Pathological aspects of esophagus and stomach-III (Hepatitis) Hepatitis Dr.Ashraf Abdelfatah Deyab Assistant Professor of Pathology Collage of Medicine

Pathological of the liver- Hepatitis (Objectives) w 1- Discuss Hepatitis w 2- The etio-pathogenesis of hepatitis w 3- Morphologic features of hepatitis. w 4- Clinical features& common w complications. w Suggested reading: Robbin’s Basic Pathology, 8 th Ed. Page

3 Liver -Microscopic Anatomy Fall 10A Jalan

4 Zones of Hepatocytes Portal Triad Central Vein Fall 10A Jalan

WHAT IS HEPATITIS ? w HEPATITIS is a serious disease caused by different insulting agents,(infections, autoimmune, hepatotoxicity, etc...), forming inflammatory diseases w Among inflammatory disorders are, viral infection is by far the most frequent. w There are various strains of viral hepatitis which can cause lifelong infection, leading to: w 1) Cirrhosis ( scarring) of the liver. w 2) Liver cancer. w 3) Liver failure, and death.

HEPATITIS – classified acoording to causes into w ACUTE: w Viral hepatitis  Non - viral infection w Alcohol w Toxins w Drugs w Ischemic hepatits w Autoimmune w CHRONIC: Others w Viral hepatitis * Bacterial w Alcohol * Parasitic& w Drugs Helminthic w Non-alcoholic steatohepatitis w Autoimmune w Heredity

VIRAL HEPATITIS -CAUSES w 1) However, unless otherwise specified the term viral hepatitis is applied for infections caused by a group of viruses known as hepatotropic virus (hepatitis viruses A, B, C, D, E and G ) that have a particular affinity for the liver. w _________________________________________ Other Systemic viral infections-involve the liver as w (2) Infectious mononucleosis(EBV)-mild acute w (3) CMV infection, -newborn& immunosup. w (4) Yellow fever (yellow fever virus),-serious. w 5) Adenovirus, Herpesvirus, or enterovirus infections.

the most common risk factors w Intravenous drug abuse. w Multiple sex partners. w Having had surgery or history of transfusion within the last 6 month. w Needle stick injury. w Employment in medical or dental fields. w Unknown

The etio-pathogenesis of hepatitis

Commonest Causes of Viral hepatitis w Hepatitis viruses A. w Hepatitis viruses B. w Hepatitis viruses C. w Hepatitis viruses D. w Hepatitis viruses E w Hepatitis viruses G

HEPATITIS A w Hepatitis A: w * Fa mily :Hepatovirusto-picornavirus, RNA,. w * Mean incubation: 15–40 days. w *Acute self-limited form, never be chronic. w * ORO-FECAL -consump. raw or steamed shellfish. w * Age group- child, Immunization& hygienic measures for prevention. w HAV itself does not seem to be cytopathic, Cellular immunity e.g. CD8+ T cells, plays a key role in hepatocellular injury. w Diagnosis- detection of serum IgM, +LFT

Sequence of serologic markers in acute hepatitis A viral hepatitis. Acute Hepatitis : Acinar zone- inflammation Acute Hepatitis A; hepatocytes destruction\necrosis Acute Hepatitis; Portal inflammation\lymphocytes, plasma Acute Hepatitis ; Cholestasis& MQ reaction

HEPATITIS B VIRUS is global health problem??

VIRAL B HEPATITIS w Hepatitis B: 1\3 worldwide infected,400M had chronic phase of the disease (Asia), Prevalence >8% Africa, Asia, <2% Europe. w Hepadnavirus, DNA, incubation:1–4 months, TRANSMISSION : blood and body fluids, IV drug abusers, sexual transmission. w HBV can produce these clinical sequences: w Acute hepatitis with recovery & clearance of virus >> Fulminant hepatitis with massive liver necrosis. w Persistent infection>>Non-progressive chronic hepatitis OR >> Progressive chronic disease ending in cirrhosis. w Subclinical>> 100% recovery. w Healthy carrier w w

The potential outcomes of hepatitis B infection in adults

HEPATITIS B VIRUS

VIRAL B HEPATITIS w The HBV genome contains (4) open reading frames coding for: w * A nucleocapsid “core” protein (HBcAg, hepatitis B core antigen). w * HBeAg (hepatitis B “e” antigen) is longer polypeptide transcript with a precore &core region, w * Envelope glycoproteins (HBsAg, hepatitis B surface antigen), consist of 3 related proteins:large (Pre-S1, Pre- S2, S), middle(Pre S1,Pre S2) and small (S only) w * A polymerase (Pol) that exhibits both DNA polymerase activity and reverse transcriptase activity. w * HBx protein - necessary for virus replication and may act as a transcriptional & transactivator of the viral genes.

HOW THE VIRUS REPRODUCES ?? Pathogenesis 1) First the virus attached to a liver cell membrane 2)The virus is then transported into the liver cell.

3) The core particle releases it’s contents of DNA and DNA polymerase into the liver cell nucleus.

w Once within the cell nucleus the hepatitis B DNA causes the liver cell to produce, via messenger RNA ; HBs protein, HB c protein, DNA polymerase, the HB e protein, and other undetected protein and enzymes w DNA polymerase causes the liver cell to make copies of hepatitis B DNA from messenger RNA.

The cell then assembles ’live’ copies of virus.

Excess numbers of surface proteins produced >>> stick together to form small spheres and chains >>>>> “ ground glass” appearance Ground-glass appearance- Hepatitis B virus Hepatocytes nuclei stained positive for HBc - HBV

Sequence of serologic markers for hepatitis B viral hepatitis (A) acute infection with resolution and (B) progression to chronic

Hepatitis C w RNA virus, Flaviridae w Risk factor: Parenteral; percutaenous, permucosal, intranasal cocaine w Incubation 7–8 weeks w Frequency of chronic liver disease 80%, usually end with cirrhosis. w Diagnosis: PCR; ELISA for antibody detection. w Liver biopsy- morphology shows: w Portal lymphoid follicles, Granuloma-like A few parenchymal infiltrate+ Focal necrosis + apoptosis. + Bile-duct damage + Steatosis w Portal tract- lymphoid follicle Hepatocytes inflammation + steatosis Hepatocytes: Focal cells necrosis + inflammation

Hepatitis D “delta” w RNA VIRUS, developed in certain setting: 1) Co-infection with HBV-infection “both”, result in Acute Hepatitis, self limited, elimination occur e HBV, or can >> PROGRESS TO CHRONIC. 2) Super-infection in chronic carrier with HBV: presented with 1 st Acute phase& 2 nd chronic phase 3) Latent infection observed in liver transplant setting w Risk factor: Parenteral; percutaenous, permucosal route w Prevention; immunization of HBV also prevent HDV. w Diagnosis: IgM anti-HDV& HDAg, IgM –HBc.

Hepatitis E virus w RNA, Hepevirus genus a\w chronic liver disease w HEV is a zoonotic disease with animal reservoirs, such as monkeys, cats, pigs, and dogs (india, Asia) w 30% to 60% of cases of sporadic acute hepatitis in India. w A characteristic feature of HEV infection is the high mortality rate among pregnant women, 20%. w Risk factor: enterically trans-mitted, water-borne infection w Diagnosis : IgM for HEV, PCR in stool and serum

HEPATITIS MARKERS: w HBsAg: Present in acute or chronic infection. w HBsAb: Present in recovery or immunization. w Anti -HB Core: May be “Total” (IgG& IgM) or IgM. Lifelong marker of past and active infection in either acute or chronic. w HBeAg: Acute infection, indicate infectivity. w Anti-Hbe: Usually prognostic for resolution. w ____________________________________ w HAV-Total and HAV-IgM: Anti -HAV. w Anti-HCV: 3 rd G ELISA (IgG)+ PCR (RNA)

BACTERIAL, PARASITIC, AND HELMINTHIC INFECTIONS  Bacteria- Staph. aureus (toxic shock syndrome), Salmonella typhi (typhoid fever), T. pallidum (2nry tertiary syphilis)  Induce varying degrees of hepatocellular cholestasis : bacteria may proliferate in a biliary tree-complete obstruction or through effects of cytokines released by Kupffer cells and endothelial cells, in response to circulating endotoxin-called ascending cholangitis. w Parasitic and helminthic infections:include malaria, schistosomiasis, strongyloidiasis, cryptosporidiosis, leishmaniasis, echinococcosis, and liver flukes “Fasciola hepatica”. w Liver abscesses- pyogenic : caused by echinococcal and amebic infections, route: arterial, portal, direct, migration “biliary tree”, penetrating injury

HEPATITIS - MORPHOLOGY: 1- ACUTE HEPATITIS 2- CHRONIC HEPATITIS

HEPTITIS-Morphological features w The morphologic changes in acute and chronic viral hepatitis can be mimicked by drug reactions or autoimmune liver disease. w Liver biopsy: Tissue alterations caused by acute infection with HAV, HBV, HCV, and HEV are generally similar, as is the chronic hepatitis caused by SAME VIRSUSES. w w Proper assessment of morphological changes needed: w Clinical information\presentation - correlation w Liver Function Tests. w Serological investigations (Viral profile\markers)

Acute Hepatitis- Morphology 1) Hepatocyte injury- diffuse swelling (ballooning degeneration) w Empty cytoplasm only scattered eosinophilic remnants. 2) Bile plugs brown pigmentation in canaliculi & hepatocytes- indicate cholestasis, this due to cessation of the contractile activity of the pericanalicular actin microfilament web. 3) Lobular inflammation with inter-phase & ductular reaction. 3) Morphological types of Hepatocytes death: a) Rupture of cell membrane leads to cell death& focal loss of hepatocytes. The sinusoidal collagen reticulin framework collapses and scavenger MQ aggregates at sites of cell loss. w b) Apoptosis, caused by anti-viral cytotoxic (effector) T cells, shrunken in size, phagocytes, not exists. w c) Confluent necrosis of hepatocytes may lead to bridging necrosis(portal-to-portal, central-to-central, or portal-to- central regions of adjacent lobules (in severe cases)

Acute hepatitis- MORPHOLOGY cells injury& ballooning Lobular inflammation

Chronic HEPTITIS-Morphology 1) Mild\ Silent\ to severe forms 2) Portal Inflammation: lymphpcytes, MQ, plasma cells, Neutrophils or eosinophils. 3) Liver architecture is well preserved. 4) Interface hepatitis and bridging necrosis(portal-to- portal& portal-to-terminal hepatic veins. 5) The hallmark of chronic liver damage is the deposition of fibrous tissue.- portal fibrosis, linking of fibrous septa (bridging fibrosis), (STAGING system to assess severity) 6) Liver cirrhosis: continued loss of hepatocytes and fibrosis results in cirrhosis: chr. varying sizes Nodules, broad scars viral hepatitis, autoimmune hepatitis, hepatotoxins (carbon tetrachloride, mushroom poisoning), pharmaceutical drugs (acetaminophen, α-methyldopa), and even alcohol A

Chronic HEPTITIS-Morphology w However a few features of chronic hepatitis are indicate viral hepatitis etiology w HBV-infected hepatocytes may show a cytoplasm packed with spheres and tubules of HBsAg, producing a finely granular cytoplasm (“ground-glass hepatocytes). w HCV-infected livers frequently show lymphoid aggregates within portal tracts, ductular reactive change and focal lobular regions of hepatocyte macrovesicular steatosis.

HBV infection: parenchyma showing hepatocytes with diffuse granular cytoplasm,(ground glass )

Chronic Hepatitis: HCV infection

Liver cirrhosis

Acute versus chronic hepatitis w Panacinar changes, worst in zone 3 w Lesions mainly acinar w Cholestasis and macrophage reaction common w May be confluent necrosis w Portal and periportal areas often most affected w Cholestasis rare w Fibrosis w Ground-glass cells in chronic hepatitis B

Fulminant Hepatic Failure w HBV, HAV, HCV, Herpes, toxin& drugs. w Severe necrotizing process. w Entire liver or only random areas may be involved. w little inflammatory reaction. w Massive influx of macrophages for phagocytosis w If pt. survive hepatocytes replication started with ductular reaction

Acute versus chronic hepatitis w Panacinar changes, worst in zone 3 w Lesions mainly acinar w Cholestasis and macrophage reaction common. w May be confluent necrosis w Portal and periportal areas often most affected. w Cholestasis rare. w Fibrosis. w Ground-glass cells in chronic hepatitis B

HEPATITIS - CLINICAL FEATURES & COMPLICATIONS h

The potential outcomes of hepatitis B infection in adults

Clinicopathologic Syndromes of Viral Hepatitis w Several clinical syndromes may develop : 1) Acute asymptomatic infection with recovery, HAV,HBV- sub-clinical confirm by e=; (serologic evidence only). 2) Acute symptomatic hepatitis with recovery, anicteric phase or icteric phase or convalescence. 3) Chronic hepatitis, without or with progression to cirrhosis. 4) Fulminant hepatitis with massive to submassive hepatic necrosis.(HBV) 5) HAV and HEV do not cause chronic hepatitis. 6) HBV and HCV usually develop chronic hepatitis. 5) Other causes of Chronic hepatitis, including chronic alcoholism, drugs (e.g., isoniazid, α-methyldopa, methotrexate), toxins, Wilson disease, α 1 -antitrypsin deficiency, and autoimmunity.

HEPATITIS – Clinical feature symptoms w ACUTE : w I. Acute asymptomatic w II. Acute symptomatic w Malaise w Muscle and join ache\ Fever\ Nausea or vomiting w Loss of apetite w Abdominal pain w Dark urine w Jaundice (+\-) w CHRONIC : w Malaise, tiredness, weakness w Weight loss w Peripheral oedema w Ascites The Carrier State. -reservoirs for infection -“healthy carrier” without HBeAg

HEPATITIS Common complications w ACUTE : w confluent necrosis. w Fulminant hepatitis B. w chronic hepatitis w CHRONIC : w Scarring of the liver (cirrhosis) (HBV, HCV) w Liver cancer. w Liver failure. w Co-Hepatitis D infection following HBV disaese w Kidney problems- child w Neurologic complications Guillain-Barré syndrome polyneuropathy. w Co –infection HIV