Viral hepatitis

Pathology

1. VIRAL HEPATITIS DR NOOPUR PATIL JR1 PATHOLOGY

2. NORMAL HISTOLOGY OF LIVER The hepatic parenchyma is composed of numerous hexagonal or pyramidal classical lobules. Each lobule has a central tributary from the hepatic vein and at the periphery are 1 – 5 portal tracts or triads containing branches of bile ducts, portal vein and hepatic artery. Cords of hepatocytes and sinusoids radiate from central vein to portal triads .

3. NORMAL HISTOLOGY OF LIVER Blood supply to the liver parenchyma flows from the portal triads to the central vein . -The liver has a dual blood supply: the portal vein provides 60% to 70% the hepatic artery supplies 30% to 40%. Parenchyma of liver lobule is divided into: Zone 1: periportal area Zone2: Intermediate mid-zonal area Zone3: Centrilobular area

4. Viral hepatitis is applied for hepatic infections caused by a group of viruses known as hepatotropic virus that have a particular affinity for the liver. Hepatitis viruses A, B, C, D and E . Systemic viral infections that can involve liver include: Infectious mononucleosis – may cause mild hepatitis during the acute phase. Yellow fever- Major and serious cause of hepatitis in tropical countries. Cytomegalovirus – newborn and immunocompromised patients. Infrequently - rubella, adenovirus, herpes virus, enterovirus .

5. ACUTE HEPATITIS It is the acute inflammatory involvement of liver caused by hepatotropic viruses. ETIOLOGY : 1.Hepatitis A virus ( HAV) 2.Hepatits B virus (HBV) 3.Hepatitis C virus (HCV) 4.Hepatitis D virus (HDV) 5.Hepatitis E virus (HEV) Other transfusion transmitted agents – hepatitis G virus and TT virus has been identified but do not cause hepatitis.

6. ACUTE VIRAL HEPATITIS CLINICAL FEATUTES: Course of acute viral hepatitis is divided into four phases: 1.Incubation period 2.Pre - icteric – phase 3.Icteric phase 4.Convalescent period 1.INCUBATION PERIOD : Varies according to the responsible agent. Hepatitis A: 15 – 45 days Hepatitis B and D : 30 - 80 days Hepatitis C:15 – 160 days Hepatitis E: 15 – 60 days.

7. 2.PREICTERIC PHASE: Several days to more than one week. Features are anorexia, fever, fatigue, malaise, nausea, vomiting and abdominal pain. 3.ICTERIC PHASE: Appearance of dark urine, followed by pale stools, yellowish discoloration of mucous membranes, conjunctiva, sclera and skin Mild weight (2.5 – 5 kg ) loss. Liver becomes enlarged and tender may be associated with right upper quadrant pain and discomfort. Splenomegaly and cervical lymph- adenopathy in 10 – 20 % of cases. 4.RECOVERY PHASE : Constitutional symptoms disappear. Liver enlargement and abnormalities in liver biochemical tests still evident. Duration is Prolonged in acute hepatitis B and C: 3 – 4 months Hepatitis A and E : 1 – 2 months.

8. MACROSCOPIC APPEARANCE : Initially the liver is swollen and red. capsule is edematous and tense. Exuded tissue fluid may be seen on the capsular surface. Focal depressions-localized sub capsular necrosis and collapse. Severe cholestasis – colour of liver is bright yellow or green .

9. MICROSCOPY : 1.Spotty (focal) necrosis :death of a single hepatocyte or adjacent hepatocytes accompanied by inflammatory infiltrate – lymphocytes and macrophages 2.Acidophil body or councilman body : first described by Councilman in 1890. Earliest degenerative cellular injury that can be demonstrated histologically. Parenchymal cell borders concave on all sides. Cytoplasm is intensely eosinophilic , homogenous and granular, nucleus is basophilic. 3.Ballooning degeneration : balloon cell type swelling and rounding of cells, cytoplasm is pale and granular. 4.Cholestasis : canalicular bile plugs in canaliculi and brown pigmentation of hepatocytes. 5.Bridging necrosis : confluent necrosis of parenchyma linking portal tract to central vein.This feature in acute hepatitis signifies a very severe injury.

10. 6.Lobular disarray : the acinus or lobule is totally disarrayed due to ballooning, acidophil body formation , kupffer cell hyperplasia,inflammation . 7.Regenerative phenomenon : mitoses are typical of early stage, bi and multinucleate cells of late stage. 8.Ductular proliferation : increased formation of bile ductules in fibrosed and enlarged portal tracts. 9.Kupffer cell hyperplasia

11. SPOTTY NECROSIS 3.BALLOONING DEGENERATION BILE DUCT SWELLING

12. ACUTE HEPATITIS – KUPFFER CELL AND PORTAL TRACT MACROPHAGES CONTAIN IRON – PERLS STAIN ACUTE HEPATITIS – CLUMPS OF HYPERTROPHIED KUPFFER CELLS – Di-PAS

13. Benign self-limited disease with an incubation period of 3 to 6 weeks. Does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis. Small, non-enveloped, positive-strand RNA picornavirus that occupies its own genus, Hepatovirus . Icosahedral capsid 27 nm diameter and can be cultured in vitro . HAV is spread by ingestion of contaminated water and foods and is shed in the stool for 2 to 3 weeks before and 1 week after the onset of jaundice. Specific IgM antibody against HAV appears in blood at the onset of symptoms, constituting a reliable marker of acute infection. Fecal shedding of the virus ends as the IgM titer rises. Hepatitis A Virus

14. SEROLOGY: HAV is shed in the stool for 2- 3 weeks before and one week after the onset of jaundice . As HAV viremia is transient, blood borne transmission of HAV occurs rarely, therefore donated blood is not screened for this virus . IgM anti – HAV antibody appears in the serum at the onset of symptoms of acute Hepatitis A . Fecal shedding of the virus ends as IgM titre rises IgM response begins to decline in a few months and is followed by the appearance of IgG . IgG persists for life, giving immunity against re infection by all strains of HAV.

15. HEPATITIS A MICROSCOPY: Periportal pattern of inflammation and necrosis – Interface hepatitis, with little or no perivenular necrosis. Plasma cells are prominent Perivenular cholestasis with little or no hepatocellular necrosis. In some patients ,there is classic perivenular hepatitis with hepatocellular ballooning,multinucleation and necrosis. In fulminant forms - panlobular necrosis.

16. Hepatitis B Virus HBV can produce Acute hepatitis with recovery and clearance of the virus Non-progressive chronic hepatitis Progressive chronic disease ending in cirrhosis Fulminant hepatitis with massive liver necrosis An asymptomatic carrier state HBV-induced chronic liver disease is an important precursor for the development of hepatocellular carcinoma.

17. HBV has a prolonged incubation period ( 4–26 weeks). Nucleo capsid “core” protein ( HBcAg , hepatitis B core antigen) HBeAg (hepatitis B “e” antigen) Envelope glycoproteins ( HBsAg , hepatitis B surface antigen) Polymerase (Pol) that exhibits both DNA polymerase activity and reverse transcriptase activity. HBxprotein , necessary for virus replication

18. HBV infection Proliferative phase integrative phase Episomal forms viral DNA is Expression of HBsAg , incorporated into HBsAg + MHC class I host genome Molecules activation of CD8+ cytotoxic T cells Hepatocyte destruction

19. MICROSCOPY : Features unique to hepatitis B : More extensive parenchymal abnormalities Less cholestasis and portal inflammation Features are similar to hepatitis A including ballooning degeneration, acidophil bodies, focal hepato - cellular necrosis, extensive peri - portal involvement, regenerative changes. Distinguishing feature of chronic hepatitis B is ground – glass appearance .

20. SEROLOGY : HBsAg appears before the onset of symptoms peaks during overt disease, declines to undetectable levels in 3 – 6 months HBeAg , HBV – DNA, DNA polymerase appear in the serum soon after HBsAg - all signify acute viral replication. IgM anti – HBc becomes detectable in the serum shortly before the onset of symptoms Anti – HBe is detectable shortly after the disappearance of HBeAg - indicating the acute infection has peaked and is on the wane. IgG anti HBs does not rise until the acute disease is over – not detectable for a few weeks to several months after the disappearance of HBsAg .

21. Hepatitis C Virus The incubation period for HCV hepatitis ranges from 2 to 26 weeks. HCV RNA is detectable in blood for 1 to 3 weeks, coincident with elevations in serum transaminases. Persistent infection and chronic hepatitis are the hallmarks of HCV infection. Episodic elevations in serum aminotransferases, with intervening normal or near-normal periods.

22. MICROSCOPY : Relative paucity of inflammation. Marked increase in activation of sinusoidal lining cells, lymphoid aggregates Presence of fat Bile duct lesions – biliary epithelial cells appear to be piled up without interruption of the basement membrane. SEROLOGY : HCV RNA is detected in the blood for 1 -3 weeks coincident with elevation in serum trans- aminases In symptomatic acute HCV infection, anti HCV antibodies are detectable only in 50 – 70% of patients In the remaining patients, anti HCV antibodies emerge after 3 – 6 weeks .

23. Hepatitis D Virus RNA virus that is dependent for its life cycle on HBV . HBsAg necessary for development of complete HDV virions . Infections Co-infection of HBV and HDV Superinfection with HDV in a chronic HBsAg carrier Helper-independent latent infection may be seen in liver transplants

24. PATHOLOGY : Features of acute hepatitis are present if co – infection HBV and HDV have occurred. Features of both acute and chronic hepatitis are present if acute HBV infection is superimposed on chronic HBV infection In acute hepatitis, inflammatory cells primarily lymphocytes and macrophages are prominent in parenchyma and portal areas . Changes are patchy and focal The single distinguishing feature is the sanded nucleus ( sometimes seen in hepatitis B ). In hepatitis D this feature is due to HDAg accumulating in the nucleus of infected cells. Hepatocytes are swollen and undergo eosinophilic necrosis.

25. TYPE D HEPATITIS – IMMUNOPEROXIDASE STAIN - POSITIVE STAINING IN NUCLEI TYPE D HEPATITIS – IMMUNOPEROXIDASE STAIN - POSITIVE STAINING IN NUCLEI

26. SEROLOGY : HDV RNA is detectable in the blood and liver just prior to and in the early days of acute symptomatic disease. IgM anti – HDV is the most reliable indicator of recent HDV exposure, although its appearance is late and frequently short lived Acute co – infection by HDV and HBV is indicated by detection of IgM against both HDAg and HBcAg .

27. Hepatitis E Virus Enterically trans-mitted , water-borne infection that occurs primarily in young to middle-aged adults. Incubation period following exposure is 6 weeks . HEV RNA and HEV virions can be detected by PCR in stool and serum.

28. MICROSCOPY : includes classic and cholestatic types of acute viral hepatitis. Classic Type : focal hepatocyte necrosis, swollen hepatocytes, lymphocytic infiltration Cholestatic form : features of canalicular cholestasis, gland - like transformation of hepatocytes In fatal cases, extensive necrosis and collapse of parenchyma is present. TYPE E HEPATITIS – ACUTE HEPATITIS WITH HEPATOCYTE SWELLING AND LOBULAR MONONUCLEAR INFILTRATE

29. Hepatitis G Virus A flavivirus bearing similarities to HCV (also referred to as GBV-C). HGV is transmitted by contaminated blood or blood products , and via sexual contact. HGV is inappropriately named. Replicate in the bone marrow and spleen. HGV commonly co-infects individuals infected with the human immunodeficiency virus (HIV; prevalence 35 %) Curiously this dual infection is somewhat protective against HIV disease .

30. Clinico -pathologic Syndromes Acute asymptomatic infection with recovery (serologic evidence only). Acute symptomatic hepatitis with recovery, anicteric or icteric. Chronic hepatitis , without or with progression to cirrhosis. Fulminant hepatitis with massive to submassive hepatic necrosis . Carrier State

31. COMPLICATIONS Hepatitis A : Relapsing hepatitis weeks to months after apparent recovery from acute hepatitis. Cholestatic hepatitis - protracted cholestatic jaundice and pruritis. Fulminant hepatitis seen in hepatitis B, D and E. Acute hepatitis B : chronic hepatitis Acute hepatitis C : chronocity is seen in 85 – 90 % of patients. Cirrhosis develops in 20 % of patients in 10 – 20 years.

32. PROGNOSIS ACUTE VIRAL HEPATITIS: Hepatitis A : All previously healthy patients recover completely. Case fatality is 0.1%. Hepatitis B : 95 - 99 % of patients recover. Case fatality is 0.1 %. Hepatitis C :Fatalities are rare. Hepatitis E : Fatalities 1 -2 %,in pregnant women 10 - 20 %. Hepatitis D + Hepatitis B : Super-infection: Fatality is 5%. Co-infection: Fatality is 20 %.

33. LAB DIAGNOSIS OF ACUTE HEPATITIS

34. DIFFERENTIAL DIAGNOSIS OF ACUTE HEPATITIS 1.Infectious mononucleosis : liver cell damage is minimal and aypical lymphocytes are seen in sinusoid and portal tracts. 2.Herpes simplex and cytomegalovirus infection : necrosis is confluent and lymphoid infiltrate is present in sinusoids. 3.Drugs : Idiosyncracy – poorly developed or absent portal inflammation, abundant neutrophils or eosinophils, granuloma formation, sharply defined perivenular necrosis ,cholestatic features with duct damage.Acetaminophen – uniform pattern of perivenular necrosis with minimal inflammation.

35. DIFFERENTIAL DIAGNOSIS OF ACUTE HEPATITIS 4.Alcoholic hepatitis: ballooning of hepatocytes is perivenular and accompanied by neutrophilic infiltrate, fatty change ,mallory bodies 5.Cholestasis: changes are limited to cholsttic areas. 6.Autoimmune hepatitis : plasma cell infiltrate, serum markers for viral hepatitis are absent.