patoloji-ders-notlari

Title

Serdar Balcı

Viral and Autoimmune Hepatitis

Serdar BALCI, MD

VIRAL HEPATITIS

Robbins Basic Pathology

MacSween’s Pathology of the Liver 6th Ed

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

The risk of hepatocellular carcinoma

0.02% per year for chronic hepatitis B

2.5% per year when cirrhosis has developed

Robbins Basic Pathology

Hepatitis B

HBV replication does not involve the integration of the virus in the DNA of the host cell

Integrated HBV frequently is found in cells

The integrated viruses generally have large deletions and rearrangements and usually become inactive

• HBcAg
  • The precore/core region of a nucleocapsid “core” protein, the hepatitis B core antigen
  • retained in the infected hepatocyte
• HBeAg
  • a precore protein
  • secreted into blood and is essential for the establishment of persistent infection
• HBsAg
  • Envelope glycoprotein
  • surface antigen
  • produced and secreted into the blood in massive amounts
  • Blood HBsAg is immunogenic
• A DNA polymerase
  • error-prone reverse transcriptase activity
  • generates mutations in the genomes of replicating virus at a high rate
• HBV-X protein
  • transcriptional transactivator for many viral and host genes
  • required for viral infectivity
  • may have a role in the development of hepatocellular carcinoma by regulating p53 degradation and expression

MacSween’s Pathology of the Liver 6th Ed

Robbins Basic Pathology

Robbins Basic Pathology

Innate immunity protects the host during the initial phases of the infection

A strong response by virus-specific CD4+ and CD8+ interferon γ–producing cells is associated with the resolution of acute infection

HBV does not cause direct hepatocyte injury

Hepatocyte damage results from killing of the virus-infected cells by CD8+ cytotoxic T cells

Chronic HBV infection

Some hepatocytes may have viral genomes integrated into the host genome

If surface antigen gene integrates cell produces it

Usually in such cells full viral replication does not take place

The antigen just accumulates in these cells

**Large cytoplasmic inclusion consisting of endoplasmic reticulum stuffed with surface antigen **

Fine, smoothly granular appearance similar to that of ground glass

Rosai and Ackerman’s Surgical Pathology

**Chronic viral hepatitis B: viral replicative phase. Hepatitis B core antigen **

Rosai and Ackerman’s Surgical Pathology

**Chronic viral hepatitis B: viral replicative phase. Hepatitis B surface antigen **

Rosai and Ackerman’s Surgical Pathology

**Chronic viral hepatitis B: viral nonreplicative (integration) phase. Hepatitis B surface antigen **

Ground-glass hepatocytes in chronic hepatitis B, caused by accumulation of HBsAg in cytoplasm, have large, pale, finely granular, pink cytoplasmic inclusions on hematoxylin-eosin staining

Robbins Basic Pathology

Robbins Basic Pathology

Hepatitis C

Subclassified into six genotypes, based on the genetic sequence

Infected person may carry many HCV variants

The risk of hepatocellular carcinoma is 1% to 4% per year

Robbins Basic Pathology

Anti-HCV antibodies develop within weeks to a few months, they do not confer effective immunity

Strong immune responses involving CD4+ and CD8+ cells are associated with self-limited HCV infections

It is not known why only a minority of persons are capable of clearing HCV infection

Persistent infection is the hallmark of HCV infection, occurring in 80% to 85% of patients with subclinical or asymptomatic acute infection

Robbins Basic Pathology

Robbins Basic Pathology

• Typical features of chronic hepatitis
• Fatty change
  • Altered lipid metabolism in infected hepatocytes
  • Insulin resistance
• Lymphoid infiltrates in portal tracts, sometimes with fully formed lymphoid follicles
• Bile duct injury
  • Direct infection of cholangiocytes by the virus

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In HBV and HCV infection, circulating antibody-antigen complexes produce immune-complex disease in the form of vasculitis (subcutaneous or visceral) and glomerulonephritis

Cryoglobulinemia is found in 50% of patients with hepatitis C

Robbins Basic Pathology

Hepatitis D Virus

• Delta hepatitis virus
• Arises in two settings
• Acute coinfection after exposure to serum containing both HDV and HBV
  • Most coinfected persons clear the viruses and recover completely
• Superinfection of a chronic carrier of HBV with a new inoculum of HDV
  • Most superinfected persons there is an acceleration of hepatitis, progressing to more severe chronic hepatitis 4 to 7 weeks later

Robbins Basic Pathology

Hepatitis E

HEV hepatitis is an enterically transmitted, waterborne infection occurring primarily beyond the years of infancy

Endemic in India

Epidemics from Asia, sub-Saharan Africa, and Mexico

Sporadic infection seems to be uncommon

In most cases, the disease is self-limited; not associated with chronic liver disease or persistent viremia

High mortality rate among pregnant women, approaching 20%

Clinical Features and Outcomes for Viral Hepatitis

• A number of clinical syndromes may develop after exposure to hepatitis viruses
• Asymptomatic acute infection
  • Serologic evidence only
• Acute hepatitis
  • Anicteric or icteric
• Fulminant hepatitis
  • Submassive to massive hepatic necrosis with acute liver failure
• Chronic hepatitis
  • With or without progression to cirrhosis
• Chronic carrier state
  • Asymptomatic without apparent disease

Other Viral Infections of the Liver

• Epstein-Barr virus (EBV)
  • mild hepatitis during the acute phase of infectious mononucleosis
• Cytomegalovirus infection
  • newborn or immunocompromised
  • typical cytomegalic changes of that virus in almost any cell of the liver, hepatocytes, cholangiocytes, and endothelial cells
• Herpes simplex
  • infect hepatocytes in newborns or the immunosuppressed
  • appearance of the characteristic cytopathic changes and hepatic necrosis
• Yellow fever
  • major and serious cause of hepatitis in tropical countries
  • causes hepatocyte apoptosis, can be extensive
  • Apoptotic hepatocytes are intensely eosinophilic, Councilman bodies
• Rubella virus, adenovirus, or enterovirus infections
  • Infants, immunosuppressed

EBV

CMV

HSV

Yellow fever

Rubella

Adenovirus

Enterovirus

Liver Abscesses

• Amebic
• Other protozoal and helminthic organisms
• Bacterial abscesses
  • more common in developed countries
  • representing a complication of an infection elsewhere
• The organisms reach the liver:
  • Ascending infection in the biliary tract (ascending cholangitis)
  • Vascular seeding, either portal or arterial, predominantly from the gastrointestinal tract
  • Direct invasion of the liver from a nearby source
  • A penetrating injury

Autopsy Pathology: A Manual and Atlas

Granulomatous Disease

Fungal or acid-fast organisms

Systemic sarcoidosis

Duct destructive lesions in primary biliary cirrhosis

Parasites

Drug- or toxin-induced injury

AUTOIMMUNE HEPATITIS

Autoimmune Hepatitis

• Female predominance (70%)
• No serologic evidence of viral infection
• Elevated serum IgG (levels greater than 2.5 g/dL)
• High titers of autoantibodies in 80% of cases
• The presence of other forms of autoimmune diseases, seen in up to 60% of patients
  • Rheumatoid arthritis, thyroiditis, Sjögren syndrome, and ulcerative colitis

Circulating antinuclear antibodies

Anti–smooth muscle antibodies

Liver/kidney microsomal antibody

Anti–soluble liver/pancreas antigen antibody

• Type 1 : Patients have
  • antinuclear (ANA)
  • anti-smooth muscle (SMA)
  • anti-actin (AAA)
  • anti-soluble liver antigen/liver-pancreas antigen (SLA/LP)
  • Associated with HLA-DR3
• Type 2 : Patients have
  • anti-liver kidney microsome-1 (ALKM-1)
  • anti-liver-cytosol-1 (ALC-1)
• Main effectors of cell damage in autoimmune hepatitis are believed to be CD4+ helper cells
• Mononuclear infiltrate in autoimmune hepatitis frequently has abundant plasma cells
• Mild to severe chronic hepatitis
• Response to immunosuppressive therapy usually is dramatic, although a full remission of disease is unusual
• The overall risk of cirrhosis is 5%
  • main cause of death

Early phase of severe cell injury and inflammation followed by rapid scarring

This early wave of hepatocyte damage and necrosis usually is subclinical

Clinical evolution correlates with a limited number of histologic patterns

Very severe hepatocyte injury associated with widespread confluent necrosis

Marked inflammation concurrent with advanced scarring

Burned-out cirrhosis, associated with little ongoing cell injury or inflammation