CHRONIC HEPATITIS IN CHILDREN

1. CHRONIC HEPATITIS IN CHILDREN

2. CLASSIFICATION * • Viral • Autoimmune • Drug induced • Metabolic

3. VIRAL * • Hepatitis B • Hepatitis C • Hepatitis D

4. Clinics * • No sign or verysubtlesigns • Yellow discoloration of the sclera, skin, and mucous membranes hyperbilirubinemia. Clinically apparent jaundice in children and adults occurs when the serum concentration of bilirubin reaches 2–3 mg/dL (34–51 μmol/L); however, the neonate may not appear icteric until the bilirubin level is over 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 may appear only mildly jaundiced, but has dark urine or acholic (light-colored) stools • Intense generalized itching may occur in patients with cholestasis (conjugated hyperbilirubinemia • Enlargement of the liver can be due to several mechanisms in viral—acute andchronicdiseases, specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman disease, 1-antitrypsin deficiency, Wilson disease, hypervitaminosis A, neonatal ironstoragedisease • Vascular spiders (telangiectasias), characterized by central pulsating arterioles from which small, wiry venules radiate, may be seen in patients with chronic liver disease, usually most prominent in the face and chest. These are presumably reflective of altered estrogen metabolism in the presence of hepatic dysfunction. • PALMAR ERYTHEMAmost noticeable over the thenar and hypothenar eminences and on the tips of the fingers • Xantomas: deposition of lipid in the dermis and subcutaneous tissue. Brown nodules may develop first over the extensor surfaces of the extremities; rarely, xanthelasma of the eyelids develops.

5. PORTAL HYPERTENSION. * ASCITES VARICEAL HEMORRHAGE HEPATIC ENCEPHALOPATHY: ENDOCRINE ABNORMALITIES. RENAL DYSFUNCTION (functional renal failure in patients with end-stage liver disease) RECURRENT CHOLANGITIS. Nonspecific signs of acute and chronic liver disease include anorexia, abdominal pain or distentionmalnutrition and growth failure,bleeding, which may be due to altered synthesis of coagulation factors

6. Laboratory * • Acute livercellinjury (parenchymaldisease) in viral hepatitisreflects in markedincreases in serumaminotransferaselevels • Cholestasis (obstructive disease) involvesregurgitation of bile componentsintoserum; theserumlevels of total andconjugatedbilirubinandserum bile acids are elevated. Elevations in serumalkalinephosphatase, 5′ nucleotidase (5′ NT), andγ-glutamyltranspeptidase (GGT) levels are alsosensitiveindicators of obstruction or inflammation of thebiliarytract. • Severity : hypoglycemia, hyperammonemia, electrolyteimbalance, continuedhyperbilirubinemia, markedhypoalbuminemia, or prolonged PT or INR unresponsiveto parenteral administration of vitamin K). .

7. * • An elevation in the conjugated bilirubin level provides a relatively sensitive index of hepatocellular disease and hepatic excretory dysfunction • Cholesterol levels may is markedly elevated in patients with cholestasis, whether the cause is intrahepatic or extrahepatic. On the other hand, with acute liver disease, such as hepatitis, serum cholesterol levels may be depressed

8. IMAGING * • Ultrasonography (US) provides information about the size, composition, and blood flow of the liver. Increased echogenicity is observed with fatty infiltration, and mass lesions as small as 1–2 cm may be shown. US has replaced cholangiography in detecting stones in the gallbladder or biliary tree • Computed tomography (CT) scanning provides information similar to that obtained by US but is less suitable for use in patients younger than 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. Magnetic resonance imaging (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. • Radionuclide scanning relies on selective uptake of a radiopharmaceutical agent

9. Liver biopsy is the undisputed best way to assess liver fibrosis or * cirrhosis; however, it is an invasive procedure that can cause rare, but potentially life-threatening complications; less invasive ways to diagnose liver disease, developing and testing clinical tools, like the Original European Liver Fibrosis Panel and transient elastography.

10. HEPATITIS B * • Hepatitis B S Ag > 6 months • Variable biochemical tests • Congenital ( 85% rate) or acquired • Other Markers: DNA PCR, HBe Ag, Anti-HB c , Anti- HB e • 1-5% of acute attacks become chronic • 70 % cirrhosis • HCC carcinoma ( monitor alpha fetoprotein)

11. HEPATITIS B * • Hepatitis B vaccine • Hepatitis immunoglobulin • Treatment: Interferon or Lamuvidine.

12. * • HBV is a 42-nm-diameter member of the Hepadnaviridae family, a noncytopathogenic, hepatotropic group of DNA viruses. HBV has a circular, partially double-stranded DNA genome • The surface of the virus includes two particles designated hepatitis B surface antigen (HBsAg): • The inner portion of the virion contains hepatitis B core antigen (HBcAg), the nucleocapsid that encodes the viral DNA, and a nonstructural antigen called hepatitis B e antigen (HBeAg), • HBeAg serves as a marker of active viral replication. Replication of HBV occurs predominantly in the liver but also occurs in the lymphocytes, spleen, kidney, and pancreas.

13. Chronic hepatitis B remains a major public health problem, affecting approximately about 350 million people globally. The number of hepatitis B virus (HBV) infected children has not been fully documented. The natural history of HBV infection reflects the dynamic host-virus interactions related to the condition of the host immune system; hence, the clinical course of HBV differs between children and adults. The immaturity of immune system in young children is responsible for the fact that nearly 90% of HBV infections acquired in infancy and 40-70% HBV infections before the age of 3 years result in chronic carrier state of the virus. Therefore a large population is in need of effective and save treatment of this disease. Significant advances have been made during the last decades in the treatment of chronic hepatitis B. The epidemiological situation of HBV infection, its natural history, clinical outcome with its serious long-term consequences and therapeutical approach in children are reviewed in the paper.

14. HEPATITIS C * • Congenital 1-10% or acquired • Anti HCV: maternal persist up to 18 months, takes 6 weeks to show. • HCV RNA: I U • 6 genotypes 1-6- geographically variable and determines the response to therapy • Peg-Interferon and Ribavirin ( duration depends on genotype)

15. The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease. Inthe United States, the Centers for Disease Control and prevention estimates that there are more than 2.7 million people with ongoingHCVinfection. • HCVis the leadingcause of death from liver disease in the United States. .

17. Liver transplantation * • This procedure is an effective form of therapy for patients with decompensated cirrhosis caused by autoimmune hepatitis. This procedure also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis. • The long-term outlook after liver transplantation is excellent, with 5-year survival rates reported at 90% or more. Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.

18. HEPATITIS D * • Co-infection with B • Outcome similar to B

19. Autoimmune hepatitis * • Autoimmune hepatitis is now accepted as a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis. Immune serum markers frequently are present, and the disease often is associated with other autoimmune diseases. • Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.

20. Autoimmune * • 2 Types serologically • ASMA, LKM ( liverkidneymicrosomes) • Hypergammaglobuliniemia • Elevated LFT • Treatment: Prednisone and Azathioprine. • High relapse rate

21. Pathophysiology * • autoimmunehepatitisistheresult of a cell-mediatedimmunologicattack. T • thisattackisdirectedagainstgeneticallypredisposedhepatocytes. Aberrant display of humanleukocyte antigen (HLA) class II on thesurface of hepatocytesfacilitatesthepresentationof normal livercell membrane constituentstoantigen-processingcells. Theseactivatedcells, in turn, stimulate theclonalexpansion of autoantigen-sensitizedcytotoxic T lymphocytes. • cytotoxic T lymphocytes infiltrate livertissue, releasecytokines, andhelptodestroylivercells.

22. The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection), chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens. Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This condition is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients. HLA DR3-positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy; these patients are younger than other patients at the time of their initial presentation. HLA DR4-positive patients are more likely to develop extrahepatic manifestations of their disease

23. CLINICS * • Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis. • Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve spontaneously; however, patients invariably develop signs and symptoms of chronic liver disease. Other patients experience rapid progression of the disease to acute liver failure, as marked by coagulopathy and jaundice. Ascites and hepatic encephalopathy also may ensue.

24. The chronic hepatitis associated with autoimmune * hepatitis may range in severity from a subclinical illness without symptoms and with abnormal results on liver chemistries to a disabling chronic liver disease. Symptoms and physical examination findings may stem from the various extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following: • Fatigue • Upper abdominal discomfort • Mild pruritus • Anorexia • Myalgia • Diarrhea • Cushingoid features • Arthralgias • Skin rashes (including acne) • Edema • Hirsutism • Amenorrhea • Chest pain from pleuritis • Weight loss and intense pruritus (unusual)

25. POZITIVE DIAGNOSIS * • Evidence for an autoimmunepathogenesisincludesthefollowing: • Hepatic histopathologiclesionscomposedpredominantly of cytotoxic T cellsand plasma cells • Circulatingautoantibodies (ie, nuclear, smoothmuscle, thyroid, liver-kidneymicrosomal, solubleliver antigen, hepatic lectin) • Association withhypergammaglobulinemiaandthepresence of a rheumatoid factor • Association withotherautoimmunediseases • Responseto steroid and/or immunosuppressivetherapy

26. * • Antinuclear antibody (ANA), primarily in a homogenous pattern • Anti–smooth muscle antibody (ASMA) directed at actin • Anti–liver-kidney microsomal antibody (anti–LKM-1) • Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18 • Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin • Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis. • Antiphospholipid antibodies

27. * • Hematologic complications • Hematologic manifestations of hypersplenism • Autoimmune hemolytic anemia • Coombs-positive hemolytic anemia • Pernicious anemia • Idiopathic thrombocytopenic purpura • Eosinophilia • Gastrointestinal complications • Inflammatory bowel disease (6%): The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of cholangiography to exclude PSC. • Celiac disease: One recent study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease.17 • Proliferative glomerulonephritis • Fibrosing alveolitis • Pericarditis and myocarditis • Endocrinologic complications • Graves disease (6%) and autoimmune thyroiditis (12%) • Juvenile diabetes mellitus • Rheumatologic complications • Rheumatoid arthritis and Felty syndrome • Sjögren syndrome • Systemic sclerosis • Mixed connective-tissue disease • Erythema nodosum • Leukocytoclastic vasculitis: Patients may present with symptoms of leg ulcers. • Febrile panniculitis • Lichen planus • Uveitis

28. TREATMENT • Prednisoneonly (1,5 -2 mg/kg/d) or • Prednisone + Azathioprine (1,5 -2 mg/kg/d) • Initial RegimenPrednisone, 2 mg/kg/d (up to 60 mg/d),for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d • Maintenance Regimena. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg dailyb. Azathioprine at constant dose if added initiallyc. Continue daily prednisone dose with or without azathioprine or switch toalternate day prednisone dose adjusted to response with or without azathioprine • End Pointa. Normal liver tests for 1-2 years during treatmentb. No flare during entire intervalc. Liver biopsy examination discloses no inflammation 1,5 -2 mg/kg/d)

29. Drug Related *

30. Drug Related * • Dose related: 6 MP, methotrexate and acetaminophen • Idiosyncratic: phenytoin, phenobarbital and carbamezipine

31. Metabolic *

32. Wilson Disease * • Autosomal recessive defect in Copper metabolism • Copper accumulation in vital organs (hepatic tissue, nervous system) leading to cirrhosis • Ceruloplasmin and 24 urine collection for copper

33. Alpha 1 Antitrypsin Deficiency * • Defective production of protein leads to hepatic accumulation and cirrhosis • AR • Variable course • 2nd cause for liver transplant in children

34. Galactosemia * • Defect in Galactose uridyl transferase • Galactose 1 phosphate accumulation is toxic • Dietary elimination

35. Bile Acid Synthetic Defects • Disorders result from abnormal synthesis of bile acids • Cholestasis in infancy is the main manifestation • Ursodeoxycholic acid (Actigall) is used for the treatment

36. Reye syndrome presented most commonly at approximately 6 yr of age, with most cases in the 4–12-yr age range • Usuallyquiet, lethargicandsleepy, vomiting, laboratoryevidence of liverdysfunction   II.  Deep lethargy, confusion, delirium, combative, hyperventilation, hyper-reflexic   III.  Obtunded, light coma ± seizures, decorticate rigidity, intact pupillarylightreaction   IV.  Seizures, deepening coma, decerebraterigidity, loss of oculocephalicreflexes, fixedpupils   V.    Coma, loss of deep tendon reflexes, respiratoryarrest, fixeddilatedpupils, flaccidity/decerebrate (intermittent); isoelectricelectroencephalogram

37. CIRRHOSIS

38. The Metavir scoring system is used to assess fibrosis. Stage 0 indicates absent fibrosis, stages 1 and 2 are considered low-grade fibrosis, stage 3 is considered high-grade fibrosis, and stage 4 is cirrhosis. • Steatosis (fat accumulation in the liver)

39. Fulminant hepatic failure

40. Fulminant hepatic failure : a clinical syndrome resulting from massive necrosis of hepatocytes or from severe functional impairment of hepatocytes in a patient who does not have a pre-existing liver disease. The disorder usually evolves over a period of fewer than 8 wk. • Fulminant hepatic failure is a complication of viral hepatitis (A, B, D, E, possibly C, and others). An unusually high risk of fulminant hepatic failure occurs in young people who have combined infections with the hepatitis B virus (HBV) and hepatitis D • The diseaseoccurssporadicallyandusuallywithoutthe parenteral riskfactors of HBV or HCV. Epstein-Barr virus, herpes simplex virus, adenovirus, enterovirus, cytomegalovirus, parvovirus B19, andvaricella-zosterinfectionsmay produce fulminant hepatitis in children • Varioushepatotoxicdrugsandchemicalsmayalsocause fulminant hepatic failure. Predictableliverinjurymayoccurafterexposureto carbon tetrachlorideandAmanitaphalloidesmushroom or afteracetaminophenoverdose

41. massive destruction of hepatocytes may represent both a direct cytotoxic effect of the virus hyperimmune response to the virus that underlies the massive liver necrosis formation of hepatotoxic metabolites that bind covalently to macromolecular cell constituents is involved in the liver injury produced by drugs such as acetaminophen and isoniazid;

42. CLINICS * • Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting, and abdominal pain are common. • A rapid decrease in liver size without clinical improvement is an ominous sign. • A hemorrhagic diathesis and ascites may develop. Patients should be closely observed for hepatic encephalopathy, which is initially characterized by minor disturbances of consciousness or motor function. • Irritability, poor feeding, and a change in sleep rhythm may be the only findings in infants; asterixis may be demonstrable in older children. • Patients are often somnolent or confused or combative on arousal and eventually may become responsive only to painful stimuli. Patients may rapidly progress to deeper stages of coma

43. Laboratory Findings * • Serum direct and indirect bilirubin levels and serum aminotransferase activities may be markedly elevated. However, serum aminotransferase activities do not correlate well with the severity of the illness and may actually decrease as a patient deteriorates. • The blood ammonia concentration is usually increased, but hepatic coma can occur in patients with a normal blood ammonia level. • Prothrombin time is always prolonged and often does not improve after parenteral administration of vitamin K. • Hypoglycemia can occur, particularly in infants. Hypokalemia, hyponatremia, metabolic acidosis, or respiratory alkalosis may develop.

44. Treatment * • advanced hepatic coma should be treated in an intensive care unit where continuous monitoring of vital functions is possible. • endotrachealintubation , mechanical ventilation and supplemental oxygen • electrolyte and glucose solutions should be administered intravenously to maintain urine output, to correct or prevent hypoglycemia

45. * • Parenteral supplementation with calcium, phosphorus, and magnesium may be required. • Coagulopathy should be treated with parenteral administration of vitamin K and may require fresh frozen plasma; disseminated intravascular coagulation may also occur. Plasmapheresis may permit temporary correction of the bleeding diathesis without resulting in volume overload. Continuous hemofiltration is useful for management of fluid overload and acute renal failure. • Antacids or H2 receptor blockers or both should be considered because of the high risk of gastrointestinal bleeding.

46. * • Patients should be monitored for infection, sepsis, pneumonia, peritonitis, and urinary tract infections. At least 50% of patients experience serious infectionș ATB • Cerebral edema is an extremely serious complication that responds poorly to measures such as corticosteroid administration and osmotic diuresis • Gastrointestinal hemorrhage, infection, constipation, sedatives, electrolyte imbalance, and hypovolemia may precipitate encephalopathy and should be identified and corrected. • Protein intake should be restricted or eliminated. The gut should be purged with several enemas. Lactulose should be given every 2–4 hr orally or by nasogastric tube in doses (10–50 mL) sufficient to cause diarrhea. • Overall mortality exceeds 70%.