Chronic Hepatitis C Pathology
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Hepatitis C is an infectious hepatitis caused by hepatitis C virus (HCV).This systemic viral infection predominantly involves the liver hepatocytes and can result in both acute and chronic liver diseases.
HCV can also be detected in the peripheral blood, particularly in mononuclear cells. The extrahepatic pool of HCV is the major source of recurrent hepatitis C in orthotopic liver transplant recipients.
Hepatitis C is a global disease. It is estimated that about 3% of the world’s population, approximately 200 million people, have been infected with HCV. [1] The Centers for Disease Control and Prevention estimate that almost 4 million Americans are chronically infected with HCV. [2] Most liver transplantations performed in the United States are for chronic hepatitis C. Hepatitis C accounts for 12,000 deaths each year. [2, 3]
Following the identification of hepatitis A and hepatitis B, this disorder was categorized in 1974 as “non-A, non-B hepatitis.” In 1989, the hepatitis C virus was identified and found to account for most cases of non-A, non-B hepatitis. HCV was most commonly acquired through transfusion of blood products before blood screening assays were developed and implemented in 1990. [3]
The incidence of hepatitis C has declined from 175,000 cases per year to about 30,000 cases per year since 1990. Currently, injection drug use accounts for approximately 60% of new infections. Other risks include sexual transmission, vertical transmission, and occupational exposure. [2]
HCV infection can result in both acute and chronic hepatitis. The acute process is most often asymptomatic with a clinically mild course. The clinical symptoms, if present, are similar to those of other acute viral hepatitis, including malaise, nausea, jaundice, and right upper quadrant pain, which typically last for 2-12 weeks. However, fulminant hepatitis is very rare in acute hepatitis C. HCV RNA can be detected in serum via polymerase chain reaction (PCR) as early as a few days following exposure, which is the earliest diagnostic marker. levels of serum aminotransferases become elevated approximately 6-12 weeks after exposure, and anti-HCV enzyme-linked immunoassay (ELISA) test results become positive 8 weeks after exposure.
Approximately 80% of patients with acute hepatitis C develop chronic infection that manifests as persistent HCV RNA detected in the blood with or without abnormal liver function test results for more than 6 months. [4, 5] Most patients with chronic hepatitis C have no or only mild symptoms, including fatigue, anorexia, and nausea.
Anti-HCV antibody is not protective, and its level does not necessarily remain elevated in patients with chronic hepatitis C.
The most important outcome of chronic hepatitis C is the progression to cirrhosis and hepatocellular carcinoma. It is estimated that up to 25% of patients with chronic hepatitis C will develop cirrhosis within 20 years. [6, 7] Hepatocellular carcinoma associated with HCV occurs almost exclusively in those with cirrhosis. Once cirrhosis is established, hepatocellular carcinoma develops at an annual rate of 1%-5%. [3]
A study investigated the impact of oxidative stress and iron deposition on hepatocellular carcinoma development after therapy with pegylated interferon (PegIFN)+ribavirin in chronic hepatitis C patients. The study concluded that the measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of hepatocellular carcinoma development after interferon therapy. The study also reported that low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in chronic hepatitis C patients. [8]
The histological features of acute hepatitis C differ very little from other acute viral hepatitis. The essential components include inflammatory cell infiltrate and hepatocellular injury with predominantly lobular involvement.
Several forms of hepatocyte injury can be seen under light microscopy, including ballooning degeneration (severe swelling), focal necrosis, and acidophil bodies (apoptosis). Acidophil body is a dense eosinophilic hepatocellular debris that is sometimes fragmented. The distribution of hepatocyte injury can be multifocal or panacinar. Severe cases may have confluent hepatocellular necrosis, predominantly in the centrilobular region. Unlike other viral hepatitis, massive hepatocellular necrosis is rarely seen in hepatitis C. The inflammatory infiltrate is composed predominantly of lymphocytes, sometimes plasma cells, eosinophils, neutrophils in the lobules and surrounding dead hepatocytes.
The protal tracts always demonstrate some inflammatory infiltrate. In contrast to the predominant portal activity in chronic hepatitis, the portal inflammation is typically proportional to or less than the lobular activity in acute hepatitis. The inflammatory infiltrate is composed of lymphocytes, plasma cells, eosinophils, and neutrophils.
In addition, cholestasis, Kupffer cell activation, endotheliitis, bile duct injury, ductular reaction, hepatocele regeneration, and mild fatty changes can also be seen.
In contrast to the lobular activity in acute hepatitis, the portal activity is the predominant histologic picture in chronic hepatitis C. The most characteristic feature of chronic hepatitis is the lymphoid aggregate or follicle in the portal tract.
Although lymphoid follicle is not highly specific, it is much more common and prominent in hepatitis C than other viral hepatitis. The inflammatory infiltrate is composed of predominantly lymphocytes and plasma cell, which is confined to the portal tract in the mild form of hepatitis. Interlobular bile ducts are often damaged, as manifested by lymphocytic infiltration within the ductal wall, nuclear crowding, and intracytoplasmic vacuoles in the ductal epithelial cells.
In the more severe cases, the portal inflammation extends into the adjacent periportal parenchyma and results in hepatocyte injury at the interface (interface hepatitis). Interface hepatitis can be easily identified by the irregular limiting plate of the hepatocytes with associated hepatocyte apoptosis and inflammatory infiltrate. Bile ductal injury and mild vasculitis may be present in the portal tract. However, loss of bile ducts or severe vasculitis is exceedingly rare in chronic hepatitis C.
Besides the interface hepatitis, the histological findings also include spotty acidophil bodies and lymphocyte infiltrates in the lobules. There are hypertrophic Kupffer cells associated with necrotic hepatocellular debris. More severe lobular activity may suggest an exacerbation of the chronic hepatitis or superimposed acute hepatitis of another etiology. Another characteristic but nonspecific feature is mild fatty change. It is more common in hepatitis C than other forms of chronic viral hepatitis. Different than the zone 3 accentuated steatosis seen in metabolic syndrome, chronic hepatitis C–related steatosis is typically randomly distributed.
In the posttransplantation setting, it can be difficult to distinguish recurrent hepatitis C from acute cellular rejection. Endotheliitis and lymphocytic cholangitis can be seen in both conditions. In hepatitis C, the endotheliitis is usually mild. In contrast, acute cellular rejection has more severe endotheliitis.
Persistent inflammation and hepatocellular injury lead to the fibrosis. Progressive interface hepatitis is followed by periportal fibrosis and portal-to-portal and even portal-to-central bridging fibrosis. The bridging fibrosis and regenerative nodule of the hepatocytes significantly distort the normal architecture and result in cirrhosis.
Several scoring systems to evaluate the necroinflammation (grade) and fibrosis (stage) for chronic hepatitis have been proposed. The most common include Metavir, histologic activity index (HAI, also known as the modified Knodell or Ishak score), and Batts & Ludwig scheme. In general, grading is based on portal inflammation, interface hepatitis, lobular inflammation, and necrosis; staging is based on the extent of fibrosis. The results are comparable from different scoring system.
An example is the Batts & Ludwig scheme (below).
Activity is classified as 0-4, as follows:
Grade 0: No significant inflammation or necrosis
Grade 1 (minimal activity): Portal inflammation with predominantly mononuclear cells almost entirely confined to the portal areas, no interface hepatitis or lobular inflammatory foci
Grade 2 (mild activity): Mild portal inflammation, interface hepatitis, and scant lobular spotty necrosis
Grade 3 (moderate activity): Moderate portal inflammation, interface hepatitis, and lobular spotty necrosis
Grade 4 (severe activity): Marked portal inflammation, interface hepatitis, and lobular necrosis, including bridging necrosis
Fibrosis is classified as 0-4, as follows:
Stage 0: No fibrosis
Stage 1: Fibrous portal expansion
Stage 2: Periportal fibrous extension
Stage 3: Fibrous septa formation, including portal-to-central bridging fibrosis
Stage 4: Cirrhosis
Studies have been conducted to explore the immunohistochemical marker. However, commercially available and universally reproducible antibodies for HCV immunohistochemistry are still lacking.
HCV is a positive, single-strand RNA virus in the genus Flavivirus. There are 6 major HCV genotypes and more than 50 minor subtypes. The geographical distribution of these genotypes and subtypes varies significantly. Genotype 1 HCV is the most common in the United States and is associated with a lower rate of response to treatment. The significant genetic variability hinders the development of HCV vaccine. [1]
Up to 25% of patients with chronic hepatitis C will develop cirrhosis within 20 years. Many host factors increase this risk, including older age at time of infection, male sex, concurrent chronic hepatitis B virus (HBV) infection, high alcohol consumption, and an immunosuppressed state such as that associated with human immunodeficiency virus (HIV) infection. [3]
Factors associated with successful therapy with interferon and ribavirin include genotypes other than 1, lower baseline viral levels, less fibrosis or inflammation on liver biopsy, and lower body weight or body surface area.
The differential diagnosis includes the following:
Lymphoma
Other viral hepatitis, including hepatitis A, hepatitis B, and hepatitis D, among others
Primary sclerosing cholangitis
Steatohepatitis
[Guideline] Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998 Oct 16. 47(RR-19):1-39. [Medline].
NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002 Jun 10-12. 19(3):1-46. [Medline].
Barrera JM, Bruguera M, Ercilla MG, et al. Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C. Hepatology. 1995 Mar. 21(3):639-44. [Medline].
Farci P, Alter HJ, Wong D, et al. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med. 1991 Jul 11. 325(2):98-104. [Medline].
Tong MJ, Lai PP, Hwang SJ, et al. Evaluation of sexual transmission in patients with chronic hepatitis C infection. Clin Diagn Virol. 1995 Jan. 3(1):39-47. [Medline].
Yano M, Kumada H, Kage M, et ak. The long-term pathological evolution of chronic hepatitis C. Hepatology. 1996 Jun. 23(6):1334-40. [Medline].
Takahashi M, Yamada G, Miyamoto R, Doi T, Endo H, Tsuji T. Natural course of chronic hepatitis C. Am J Gastroenterol. 1993 Feb. 88(2):240-3. [Medline].
Nanba S, Ikeda F, Baba N, et al. Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C. J Clin Pathol. 2016 Mar. 69(3):226-33. [Medline].
Previsani N, Lavanchy D. Hepatitis C. WHO (2002). Available at http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html. Accessed: October 1, 2010.
Wei Xiong, MD, PhD Associate Professor of Pathology, University of British Columbia Faculty of Medicine, Canada
Wei Xiong, MD, PhD is a member of the following medical societies: United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
Matthew M Yeh, MD, PhD Associate Professor, Department of Pathology, University of Washington School of Medicine
Matthew M Yeh, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Society for Clinical Pathology, College of American Pathologists, United States and Canadian Academy of Pathology, Washington State Medical Association
Disclosure: Nothing to disclose.
Nirag C Jhala, MD, MBBS Director of Anatomic Pathology, Director of Cytopathology, Temple University Hospital; Professor of Pathology and Laboratory Medicine, Temple University School of Medicine
Nirag C Jhala, MD, MBBS is a member of the following medical societies: American Society of Cytopathology, Biomedical Engineering Society, College of American Pathologists, International Academy of Cytology, United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
Chronic Hepatitis C Pathology
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