LIVER DISEASE

1. LIVER DISEASE ACUTE HEPATITIS

2. CAUSES OF ACUTE HEPATITIS • Viruses - hepatotropic viruses A,B,C,D,E,(F,G), “non-A-E.” - others,eg,Epstein-Barr virus, cytomegalovirus, herpes simplex virus, yellow fever. • Other organisms. • Drugs, herbal remedies. • Alcohol.

3. ACUTE VIRAL HEPATITIS • Incubation period - depends on the particular hepatotropic virus. • Clinical features - malaise, anorexia, nausea. - +/- pyrexia, upper abdominal pain. - jaundice, +/- dark urine and pale stool. - tender hepatomegaly. Note: can be asymptomatic and/or anicteric. • Blood tests - those of “hepatocellular” jaundice. - viral markers.

4. MORPHOLOGY OF VIRAL HEPATITIS • Alternating ballooning degeneration and necrosis of liver cells. The latter occuring as lysis with focal loss of hepatocytes (“spotty necrosis”) or apoptosis evidenced by acidophil bodies. • Lymphocytic infiltrate in the parenchyma and portal tracts. This infiltrate decreases with time as resolution occurs. • Phagocytic cells (Kupffer cells) increase with time to remove debris. • Cholestasis may be present in zone 3 (perivenular). • Hepatocyte regeneration occurs concurrently. • Variations - confluent liver cell necrosis may occur in different patterns - bridging hepatic necrosis (portal-venular; venular-venular) - panacinar - periportal (interface hepatitis). • The necroinflammatory process centres on the liver parenchyma, is pan-acinar but maximal in zone 3 (perivenular).

7. POSSIBLE OUTCOME OF VIRAL HEPATITIS • Resolution - +/- relapses +/- protracted course. • Fulminant hepatitis - 1% or less. (HAV & HBV causes about 12 % of cases of fulminant hepatitis). Massive liver necrosis (panacinar necrosis). Death in liver failure. • Chronic hepatitis - 5 - 10% but much higher in HCV. Some types do not progress to chronicity. • Cirrhosis - +/- hepatocellular carcinoma.

8. Hepatitis A virus (HAV) • Virus - RNA 27nm. Picornavirus group. Enterovirus. • Pathogenesis - mixed cell mediated and humoral immune response. • Epidemiology - spread by faecal-oral route. - endemic in some countries. - epidemics occur. • Course - incubation period 15 - 50 days. - mild or asymptomatic in children, more severe in adults. - fulminant in less than 1%. - no chronicity.

9. Hepatitis B virus (HBV) • Virus - DNA 42nm. Hepadna virus. • Pathogenesis - damage due to the body’s immune reaction, T-cell cytotoxicity (CD8+/CD4+ lymphocytes) Antibody-dependent cellular cytotoxicity Antibody/complement-mediated cytotoxicity Cytokine cytotoxicity (interferon,interleukin,TNF). • Epidemiology - spread by parenteral route (blood/blood products). - horizontal and vertical transmission. - marked geographical variation. • Course - incubation period 50 - 160 days. - tends to be severe; can be asymptomatic. - fulminant in less than 1%. - chronicity in 5 -10% of whom 15 - 20% develop cirrhosis. - risk of hepatocellular carcinoma.

10. Hepatitis C virus (HCV) • Virus - RNA 30-38nm. Hepacivirus, a sub genus of Flaviviridae. • Pathogenesis - cytopathic and immune mediated damage, CD4+, CD8+, NK cells. • Epidemiology - parenteral route (blood/blood products) in 60%. - in 40% the means of infection is uncertain (“sporadic” or “community acquired”). • Course - incubation period 15 - 160 days. - usually asymptomatic; mild illness if symptomatic. - extrahepatic manifestations occur. - chronicity in 70 - 90% of whom 20% develop cirrhosis. - risk of hepatocellular carcinoma.

11. Hepatitis D virus (HDV) • Virus - incomplete single stranded RNA. - requires HBV in order to replicate. • Pathogenesis - directly hepatotoxic. • Epidemiology - parenteral route. • Course - co-infection with HBV = severe but usually self-limiting hepatitis (fulminant in 4%). - superinfection on already existing HBV = severe hepatitis (fulminant in 8%) with chronicity +/- cirrhosis in over 70%.

12. Hepatitis E virus (HEV) • Virus - RNA 32 - 34nm. • Epidemiology - faecal-oral route. - epidemics in Asia, Africa, S.America. • Course - usually mild. - fulminant in 2% but in 10-20% of pregnant women when it carries a high mortality. - no chronicity.

13. Other hepatitis viruses • Hepatitis F (HFV). Toga virus-like particles seen in a very few patients with fulminant hepatitis but also a designation given to othr agents so not an officially designated virus. • Hepatitis G (HGV). RNA virus of Flavivirus group, spread by parenteral route but not thought to be pathogenic. • Other viruses. Some known, but some remain to be identified (there are cases of hepatitis which cannot be proven to be due to the presently known viruses).

14. CHRONIC HEPATITIS • Chronic hepatitis is an inflammation of the liver continuing without improvement for at least 6 months. • Is a clinico-pathological syndrome, not a single disease. • Has several causes. • Is characterised by varying degrees of inflammation, necrosis and usually fibrosis. • It may or may nor be associated with cirrhosis (cirrhosis may already be established at the time of diagnosis).

15. CLASSIFICATION ACCORDING TO AETIOLOGY • Chronic viral hepatitis B, C, B+D. • Chronic viral hepatitis NOS (unknown). • Autoimmune hepatitis. • Chronic drug induced hepatitis. • Chronic hepatitis of unknown cause (cryptogenic). Conditions to be considered in the differential diagnosis include - primary biliary cirrhosis. - primary sclerosing cholangitis. - Wilson’s disease. - alpha-1-antitrypsin deficiency. - alcoholic liver disease.

16. CLINICAL FEATURES • Fatigue, anorexia, +/- dyspepsia, malaise. • May present with jaundice. • Can be asymptomatic and be discovered incidentally. • May present with evidence of cirrhosis. • Can directly follow unresolved acute hepatitis. • Signs of chronic liver failure may be present, spider naevi etc. • Worsening liver failure with hepatic encephalopathy may ensue. • Laboratory blood tests show (usually mild) rise in transaminases but can be normal.

17. MORPHOLOGY OF CHRONIC HEPATITIS • Lymphocytes +/- plasma cells in portal tracts. • Extension of inflammatory infiltrate into adjacent parenchyma (periportal or zone 1) with loss of liver cells, a feature known as interface hepatitis. • Spotty necrosis and inflammation in liver acini. There may be bridging hepatic necrosis. • Fibrosis of portal tracts with progression to portal to portal and portal to venular bridging necrosis • The necroinflammatory process centres on portal tracts. • Liver biopsy necessary for diagnosis and used to grade and stage the disease and monitor response to therapy. Grading = the degree of interface hepatitis and acinar necroinflammation. This determines the grade of activity. Staging = the degree of fibrosis and architectural change from involvement of a few tracts up to and including cirrhosis.

19. CHRONIC HEPATITIS B • Worldwide 2 billion have been infected, 350 million are carriers. • Prevalence >8% Asia & Africa,2-7% S&E Europe,<2%W.Europe/USA. • Especially likely to occur in men, neonates and adults with impaired immunity. • Usually mild hepatitis histologically with characteristic “ground glass” hepatocytes due to HBsAg in proliferated smooth endoplasmic reticulum. • Diagnosed by detecting HBV markers in blood and in the liver, HBsAg in hepatocyte cytoplasm and HBcAg in nuclei. • Occasionally immune complex disease develops resulting in vasculitis or glomerulonephritis. • Risk of hepatocellular carcinoma once cirrhosis develops, but may occur without cirrhosis in areas of high incidence.

20. CHRONIC HEPATITIS C • Worldwide 400 million are carriers. • The cause of almost 50% of chronic liver disease in the Western world with the potential to become the most common cause. • Over 50% of patients with unexplained cirrhosis or hepatocellular carcinoma have anti-C antibodies. • Characterised by a fluctuating clinical, biochemical and histological course due mainly to development of quasi species of the virus. • Usually histologically mild but 20% develop cirrhosis and therefore risk of hepatocellular carcinoma. Lymphoid aggregates, bile duct damage and fatty change are histological pointers to HCV infection. • Diagnosed by detection of viral RNA in blood by PCR. • Can cause immune complex disease. 35% develop cryoglobulinemia.

21. THE LIVER IN INFECTIOUS DISEASES • Viruses - viral haemorrhagic fevers, herpes group, HIV with opportunistic infections in AIDS. • Bacteria - bacterial septicaemia. - pyogenic organisms - liver abscess. - organisms causing granulomas, eg tuberculosis, brucellosis, typhoid fever, Q-fever. - spirochaetes, eg syphilis and leptospirosis (Weil’s disease). • Fungi - Candida, Aspergillus, Histoplasma. • Parasites - malaria, amoebic “abscess”, ascariasis, hydatid disease, Schistosoma, Clonorchis, Opisthorchis. • Neonatal hepatitis - characterised by multinucleated giant hepatocytes. Several causative organisms have been identified but most are of unknown aetiology.

22. AUTOIMMUNE HEPATITIS • More common in females (78%) than in males. • Any age but especially young women and perimenopausal women. • Up to 60% have other forms of autoimmune disease eg rheumatoid arthritis, thyroiditis, Sjogren’s syndrome, ulcerative colitis. • HLA B8 and HLA DR3 frequent. • High titres of IgG and antibodies to various bacterial and viral antigens. • High titres of antinuclear (ANA), antismooth muscle (SMA), and/or antiliver/kidney microsomes (anti-LKM1) antibodies. • Reduced number and function of suppressor T lymphocytes. • Is a cytotoxic T-cell attack on hepatocytes. • Severe chronic hepatitis histologically with marked interface hepatitis and numerous plasma cells in the inflammatory infiltrate. • Responds well to steroids. Liver transplantation may be necessary. • Untreated 40% die of liver failure in 6mo. 40% of survivors -> cirrhosis.