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Hepatology

Hepatology. Chronic liver diseases. chronic viral hepatitis, Wilson disease, a1-antitrypsin deficiency, hemochromatosis, drug-induced liver disease, nonalcoholic steatohepatitis, the immune cholangiopathies of primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC),

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Hepatology

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  1. Hepatology

  2. Chronic liver diseases • chronic viral hepatitis, • Wilson disease, • a1-antitrypsin deficiency, • hemochromatosis, • drug-induced liver disease, • nonalcoholic steatohepatitis, • the immune cholangiopathies of primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), • autoimmune hepatitis.

  3. Chronic liver diseases • Chronic liver disease generally progresses slowly from hepatitis to cirrhosis, often over 20 to 40 years.

  4. Cirrhosis is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules.

  5. Aminotransferases • Hepatocytes injuries • ALT normally found largely in the liver. • AST is normally found in a diversity of tissues including liver, heart, muscle, kidney, and brain • Linked to the biliary tract • GGTP cholestasis and is raised in chronic alcohol toxicity • ALP cholestasis

  6. Increased total bilirubin causes jaundice, and can signal a number of problems: • 1. Prehepatic: Increased bilirubin production: hemolytic anemias and internal hemorrhage. • 2. Hepatic: reflected as deficiencies in bilirubin metabolism (e.g. reduced hepatocyte uptake, impaired conjugation of bilirubin, and reduced hepatocyte secretion of bilirubin). Some examples would be cirrhosis and viral hepatitis. • 3. Posthepatic: Obstruction of the bile ducts, reflected as deficiencies in bilirubin excretion

  7. WILSON DISEASE • Wilson disease, an autosomal recessive disorder of copper overload. • Inadequate biliary copper excretion leads to copper accumulation in the liver, brain, kidneys, and corneas.

  8. WILSON DISEASE • Wilson's disease manifests as neurological or psychiatric symptoms and liver disease. • The condition is due to mutations in the Wilson disease protein (ATP7B) gene

  9. THE COPPER PATHWAY • Dietary copper is absorbed in the upper intestine, and binds to circulating albumin. Albumin transports copper to a variety of tissues; most is transported to the liver. • The majority of ingested copper is excreted via the bile; a small fraction is excreted in urine.

  10. THE COPPER PATHWAY • Two major disturbances of copper disposition in Wilson disease are a reduction in the rate of incorporation of copper into ceruloplasmin and a decrease in biliary excretion of copper.

  11. WILSON DISEASE • Age at onset of symptoms is usually from 3 to about 40 years.

  12. Manifestation of Wilson disease • chronic hepatitis • fulminant liver disease with acute hemolysis, • a progressive neurologic disorder • isolated acute hemolysis, • psychiatric illness.

  13. Hepatic Presentation of Wilson disease • The chronic Wilson disease occurs in children is symptomatic or not, with hepatomegaly, persistently elevated serum levels of aminotransferases.

  14. Hepatic Presentation of Wilson disease • Fulminant hepatic failure with jaundice, severe coagulopathy and encephalopathy. • Acute intravascular hemolysis is usually present. • Disproportionately low aminotransferases (usually much less than 1500 U/L). • Bilirubin is often disproportionately elevated as a result of hemolysis. • These patients do not respond well to chelation treatment and require urgent liver transplantation.

  15. Neurologic Presentation of Wilson disease • Patients with the neurologic manifestation nevertheless have hepatic involvement often asymptomatic. • Neurologic involvement follows two main patterns: - movement disorder -tremors, poor coordination, and loss of fine motor control - rigid dystonia - spastic dystonic disorders with mask-like facies, rigidity and gait disturbance,clumsiness and pseudobulbar involvement.

  16. Psychiatric Presentation of Wilson disease - depression, - phobias or compulsive behaviors, - aggressive or antisocial behavior.

  17. Ocular Signs • Slit-lamp examination may reveal Kayser-Fleischer rings. • The classic Kayser-Fleischer ring, found at the limbus, is caused by copper deposition in Descemet's membrane.

  18. Ocular Signs • 95% patients with a neurologic or psychiatric manifestation of Wilson disease have Kayser-Fleischer rings. • Kayser-Fleischer rings may be absent in 15% to 50% of patients with hepatic involvement.

  19. WILSON DISEASE • Typically, more than 95% of patients have been considered to have a low ceruloplasmin concentration.

  20. DIAGNOSIS • mild to moderate elevations of serum aminotransferases (serum levels of ALT may be much lower than serum levels of AST), • low serum ceruloplasmin concentration, • low serum copper concentration, • 24-hr urinary copper excretion rate

  21. DIAGNOSIS • a provocative test of urinary copper excretion in which penicillamine (500 mg orally every 12 hr) is given while a 24-hr urinary collection • patient with Wilson disease excretes increased copper in the urine

  22. DIAGNOSIS-liver biopsy • Hepatic tissue copper content greater than 250 µg per gram of dry weight is considered diagnostic of Wilson disease.

  23. Treatment • chelator therapy:penicillamine, trien (trientine), zincPenicillamine increases urinary excretion of copper. Trientine increases urinary copper excretion and may interfere with intestinal absorption of copper Zinc interferes with absorption of copper from the gastrointestinal tract.

  24. AUTOIMMUNE HEPATITIS

  25. Diagnosis of autoimmune hepatitis • periportal hepatitis, • hypergammaglobulinemia, • autoantibodies autoantibodies,

  26. Antibodies • antinuclear antibodies (ANA), • smooth muscle antibodies (SMA), • antibodies to liver/kidney microsome type 1 (anti-LKM1) • antibodies to soluble liver antigen (anti-SLA), • antibodies to liver/pancreas (anti-LP) antigen, • antibodies to liver cytosol type 1 (anti-LC1)

  27. Autoimmune Hepatitis • Type 1 • Type 2 • Type 3

  28. Type 1 autoimmune hepatitis • Type 1 autoimmune hepatitis is characterized by the presence of SMA and/or ANA in serum. • 78% of patients are women, • 41% have concurrent extrahepatic immunologic diseases, including autoimmune thyroiditis, Graves' disease, chronic ulcerative colitis (CUC) and rheumatoid arthritis.

  29. Type 2 Autoimmune Hepatitis • Type 2 autoimmune hepatitis is characterized by the presence of anti-LKM1 in serum. • The disease afflicts mainly children (aged 2 to 14 years) and less commonly adults. • Patients with type 2 disease progress to cirrhosis more frequently than those with type 1 disease.

  30. Type 3 Autoimmune Hepatitis • Type 3 autoimmune hepatitis is characterized by the presence of anti-SLA in serum.

  31. Autoimmune Hepatitis-laboratory indices • elevated of aminotransferases levels • positive to SMA, ANA, or anti-LKM1 • hypergammaglobulinemia is polyclonal, but the immunoglobulin G fraction predominates

  32. Autoimmune Hepatitis • Prednisone alone or a prednisone (60 mg/day) in combination with azathioprine(2 mg/kg/day). • Corticosteroid with azathioprine therapy is continued until remission inflammatory indices and histologic improvement to normal or minimal activity

  33. PRIMARY BILIARY CIRRHOSIS(PBC) • PBC is a chronic cholestatic liver disease involving the interlobular and septal bile ducts. • This disorder is characterized by progressive inflammatory destruction of these bile ducts with the development of portal and periportal inflammation, subsequent fibrosis, and eventually cirrhosis.

  34. PRIMARY BILIARY CIRRHOSIS(PBC) • The cause of PBC is an autoimmune disease.

  35. PRIMARY BILIARY CIRRHOSIS(PBC) • 90% of the patients are women, with a median age at the time of diagnosis in the early 50s.

  36. PRIMARY BILIARY CIRRHOSIS(PBC) • Up to 25% of patients with PBC diagnosed with asymptomatic disease. • Symptomatic Disease - fatigue - pruritus or itching - jaundice - symptoms of portal hypertension

  37. PRIMARY BILIARY CIRRHOSIS(PBC)-diagnosis • antimitochondrial antibodies (AMA) • elevated alkaline phosphatase levels, • hypercholesterolemia, • IgM elevation • mildly elevated transaminase levels • hyperbilirubinemia • liver biopsy-chronic nonsuppurative destructive cholangitis

  38. PRIMARY BILIARY CIRRHOSIS-therapy(PBC) • Ursodeoxycholic acid.

  39. PRIMARY BILIARY CIRRHOSIS(PBC) • Liver transplantation is the treatment of choice for patients with advanced PBC.

  40. PRIMARY BILIARY CIRRHOSIS(PBC) • Treatment of pruritus in cholestasis usually relies on the use of antihistamines. • Cholestyramine, Rifampin - for control of pruritus.

  41. LIVER DISEASE CAUSED BY DRUGS, ANESTHETICS, AND TOXINS • Hepatotoxicity is liver injury caused by drugs and other chemicals. • Adverse drug reactions are noxious, unintentional effects that occur at doses used for prophylaxis and therapy.

  42. LIVER DISEASE CAUSED BY DRUGS, ANESTHETICS, AND TOXINS • Genetic determinants could predispose to drug-induced liver disease.

  43. LIVER DISEASE CAUSED BY DRUGS, ANESTHETICS, AND TOXINS The liver is the main site of drug metabolism. (include oxidation, reduction, and hydrolytic reactions).

  44. LIVER DISEASE CAUSED BY DRUGS, ANESTHETICS, AND TOXINS • Immunopathogenic mechanism - formation of drug-induced autoantibodies (e.g., liver-kidney microsomal antibodies) directed against microsomal enzymes.

  45. Acetaminophen (paracetamol) • Acetaminophen (paracetamol) is a widely used analgesic that is available without a prescription. • It is very safe when taken in the recommended therapeutic dose of 1 to 4 g/day,

  46. Acetaminophen (paracetamol) • Single doses of acetaminophen exceeding 7 to 10 g may cause liver injury. Severe liver injury (ALT >1000 IU/L) or fatal cases usually involve doses of at least 15 to 25 g. • Conversely, among heavy drinkers, daily doses of 2 to 6 g have been associated with fatal hepatotoxicity.

  47. Acetaminophen (paracetamol) • After 48 to 72 hr, ALT may be elevated, and symptoms such as anorexia, nausea and vomiting, fatigue, and malaise may occur. • Pain over the liver may be pronounced. • Levels of ALT are often between 2000 and 10,000 IU/L

  48. Acetaminophen • In patients presenting within 4 hr of acetaminophen ingestion, the stomach should be emptied with a wide-bore gastric tube.

  49. Acetaminophen • NAC (N-acetylocysteina)decreases mortality of acetaminophen-when administered 16 to 36 hr after self-poisoning.

  50. Methotrexate-Induced Hepatic Fibrosis • caused severe hepatic fibrosis and cirrhosis

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