LIVER DISEASE

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LIVER DISEASE

• ACUTE HEPATITIS

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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.

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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.

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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).

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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.

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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.

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Hepatitis B virus (HBV)

• Virus - DNA 42nm. Hepadna virus.
• Pathogenesis - damage due to the bodys 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.

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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.

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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.

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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.

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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).

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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).

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CLASSIFICATION ACCORDING TO AETIOLOGY

• Chronic viral hepatitis B, C, BD.
• 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. - Wilsons
  disease. - alpha-1-antitrypsin
  deficiency. - alcoholic liver disease.

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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.

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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.

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CHRONIC HEPATITIS B

• Worldwide 2 billion have been infected, 350
  million are carriers.
• Prevalence gt8 Asia Africa,2-7 SE
  Europe,lt2W.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.

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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.

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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
  (Weils 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.

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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, Sjogrens
  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 -gt cirrhosis.