Theme :
Functional and organic diseases of hepatobiliary system in children. Etiology, pathogenesis, clinical features, diagnostics, treatment and prophylaxis.
Liver disease can often be life threatening and difficult to recognize. The clinical presentation varies depending on the etiology and severity of the liver insult. Knowledge of the varied manifestations, a high index of suspicion, and use of clinical diagnostic skills are the 1st steps in identifying pediatric liver disease.
Topographic anatomy of the digestive system
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Topographic anatomy of the liver
PATHOLOGIC MANIFESTATIONS
Alterations in hepatic structure and function can be acute or chronic, with varying patterns of reaction of the liver to cell injury. Hepatocyte injury can result in inflammatory cell infiltration or cell death (necrosis), which may be followed by a healing process of scar formation (fibrosis) and, potentially, nodule formation (regeneration). Cirrhosis is the end result of any progressive liver disease.
Injury to individual hepatocytes can result from viral infection, drugs or toxins, hypoxia, immunologic disorders, or inborn errors of metabolism. The evolving process leads to repair, continuing injury with chronic changes, or, in rare cases, to massive hepatic damage.
Cholestasis is an alternative or concomitant response to injury caused by extrahepatic or intrahepatic obstruction to bile flow. Accumulation in serum of substances normally excreted in bile, such as conjugated bilirubin, cholesterol, bile acids, and trace elements, occurs. Bile pigment accumulation in liver parenchyma can be seen in liver biopsy. In extrahepatic obstruction, bile pigment may be visible in the intralobular bile ducts or throughout the parenchyma as bile lakes or infarcts. In intrahepatic cholestasis, an injury to hepatocytes or an alteration in hepatic physiology leads to a reduction in the rate of secretion of solute and water. Likely causes include alterations in: enzymatic or canalicular transporter activity, permeability of the bile canalicular apparatus, organelles responsible for bile secretion, or ultrastructure of the cytoskeleton of the hepatocyte. The end result can be clinically indistinguishable from obstructive cholestasis.
Cirrhosis, defined histologically by the presence of bands of fibrous tissue that link central and portal areas and form parenchymal nodules, is a potential end stage of any acute or chronic liver disease. Cirrhosis can be posthepatitic (after acute or chronic hepatitis) or postnecrotic (after toxic injury), or it can follow chronic biliary obstruction (biliary cirrhosis). Cirrhosis can be macronodular, with nodules of various sizes (up to
Primary tumors of the liver are discussed in Chapter 504 . The liver can be secondarily involved ieoplastic (metastatic) and non-neoplastic (storage diseases, fat infiltration) processes as well as a number of systemic conditions and infectious processes. The liver can also be affected by chronic passive congestion or acute hypoxia, with hepatocellular damage.
CLINICAL MANIFESTATIONS
HEPATOMEGALY.
Enlargement of the liver can be due to several mechanisms ( Table 1 ). Normal liver size estimations are based on age-related clinical indices, such as: the degree of extension of the liver edge below the costal margin; the span of dullness to percussion; or the length of the vertical axis of the liver, as estimated from imaging techniques. In children, the normal liver edge can be felt up to
TABLE 1 — Mechanisms of Hepatomegaly
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INCREASE IN THE NUMBER OR SIZE OF THE CELLS INTRINSIC TO THE LIVER |
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Storage |
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Fat:malnutrition, obesity, metabolic liver disease (diseases of fatty acid oxidation and Reye syndrome–like illnesses), lipid infusion (total parenteral nutrition), cystic fibrosis, diabetes mellitus, medication related, pregnancy |
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Specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman disease |
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Glycogen:glycogen storage diseases (multiple enzyme defects); total parenteral nutrition; infant of diabetic mother, Beckwith syndrome |
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Miscellaneous: α1-antitrypsin dificiency, |
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Inflammation |
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Hepatocyte enlargement (hepatitis) |
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Viral:acute and chronic |
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Bacterial:sepsis, abscess, cholangitis |
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Toxic:drugs |
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Autoimmune |
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Kupffer cell enlargement |
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Sarcoidosis |
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Systemic lupus erythematosus |
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Mast cell activating syndrome |
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INFILTRATION OF CELLS |
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Primary Liver Tumors |
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Benign |
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Hepatocellular |
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Focal nodular hyperplasia |
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Nodular regenerative hyperplasia |
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Hepatocellular adenoma |
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Mesodermal |
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Infantile hemangioendothelioma |
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Mesenchymal hamartoma |
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Cystic masses |
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Choledochal cyst |
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Hepatic cyst |
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Hematoma |
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Parasitic cyst |
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Pyogenic or amebic abscess |
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Malignant |
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Hepatocellular |
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Hepatoblastoma |
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Hepatocellular carcinoma |
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Mesodermal |
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Angiosarcoma |
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Undifferentiated embryonal sarcoma |
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Secondary or metastatic processes |
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Lymphoma |
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Leukemia |
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Histiocytosis |
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Neuroblastoma |
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Wilms tumor |
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INCREASED SIZE OF VASCULAR SPACE |
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Intrahepatic obstruction to hepatic vein outflow |
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Veno-occlusive disease |
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Hepatic vein thrombosis (Budd-Chiari syndrome) |
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Hepatic vein web |
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Suprahepatic |
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Congestive heart failure |
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Pericardial disease |
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Tamponade |
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Constrictive pericarditis |
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Hematopoietic:sickle cell anemia, thalassemia |
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INCREASED SIZE OF BILIARY SPACE |
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IDIOPATHIC (? “BENIGN”) |
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The liver span increases linearly with body weight and age in both sexes, ranging from ≈4.5–5.0 cm at 1 wk of age to ≈7–8 cm in boys and 6.0–6.5 cm in girls by 12 yr of age. The lower edge of the right lobe of the liver extends downward (Riedel lobe) and is palpable as a broad mass in some normal people. An enlarged left lobe of the liver is palpable in the epigastrium of some patients with cirrhosis. Downward displacement of the liver by the diaphragm (hyperinflation) or thoracic organs can create an erroneous impression of hepatomegaly.
Examination of the liver should note the consistency, contour, tenderness, or the presence of any masses or bruits, as well as assessment of spleen size. Documentation of the presence of ascites and any stigmata of chronic liver disease is important.
Ultrasonography is useful in assessment of liver size and consistency, as well as gallbladder size. Hyperechogenic hepatic parenchyma can be seen with metabolic disease (glycogen storage disease) or fatty liver (obesity, malnutrition, hyperalimentation, corticosteroids).
Gallbladder length normally varies from 1.5–5.5 cm (average, 3.0) in infants to 4–8 cm in adolescents; width ranges from 0.5 to
JAUNDICE (ICTERUS).
Yellow discoloration of the sclera, skin, and mucous membranes is a sign of hyperbilirubinemia (see Chapter 102.3 ). Clinically apparent jaundice in children and adults occurs when the serum concentration of bilirubin reaches 2–3 mg/dL (34–51 μmol/L); the neonate may not appear icteric until the bilirubin level is >5 mg/dL (85 μmol/L). Jaundice may be the earliest and only sign of hepatic dysfunction. Liver disease must be suspected in the infant who appears only mildly jaundiced but has dark urine or acholic (light-colored) stools. Immediate evaluation to establish the cause is required.
Measurement of the total serum bilirubin concentration allows quantitation of jaundice. Bilirubin occurs in plasma in four forms: unconjugated bilirubin tightly bound to albumin; free or unbound bilirubin (the form responsible for kernicterus, because it can cross cell membranes); conjugated bilirubin (the only fraction to appear in urine); and δ fraction (bilirubin covalently bound to albumin), which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease. The δ fraction permits conjugated bilirubin to persist in the circulation and delays resolution of jaundice. Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and δ bilirubin. An elevation of serum bile acids is frequently seen in the presence of any form of cholestasis.
Investigation of jaundice in an infant or older child must include determination of the accumulation of both unconjugated and conjugated bilirubin. Unconjugated hyperbilirubinemia may indicate increased production, hemolysis, reduced hepatic removal, or altered metabolism of bilirubin ( Table 2 ). Conjugated hyperbilirubinemia reflects decreased excretion by damaged hepatic parenchymal cells or disease of the biliary tract, which may be due to obstruction, sepsis, toxins, inflammation, and genetic or metabolic disease ( Table3 ).
TABLE 2 — Differential Diagnosis of Unconjugated Hyperbilirubinemia
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INCREASED PRODUCTION OF UNCONJUGATED BILIRUBIN FROM HEME |
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Hemolytic disease (hereditary or acquired) |
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Isoimmune hemolysis (neonatal;acute or delayed transfusion reaction; autoimmune) |
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Rh incompatibility |
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ABO incompatibility |
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Other blood group incompatibilities |
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Congenital spherocytosis |
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Hereditary elliptocytosis |
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Infantile pyknocytosis |
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Erythrocyte enzyme defects |
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Hemoglobinopathy |
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Sickle cell anemia |
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Thalassemia |
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Others |
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Sepsis |
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Microangiopathy |
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Hemolytic-uremic syndrome |
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Hemangioma |
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Mechanical trauma (heart valve) |
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Ineffective erythropoiesis |
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Drugs |
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Infection |
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Enclosed hematoma |
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Polycythemia |
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Diabetic mother |
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Fetal transfusion (recipient) |
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Delayed cord clamping |
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DECREASED DELIVERY OF UNCONJUGATED BILIRUBIN (IN PLASMA) TO HEPATOCYTE |
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DECREASED BILIRUBIN UPTAKE ACROSS HEPATOCYTE MEMBRANE |
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Presumed enzyme transporter deficiency |
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Competitive inhibition |
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Breast milk jaundice |
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Lucey-Driscoll syndrome |
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Drug inhibition (radiocontrast material) |
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Miscellaneous |
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Hypothyroidism |
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Hypoxia |
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Acidosis |
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DECREASED STORAGE OF UNCONJUGATED BILIRUBIN IN CYTOSOL (DECREASED Y AND Z |
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PROTEINS) |
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DECREASED BIOTRANSFORMATION (CONJUGATION) |
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Neonatal jaundice (physiologic) |
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Inhibition (drugs) |
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Hereditary (Crigler-Najjar) |
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Type I (complete enzyme deficiency) |
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Type II (partial deficiency) |
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Gilbert disease |
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Hepatocellular dysfunction |
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ENTEROHEPATIC RECIRCULATION |
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Breast milk jaundice |
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Intestinal obstruction |
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Ileal atresia |
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Hirschsprung disease |
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Cystic fibrosis |
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Pyloric stenosis |
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Antibiotic administration |
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TABLE 352-3 — Differential Diagnosis of Neonatal and Infantile Cholestasis
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INFECTIOUS |
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Generalized bacterial sepsis |
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Viral hepatitis |
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Hepatitis A, B, C (rare) |
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Cytomegalovirus |
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Rubella virus |
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Herpes virus: HSV, HHV 6 and 7 |
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Varicella virus |
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Coxsackievirus |
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Echovirus |
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Reovirus type 3 |
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Parvovirus B19 |
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HIV |
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Others |
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Toxoplasmosis |
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Syphilis |
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Tuberculosis |
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Listeriosis |
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TOXIC |
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METABOLIC |
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Disorders of amino acid metabolism |
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Tyrosinemia |
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Disorders of lipid metabolism |
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Wolman disease |
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Niemann-Pick disease (type C) |
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Gaucher disease |
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Disorders of carbohydrate metabolism |
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Galactosemia |
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Fructosemia |
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Glycogenosis IV |
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Disorders of bile acid biosynthesis |
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Other metabolic defects |
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α1-Antitrypsin deficiency |
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Cystic fibrosis |
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Idiopathic hypopituitarism |
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Hypothyroidism |
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Zellweger (cerebrohepatorenal) syndrome |
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Neonatal iron storage disease |
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Indian childhood cirrhosis/infantile copper overload |
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Congenital disorders of glycosylation |
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Mitochrondrial hepatopathies |
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Citrin deficiency |
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GENETIC/CHROMOSOMAL |
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INTRAHEPATIC CHOLESTASIS SYNDROME |
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EXTRAHEPATIC DISEASES |
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MISCELLANEOUS |
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PRURITUS.
Intense generalized itching, often with skin excoriation, can occur in patients with cholestasis (conjugated hyperbilirubinemia). Pruritus is unrelated to the degree of hyperbilirubinemia; deeply jaundiced patients can be asymptomatic. Although retained components of bile are likely important, the cause is probably multifactorial, as evidenced by the symptomatic relief of pruritus after administration of various therapeutic agents including bile acid–binding agents (cholestyramine), choleretic agents (ursodeoxycholic acid), opiate antagonists, antihistamines, and antibiotics (rifampin). Surgical diversion of bile (partial external biliary diversion) has provided relief for medically refractory pruritus.
SPIDER ANGIOMAS.
Vascular spiders (telangiectasias), characterized by central pulsating arterioles from which small, wiry venules radiate, may be seen in patients with chronic liver disease; these are usually most prominent on the face and chest. They are presumably reflective of altered estrogen metabolism in the presence of hepatic dysfunction.
PALMAR ERYTHEMA.
Blotchy erythema, most noticeable over the thenar and hypothenar eminences and on the tips of the fingers, is also noted in patients with chronic liver disease. This may be due to vasodilation and increased blood flow.
XANTHOMAS.
The marked elevation of serum cholesterol levels (to >500 mg/dL) associated with chronic cholestasis can cause the deposition of lipid in the dermis and subcutaneous tissue. Browodules may develop, 1st over the extensor surfaces of the extremities; rarely, xanthelasma of the eyelids develops.
PORTAL HYPERTENSION.
The portal vein drains the splanchnic area (abdominal portion of the gastrointestinal tract, pancreas, and spleen) into the hepatic sinusoids. Normal portal pressure gradient, the pressure difference between the portal vein and the systemic veins (hepatic veins or inferior vena cava), is 3–6 mm Hg. Clinically significant portal hypertension exists when pressure exceeds a threshold of
ASCITES.
The onset of ascites in the child with chronic liver disease means that the two prerequisite conditions for ascites are present: portal hypertension and hepatic insufficiency. Ascites can also be associated with nephrotic syndrome and other urinary tract abnormalities, metabolic diseases (such as lysosomal storage diseases), congenital or acquired heart disease, and hydrops fetalis. Factors favoring the intra-abdominal accumulation of fluid include: decreased plasma colloid osmotic pressure, increased capillary hydrostatic pressure, increased ascitic colloid osmotic fluid pressure, and decreased ascitic fluid hydrostatic pressure. Abnormal renal sodium retention must be considered.
VARICEAL HEMORRHAGE.
Gastroesophageal varices are the more clinically significant portosystemic collaterals because of their propensity to rupture and cause life-threatening hemorrhage. Variceal hemorrhage results from increased pressure within the varix, which leads to changes in the diameter of the varix and increased wall tension. When the variceal wall strength is exceeded, physical rupture of the varix results. Given the high blood flow and pressure in the portosystemic collateral system, coupled with the lack of a natural mechanism to tamponade variceal bleeding, the rate of hemorrhage can be striking.
ENCEPHALOPATHY.
Hepatic encephalopathy can involve any neurologic function, and it can be prominent or present in subtle forms such as deterioration of school performance, depression, or emotional outbursts. It can be recurrent and precipitated by intercurrent illness, drugs, bleeding, or electrolyte and acid-base disturbances. The appearance of hepatic encephalopathy depends on the presence of portosystemic shunting, alterations in the blood-brain barrier, and the interactions of toxic metabolites with the central nervous system. Postulated causes include altered ammonia metabolism, synergistic neurotoxins, or false neurotransmitters with plasma amino acid imbalance.
ENDOCRINE ABNORMALITIES.
Endocrine abnormalities are more common in adults with hepatic disease than in children. They reflect alterations in hepatic synthetic, storage, and metabolic functions, including those concerned with hormonal metabolism in the liver. Proteins that bind hormones in plasma are synthesized in the liver, and steroid hormones are conjugated in the liver and excreted in the urine; failure of such functions can have clinical consequences. Endocrine abnormalities can also result from malnutrition or specific deficiencies.
RENAL DYSFUNCTION.
Systemic disease or toxins can affect the liver and kidneys simultaneously, or parenchymal liver disease can produce secondary impairment of renal function. In hepatobiliary disorders, there may be renal alterations in sodium and water economy, impaired renal concentrating ability, and alterations in potassium metabolism. Ascites in patients with cirrhosis may be related to inappropriate retention of sodium by the kidneys and expansion of plasma volume, or to sodium retention mediated by diminished effective plasma volume. Hepatorenal syndrome (HRS) is defined as functional renal failure in patients with end-stage liver disease. The pathophysiology of HRS is poorly defined, but the hallmark is intense renal vasoconstriction (mediated by hemodynamic, humoral, or neurogenic mechanisms) with coexistent systemic vasodilation. The diagnosis is supported by the findings of oliguria (<1 mL/kg/day), a characteristic pattern of urine electrolyte abnormalities (urine sodium of <10 mEq/L, fractional excretion of sodium of <1%, urine : plasma creatinine ratio <10, and normal urinary sediment), absence of hypovolemia, and exclusion of other kidney pathology. The best treatment of HRS is timely liver transplantation, as complete renal recovery can be expected.
PULMONARY INVOLVEMENT.
Hepatopulmonary syndrome is characterized by the typical triad of hypoxemia, intrapulmonary vascular dilations, and liver disease. There is intrapulmonic right-to-left shunting of blood, which results in systemic desaturation. It should be suspected and investigated in the child with chronic liver disease with history of shortness of breath or exercise intolerance and clinical examination findings of cyanosis (particularly of the lips and fingers), digital clubbing, and oxygen saturations <96%, particularly in the upright position. Treatment is timely liver transplantation; successful pulmonary resolution follows.
RECURRENT CHOLANGITIS.
Ascending infection of the biliary system is often seen in pediatric cholestatic disease, due most commonly to gram-negative enteric organisms, such as Escherichia coli, Klebsiella, Pseudomonas, and Enterococcus. Liver transplantation is the definitive effective treatment for recurrent cholangitis in the child with chronic cholestatic liver disease, especially when medical therapy is not effective.
MISCELLANEOUS MANIFESTATIONS OF LIVER DYSFUNCTION.
Nonspecific signs of acute and chronic liver disease include: anorexia, which often affects patients with anicteric hepatitis and with cirrhosis associated with chronic cholestasis; abdominal pain or distention resulting from ascites, spontaneous peritonitis, or visceromegaly; malnutrition and growth failure; and bleeding, which may be due to altered synthesis of coagulation factors (biliary obstruction with vitamin K deficiency or excessive hepatic damage) or to portal hypertension with hypersplenism. In the presence of hypersplenism, there can be decreased synthesis of specific clotting factors, production of qualitatively abnormal proteins, or alterations in platelet number and function. Altered drug metabolism may prolong the biologic half-life of commonly administered medication.
Evaluation of Patients with Possible Liver Dysfunction
Adequate evaluation of an infant, child, or adolescent with suspected liver disease involves an appropriate and accurate history, a carefully performed physical examination, and skillful interpretation of signs and symptoms. Further evaluation is aided by judicious selection of diagnostic tests, followed by the use of imaging modalities or a liver biopsy. Most of the so-called liver function tests do not measure specific hepatic functions: a rise in serum aminotransferase levels reflects liver cell injury, an increase in immunoglobulin levels reflects an immunologic response to injury, or an elevation in serum bilirubin levels can reflect any of several disturbances of bilirubin metabolism (see Table 352-2 and Table 352-3 ). Any single biochemical assay provides limited information, which must be placed in the context of the entire clinical picture. The most cost-efficient approach is to become familiar with the rationale, implications, and limitations of a selected group of tests so that specific questions can be answered. Young infants with cholestatic jaundice should be evaluated promptly to identify those patients needing surgical intervention.
For a patient with suspected liver disease, evaluation addresses the following issues in sequence: Is liver disease present? If so, what is its nature? What is its severity? Is specific treatment available? How can we monitor the response to treatment? and What is the prognosis?
BIOCHEMICAL TESTS.
Laboratory tests commonly used to screen for or to confirm a suspicion of liver disease include measurements of serum aminotransferase, bilirubin (total and fractionated), and alkaline phosphatase (AP) levels, as well as determinations of prothrombin time (PT) or international normalized ratio (INR) and albumin level. These tests are complementary, provide an estimation of synthetic and excretory functions, and may suggest the nature of the disturbance (inflammation or cholestasis).
Acute liver cell injury (parenchymal disease) in viral hepatitis, drug- or toxin-induced liver disease, shock, hypoxemia, or metabolic disease is best reflected by marked increases in serum aminotransferase levels. Cholestasis (obstructive disease) involves regurgitation of bile components into serum; the serum levels of total and conjugated bilirubin and serum bile acids are elevated. Elevations in serum AP, 5′ nucleotidase (5′NT), and γ-glutamyl transpeptidase (GGT) levels are also sensitive indicators of obstruction or inflammation of the biliary tract.
The severity of the liver disease may be reflected in clinical signs (the occurrence of encephalopathy, variceal hemorrhage, worsening jaundice, apparent shrinkage of liver mass owing to massive necrosis, or onset of ascites) or in biochemical alterations (hypoglycemia, hyperammonemia, electrolyte imbalance, continued hyperbilirubinemia, marked hypoalbuminemia, or a prolonged PT or INR that is unresponsive to parenteral administration of vitamin K).
Fractionation of the total serum bilirubin level into conjugated and unconjugated bilirubin fractions helps to distinguish between elevations caused by hemolysis and those caused by hepatic dysfunction. A predominant elevation in the conjugated bilirubin level provides a relatively sensitive index of hepatocellular disease or hepatic excretory dysfunction, whereas elevation in aminotransferase levels are more highly sensitive indices of hepatocellular damage.
Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase) is liver specific, whereas aspartate aminotransferase (AST, serum glutamic-oxaloacetic transaminase) is derived from other organs in addition to the liver. The most marked rises of both AST and ALT levels may occur with acute hepatocellular injury; a several thousand–fold elevation can result from acute viral hepatitis, toxic injury, hypoxia, or hypoperfusion. After blunt abdominal trauma, parallel elevations in aminotransferase levels may provide an early clue to hepatic injury. A differential rise or fall in AST and ALT levels can sometimes provide useful information. In acute hepatitis, the rise in ALT may be greater than the rise in AST. In alcohol-induced liver injury, fulminant echovirus infection, and various metabolic diseases, more predominant rises in the AST level are reported. In chronic liver disease or in intrahepatic and extrahepatic biliary obstruction, AST and ALT elevations may be less marked. Nonalcoholic steatohepatitis (NASH) and other forms of nonalcoholic fatty liver disease are chronic liver disorders seen in obese children presenting with elevated serum aminotransferase levels. The notable characteristic is the similar histology to alcoholic-induced liver injury in the absence of alcohol abuse.
Hepatic synthetic function is reflected in serum albumin and protein levels and in the PT or INR. Examination of serum globulin concentration and of the relative amounts of the globulin fractions may be helpful. Patients with autoimmune hepatitis often have high gamma-globulin levels and increased titers of anti–smooth muscle, antinuclear, and anti–liver-kidney-microsome antibodies. Antimitochondrial antibodies may also be found in patients with autoimmune hepatitis. A resurgence in α-fetoprotein levels may suggest hepatoma, hepatoblastoma, or hereditary tyrosinemia. Hypoalbuminemia caused by depressed synthesis can complicate severe liver disease and serve as a prognostic factor. Deficiencies of factor V and of the vitamin K–dependent factors (II, VII, IX, and X) can occur in patients with severe liver disease or fulminant hepatic failure. If the PT or INR is prolonged as a result of intestinal malabsorption of vitamin K (resulting from cholestasis) or decreased nutritional intake of vitamin K, then parenteral administration of vitamin K should correct the coagulopathy, leading to normalization within 12–24 hr. Unresponsiveness to vitamin K suggests severe hepatic disease. Persistently low levels of factor VII are evidence of a poor prognosis in fulminant liver disease.
Interpretation of results of biochemical tests of hepatic structure and function must be made in the context of age-related changes. The activity of AP varies considerably with age. Normal growing children have significant elevations of serum AP activity originating from influx into serum of the isoenzyme that originates in bone, particularly in rapidly growing adolescents. Therefore, an isolated increase in AP does not indicate hepatic or biliary disease if other liver function test results are normal. Other enzymes such as 5′NT and GGT are increased in cholestatic conditions, and may be more specific for hepatobiliary disease. 5′NT is not found in bone. GGT exhibits high enzyme activity in early life that declines rapidly with age. Cholesterol concentrations increase throughout life. Cholesterol levels may be markedly elevated in patients with intra- or extrahepatic cholestasis and decreased in severe acute liver disease such as hepatitis.
Interpretation of serum ammonia values must be carried out with caution because of variability in their physiologic determinants and the inherent difficulty in laboratory measurement.
LIVER BIOPSY.
Liver biopsy combined with clinical data can suggest a cause in most cases. Specimens of liver tissue can be used: to provide a precise histologic diagnosis in patients with neonatal cholestasis, chronic active hepatitis, metabolic liver disease, suspected Reye syndrome, intrahepatic cholestasis (paucity of bile ducts), congenital hepatic fibrosis, or undefined portal hypertension; for enzyme analysis to detect inborn errors of metabolism; and for analysis of stored material such as iron, copper, or specific metabolites. Liver biopsies can monitor responses to therapy or detect complications of treatment with potentially hepatotoxic agents, such as aspirin, anti-infectives (erythromycin, minocycline, ketoconazole, isoniazid), antimetabolites, antineoplastics, or anticonvulsant agents.
In infants and children, needle biopsy of the liver is easily accomplished percutaneously. The amount of tissue obtained, even in small infants, is usually sufficient for histologic interpretation and for biochemical analyses, if the latter are deemed necessary. Percutaneous liver biopsy can be performed safely in infants as young as 1 wk of age. Patients usually require only conscious sedation and local anesthesia. Contraindications to the percutaneous approach include prolonged PT or INR; thrombocytopenia; suspicion of a vascular, cystic, or infectious lesion in the path of the needle; and severe ascites. If administration of fresh frozen plasma or of platelet transfusions fails to correct a prolonged PT, INR, or thrombocytopenia, a tissue specimen can be obtained via alternative techniques. Considerations include either the open laparotomy (wedge) approach by a general surgeon, or the transjugular approach under ultrasound and fluoroscopic guidance by an experienced pediatric interventional radiologist in an appropriately equipped fluoroscopy suite. The risk of development of a complication such as hemorrhage, hematoma, creation of an arteriovenous fistula, pneumothorax, or bile peritonitis is small.
HEPATIC IMAGING PROCEDURES.
Various techniques help define the size, shape, and architecture of the liver and the anatomy of the intrahepatic and extrahepatic biliary trees. Although imaging may not provide a precise histologic and biochemical diagnosis, specific questions can be answered, such as whether hepatomegaly is related to accumulation of fat or glycogen or is due to a tumor or cyst. These studies may direct further evaluation such as percutaneous biopsy and make possible prompt referral of patients with biliary obstruction to a surgeon. Choice of imaging procedure should be part of a carefully formulated diagnostic approach, with avoidance of redundant demonstrations by several techniques.
A plain roentgenographic study may suggest hepatomegaly, but a carefully performed physical examination gives a more reliable assessment of liver size. The liver may appear less dense thaormal in patients with fatty infiltration or more dense with deposition of heavy metals such as iron. A hepatic or biliary tract mass may displace an air-filled loop of bowel. Calcifications may be evident in the liver (parasitic or neoplastic disease), in the vasculature (portal vein thrombosis), or in the gallbladder or biliary tree (gallstones). Collections of gas may be seen within the liver (abscess), biliary tract, or portal circulation (necrotizing enterocolitis).
Ultrasonography (
CT scanning provides information similar to that obtained by US but is less suitable for use in patients <2 yr of age because of the small size of structures, the paucity of intra-abdominal fat for contrast, and the need for heavy sedation or general anesthesia. MRI is a useful alternative. Magnetic resonance cholangiography can be of value in differentiating biliary tract lesions. CT scan or MRI may be more accurate than US in detecting focal lesions such as tumors, cysts, and abscesses. When enhanced by contrast medium, CT scanning may reveal a neoplastic mass density only slightly different from that of a normal liver. When a hepatic tumor is suspected, CT scanning is the best method to define anatomic extent, solid or cystic nature, and vascularity. CT scanning can also reveal subtle differences in density of liver parenchyma, the average liver attenuation coefficient being reduced with fatty infiltration. Increases in density may occur with diffuse iron deposition or with glycogen storage. In differentiating obstructive from nonobstructive cholestasis, CT scanning or MRI identifies the precise level of obstruction more frequently than US. Either CT scanning or US may be used to guide percutaneously placed fine needles for biopsies, aspiration of specific lesions, or cholangiography.
Radionuclide scanning relies on selective uptake of a radiopharmaceutical agent. Commonly used agents include: technetium 99m-labeled sulfur colloid, which undergoes phagocytosis by Kupffer cells; 99mTc-iminodiacetic acid agents, which are taken up by hepatocytes and excreted into bile in a fashion similar to bilirubin; and gallium 67, which is concentrated in inflammatory and neoplastic cells. The anatomic resolution possible with hepatic scintiscans is generally less than that obtained with CT scanning, MRI, or US.
The 99mTc-sulfur colloid scan can detect focal lesions (tumors, cysts, abscesses) >2–3 cm in diameter. This modality can help to evaluate patients with possible cirrhosis and with patchy hepatic uptake and a shift of colloid uptake from liver to bone marrow.
The 99mTc-substituted iminodiacetic acid dyes may differentiate intrahepatic cholestasis from extrahepatic obstruction in neonates. Imaging results are best when scanning is preceded by a 5–7 day period of treatment with phenobarbital to stimulate bile flow. After intravenous injection, the isotope is normally detected in the bowel within 1–2 hr. In the presence of extrahepatic obstruction, excretion of the isotope is delayed; accordingly, serial scans should be made for up to 24 hr after injection. Early in the course of biliary atresia, hepatocyte function is usually good; uptake (clearance) occurs rapidly, but excretion into the intestine is absent. In contrast, uptake is poor in parenchymal liver disease, such as neonatal hepatitis, but excretion into the bile and intestine eventually ensues.
Cholangiography, direct visualization of the intrahepatic and extrahepatic biliary tree after injection of opaque material, may be required in some patients to evaluate the cause, location, or extent of biliary obstruction. Percutaneous transhepatic cholangiography with a fine needle is the technique of choice in infants and young children. The likelihood of opacifying the biliary tract is excellent in patients in whom CT scanning, MRI, or ultrasonography demonstrates dilated ducts. Percutaneous transhepatic cholangiography has been used to outline the biliary ductal system.
Endoscopic retrograde cholangiopancreatography (ERCP) is an alternative method of examining the bile ducts in older children. The papilla of Vater is cannulated under direct vision through a fiberoptic endoscope, and contrast material is injected into the biliary and pancreatic ducts to outline the anatomy.
Selective angiography of the celiac, superior mesenteric, or hepatic artery can be used to visualize the hepatic or portal circulation. Both arterial and venous circulatory systems of the liver can be examined. Angiography is frequently required to define the blood supply of tumors before surgery and is useful in the study of patients with known or presumed portal hypertension. The patency of the portal system, the extent of collateral circulation, and the caliber of vessels under consideration for a shunting procedure can be evaluated. MRI can provide similar information.
DIAGNOSTIC APPROACH TO INFANTS WITH JAUNDICE
The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has published a guideline for the evaluation of infants 2–8 wk of age with jaundice. The guideline is used to distinguish cholestatic from non-cholestatic jaundice as the cholestatic disorders are more serious. Well-appearing infants may have cholestatic jaundice. Biliary atresia and neonatal hepatitis are the most common causes of cholestasis in early infancy. Biliary atresia portends a poor prognosis unless it is identified early. The best outcome for this disorder is with early surgical reconstruction (45–60 days of age). History, physical examination, and the detection of a conjugated hyperbilirubinemia via examination of total and direct bilirubin are the 1st steps in evaluation of the jaundiced infant ( Fig. 352-1 ). Consultation with a pediatric gastroenterologist should be sought early in the course of the evaluation.
Hereditary diseases of bile ducts: floating gallbladder, aplasia of the gallbladder, duplex gallbladder.
Cholelitiasis: inflammation of biliary ducts with formation of the stones (petros).
Clinical symptoms: sharp acute pain, localisation in the right subcostal area, radiating of the right mandibular area and right shoulder. Pain accompanied by dispeptic syndrome, tachypnea. On X-ray, intravenous cholangiagram one can see stones.
A stone in the liver
Cyst of the liver
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A stone in the goal bladder
Chronic cholecystocholangitis.
Inflammation of biliary cyst, cystic duct and biliary ducts.
Clinical symptoms: pain, localisation in the right subcostal area, around the navel, belching, vomiting, nausea, furred tongue, marked tenderness in the right subcostal area, vassel “stars “ on the skin.
Diagnosis: ther is elevation of serum bilirubin level, serum aminotransferase levels, serum albumin is low, and gamma globulin is elevated.
Lamblia cysts in bile and in feces;
Investigation of duodenal contents; damaging of concentration of biliary bilirubin, protein, decreasing of the quantity of the bile acids in C-portion ( hepatic bile ) and B-portion ( cystic bile), Lamblias, leucocytes.
Ultrasonic signs of the chronic cholecystitis
Hepatitis B
Hepatitis B is a viral disease with a high incidence and prevalence worldwide. Hepatitis B can cause acute and chronic liver disease. The clinical presentation ranges from subclinical hepatitis to symptomatic hepatitis and, in rare instances, fulminant hepatitis. Long-term complications of hepatitis B include cirrhosis and hepatocellular carcinoma. Perinatal or childhood infection is associated with few or no symptoms, but it has a high risk of becoming chronic. A limited number of medications can be used to effectively treat chronic hepatitis B; a safe and effective vaccine is available to prevent hepatitis B infection caused by the hepatitis B virus (HBV).
Pathophysiology: HBV is a double-stranded DNA virus of the Hepadnaviridae family. HBV is a hepatotropic virus that replicates in the liver and causes hepatic dysfunction. HBV is transmitted by percutaneous or permucosal exposure to infectious body fluids, by sexual contact with an infected person, and by perinatal transmission from an infected mother to her infant. Persons with chronic HBV infection are predisposed to chronic liver disease and have a greater then 200-fold increased risk of hepatocellular carcinoma.
Fulminant hepatic failure occurs in approximately 0.1-0.5% of patients and is believed to be caused by massive immune-mediated lysis of infected hepatocytes. A variety of extrahepatic manifestations, including urticarial rashes, arthralgia, and arthritis, are associated with acute clinical and subclinical HBV infection, as well as multiple immune-complex disorders such as Gianotti-Crosti syndrome (papular acrodermatitis), necrotizing vasculitis, and hypocomplementemic glomerulonephritis. HBV is associated with 20% of the cases of membranous nephropathy in children. Essential mixed cryoglobulinemia, pulmonary hemorrhage related to vasculitis, acute pericarditis, polyserositis, and Henoch-SchЖnlein purpura have been reported in association with HBV infection.
Clinical
History: The incubation period for HBV infection ranges from 6 weeks to 6 months, and the clinical manifestations depend on the age at infection, level of HBV replication, and host’s immune status.
Perinatally infected infants generally have no clinical signs or symptoms, and infection produces typical illness in only 5-15% of children aged 1-5 years.
Older children and adults are symptomatic in 33-50% of infections.
Clinical signs and symptoms of acute HBV infection include anorexia, nausea, malaise, vomiting, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, coryza, jaundice, dark urine, clay-colored or light stools, and abdominal pain.
Fulminant hepatitis occurs in 1-2% of persons with acute disease and has a case/fatality ratio of 63-93%.
Physical:
On physical examination, with the onset of clinical jaundice, the liver becomes enlarged and tender, and the patient may have right upper quadrant pain and discomfort.
Splenomegaly and cervical adenopathy are present in 10-20% of patients with acute hepatitis.
A few spider angiomas may appear during the icteric phase and disappear during convalescence, although angiomas are rare.
Percussion of liver
Palpation of liver
The lower edge of the liver is sometimes palpable in infants and young children as a superficial mass 1 to
Paediatrics : Clinical Examinations – Examination of the liver
Digestive Diagnostic Procedures for Children
In order to reach a diagnosis for digestive and liver problems, a thorough and accurate medical history must be taken by the doctor, noting the symptoms your child has experienced and any other pertinent information. A physical examination is also done to help assess the problem more completely.
Some patients need to undergo a more extensive diagnostic evaluation, which may include laboratory tests, imaging tests, or endoscopic procedures. These tests may include any, or all, of the following:
Laboratory tests:
· Albumin level. A sample of blood is obtained from your child’s vein. Below-normal levels of albumin, a protein made by the liver, found in the bloodstream are associated with many chronic liver disorders.
· Bilirubin level. A sample of blood is taken from your child’s vein. Bilirubin is produced by the liver and is excreted in the bile. Elevated levels of bilirubin may indicate an obstruction of bile flow or a defect in the processing of bile by the liver.
· Complete blood count (CBC). A sample of blood is taken from your child’s finger or vein, and the different types of cells in the bloodstream are examined. White blood cells multiply when infection is present. Red blood cells will be present in smaller amounts than normal if blood has been lost, if the diet has been inadequate, or with certain diseases.
· Electrolyte tests. A sample of blood is taken from your child’s vein, and the amounts of minerals known as electrolytes are measured, including sodium, potassium, calcium, and glucose. These minerals are important for the body to function properly. Children who have lost large amounts of fluid due to vomiting or diarrhea often lose large amounts of the various electrolytes as well. Your child’s doctor uses electrolyte tests to help determine when your child might need extra fluids given intravenously or other medications to help with dehydration and mineral loss.
Imaging tests:
· Computed tomography scan (CT or CAT scan). A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body.
scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays. Your child will lie on a bed that moves into a doughnut shaped machine that takes many pictures of different areas of the body. Because the machine is noisy, and because your child may need to lie still for awhile with his or her arms over the head, a sedative might be given to help your child rest during the procedure.
· Ultrasound. A diagnostic imaging technique that uses high-frequency sound waves and a computer to create images of blood vessels, tissues, and organs. Ultrasounds are used to view internal organs as they function, and to assess blood flow through various vessels. Gel is applied to the area of the body being studied, such as the abdomen, and a wand called a transducer is placed on the skin. The transducer sends sound waves into the body that bounce off organs and return to the ultrasound machine, producing an image on the monitor. A picture or video tape of the test is also made so it can be reviewed in the future.
·
· Magnetic resonance cholangiopancreatography (MRCP). This uses magnetic resonance imaging (MRI) to obtain pictures of the bile ducts. The machine uses radio waves and magnets to scan internal organs and tissues.
· Capsule endoscopy. A capsule endoscopy helps doctors examine the small intestine, because traditional procedures, such as an upper endoscopy or colonoscopy, cannot reach this part of the bowel. This procedure is helpful in identifying causes of bleeding, detecting polyps, inflammatory bowel disease, ulcers, and tumors of the small intestine. A sensor device is placed on a patient’s abdomen and a pillcam (capsule endoscope) is swallowed. The pillcam passes naturally through the digestive tract while transmitting video images to a data recorder. The data recorder is secured to a patient’s waist by a belt for eight hours. Images of the small bowel are downloaded on a computer from the data recorder. The images are reviewed by a doctor on a computer screen. Normally, the pillcam passes through the colon and is eliminated in the stool within 24 hours.
· Liver biopsy. A liver biopsy helps diagnose liver diseases. A small sample of liver tissue is obtained with a special biopsy needle and examined for abnormalities. Children are sometimes given medication to minimize their anxiety during the procedure. A small area of skin over the liver is numbed with a local anesthetic. The anesthetic is then injected deeper under the skin to numb the area that the biopsy needle will pass through and reduce the discomfort of the test. The biopsy needle is quickly inserted through the skin and into the liver, and then withdrawn. Sometimes, an ultrasound of the liver is done at the same time to help the doctor know exactly where to obtain the tissue samples. After a liver biopsy, a health care professional will observe the child for bleeding problems for a few hours. Pain medications will be given, if needed.
Causes:
HBV, a DNA virus in the Hepadnaviridae family, causes hepatitis B.
Several well-characterized groups in the United States have an increased risk of hepatitis B infection, including injecting drug users, homosexual men, persons who have heterosexual contact with multiple partners, household contacts of persons with chronic hepatitis B infection, hemophiliacs, hemodialysis patients and staff, and persons with occupational exposure to blood and infectious body fluids.
Lab Studies:
Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are hallmarks of acute hepatitis. Values as high as 1000-2000 IU/L are typical, with ALT values higher than AST values. In patients with hepatitis, increases in bilirubin levels often lag behind increases in aminotransferase levels. The prothrombin time is the best indicator of prognosis. Alpha-fetoprotein levels as high as 8000 ng/mL also may be seen.
Because the symptoms of acute HBV infection and the laboratory indicators of hepatocellular dysfunction are indistinguishable from those of other forms of viral hepatitis, definitive diagnosis depends on serologic testing for HBV infection.
Acute HBV infection is characterized by the presence of HBsAg in the serum. This appears before the onset of symptoms and the elevation of ALT values, with the development of immunoglobulin M (IgM)–class antibody to hepatitis B core antigen (HBcAg).
Hepatitis B antigen (HBeAg), HBV DNA, and DNA polymerase also are detectable during acute infection.
During convalescence, HBsAg and HBeAg are cleared, and immunoglobulin G (IgG) antibodies to HBsAg, HBcAg, and HBeAg develop.
Hepatitis B surface antibody (HBsAb) is a protective antibody that neutralizes the virus, although the coexistence of HBsAg and HBsAb has been reported in approximately 25% of HBsAg-positive individuals. HBsAb, but not hepatitis B core antibody (HBcAb), is detected in persons who have received the hepatitis B vaccine.
Total HBcAb, including IgM and IgG, indicates exposure to the virus and viral replication. HBcAb appears shortly after HBsAg in acute disease and persists for life; therefore, HBcAb is not a good marker for acute disease.
Detection of IgM HBcAb is diagnostic of acute HBV infection. The carrier state is defined by the presence of HBsAg in the serum for 6 months or longer after its initial detection.
The presence of HBsAg alone does not necessarily indicate replication of complete virions, and patients may not have symptoms or liver damage.
In contrast, chronic replication of HBV virions is characterized by the persistence of circulating HBsAg, HBeAg, and HBV DNA, usually with HBcAb.
The major clinical role of serum HBV DNA assays is the assessment of the candidacy of patients with chronic HBV infection for antiviral therapy and their response to it. Tests for HBV DNA in serum rarely help in identifying HBV as the cause of liver disease in HBsAg-negative patients; knowledge of this fact is especially important in patients with fulminant hepatitis B in whom HBsAg may have cleared by the time they seek care.
Ultrasonic signs of the chronic hepatitis
Procedures:
Patients with signs of chronic disease may require a liver biopsy to assess the extent of histologic involvement and response to therapeutic protocols.
Deterrence/Prevention:
Hepatitis B is one of the major diseases of mankind that can be prevented with vaccination. Two types of recombinant hepatitis B vaccines are licensed for use in the United States; both are effective and safe.
Universal vaccination refers to the administration of HBV vaccine to all infants as a part of the routine childhood immunization schedule and to all children younger than 11 or 12 years who have not previously received a vaccine. Rapid (0-, 1-, and 2-mo) and standard (0-, 1-, 6-mo) schedules have identical efficacy.
Passive immunization refers to the administration of preformed human or animal antibody, in the form of hepatitis B immunoglobulin (HBIG), to patients after or just before exposure.
The current recommendation for neonates of HBsAg-positive mothers is to administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within 12 hours of birth.
In infants of infected mothers, combined treatment with the vaccine and HBIG has 79-98% efficacy in preventing chronic HBV infection.
Complications:
Fulminant hepatitis is the most feared complication of viral hepatitis. Fulminant hepatitis is observed primarily in hepatitis B (>50% of fulminant hepatitis cases) and in delta hepatitis. Patients typically present with signs and symptoms of hepatic encephalopathy that may evolve to deep coma. Usually, the liver is small, and the prothrombin time is excessively prolonged.
The most severe complications of chronic hepatitis B infection are cirrhosis and hepatocellular carcinoma.
Rare complications of viral hepatitis are as follows:
Pancreatitis
Myocarditis
Atypical pneumonia
Aplastic anemia
Transverse myelitis
Peripheral neuropathy
Portal hypertension ,cirrhosis
Prognosis:
In acute hepatitis B, 90% of patients have a favorable course and recover completely.
Patients of advanced ages and those with serious underlying medical disorders, such as congestive heart failure (CHF), severe anemia, and diabetes mellitus, may have a prolonged course and are more likely to have severe hepatitis.
Cholecystitis
Cholecystitis is an inflammation of the gallbladder, a small sack-like organ located in the upper right-hand side of the abdomen. In a healthy individual, the gallbladder temporarily stores bile, a substance produced by the liver that helps the body digest fat. After a meal, particularly a high-fat meal, bile passes from the gallbladder through the cystic and common bile ducts and into the small intestine where it helps process fats.
Cholecystitis, which has long been considered an adult disease, is quickly gaining recognition in pediatric practice because of the significant documented increase in nonhemolytic cases over the last 20 years. Gallbladder disease is common throughout the adult population, affecting as many as 25 million Americans and resulting in 500,000-700,000 cholecystectomies per year. Although gallbladder disease is much more rare in children, with 1.3 pediatric cases occurring per every 1000 adult cases, pediatric patients undergo 4% of all cholecystectomies. In addition, acalculous cholecystitis, uncommon in adults, is not that unusual in children with cholecystitis. Because of the increasing incidence of gallstones and the disproportionate need for surgery in the pediatric population, consider cholecystitis and other gallbladder diseases in the differential diagnosis in any pediatric patient with jaundice or abdominal pain in the right upper quadrant, particularly if the child has a history of hemolysis.
Pathophysiology: Cholecystitis is defined as inflammation of the gallbladder and is traditionally divided into acute and chronic subtypes. These subtypes are considered to be 2 separate disease states; however, evidence suggests that the 2 conditions are closely related, especially in the pediatric population. Most gallbladders that are removed for acute cholecystitis show evidence of chronic inflammation, supporting the concept that acute cholecystitis may actually be an exacerbation of chronic distension and tissue damage. Cholecystitis may also be considered calculous or acalculous, but the inflammatory process remains the same.
Chronic cholecystitis is most often related to gallstone disease but has been documented without gallstones. Its course may be insidious or involve several acute episodes of obstruction. The initiating factor is thought to be the supersaturation of bile, often with cholesterol crystals and/or calcium bilirubinate, which contributes to stone formation and inflammation. These processes lead to chronic obstruction, decreased contractile function, and biliary stasis, which contribute to further inflammation of the gallbladder wall. Biliary stasis also permits the increased growth of bacteria, usually Escherichia coli and enterococci, which may irritate the mucosa and increase inflammatory response. Chronic acalculous cholecystitis is less understood, but it may result from a functional deficiency of the gallbladder, which leads to spasm and an inability to appropriately empty its contents, causing chronic bile stasis.
Acute calculous cholecystitis results from a more sudden obstruction of the cystic duct by gallstones, which results in distension of the sac, edema, and bile stasis with bacterial overgrowth. These events lead to inflammation and a local release of lysolecithins, which further exacerbates the inflammatory process. In addition, edema of the wall and duct reinforces obstruction and may cause ischemia of the local tissue, releasing still more inflammatory mediators. Local lymph node hypertrophy and duct torsion or congenital anomalies may further complicate the obstructive process. As obstruction and inflammatory tissue damage progress, bacteria may proliferate. Bile cultures are positive in 75% of cases, usually with E coli, enterococci, or Klebsiella species. Bacterial infection most likely follows tissue damage, but after colonization, the severity of the disease can dramatically worsen. This cascade of events quickly leads pain and, possibly, a toxic appearance.
Acute acalculous cholecystitis develops in a similar manner but from different etiologic factors than acute calculous cholecystitis. Acute acalculous cholecystitis is most often associated with systemic illness, whether chronic or critical and acute. Increased mucous production, dehydration, and increased pigment load all are factors that increase cholesterol saturation and biliary stasis, whereas hyperalimentation, assisted ventilation, intravenous narcotics, ileus, and prolonged fasting contribute to cholestatic hypofunction. These conditions allow the formation of biliary sludge and may lead to obstruction. The resulting inflammation and edema lead to compromised blood flow and bacterial infection, as in acute calculous cholecystitis; however, the compromised blood flow appears more central in acute acalculous cholecystitis because acute acalculous cholecystitis can occur in vasculitides (eg, Kawasaki disease, periarteritis nodosa) presumably because of direct vascular compromise.
Physical: The physical examination in acute cholecystitis usually reveals right upper quadrant tenderness. The classic triad is right upper quadrant pain, fever, and leukocytosis. The patient may have abdominal guarding and a positive Murphy sign, ie, arrest of inspiration on deep palpation of the gallbladder in the right upper quadrant of the abdomen. Omental adherence to the inflamed gallbladder combined with distension may create a palpable mass between the 9th and 10th costal cartilages. The ductal system may become inflamed, causing cholangitis. In 50% of these cases, the examiner may find a Charcot triad.
Charcot triad: This combination of right upper quadrant pain, fever, and jaundice is indicative of obstruction to the common bile duct and the presence of acute cholangitis. The Charcot triad is considered a medical emergency, and patients require immediate intervention.
Biliary colic versus chronic cholecystitis: Performing a physical examination may be the only way to distinguish biliary colic from chronic cholecystitis. In chronic cholecystitis, the patient usually complains of tenderness to palpation in the right upper quadrant; however, the differentiation may be trivial given the high likelihood of chronic cholecystitis in the presence of recurring biliary colic.
Causes: Cholelithiasis is the most common cause of acute or chronic cholecystitis in adults and children. Three major types of gallstones may form, although most gallstones have components of more than one type. Cholesterol gallstones are radiolucent and are composed of cholesterol (>50%), calcium salts, and glycoproteins. They form within the gallbladder and migrate to the bile duct. Pigment gallstones are black, often radiopaque, and usually associated with hemolytic diseases. Radiopacity and color are related to an increased concentration of calcium bilirubinate, which interacts with mucin glycoproteins to form gallstones. These gallstones also form within the gallbladder and migrate to the ductal system. Brown gallstones, in contrast, form within the ductal system and are orange, soft, and greasy. They are composed of calcium salts of bilirubin, stearic acid, lecithin, and palmitic acid. These gallstones are more often associated with infection.
In rural Asia, infections with Opisthorchis sinensis or Ascaris lumbricoides are predisposing conditions. In the United States, these gallstones are more rare, although they have been found after cholecystectomy in which the bile was infected (most often by E coli) and in infants and children infected with Staphylococcus, Enterobacter, Citrobacter, and Salmonella species. In addition, chronic urinary tract infections may predispose individuals to the formation of these gallstones, and isolated gallstones associated with Ascaris have been recorded in the United States.
All gallstones require similar conditions to form. First, the bile must be supersaturated either by cholesterol or bilirubin. Second, chemical kinetics must favor nucleation of cholesterol. This occurs when cholesterol is no longer soluble in bile. Finally, stasis of the gallbladder allows cholesterol or calcium bilirubinate crystals to remain long enough to aggregate to form gallstones.
Many disease processes can precipitate or foster these events. Infection induces the deconjugation of bilirubin glucuronide, thereby increasing the concentration of unconjugated bilirubin in the bile. Hemolysis overwhelms the conjugation abilities of the liver, increasing the amount of unconjugated bilirubin in the bile. Hemolytic diseases include hereditary spherocytosis, sickle cell disease, thalassemia major, hemoglobin C disease, and possible uncontrolled glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Multiple blood transfusions also increase the pigment load, which predisposes the bile to the formation of biliary sludge.
Dehydration, whether primary or secondary to shock or sepsis, concentrates the bile, increasing viscosity and allowing supersaturation. CF is associated with increased mucous production and may cause a similar scenario. Gallstones remain the most common cause of cholecystitis. Although acalculous cases significantly contribute to incidence of cholecystitis, most acalculous cases are related to systemic illness and risk factors rather than epidemiologic determinants. Therefore, the discussion of epidemiology focuses on the development of cholelithiasis.
Acalculous cholecystitis
The aforementioned diseases may also contribute to the development of acalculous cholecystitis because the formation of gallstones is not necessary for the obstruction of the bile duct. In addition, acalculous cholecystitis has been heavily associated with local inflammation, endocarditis, vasculitides, and systemic infection. Implicated infections include those occurring in typhoid fever, scarlet fever, measles, and AIDS and those caused by mycoplasma, Streptococcus (groups A and B), and gram-negative organisms, such as Shigella and E coli.
Acalculous cholecystitis may also occur postoperatively. Tsakayannis et al observed acute cholecystitis occurring after open-heart surgery in 4 of their patients, although it is more commonly observed in other nonbiliary surgeries and trauma. Shock, sepsis, hyperalimentation, prolonged fasting, intravenous narcotics, and multiple transfusions were the most common risk factors for the development of acute acalculous cholecystitis. The presence of 4 or more of these risk factors is highly predisposing.
Other unusual causes
Gallstones may also be caused by medications. Furosemide, octreotide, ceftriaxone, and cyclosporine have all been associated with gallstone disease. Ceftriaxone causes a reversible pseudolithiasis through several mechanisms. Ceftriaxone displaces bilirubin on albumin, thereby increasing the blood concentration of unconjugated bilirubin. Ceftriaxone is also secreted in bile, and calcium salts of ceftriaxone have been found in biliary sludge.
Risk factors associated with gallstone formation are prolonged fasting and age older than 24 months. Lasix has also been implicated in gallbladder disease, but it usually is only a compounding factor in the presence of prematurity, sepsis, or small-bowel disease. Cyclosporine may be lithogenic, but it seems to require high drug levels and hepatotoxicity. Finally, ileal disease or resection has been correlated with cholelithiasis in adults and children, although the risks associated with resection seem to be highest after puberty. These patients have an increased cholesterol secretion and a lowered bile acid secretion, which leads to cholesterol supersaturation.
Lab Studies:
In assessing for cholecystitis, appropriate laboratory studies include a CBC, gamma-glutamyltransferase (GGT) assessment, amylase measurement, urinalysis, direct and indirect bilirubin tests, alkaline phosphatase measurement, and transaminase levels. In acute cholecystitis, the WBC count is elevated, with a predominance of polymorphonuclear cells and bands. Bilirubin, alkaline phosphatase and GGT levels rise secondary to a blocked biliary system. The traditional cholestatic picture involves direct hyperbilirubinemia, with a direct-to-indirect ratio approaching 1:1. Amylase may be elevated even in the absence of obstructive pancreatitis. In addition, transaminases may show mild elevation but not a significant increase, unless obstruction has been severe enough to cause hepatocyte damage. Transaminase levels are more likely to rise early in patients with obstruction of the common bile duct.
Imaging Studies:
Plain abdominal radiography may be used for initial screening in abdominal pain. Calcifications representing radiopaque gallstones may be observed in the gallbladder or ductal system. Radiopaque gallstones contain more calcium bilirubinate and are more common in the pediatric population, especially in infants and children. In addition, complications such as porcelain gallbladder and emphysematous cholecystitis may be visible on radiographs, although these complications are rare in children.
Abdominal ultrasonography has become the diagnostic tool of choice in evaluating cholelithiasis. The accuracy of abdominal ultrasonography in depicting gallstones is estimated to be more than 95%, but its reliability in the accurate diagnosis of acute cholecystitis is more limited. Ultrasonographic findings in acute cholecystitis include a discrete echodensity representing the gallstone, the presence of sludge, and, possibly, ductal anomalies or dilation. The gallbladder may be dilated with thickened walls. Imhof et al found gallbladder wall thickness of more than
Oral cystography has been used in the past, but is now largely ignored because of the refinement of ultrasonography. Oral cystography involves the ingestion of contrast material that is secreted in the bile. Lack of visualization of the gallbladder indicates cholelithiasis. This procedure is limited by liver dysfunction and malabsorption. In addition, the contrast tablets have been associated with emesis and diarrhea, further complicating effectiveness.
The most accurate tool in the diagnosis of acute cholecystitis is biliary scintography, otherwise known as the hepatic 2,6-dimethyliminodiacetic acid or hepatoiminodiacetic acid (HIDA) scanning. This procedure involves the intravenous injection of substances labeled with technetium 99m, taken into the hepatocytes, and excreted into the biliary system. Normal hepatic uptake without gallbladder visualization is diagnostic, but false positive results occur with decreased biliary function secondary to prolonged fasting and the use of hyperalimentation. Morphine augmentation of this test has been shown to decrease false positive results. Induced spasm of the sphincter of Oddi increases biliary pressure and enhances gallbladder filling. This test may be unnecessary, however, because the clinical diagnosis and treatment are determined by the symptoms and presence of gallstones or sludge. Ultrasonography has proved its usefulness in depicting gallstones, does not rely on contrast, and, therefore, may be safer.
Other imaging techniques that can be used in the diagnosis of cholecystitis include MRI and CT, especially in cases in which ultrasonography is not helpful. Ultrasonographic results may be compromised by ileus, surgical incisions, and coexisting diseases, especially those found in patients who are critically ill. MRI and CT may be more sensitive than ultrasonography in detecting inflammation within and around the gallbladder. In addition, the presence of other sources of abdominal sepsis are more easily discovered and treated by means of MRI and CT.
Other Tests:
Other tests associated with the diagnosis and treatment of cholecystitis include cholecystokinin (CCK) stimulation, intraoperative cholangiography, and endoscopic retrograde cholangiopancreatography (ERCP). CCK stimulation may be employed during other imaging studies, such as cholescintigraphy. Gallbladder dyskinesia after CCK administration is diagnostic of gallbladder hypofunction and may be useful in discerning acalculous or chronic cholecystitis and acute inflammation.
Intraoperative cholangiography, whether intravenous or percutaneous, is widely used for the visualization of the gallbladder and ductal system. However, cholangiography can be time-consuming and an added expense to the patient, although some data show no statistical difference in operative time with and without its use. Consider cholangiography for any risk of obstruction of the common bile duct. Indications are a history of jaundice, pancreatitis, dilated common bile duct, and the presence of small gallstones. The benefits of using cholangiography have not been proven for routine cholecystectomy, routine screening for congenital anomalies, or assessment of the common bile duct for obstruction in the absence of clinical suspicion.
If the patient displays signs and symptoms of choledocholithiasis, ERCP may also be used preoperatively for exploration of the common bile duct. This procedure is both diagnostic and therapeutic because it may be used for stent placement, basket retrieval, or papillotomy to allow passage of gallstones; however, available choledochoscopes may be too large for small patients.
Procedures:
One alternative to cholecystectomy is percutaneous transhepatic cholecystostomy. In this approach, thread a catheter directly into the gallbladder and place it to allow gravity drainage. Cholecystostomy is especially useful in acalculous cholecystitis and in seriously ill patients with simple gallstones in whom obstruction of the common bile duct is ruled out. Because cholecystectomy is the standard of care for cholecystitis, cholecystostomy is usually reserved for seriously ill patients who may not tolerate surgery.
Choledocholithiasis complicates the picture of cholecystitis and usually requires adjunctive procedures to cholecystectomy. If obstruction of the common bile duct is suspected preoperatively, perform ERCP before surgery with papillotomy, stent placement, or basket retrieval. If gallstones are found intraoperatively, several techniques can be used. The common bile duct can be flushed with saline or opened and explored. Additionally, an endoscope or nephroureteroscope may be used intraoperatively for basket retrieval.
X-ray examination of the goal bladder
Diseases of the Gallbladder
ANOMALIES.
The gallbladder is congenitally absent in about 0.1% of the population. Hypoplasia or absence of the gallbladder can be associated with extrahepatic biliary atresia or cystic fibrosis. Duplication of the gallbladder occurs rarely.
ACUTE HYDROPS ( TABLE 363-1 ).
Acute noncalculous, noninflammatory distention of the gallbladder can occur in infants and children. It is defined by the absence of calculi, bacterial infection, or congenital anomalies of the biliary system. The disorder may complicate acute infections, but the cause is ofteot identified. Hydrops of the gallbladder may also develop in patients receiving long-term parenteral nutrition, presumably as a result of gallbladder stasis during the period of enteral fasting. Hydrops is distinguished from acalculous cholecystitis by the absence of a significant inflammatory process and a generally benign prognosis.
TABLE 363-1 — Conditions Associated with Hydrops of the Gallbladder
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Affected patients usually have right upper quadrant pain with a palpable mass. Fever, vomiting, and jaundice may be present and are usually associated with a systemic illness such as streptococcal infection. Ultrasonography shows a markedly distended, echo-free gallbladder, without dilatation of the biliary tree. Acute hydrops is usually treated conservatively with a focus on supportive care and managing the intercurrent illness; cholecystostomy and drainage are rarely needed. Spontaneous resolution and return of normal gallbladder function usually occur over a period of several weeks. If a laparotomy is required, a large, edematous gallbladder is found to contain white, yellow, or green bile. Obstruction of the cystic duct by mesenteric adenopathy is occasionally observed. Cholecystectomy is required if the gallbladder is gangrenous. Pathologic examination of the gallbladder wall shows edema and mild inflammation. Cultures of bile are usually sterile.
CHOLECYSTITIS AND CHOLELITHIASIS.
Acute acalculous cholecystitis is uncommon in children and is usually caused by infection. Pathogens include streptococci (groups A and B), gram-negative organisms, particularly Salmonella and Leptospira interrogans. Parasitic infestation with ascaris or Giardia lamblia may be found. Calculous cholecystitis may rarely follow abdominal trauma or burn injury or is associated with a systemic vasculitis, such as periarteritis nodosa.
Clinical features include right upper quadrant or epigastric pain, nausea, vomiting, fever, and jaundice. Right upper quadrant guarding and tenderness are present. Ultrasonography discloses an enlarged, thick-walled gallbladder, without calculi. Serum alkaline phosphatase (ALP) activity and direct-reacting bilirubin levels are elevated. Leukocytosis is usual.
Patients may recover with treatment of systemic and biliary infection. Since the gallbladder can become gangrenous, daily ultrasonography is useful in monitoring gallbladder distention and wall thickness. Cholecystectomy is required in patients who fail to improve with conservative management. Cholecystostomy drainage is an alternative approach in a critically ill patient.
Cirrhosis and chronic cholestasis also increase the risk for pigment gallstones. Sick premature infants may also have gallstones; their treatment is often complicated by such factors as bowel resection, necrotizing enterocolitis, prolonged parenteral nutrition without enteral feeding, cholestasis, frequent blood transfusions, and use of diuretics. Cholelithiasis in premature infants is often asymptomatic and may resolve spontaneously. Brown pigment stones are found in infants with obstructive jaundice and infected intra- and extrahepatic bile ducts. These stones are usually radiolucent, owing to a lower content of calcium phosphate and carbonate and a higher amount of cholesterol than in black pigment stones. Biliary dyskinesia, a disorder of impaired gallbladder contractility, is an abnormality predisposing to gallstones in late childhood and teenage years.
Cholesterol cholelithiasis in children most frequently affects obese adolescent girls. Cholesterol gallstones are also found in children with disturbances of the enterohepatic circulation of bile acids, including patients with ileal disease and bile acid malabsorption, such as those with ileal resection, ileal Crohn disease, and cystic fibrosis. Pigment stones can also occur in these patients.
Cholesterol gallstone formation seems to result from an excess of cholesterol in relation to the cholesterol-carrying capacity of micelles in bile. Supersaturation of bile with cholesterol, leading to crystal and stone formation, could result from decreased bile acid or from an increased cholesterol concentration in bile. Other initiating factors that may be important in stone formation include gallbladder stasis or the presence in bile of abnormal mucoproteins or bile pigments that may serve as a nidus for cholesterol crystallization.
Prolonged use of high-dose ceftriaxone, a third-generation cephalosporin, has been associated with the formation of calcium-ceftriaxone salt precipitates (biliary pseudolithiasis) in the gallbladder. Biliary sludge or cholelithiasis can be detected in >40% of children treated with ceftriaxone for at least 10 days. In rare cases, children become jaundiced and develop abdominal pain; precipitates usually resolve spontaneously within several months after discontinuation of the drug.
Acute or chronic cholecystitis is often associated with gallstones. The acute form may be precipitated by impaction of a stone in the cystic duct. Proliferation of bacteria within the obstructed gallbladder lumen can contribute to the process and lead to biliary sepsis. Chronic calculous cholecystitis is more common. It can develop insidiously or follow several attacks of acute cholecystitis. The gallbladder epithelium commonly becomes ulcerated and scarred.
The most important clinical feature of cholelithiasis is recurrent abdominal pain, which is often colicky and localized to the right upper quadrant. An older child may have intolerance for fatty foods. Acute cholecystitis may be the 1st manifestation, with fever, pain in the right upper quadrant, and often a palpable mass. Jaundice occurs more commonly in children than adults. Pain may radiate to an area just below the right scapula. A plain roentgenogram of the abdomen may reveal opaque calculi, but radiolucent (cholesterol) stones are not visualized. Accordingly, ultrasonography is the method of choice for gallstone detection. Hepatobiliary scintography is a valuable adjunct in that failure to visualize the gallbladder provides evidence of cholecystitis.
Cholecystectomy is curative. Laparoscopic cholecystectomy is routinely performed in symptomatic infants and children with cholelithiasis. Common bile duct stones are unusual in children, occurring in 2–6% of cases with cholelithiasis, often in association with obstructive jaundice and pancreatitis. Operative cholangiography should be done at the time of surgery, however, to detect unsuspected common duct calculi. Endoscopic retrograde cholangiography with extraction of common duct stones is an option before laparoscopic cholecystectomy in older children and adolescents.
Asymptomatic patients with cholelithiasis pose a more difficult management problem. Studies in adults indicate a lag time of more than a decade between initial formation of a gallstone and development of symptoms. Spontaneous resolution of cholelithiasis has been reported in infants and children. If surgery is deferred for any patient, however, parents should be counseled about signs and symptoms consistent with cholecystitis or obstruction of the common bile duct by a gallstone. In patients with chronic hemolysis or ileal disease, cholecystectomy can be carried out at the same time as another surgical procedure. Since laparoscopic surgery can safely be performed in children with sickle cell disease, elective cholecystectomy is being done more frequently at the time of gallstone diagnosis, before symptoms or complications develop. In cases associated with liver disease, severe obesity, or cystic fibrosis, the surgical risk of cholecystectomy may be substantial so that the risks and benefits of the operatioeed to be carefully considered.
Biliary Dyskinesia
Definition – is a disorder of the sphincter’ tonus and kinetics of the gall-bladder and bile ducts.
Classification
hypertonic-hyperkinetic dyskinesia
hypotonic-hypokinetic dyskinesia
Clinical manifestation of hypertonic-hyperkinetic dyskinesia
Duration of the disease up to 1 yr.
Pain syndrome
Dyspeptic syndrome
Manifestations of vegetative dysfunction, neurotic symptoms
Clinical manifestation of hypotonic-hypokinetic dyskinesia
• Pain syndrome
• Dyspeptic syndrome
• Hepatomegaly
• Gallbladder symptoms are positive
Plan of examination
• Fool blood count
• Biochemical test of blood
• Serum aminotransferase
• Serum bilirubin (predominantly the direct reacting fraction)
• Serum alkaline phosphatase
• Albumin and globulin level
• Stool test
• USE of the abdominal cavity + cholekynetics for functional investigations
Treatment of hypertonic-hyperkinetic dyskinesia
1. Diet N 5
2. Spasmolitics:
platyphyllini hydrotartratis (amp. 0.2 % 1 ml)
papaverini hydrochloridum (tab. 0.01, amp. 2 % 2 ml)
no-spa (tab. 0.04 or amp. 2 % 2 ml)
3. Choleretic:
cholagon
allocholum
cholenzynum
galstena
hepabene
Treatment of hypotonic-hypokinetic dyskinesia
1. Diet N 5
2. Prokinetic: motilium, domperidone (tabl.
3. Choleretic and cholekinetic drugs:
cholagon
allocholum
cholenzynum
galstena
hepabene
chophytol
Treatment of hepatitis
Medical Care: No specific treatment is available for persons with acute HBV infection. Supportive and symptomatic care is the mainstay of therapy for most patients.
Surgical Care:
Liver transplantation for decompensated liver disease
Surgical resection of hepatocellular carcinoma
Diet: A high-energy diet is desirable, and because many patients may have nausea late in the day, they best tolerate their major caloric intake in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot eat.
Activity: Although forced and prolonged bed rest is not essential for full recovery, many patients feel better with restricted physical activity.
Alpha interferon (IFN-a) has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid-1980s, although only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues famciclovir, lobucavir, and adefovir dipivoxil directly block the replication of HBV; they are highly effective, bioavailable, and extremely well tolerated. To date, only IFN-a and lamivudine are FDA-approved for this indication.
Interferon-therapy:
Intron А (α2b-Interferon),
Form of production – vial with 3 and 5 М units
<!–[if !supportLists]–>2. <!–[endif]–>Viferon (α2- Interferon+ vit. E and C)
Form of production rectal suppository
Viferon 1 – 150000 units
Viferon 2 – 500000 units
Viferon 3 – 1000000 units
Viferon 4 – 2000000 units.
<!–[if !supportLists]–>3. <!–[endif]–>Pegasis (peginterferon α-2а)
Form of production syrette with 135 mcg and 180 mcg
Hepatoprotectors
<!–[if !supportLists]–>n <!–[endif]–>Heptral (tabl.-
<!–[if !supportLists]–>n <!–[endif]–>Ursophalk (cap. 250 mg) 8-10 mg/kg/day
<!–[if !supportLists]–>n <!–[endif]–>Essentiale (cap., amp.) 1-2 cap. 3 times a day
<!–[if !supportLists]–>n <!–[endif]–>Carsil (dragee) 1-2 dragee 3 times a day
<!–[if !supportLists]–>n <!–[endif]–>Hepabene 1-2 dragee 3 times a day
<!–[if !supportLists]–>n <!–[endif]–>Thiotriazolinum 1 tabl. 3 times a day
<!–[if !supportLists]–>n <!–[endif]–>Chophytol 1-2 tabl. 3 times a day
]Drug Category: Antiviral agents — Interferon may prevent the progression of acute hepatitis to the chronic stage and promote more rapid resolution of viremia and normalization of serum aminotransferase levels. Several nucleoside analogues are active against HBV. The most widely used and studied is lamivudine, which has produced promising responses. However, relapse rates tend to be high after treatment is discontinued.
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DrugName |
Alpha interferon 2b (Intron A) — Interferons (IFNs) are proteins produced by host cells in response to viral infection. Three interferons have been identified, and each has antiviral and immunoregulatory actions: IFN-a is produced by B lymphocytes and monocytes; IFN-b, by fibroblasts; and IFN-g, by T helper and NK cells. Immunomodulatory effects of IFNs are mediated by an increase in HLA class I antigen and FC receptor expression, an increased CD4/CD8 ratio, and activation of NK cell pathways. Ideally, candidates for IFN therapy have evidence of ongoing viral replication (presence of HBeAg or HBV DNA) for at least 6 mo and either persistently increased serum aminotransferase activity or evidence of chronic hepatitis B infection at liver biopsy. Before IFN therapy, screening patients for at least 4-6 mo to identify those who may be entering a period of spontaneous seroconversion to HBeAb is often beneficial. Clinical variables associated with a favorable response to therapy are high pretherapy aminotransferase levels, low HBV DNA levels, and active disease at liver biopsy. Other less useful variables include female sex, acquisition of infection in adulthood, heterosexuality, HIV antibody negativity, and history of acute hepatitis. Responses to IFN-a-2b, is defined as a sustained loss of HBeAg and HBV DNA with a normalization or near normalization of ALT levels for at least 6 mo after therapy, is observed in 25-40% of patients. Controlled studies of IFN in children reveal comparable responses in primary non-Asian children. Chinese children respond poorly to IFN therapy. Safety and effectiveness in patients aged from 1-17 years have been established. |
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Adult Dose |
5 million |
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Pediatric Dose |
High dose: 7.5-10 million U/m2 3 times per wk |
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Contraindications |
Documented hypersensitivity; decompensation (cirrhosis) |
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Interactions |
Interactions with other medications have not been evaluated fully; use caution with potentially myelosuppressive agents such as zidovudine; combination with theophylline decreases theophylline clearance, increasing theophylline levels by 100% |
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Precautions |
IFN does not appear to protect against hepatocellular carcinoma; treatment is associated with frequent adverse events; dose reduction is required in at least 20% of patients treated with recommended regimen; discontinuation of treatment is necessary in <5% of instances; most patients have influenza-like illness with fever, chills, myalgia, and headaches 6-8 hours after first injection; symptoms improve or disappear with subsequent injections; patients benefit from premedication with acetaminophen or NSAIDs Psychiatric adverse effects, especially depression, occur in about 15% of patients; frank delirium and suicidal ideation have been reported IFN decreases the platelet count by 30-50%, total white cell count by 20-40%, and hematocrit level slightly; changes are clinically insignificant and often return to normal after treatment is discontinued; can induce an autoimmune diathesis; associated with clinically significant worsening or unmasking of autoimmune conditions; autoantibodies, such as antinuclear, anti√smooth muscle, antithyroid, and insulin antibodies, develop in >50% of patients treated for 4 mo; thyroid abnormalities infrequent; evaluate serum TSH levels prior to therapy Acute, serious, hypersensitivity reactions (rare) require immediate discontinuation; transient rashes have occurred after injection but have not required treatment interruption; may exacerbate preexisting psoriasis |
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Drug Name |
Lamivudine (Epivir-HBV) — Only nucleoside analogue approved by the FDA for chronic HBV treatment. It inhibits HBV DNA polymerase. Lamivudine use should be considered in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine for cases that fail or are unlikely to respond to interferon or patients who cannot tolerate interferon. Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HBeAb. Emergence of resistance is the major drawback of nucleoside analogue monotherapy. The proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because the resistant strains of HBV seem to be attenuated and are associated with only mild liver injury. Combination therapy with 2 or 3 nucleoside analogues may delay or prevent emergence of viral resistance, but clinical trials are needed. Safe and effective in children aged 2-17 y. Epivir-HBV contains 100 mg/tab or 5 mg/mL in oral solution; Epivir contains 150 mg/tab or 10 mg/mL in oral solution. |
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Adult Dose |
100 mg/d PO |
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Pediatric Dose |
<12 years: 3 mg/kg/d |
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Contraindications |
Documented hypersensitivity |
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Interactions |
Trimethoprim/sulfamethoxazole increases bioavailability of lamivudine; lamivudine increases concentration of zidovudine when administered concurrently |
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Precautions |
Caution in pediatric patients with history of prior antiretroviral nucleoside exposure, pancreatitis, or other significant risk factors for pancreatitis; new-generatioucleoside analogues appear to be remarkably free of adverse effects; mild constitutional symptoms such as malaise, fatigue, headache, nausea, and abdominal discomfort have been reported; aminotransferase levels increase in 30-40% of patients; lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported (mostly in women); obesity and prolonged exposure to nucleosides may be risk factors; physician experienced in managing chronic hepatitis B should assess patients before treatment; safety and efficacy is not established in patients with decompensated liver disease or organ transplants, in pediatric patients, and in patients dually infected with HBV, HCV, hepatitis delta, or HIV; reduced dose recommended in impaired renal function |
Hepatic excretory function and bile flow are closely related to bile acid excretion and recirculation. Bile acids, the major products of cholesterol degradation, are incorporated into mixed micelles with cholesterol and phospholipid. These micelles act as an efficient vehicle for solubilization and intestinal absorption of lipophilic compounds, such as dietary fats and fat-soluble vitamins. Secretion of bile acids is the major determinant of bile flow in the mature animal. Accordingly, maturity of bile acid metabolic processes affects overall hepatic excretory function, including biliary excretion of endogenous and exogenous compounds.
In humans, the two primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver. Before excretion, they are conjugated with glycine and taurine. In response to a meal, contraction of the gallbladder delivers bile acids to the intestine to assist in fat digestion and absorption. After mediating fat digestion, the bile acids themselves are reabsorbed from the terminal ileum through specific active transport processes. They return to the liver via portal blood, are taken up by liver cells, and are re-excreted in bile. In an adult, this enterohepatic circulation involves 90–95% of the circulating bile acid pool. Bile acids that escape ileal reabsorption reach the colon, where the bacterial flora, through dehydroxylation and deconjugation, produce the secondary bile acids, deoxycholate and lithocholate. In an adult, the composition of bile reflects the excretion of the primary and also the secondary bile acids, which are reabsorbed from the distal intestinal tract.
Neonates have inefficient ileal reabsorption of bile acids and a low rate of hepatic clearance of bile acids from portal blood. The latter results in elevated serum concentrations of bile acids in healthy newborns, often to levels that would suggest liver disease in older individuals. The size of the bile acid pool in a neonate is about half that of an adult, and the bile acid concentration in the proximal intestinal lumen is similarly decreased to levels that are frequently below the concentration required for micelle formation (2 mM); accordingly, absorption of dietary fats and fat-soluble vitamins is reduced, albeit not sufficiently to produce malabsorption. Transient phases of “physiologic cholestasis” and “physiologic steatorrhea” have a role in the nutrition of low birthweight infants but are of minor importance to healthy full-term newborns. Beyond the neonatal period, disturbances in bile acid metabolism may be responsible for diverse effects on hepatobiliary and intestinal function ( Table 351-2 ).
TABLE 351-2 — Causes of Impaired Bile Acid Metabolism and Enterohepatic Circulation
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DEFECTIVE BILE ACID SYNTHESIS OR TRANSPORT |
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ABNORMALITIES OF BILE ACID DELIVERY TO THE BOWEL |
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LOSS OF ENTEROHEPATIC CIRCULATION OF BILE ACIDS |
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BILE ACID MALABSORPTION |
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Primary bile acid malabsorption (absent or inefficient ileal active transport) |
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Secondary bile acid malabsorption |
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Ileal disease or resection |
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Cystic fibrosis |
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DEFECTIVE UPTAKE OR ALTERED INTRACELLULAR METABOLISM |
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VIRAL HEPATITIS
Acute hepatite can occur or be mimicked in a variety of infectious diseases (cytomegalovirus, Epstein-Barr virus, toxoplasmosis, rubella, scarlet fever, secondary syphilis, salmonellosis, amoebic liver abscess and malaria) in which the liver is not the primary target of infection. Viral infection is the most frequent cause of hepatite in patients, younger than 14 years old. The prophylaxis and treatment of hepatite depends on the identity of the viral etiology.
HEPATITIS A THROUGH E
DEFINITION. Viral hepatitis is a major health problem in developing and developed countries. Recent advances in the field of molecular biology have aided identification and understanding of the pathogenesis of the five viruses that are now known to cause hepatitis as their primary disease manifestation. These hepatotropic viruses are designated hepatitis A, B, C, D, and E. Many other viruses can cause hepatitis as part of their clinical spectrum including herpes simplex, cytomegalovirus, Epstein-Barr, varicella, human immunodeficiency, adenovirus enteroviruses, and arboviruses. Hepatic involvement with these viruses is usually only one component of a multisystem disease.
The five hepatitis viruses are a heterogenous group of viruses that cause similar acute clinical illness. Hepatitis A, C, D, and E are RNA viruses representing four different families, and hepatitis B is a DNA virus.
Hepatitis A and E are not known to cause chronic illness, whereas hepatitis B, C, and D cause important morbidity and mortality through chronic infections. In the
HEPATITIS A
ETIOLOGY. HAV is a 27-nm diameter, RNA-containing virus that is a member of the Picornavirus family. It was isolated originally from stools of infected patients. Laboratory strains of HAV have been propagated in tissue culture. Acute infection is diagnosed by detecting immunoglobulin (Ig)M (IgM) antibodies (anti-HAV) by radioimmunoassay or, rarely, by identifying viral particles in stool.
EPIDEMIOLOGY. HAV infections occur throughout the world but are most common in developing countries, where the prevalence rate approaches 100% in children by the age of 5 yr. In the
PATHOLOGY.
The acute response of the liver to HAV is similar to that of the other four hepatitis viruses. The entire liver is involved with necrosis, most marked in the centrilobular areas, and increased cellularity, which is predominant in the portal areas. The lobular architecture remains intact, although balloon degeneration and necrosis of parenchymal cells occur initially. Fatty change is rare. A diffuse mononuclear cell inflammatory reaction causes expansion in the portal tracts; bile duct proliferation is common, but bile duct damage is not often found. Diffuse Kupffer cell hyperplasia is present in the sinusoids along with infiltration of polymorphonuclear leukocytes and eosinophils. Neonates respond to hepatic injury by forming giant cells. In fulminant hepatitis, total destruction of the parenchyma occurs, leaving only connective tissue septa. By 3 months after the onset of acute hepatitis resulting from HAV, the liver usually is normal morphologically.
Hepatocyte
Other organ systems can be affected during HAV infection. Regional lymph nodes and the spleen may be enlarged. The bone marrow may be moderately hypoplastic, and aplastic anemia has been reported. Small-intestine tissue may show changes in villous structure, and ulceration of the gastrointestinal tract can occur, especially in fatal cases. Acute pancreatitis and myocarditis have been reported rarely, and renal, joint, and skin involvement may result from circulating immune complexes.
PATHOGENESIS.
Injury in acute hepatitis is caused by several mechanisms. The initial injury in hepatitis A is thought to be cytopathic. Regardless of the mechanism of initial injury to the liver, damage from the five hepatitis viruses is evident in three main ways. The first is a reflection of injury to the hepatocytes, which release alanine aminotransferase (ALT, formerly serum glutamate pyruvate transaminase) and aspartate aminotransferase (AST, formerly serum glutamic-oxaloacetic transaminase) into the bloodstream. The ALT is more specific to the liver than the AST, which also can be elevated after injury to erythrocytes, skeletal muscle, or myocardial cells. The height of elevation does not correlate with the extent of hepatocellular necrosis and has little prognostic value. In some cases, a falling aminotransferase level may predict a poor outcome if the decline occurs in conjunction with a rising bilirubin and prolonged prothrombin time (PT). This combination of findings indicates that massive hepatic injury has occurred, resulting in few functioning hepatocytes. Another enzyme, lactate dehydrogenase is even less specific to liver than AST and usually is not helpful in evaluating liver injury. Viral hepatitis is also associated with cholestatic jaundice, in which both direct and indirect bilirubin levels are elevated. Jaundice results from obstruction of biliary flow and damage to hepatocytes. Elevations of serum alkaline phosphatase, 5-nucleotidase, g-glutamyl transpeptidase, and urobilinogen all can reflect injury to the biliary system. Abnormal protein synthesis by hepatocytes is reflected by increased PT. Because of the short half-life of these proteins, the PT is a sensitive indicator of damage to the liver. Serum albumin is another liver-manufactured serum protein, but its longer half-life limits its relevance for monitoring acute liver injury. Cholestasis results in a decreased intestinal bile acid pool and decreased absorption of fat-soluble vitamins. Hepatic injury also may result in changes in carbohydrate, ammonia, and drug metabolism.
CLINICAL MANIFESTATIONS.
The onset of HAV infection usually is abrupt and is accompanied by systemic complaints of fever, malaise, nausea, emesis, anorexia, and abdominal discomfort. This prodrome may be mild and often goes unnoticed in infants and preschool-age children. Diarrhea often occurs in children, but constipation is more common in adults. Jaundice may be so subtle in young children that it can be detected only by laboratory tests. When they occur, jaundice and dark urine usually develop after the systemic symptoms. In contrast to HAV infections in children, most HAV infections in adults are symptomatic and can be severe. Symptoms of HAV infection include right upper quadrant pain, dark-colored urine, and jaundice. The duration of symptoms usually is less than 1 mo, and appetite, exercise tolerance, and a feeling of well-being gradually return. Almost all patients with HAV infection will recover completely, but a relapsing course can occur for several months. Fulminant hepatitis leading to death is rare, and chronic infection does not occur.
DIAGNOSIS. The diagnosis of HAV infection should be considered when a history of jaundice exists in family contacts, friends, schoolmates, day-care playmates, or school personnel or if the child or family has traveled to an endemic area. The diagnosis is made by serologic criteria; liver biopsies rarely are performed. Anti-HAV is detected at the onset of symptoms of acute hepatitis A and persists for life. The acute infection is diagnosed by the presence of IgM anti-HAV, which can be detected for 3–12 mo; thereafter, IgG anti-HAV is found. The virus is excreted in stools from 2 wk before to 1 wk after the onset of illness. Rises are almost universally found in ALT, AST, bilirubin, alkaline phosphatase 5´-nucleotidase, and g-glutamyl transpeptidase and do not help to differentiate the cause. The PT should always be measured in a child with hepatitis to help assess the extent of liver injury; prolongation is a serious sign mandating hospitalization.
DIFFERENTIAL DIAGNOSIS.
The possible causes of hepatitis vary somewhat by age. Physiologic jaundice, hemolytic disease, and sepsis ieonates usually are distinguished easily from hepatitis. After the immediate newborn period, infection remains an important cause of hyperbilirubinemia, but metabolic and anatomic causes (biliary atresia and choledochal cysts) also must be considered. The introduction of pigmented vegetables into the infant’s diet may result in carotenemia, which may be mistaken for jaundice.
In later infancy and childhood, hemolytic-uremic syndrome may be mistaken initially for hepatitis. Reye and Reye-like syndromes present in a similar fashion to acute fulminating hepatitis. Jaundice also may occur with malaria, leptospirosis, and brucellosis and with severe infection in older children, particularly in those with malignant disorders or with immunodeficiency. Gallstones may obstruct biliary drainage and cause jaundice in adolescents as well as in children with chronic hemolytic processes. Hepatitis may be the initial presentation of
Medications, including acetaminophen overdose, valproic acid, and various hepatotoxins, can be associated with a hepatitis-like picture. Drugs well tolerated in healthy children may cause hepatic dysfunction in children with certain illnesses.
COMPLICATIONS.
Children almost always recover from HAV infection. Rarely, fulminant hepatitis can occur, in which a progressive rise in serum bilirubin is accompanied by an initial rise in aminotransferases followed by a fall to normal or low values. Hepatic synthetic function decreases and the PT becomes prolonged, often accompanied by bleeding. The serum albumin falls, causing edema and ascites. The ammonia usually rises and the sensorium becomes altered, progressing from drowsiness to stupor and then deep coma. Progression to end-stage disease and death can occur in less than 1 wk, or can develop more insidiously.
PREVENTION. The recent development of highly immunogenic and safe formalin-killed vaccines marks a major advance in the prevention of hepatitis A. Vaccination of young children in endemic areas is unnecessary because the disease is almost always asymptomatic or mild and confers lifelong immunity. In industrialized countries, vaccination of high-risk children may be of benefit because these children can become carriers of the disease and could infect older siblings and parents who are at greater risk for more severe disease. Vaccination will be of special value to unexposed travelers from developed countries when they travel to hepatitis A–endemic areas.
Enteric precautions should be observed for hospitalized, infected patients who are incontinent of stool or who are in diapers. Careful hand washing is necessary, particularly after changing diapers and before preparing or serving food. Persons infected with HAV are contagious for about 1 wk after onset of jaundice. There is no need to isolate older, continent children, but their stools and fecally contaminated materials should be treated with precautions, and strict hand washing should be practiced.
Standard pooled Ig is effective in modifying clinical manifestations of HAV infection. The prophylactic value is greatest when given early in the incubation period and declines thereafter. Ig is recommended for all susceptible individuals traveling to developing countries. Unimmunized household contacts should receive a single intramuscular dose of Ig as soon as possible after exposure. This is effective in preventing clinical hepatitis, although infection may still occur. Giving Ig more than 2 wk after exposure is not indicated.
Ig is not recommended routinely for sporadic, nonhousehold exposures (e.g., protection of hospital personnel or schoolmates). Mass administration of Ig to schoolchildren has been used when epidemics have been school centered. When HAV occurs in a child-care center with childreot yet toilet trained, Ig should be administered to all children and personnel. It also is advisable to administer Ig to family members of children in diapers.
HEPATITIS B
ETIOLOGY.
HBV is a 42-nm diameter member of the hepadnavirus family, a noncytopathogenic, hepatotropic group of DNA viruses. HBV has a circular, partially double-stranded DNA genome composed of approximately 3,200 nucleotides. Four genes have been identified: the S, C, X, and P genes. The surface of the virus includes two particles designated hepatitis B surface antigen (HBsAg): a 22-nm diameter spherical particle and a 22-nm wide tubular particle with a variable length of up to 200 nm. The inner portion of the virion contains hepatitis B core antigen (HBcAg) and a nonstructural antigen called hepatitis B e antigen (HBeAg), a nonparticulate–soluble antigen derived from HBcAg by proteolytic self-cleavage. Replication of HBV occurs predominantly in the liver but also occurs in lymphocytes, spleen, kidney, and pancreas.
EPIDEMIOLOGY. Worldwide, the areas of highest prevalence of HBV infection are subSaharan Africa,
The most important risk factor for acquisition of hepatitis B infection in children is perinatal exposure to an HBsAg-positive mother. The risk of transmission is greatest if the mother also is HBeAg positive; 70–90% of their infants become chronically infected if untreated. During the neonatal period, hepatitis B antigen is present in the blood of 2.5% of infants born to affected mothers, indicating that intrauterine infection occurred. In most cases, antigenemia appears later, suggesting that transmission occurred at the time of delivery; virus contained in amniotic fluid or in maternal feces or blood may be the source. Although most infants born to infected mothers become antigenemic from 2–5 mo of age, some infants of HBsAg-positive mothers are not affected until later ages.
HBsAg has been demonstrated inconsistently in milk of infected mothers. Breast-feeding of unimmunized infants by infected mothers does not appear to confer a greater risk of hepatitis on offspring than does artificial feeding despite the possibility that cracked nipples may result in the ingestion of contaminated maternal blood by the nursing infant.
Other important risk factors for HBV infection in children include intravenous acquisition by drugs or blood products, sexual contact, institutional care, and contact with carriers. Chronic HBV infection, which is defined as being HBsAg positive for 6 or more mo, is associated with chronic liver disease and with primary hepatocellular carcinoma, the most important cause of cancer-related death in the Orient.
HBV is present in high concentrations in blood, serum, and serous exudates and in moderate concentrations in saliva, vaginal fluid, and semen. For these reasons, efficient transmission occurs through blood exposure and sexual contact. The incubation period ranges from 45–160 days, with a mean of about 100 days.
PATHOLOGY.
The acute response of the liver to HBV is the same as that for all the hepatitis viruses. Persistence of histologic changes in patients with hepatitis B, C, or D indicates development of chronic liver disease.
PATHOGENESIS.
Hepatitis B, unlike the other hepatitis viruses, is a noncytopathic virus that probably causes injury by immune-mediated mechanisms. The first step in the process of acute hepatitis is infection of hepatocytes by HBV, resulting in the appearance of viral antigens on the cell surface. The most important of these viral antigens may be the nucleocapsid antigens, HBcAg and HBeAg, a cleavage product of HBcAg. These antigens, in combination with class I major histocompatibility (MHC) proteins, make the cell a target for cytotoxic T-cell lysis.
The mechanism for development of chronic hepatitis is less well understood. To permit hepatocytes to continue to be infected, the core protein or MHC class I protein may not be recognized, the cytotoxic lymphocytes may not be activated, or some other as yet unknown mechanism may interfere with destruction of hepatocytes. For cell-to-cell infection to continue, some virus-containing hepatocytes must survive.
Immune-mediated mechanisms also are involved in the extrahepatic conditions that can be associated with HBV infections. Circulating immune complexes containing HBsAg can occur in patients who experience associated polyarteritis, glomerulonephritis, polymyalgia rheumatica, mixed cryoglobulinemia, and the Guillain-Barré syndrome.
Mutations of HBV are more common than for the usual DNA viruses, and a series of mutant strains have been recognized. The most important is one that results in failure to express HBeAg and has been associated with development of severe hepatitis and perhaps more severe exacerbations of chronic HBV infection.
CLINICAL MANIFESTATIONS.
Many cases of HBV infection are asymptomatic, as evidenced by the high carriage rate of serum markers in persons who have no history of acute hepatitis. The usual acute, symptomatic episode is similar to HAV and hepatitis C virus (HCV) infections but may be more severe and is more likely to include involvement of skin and joints. The first clinical evidence of HBV infection is elevation of ALT, which begins to rise just before the development of lethargy, anorexia, and malaise, about 6–7 wk after exposure. The illness may be preceded in a few children by a serum sickness–like prodrome including arthralgia or skin lesions, including urticarial, purpuric, macular, or maculopapular rashes. Papular acrodermatitis, the Gianotti-Crosti syndrome, also may occur. Other extrahepatic conditions associated with HBV infections include polyarteritis, glomerulonephritis, and aplastic anemia. Jaundice, which is present in about 25% of infected individuals, usually begins about 8 wk after exposure and lasts for about 4 wk. In the usual course of resolving HBV infection, symptoms are present for 6–8 wk. The percentage of people in whom clinical evidence of hepatitis develops is higher for hepatitis B than for hepatitis A, and the rate of fulminant hepatitis also is greater. Chronic hepatitis also occurs, and the chronic active form can result in cirrhosis and hepatocellular carcinoma.
On physical examination, skin and mucous membranes are icteric, especially the sclera and the mucosa under the tongue. The liver usually is enlarged and tender to palpation. When the liver is not palpable below the costal margin, tenderness can be demonstrated by striking the rib cage over the liver gently with a closed fist. Splenomegaly and lymphadenopathy are common.
DIAGNOSIS.
The serologic pattern for HBV is more complex than for HAV and differs depending on whether the disease is acute, subclinical, or chronic.
Routine screening for hepatitis B requires assay of at least two serologic markers. HBsAg is the first serologic marker of infection to appear and is found in almost all infected persons; its rise coincides closely with the onset of symptoms. HBeAg is often present during the acute phase and indicates a highly infectious state. Because HBsAg levels fall before the end of symptoms, IgM antibody to hepatitis B core antigen (IgM anti-HBcAg) also is required because it rises early after infection and persists for many months before being replaced by IgG anti-HBcAg, which persists for years. IgM anti-HBcAg usually is not present in perinatal HBV infections. Anti-HBcAg is the most valuable single serologic marker of acute HBV infection because it is present almost as early as HBsAg and continues to be present later in the course of the disease when HBsAg has disappeared. Only anti-HBsAg is present in persons immunized with hepatitis B vaccine, whereas anti-HBsAg and anti-HBcAg are detected in persons with resolved infection.
COMPLICATIONS.
Acute fulminant hepatitis occurs more frequently with HBV than with the other hepatitis viruses, and the risk of fulminant hepatitis is further increased when there is coinfection or superinfection with HDV. Mortality from fulminant hepatitis is greater than 30%. Liver transplantation is the only effective intervention; supportive care aimed at sustaining the patient while providing the time needed for regeneration of hepatic cells is the only other option.
HBV infections also can result in chronic hepatitis, which can lead to cirrhosis and primary hepatocellular carcinoma. Interferon alpha-2b is available for treatment of chronic hepatitis B in persons 18 years of age or older with compensated liver disease and HBV replication. Membranous glomerulonephritis with deposition of complement and HBeAg in glomerular capillaries is a rare complication of HBV infection.
PREVENTION.
Universal immunization of infants with hepatitis B vaccine is now recommended by the
Infants born to HBsAg-positive women should receive vaccine at birth, 1 mo, and 6 mo of age. The first dose should be accompanied by administration of 0.5 mL of hepatitis B immunoglobulin (HBIG) as soon after delivery as possible because the effectiveness decreases rapidly with increased time after birth. The AAP recommends that infants born to HBsAg-negative women receive the first dose of vaccine at birth, the second at 1–2 mo of age, and the third between 6 and 18 mo of age.
The methods of prevention of hepatitis B infection depend on the conditions under which the person is exposed to hepatitis B, and the dose is dependent on the age of the person.
HEPATITIS C
ETIOLOGY. HCV is now recognized as the cause of almost all of the parenterally acquired cases of what was previously known as non-A, non-B hepatitis. The virus has not been isolated but has been cloned using recombinant DNA technology. Molecular biologic analysis has demonstrated that HCV is a single-strand RNA virus that has been classified as a separate genus within the Flaviviridae family. HCV is an enveloped virus, 50–60 nm in size, that is transmitted mainly by blood or blood products, intravenous drug use, and sexual contact. Chronic liver disease is common in infected individuals.
EPIDEMIOLOGY.
The most important risk factors for HCV transmission in the
PATHOLOGY. The pattern of acute injury is similar to that of the other hepatitis viruses. In chronic cases, lymphoid aggregates or follicles in portal tracts are seen either alone or as part of a general inflammatory infiltration of the tracts.
PATHOGENESIS. HCV appears to cause injury primarily by cytopathic mechanisms, but immune-mediated injury also may occur. The cytopathic component appears to be mild, because the acute form is typically the least severe of all hepatitis virus infections; HCV rarely is fulminant.
CLINICAL MANIFESTATIONS.
The clinical pattern of the acute infection is usually similar to that of the other hepatitis viruses. HCV is the most likely hepatitis virus to cause chronic infection; about two thirds of post-transfusion infections and about one third of sporadic, community-acquired cases will become chronic. Typically, a fluctuating pattern of aminotransferase elevations occurs in about 80% of those in whom chronic HCV develops. Although chronic elevations of aminotransferase levels are common, chronic HCV will progress to cirrhosis in only about half of the patients, or about 25% of all those initially infected. Primary hepatocellular carcinoma can develop in patients with cirrhosis, but HCV is less effective than HBV in causing primary hepatocellular carcinoma. The hepatocellular carcinoma associated with HCV probably results from chronic inflammation and necrosis rather than an oncogenic effect of the virus.
Hepatitis C in the newborn
DIAGNOSIS.
The clinically available serologic assays for HCV are based on development of antibodies to HCV antigens because no detectable antigens have been found in blood. The assays are used mainly for detection of chronic hepatitis C because they remain negative for at least 1–3 mo after the clinical onset of illness. The second-generation assays are the current standard and test for three of the five known antigenic epitopes. They have improved sensitivity over the first-generation tests but still have a 10% false-negative rate. Assays for viral RNA (polymerase chain reaction [PCR], in situ hybridization) are costly, time consuming, and available only in research situations.
COMPLICATIONS.
The risk of fulminant hepatitis is low with HCV, but the risk for chronic hepatitis is the highest among the hepatitis viruses. The usual chronic course is mild even when cirrhosis develops; long-term follow-up indicates that the overall mortality of persons with transfusion-acquired HCV is no different from that of noninfected controls. Interferon alpha-2b is available for treatment of chronic hepatitis in persons 18 yr of age or older with compensated liver disease who have a history of blood or blood product exposure or who are HCV antibody positive or both.
PREVENTION.
There is no vaccine available, and none may be developed because animal studies suggest that HCV infection does not lead to protective immunity; the same individual can be infected multiple times with the same virus. Ig has not proven to be of benefit. Ig manufactured in the
HEPATITIS D
ETIOLOGY.
Hepatitis D virus (HDV), the smallest known animal virus, is considered defective because it cannot produce infection without a concurrent HBV infection. The 36-nm diameter virus is incapable of making its own coat protein; its outer coat is composed of excess HBsAg from HBV. The inner core of the virus is single-stranded circular RNA, which expresses the HDV antigen.
EPIDEMIOLOGY. HDV infection cannot occur without HBV as a helper virus. Two patterns of infection are seen. Transmission usually occurs by intrafamilial or intimate contact in areas of high prevalence, which are primarily developing countries. In areas of low prevalence, such as the
PATHOLOGY. There are no distinguishing features of liver disease in HDV hepatitis except that the damage is usually more severe.
PATHOPHYSIOLOGY.
In contrast to HBV, HDV causes injury directly by cytopathic mechanisms. Many of the most severe cases of hepatitis B appear to be due to combined infection with HBV and HDV. Coinfection with HBV and HDV occurs most frequently in areas of high prevalence. The second mechanism of pathogenesis is superinfection of a person who has chronic HBV, which is more common in developed countries.
CLINICAL MANIFESTATIONS.
The symptoms of hepatitis D infection are similar to but usually more severe than those of the other hepatitis viruses. The clinical outcome for HDV infection depends on the mechanism of infection. In coinfection, acute hepatitis, which is much more severe than for HBV alone, is common, but the risk for chronic hepatitis is low. In superinfections, acute illness is rare, whereas chronic hepatitis is common. However, the risk of fulminant hepatitis is highest in superinfection. Hepatitis D should be considered in any child who experiences acute hepatic failure.
DIAGNOSIS.
The virus has not been isolated, and no circulating antigen has been identified. The diagnosis is made by detecting IgM antibody to HDV; the antibodies to HDV develop about 2–4 wk after coinfection and about 10 wk after superinfection. PCR assays for viral RNA are available but only as a research tool.
COMPLICATIONS. HDV must be considered in all cases of fulminant hepatitis.
PREVENTION. There is no vaccine for hepatitis D. However, because HDV cannot occur without hepatitis B infection, HBV prevention eliminates HDV. HBIG and hepatitis B vaccines are used for the same indications as hepatitis B.
HEPATITIS E
ETIOLOGY. Hepatitis E virus (HEV) has not been isolated but has been cloned using molecular techniques. This RNA virus has a nonenveloped, sphere shape with spikes and is similar to the caliciviruses. Infection is associated with shedding of 27- to 34-nm particles in the stool.
EPIDEMIOLOGY. Hepatitis E is the epidemic form of what was formally called non-A, non-B hepatitis. Infection is transmitted enterically, the highest prevalence has been reported in the Indian subcontinent, the Middle East, and
PATHOLOGY. The pathologic findings are similar to those of the other hepatitis viruses.
PATHOGENESIS. HEV appears to act as a cytopathic virus.
CLINICAL MANIFESTATIONS. The clinical illness in hepatitis E is similar to that of hepatitis A, the other enterically transmitted virus, but it is often more severe. Both viruses produce only acute disease; chronic illness does not occur. In addition to causing more severe illness than HAV, hepatitis E affects older patients, with a peak incidence between 15 and 34 yr. Another important clinical difference is that HEV has a high fatality rate in pregnant women.
DIAGNOSIS.
Recombinant DNA technology has resulted in the development of an antibody to HEV particles, but serologic tests are not yet commercially available. IgM antibody to viral antigen becomes positive after about 1 wk of illness.
PREVENTION.
No vaccines are available, and there is no evidence that Ig is effective in preventing hepatitis E infections. However, Ig pooled from patients in endemic areas may prove to be effective.
Short statement of the material
Acute hepatitis is a continuing hepatic inflammatory process manifested by elevated hepatic transaminase level, lasting less than 6 mo and accompanied with pain, dyspeptic, intoxication and cholestatic syndromes
Etiology
· HAV is RNA-containing virus 27-30 nm in diameter;
· HBV is DNA-containing virus from HepaDNA viruses family of, 42 nm in diameter;
· HCV is virus 22-60 nm in diameter, probably flavivirus family;
· HDV is virus 35-37 nm in diameter with small RNA and HB virus shell;
· HEV is virus-like particle of spherical form 27 nm in diameter;
· HGV, HFV, TTV – viruses are insufficiently known.
Epidemiology:
Source of infection – carries of viruses, ill person;
Way of spreading – alimentary for HAV and HEV;
parenteral and vertical, sexual, micro traumas for HBV, HCV, HD, HFV and TTV; Susceptibility is high.
HAV, HEV
ü the source is a patient with typical and atypical forms of infection, and viral carrier;
ü the mechanism of transmission is fecal-oral, usually realized by the contaminated food, water and by direct contact;
ü receptivity – HAV 70-80 % (children elder than 1 year), HEV is probably high.
HBV, HCV, HDV
ü source – viral carriers, patients with acute and chronic forms;
ü mechanism of transmission:
ü parenteral;
• vertical (transplacental, at breast feeding);
• sexual (micro trauma);
• domestic (micro trauma);
ü receptivity is the greatest at children of early age, people elder than 30 years.
Pathogenesis:
Hepatitis A, E
1. Inoculation of the pathogen (entrance gate – small intestine).
2. Viremia.
3. Viral fixation on hepatocytes, intracellular localization.
4. Primary replication of the virus.
5. Excretion with a goal to intestine.
6. Part of the viruses caused viremia (prodromal period of the disease).
7. Activation of immune system, that causes cytolysis, mesenchimal inflammation and cholestasis.
8. Immune response, elimination of the virus.
Hepatitis B
1. Inoculation of the pathogen.
2. Viremia.
3. Viral integration and replication in hepatocytes, also may be in blood cells, bone marrow, lymph nodes, spleen.
4. Activation of immune system, that causes cytolysis, mesenchimal inflammation and cholestasis.
5. Immune response, elimination or persistence of the virus.
Hepatitis C
1. Inoculation of the pathogen.
2. Viremia.
3. Viral integration and replication in hepatocytes, also may be in blood cells, bone marrow, lymph nodes, spleen.
4. Activation of immune system with low immune response.
5. Mutation changeability of the virus.
6. Persistence of the virus.
Hepatitis D
Need virus hepatitis B for its replication, develops only in infected HBV patients.
Classification
Type: –
ü typical (jaundice);
ü atypical:
§ without jaundice (unicteric hepatitis);
§ effaced;
§ subclinical hepatitis.
§ Cholestatic hepatitis
§ Fulminant hepatitis
Severity:
ü mild
ü moderate
ü severe
Course:
ü acute (2-3 months);
ü prolonged (3-6 months);
ü chronic.
Periods:
• Incubation
• Pre-icteric
• Icteric
• Post-icteric
• Convalescent
Diagnostic criterions of incubation period
· absence of clinical signs
· viral antigens are present in blood
· alanine aminotranspherase, aspartate aminotranspherase may be enlarged.
Prodromal (prejaundice, preicteric) period
· headache
· rashes (often in HBV-hepatitis)
· Arthralgias Carole’s triad
· “flu like syndrome”
· dyspepsia
· hepatomegaly, pain in right costochondrial rib, epigastrium
· in the end – appearing of clay-colored stools
· Enlargement of ALAT and ASAT, urobilinuria, special hepatitis markers.
Jaundice (icteric) period
· Jaundice of mucous membranes, sclera, and skin (photo).
· Urobilinuria, bilirubinuria.
· Hepatomegaly (photo), tenderness of liver.
· ALAT and ASAT are maximally enlarged.
· Hyperbilirubinemia with conjugate bilirubin prevalence.
· skin rashes
· hemorrhagic syndrome
· splenomegaly
Laboratory tests
Prodromal period
· Enlargement of ALAT and ASAT, urobilinuria.
· Anti-HAV Ig M, HAV-RNA (hepatitis A).
· HBsAg, HBeAg, HBV-DNA and anti-НВс IgM (hepatitis B).
· HBsAg, HBeAg, HBV-DNA, anti-НВс IgM and HDVAg, HDV-RNA (hepatitis delta coinfection).
· HCV-RNA (hepatitis C).
· Anti-HEV Ig M, HEV-RNA (hepatitis E).
Jaundice period
Nonspecific tests
· enlargement of ALAT and ASAT ,
· hyperbilirubinemia with conjugate bilirubin prevalence,
· marking of bile pigment in urine,
· increased sediment tymol test
· decreased sulemic test (severe hepatitis B)
· decreased prothrombine index, fibrinogen
· in cholestasis alkaline phosphatase, cholesterol, GGTP are increased
Specific tests (markers)
· Anti-HAV Ig M, HAV-RNA (hepatitis A).
· HBsAg, HBeAg, HBV-DNA and anti-НВс IgM (hepatitis B).
· HBsAg, HBeAg, HBV-DNA, anti-НВс IgM and HDVAg, anti-HDV IgM, HDV-RNA.(hepatitis delta coinfection)
· HCV-RNA, anti-HCVcore IgM and IgG (acute hepatitis C).
· Anti-HEV Ig M, HEV-RNA (hepatitis E).
Severity criterions (in icteric period)
|
Signs |
Mild |
Moderate |
Severe |
|
Degree of intoxication in preicteric period, body temperature |
mild, short, subfebrile |
Moderate, t 38-39 °С (in preicteric period) |
Severe, t° 39 and more |
|
Jaundice |
mild |
Mild-to moderate |
severe |
|
Liver size increases |
Up to 2 сm |
On 2- |
More than |
|
Bilirubin increase indirect bilirubin increase |
Up to 85 mcmol/l Up to 25 |
85-200 25-50 |
> 200 > 50 |
|
Aminotranspherases level |
5-10 times more thaorm
|
10-15 times more thaorm |
15-30 times more thaorm |
|
Protrombin index |
70-80 %
|
60-70 % |
< 60% |
|
Tymol test |
Mild increased |
moderately increased |
Very increased |
|
Normalization of the liver sizes |
On 25-35 day from the beginning |
On 40-50 day |
On 50-60 day |
|
When the jaundice appears the toxic sign |
Decreased |
Continue for 2-3 days
|
continue, sometimes increases |
|
splenomegaly |
–– |
In 1.5 % |
Is typical |
|
Diuresis |
normal |
decreased |
Severe decreased |
|
Sulemic test |
normal |
normal |
decreased |
|
Duration of icteric phase |
7-10 days |
1-2 wks |
2-3 wks |
Posticteric period
· Urine becomes lighter
· Stools darker
· Jaundice fades
· Decreasing ALAT, ASAT
· Decreasing of the liver sizes
· Normalization of bilirubin, ALAT and ASAT, other indexes, later – sediment tymol test
· Anti-HAV Ig G, HAV-RNA (hepatitis A).
· Anti-НВс IgM , anti-Нве IgM, later- anti-НВс (total) IgM and anti-НВс IgG (hepatitis B).
· Anti-НВс IgM , anti-Нве IgM, later- anti-НВс (total) IgM and anti-НВс IgG and anti-HDV IgG (hepatitis D).
· Anti-HCVcore IgG (past hepatitis C).
· Anti-HCVcore IgG, anti-HCV NS in hepatitis C latent phase.
· Anti-HCVcore IgM and IgG (with IgM predominance), anti-HCV NS and HCV-RNA in hepatitis C reactivation phase.
· Anti-HEV Ig G (hepatitis E).
Fulminant form criteria:
ü Acute failure of the liver
ü Confusion and drowsiness
ü Delirium and convulsions
ü Liver gets smaller
ü Coma I-II ESG is abnormal
ü Hepatic smell
ü Hemorrhagic syndrome
ü Encephalopathy
ü Decreasing of diuresis
ü Total bilirubin is increased
ü Protrombin time is prolonged
ü Decreasing of ALAT, ASAT
ü Decreasing of proteins
Atypical (unicteric, effaced, subclinical) forms criteria:
ü Contact with patient who had hepatitis
ü Hepatomegaly
ü increasing of ALAT, ASAT, tymol test
Outcome of disease
For HAV, HEV
ü Recovering
ü Residual fibrosis of liver (posthepatitis hepatomegaly)
ü Biliary dyskinesia
ü Chronic cholecystitis and cholecystocholangitis
For HBV, HCV , HDV
ü Recovering
ü Residual fibrosis of liver (posthepatitis hepatomegaly)
ü Biliary dyskinesia
ü Chronic cholecystitis and cholecystocholangitis
ü transition in chronic hepatitis;
ü cirrhosis
ü hepatic carcinoma
ü death.
Diagnosis example: Hepatitis A, typical form, icteric period, mild severity, acute course
Differential diagnosis
Prejaundice period:
ü viral upper respiratory tract infections,
ü bowel infection,
ü acute appendicitis,
ü diseases caused by parasites,
ü acute pancreatitis.
Jaundice period:
ü suprahepatic icterus (hemolytic anemia),
ü hepatic icterus (Gilbert, Krigler-Nadjar syndrome, infectious mononucleosis, leptospirosis, pseudotuberculosis, congenital liver diseases, ),
ü subhepatic icterus (mechanical jaundice).
Differential diagnosis of viral hepatitis
|
Signs |
HB |
HA |
HC |
HE |
HD |
|
Patients age |
All age groups |
Elder than 1 yr. |
All age groups |
Elder than 1 yr. |
All age groups |
|
Incubation period |
2-6 mo. |
14-45 days |
2 wks. – 3 mo. |
15-45 days |
2 wks. – 6 mo. |
|
Початок хвороби |
subacute |
acute |
subacute |
acute |
acute |
|
Intoxication in preicteric period |
mild |
moderate |
mild |
moderate |
Often moderate |
|
Intoxication in icteric period |
severe |
mild |
Absent or mild |
Absent or mild |
severe |
|
Allergic rashes |
May be present |
Absent |
May be present |
Absent |
May be present |
|
Severity |
Often moderate and severe |
Mild and moderate |
Mild and moderate |
Mild |
Severe and fulminant |
|
Duration of the icteric period |
3-5 wks |
1-1.5 wks |
2 wks |
1-2 wks |
2-8 wks |
|
transition in chronic hepatitis |
Often – primary chronic |
–– |
in 50 % |
–– |
often |
|
Tymol test |
Often normal |
elevated |
Moderately elevated |
high |
Moderately elevated |
|
Specific markers |
HbsAg HbeAg anti НВс IgМ |
anti HAV IgМ |
anti HCV РНК HCV |
anti HEV |
HBsAg, anti НВс, anti HDV IgМ. |
Treatment:
Basic treatment:
ü bed regimen up to intoxication disappear,
ü half-bed regimen (up to icterus disappear, normalization of ALAT, ASAT)
ü special diet (diet N 5),
o Exclude heavy fats (like pork), spices, fried foods, “fast food””; avoid stimulators of gastrointestinal secretions, the diet must be rich by metionine, lecithin, and choline to stimulate synthesis of proteins and enzymes in the liver. Diet with normal value of proteins and vitamins, with restriction of fats and carbohydrates is administered, also restrict salt.
o Foods boiled, steamed and baked are recommended; food taking 5 times daily
Treatment of mild hepatitis – only basic therapy
Treatment of moderate hepatitis
ü basic therapy
ü peroral detoxication 40-50 ml/kg with water balance control
ü enterosorption 1-2 wks (in case of cholestatic variant)
ü choleretics from the 3-d week of disease
• cholagon
• allocholum
• cholenzym
• galstena
• hepabene
Treatment of severe hepatitis
• basic therapy,
• intravenous detoxication therapy (total – 50-100 ml/kg/day):
– 0.9 % NaCl, Ringer’s solution,
– Ringer’s lactate solution,
– 5 % glucose,
– albumin 5 ml/kg;
• enterosorption 2-3 wks,
• lactulose for 10-14 days,
• desoxycholic acid (ursophalk) in case of cholestasis 10 mg/kg,
• prednizone (in possibility of fulminant form development) and for infants before 1 year with unfavorable premorbid background): in daily dose 2-3 mg/kg 4 times per day divided in equal doses during 7-10 days,
• Hepatoprotectors in severe cases in posticteric period
• Heptral (tabl. –
• Essentiale (caps., amp.) 1-2 cap. 3 times a day,
• Carsil (dragee) 1-2 dragee 3 times a day,
• Hepabene 1-2 dragee 3 times a day,
• Thiotriazolinum 1 tabl. 3 times a day,
• Chophytol 1-2 tabl. 3 times a day.
Treatment of fulminant form
• straight bed regimen,
• diet N 5a with protein restriction up to 40 %,
• intravenously:
• prednizone 10-15 mg/kg/day divided in 4 equal doses,
• detoxication therapy (total – 50-100 ml/kg/day) with diuresis control:
• 0.9 % NaCl, Ringer’s solution,
• Ringer’s lactate solution,
• 5 % glucose,
• albumin 5 ml/kg;
• extracorporeal detoxication in case of ineffective previous therapy (plasmapheresis),
• hyperbaric oxygenation,
• in case of edema, ascytis – water-electrolyte balance correction,
• K-serving diuretics (verospiron, triampur),
• Fresh frozen plasma 10 ml/kg as coagulation factors donator,
• Heparin 100-300 IU/kg in possibility of DIC-syndrome development,
• Protease-inhibitors (trasilol, contrical, gordox) in case of DIC-syndrome development,
• Antibacterial therapy for bacterial complication prevention (less hepatotoxic medicine),
• Enema and stomach-washing,
• Lactulose for 10-14 days.
Discharge from the hospital, supervision, control:
ü patients with mild and moderate forms can be treated at home;
ü discharge on 15-20 day of illness with the remaining phenomena (hepatomegaly, slight increased ALAT, ASAT, dysproteinemia);
ü Finish treatment in dispensary cabinet: first examination – in 7 days, then – in 1, 3, 6 months. In absence of the remaining phenomena – stop dispensarization;
ü can visit school on 40-50 day, release from physical education on 3-6 months, sport – 12 months
Prophylaxis of A, E hepatitis
· Early isolation of ill person.
· Looking after contacts, laboratory test every 10 – 15 days.
· Personal hygiene.
· Disinfection in the epidemic focus.
· Passive prophylaxis by human immune globulin.
Prophylaxis of parenteral hepatitis
· Early isolation of ill person.
· Sterilization of instrument.
· Passive prophylaxis by human immune globulin.
For hepatitis B active prophylaxis: after the birth, in 1, 6 months. When mother is HBs Ag positive – after the birth, in 1, 2, 12 months.
