Chronic adrenocortical insufficiency

June 4, 2024
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Chronic adrenocortical insufficiency. acute adrenocortical insufficiency.

 Hormonal active tumors of adrenal glands.

 

Adrenal glands

Adrenals are a pair of triangular structures located on top of the kidney and weighting approximately 5 g each.

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Vascularization: a. renalis superior (from a. phrenica inferior), a. suprarenalis media (from aorta abdominalis), a suprarenalis inferior (from a. renalis). Innervation: n. splanchnicus major (through plexus celiacus and plexus renalis), fibrae n. vagus and n. phrenicus).

http://www.completewellbeingsolutions.com/images/Adrenal-color.jpg

http://www.completewellbeingsolutions.com/adrenal.html

 

Anatomy of adrenal glands

The adrenals are divided into an outer area, the cortex, which accounts for about four fifth of the gland, and inner area or medulla. The cortex originates from mesodermal tissue and the medulla from the ectodermal tissue.

Adrenal cortex include three zones:

 

Pict. Structure of adrenals.

 

         Glomerular (glomerulosa) (produces mineralocorticoids (e.g., aldosterone) by the action of the enzyme aldosterone synthase (also known as CYP11B2));

         fascicular (fasciculata) (produces glucocorticoids (e.g., cortisol (hydrocortisone) such as 11-deoxycorticosterone, corticosterone, and cortisol);

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         reticular (reticularis) (produces androgens (dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone)).

         A fetal zone, unique to primates, produces dehydroepiandrosterone, a precursor of both androgens and estrogens. This zone involutes within the first few months of postnatal life.

        Under normal unstressed conditions, the human adrenal glands produce the equivalent of 35–40 mg of cortisone acetate per day or 7 to 8 mg prednisone.

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Pict. Steroid Hormones  synthesis

 (eglobalmed.com)

 

Regulation of aldosterone synthesis in the human body.

regu

Humans possess two mitochondrial 11 β-hydroxylase isoenzymes that are responsible for cortisol and aldosterone synthesis (designated CYP11B1 and CYP11B2) (pict.). Both are encoded on chromosome 8. CYP11B1, which is responsible for conversion of 11-deoxycortisol to cortisol, is expressed only in the zona reticularis. CYP11B2, which is responsible for the conversion of corticosterone to aldosterone, is expressed only in the zona glomerulosa. CYP11B1 activity is stimulated by ACTH, whereas CYP11B2 is stimulated by angiotensin II or hypokalemia.

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www.nature.com

Action of mineralocorticoids:

         regulation of electrolyte balance in the organism (increasing the level of sodium (by sodium retention in distal nephron, colon, salivary gland, sweat glands) and decreasing the level of potassium (by excretion)).

        Production of aldosterone requires persistent calcium entry through low-voltage activated Ca2+ channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ channels entry. However, mouse zona glomerulosa cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity; this innate electrical excitability of zona glomerulosa cells provides a platform for the production of a recurrent Ca2+ channels signal that can be controlled by angiotensin II and extracellular potassium, the 2 major regulators of aldosterone production.

 

Regulation of glucocorticoids synthesis in the human body.

Cortisol secretion is regulated by ACTH, which, in turn, is regulated by CRH from the hypothalamus. Serum cortisol inhibits secretion of CRH and ACTH, thus preventing excessive secretion of cortisol from the adrenal glands. Adrenal androgen secretion is regulated partially by ACTH but also by other unknown factors. ACTH not only stimulates cortisol secretion, it also promotes growth of the adrenal cortex in conjunction with growth factors such as insulinlike growth factor IGF-1 and IGF-2.

The cortisol levels in the blood show a circadian rhythm.

regulation

Pict. Regulation of secretion of glucocorticoids

Action of glucocorticoids (cortisol is the main glucocorticoid under normal conditions):

         increasing of  glycogen synthesis in liver and decreasing of glucose utilization by peripheral tissues;

          increasing gluconeogenesis;

         increasing of protein synthesis in liver and decreasing of its synthesis in muscles and increasing of protein destruction in muscles;

         increasing of lipolisis;

         anti-inflammatory function and immunomodulation;

         cardiovascular regulation (increasing of blood pressure).

 

Adrenal medulla: chromafn cells are the major cell type in adrenal medulla and play a fundamental role inthe response to a variety of stress situations. Chromafn cells are neuroendocrine cells specialized for thesynthesis, storage and release of catecholamines, mainly epinephrine (EP) and norepinephrine (NE), that upon stimulation are directly released into the bloodstream through regulated exocytosis. (Catecholamines are produced from the tyrosine (organism takes it from the meal or from the phenilalanine in the liver) → dioxyphenilalanine (DOPA) → dopamine (it goes into blood only from some neurons of the central nervous system) → norepinephrine (noradrenaline) (it goes into blood only from sympathetic teleneurons) → epinephrine (adrenaline) (it goes into blood only from adrenal medulla).

         

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Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO). The principle urinary metabolic products of epinephrine and norepinephrine are the metanephrines and vanillylmandalic acid (VMA).

 

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Action of catecholamines:

         modulate vascular tone;

         increase heart rate;

         antagonize insulin action etc.

Catecholamines have several different actions on the organism, particularly on the cardiovascular system,smooth muscle and adipose tissue by activating specic proteins on the surface of plasma membrane:the adrenoceptors. Adrenoceptors are members of the Gproteincoupled receptor (GPCR) family that form the inter face between the endogenous catecholamines, EP and NE, and a wide array of target cells in the body to mediate the biological effects of the sympathetic nervous system. To date,nine different adrenoceptor subtypes have been identied, three a 1 -adrenoceptors ( a 1A , a 1B and a 1D ), three a 2 -adrenoceptors ( a 2A , a 2B and a 2C ), and three b –adrenoceptors ( b 1 , b 2 and b 3 ).

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Regulation of catecholamines secretion:

         Chromafn cells are cholinergically innervated by splanchnicnerve from the sympathetic nervous system. Acetylcholine (ACh)released upon stimulation of the splanchnic nerve, activates nico-tinic acetylcholine receptors on chromafn cells to induce mem-brane depolarization, that induce open voltage-gated calcium(Ca2+) channels (VGCCs), enhancing Ca2+ entry, that triggers cate-cholamine release.

 

Chronic adrenocortical insufficiency

It is an insidious and usually progressive disease resulting from adrenocortical hypofunction.

In 1855, Thomas Addison described a clinical syndrome characterised by wasting and hyperpigmentation, and identified its cause as destruction of the adrenal gland. However, life-saving glucocorticoid-replacement therapy for the condition did not become available until 1949, when Kendall, Sarett, and Reichstein first synthesised cortisone. Furthermore, despite this breakthrough, 150 years on there are still many advances and challenges with respect to the management of individuals with adrenal insufficiency. Frequency:

The calculated incidence of primary adrenal insufficiency is approximately 5-6 cases per million persons per year. Secondary adrenal insufficiency has an estimated prevalence of 150–280 per million.

 

Mortality/Morbidity:

Adrenal insufficiency is a potentially fatal disease if unrecognized and untreated. Death usually results from hypotension or cardiac arrhythmia secondary to hyperkalemia.

Race: Adrenal insufficiency exhibits no racial predilection.

Sex:

·                Autoimmune adrenal insufficiency is more common in females than males.

·                Adrenal insufficiency due to adrenoleukodystrophy is limited to males because it is X-linked, as is a form of congenital adrenal hypoplasia, termed adrenal hypoplasia congenita (AHC). Both conditions are relatively rare.

·                Secondary adrenal insufficiency due to a deficiency of ACTH or CRH, or to a lack of ACTH receptors, is equally common among males and females.

Age: Autoimmune adrenal insufficiency is more common in adults than in children. Congenital causes, such as congenital adrenal hyperplasia (CAH), congenital adrenal hypoplasia, and defects in the ACTH receptor, are more commonly recognized in childhood.

 

Classification.

1.     Primary adrenocortical insufficiency (Addison’s disease).

2.     Secondary adrenocortical insufficiency .

Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.

 

Etiology of

primary adrenocortical insufficiency:

1.           In developed countries, the most common cause is autoimmune destruction (50 – 65 %) of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder

·   Type 1 autoimmune polyglandular syndrome presents in the first decade of life and is transmitted as an autosomal recessive disorder with all or some of the following:

o              Adrenal failure

o              Hypoparathyroidism

o              Hypothyroidism

o              Gonadal failure

o              Diabetes mellitus type 1

o              Vitiligo

o              Alopecia

o              Pernicious anemia

o              Chronic mucocutaneous candidiasis

APS type 1, also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), arises in up to 15% of patients with autoimmune adrenalitis.

 

·                    Type 2 autoimmune polyglandular syndrome consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. This condition presents in the second and third decades of life and is transmitted as an autosomal disorder with variable penetrance. APS type 2 is the most frequently seen APS and comprises adrenal insufficiency and autoimmune thyroid disease. The clinical spectrum also includes primary gonadal failure, type 1 diabetes mellitus, and other autoimmune diseases such as vitiligo, chronic atrophic gastritis, or coeliac disease. APS type 2 occurs with autosomal-dominant inheritance with incomplete penetrance, and shows a strong association with HLA- DR3 12,43 and CTLA-4 The combination of adrenal insufficiency with other autoimmune disorders, but without thyroid disease, is classified as APS type 4, and APS type 3 involves autoimmune thyroid disease but not adrenal insufficiency.

               

 

2. Less common causes of adrenal failure include the following:

1)    Tuberculosis;

Adrenal Glands                                                    image022.png

                            Pic. Normal adrenal glands pic.                                                                       Pic. Tuberculosis destruction of adrenal glands

(Photograph © 1993 Joseph R. Siebert/Custom Medical Stock Photo.)

 

2)    neoplasm, metastatic carcinoma;

3)    X-linked adrenoleukodystrophy is caused by a mutation in the  ABCD1 gene, 46 which encodes a peroxisomal membrane protein (adrenoleukodystrophy protein), 47 leading to accumulation of very-long-chain fatty acids (>24 carbon atoms). The clinical picture comprises adrenal insufficiency and neurological impairment due to white- matter demyelination. The two major forms are cerebral adrenoleukodystrophy (50% of cases; early childhood manifestation; rapid progression) and adrenomyelo- neuropathy (35% of cases; onset in early adulthood; slow progression) with restriction of demyelination to spinal cord and peripheral nerves. 16 Adrenal insufficiency can precede the onset of neurological symptoms and is the sole manifestation of disease in 15% of cases

4)    inflammatory necrosis;

5)    amyloidosis;

6)    bilateral adrenal hemorrhage or infarction, intra – adrenal hemorrhage (Waterhouse – Friedrichsen syndrome following meningococcal septicemia);

7)    heamochromatosis (may cause either primary or secondary adrenal insufficiency. Iron deposition in the pituitary and/or adrenal glands in multiply transfused patients with thalassemia patients also may cause adrenal insufficiency);

8)    bilateral adrenalectomy;

3. Congenital primary adrenal insufficiency

o        Congenital disease may occur from adrenal hypoplasia or hyperplasia.

o        Adrenal hypoplasia congenita (AHC), inherited as an X-linked disorder, is caused by deletion of the DAX1 gene on chromosome X and often is part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. An alternate form, also X-linked, has been described characterized by intrauterine growth retardation and skeletal and genital anomalies. A third form of AHC is autosomal recessive.

o        CAH results from a deficiency of 1 of several enzymes required for adrenal synthesis of cortisol. Adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of CAH is caused by a steroid 21-hydroxylase deficiency.

o        Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused either by a mutation in the steroid acute regulatory protein or a mutation in the cholesterol side chain cleavage gen. This disease causes a defective synthesis of all adrenocortical hormones and, in its complete form, is lethal.

o        Mutations or deletions of P450 oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17 hydroxylase, 21 hydroxylase, and 17-20 lyase activities resulting in adrenal insufficiency often accompanied by primary hypogonadism.

 

 

Etiology of

secondary adrenocortical insufficiency:

1)    Most cases are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks’ exposure to pharmacological doses of glucocorticoids can cause CRH-ACTH-adrenal axis suppression. Suppression can be so great that acute withdrawal or stress may prevent the axis from responding with sufficient cortisol production to prevent an acute adrenal crisis. Recently, treatment with megesterol acetate, an orixegenic agent, has resulted in iatrogenic adrenal suppression, presumably through glucocorticoid properties of megesterol acetate.

2)    hypothalamic or pituitary disease (primary injury of these organs leads to insufficiency of ACTH secretion that cause the two – side atrophy of adrenal glands).

Pathogenesis.

Cortisol deficiency contributes to the hypotension and produces in carbohydrate, fat, and protein metabolism, and severe insulin sensitivity. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and diminished liver glycogen result. Weakness, due in part to deficient neuromuscular function follows. Resistance to infection, trauma, and other stress is diminished because of reduced adrenal output. Cardiac output is reduced and circulatory failure can occur. Reduced cortisol blood levels result in increased pituitary ACTH production and an increase in beta – lipotropin, which has melanocyte – stimulating activity and produces the hyperpigmentation of skin and mucous membranes characteristic of Addison’s disease.

There is increased excretion of Na and decreased excretion of K chiefly in the urine, but also in the sweat, saliva, and gastrointestinal tract. Low blood concentrations of Na and Cl and high serum K result. These changes in electrolyte balance produce increased water excretion with severe dehydration, increased plasma concentration, decreased circulatory volume, hypotension, and circulatory collapse.

Symptoms and signs.

Presentation may be acute and chronic. Frequently clinical signs of the primary chronic adrenocortical insufficiency are manifested in that time when adrenocortical tissue is destroyed on 70-90 %.

The most common complaints are: weakness, malaise, weight loss, anorexia, depression.

image024.png

Pic. Weakness of posterior extremitas in dog after adrenalectomy

Objective examination:

1.     Increased pigmentation (in patients with primary adrenal insufficiency) is characterized by diffuse tanning of both exposed and nonexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces, black freckles over the forehead, face, neck, and shoulders; bluish – black discoloration of the areolas and the mucous membranes of the lips, mouth, rectum and vagina are common. After compensation hyperpigmentation will decrease. Patients in 15 – 20 % of cases may have areas of vitiligo (depigmentation)  as the sign of autoimmune process.

 

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2.     Hypotension or postural hypotension (88 – 90 %) with syncopal attacks can occur.

3.     Tachycardia.

4.     Weight loss (due to dyspeptic syndrome, true muscle tissue catabolism, dehydration).

5.     Anorexia, nausea, vomiting, abdominal pain, diarrhea are often.  Gastritis, ulcer disease can occur.

6.     Decreased cold tolerance, with hypometabolism may be noted.

7.     Sexual disorders.

8.     Neurologic and psychiatric disorders: decreasing of the memory, mental activity, concentration of attention, depressions, hallucinations can occur due to chronic hypoglycemia which leads to changes of metabolism in brain tissue.

9.     Hypoglycemia.

There are three stages of severity: mild, moderate and severe.

THE LANCET • Vol 361 • May 31, 2003 • www.thelancet.com

 

Laboratory findings.

·                Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:

o               Electrolytes

o               Fasting blood sugar

o               Serum ACTH

o               Plasma renin activity

o               Serum cortisol

o               Serum aldosterone

1.     A low serum Na level and a high serum K level together with a characteristic clinical picture suggest the possibility of Addison’s disease.

2.     Adrenal insufficiency can be specifically diagnosed by:

         low levels of plasma glucocorticoids and mineralocorticoids, or urinary 17 – hydroxycorticosteroid (17 – OHCS) or 17 – ketogenic steroid (17 – KGS);

         demonstrating failure to increase plasma cortisol levels, or urinary 17 – OHCS or 17 – KGS excretion, upon administration of ACTH (in patients with primary adrenal insufficiency).

3.     To distinguish between primary and secondary adrenal insufficiency, me have to find the level of plasma ACTH: primary shows increased, and secondary shows decreased level: when plasma ACTH determination is not available, 0.25 mg of cosyntropin or depo-senacten(a synthetic ACTH that has fewer side effects than the natural preparations) may be infused IV (after dilution with dextrose or sodium chloride solution) over a period of 8 h daily for 2 days. Patients with primary adrenocortical insufficiency will show a little or no increase in plasma cortisol or 24 – h urinary corticosteroid levels. Those with secondary adrenocortical insufficiency  will have a significant increase in plasma cortisol or 24 – h urinary corticosteroid levels.

 

·                So, when hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.

o               Interpret random serum cortisol concentrations within the context from which they were obtained. (For example, adrenal insufficiency is unlikely in an otherwise healthy individual with an serum cortisol concentration more than 10 mcg/dL. Yet a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient highly suggests adrenal insufficiency.)

o               A diagnosis of adrenal insufficiency is confirmed by a serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity, or a concentration lower than that level obtained 60 minutes following cosyntropin administration.

o               Diagnosis also is confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes following cosyntropin administration.

o               Note that these guidelines do not apply to premature and low birth weight infants, who have much lower cortisol secretion.

·                If serum cortisol is low with elevated ACTH, measure antiadrenal antibodies. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, often are found in autoimmune adrenal disease.

·                Cosyntropin administration is controversial because whether the best dose is the standard 250 mcg, the 1 mcg, or the low 0.5 mcg/m2 is unresolved, particularly in the pediatric age group. The standard dose, therefore, is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiological.

·                When serum cortisol response to cosyntropin is subnormal, but serum ACTH is not elevated, confirm the possibility of central adrenal insufficiency. In this context, a 6-hour or 3-day treatment with ACTH can produce a normal cortisol response, confirming that initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered IV over the 6 hours. If the 3-day test is chosen, administer 25 mg/m2 of ACTH gel IM every 12 hours for the 3 days. Plasma cortisol should increase to more than 40 mcg/dL in response to either of these tests. Alternatively, 24-hour urinary 17-hydroxysteroid concentrations should increase 5-10 fold in response to the 3-day ACTH stimulation test.

·                If the patient has recent onset (ie, <10 d) of central adrenal insufficiency (as in a recent surgery in the hypothalamus or pituitary regions), resorting to a more cumbersome and risk-bearing insulin tolerance test or metyrapone stimulation test may be preferable. These conditions are the only real indication for performing these tests in a patient with adrenal insufficiency

·                An insulin tolerance test requires IV administration of insulin (usually 0.05-0.15 units regular insulin/kg) to induce a 50% drop in blood sugar. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the blood sugar drops by at least 50%. In response to this hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 20 mcg/dL. This test involves some risk of hypoglycemic seizure; therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overly symptomatic.

·                Standard metyrapone stimulation tests involve administering 300 mg/m2 metyrapone in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, the last enzyme step in cortisol synthesis, the cortisol precursor 11-deoxycortisol increases in the plasma. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours following the last dose of metyrapone or a 2- to 3-fold increase in 24-hour urinary 17-hydroxycorticosteroid concentrations (which include tetrahydro compound S [urinary metabolite of 11-deoxycortisol]), on the day or day following metyrapone administration. This test is cumbersome and carries some risk of inducing an adrenal crisis.

·                When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If the test results for antiadrenal antibodies are negative, search for another etiology such as TB, adrenal hemorrhage, or adrenoleukodystrophy.

·                The standard ovine or human CRH stimulation test is reliable in the diagnosis and differential diagnosis of adrenal insufficiency.

o               Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses.

o               Patients with primary glucocorticoid deficiency have elevated ACTH concentrations basally and after CRH administration.

o               Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they suffer from a primary pituitary deficiency, or these patients have exaggerated responses if their problem is tertiary.

o              

 

http://www.aafp.org/afp/2006/0115/afp20060115p283-f1.gifImaging Studies:

1.            ECG: K > 6.5 mEq/L causes further slowing of conduction with widening of the QRS interval, disappearance of the P wave, and nodal and escape ventricular arrhythmias. Finally, the QRS complex degenerates into a sine wave pattern, and ventricular fibrillation or asystole ensues.

 

2.            The EEG shows alized slowing of the α – rhythm.

3.            CT is the imaging study of choice and helps identify adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT.

4.            Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.

5.            Ultrasonography is a poor imaging modality for investigation of the adrenal glands.

6.            Iodocholesterol scanning is not particularly useful.

 

 

Procedures:

·                CT-guided fine-needle aspiration sometimes helps diagnose the etiology of infiltrative adrenal diseases.

Histologic Findings:

Findings depend on the underlying cause. In cases of autoimmune adrenal failure, the adrenal gland is destroyed by lymphocytic infiltration. Granulomatous changes within the adrenal glands indicate tuberculous adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency shows hemorrhagic destruction of adrenals. Fungal disease produces typical pictures.

 

Differential diagnosis.

         primary and secondary adrenocortical insufficiency (patients with secondary adrenal insufficiency are not hyperpigmented, they have relatively normal electrolyte values; those with panhypopituitarism have depressed thyroid and gonadal function; tests to differentiate primary and secondary adrenal insufficiency were discussed earlier);

Primary                        and                      secondary

adrenal insufficiency

 

         hyperpigmetation due to bronchogenic carcinoma, ingestion of heavy metals such as iron or silver, chronic skin conditions or hemochromatosis; Peutz – Jeghers syndrome (pigmentation of the buccal and rectal mucosa);

         hyperinsulinism;

         neuropsychiatric weakness;

         anorexia nervosa:

         diseases of the gastrointestinal tract.

 

Treatment.

I.              Etiologic: appropriate treatment of complicating infections (e.g., tuberculosis).

II.           Pathogenic:

1.     Diet (enough quantity of proteins, vitamins, salt and water).

2.     Glucocorticoids (normally, glucocorticoids are secreted maximally in the early morning hours, little being secreted at night).

Average dosage is:

         cortisol: 20 – 25 mg daily;

         prednisolone 5 – 7.5 mg daily;

         hydrocortisone 30 – 40 mg orally daily.

http://www.scielo.br/img/revistas/rboto/v74n6/en_a17fig02.jpg

Louzada P, Sarti W. Corticosteróides. In Campos CAH, Costa HOO, editores. Tratado de Otorrinolaringologia. São Paulo: Roca; 2002. p.243-9.    

2/3 of the dose can be given in the morning and 1/3 in the afternoon. Night doses should be avoided, as they may produce insomnia.

3.      Mineraloocorticoids.

DOCSA 5 mg orally daily should be used in patients with severe and moderate duration or fludrocortisone 0.1 – 0.2 mg orally once a day is recommended (this mineralocorticoid replaces aldosterone, some times it is necessary to reduce the dose to 0.05 mg every 2nd day on initial institution of  therapy because of ankle edema, but the patient usually adjusts and can then take the larger doses)

4.     Intercurrent illnesses (e.g., infections) should be regarded as potentially serious and the patient should double his dosage until he is well.

5.     If nausea or vomiting preclude oral therapy, medical attention should be sought immediately and parental therapy started.

 

ACUTE adrenocortical insufficiency

is a medical emergency caused by sudden marked insufficiency of adrenocortical hormones.

 

Precipitating factors.

1)    stress (infection (especially with septicemia, trauma, surgery, prolonged fasting, salt loss due to excessive sweating during hot weather);

2)    sudden withdrawal of adrenocortical hormone therapy in patients with chronic insufficiency.

 

Clinical features.

An adrenal crisis is characterized by:

         profound asthenia,

         severe pains in the abdomen, lower back or legs;

         nausea, vomiting diarrhea;

         peripheral vascular collapse;

         renal shutdown with azotemia.

         Body temperature may be subnormal, through severe hyperthermia due to infection is often seen.

        

 

Treatment.

Therapy should be instituted immediately once a provisional diagnosis of adrenocortical failure has been made.

1)    hydrocortisone 100 – 150 mg as a water – soluble ester (usually the succinate or phosphate) is injected IV over 30 seconds, followed by infusion of 1 L of 5 % glucose – in – saline solution containing 100 mg hydrocortisone ester given over 2 h. Additional saline is given until dehydration and hyponatremia have been corrected. Hydrocortisone therapy is given continuously to a total dosage in 24 h of 400 – 600 – 800 mg. Mineralocorticoids are not required when high – dose hydrocortisone is given. Restoration of BP and general improvement may be expected within 1h or less after the initial dose of hydrocortisone. Vasopressors may be needed until the full effect of hydrocortisone is apparent (a delay in instituting corticosteroid therapy may result in the patient’s death, particularly if hypoglycemia and hypotension are present). A total dose of hydrocortisone 150 mg is usually given over the second 24-h period if the patient is markedly improved, and 75 mg is given on the third day. Maintenance oral doses of hydrocortisone (30 mg) and fludrocortisone acetate (0.1 mg) are given daily there – after. Recovery depends upon treatment of the underlying cause and adequate hydrocortisone therapy.

2)    Treatment of complications (hyperpyrexia, psychotic reactions).

3)   

 

Prognosis.

With a substitution therapy, the prognosis is excellent and a patient with Addison’s disease should be able to lead a full life.

 

Types of cancer which occur in the adrenal glands

Carcinomas may arise in the adrenal cortex (adrenocortical carcinomas) or the adrenal medulla (malignant pheochromocytomas). They also may metastasize to the adrenals from other primary sites.

Approximately 50-70% adrenocortical carcinomas secrete steroid hormones, whereas 30-50% are nonfunctioning.

Functioning adrenocortical carcinomas secrete aldosterone, cortisol, or androgens-alone or in combination. Excessive aldosterone (Conn’s syndrome) causes hypertension and hypokalemia. Cortisol overproduction results in Cushing’s syndrome. Excessive androgen secretion causes hirsutism and virilization in women and precocious puberty in children but is often asymptomatic in men.

Nonfunctioning adrenocortical carcinomas present clinically as abdominal or flank pain or as an adrenal mass discovered incidentally during an imaging procedure.

Malignancy is strongly suggested by tumor size > 6 cm, evidence of locally invasive or metastatic disease to the liver or lungs, and elevated urinary 17-ketosteroid excretion. The diagnosis of malignancy is ofteot suspected, however, until histologic examination after tumor removal.

Treatment for an adrenocortical carcinoma

The treatment of choice is surgery.

Mitotane, an adrenal cytotoxic agent, has produced partial or complete tumor regression, reduced production of adrenal hormones, and improved survival ionrandomized, noncontrolled trials.

The combination of mitotane with etoposide, cisplatin, and doxorubicin has shown some promise, but responses to chemotherapy have, in general, been disappointing.

Radiation therapy has not been shown to be effective with these tumors.

What tumors metastasize to the adrenal glands?

The vascular adrenal glands are a frequent site of bilateral metastatic spread from cancers of the lung, breast, stomach, pancreas, colon, and kidney, and from melanomas and lymphomas.

Incidental adrenal masses should be assessed for evidence of malignancy and excess hormone secretion. Size is the best predictor of cancer; 25% of masses > 6 cm in size are malignant whereas < 2% of those that are < 4 cm in size are malignant. The most common hormonal disorder is subclinical Cushing’s syndrome; the most risky is pheochromocytoma. Accordingly, the recommended hormone evaluation is a 1-mg overnight dexamethasone suppression test and plasma-free metanephrine measurement; patients with hypertension should also have plasma aldosterone and renin levels measured. Surgery is indicated for tumors > 6 cm in size, for those 4-6 cm in size with other radiologic features suggesting cancer or rapid growth on follow-up, for pheochromocytomas and for other overt hormonal syndromes.

Nonfunctioning masses > 6 cm and all hormone-secreting tumors should be removed surgically. Some experts recommend a size cutoff of 4.5 cm for surgery. Smaller masses should be reassessed in 3-6 months, then annually, and removed if growth occurs or if excess hormone secretion develops.

 

Hormonal active tumors of adrenal glands.

Adrenal tumors often are characterized by the hormones that they secrete:

  • Aldosterone tumor (Conn‘s Syndrome) = adrenal tumor making aldosterone: often presenting with new hypertension and low potassium . This syndrome is named after the former UMICH endocrinologist who discovered and characterized this syndrome.

  • Cushing’s Syndrome = adrenal tumor making excessive cortisol: often presenting with new hypertension, diabetes, central obesity.

  • Virilizing adrenal tumor = adrenal tumor making excessive androgens (like testosterone) often presenting with new hirsuitism (hair growth), increased muscle mass, acne and amenorhea (loss of periods) in a female.

  • Feminizing adrenal tumor = adrenal tumor making excessive estrogens often presenting with new gynecomastia (breast growth in a man) and impotence in a male.

  • Pheochromocytoma = adrenal tumor making excessive adrenaline often presenting with new hypertension, headaches, sweating, palpitations and panic attacks.

Adrenal tumors are classified by their growth characteristics:

  • Adrenal adenoma: adrenal tumor that is benign

  • Adrenal carcinoma: adrenal tumor that is malignant

  • Adrenocortical carcinoma (ACC): rare, but very deadly. This type of cancer develops in the outer layer, called the cortex, of the two small adrenal glands that sit on top of each kidney. About 600 new cases are diagnosed each year in the United States, or about one to two cases per million people.

  • Adrenocortical cancer: most common in either the first or fifth decade of life. Because it produces symptoms in children, pediatric adrenal cancer is often diagnosed and treated at an early stage. Five-year survival rates in children are greater than 50%.

·         An adrenal gland tumor can sometimes overproduce hormones. When it does, the tumor is called a functioning tumor. An adrenal gland tumor that does not produce hormones is called a nonfunctioning tumor. A tumor can start in an adrenal gland (called a primary adrenal tumor), or it can begin in another organ, such as the lungs, and then metastasize (spread) to the adrenal glands. The symptoms and treatment of an adrenal gland tumor depend on whether the tumor is functioning or nonfunctioning, what hormone(s) is overproduced, and whether the tumor is a primary adrenal gland tumor or a metastases from cancer of another organ.

Adrenal cortical adenomas  commonly arise from the zona fasciculata, although all three zones can give rise to benign or malignant tumors. Adrenal cortical adenomas may be functioning or nonfunctioning.1 These tumors are usually positive for melan A by immunostaining . Many small adenomas <3cm in diameter are discovered accidentally during working up for various other conditions. These tumors are referred to as ‘incidentalomas’. One of the major problems in diagnostic endocrine pathology is distinguishing adrenal cortical adenomas from carcinomas. This is especially true with borderline lesions compared with small adenomas <20g or very large tumors >500g that are usually obvious carcinomas.

Adrenal cortical carcinoma may be functioning malignancies in some cases, whereas in other cases they are nonfunctioning.The gross appearance of adrenal cortical carcinoma can be very helpful in making the diagnosis. Most carcinomas in adults are >100g, whereas adenomas generally weigh 50g or less. Adrenal cortical tumors weighing <50g have, on occasion, metastasized, but this is extremely uncommon. In pediatric patients, however, adrenal cortical adenomas may weigh up to 500g. In addition to tumor weight, the presence of necrosis usually indicates an adrenal cortical carcinoma unless the necrosis resulted from a traumatic insult such as FNA. A variegated appearance with nodularity and intersecting fibrous bands should also suggest the possibility of a carcinoma.

Various studies have outlined specific criteria used to diagnose adrenal cortical carcinomas. The criteria of Weiss are most useful because of their reliance on histologic features. These include high nuclear grade, mitotic rate >5 per 50 HPF, atypical mitotic figures, eosinophilic tumor cells (≥75% of tumor), diffuse architecture (≥33% of tumor), necrosis, venous invasion (smooth muscle in wall), sinusoidal invasion (no smooth muscle in wall) and capsular invasion Three or more of the nine criteria are indicative of an adrenal cortical carcinoma, whereas two or less would be more in keeping with an adenoma.

 

PHEOCHROMOCYTOMA

        Pheochromocytomas (‘dusky colored tumor’) are chromaffin-derived tumors that develop in the adrenal gland. Tumors that arise outside the adrenal gland are termed extra-adrenal pheochromocytomas or paragangliomas. When the tumor is immersed in chromaffin salts or other weak oxidizing agents, it develops the dusky color. Most tumors are sporadic and benign. Malignant pheochromocytomas comprise only about 10% of all pheochromocytomas. Signs and symptoms are similar to these in patients with benign disease; however, catecholamine production and the degree of hypertension may be more marked with metastatic disease. The reported incidence is about 0.4–9.5 per 106 people. The tumors occur most frequently in the fourth and fifth decades. Familial tumors develop at a younger age. Most familial tumors are bilateral, whereas sporadic tumors are unilateralIt is a tumor of chromaffin cells that secrete catecholamines. About 30% of pheochromocytomas occur as part of hereditary syndromes. Although pheochromocytoma has classically been associated with 3 syndromes—von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1 (NF1)—there are now 10 genes that have been identified as sites of mutations leading to pheochromocytoma. These different genes produce tumors with different ages of onset, secretory profiles, locations, and potential for malignancy.

        Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells. Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias. If the diagnosis of a pheochromocytoma is overlooked, the consequences could be disastrous, even fatal; however, if a pheochromocytoma is found, it is potentially curable.

        Pheochromocytomas are rare, reportedly occurring in 0.05–0.2% of hypertensive individuals. This accounts for only a portion of cases, however, as patients may be completely asymptomatic. A retrospective study from the Mayo Clinic revealed that in 50% of cases of pheochromocytoma, the diagnosis was made at autopsy. Approximately 10% of pheochromocytomas are discovered incidentally.

The term pheochromocytoma (phios means dusky, chroma means color, and cytoma means tumor) refers to the color the tumor cells acquire when stained with chromium salts.

pheochromocytomas

In about 80 – 90 % of cases, pheochromocytomas are found in the adrenal medulla, but may also be found in other tissues derived from neural crest cells (e.g., tumors may be found in the paraganglia of the sympathetic chain, retroperitoneally along the course of the aorta, in the carotid body, in the organ of Zuckerkandl (at the aortic bifurcation) in the GU system, in the brain, and in the dermoid cysts. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to the origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies.

localis of pheochro

 Pict. Localization of pheochromocytomas.

 

Etiology is unknown. Pheochromocytomas are known to occur in certain familial syndromes. These include MEN 2A and 2B, neurofibromatosis (von Recklinghausen disease), and VHL disease. The MEN 2A and 2B syndromes, which are autosomally inherited, have been found to have germline mutations in the ret proto-oncogene. The ret proto-oncogene, located on chromosome 10, encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation. Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases. Pheochromocytomas occur in 1% of neurofibromatosis cases. VHL syndrome is associated with pheochromocytomas, cerebellar hemangioblastomas, and renal cell carcinoma.

 

Malignancy

Approximately 10% of pheochromocytomas and 35% of extra-adrenal pheochromocytomas are malignant. Only the presence of metastases defines malignancy. However, specific histologic features help to differentiate adrenal pheochromocytomas with a potential for biologically aggressive behavior from those that behave in a benign fashion. Among the features that suggest a malignant course are large tumor size and an abnormal DNA ploidy pattern (aneuploidy, tetraploidy). Common metastatic sites include bone, liver, and lymph nodes.

 

o               MEN 2A (Sipple syndrome) is characterized by medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas, and Hirschsprung disease. Over 95% of cases of MEN 2A are associated with mutations in the ret proto-oncogene affecting 1 of 5 codons in exon 10 (codons 609, 611, 618, 620) or exon 11 (codon 634).

o               Medullary thyroid carcinoma, pheochromocytoma, mucosal neurofibromatosis, intestinal ganglioneuromatosis, Hirschsprung disease, and a marfanoid body habitus characterize MEN 2B. A germline missense mutation in the tyrosine kinase domain of the ret proto-oncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B.

o               Pheochromocytoma, cerebellar hemangioblastoma, renal cell carcinoma, renal and pancreatic cysts, and epididymal cystadenomas are associated with VHL disease. One study found that this syndrome was present iearly 19% of patients with pheochromocytomas (Neumann, 1993). More than 75 germline mutations have been identified in a VHL suppressor gene located on chromosome 3.

o               Congenital anomalies (often benign tumors) of the skin, nervous system, bones, and endocrine glands characterize neurofibromatosis, or von Recklinghausen disease. Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis.

o               Other neuroectodermal disorders associated with pheochromocytomas include tuberous sclerosis (Bourneville disease, epiloia) and Sturge-Weber syndrome.

o               Pheochromocytomas may produce calcitonin, opioid peptides, somatostatin, corticotropin, and vasoactive intestinal peptide. Corticotropin hypersecretion has caused Cushing syndrome, and vasoactive intestinal peptide overproduction causes watery diarrhea.

 

 

Classification.

1.     Paroxysmal form (45 %).

2.     Permanent form (50 %):

         with crisis;

         without crises.

3.     Latent or silent form (nonsymptomatic).

Clinical features

is due to secretion of one or more of the catecholamine hormones or precursors: norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine.

·                Clinical signs

o               The most prominent feature is hypertension (paroxysmal in 50% of cases)

Precipitants of a hypertensive crisis include the following

  • Anesthesia induction

  • Opiates

  • Dopamine antagonists: Eg, metoclopramide

  • Cold medications

  • Beta blockers

  • Drugs that inhibit catecholamine reuptake: Eg, tricyclic antidepressants and cocaine

  • Childbirth

o               Postural hypotension: This results from volume contraction.

o               Hypertensive retinopathy

Video

o               Hypertrophy of left ventricle

Video

o               Weight loss

o               Pallor

o               Fever

o               Tremor

o               Neurofibromas

o               Café au lait spots: These are patches of cutaneous pigmentation, which vary from 1-10 mm and occur any place on the body. Characteristic locations include the axillae and intertriginous areas (groin). They vary from light to dark brown, hence the name café au lait.

o               Tachyarrhythmias

o               Pulmonary edema

o               Cardiomyopathy

o               cold and clammy skin, severe headache, angina, palpitation,

o               visual disturbances,

o               dyspnea, parasthesias,

o               nausea, vomiting, epigastric pain, constipation or diarrhea and a sense of impending doom are common; some or all of these symptoms and signs may occur in any patient.

Duration of hypertensive crisis is variable, lasting from a seconds or few minutes to a days., but 50 % of the paroxysms last less than 15 min. Permanent form of the disease’s duration looks like malignant hypertension. Nonsymptomatic form of the disease is rare.

The severity of the retinopathy and cardiomegaly is often less extensive than might be expected for the degree of hypertension present.

 

Laboratory features and investigations.

1.     Hyperglycemia

2.     Hypercalcemia

3.     Erythrocytosis

4.     An increased  3-h (24-h) urinary excretion of epinephrine, norepinephrine and their metabolic products (VMA or metanephrines).

5.     Increased plasma epinephrine, norepinephrine.

 

Imaging Studies

CT scanning or MRI of the abdomen for the localization of the adrenal and extra – adrenal tumors  is useful.

·                Over 90 % of pheochromocytomas are located within the adrenal glands, and 98 % are within the abdomen. Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of the sympathetic nervous system. They may occur anywhere from the base of the brain to the urinary bladder. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies.

·                Only perform imaging studies after biochemical studies have confirmed the diagnosis of a pheochromocytoma. MRI is preferred over CT scanning. MRI has a reported sensitivity of up to 100% in detecting adrenal pheochromocytomas , does not require contrast, and does not expose the patient to ionizing radiation. MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas. Typically, (approximately 70% of cases), pheochromocytomas appear hyperintense on T2-weighted images because of their high water content.

phoech 

Pict. Abdominal MRI showing right-sided pheochromocytoma

Pheochromocytoma

Pict. Pheochromocytoma (adrenal paraganglioma) on CT and MRI. There is strong enhancement on enhanced CT and very high signal intensity on T2-weighten MRI

 (http://www.radiologyassistant.nl)

 

·                CT scanning of the abdomen has an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater. CT scanning is less accurate for lesions smaller than 1 cm. Diferentiating an adenoma from a pheochromocytoma is more difficult using CT scanning. While most pheochromocytomas have CT attenuation greater than 10 Hounsfield units (HU), they rarely contain sufficient intracellular fat to have an attenuation of less than 10 HU. In addition, most pheochromocytomas have enhancement loss that is similar to that of adrenal metastases and significantly less than that of adrenal adenomas. However, in patients in whom pheochromocytomas are strongly suspected, adrenal pheochromocytomas cannot be entirely excluded from the list of differential diagnoses of adrenal neoplasms with less than 10-HU attenuation value and greater than 60% washout on delayed scanning.

·                A scan with iodine I 131–labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a pheochromocytoma is confirmed biochemically but CT scanning or MRI do not show a tumor. The molecular structure of iodine I 123 MIBG resembles norepinephrine and concentrates within adrenal or extra-adrenal pheochromocytomas. This isotope has a short half-life and is expensive. It frequently is used in cases of familial pheochromocytoma syndromes, recurrent pheochromocytoma, or malignant pheochromocytoma. In the United States, only 131I-labeled MIBG is available, whereas 123I MIBG is used in Europe and Japan.

pheo 

Pict. MIBGscan of left adrenal pheochromocytoma

 

·                A somatostatin receptor analog indium In 111 pentetreotide is less sensitive than MIBG and may be used to visualize pheochromocytomas that do not concentrate MIBG.

·                Positron emission tomography (PET) scanning has been used as an imaging modality and has shown promising results. PET of 18F-fluorodeoxyglucose, which is selectively concentrated as part of the abnormal metabolism of many neoplasms, has been demonstrated to detect occult pheochromocytomas. Pheochromocytomas usually show increased uptake on PET scanning, as do adrenal metastases. The most impressive results to date have been with 6-[18F] fluorodopamine PET scanning and carbon 11 hydroxyephedrine PET scanning. Results of these studies suggest that PET scanning performed with both of these radioisotopes is extremely useful in the detection and localization of pheochromocytomas. Further study results with these agents are eagerly awaited.

Histologic Findings:

can help in differentiation of benign and malignant tumors.

 

.1

Pict This higher power field emphasizes the variety of sizes and

shapes and nuclear pleomorphism of the cluster of cells that make up even a benign pheochromocytoma.

 

Differential diagnosis:

 hypertensive disease, symptomatic hypertension.

 

Treatment.

Surgical resection of the tumor is the treatment of choice and usually results in cure of the hypertension. Careful treatment with alpha- and beta-blockers is required preoperatively to control blood pressure and prevent intraoperative hypertensive crises.

·                Start alpha blockade with phenoxybenzamine 7-10 days preoperatively to allow for expansion of blood volume.

·                The patient should undergo volume expansion with isotonic sodium chloride solution. Encourage liberal salt intake.

·                Initiate a beta-blocker only after adequate alpha blockade. If beta blockade is started prematurely, unopposed alpha stimulation could precipitate a hypertensive crisis.

·                Administer the last doses of oral alpha- and beta-blockers on the morning of surgery.

Surgical Care

Both an experienced anesthesiologist and an experienced surgeon are crucial to the success of the operation. Surgical mortality rates are less than 2-3% with an experienced anesthesiologist and surgeon.

·                Administer stress-dose steroids if bilateral resection is planned.

 

·                An anterior midline abdominal approach was used in the past; however, in current practice, laparoscopic adrenalectomy is the preferred procedure for lesions smaller than 8 cm.

laparoscopic adren 

Pict. Laparoscopic adrenalectomy

 

If the pheochromocytoma is intra-adrenal, remove the entire adrenal gland. In the case of a malignant pheochromocytoma, resect as much of the tumor as possible.

 

Medical therapy is used for preoperative preparation prior to surgical resection, acute hypertensive crises, and primary therapy for patients with metastatic pheochromocytomas. Preoperative preparation requires combined alpha and beta blockade to control blood pressure and to prevent an intraoperative hypertensive crisis. Alpha-adrenergic blockade, in particular, is required to control blood pressure and prevent a hypertensive crisis. High circulating catecholamine levels stimulate alpha-receptors on blood vessels and cause vasoconstriction.

Phenoxybenzamine (Dibenzyline) is the preferred alpha-blocker in preparation for surgery. After effective alpha blockade, administer a beta-blocker. Beta-blockers are needed to control the tachycardia associated with high circulating catecholamine levels and alpha blockade. Beta-adrenergic blockers are used if significant tachycardia occurs after alpha blockade. Only administer beta-adrenergic blockers after adequate alpha blockade because unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis. Noncardioselective beta-blockers, such as propranolol (Inderal) or nadolol (Corgard), are often used; however, cardioselective agents, such as atenolol (Tenormin) and metoprolol (Lopressor), also may be used.

Labetalol (Trandate, Normodyne) is a noncardioselective beta-adrenergic blocker and selective alpha-adrenergic blocker that has been shown to be effective in controlling hypertension associated with pheochromocytoma. It has also been associated with paradoxic episodes of hypertension thought to be secondary to incomplete alpha blockade. Thus, its use in the preoperative treatment of patients with pheochromocytoma is controversial.

 

During surgery, intravenous phentolamine, a rapid-acting alpha-adrenergic antagonist, is used to control blood pressure. Rapid-acting intravenous beta-blockers, such as esmolol, are also used to normalize blood pressure. Selective alpha1-blocking agents, such as prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura), have more favorable adverse effect profiles and are used when long-term therapy is required (metastatic pheochromocytoma). These medications are not used to prepare patients for surgery because of their incomplete alpha blockade.

 

During crisis a combination of α- and β- adrenergic blocking agents (phentolamine (tropaphen) 2 – 4 mg every 5 – 10 min till stopping of the crisis, phenoxybenzamine 10 – 20 mg 3 – 4 times daily, propranolol 30 – 60 mg/day) and infusion of  sodium nitroprusside.

 

Primary aldosteronism

is a generic term for a group of disorders, in which excessive production of aldosterone by the zona glomerulosa of the adrenal cortex occurs independently of normal renin-angiotensin stimulation.

These primary disorders of the adrenal system are distinct from forms of secondary hyperaldosteronism due to excessive renin, such as renal artery stenosis.

The five clinical entities comprising primary aldosteronism includ:

         solitary aldosterone-producing adenoma (APA),

         bilateral hyperplasia of the zona glomerulosa (also known as idiopathic hyperaldosteronism [IHA]),

         primary adrenal hyperplasia (PAH),

         adrenal carcinoma, and

         glucocorticoid-remediable aldosteronism.

The most common manifestation of hyperaldosteronism is hypertension. It is estimated that 0.05-12% of the hypertensive population may have primary aldosteronism. Primary aldosteronism affects more women than men and occurs most commonly in the third through fifth decades of life.

Aldosterone normally acts at the renal distal convoluted tubule to stimulate reabsorption of sodium ions (Na+), as well as secretion of potassium (K+) and hydrogen ions (H+), and at the cortical and medullary collecting ducts to cause direct secretion of H+.

Excess secretion of aldosterone in primary aldosteronism results in hypertension, hypokalemia, and metabolic alkalosis; hypomagnesemia may occur.

Spontaneous hypokalemia (K < 3.5 mEq/L) occurs in 80% of cases of primary aldosteronism; the remaining patients develop hypokalemia within 3-5 days of initiation of liberal sodium intake (150 mEq/day).

Most symptoms are manifestations of hypokalemia: weakness, muscle cramping, paresthesias, headaches, palpitations, polyuria, and polydipsia. Hyperglycemia due to insulinopenia occurs in approximately 25% of patients.

Unfortunately, there is no single specific and sensitive screening test. One method of screening the hypertensive, hypokalemic patient is to obtain concomitant PA and PRA values. A PA/PRA ratio (PA ig/dL; PRA ig/mL/h) that exceeds 20 raises the possibility of primary aldosteronism. Most antihypertensive agents do not affect the PA/PRA ratio; spironolactone, however, must be discontinued for 6 weeks before screening. A 24-hour urine collection for aldosterone should also be collected. Because 12% of patients may have PA/PRA ratios lower than 20, review of the urinary aldosterone value is helpful. Urinary excretion of aldosterone (18-monogluconide) that exceeds 12 mg/day is also suggestive of primary aldosteronism.

It is important to differentiate APA from IHAAPA is amenable to surgical resection of the involved adrenal gland, whereas IHA is usually treated medicallyAPAs produce greater amounts of aldosterone and can be stimulated by ACTH.

Patients with APA, therefore, have greater PA levels at 8:00 AM, and these levels decrease over the ensuing 4 hours as normal secretion of ACTH diminishes. Patients with IHA, on the other hand, have somewhat lower levels of PA at 8:00 AM, and they experience an increase with upright ambulation. Finally, APAs produce large amounts of 18-OHB; levels > 100 ng/dL occur only in APA and PAH.

Computed tomography (CT) or magnetic resonance imaging (MRI). To a limited extent, both localizing procedures may aid in identifying the cause of primary aldosteronism. A large APA may be discernible on high-resolution CT, which at some institutions can identify adenomas as small as 5 mm. MRI at present performs, as well as CT, in identifying APA but involves higher cost and longer scan time. The diagnostic accuracy of MRI or CT in preoperatively localizing an APA is approximately 70-85%. Neither modality is able to differentiate IHA from a small APA. Adrenal carcinoma, a rare cause of excessive aldosterone, is easily identified with either modality.

Treatment

After the APA is localized, unilateral adrenalectomy is performed. Laparoscopic resection is now widely available and is preferable to the “standard” posterior approach. One year postoperatively, 70% of patients are normotensive. By the fifth postoperative year, only 53% remaiormotensive. Normal potassium balance tends to be permanent.

Pharmacologic therapy of IHAis quite effective.

1) The agent of choice is spironolactone (50-200 mg b.i.d.), a competitive inhibitor of aldosterone. Hypokalemia corrects dramatically, whereas hypertension responds after 4-8 weeks. Unfortunately, spironolactone also inhibits synthesis of testosterone and peripheral action of androgens, causing decreased libido, impotence, and gynecomastia in men. Eplerenone (50 mg b.i.d.) is a recently developed aldosterone antagonist without many of the side effects of spironolactone.

2) In patients intolerant of spironolactone, amiloride (5-15 mg b.i.d.) corrects hypokalemia within several days. A concomitant antihypertensive agent is usually necessary to reduce blood pressure. Success also has been reported in cases of IHA treated with calcium channel blockers (calcium is involved in the final common pathway for production of aldosterone) and angiotensin-converting enzyme (ACE) inhibitors (IHA appears to be sensitive to low concentrations of angiotensin II).

Management of a patient with PAH. During evaluation, these rare cases appear to be APA. Screening and confirmatory tests, seemingly indicate an APA. Levels of 18-OHB exceed 100 mg/dL. Localizing tests are consistent with APA, and patients usually undergo surgical resection of a nodular hyperplastic gland. The diagnosis is made retrospectively, but surgery is curative.

A patient with glucocorticoid-remediable aldosteronism have to be managed with low doses of dexamethasone (0.75 mg/day) or any of the agents used for therapy of IHA (see above) may be effective.

 

Congenital adrenal hyperplasia (CAH)

is a family of inherited disorders that result from a decrease in the activity of one of the various enzymes required for the biosynthesis of cortisol. These defects are inherited as autosomal recessive traits and are manifested during both prenatal and postnatal life.

Defects in any of the enzymes required for the synthesis of cortisol from cholesterol can lead to CAH, including steroidogenic acute regulatory (StAR) protein, which is essential in transporting cholesterol to the mitochondria; 3 β-hydroxysteroid dehydrogenase, which is responsible for cholesterol side-chain cleavage; and three hydroxylases, CYP 17 (17 α-hydroxylase), CYP21A2 (21-hydroxylase), and CYP11B1 (11 β-hydroxylase).

All of the enzyme defects leading to CAH are autosomal recessive disorders, that is, both copies of the involved gene must be abnormal for the condition to occur.

The process of adrenal hyperplasia begins in utero. Reduced production of cortisol in the fetus, due to decreased activity of one of the enzymes needed for cortisol synthesis, results in lowered levels of serum cortisol. Cortisol normally acts through a negative feedback loop to inhibit the secretion of ACTH by the pituitary gland and corticotropin-releasing hormone (CRH) by the hypothalamus. Thus, the low serum cortisol levels that occur in a person with CAH increase the secretion of ACTH and CRH in an attempt to stimulate the adrenal glands to overcome the enzyme block and to return the serum cortisol level to normal. As this process continues over time, the elevated levels of serum ACTH stimulate growth of the adrenal glands, leading to hyperplasia.

Adrenal crisis in the newborn period is the most serious consequence of CAH. It usually occurs with genetic defects that result in severe reductions in enzyme activity. It is especially insidious in genetic males who do not have ambiguous genitalia as a clue to the diagnosis. Overall, about two-thirds of patients with 21-hydroxylase deficiency have the salt-wasting form. These patients have decreased production of DOC and aldosterone, which results in hypotension, volume depletion, hyponatremia, hyperkalemia, and increased renin activity. The degree of residual activity of the defective enzyme varies greatly from one affected family to another, depending on the specific genetic alteration

Clinical consequences of CAH in females

Many of the precursors and metabolites that build up behind the blocked enzymes 21-hydroxylase, 11 β-hydroxylase, or 3β-hydroxysteroid dehydrogenase are androgens. They may cause the following:

·                Masculinization of the external genitalia of a genetic female fetus, leading to ambiguous genitalia at birth (female pseudohermaphroditism).

·                Behaviors more typical of boys during childhood in terms of toy preference, rough play, and aggressiveness. (However, most females are heterosexual and their sexual identity is invariably female.)

·                Rapid growth during early childhood with ultimate short stature as an adult due to early closure of epiphyses.

Children with nonclassic CAH (also called late-onset CAH) usually are asymptomatic and have normal external genitalia but later present with the following:

·                Premature puberty

·                Severe cystic acne

·                Hirsutism

·                Oligomenorrhea

·                Infertility

Newborn males with CAH due to deficiency of 21-hydroxylase or 11 β-hydroxylase do not have ambiguous genitalia. Due to typical normal physical appearance, it is often difficult to detect an affected male, especially when symptoms of salt-wasting occur after the first week of life. Later in childhood or early adulthood, males can present with the following:

·                Premature puberty

·                Advanced height in early childhood with ultimate short stature

·                Acne

·                Testicular enlargement due to adrenal rests

·                Infertility (rare)

How is the diagnosis of CAH confirmed?

Because one does not know which enzyme is deficient in a newborn with suspected CAH (unless the family has a documented history of a particular enzyme defect), serum levels of all steroids that may be in the affected biosynthetic pathway can be measured before and after the administration of 250 μg of ACTH. Urinary measurement of these steroids by gas chromatography/mass spectroscopy has recently become economically feasible. Plasma renin activity and aldosterone levels should also be measured to assess the adequacy of aldosterone synthesis. Determination of which steroid levels are supranormal and which are low facilitates localization of the exact enzyme block.

 

KEY POINTS: CAH

1.            CAH, the most common inherited disease, is a group of autosomal recessive disorders, the most frequent of which is 21-hydroxylase deficiency.

2.            The most serious consequences of CAH are ambiguous genitalia at birth, neonatal salt-wasting, short stature, and premature puberty.

3.            CAH is diagnosed through measurement of cortisol precursors before and 1 hour after the intravenous administration of 250 μg of synthetic ACTH.

4.            Predicted adult height can be achieved through early diagnosis, lower doses of corticosteroids in the first year of life, and the use of fludrocortisone even in those who are salt-wasters genetically but not clinically.

5.     CAH is a rare cause of ambiguous genitalia in a genetic male.

Treatment

The most important goal of treatment is to prevent salt loss and adrenal crisis in the newborn period. This goal requires the prompt administration of glucocorticoids and, in many cases, mineralocorticoids, as well as careful monitoring of salt intake. This treatment not only replaces the deficient hormones but also suppresses elevated serum ACTH levels, thereby reducing adrenal production of androgenic precursors and metabolites. Such treatment may be given presumptively while awaiting the results of definitive laboratory tests and then discontinued if the tests are not confirmatory.

Surgical correction of ambiguous genitalia, such as repair of labioscrotal fusion, usually is carried out at a later time. Single-stage surgery is now implemented between 2 and 6 months of life.

The preferred glucocorticoid for chronic replacement is hydrocortisone because of its short half-life, which minimizes growth suppression in children. It is sometimes extremely difficult or impossible to find a dosage of glucocorticoid that normalizes production of androgen without impairing growth. In such situations, mineralocorticoids (fludrocortisone) and/or spironolactone/flutamide (androgen receptor blockers that prevent virilization) in combination with the aromatase inhibitor testolactone (which prevents estrogen-induced epiphyseal fusion) may be useful adjunctive therapy in combination with nonsuppressive replacement doses of glucocorticoids. Rarely, adrenalectomy has been used for difficult-to-control patients since treatment of adrenal insufficiency is relatively much simpler.

In adolescents and adults: prednisone or dexamethasone may be used once growth has been completed.

 

Cushing’s syndrome

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids.

 

The source of cortisol excess can be:

         the adrenal gland (endogenous Cushing’s syndrome);

Pict. Adrenal adenoma

         administration of supraphysiologic doses of a glucocorticoid (exogenous Cushing’s syndrome).

 

Endogenous Cushing’s syndrome can be:

1)    ACTH – dependent, caused by:

         increased pituitary ACTH secretion (it has frequently been reffered to as Cushing’s disease, implying a partucular physiologic abnormality. Patients with Cushing’s disease may have a basophilic adenoma of the pituitary, or a chromophobe adenoma. In some cases, no histologic abnormality is found in the pituitary despite clear evidence of ACTH overproduction. Microadenomas, which are difficult to visualize radiographically, are often the cause);

. http://neurosurgery.ucla.edu/images/Pituitary%20Program/NonFunction_MRI.jpg 

Pict. Pituitary MRI – basophilic adenoma of the pituitary

 

         nonpituitary ACTH secretion by nonendocrine tumors;

2)    Non – ACTH – dependent:

         caused by cortisol secretion by benign or malignant adrenal tumors;

         micronodular or macronodular dysplasia of the adrenal (the condition occurs most commonly in children and young adults).

In pituitary-dependent Cushing’s syndrome, increased secretion of endogenous ACTH leads to bilateral adrenal hyperplasia and cortisol overproduction. ACTH secretion continues despite high circulating cortisol, indicating an ab­normality in the feedback mechanism. A good number of these patients harbor a pituitary microadenoma which secretes ACTH. Despite normal x-rays of the sella, including tomograms, the neurosurgeon often finds and removes the microadcnoma through the transsphenoidal route. Pituitaty – dependent adrenal hyperplasia accounts for about 60 to 70 percent of endogenous Cushing’s syndrome cases.

A polypeptide that resembles pituitary ACTH in its biologic and immunologic action can be secreted by a great variety of nonendocrine tumors, particularly oat cell carcinoma of the lung, but also by carcinoid bronchial adenomas, and by carcinomas of the prostate, ovaries, and pancreas, as well as others. Nonpituitary ACTH stimulates the adrenals to hypertrophy and to overproduce cortisol. Because the feedback mechanism is intact, pituitary ACTH secretion is suppressed by cortisol.

In patients with adrenal tumors, the excessive production of cortisol suppresses endogenous secretion of ACTH by the pituitary gland. An adrenal tumors is foud in 20 percent of the patients.

Exogenous, or iatrogenic, Cushing’s syndrome is caused by administration of supraphysiologic doses of glucocorticoids. Besides cortisol, other synthetic steroids with glucocorticoid activity have the ability to suppress ACTH secretion by the anterior pituitary. Adrenal atrophy and a decrease in cortisol secretion then result. Although the patients exibits the clinical manifestations of Cushing’s syndrome, adrenal insufficiency may actually occur if the steroid is discontinued abruptly. Because of the widespread use of glucocorticoids, iatrogenic Cushing’s syndrome is the most common type.

History:

·               Patients with Cushing syndrome may complain of weight gain, especially in the face, supraclavicular region, upper back, and torso.

·               Frequently, patients notice changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning.

·               Women may complain of irregular menses and hirsutism.

·               Because of progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms.

·               Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop.

·               New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur.

·               Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, polyuria and nocturia, visual problems, or galactorrhea.

·               If sufficient mass effect from the tumor is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, and hypogonadism may develop.

·               In addition, look for the following:

o               Irregular menses or amenorrhea in women and decreased libido, infertility, and impotence in men

o               Polyuria or polydipsia from diabetes mellitus or diabetes insipidus

o               Impaired wound healing or predisposition to infections from immunosuppression

·               When rapid onset of glucocorticoid excess occurs, virilization in women or feminization in men may be seen. This scenario suggests an adrenal carcinoma as the underlying cause of the Cushing syndrome.

 

Physical:

Кушинга

Obesity

o              Patients may have increased adipose tissue in the face (moon facies), upper back at the base of the neck (buffalo hump), and above the clavicles (supraclavicular fat pads).

109 

Pict.Moon face.

o              Central obesity  with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.

cushings syndrome 

Pict. Central obesity

Skin

o              Facial plethora may be present, especially over the cheeks.

105

 Pict. Facial plethora

o              Violaceous striae, usually more than 1 cm in width, is observed most commonly over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts .

 

Pict. Striae.

o              Ecchymoses may be present.

o              Patients may have telangiectasias and purpura.

o              Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident.

o              Hirsutism and male pattern balding may be present in women.

o              Patients may have increased lanugo facial hair.

o              Steroid acne, consisting of papular or pustular lesions over the face, chest, and back, may be present.

o              Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over the elbows, around the neck, and under the breasts.

Cardiovascular and renal

o              Hypertension may be present.

o              Volume expansion may occur, with edema from sodium and water retention.

o              Diabetes mellitus may be present.

Gastroenterologic

o              Peptic ulceration may occur with or without symptoms.

o              Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).

Endocrine

o              Hypothyroidism may occur from anterior pituitary tumors, which can interfere with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function.

o              Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.

o              Other pituitary function may be interrupted. Possibilities include polyuria and nocturia from diabetes insipidus.

o              Menstrual irregularities, amenorrhea, and infertility may occur due to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing hormone-releasing hormone (LHRH) pulse generation.

o              Low testosterone levels in men may lead to decreased testicular volume from inhibition of LHRH and LH/FSH function.

o              Low estrogen levels in women may result from inhibition of LHRH and LH/FSH function.

o              Increased synthesis of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides may occur.

o              With severe hypercortisolism, hypokalemic metabolic alkalosis may occur.

Skeletal/muscular

o              Proximal muscle weakness may be evident.

.50

Atrophy of muscles

o              Osteoporosis may lead to incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip also is possible from glucocorticoid excess.

Neuropsychological

o              Patients may experience emotional liability, fatigue, and depression.

o              Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasm.

o             

 

Adrenal crisis

o               Patients with cushingoid features may present to the emergency department in adrenal crisis. Adrenal crisis may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. It also may occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor.

o               Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium level or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.

o              

 

Diagnosis.

There are two phases of investigation:

         confirmation of the presence or absence of Cushing’s syndrome;

         differential diagnosis of its case.

1.     Exogenous Cushing’s syndrome should offer no problems in diagnosis since a history of chronic ingestion of suprapliysiologic doses of glucocorlicoids is usually present. However, occasionally patients deny, either deliberately or because of ignorance, that they have been taking the glucocorticoid. In this case, the diagnosis can easily be made by obtaining a blood sample at 8 a.m. for corlisol and ACTH, both of which are characteristically low. Glucocorlicoids suppress ACTH secretion, causing adrenal atrophy and decreased cortisol syn­thesis. Current radioimmunoassay techniques for measuring cortisol in plasma are very specific and do not detect appreciable quantities of any of the synthetic glucocorticoids (prednisone, prednisolone, dexamethasone, etc.) that the patient may be taking. Cortisol is unlikely to yield a significant plasma level as well since the steroid has a short half-life; it disappears from blood 4 to 8 h after oral administration. If a plasma ACTH assay is not available, a plasma cortisol determination is sufficient.

2.     Single-dose dexamethasone suppression test. This is the pre­ferred procedure for screening patients for Cushing’s syndrome. The patient ingests 1.0 mg of dexamethasone at bedtime (10 to 12 p.m.), and a blood sam­ple for plasma cortisol is obtained the following morning at 8 a.m. Iormal patients, the steroid suppresses plasma cortisol below 5 mkg/dl. whereas patients with Cushing’s syndrome do not respond and cortisol values of greater than 20 mkg/dl are not unusual. This procedure is simple, convenient, and inexpensive since it does not require hospitalization. It is also very reliable, being accurate in about 95 percent of the patients. A few patients with Cushing’s syndrome will respond to 1.0 mg of dexamethasone by suppression of plasma cortisol. If the clinical suspicion is strong, 0.5 mg of dcxamethasone should be given and cortisol determination should again be made. This procedure takes advantage of the fact that while normal subjects suppress equally well with 0.5 and 1.0 mg of dexathasone, the few patients with Cushing’s syndrome who suppress with 1.0 mg will not suppress with the lower dosage.

(There are a few clnical situations in which failure of dexamethasone suppression occurs in the absence of Cushing’s syndrome. Patients who are under acute stress, particularly those with fever and infections, and depressed individuals may not respond to dexamelhasone. Therapy with estrogen, and occasionally phenobarbital or phenothiazines may alter the response to dexamethasone. To some extent, all these drugs induce the hepatic microsomal enzymes that metabolize dexamethasone, and acceleration of the hepatic metabolism of the steroid results in insufficient plasma levels to yield a normal response. In these conditions, and in any others in which an abnormality in the metabolism of dexamethasone is suspected, simultaneous quantitation of the plasma dexamethasone concentration offers extremely useful information. Compared with individuals who exhibit no abnormalities in the metabolism of the steroid, individuals with altered hepatic metabolism have a much lower plasma concentration. Estrogens also increase the synthesis of corticusteroid-binding globulin (CBG) by the liver. Since plasma cortisol assays measure both bound and free cortisol, values are high in people on estrogen medication.)

3.     48 – hour low dose dexamethasone test. The results obtained with the single-dose dexamethasone suppression test are comparable to those of the first suppression test developed by Liddle. In this procedure, eight 0.5-mg doses of dexamethasone at 6-h intervals are given orally; 24-h urine samples for 17-hydroxycorticosteroids (17-OHCS) excretion are collected before and during dexamethasone administration. Iormal subjects, 17-OHCS values are below 3 mg per 24 h on the second dexamethasone day. Patients with Cushing’s syndrome fail to suppress. Not only is this test less convenient and more expensive but it may not be accurate if incomplete urine collections have been obtained.

4.     High-dose dexamethasone suppression test. After the oral administration of a single dose of 4.0 mg of dexamethasone between 10 p.m. and midnight, the measured 8 a.m. cortisole the following morning is less than 2 mkg/dl iormal individuals. Patients with pituitary-dependent Cushing’s syndrome demonstrate a plasma cortisol suppression of more than 50 % compared with the baseline values. Those wiyh adrenal tumors or nonpituitary ACTH-secreting tumors do not respond. (This procedure is comparable to the high-dose dexamethasone suppression test developed by Liddle(2.0 mg dexamethasone every 6 h for eight doses with three 24-h urine sample collections for 17-OHCS, one collection before and two during dexamethasone administration). The single-dose 4.0 mg dexamethasone suppression test is simpler, less expensive, and more convinient.

5.     radiologic diagnosis includes X-ray examination for a pituitary tumor, and computed tomography which is the most popular procedure for visualizing the adrenals in patients with Cushing’s syndrome.

 

Treatment.

surgery. If clinical manifestations are severe and definitive correction is immediately required, surgery will be the procedure of choice for most patients with Cushing’s syndrome. Pituitary surgery is the preferred therapeutic modality for pituilary-dependent Cushing’s syndrome. The transsphenoidal route is most commonly utilized, but transfruntal exploration may be required for large tumors or areas where there is extrasellar extension. There is general agreement that once the diagnosis of pituitary-dependent Cushing’s syndrome has been established the pituitary should be explored with or without radiologic evidence of a pituitary tumor. Operative morbidity of pituitary surgery is 2 to 5 %. Transphenoidal hypophysectomia is usually successfulwhen carried out by an experienced  neurosurgeon. While the majority of patients may be cured by this operation and normal pituitary function will remain intact, recurrences occur and may appear months or years after the operation.

Because a pituitary adenoma is not found in all cases, complete tumor removal is difficult, and recurrences arise following adenomectomy, partial or even total hypophysectomy has been recommended by some clinicians. With partial hypophyseclomy best results are obtained by removing the central mucoid zone which contains most of the ACTH-secreting cells. With total hypophysectomy, the problem of recurrences is resolved but hypopituitarism develops, necessitating permanent hormone-replacement therapy. Therefore, indiscriminate use of total hypophysectomy is not justified. Adrenalectomy is the treatment of choice in patients with adrenal tumors. Since the lesion is unilateral in most cases, only one adrenal is removed. Therapy with glucocorticoids, is required for as long as a year because of chronic suppression of ACTH secretion and atrophy of the contralaleral adrenal.

Bilateral adrenalectomy is utilized to treat patients with primary adrenocortical nodular dysplasia. although a few patients with this condition have responded to hypophyseclomy. Bilateral adrenalectomy is a difficult procedure, with an operative mortality of 4 to 10 percent of patients. There is a recurrence of the disease as the result of hyperplastic remnant in 10 percent of patients, and development of hyperpigmentation with rapid growth of pituitary tumors in 10 to 20 percent.

In patients with nonpituitary tumors that are secreting ACTH, surgery or chemotherapy my be helpful. In patients with severe hypercortisolism that is not controlled by surgery or drugs, bilateral adrenalectomy may be necessary . The changes produced by Cushing’s disease are partially reversible (after several months).

cush before - afterl 

Pict. Female before and after adrenalectomy

 

pituitary irradiation. If clinical manifestations are not severe, pituitary irradiation may be tried initially. Pituitary irradiation is delivered by means of conventional cobalt radiotherapy (4500 rads), by proton-beam irradiation, or by pituitary implantation of radioactive material. Conventional cobalt radiotherapy has a cure rate in 46 to 83 percent of patients. Two-thirds of these patients experience a complete resolution of the signs and symptoms, and the others man­ifest some degree of improvement. The response is better in younger individuals. Improvement, however, is slow and may take 6 to 18 months. Radiation effects continue for many years, and the incidence of hypopituitarism is 80 percent at 20 years. If there is no response to pituitary irradiation after 6 month, adrenalectomy is indicated.

drugs. Several drugs have been used to treat patients with Cushing’s syn­drome. Improvement of the clinical manifestations is the result of a decrease in ACTH secretion by the pituitary gland or cortisol secretion by the adrenals.

Cyproheptadine (Periactin) and peritol have been helpful in some patients with pituitary-dependent Cushing’s syndrome. Cyproheptadine has peripheral and central antiserotonergic, antihistaminergic, anticholinergic, and antidopaminergic actions, but the inhibition on ACTH secretion is the result off its antiserotonin effect on the hypothalamus. The drug is administered orally at an initial dose of 4 mg three times a day, which is increased to a maximum dose of 4 mg every 4 h over 2 to 4 weeks. Clinical and biochemical responses occur within 2 to 3 months after initiation of therapy, and the return of dexamethasone suppressibility and ACTH and cortisol periodicity are observed by 6 to 12 months. Remission of the disease occurs in 30 to 50 percent of the patients and the longest duration of remission has been 5 years. Although a few cases of permanent remission after discontinuation of the drug have been reported, relapse is the rule. Cyproheptadine can be used in combination with pituitary irradiation. The drug is given for 4 to 6 months to control symptoms before the effects of irradiation are manifested. The two major side effects are hyperphagia (with weight gain) and somnolence. The dopamine agonist bromocrip­tine is very useful. The usual dose is 2.5 mg three times a day. But the therapy has to be began from the ¼ of a tablet (2.5 mg) at a bedtime for 3 to 4 days (because of its side effect such as somnelence), then it has to be increased on ¼ of a tablet each 3 days to 7.5 mg.

Several adrenal cortisol inhibitors are available to treat patients with Cushing’s syndrome, particularly those with adrenal carcinomas or nonpi-tuitary ACTH-secreting tumors. Mitotane, Lysodren inhibit adrenal growth and interferes with cortisol synthesis by blocking the conversion of cholesterol into pregnenolone. The dose is 1 to 10 g/day. Side effects in­clude gastrointestinal complaints, sedation, depression, and adrenal insufficiency. Because of its inhibitory effect on adrenal growth, the drug is preferred for the treatment of adrenal cancer. Aminoglutethimide (Cytadren, Elipten) inhibits the conversion of cholesterol into pregnenolone as well, but it does not have any effect on adrenal growth. The usual dose is 250 to 500 mg four times a day. Side effects are gastrointestinal complaints, drowsiness, skin rash, goiter, and adrenal insufficiency. Metyrapone (Metopirone) inhibits the last step in cortisol synthe­sis – the conversion of 11-deoxycortisol into cortisol. Effective doses range from1 to 4 g/day. Better results are obtained when metyrapone is administered every 2 h rather than every 4 h. Hirsutism is the most frequent problem with prolonged metyrapone usage. Trilostane, at a dosage of 0.25 to 1.0 g/day, can reduce corti­sol synthesis effectively. A combination of two drugs, such as aminoglutethimide and metyrapone, usually is more effective than any drug alone. Problems shared by all of these drugs are (1) the fact that their effects cease as the result of both a compensatory increase in ACTH secretion and of stimulation of partially suppressed adrenals and (2) the development of adrenal insufficiency. These prob­lems can be minimized by administering physiologic amounts of a glucocorticoid, such as 0.5 mg/day of dexamethasone. If hypotension and electrolyte problems develop, 0.1 mg/day of the mineralocorticoid 9-alfa-fluorohydrocortisone (Florinef) should be given.

 

 

References.

А. Main

1.            Davidson’s Principles and Practice of Medicine (1st Edition) / Edited by  N. R. Colledge, B. R. Walker,   S. H. Ralston. – Philadelphia : Churchill Livingstone, 2010. – 1376 p.

2.            Harrison’s Principles of Internal Medicine (18th edition) / D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J. Loscalzo,. New York : McGraw-Hill Education – Europe, 2011. – 4012 p.

3.            Kumar and Clark’s Clinical Medicine (8th Revised edition) (With studenrconsult Online Access) / Edited by P. Kumar, M. L. Clark . London : Elsevier Health Sciences, 2012. – 1304 p.

 

B. Additional

1. Greenspan’s Basic and Clinical Endocrinology ( 9th Revised edition) / David G. Gardner, Dolores M. Shoback. – New York : McGraw-Hill Education – Europe, 2011. –  880 p.

2. Oxford Handbook of Endocrinology and Diabetes ( 2nd Revised edition) / John A. H. Wass, Helen Turner. – Oxford : Oxford University Press, 2009.  – 952 p.

3. Williams Textbook of Endocrinology (12th Revised edition) / Shlomo Melmed, Kenneth S. Polonsky, P. Reed Larsen, Henry M. Kronenberg, 2011. – 1897 p.

4. Harrison‘s Endocrinology (2nd edition) / J.Larry Jameson. – New York : McGraw-Hill Education – Europe, 2010. – 560 p.

5. Oxford Textbook of Endocrinology and Diabetes (2nd Revised edition) / Edited by John A. H. Wass, Paul Stewart, Stephanie A. Amiel, Melanie J. Davies. – Oxford : Oxford University Press, 2011. – 2160 p.

6. Web-sites:

http://emedicine.medscape.com/endocrinology

 

 

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