as metabolic control improves.

Urinary albumin

Beginning at age 12 years, perform an annual urinalysis to test for a slightly increased AER, referred to as microalbuminuria, which is an indicator of risk for diabetic nephropathy.

Renal function tests

If the child is otherwise healthy, renal function tests are typically not required.

Blood Glucose

Apart from transient illness-induced or stress-induced hyperglycemia, a random whole-blood glucose concentration of more than 200 mg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood glucose concentration that exceeds 120 mg/dL (7 mmol/L). In the absence of symptoms, the physician must confirm these results on a different day. Most children with diabetes detected because of symptoms have a blood glucose level of at least 250 mg/dL (14 mmol/L).

Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.

Glycated Hemoglobin

Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) are the result of a nonenzymatic reaction between glucose and hemoglobin. A strong correlation exists between average blood glucose concentrations over an 8- to 10-week period and the proportion of glycated hemoglobin. The percentage of HbA1c is more commonly measured. (Measurement of HbA1c levels is the best method for medium-term to long-term diabetic control monitoring.)

An international expert committee composed of appointed representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others recommended HbA1c assay for diagnosing diabetes mellitus. The committee recommended that an HbA1c level of 6.5% or higher be considered indicative of diabetes, with diagnostic confirmation being provided through repeat testing (unless clinical symptoms are present and the glucose level is >200 mg/dL). Glucose measurement should remain the choice for diagnosing pregnant women or be used if HbA1c assay is unavailable. The committee cited the following advantages of HbA1c testing over glucose measurement:

–                                 Captures long-term glucose exposure

–                                 Has less biologic variability

–                                 Does not require fasting or timed samples

–                                 Is currently used to guide management decisions

The Diabetes Control and Complications Trial (DCCT) found that patients with HbA1c levels of around 7% had the best outcomes relative to long-term complications. Most clinicians aim for HbA1c values of 7-9%. Values of less than 7% are associated with an increased risk of severe hypoglycemia; values of more than 9% carry an increased risk of long-term complications. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends a target level of 7.5% (58 mmol/mol) or less for all children.

Normal HbA1c values vary according to the laboratory method used, but nondiabetic children generally have values in the low-normal range. At diagnosis, diabetic children unmistakably have results above the upper limit of the reference range. Check HbA1c levels every 3 months.

Many different methods of measuring HbA1c are available, and the variations between the different assays can be considerable and unpredictable.

A working group was established in 1995 by the International Federation of Clinical Chemists (IFCC) to find a better method of standardizing the various assays. This resulted in a global standard that is gradually being implemented. As a result, HbA1c will be reported as millimole per mole (mmol/mol) instead of as a percentage. The current target range of 7-9% is set to be replaced with values of 53-75 mmol/mol.

Microalbuminuria

Microalbuminuria is the first evidence of nephropathy. The exact definition varies slightly between nations, but an increased AER is commonly defined as a ratio of first morning-void urinary albumin levels to creatinine levels that exceeds 10 mg/mmol, or as a timed, overnight AER of more than 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. Glomerular hyperfiltration occurs, as do abnormalities of the glomerular basement membrane and glomeruli. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.

Oral Glucose Tolerance Test

Although unnecessary in the diagnosis of type 1 diabetes mellitus, an oral glucose tolerance test (OGTT) can exclude the diagnosis of diabetes when hyperglycemia or glycosuria are recognized in the absence of typical causes (eg, intercurrent illness, steroid therapy) or when the patient’s condition includes renal glucosuria.

Obtain a fasting blood sugar level, then administer an oral glucose load (2 g/kg for children aged < 3 y, 1.75 g/kg for children aged 3-10 y [max 50 g], or 75 g for children aged >10 y). Check the blood glucose concentration again after 2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) or a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. However, mild elevations may not indicate diabetes when the patient has no symptoms and no diabetes-related antibodies.

A modified OGTT can also be used to identify cases of MODY (which often present as type 1 diabetes) if, in addition to blood glucose levels, insulin or c-peptide (insulin precursor) levels are measured at fasting, 30 minutes, and 2 hours. Individuals with type 1 diabetes mellitus cannot produce more than tiny amounts of insulin. People with MODY or type 2 diabetes mellitus show variable and substantial insulin production in the presence of hyperglycemia.

Approach Considerations

All children with type 1 diabetes mellitus require insulin therapy. The following are also required in treatment:

–         Blood glucose testing strips

–         Urine ketone testing tablets or strips

–         Blood ketone testing strips

Strategies to help patients and their parents achieve the best possible glycemic management are crucial. A 2-year randomized clinical trial found that a practical, low-intensity behavioral intervention delivered during routine care improved glycemic outcomes.

A well-organized diabetes care team can provide all necessary instruction and support in an outpatient setting. The only immediate requirement is to train the child or family to check blood glucose levels, to administer insulin injections, and to recognize and treat hypoglycemia. The patient and/or family should have 24-hour access to advice and know how to contact the team. Children should wear some form of medical identification, such as a medic alert bracelet or necklace.

Awareness of hypoglycemia becomes impaired over time, and severe hypoglycemia can occur without warning. Hypoglycemia is more likely to affect people who maintain low blood sugar levels and who already suffer frequent hypoglycemic attacks. Overzealous or inadequate treatment of hypoglycemia can lead to serious consequences.

Failure to regularly examine for diabetic complications in patients with type 1 diabetes mellitus, especially renal and ophthalmic ones, can be detrimental.

Inpatient care

Where a diabetes care team is available, admission is usually required only for children with DKA. In addition, children with significant dehydration, persistent vomiting, metabolic derangement, or serious intercurrent illness require inpatient management and intravenous rehydration.

Diabetes in pregnancy

Pregnancies should be planned and carefully managed to achieve healthy outcomes for mother and infant. Preconceptual normalization of blood sugars and folic acid supplements (at least 5 mg/d) reduce the otherwise increased risk of congenital heart disease and neural tube defects. Blood sugar control during pregnancy must be strict to avoid hypoglycemia, which may damage the fetus, and persistent hyperglycemia, which leads to fetal gigantism, premature delivery, and increased infant morbidity and mortality. DKA during pregnancy may result in fetal death.

Diet

Dietary management is an essential component of diabetes care. Diabetes is an energy metabolism disorder, and consequently, before insulin was discovered, children with diabetes were kept alive by a diet severely restricted in carbohydrate and energy intake. These measures led to a long tradition of strict carbohydrate control and unbalanced diets. Current dietary management of diabetes emphasizes a healthy, balanced diet that is high in carbohydrates and fiber and low in fat.

The following are among the most recent dietary consensus recommendations (although they should be viewed in the context of the patient’s culture):

–         Carbohydrates – Should provide 50-55% of daily energy intake; no more than 10% of carbohydrates should be from sucrose or other refined carbohydrates

–         Fat – Should provide 30-35% of daily energy intake

–         Protein – Should provide 10-15% of daily energy intake

The aim of dietary management is to balance the child’s food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia.

The ability to estimate the carbohydrate content of food (carbohydrate counting) is particularly useful for children who receive fast-acting insulin at mealtimes either by injection or insulin pump, as it allows for a more precise matching of food and insulin. Adequate intake of complex carbohydrates (eg, cereals) is important before bedtime to avoid nocturnal hypoglycemia, especially for children getting twice-daily injections of mixed insulin.

The dietitian should develop a diet plan for each child to suit individual needs and circumstances. Regularly review and adjust the plan to accommodate the patient’s growth and lifestyle changes.

Low-carbohydrate diets as a management option for diabetes control have regained popularity. Logic dictates that the lower the carbohydrate intake, the less insulin is required. No trials of low-carbohydrate diets in children with type 1 diabetes mellitus have been reported, and such diets cannot be recommended at the present.

Activity

Type 1 diabetes mellitus requires no restrictions on activity; exercise has real benefits for a child with diabetes. Current guidelines are increasingly sophisticated and allow children to compete at the highest levels in sports. Moreover, most children can adjust their insulin dosage and diet to cope with all forms of exercise.

Children and their caretakers must be able to recognize and treat symptoms of hypoglycemia. Hypoglycemia following exercise is most likely after prolonged exercise involving the legs, such as walking, running or cycling. It may occur many hours after exercise has finished and even affect insulin requirements the following day. A large, presleep snack is advisable following intensive exercise.

Long-Term Monitoring

Regular outpatient review with a specialized diabetes team improves short- and long-term outcomes. Most teams have a nurse specialist or educator, a dietitian, and a pediatrician with training in diabetes care. Other members can include a psychologist, a social worker, and an exercise specialist. Involvement with the team is intense over the first few weeks after diagnosis while family members learn about diabetes management.

Conduct a structured examination and review at least once annually to examine the patient for possible complications. Examination and review should include the following:

–         Growth assessment

–         Injection site examination

–         Examination of the hands, feet, and peripheral pulses for signs of limited joint mobility, peripheral neuropathy, and vascular disease

–         Evaluation for signs of associated autoimmune disease

–         Blood pressure

In individuals aged 11 years or older, further examination should include the following:

–                                 Retinoscopy or other retinal screening, such as photography

–                                 Urine examination for microalbuminuria

Medication Summary

Insulin is always required to treat type 1 diabetes mellitus. Originally, all insulin was derived from the highly purified pancreatic extracts of pigs and cattle, and this form of insulin is still available. Human insulin was later manufactured using recombinant deoxyribonucleic acid (DNA) technology. “Designer” insulins are also now being produced; they are based on the human molecule and are tailored to meet specific pharmacologic targets, particularly duration of action. Insulin must be given parenterally, and this effectively means subcutaneous injection.

Alternatives to injecting insulin have been constantly sought, including an inhaled form of insulin. Several products were in development, and one (Exubera) was licensed for use but failed to generate sufficient market penetration to justify continued production. The search for alternatives continues, including oral sprays, sublingual lozenges, and delayed-absorption capsules.

Insulin has 4 basic formulations: ultra ̶ short-acting (eg, lispro, aspart, glulisine), traditional short-acting (eg, regular, soluble), medium- or intermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, ultralente, glargine).

Regular or soluble insulin is bound to either protamine (eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duration of action. Combinations of isophane and regular, lispro, or aspart insulins are also available in a limited number of concentrations that vary around the world, ranging from 25:75 mixtures (ie, 25% lispro, 90% isophane) to 50:50 mixtures. The following image illustrates the activity profile of various insulins.

The development of insulin analogues has attempted to address some of the shortcomings of traditional insulin. Insulins lispro, glulisine, and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia. (See the graph below.) They are also more suitable for use with insulin pumps. An intermediate-acting insulin (detemir) has a similar profile of action to isophane but is more pharmacologically predictable and is less likely to cause weight gain, whereas glargine has a relatively flat profile of action, lasting some 18-26 hours. Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates.

Representation of activity profile of some available insulins.

The FDA issued an early communication to health care practitioners regarding 4 published observational studies that described the possible association of insulin glargine (Lantus) with an increased risk of cancer.Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that which is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raised further questions about the actual risk and, therefore, further evaluation is warranted.

The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

With so many various insulins and mixtures available, a wide range of possible injection regimens exist. These can be broadly categorized into 4 types, as follows:

–         Twice-daily combinations of short- and intermediate-acting insulin.

–         Multiple injection regimens using once-daily or twice-daily injections of long-acting or intermediate-acting insulin and short-acting insulins given at each meal

–         A combination of the above 2 regimens, with a morning injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection of intermediate- or long-acting insulin

–         Continuous subcutaneous insulin infusion (CSII) using an insulin pump

Although controlled clinical trials suggest improved short-term metabolic control in children using multiple injections or CSII, international comparisons do not support any particular insulin regimen, and all have their advantages and disadvantages.

A wide variety of insulin-injection devices are available, including a simple syringe and needle, semiautomatic pen injector devices, and needle-free jet injectors. Increasing numbers of young people use insulin pumps to deliver continuous subcutaneous insulin, with bolus doses at meal times.

When prescribing, tailor the insulin dose to the individual child’s needs. For instance, if using a twice-daily regimen, then, as a rule of thumb, prepubertal children require between 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and 30-40% in the evening. Insulin resistance is a feature of puberty, and some adolescents may require as much as 2 U/kg/d. About one third of the administered insulin is a short-acting formulation and the remainder is a medium- to long-acting formulation. Basal bolus regimens have a higher proportion of short-acting insulin. Typically, 50% of the total daily dose is given as long- or intermediate-acting insulin. CSII uses only short-acting insulins, most often the analogues lispro or aspart. Typically, they also have around 50% of the insulin given at a basal rate; the remainder is given as food-related boluses.

ntidiabetic Agents

Class Summary

These agents are used for the treatment of type 1 diabetes mellitus, as well as for type 2 diabetes mellitus that is unresponsive to treatment with diet and/or oral hypoglycemics.

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Insulin detemir (Levemir)

 

This agent is indicated for daily or twice-daily subcutaneous administration for adults and pediatric patients with type 1 diabetes mellitus; it is also indicated for adults with type 2 diabetes mellitus who require long-acting basal insulin for hyperglycemic control. The duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). Prolonged action is a result of the slow systemic absorption of detemir molecules from the injection site.

Insulin detemir’s primary activity is regulation of glucose metabolism. It binds to insulin receptors and lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat. The drug also inhibits glucose output from the liver. It inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

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Insulin lispro (Humalog)

Onset of action for insulin lispro is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 2-4 hours.

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Regular insulin (Humulin R, Novolin R)

Onset of action is 0.25-1 hours, peak activity is 1.5-4 hours, and duration of action is 5-9 hours.

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Insulin NPH (Humulin N, Novolin N)

Onset of action is 3-4 hours, peak effect is in 8-14 hours, and usual duration of action is 16-24 hours.

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Insulin aspart (NovoLog)

 

Onset of action is 10-30 minutes, peak activity is 1-2 hours, and duration of action is 3-6 hours. Insulin aspart is homologous with regular human insulin, with the exception of the single substitution of the amino acid proline with aspartic acid in position B28. The drug is produced by recombinant DNA technology. Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. It inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis. Insulin is the principal hormone required for proper glucose use iormal metabolic processes.

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Insulin glargine (Lantus)

This is a long-acting insulin analogue. Its typical onset of action is 1-2 hours, and its duration is 20-26 hours.

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Insulin glulisine (Apidra)

Insulin glulisine is a human insulin analog produced by recombinant DNA technology using a nonpathogenic laboratory strain of Escherichia coli (K12). It differs from human insulin by replacement of asparagine at the B3 position with lysine, and the replacement of lysine at the B29 position with glutamic acid. Insulin regulates glucose metabolism by stimulating peripheral glucose uptake by skeletal muscle and fat, and inhibits hepatic glucose production.

Glucose lowering with insulin glulisine is equipotent to that of regular human insulin when it is administered intravenously. After subcutaneous administration, insulin glulisine has a more rapid onset and a shorter duration of action than does regular human insulin. It is useful for the regulation of mealtime blood glucose elevation.

 

Thyroid glands disorders.

Goiter.

Definition. A goiter is an enlargement of the thyroid gland resulting from several different pathogenic mechanisms (Fig. 1, Fig. 2). The incidence of goiter increases with advancing age and is more common in girls at all ages. The presence of goiter does not correlate with thyroid function, i.e. patients may be euthyroid, hypothyroid or hyperthyroid, although most children are clinically euthyroid.

Fig. 1. Thyroid gland structure (normal).

Fig. 2. A diffusely enlarged thyroid gland associated with hyperthyroidism is known as Grave’s disease. At low power here, note the prominent infoldings of the hyperplastic epithelium.

The WHO proposes a simplified classification based on the significance of goitre:

Group 0: normal thyroid, no palpable or visible goitre

Group 1: enlarged thyroid, palpable but not visible when the neck is in the normal position

Group 2: thyroid clearly visible when the neck is in the normal position

A. Simple goiter (the convertible terms are  colloid goiter, adolescent goiter, nontoxic goiter) is an acquired enlargement of the thyroid gland with normal function that is not caused by an inflammatory process or a tumor. At least 25 % of all children with thyroid enlargement have a simple goiter. The gland tends to be symmetric, smooth and of normal texture. For diagnosis we need normal function tests, negative thyroid antibodies, normal radioactive iodine (RAI) scan (not usually indicated).

Treatment. Thyroxin is usually not advocated when the gland is cosmetically insignificant. No other treatment is recommending exept periodic reassessment.

B. Endemic goiter occurs predominantly in iodine-deficient areas. Extreme deficiency occurs when daily urine contains less then 25 mg of iodine; moderate deficiency occurs when it is 25-50 mg and an adequate intake is reflected by an excretion of 100-200 mg/day.

Laboratory findings. The thyroxine (T₄) level is slightly low, triiodthyronine (T₃) level is normal or midly high and thyroid-stimulating hormone (TSH) level is elevated, but these patient are clinically euthyroid.

Treatment. We use iodine and (or) T₄, which either interrupts the cycle, leading to a decrease in TSH secretion and regression of the goiter.

For prevention in populations living in iodine deficient areas where iodised salt is not available and for curative treatment of patients with goitre: use iodised oil, according to national protocols. For information (according to the WHO):

 

Curative and preventive single-doses are the same. Oral treatment is preferred. Use injectable iodised oil for prevention only if annual administration of oral iodised oil is not possible. The target populations are pregnant and breastfeeding women, women of childbearing age and children.

In children, goitre disappears after several months. It disappears more slowly (or never) in adults despite restoration of normal thyroid function in 2 weeks. Surgery is only indicated for patients with local mechanical dysfunction.

Fig.5.

 

 

Fig. 6

.

C. Diffuse toxic goiter (the convertible terms are  thyrotoxicosis, Graves disease) is the most common cause of hyperthyroidism. Toxic multinodular goiter is rare in children. It is found mainly in the elderly and the middle-aged. The clinical symptoms are nervousness, tachycardia, muscle tremor, insatiable appetites, weight loss, wide-eyed stare, warm and moist skin.

Fig. 7. Thyrotoxicosis.

Laboratory findings. Serum T₃ and T₄ are increased. Serum TSH, measured by the sensitive methods, is undetectable or subnormal.

Treatment. We use antithiroid drugs (propylthiouracil, mercasolil, methimazole), beta-adrenergic blockers (propranolol), sometimes corticosteroids and sedatives. The effective therapy of hyperthyroidism is subtotal thyroidectomy.

Hypothyroidism

Definition. Hypothyroidism is the condition resulting from a lack of the effects of thyroid hormone on body tissues. Because thyroid hormone affects growth and development and regulates many cellular processes, the absence or deficiency of thyroid hormone has many detrimental consequences.

Etiology. The main causes of hypothyroidism in children are:

–              Maldevelopment  hypoplasia or aplasia of thyroid gland

–              Inborn deficiencies of biosynthesis or action of thyroid hormone

–              Hashimoto thyroiditis

–              Hypopituitarism or hypothalamic disease

–              Severe iodine deficiency

Clinical features. Patients  with hypothyroidism may complain of forgetfulness, reduced memory, mental slowing, depression, paresthesia. There may be bradycardia, quiet heart sounds, constipation, oedemata, anemia. Dry cool skin and hypothermia are common. Growth and development of children are retarded.

Fig.8. Congenital hypothyroidism.      Fig. 9. Acquired hypothyroidism.

 

Laboratory findings. Because of the sensitivity of the serun TSH level as an indicator of primery hypothyroidism, serum TSH may be the best method to screen for the disorder. Its range is elevated usually, with the exception of central hypothyroidism. Serum T₃ and T₄ are low as a rule but their ranges may be normal or subnormal too.

Therapy. The most adequate is the therapy of replacement: synthetic triodothyronine and T₃-T₄ combination. Also we use vitamins, neurotropic drug, therapeutic physical training, speech therapist.

Thyroiditis

A. Hashimoto thyroiditis (chronic thyroiditis, autoimmune thyroiditis)

Etiology. Hashimoto thyroiditis is an organ-specific autoimmune disorder. The basic defect underlying this disease is not entirely clear, although current evidence suggests an abnormality in suppressor T lymphocytes that allows helper T lymphocytes to interact with specific antigens directed against the thyroid cell. A genetic predisposition is also suggested.

Clinical features. Physical examination usually discloses a symmetrically enlarged, very firm goiter; a pebby or knobby consistency is common.

Laboratory findings. Approximately 80 % of patients with Hashimoto thyroiditis have normal circulating T₃, T₄ and TSH levels at the time of diagnosis. Antithyroglobulin antibodies and antithyroperoxidase antibodies are measurable in more than 85 % of patients with Hashimoto thyroiditis.

Treatment. Thyroid hormone in full replacement dosages is the treatment of choice. The aim is to decrease the goiter, especially in patients with significant enlargement goiter, which causes the symptoms of dysphagia or other discomfort. When there is a rapidly enlarging goiter we use glucocorticoids. Surgery is indicated only if significant pressure symptoms occur.

B. Acute thyroiditis

Etiology. This rare disorder is usually due to a bacterial pathogen, most commonly Staphylococcus hemolitica, Streptococcus hemolitica, Streptococcus pneumoniae or anaerobic streptococcal organisms.

Clinical features. Fever, chills and other systemic signs or symptoms of abscess formation are present. Anterior neck pain and swelling are usual, with pain occasionally radiating to the ear or mandible. The physical examination suggests the presence of an abscess, with erythema of the skin, marked tenderness to palpation and at times fluctuance.

Laboratory findings. Leukocytosis with a left shift is usually present. Patients are euthyroid usually.

Treatment. Parenteral antibiotics should be administrated according to the specific pathogen identified. If fluctuance is present, incision and drainage might be required.

Parathyroid glands disorders.

Hypoparathyroidism. Etiology. The causes of parathyroid failure and resistance to parathyroid hormone (PTH) are absence or genetic defect in PTH biosynthesis, autoimmune destruction of parathyroid gland, reduced PTH secretion and resistance to PTH as a consequence of hypomagnesemia.

Fig. 5. Parathyroid gland structure (normal).

 

Clinical features. There may be tetany, convulsive syndrome (titanic more typical), karpopedal spasm, paresthesiae, muscle weakness, tiredness, Trousseau and Hvostek symptoms, cataract; hair, nails and skin affection, growth failure,  hypocalcemia, hyperphosphatemia.

A. Idiopathic hypoparathyroidism is a rare form of hypoparathyroidism. Several varieties of the disorder exist, both as sporadic and familiar condition. This disorder occurs as part of type I autoimmune polyglandular syndrome, as isolated idiopatic hypoparathyroidism, as part of Kearns-Sayre syndrome or due to congenital aplasia or dysgenesis of the parathyroids. The diagnosis of idiopatic hypoparathyroidism is generally one of exclusion. Demonstration of low to absent levels of PTH in the presence of hypocalcemia, frequently with hyperphosphatemia and with no evidence for magnesium depletion, strongly supports this diagnosis.

B. Surgical hypoparathyroidism. Surgical damage to or removal of parathyroid tissue accounts for the majority of cases of loss of parathyroid function.

Treatment. The aim of the hypoparathyroidism therapy is the correction of hypocalcemia. Although mild hypocalcemia might not require therapy, any neonate with a serum calcium level below 7,5 mg/dl (Ca²⁺ less then 2,8 mg/dl) or an older child with a serum calcium level less then 8-8,5 mg/dl should be treated to prevent tetany and other symptoms.

–              Acute. In acute symptomatic hypocalcemia intravenous therapy is required. It should be used 20-50 mg/kg /day of elemental calcium. When a central line is available, the calcium gluconate can be diluted with saline or dextrose infusion fluids and given continuosly.

–              Chronic. In the absence of tetany, seizures and severe degrees of hypocalcemia, oral therapy will suffice. A dosage of 50 mg/kg/day of elemental calcium is generally prescribed. Chronic hypocalcemia, exept in the mildest cases, is treated by the administration of vitamin D or its metabolites. Also the terapy of replacement by parathyroidin is used.

Hyperparathyroidism. Etiology. The main causes of the hyperparathyroidism are: primery congenital PTH hyperproduction, hyperplasia of hyperparathyroid glands, chronic renal diseases, Fankoni syndrome and malignant processes in hyperparathyroid glands.

Clinical features. Patients with hyperparathyroidism may suffer from “renal stones, painful bones, abdominal groans, psychic moans and fatigue overtones”. Symptoms often include polydipsia, polyuria, nocturia, constipation, increases fatigue, weakness and musculosceletal aches and pains.

Specialized tests:

–              Hydrocortisone suppression test

–              1,25-Dihydroxyvitamin D

–              Tubular resorption of phosphorus

Treatment. There is a general agreement that patients with symptomatic hyperparathyroidism and all patients with a serum calcium level 1 mg/dl above the upper limits of normal should be treated by parathyroidectomy. Operative treatment, however is not urgent and in all patients the diagnosis must be certain.

 The patients with hypercalcemic crisis should be treated with vigorous hydration. Calcium antagonists, calcitrinum, glucocorticoids and hemodialysis are applied if nessesary.

Laboratory tests. For diagnostic of hyperparathyroidism if patient have hypercalcemia are usefull:

General tests (serum):                               Other tests:

–              Calcium, phosphorus                      Urinalisis   

–              Parathyroid hormone                      24-hour urinary calcium

–              Chloride                                          Chest radiograph

–              Alcaline phosphatase, pH               Intravenous pyelogram

–              Protein electrophoresis

–              Uric acid

–              Creatinine, hematocrit

Thyroid Function in Preterm Babies

Postnatal thyroid function in preterm babies is qualitatively similar but quantitatively reduced compared with that of term infants. The cord serum T₄ is decreased in proportion to gestational age and birthweight. The postnatal TSH surge is reduced, and infants with complications of prematurity, such as respiratory distress syndrome, actually experience a decrease in serum T₄ in the 1st wk of life. As these complications resolve, the serum T₄ gradually increases so that generally by 6 wk of life it enters the T₄ range seen in term infants. Serum free T₄ concentrations seem less affected, and when measured by equilibrium dialysis, these levels are ofteormal. Preterm babies also have a higher incidence of transient TSH elevations and apparent transient primary hypothyroidism. Premature infants <28 wk of gestation might have problems resulting from a combination of immaturity of the hypothalamic-pituitary-thyroid axis and loss of the maternal contribution of thyroid hormone and so may be candidates for temporary thyroid hormone replacement; further studies are needed.

Clinical Manifestations

Most infants with congenital hypothyroidism are asymptomatic at birth, even if there is complete agenesis of the thyroid gland. This situation is attributed to the transplacental passage of moderate amounts of maternal T₄, which provides fetal levels that are approximately 33% of normal at birth. Despite this maternal contribution of thyroxine, hypothyroid infants still have a low serum T₄ and elevated TSH level and so will be identified by newborn screening programs.

The clinician depends on neonatal screening tests for the diagnosis of congenital hypothyroidism. Congenital hypothyroidism is twice as common in girls as in boys.

It can be suspected and the diagnosis established during the early weeks of life if the initial but less characteristic manifestations are recognized. Birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain. Prolongation of physiologic jaundice, caused by delayed maturation of glucuronide conjugation, may be the earliest sign. Feeding difficulties, especially sluggishness, lack of interest, somnolence, and choking spells during nursing, are often present during the 1st mo of life. Respiratory difficulties, due in part to the large tongue, include apneic episodes, noisy respirations, and nasal obstruction. Affected infants cry little, sleep much, have poor appetites, and are generally sluggish.

There may be constipation that does not usually respond to treatment. The abdomen is large, and an umbilical hernia is usually present.

The temperature is subnormal, often lower, and the skin, particularly that of the extremities, may be cold and mottled. Edema of the genitals and extremities may be present. The pulse is slow, and heart murmurs,cardiomegaly, and asymptomatic pericardial effusion are common.

Macrocytic anemia is often present and is refractory to treatment with hematinics. Because symptoms appear gradually, the clinical diagnosis is often delayed.

Approximately 10% of infants with congenital hypothyroidism have associated congenital anomalies. Cardiac anomalies are most common, but anomalies of the nervous system and eye have also been reported. Infants with congenital hypothyroidism may have associated hearing loss.

If congenital hypothyroidism goes undetected and untreated, these manifestations progress. Retardation of physical and mental development becomes greater during the following months, and by 3-6 mo of age the clinical picture is fully developed.

When there is only partial deficiency of thyroid hormone, the symptoms may be milder, the syndrome incomplete, and the onset delayed. Although breast milk contains significant amounts of thyroid hormones, particularly T₃, it is inadequate to protect the breast-fed infant who has congenital hypothyroidism, and it has no effect oeonatal thyroid screening tests.

The child’s growth will be stunted, the extremities are short, and the head size is normal or even increased. The anterior and posterior fontanels are open widely; observation of this sign at birth can serve as an initial clue to the early recognition of congenital hypothyroidism. Only 3% of normal newborn infants have a posterior fontanel larger than 0.5 cm. The eyes appear far apart, and the bridge of the broad nose is depressed. The palpebral fissures are narrow and the eyelids are swollen. The mouth is kept open, and the thick, broad tongue protrudes. Dentition will be delayed. The neck is short and thick, and there may be deposits of fat above the clavicles and between the neck and shoulders. The hands are broad and the fingers are short. The skin is dry and scaly, and there is little perspiration. Myxedema is manifested, particularly in the skin of the eyelids, the back of the hands, and the external genitals. The skin shows general pallor with a sallow complexion. Carotenemia can cause a yellow discoloration of the skin, but the sclerae remain white. The scalp is thickened, and the hair is coarse, brittle, and scanty. The hairline reaches far down on the forehead, which usually appears wrinkled, especially when the infant cries.

Development is usually delayed. Hypothyroid infants appear lethargic and are late in learning to sit and stand.The voice is hoarse, and they do not learn to talk. The degree of physical and mental retardation increases with age. Sexual maturation may be delayed or might not take place at all. The muscles are usually hypotonic, but in rare instances generalized muscular pseudohypertrophy occurs.

Some infants with mild congenital hypothyroidism have normal thyroid function at birth and so are not identified by newborn screening programs. In particular, some children with ectopic thyroid tissue (lingual, sublingual, subhyoid) produce adequate amounts of thyroid hormone for many years, or it eventually fails in early childhood.

Manifestation of the light forms of congenital hypothyroidism can be observed in any age of children, but mostly in the period of the first growth jump (4-6 years).

Laboratory Findings

In many countries, infants with congenital hypothyroidism are identified by newborn screening programs. Blood obtained by heel-prick between 2 and 5 days of life is placed on a filter paper card and sent to a central screening laboratory. Many newborn screening programs in North America and Europe measure levels of T₄, followed by measurement of TSH when T₄ is low. This approach identifies infants with primary hypothyroidism, some with hypothalamic or pituitary hypothyroidism, and infants with a delayed increase in TSH levels. Other neonatal screening programs in North America, Europe, Japan, Australia, and New Zealand are based on a primary measurement of TSH. This approach detects infants with primary hypothyroidism and can detect infants with subclinical hypothyroidism (normal T₄, elevated TSH), but it misses infants with delayed TSH elevation and with hypothalamic or pituitary hypothyroidism.

Serum levels of T₄ or free T₄ are low; serum levels of T₃ may be normal and are not helpful in the diagnosis. If the defect is primarily in the thyroid, levels of TSH are elevated, often to >100 mU/L. Serum levels of thyroglobulin are usually low in infants with thyroid agenesis or defects of thyroglobulin synthesis or secretion, whereas they are elevated with ectopic glands and other inborn errors of thyroxine synthesis, but there is a wide overlap of ranges.

Retardation of osseous development can be shown radiographically at birth in about 60% of congenitally hypothyroid infants and indicates some deprivation of thyroid hormone during intrauterine life. The distal femoral epiphysis, normally present at birth, is often absent.

X-ray of the skull show large fontanels and wide sutures; intersutural bones are common. The sella turcica is often enlarged and round; in rare instances, there may be erosion and thinning. Formation and eruption of teeth can be delayed. Cardiac enlargement or pericardial effusion may be present.

Scintigraphy can help to pinpoint the underlying cause in infants with congenital hypothyroidism, but treatment should not be unduly delayed for this study.

Ultrasonographic examination of the thyroid is helpful, but studies show it can miss some ectopic glands shown by scintigraphy. The electrocardiogram may show low-voltage P and T waves with diminished amplitude of QRS complexes and suggest poor left ventricular function and pericardial effusion. Echocardiography can confirm a pericardial effusion. The electroencephalogram often shows low voltage. In children >2 yr of age, the serum cholesterol level is usually elevated. Brain MRI before treatment is reportedly normal, although proton magnetic resonance spectroscopy shows high levels of choline-containing compounds, which can reflect blocks in myelin maturation.

Treatment

Levothyroxine L-thyroxine is considered to be the best drug. Initial dose of it – 10-14  mkg/kg/day provides normalization of level Т4 for newborns during 1 week. Total dose of levothyroxine with age is gradually increased, and dose per kilogram of body mass is reduced.   

Table. Levothyroxine doses for treatment of congenital hypothyroidism

 

Evaluation of the treatment efficiency and correction of levothyroxine dose is conducted approximately monthly in the first 6 mo of life, and then every 2-3 mo between 6 mo and 2 yr. The dose of levothyroxine on a weight basis gradually decreases with age. ain criteria are speed of growth of a child, levels Т4 and TSH, detection of bone age (every 1-2 years).

   Treatment is being added by neuro– and cardiotrophic drugs, vitamins, massage, therapeutic physical training.

ACQUIRED HYPOTHYROIDISM

Epidemiology

Studies of school-aged children report that hypothyroidism occurs in approximately 0.3% (1/333). Subclinical hypothyroidism (TSH >4.5 mU/L, normal T₄ or free T₄) is more common, occurring in approximately 2% of adolescents. Acquired hypothyroidism is most commonly a result of chronic lymphocytic thyroiditis; 6% of children aged 12-19 yr have evidence of autoimmune thyroid disease, which occurs with a 2 : 1 female : male preponderance.

Etiology

ETIOLOGIC CLASSIFICATION OF ACQUIRED HYPOTHYROIDISM

Autoimmune (acquired hypothyroidism)

–        Hashimoto thyroiditis

–        Polyglandular autoimmune syndrome, types I and II

Iatrogenic

–        Propylthiouracil, methimazole, iodides, lithium, amiodarone

–        Irradiation

–        Radioiodine

–        Thyroidectomy

Systemic disease

–        Cystinosis

–        Langerhans cell histiocytosis

Hemangiomas (large) of the liver

Hypothalamic-pituitary disease

The most common cause of acquired hypothyroidism is chronic lymphocytic thyroiditis. Autoimmune thyroid disease may be part of polyglandular syndromes; children with Down, Turner, and Klinefelter syndromes and celiac disease or diabetes are at higher risk for associated autoimmune thyroid disease. In children with Down syndrome, anti-thyroid antibodies develop in approximately 30%, and subclinical or overt hypothyroidism occurs in approximately 15-20%. In girls with Turner syndrome, anti-thyroid antibodies develop in approximately 40%, and subclinical or overt hypothyroidism occurs in approximately 15-30%, rising with increasing age. In children with type 1 diabetes mellitus, approximately 20% develop anti-thyroid antibodies and 5% become hypothyroid. Williams syndrome is associated with subclinical hypothyroidism; this does not appear to be autoimmune, as anti-thyroid antibodies are negative.

Irradiation of the area of thyroid that is incidental to the treatment of Hodgkin disease or other head and neck malignancies or that is administered before bone marrow transplantation often results in thyroid damage. About 30% of such children acquire elevated TSH levels within a yr after therapy, and another 15-20% progress to hypothyroidism within 5-7 yr. Some clinicians recommend periodic TSH measurements, but others recommend treatment of all exposed patients with doses of T₄ to suppress TSH.

Protracted ingestion of medications containing iodides—for example, expectorants—can cause hypothyroidism, usually accompanied by goiter. Amiodarone, a drug used for cardiac arrhythmias and consisting of 37% iodine by weight, causes hypothyroidism in about 20% of treated children. It affects thyroid function directly by its high iodine content. Children treated with this drug should have serial measurements of T₄, T₃, and TSH. Children with Graves’ disease treated with anti-thyroid drugs (methimazole or propylthiouracil) can develop hypothyroidism. Additional drugs that can produce hypothyroidism include lithium carbonate, interferon alpha, stavudine, thalidomide, valproate (subclinical), and aminoglutethimide.

Children with nephropathic cystinosis, a disorder characterized by intralysosomal storage of cystine in body tissues, acquire impaired thyroid function. Hypothyroidism may be overt, but subclinical forms are more common, and periodic assessment of TSH levels is indicated. By 13 yr of age, two thirds of these patients require T₄ replacement.

Histiocytic infiltration of the thyroid in children with Langerhans cell histiocytosis can result in hypothyroidism.

Hypothyroidism can occur in children with large hemangiomas of the liver, because of increased type 3 deiodinase activity, which catalyzes conversion of T₄ to rT₃ and T₃ to T₂. Thyroid secretion is increased, but it is not sufficient to compensate for the large increase in degradation of T₄ to rT₃.

Any hypothalamic or pituitary disease can cause acquired central hypothyroidism. TSH deficiency may be the result of a hypothalamic-pituitary tumor (craniopharyngioma most common in children) or a result of treatment for the tumor. Other causes include cranial radiation, head trauma, or diseases infiltrating the pituitary gland, such as Langerhans cell histiocytosis.

 

Clinical Manifestations

Deceleration of growth is usually the first clinical manifestation, but this sign often goes unrecognized. Goiter, which may be a presenting feature, typically is nontender and firm, with a rubbery consistency and a pebbly surface.Weight gain is mostly fluid retention (myxedema), not true obesity. Myxedematous changes of the skin, constipation, cold intolerance, decreased energy, and an increased need for sleep develop insidiously.

Additional features include bradycardia, muscle weakness or cramps, nerve entrapment, and ataxia. Osseous maturation is delayed, often strikingly, which is an indication of the duration of the hypothyroidism. Adolescents typically have delayed puberty; older adolescent girls manifest menometrorhhagia. Younger children might present with galactorrhea or pseudoprecocious puberty. Galactorrhea is a result of increased TRH stimulating prolactin secretion. The precocious puberty, characterized by breast development in girls and macro-orchidism in boys, is thought to be the result of abnormally high TSH concentrations binding to the FSH, receptor with subsequent stimulation.

Diagnostic Methods

Children with suspected hypothyroidism should undergo measurement of serum free T₄ and TSH. Because the normal range for thyroid tests is slightly higher in children than adults, it is important to compare results to age-specific reference ranges. Measurement of antithyroglobulin and antiperoxidase (formerly, antimicrosomal) antibodies can pinpoint autoimmune thyroiditis as the cause. Generally, there is no indication for thyroid imaging. In cases with a goiter resulting from autoimmune thyroid disease, an ultrasound examination typically shows diffuse enlargement with scattered hypoechogenicity.

There are hyponatremia, macrocytic anemia, hypercholesterolemia. All these changes return to normal with adequate replacement of T_4.

Ultrasound examination is the most accurate method to follow nodule size and solid vs. cystic nature.

In children with a nodule and suppressed TSH, a radioactive iodine uptake and scan is indicated to determine if this is a “hot” or hyperfunctioning nodule.

A bone age X-ray at diagnosis is useful, in that the degree of delay approximates duration and severity of hypothyroidism.

Treatment

Levothyroxine is the treatment of choice in children with hypothyroidism. The dose on a weight basis gradually decreases with age. For children 1-3 yr, the average l-T₄ dosage is 4-6 mkg/kg/day; for 3-10 y4, 3-5 mk/kg/day; and for 10-16 yr, 2-4 mk/kg/day. Treatment should be monitored by measuring serum free T₄ and TSH every 4-6 mo as well as 6 wk after any change in dosage. In children with central hypothyroidism, where TSH levels are not helpful in monitoring treatment, the goal should be to maintain serum free T4 in the upper half of the normal reference range for age.

 

HYPERTHYROIDISM

Hyperthyroidism results from excessive secretion of thyroid hormone; during childhood, with few exceptions, it is due to Graves disease. Graves disease is an autoimmune disorder; production of thyroid-stimulating immunoglobulin (TSI) results in diffuse toxic goiter.

GRAVES DISEASE

Etiology

In the thyroid gland, T helper cells (CD4⁺) predominate in dense lymphoid aggregates; in areas of lower cell density, cytotoxic T cells (CD8⁺) predominate. The percentage of activated B lymphocytes infiltrating the thyroid is higher than in peripheral blood. A postulated failure of T suppressor cells allows expression of T helper cells, sensitized to the TSH antigen, which interact with B cells. These cells differentiate into plasma cells, which produce thyrotropin receptor–stimulating antibody (TRSAb). TRSAb binds to the receptor for TSH and stimulates cyclic adenosine monophosphate, resulting in thyroid hyperplasia and unregulated overproduction of thyroid hormone.

The ophthalmopathy occurring in Graves disease appears to be caused by antibodies against antigens shared by the thyroid and eye muscle. TSH receptors have been identified in retro-orbital adipocytes and might represent a target for antibodies. The antibodies that bind to the extraocular muscles and orbital fibroblasts stimulate the synthesis of glycosaminoglycans by orbital fibroblasts and produce cytotoxic effects on muscle cells.

Clinical Manifestations

About 5% of all patients with hyperthyroidism are <15 yr of age; the peak incidence in these children occurs during adolescence.

The clinical course in children is highly variable. Symptoms develop gradually; the usual interval between onset and diagnosis is 6-12 mo and may be longer in prepubertal children compared with adolescents. The earliest signs in children may be emotional disturbances accompanied by motor hyperactivity. The children become irritable and excitable, and they cry easily because of emotional lability. They are restless sleepers and tend to kick their covers off. Their schoolwork suffers as a result of a short attention span and poor sleep. Tremor of the fingers can be noticed if the arm is extended. There may be a voracious appetite combined with loss of or no increase in weight. Recent height measurements might show an acceleration in growth velocity.

The size of the thyroid is variable. It may be so minimally enlarged that it initially escapes detection, but with careful examination, a diffuse goiter, soft with a smooth surface, is found in almost all patients.

Exophthalmos is noticeable in most patients but is usually mild. Lagging of the upper eyelid as the eye looks downward, impairment of convergence, and retraction of the upper eyelid and infrequent blinking may be present. Ocular manifestations can produce pain, lid erythema, chemosis, decreased extraocular muscle function, and decreased visual acuity (corneal or optic nerve involvement).

The skin is smooth and flushed, with excessive sweating. Muscular weakness is uncommon but may be severe enough to result in clumsiness. Reflexes are brisk, especially the return phase of the Achilles reflex. Many of the findings in Graves disease result from hyperactivity of the sympathetic nervous system.

Tachycardia, palpitations, dyspnea, and cardiac enlargement and insufficiency cause discomfort but rarely endanger the patient’s life. Atrial fibrillation is a rare complication. Mitral regurgitation, probably resulting from papillary muscle dysfunction, is the cause of the apical systolic murmur present in some patients. The systolic blood pressure and the pulse pressure are increased.

Thyroid crisis, or thyroid storm, is a form of hyperthyroidism manifested by an acute onset, hyperthermia, severe tachycardia, heart failure, and restlessness. There may be rapid progression to delirium, coma, and death. Precipitating events include trauma, infection, radioactive iodine treatment, or surgery.

Laboratory Findings

Serum levels of thyroxine (T₄), triiodothyronine (T₃), free T₄, and free T₃ are elevated. In some patients, levels of T₃ may be more elevated than those of T₄. Levels of TSH are suppressed to below the lower range of normal. Antithyroid antibodies, including thyroid peroxidase antibodies, are often present.

Most patients with newly diagnosed Graves disease have measurable TRSAb; the two methods to measure TRSAb are thyroid-stimulating immunoglobulin (TSI) or thyrotropin-binding inhibitor immunoglobulin (TBII). Measurement of TSI or TBII is useful in confirming the diagnosis of Graves disease.

Differential Diagnosis

Differential diagnosis of Graves disease is conducted for diseases accompanied by hyperthyroidism, goiter, tachycardia. Toxic adenoma and hyper functioning cancer of thyroid gland, TTG productive pituitary adenoma developing thyrotoxicosis are rarely registered for children.    

         Differentiation of Graves disease with autoimmune thyroiditis has current importance. The last one, differently from Graves disease, is characterized by: thickening of capsule, presence of nodules, heterogeneity of echogenic structure during ultrasonic examination, mosaic accumulation of radioactive isotope during scanning, reduction of iodine absorption function of thyroid gland,increase of the antibody titer to thyreoglobulin and peroxidase, more easy course of thyrotoxicosis which has good results of conservative therapy and can terminate spontaneously.   

         Sporadic (non–toxic) goiter is characterized by absence of thyrotoxicosis, sometimes even hypothyroidism is possibleconversely, which is confirmed by detection of hormone levels.

When hyperthyroxinemia is caused by exogenous thyroid hormone, levels of free T₄ and TSH are the same as those seen in Graves disease, but the level of thyroglobulin is very low, whereas in patients with Graves disease, it is elevated.

 

Treatment

Conservative therapy is the main method of Graves disease treatment for children. On the first stage child must be admitted to hospital. Thyreostatic drugs are being prescribed, and methimazole is preferred. It is highly effective (not only blocks synthesis of thyroid hormones, but inhibits creation of auto antibodies as well) and is less toxic. The initial dosage of methimazole is 0.25-1.0 mg/kg/24 hr given once or twice daily. Smaller initial dosages should be used in early childhood. Careful surveillance is required after treatment is initiated. Rising serum levels of TSH to greater thaormal indicates overtreatment and leads to increased size of the goiter. Clinical response becomes apparent in 3-6 wk, and adequate control is evident in 3-4 mo. The dose is decreased to the minimal level required to maintain a euthyroid state.

Most studies report a remission rate of approximately 25% after 2 years of antithyroid drug treatment in children. Some studies find that longer treatment is associated with higher remission rates, with one study reporting a 50% remission rate after 4.5 years of drug treatment. If a relapse occurs, it usually appears within 3 mo and almost always within 6 mo after therapy has been discontinued. Therapy may be resumed in case of relapse. Patients older than 13 yr of age, boys, those with a higher body mass index, and those with small goiters and modestly elevated T₃ levels appear to have earlier remissions.

A β-adrenergic blocking agent such as propranolol (0.5-2.0 mg/kg/24 hr orally, divided 3 times daily) or atenolol (1-2 mg/kg orally given once daily) is a useful supplement to antithyroid drugs in the management of severely toxic patients.

Radioiodine treatment or surgery is indicated when adequate cooperation for medical management is not possible, when adequate trial of medical management has failed to result in permanent remission, or when severe side effects preclude further use of antithyroid drugs. Either of these treatments may also be preferred by the patient or parent.

Subtotal thyroidectomy is done only after the patient has been brought to a euthyroid state. This may be accomplished with methimazole over 2-3 mo. After a euthyroid state has been attained, a saturated solution of potassium iodide, 5 drops/24 hr, are added to the regimen for 2 wk before surgery to decrease the vascularity of the gland. Complications of surgical treatment are rare and include hypoparathyroidism (transient or permanent) and paralysis of the vocal cords. The incidence of residual or recurrent hyperthyroidism or hypothyroidism depends on the extent of the surgery. Most recommend near-total thyroidectomy. The incidence of recurrence is low, and most patients become hypothyroid.

The ophthalmopathy remits gradually and usually independently of the hyperthyroidism. Severe ophthalmopathy can require treatment with high-dose prednisone, orbital radiotherapy (of questionable value), or orbital decompression surgery. Cigarette smoking is a risk factor for thyroid eye disease and should be avoided or discontinued to avoid progression of eye involvement.

 THYROIDITIS

Autoimmune thyroiditis (lymphocytic thyroiditis,  Hashimoto thyroiditis)

 

Autoimmune thyroiditis (synonyms: chronic lymphocytic thyroiditis, Hashimoto’s thyroiditis) is an autoimmune disease of thyroid gland with gradual progressive destruction of thyroid cells and development of hypothyroidism. Mostly it is being detected for school age children mainly for girls.

Etiology

This typical organ-specific autoimmune disease is characterized histologically by lymphocytic infiltration of the thyroid. Early in the course of the disease, there may be hyperplasia only; this is followed by infiltration of lymphocytes and plasma cells between the follicles and by atrophy of the follicles. Lymphoid follicle formation with germinal centers is almost always present; the degree of atrophy and fibrosis of the follicles varies from mild to moderate.

A variety of different thyroid antigen autoantibodies are also involved. Thyroid antiperoxidase antibodies(TPOAbs; formerly called antimicrosomal antibodies) and antithyroglobulin antibodies are demonstrable in the sera of 90% of children with lymphocytic thyroiditis and in many patients with Graves disease. TPOAbs inhibit enzyme activity and stimulate natural killer cell cytotoxicity. Antithyroglobulin antibodies do not appear to play a role in the autoimmune destruction of the gland. Thyrotropin receptor–blocking antibodies are often present, especially in patients with hypothyroidism, and it is now believed that they are related to the development of hypothyroidism and thyroid atrophy in patients with autoimmune thyroiditis. Antibodies to pendrin, an apical protein on thyroid follicular cells, have been demonstrated in 80% of children with autoimmune thyroiditis.

Clinical Manifestations

The disorder is 2-4 times more common in girls than in boys. It can occur during the first 3 yr of life but becomes sharply more common after 6 yr of age and reaches a peak incidence during adolescence.

The most common clinical manifestations are goiter and growth retardation. The goiter can appear insidiously and may be small or large. In most patients, the thyroid is diffusely enlarged, firm, and nontender. In about 30% of patients, the gland is lobular and can seem to be nodular.

Most of the affected children are clinically euthyroid and asymptomatic; some may have symptoms of pressure in the neck, including difficulty swallowing and shortness of breath. Some children have clinical signs of hypothyroidism, but others who appear clinically euthyroid have laboratory evidence of hypothyroidism. A few children have manifestations suggesting hyperthyroidism, such as nervousness, irritability, increased sweating, and hyperactivity, but results of laboratory studies are not necessarily those of hyperthyroidism.

The clinical course is variable. The goiter might become smaller or might disappear spontaneously, or it might persist unchanged for years while the patient remains euthyroid. Most children who are euthyroid at presentation remain euthyroid, although a percentage of patients acquire hypothyroidism gradually within months or years. In children who initially have mild or subclinical hypothyroidism (elevated serum TSH, normal free T₄ level), over several years about 50% revert to euthyroidism, about 50% continue to have subclinical hypothyroidism, and a few develop overt hypothyroidism. Thyroiditis is the cause of most cases of nongoitrous (atrophic) hypothyroidism.

Laboratory Findings

Thyroid function tests (free T₄ and TSH) are ofteormal, although the level of TSH may be slightly or even moderately elevated in some patients, termed subclinical hypothyroidism. The fact that many children with lymphocytic thyroiditis do not have elevated levels of TSH indicates that the goiter may be caused by the lymphocytic infiltrations or by thyroid growth-stimulating immunoglobulins. Young children with lymphocytic thyroiditis have serum antibody titers to TPO, but the antithyroglobulin test for thyroid antibodies is positive in <50%. Levels in children and adolescents are lower than those in adults with lymphocytic thyroiditis, and repeated measurements are indicated in questionable instances because titers might increase later in the course of the disease.

Thyroid scans and ultrasonography usually are not needed. If they are done, thyroid scans reveal irregular and patchy distribution of the radioisotope, and in about 60% or more, the administration of perchlorate results in a >10% discharge of iodide from the thyroid gland. Thyroid ultrasonography shows scattered hypoechogenicity in most patients.

The definitive diagnosis can be established by biopsy of the thyroid; this procedure is rarely clinically indicated.

Treatment

If there is evidence of hypothyroidism (overt or subclinical), replacement treatment with levothyroxine (at doses specific for size and age) is indicated. The goiter usually shows some decrease in size but can persist for years.

In a euthyroid patient, treatment with suppressive doses of levothyroxine is unlikely to lead to a significant decrease in size of the goiter. Antibody levels fluctuate in both treated and untreated patients and persist for years.

Because the disease is self-limited in some instances, the need for continued therapy requires periodic reevaluation. Untreated patients should also be checked periodically.

Prominent nodules, i.e. >1.0 cm, that persist despite suppressive therapy should be examined histologically using fine needle aspiration (FNA), because thyroid carcinoma or lymphoma has occurred in patients with lymphocytic thyroiditis.

 

Disorders of the parathyroid glands

HYPOPARATHYROIDISM

Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary muscle contraction), and several other symptoms. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes.

 

 

Etiology

–         Removal of or trauma to the parathyroid glands in thyroid surgery (thyroidectomy) or other neck surgeries is a recognized cause. It is now uncommon, as surgeons generally can spare them during procedures after identifying them. In a small percentage of cases, however, they can become traumatized during surgery and/or their blood supply can be compromised. When this happens the parathyroids may cease functioning for a while or stop altogether.

–         Autoimmune invasion and destruction is the most commoon-surgical cause. It can occur as part of autoimmune polyendocrine syndromes.

–         Hemochromatosis can lead to iron accumulation and consequent dysfunction of a number of endocrine organs, including the parathyroids.

–         Absence or dysfunction of the parathyroid glands is one of the components of chromosome 22q11 microdeletion syndrome (other names: DiGeorge syndrome, Schprintzen syndrome).

–         Magnesium deficiency

–         Idiopathic (of unknown cause), occasionally familial.

Signs and symptoms

The main symptoms of hypoparathyroidism are the result of the low blood calcium level, which interferes with normal muscle contraction and nerve conduction. As a result, children with hypoparathyroidism can experience paresthesia, an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as “tetany” that affect the hands and feet. Many also report a number of subjective symptoms such as fatigue, headaches, bone pain and insomnia. Crampy abdominal pain may occur. Physical examination of someone with hypocalcemia may show tetany, but it is also possible to provoke tetany of the facial muscles by tapping on the facial nerve (a phenomenon known as Chvostek’s sign) or by using the cuff of a sphygmomanometer to temporarily obstruct the blood flow to the arm (a phenomenon known as Trousseau’s sign of latent tetany).

Diagnosis

Diagnosis is by measurement of calcium, serum albumin (for correction) and PTH in blood.

If necessary, measuring cAMP (cyclic AMP) in the urine after an intravenous dose of PTH can help in the distinction between hypoparathyroidism and other causes.

Treatment

Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium (e.g. as calcium gluconate). Generally, a central venous catheter is recommended, as the calcium can irritate peripheral veins and cause phlebitis. In the event of a life-threatening attack of low calcium levels or tetany (prolonged muscle contractions), calcium is administered by intravenous (IV) infusion. Precautions are taken to prevent seizures or larynx spasms.

The heart is monitored for abnormal rhythms until the person is stable. When the life-threatening attack has been controlled, treatment continues with medicine taken by mouth as often as four times a day.

Long-term treatment of hypoparathyroidism is with vitamin D analogs and calcium supplementation may be ineffective in some due to potential renal damage.

HYPERPARATHYROIDISM

Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels. Excessive PTH secretion may be due to problems in the glands themselves, in which case it is referred to as primary hyperparathyroidism and which leads to hypercalcaemia (raised calcium levels). It may also occur in response to low calcium levels, as encountered in various situations such as vitamin D deficiency or chronic kidney disease; this is referred to as secondary hyperparathyroidism. In all cases, the raised PTH levels are harmful to bone, and treatment is ofteeeded.

Classification

Primary

Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to adenoma, hyperplasia or, rarely, carcinoma of the parathyroid glands.

Secondary

Secondary hyperparathyroidism is due to physiological (i.e. appropriate) secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels). The most common causes are vitamin D deficiency (caused by lack of sunlight, diet or malabsorption) and chronic renal failure.

Tertiary

Tertiary hyperparathyroidism is seen in patients with long-term secondary hyperparathyroidism which eventually leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. This disorder is most often seen in patients with chronic renal failure and is an autonomous activity.

Quaternary and Quintary

Quaternary and quintary are rare conditions that may be observed after surgical removal of primary hyperparathyroidism, when it has led to renal damage that now again causes a form of secondary (quaternary) hyperparathyroidism that may itself result in autonomy (quintary) hyperparathyroidism.

Symptoms and signs

In primary hyperparathyroidism about 50% of patients have no symptoms and the problem is picked up as an incidental finding (via a raised calcium or characteristic X-ray appearances). Many other patients only have non-specific symptoms. Symptoms directly due to hypercalcaemia are relatively rare. If present, common manifestations of hypercalcaemia include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones.

In secondary hyperparathyroidism the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such as rickets, osteomalacia and renal osteodystrophy.

Diagnosis

Laboratory tests

In primary hyperparathyroidism, parathyroid hormone (PTH) levels will be either elevated or “inappropriately normal” in the presence of elevated calcium. Typically PTH levels vary greatly over time in the affected patient and (as with Ca and Ca++ levels) must be retested several times to see the pattern. The currently accepted test for PTH is “Intact PTH” which is intended to detect only relatively intact and biologically active PTH molecules.

Serum calcium or Ionized Calcium (Ca++). In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium.

Serum phosphate. In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased renal tubular phosphate reabsorption. However, this is only present in about 50% of cases. This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of renal disease.

Alkaline phosphatase. Alkaline phosphatase levels are usually elevated in hyperparathyroidism. In primary hyperthyroidism, levels may remain within the normal range, however this is ‘inappropriately normal’ given the increased levels of plasma calcium.

The gold standard of diagnosis is the Parathyroid immunoassay.

Treatment

Treatment depends entirely on the type of hyperparathyroidism encountered. Patients with primary hyperparathyroidism who are symptomatic benefit from surgery to remove the parathyroid tumor (parathyroid adenoma).

In patients with secondary hyperparathyroidism, the high PTH levels are an appropriate response to low calcium and treatment must be directed at the underlying cause of this (usually vitamin D deficiency or chronic renal failure).

 

 

How to Approach Endocrine Assessment in Severe Obesity?

Abstract and Introduction

Abstract

The increasing numbers of severely obese patients (body mass index BMI >40 kg/m²) represent a significant management challenge. These patients are at risk of obesity-related complications that may be driven by changes in endocrine function. Their care may potentially be complex at times, and therefore, an appropriate assessment strategy will be relevant to timely diagnosis and management. In this article, we discuss an approach to the endocrine assessment of the severely obese patient. We consider the clinical question in three categories that may also represent different complexities in terms of subsequent management: (i) obesity as a consequence of structural lesions at the hypothalamic–pituitary region; (ii) obesity as a consequence of inherited and genetic syndromes; and (iii) functional neuroendocrine hormone abnormalities relating to obesity. The first two categories are associated with hypothalamic dysfunction, of which hypothalamic obesity is a consequence. Additionally, the implications and difficulties associated with imaging severely obese patients are discussed from an endocrinological perspective and we provide practical guidance on which to base practice.

Introduction

High levels of obesity pose challenges to healthcare providers worldwide because of the associated complications such as diabetes, cardiovascular disease, cancers and sleep-related breathing disorders that increase morbidity and mortality. Adults with a body mass index (BMI) of 40 kg/m² or more are considered to have severe (previously termed ‘morbid’) obesity (Class III obesity by WHO classification). In the USA, the estimated prevalence of severe obesity is approximately 5·1%;^[1] in England, 3·8% of females and 1·6% of males are affected.^[2] These patients increasingly present in clinical practice, and questions concerning endocrine testing and interpretation may arise. It is known that changes ieuroendocrine function are associated with severe obesity.^[3] However, the effects of these changes may be subtle or symptoms experienced attributed solely to the presence of obesity per se, with potential for delayed identification and investigation. In this article, an approach to this clinical question is discussed. Additionally, it is important to highlight potential considerations that should be borne in mind when requesting imaging investigations for these patients.

Assessing for Hypothalamic–Pituitary Dysfunction in Severe Obesity

What Do I have to Consider?

In all cases, a detailed history and examination are essential parts of the assessment of the severely obese patient and further investigations and management should be directed accordingly. The features of disease that are associated with (for example) hypogonadism or overlap with obesity (for example, polycystic ovary syndrome and Cushing’s syndrome) should be sought. Initial investigations that should be performed include a full blood count, renal, liver and lipid profile, blood glucose, HbA1c and thyroid function, while further tests should be guided by clinical judgement based on the findings.

A useful approach when considering the underlying aetiology would be to consider three categories that represent different mechanisms that lead to hypothalamic–pituitary dysregulation: (i) structural hypothalamic lesions; (ii) inherited conditions; and (iii) patients with functional hypothalamic–pituitary changes that may develop as a result of obesity (Fig. 1). Clinical Endocrinology

 

 

 URINARY TRACT INFECTION

 

              A urinary tract infection (UTI) is an infection of the bladder and sometimes the kidneys. If the bladder is infected, it is calledcystitis. If the kidneys are infected, it is called pyelonephritis. It is important to treat UTIs so that the kidneys are not damaged.

 

                        Various symptoms are possible:

· painful urination

·  an urgent need to urinate

·  frequent urination

·   daytime and nighttime wetting

·  dribbling

·   foul-smelling urine

·   fever

·  stomachaches (especially lower abdomen)

·   vomiting.

                            

                                  Causes

 

                 Urinary tract infections are caused by bacteria. The bacteria enter the bladder by traveling up the urethra. In general, the urethra is protected, but if the opening of the urethra (or the vulva in girls) becomes irritated, bacteria can grow there. Common irritants are bubble bath and shampoos. Careless wiping after a bowel movement might also cause irritation. A rare cause of UTIs (1% of girls and 5% of boys) is obstruction of the urinary tract, which results in incomplete emptying of the bladder. Children who start and stop their stream of urine while they are going to the bathroom are more likely to get a UTI.

 

                                   Duration

 

                 With treatment, your child’s fever should be gone and symptoms should be better by 48 hours after starting the antibiotic. The chances of getting another UTI are about 50%. Read the advice on preventing UTIs to decrease your child’s risk.

                                         

Treatment

 

                Antibiotics

                Encourage child to drink extra fluids to help clear the infection.

                Fever and pain relief

       Give child acetaminophen (Tylenol) or ibuprofen (Advil) for the painful urination or for fever over 102°F (39°C).

                    Many children who get urinary tract infections have normal kidneys and bladders. But if a child has an abnormality, it should be detected as early as possible to protect the kidneys against damage.

                   

Abnormalities that could occur include the following:

 

   Vesicoureteral reflux (VUR). Urine normally flows from the kidneys down the ureters to the bladder in one direction. With VUR, when the bladder fills, the urine may also flow backward from the bladder up the ureters to the kidneys. This abnormality is common in children with urinary infections.

   Urinary obstruction. Blockages to urinary flow can occur in many places in the urinary tract. The ureter or urethra may be too narrow or a kidney stone at some point stops the urinary flow from leaving the body. Occasionally, the ureter may join the kidney or bladder at the wrong place and prevent urine from leaving the kidney in the normal way.

   Dysfunctional voiding. Some children develop a habit of delaying a trip to the bathroom because they don’t want to leave their play. They may work so hard at keeping the sphincter muscle tight that they forget how to relax it at the right time. These children may be unable to empty the bladder completely. Some children may strain during urination, causing pressure in the bladder that sends urine flowing back up the ureters. Dysfunctional voiding can lead to vesicoureteral reflux, accidental leaking, and UTIs.

Pyelonephritis is an ascending urinary tract infection that has reached the pyelum (pelvis) of the kidney (nephros in Greek). If the infection is severe, the term “urosepsis” is used interchangeably (sepsis being a systemic inflammatory response syndrome due to infection). It requires antibiotics as therapy, and treatment of any underlying causes to prevent recurrence. It is a form of nephritis. It can also be called pyelitis.

Urinary tract infections (UTIs) are common in the pediatric age group. Early recognition and prompt treatment of UTIs are important to prevent progression of infection to pyelonephritis or urosepsis and to avoid late sequelae such as renal scarring or renal failure.

                               Causes

 

Most cases of “community-acquired” pyelonephritis are due to bowel organisms that enter the urinary tract. Common organisms are E. coli (70-80%) and Enterococcus faecalis. Hospital-acquired infections may be due to coliforms and enterococci, as well as other organisms uncommon in the community (e.g. Klebsiella spp., Pseudomonas aeruginosa). Most cases of pyelonephritis start off as lower urinary tract infections, mainly cystitis and prostatitis.

                   

Risk is increased in the following situations:

Mechanical: any structural abnormalities to the kidneys and the urinary tract, vesicoureteral reflux (VUR) especially in young children, calculi (kidney stones), urinary tract catheterisation, urinary tract stents or drainage procedures (e.g. nephrostomy), neurogenic bladder (e.g. due to spinal cord damage, spina bifida.

Constitutional: diabetes mellitus, immunocompromised states

Positive family history (close family members with frequent urinary tract infections)

Infants and young children with UTI may present with few specific symptoms. Older pediatric patients are more likely to have symptoms and findings attributable to an infection of the urinary tract. Differentiating cystitis from pyelonephritis in the pediatric patient is not always possible, although children who appear ill or who present with fever should be presumed to have pyelonephritis if they have evidence of UTI.

It presents with dysuria (painful voiding of urine), abdominal pain (radiating to the back on the affected side) and tenderness of the bladder area and the side of the involved kidney (costovertebral angle tenderness) which may be elicited by performing the kidney punch. In many cases there are systemic symptoms in the form of fever, rigors (violent shivering while the temperature rises), headache, and vomiting. In severe cases, delirium may be present.

 

Severe cases of pyelonephritis lead to sepsis, a systemic response to infection characterized by fever, a raised heart rate, rapid breathing and decreased blood pressure (occasionally leading to septic shock). When pyelonephritis or other urinary tract infections lead to sepsis, it is termed urosepsis.

 

Pathophysiology

UTIs generally begin in the bladder due to ascending infection from perineal contaminants, usually bowel flora such asEscherichia coli. Ieonates, infection of the urinary tract is assumed to be due to hematogenous rather than ascending infection. This etiology may explain the nonspecific symptoms associated with UTI in these patients.

The causative agents of urinary tract infections in hospitalised infections show a different distribution from those that occur in the community…

Norm                                Pyelonephritis

 

                Normal and pyelonephritic kidneys

Acute pyelonephritis is an exudative purulent localized inflammation of the renal pelvis (collecting system) and kidney. The renal parenchyma presents in the interstitium abscesses (suppurative necrosis), consisting in purulent exudate (pus): neutrophils, fibrin, cell debris and central germ colonies (hematoxylinophils). Tubules are damaged by exudate and may contaieutrophil casts. In the early stages, glomeruli and vessels are normal. Gross pathology often reveals pathognomonic radiations of hemorrhage and suppuration through the renal pelvis to the renal cortex. Chronic infections can result in fibrosis and scarring.

Xanthogranulomatous pyelonephritis is a form of chronic pyelonephritis associated with granulomatous abscess formation and severe kidney destruction.

 

Hospital patients:

·  Escherichia coli: 40%

· Coagulase-negative staphylococci: 3%

· ‘Other’ Gram-negative bacteria: 25%

· ‘Other’ Gram-positive bacteria: 16%

· Candida albicans: 5%

· Proteus mirabilis: 11%

Community-acquired Urinary Tract Infections:

· Escherichia coli: 80%

· Coagulase-negative staphylococci: 7%

· ‘Other’ Gram-negative bacteria: 4%

· ‘Other’ Gram-positive bacteria: 3%

· Proteus mirabilis: 6%

Gram-negative bacteria other than Escherichia coli causing urinary tract infections, particularly in hospitalised patients, commonly include Klebsiella spp., Enterobacter spp., Serratia spp. and Pseudomonas aeruginosa.

After the neonatal period, bacteremia generally is not the cause of UTI. The bladder is the initial primary locus of infection with ascending disease of the upper tract (kidneys) and bacteremia as potential sequelae. Bacterial invasion of the bladder with overt UTI is more likely to occur if urinary stasis or low flow conditions exist. Some causes of these conditions are infrequent or incomplete voiding, reflux, or other urinary tract abnormalities.

Even in the absence of urinary tract abnormalities, cystitis causes vesicoureteral reflux, and it may worsen preexisting reflux. Reflux may cause development of pyelonephritis. Chronic or recurrent pyelonephritis results in renal damage and scarring that may progress to chronic renal failure if it continues or is severe.

 

                  Etiologic structure of pyelonephitis in children

 

Frequency: Prevalence varies based on age and sex.

Mortality/Morbidity: Generalized bacteremia or sepsis may develop from UTI. Approximately 30% of 1- to 3-month-old infants with UTIs are at risk for developing sepsis. The risk drops to approximately 5% in patients older than 3 months.

If left untreated, simple cystitis may progress to pyelonephritis. More severe cases have the potential for kidney damage, which may lead to hypertension or renal insufficiency.

Approximately 5-10% of children with symptomatic UTI and fever develop renal scarring.

Sex: Uncircumcised males have a higher incidence than circumcised males. Uncircumcised male infants have a higher incidence of UTI than female infants.

UTIs are more frequent in females than males at all ages with the exception of the neonatal period, during which UTI may be the cause of an overwhelming septic syndrome in male infants younger than 2 months.

Incidence is highest in sexually active adolescent females.

Age: Excluding neonates, females younger than 11 years have a 3-5% risk; boys of the same age have a 1% risk.

UTI is the source of infection in up to 6-8% of febrile infants. Conversely, approximately the same number of febrile infants are bacteremic (considering all sources, including UTI).

 

                                     CLINIC

                            Symptoms:

· flank pain or back pain,

· severe abdominal pain (occurs occasionally),

· fever,

· chills with shaking,

· warm skin, flushed or reddened skin, moist skin (diaphoresis),

· vomiting, nausea,

· fatigue, general ill feeling,

· painful urination, increased urinary frequency or urgency, need to urinate at night (nocturia), cloudy or abnormal urine color, blood in the urine, foul or strong urine odor,

· dental changes or confusion.

                          History:

Neonates

· Jaundice

· Hypothermia or fever

· Failure to thrive

· Poor feeding

· Vomiting

Infants

· Poor feeding

· Fever

· Vomiting, diarrhea

· Strong-smelling urine

Preschoolers

· Vomiting, diarrhea, abdominal pain

· Fever

· Strong-smelling urine, enuresis, dysuria, urgency, frequency

School-aged children

· Fever

· Vomiting, abdominal pain

· Strong-smelling urine, frequency, urgency, dysuria, flank pain or new enuresis

 Physical:

· Hypertension should raise suspicion of hydronephrosis or renal parenchyma disease.

· Costovertebral angle (CVA) tenderness

· Abdominal tenderness or mass

· Palpable bladder

· Dribbling, poor stream, or straining to void

· Examine external genitalia for signs of irritation, pinworms, vaginitis, trauma, or sexual abuse.

 

 

Prompt diagnosis of kidney infections in small children is important to prevent complications such as kidney scarring or the development of a blood stream infection. The symptoms of kidney infection in babies are nonspecific, meaning they do not point directly to the kidney as the source of the infection. As children reach the toddler stage, the symptoms of kidney infection become more specific to the urinary system.

 Fever is a characteristic symptom of kidney infection in young children. Especially among youngsters who are not yet talking, a fever lasting more than 48 hours may be the prominent feature of the illness. The fever associated with kidney infection is typically higher than 100.4 degrees Fahrenheit. Notably, an abnormally low body temperature may indicate infection in a newborn. A temperature which ispersistently lower than 97.7 degrees Fahrenheit despite attempts to warm the baby may indicate a kidney or other serious infection.

 

                             Diagnosis

 

Typical clinical features include urgency, frequency, burning during urination, dysuria, nocturia, and hematuria(usually microscopic but may be gross). Urine may appear cloudy and have an ammoniacal or fishy odor. Other common symptoms include a temperature of 102° F (38.9° C) or higher, shaking chills, flank pain, anorexia, and general fatigue.

A history and physical exam will be performed. Blood and urine tests will be done to identify the infection and cultures of the urine can isolate the infecting bacteria. If a kidney stone is suspected a CT scan must be done.

The diagnosis of pyelonephritis can usually be made by history, physical examination, and laboratory tests. Imaging may be necessary when the diagnosis is in question, when there are recurrent infections, or if the patient responds poorly to appropriate antibiotic therapy after three days. Computed tomography (CT) with intravenous (IV) contrast is the test of choice when evaluating the urinary tract. The most common CT finding in pyelonephritis is wedge-shaped lesions of decreased attenuation with or without swelling. Anatomic abnormalities and perinephric abscesses can also be seen on contrast-enhanced scans. Renal ultrasound is also used to evaluate the collecting system and pyelonephritis and may show ureteral dilation, suggesting obstruction. Although renal ultrasound is helpful, a CT scan is more sensitive. Magnetic resonance imaging may be used in patients who are allergic to iodinated contrast.

             The presence of nitrite and leukocytes (white blood cells) on a urine dipstick test in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Formal diagnosis is with culture of the urine; blood cultures may be needed if the source of the infection is initially doubtful.

Acute pyelonephritis (renal biopsy)

Micropreparations of kidney in acute purulent pyelonephritis:

colonies of microorganisms (blue) in the renal tubules.

Nuclear Medicine Software Suite

                  The HERMES DMSA Analysis program is primarily designed to help detect the onset of pyelonephritis in young children and to monitor the effect of treatment on infected patients. The program compares the function of each kidney with the function for a database of reference cases in order to assist detection of abnormal function.

 

Diagnosis requires urinalysis and culture. Typical findings include:

 

–         pyuria (pus in urine) — urine sediment reveals the presence of leukocytes singly, in clumps, and in casts; and, possibly, a few red blood cells

–         significant bacteriuria — more than 100,000 organisms/µl of urine revealed in urine culture

–         low specific gravity and osmolality, resulting from a temporarily decreased ability to concentrate urine

–         slightly alkaline urine pH

–         proteinuria, glycosuria, and keto-nuria — less common.

       X-rays also help in the evaluation of acute pyelonephritis. X-ray films of the kidneys, ureters, and bladder may reveal calculi,tumors, or cysts in the kidneys and urinary tract. Excretory urography may show asymmetrical kidneys.

                    If a kidney stone is suspected (e.g. on the basis of characteristic colicky pain, disproportionate amount of blood in the urine), X-rays of the kidneys, ureters and bladder (KUB) may assist in identifying radioopaque stones.

               

Abdominal radiograph in a 3-year-old child. This image shows a right staghorn calculus. Intravenous urogram in a 3-year-old child. This image shows normal function/excretion on the left, but no function is detectable on the right. A diagnosis ofxanthogranulomatous pyelonephritis was confirmed at surgery.

This delayed nephrogram phase of a subtraction-selective right renal angiogram shows an avascular lower renal mass. A diagnosis of focal xanthogranulomatous pyelonephritis was confirmed at surgery.

 

Contrast-enhanced computed tomography scan through the mid poles of the kidneys. This image shows a staghorn calculus within the right renal sinus that is associated with mild hydronephrosis, thinning of the cortex, and areas of low attenuation surrounding the calculus. The patient presented with pyrexia and leukocytosis. Ultrasonographic examination revealed a perinephric fluid collection, which was drained percutaneously (not shown). Note the air in the retroperitoneum after percutaneous drainage. At subsequent surgery, xanthogranulomatous pyelonephritis was confirmed.

                In patients with recurrent ascending urinary tract infections, it may be necessary to exclude an anatomical abnormality, such as vesicoureteral reflux (urine from the bladder flowing back into the ureter) or polycystic kidney disease.                                      Investigations that are commonly used in this setting are ultrasound of the kidneys or voidingcystourethrography.

 

Lab Studies:

Urinalysis

A urine specimen that is found to be positive for nitrite, leukocyte esterase, or blood may indicate a UTI.

Microscopic examination can evaluate for presence of WBCs (5 per high-power field), RBCs, bacteria, casts, and skin contamination (eg, epithelial cells).

A midstream clean catch is appropriate if the patient is old enough to cooperate. Clean skin around the urethral meatus and allow first urine to go into the toilet; then, collect the specimen in a sterile collection cup. Collection may be easier if girls sit facing the toilet.

A bag specimen is adequate for specific gravity. The specimen may be used if the urine bag is removed immediately after urine is deposited. (These specimens are really only useful if results of the urinalysis are negative.)

Urine culture

Urine cultures should be sent to the laboratory even if urinalysis results are inconclusive.

Results are best interpreted with knowledge of the collection method and results of the urinalysis.

A clean-catch urine sample with more than 100,000 colony-forming units (CFU) of a single organism is classic criteria for UTI.

Judgment must be used in interpreting a clean-catch specimen that reports any growth. If the specific gravity of the urine was low, 60,000-80,000 CFU may be significant.

Lower colony counts may be significant if present on a repeat culture. Contamination with perineal flora may mask an existing UTI.

Urinary tract abnormalities may be associated with multiple organisms.

Cultures with growth of more than 10,000 CFU from bladder catheterization or suprapubic aspiration should be considered significant for UTI.

Cultures from bagged urine specimens are significant only if there is no growth.

Better results may be obtained if the perineum is cleaned and dried before the bag is placed and if the collected urine is removed as soon as the patient voids.

Electrolyte abnormalities may be present.

An increased blood urea nitrogen (BUN) finding in a child older than 2 months should raise suspicion of hydronephrosis or renal parenchyma disease.

 

 

               Here is an example of an interstitial parenchymal disease. This is acute pyelonephritis. The irregular pale, raised lesions you see on the surface are collections of purulent exudate in the superficial cortex.

               This is a cross-section of a piece of a kidney showing acute suppurative pyelonephritis. The white streaks running through the medulla and the white blotches in the cortex represent purulent exudate in the tubules and in the interstitial tissue.

 

                                   Chronic pyelonephritis

                    This is an example of chronic pyelonephritis. Repeated bouts of suppurative inflammation in the cortex have resulted in widespread scarring as seen on the left, and a diminution in the overall cortical mass as seen on the right.

 

 

                                                               Treatment

 

                  As practically all cases of pyelonephritis are due to bacterial infections, antibiotics are the mainstay of treatment. Mild cases may be treated with oral therapy, but generally intravenous antibiotics are required for the initial stages of treatment. 

           The type of antibiotic depends on local practice, and may include fluoroquinolones (e.g. ciprofloxacin), beta-lactam antibiotics (e.g. amoxicillin or a cephalosporin), trimethoprim (or co-trimoxazole). Aminoglycosides are avoided due to their toxicity, but may be added for a short duration.

          A 10-day course of antibiotics is recommended, even for uncomplicated infection. It must not be used short-course therapy in children because it is more difficult to differentiate cystitis from pyelonephritis.

Drug Category: Antibiotics – Empiric antibiotics should be chosen for coverage of E.coli and for Enterococcus, Proteus, andKlebsiella species. For suspected pyelonephritis, a combination of parenteral antibiotics is recommended. Ceftriaxone is considered adequate therapy for an occult UTI in the febrile patient. For uncomplicated cystitis, oral antibiotic therapy is generally adequate.

 

 

 

 

    During the course of antibiotic treatment, serial white blood count and temperature should be closely monitored. Typically, the IV antibiotics should be continued till the patient is afebrile for at least 24 to 48 hours, then equivalent oral antibiotic agents can be given for a total of 2-week duration of treatment.

            Intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to maximize urine output.

                 I.V. antibiotics are used initially to control bacterial infection. Chronic pyelonephritis may require long-term antibiotic therapy. Commonly used antibiotics include sulfa drugs, amoxicillin, cephalosporins, levofloxacin, and ciprofloxacin.   Urinaryanalgetics such as phenazopyridine are also appropriated. Symptoms may disappear after several days of antibiotic therapy. Although urine usually becomes sterile within 48 to 72 hours, the course of such therapy is 10 to 14 days.

                   In recurrent infections, additional investigations may identify an underlying abnormality. Occasionally, surgical intervention is necessary to reduce chances of recurrence. If no abnormality is identified, some studies suggest long-term preventative (prophylactic) treatment with antibiotics, either daily or after sexual intercourse. In children at risk of recurrent UTIs, meta-analysis of the present literature indicates that not enough studies have been performed to conclude prescription of long-term antibiotics have a net positive benefit. Ingestion of cranberry juice has been studied as a prophylactic measure; while studies are heterogeneous, many suggest a benefit.

                          Cranberry juice

                   Some recommend other nutritional approaches to prevent recurrence of UTIs. Increasing fluid intake, consuming cranberry juice, blueberry juice, and fermented milk products containing probiotic bacteria, have been shown to inhibit adherence of bacteria to the epithelial cells of the urinary tract.

  Blueberry juice

                                       Probiotics

            Probiotics are described as a kind of existing bacteria that is like the healthy or good bacteria that is produced by the human body.  It is acquired chiefly in a type of dietary supplements as well as some types of food.  It is also considered beneficial as a substitute therapy in health care. But it is not regarded as a component of standard treatment.

 

 

             As of the present, probiotics are very popular among individuals who want to maintain a good balance in their digestive system.  It is considered that these live microorganisms that can be obtained in the favorite health store can give a lot of health benefits if patient has problems in his digestive tract. This statement is especially true if probiotics is taken in sufficient amounts.

 

                                           CYSTITIS

                 Cystitis is inflammation of the bladder due to an infection or irritation. Usually cystitis only affects bladder and is known as a lower urinary tract infection (UTI). If the infection goes higher this can be a more serious illness known as an upper urinary tract infection.

                Urine infection in children is common. It can cause various symptoms. A course of antibiotics will usually clear the infection quickly. In most cases, a child with a urine infection will make a full recovery with no ongoing concerns. Following the infection, tests to check on the kidneys and/or bladder are advised in some cases. The doctor must advise these tests. It depends on factors such as the child’s age, the severity of the infection, and whether it has happened before.

 

                                                Risk factors

 

                               In most cases – no

 

                   Most urine infections in children are just ‘one of those things’ and there is no underlying problem to account for it.

 

In some cases ‘retention’ of urine in the urinary tract may play a part.

 

When we pass urine, the bladder should fully empty. This helps to flush out any bacteria that may have got into the bladder since the last toilet trip. However, various abnormalities of the urinary tract can make the urine stay around in the bladder, ureters or kidney – when it should be travelling down the ureters and emptying completely out of the bladder when going to the toilet. This may allow any bacteria that get there to multiply as urine is a good ‘food’ for some bacteria. Various situations can cause some ‘retention’ of urine in the bladder or higher in the urinary tract, which increases the chance of developing a urine infection.

                    The following are the most common:

 

–   Constipation

              If large hard faeces (stools) collect in the rectum (back passage) they can press on the bladder. The bladder may theot empty fully when the child passes urine. Treating severe constipation sometimes prevents recurring urine infections.

 

–   Dysfunctional elimination syndrome

            This is a condition where a young child repeatedly ‘holds on’ to urine and/or faeces. That is, they regularly do not fully empty their bladder or rectum when they go to the toilet. There is no physical cause for this (that is, no abnormality in the urinary tract or rectum). The reason why this occurs is often unclear. Stress or emotional problems may be the underlying cause.

 

–   An abnormality of the urinary tract

           Various abnormalities of the urinary tract can cause retention of some urine. The most common condition is called ‘vesico-ureteric reflux’. This is a problem at the junction where the ureter enters the bladder. In this condition, urine is passed back (refluxes) up the ureter from the bladder from time to time. This should not happen – the urine should only flow downwards out of the bladder when going to the toilet. This condition makes urine infections more likely. Also, infected urine that refluxes from the bladder back up to the kidneys may cause kidney infection, scarring, and damage. In some cases this leads to severe kidney damage if urine infections recur frequently. Other rare problems that may be found include kidney stones, or congenital abnormalities of parts of the urinary tract.

 

– Neurological (nerve) or spinal cord disorders

             -Anything that affects the bladder emptying or sensation. These are rare in children.

– Other conditions

 

              Other conditions that increase the risk of a urine infection include having diabetes, and a poorly functioning immune system. For example, children with are having chemotherapy.

                                       

                                           CAUSES

                 Infectious agents to penetrate into the bladder in various ways:

– rising – from the urethra and the anogenital area;

– falling – from the kidney and upper urinary tract;

– lymphogenous – from adjacent pelvic organs;

– haematogenous – in the septic process;

– contact – contact with microorganisms through the wall of the bladder from adjacent foci of inflammation.

Symptoms of cystitis

                Young children, toddlers and babies can have various symptoms which may include one or more of:

 

·  Fever (high temperature)

·  Vomiting and/or diarrhea

·  Drowsiness

·  Crying, going off feeds and generally unwell

·  Appear to be in pain

·  Blood in urine (uncommon)

·  Jaundice (yellowing of the skin)

·  Cloudy or smelly urine

 

Cystitis can be painful, particularly when you pass urine, but it usually clears up within four to nine days.

                    Older children, in addition to one or more of the above symptoms, may also say that they have pain when they pass urine, and pass urine frequently. If a kidney becomes infected they may also have shivers, and complain of abdominal (tummy) pain, back pain, or a pain in a side of the abdomen. Bedwetting in a previously ‘dry’ child is sometimes due to a urine infection. Just being ‘generally unwell’ may be due to a urine infection.

                            Diagnosis

 

          A sample of urine is needed to confirm the diagnosis. Urine normally has no bacteria present, or only very few. A urine infection can be confirmed by urine tests that look for bacteria and/or the effects of infection in the urine.

  

Ideally, the sample of urine should not come into contact with skin or other materials that may contaminate it with other bacteria. Older children can do this by a ‘mid stream’ collection of urine. This is not easy to do in young children and babies.

The following are ways to get a sample of urine that is not contaminated:

 

Young children – the usual way is to catch some urine in the specimen bottle whilst in ‘full flow’. Just be ready with the open bottle as the child passes urine. (Be careful not to touch the open rim of the bottle with your fingers as this may contaminate the specimen with bacteria from your fingers.)

 

 

 

Babies – one method is to place a specially designed absorbent pad in a nappy (supplied by a doctor). Urine is sucked into a syringe from the wet pad. Another method is to use a plastic bag that sticks onto the skin and collects urine. If no pad or plastic bag is available, the following might work. Take the nappy off about one hour after a feed. Tap gently with a finger (about once a second) just above the pubic bone. (This is the bone at the bottom of the abdomen above the genitals.) Have the open bottle ready. Quite often, within about five minutes, the baby will pass urine. Try and catch some in the bottle.                      

  Bacteriuria

 

Cystoscopic pattern of cystitis

                     

Hyperdistention of bladder during                A small, reddish-brown spot on the

cystoscopy, showing glomerulations bladder mucosa, called a Hunner’sulcer                                                                       (arrow), visible during cystoscopy

(pinpoint hemorrhages or bleeding fissures).  f the bladder.

USD

Echo sings of cystitis

                                                                     

                Treatment

          A course of an antibiotic will usually clear the infection within a few days. Give lots to drink to prevent dehydration. Also, giveparacetamol to ease any pains and fever (high temperature). Sometimes, for very young babies or for severe infections, antibiotics are given directly into a vein through a ‘drip’.

 

        Therapy of acute cystitis in children should be directed to:

– The elimination of pain

– Normalization of urination disorders

– Elimination of microbial-inflammatory process in the bladder   

                        Drug treatment of acute cystitis and uretritis involves the use of antispasmodic, uroseptic and antibacterial medicines. When pain syndrome is severe the use of no-spani, belladonna, papaverin are useful.

    Cystitis is treated with antibiotic drugs. Antibiotics will be prescribed for at least 2 to 3 days and perhaps for as long as several weeks. The length of the treatment depends on the severity of the infection and on the personal history.  However, it is important that the patient completes the entire course of medication. Otherwise, the infection is likely to return. Urine must be checked after the finish taking the antibiotic. This is to make sure that the infection is truly gone.

 

           If it is experience of recurrent infections, the doctor may prescribe stronger antibiotics or take them for a longer period of time. It may be also recommend to take low-dose antibiotics as a preventive measure.

Pyridium is a medicine that decreases pain and bladder spasms. Taking pyridium will turn your urine and sometimes your sweat anorangish color.

                                   

                                                    Prognosis

 

              In most cases, the outlook is excellent. Once a urine infection is diagnosed and treated, the infection usually clears away and the child recovers fully. In many cases, a urine infection is a ‘one-off’ event. However, some children have more than one urine infection and some develop several throughout their childhood (‘recurring UTIs’).

             In some cases, an infection can be severe, particularly if a kidney becomes badly infected. This can sometimes be serious, even life threatening in a minority of cases if treatment is delayed. A bad infection, or repeated infections, of a kidney may also do some permanent damage to the kidney. This could lead to kidney problems or high blood pressure later in life.

 

                              Further tests

 

              Urine infection is common. In most cases, a child with a urine infection will make a full recovery with no ongoing concerns.

Tests are advised in some cases to check on the kidneys and/or bladder. It depends on factors such as the child’s age, the severity of the infection, and whether it has happened before.

               Children over the age of six months who have a ‘one off’ urine infection which promptly clears with treatment do not usually need any further tests.

                Children with a severe infection, or with an infection with unusual features, may warrant tests.

                Children with recurring infections of any severity may warrant tests.

               The tests that are advised may vary depending on local policies and the child’s age. There are various tests (scans, etc) that can check on the structure and function of the urinary tract (the kidneys, ureters, bladder and urethra).

               The results of the tests are normal in most cases. However, in some cases, an abnormality such as vesico-ureteric reflux may be detected. Depending on whether an abnormality is detected, and how severe it is, a kidney specialist may advise a regular daily low dose of an antibiotic. This treatment is advised in some cases to prevent further urine infections, with the ultimate aim of preventing damage to the kidneys.

 

                  

 

                                       Urethritis

Urethritis is when the opening of the urethra (tube where the urine comes out) is irritated. When this happens, the area outside the vagina (vulva) is usually irritated as well (vulvitis). This problem almost always occurs before puberty.

 

The symptoms can include:

·  Discomfort, stinging, or burning when urinating.

·  Feeling an urgent and frequent need to urinate.

·  Itching and pain in the genital area.

                       

                                         Causes

 

Irritation by chemicals in bubble bath, shampoo, or soap that was left on the genital area is almost always the cause before a child reaches puberty.

5% of young girls do get urinary tract infections (UTI), which can cause the same symptoms. A UTI is a bacterial infection of the bladder (cystitis) and sometimes the kidneys. UTIs must be treated by health care provider.

Diagnosis

 

                                         

 

 

 

                                               Prevention

                                Recommendation to mother

·   Wash the genital area with water, not soap.

·   Don’t use bubble bath before puberty. Don’t put any other soaps or shampoo into the bath water. Don’t let a bar of soap float around in the bathtub. If you are going to shampoo your child’s hair, do this at the end of the bath.

·   Keep bath time less than 15 minutes. Have your child urinate immediately after baths.

· Teach your daughter to wipe herself correctly from front to back, especially after a bowel movement.

· Encourage her to drink enough fluids each day to keep the urine light colored.

· Encourage her to urinate at least every 4 hours during the day.

· Have her wear cotton underpants. Underpants made of synthetic fibers (polyester or nylon) don’t allow the skin to “breathe.” Discourage wearing underpants during the night.

 

 

                                      Treatment

              Antibiotics are given to treat urinary tract infections. A child may begin to feel better soon after starting the antibiotic. But it is very important to finish taking the full course of antibiotics. If kidney abnormalities are found, further treatment may be needed.

                   Some children have to be admitted to the hospital for treatment. This is needed if a child is extremely ill, or is unable to keep down liquids or take antibiotics. Very young children may need to be admitted for intravenous antibiotics. Sometimes an older child does not get better on antibiotics by mouth and will also need an intravenous antibiotic.

            A variety of drugs may be prescribed based on the cause of the patient’s urethritis. Some examples of medications based on causes include:

· Clotrimazole (Mycelex) – Trichomonial

·  Fluconazole (Diflucan) – Monilial

·  Metronidazole (Flagyl) – Trichomonial

·  Nitrofurantoin – Bacterial

·  Nystatin (Mycostatin) – Monilial

·  Co-trimoxazole, which is a combination of Sulfamethoxazole and Trimethoprim in a ratio of 5 to 1 (Septrin, Bactrim) – Bacterial

 

 

                      Uncomplicated UTIs can be diagnosed and treated based on symptoms alone. Oral antibiotics such as trimethoprim,cephalosporins, nitrofurantoin, or a fluoroquinolone such as ciprofloxacin substantially shorten the time to recovery still about 50 % of women will recover without treatment within a few days or weeks. The Infectious Diseases Society of America recommends a combination of trimethoprim and sulfamethoxazole as a first line agent in uncomplicated UTIs rather than fluoroquinolones. Resistance has developed in the community to all of these medications due to their widespread use.

                  A three-days treatment with trimethoprim, TMP/SMX, or a fluoroquinolone is usually sufficient while nitrofurantoinrequires 7 days. Trimethoprim is often recommended to be taken at night to ensure maximal urinary concentrations to increase its effectiveness. While trimethoprim / sulfamethoxazole was previously internationally used (and continues to be used in the U.S. and Canada); the addition of the sulfonamide gives little additional benefit compared to the trimethoprim component alone. It is responsible however for a high incidence of mild allergic reactions and rare but potentially serious complications. For simple UTIs children often respond well to a three-day course of antibiotics.

                  Phenazopyridine can help with painful urination.

 

 

                 Differential diagnosis of pyelohephritis and low urinary infections