Extrahepatic manifestations of hepatitis C.

It is well established that chronic hepatitis C virus (HCV) infection may lead to the development of progressive liver disease and cirrhosis of liver. For example, chronic HCV leads to cirrhosis in 20% of patients over 20 to 30 years. (1) This has lead to considerable focus on the hepatic manifestations of the HCV. However, there are research studies indicating that HCV is associated with various extrahepatic manifestations including mixed cryoglobulinemia (MC), membranoproliferative glomerulonephritis (MPGN), non-Hodgkin lymphoma, Sjogren syndrome, porphyria cutaneous tarda, lichen planus, leukocytoclastic vasculitis, and various endocrine and neurologic manifestations. (1-5) Approximately 40% of patients with HCV have cryoglobulinemia with or without specific extrahepatic manifestation. (4-6) It has been suggested that focus on comorbid extrahepatic disorders may lead to better detection of HCV, improvement in these disorders due to antiviral treatment of HCV, and early diagnosis and treatment of these disorders. (7) More importantly, these manifestations can complicate the course and treatment of HCV-related liver diseases. For example, MC associated with HCV has been linked to increased fibrosis and cirrhosis of liver. Furthermore, it is possible that drug treatment of extrahepatic disorders may cause hepatotoxicity including liver failure. Hence, recognition of type and magnitude of extrahepatic disorders, including their pathophysiology, are very important to aid in awareness, early diagnosis, and specifically targeted therapy for HCV-related extrahepatic diseases.

MC is an autoimmune disease associated with chronic HCV. MC has frequently been implicated in increased fibrosis or cirrhosis in chronic HCV-infected patients. (6,8-11) The pathophysiologic mechanism of MC can also explain other extrahepatic syndromes such as MPGN, non-Hodgkin lymphoma, and leukocytoclastic vasculitis. (12-14) It has been postulated that HCV infects circulating B lymphocytes and can stimulate them to produce monoclonal immunoglobulin M (IgM) rheumatoid factor (Type II) and polyclonal IgM rheumatoid factor (Type III) leading to mixed cryoglobulinemia. (15-16) These IgM rheumatoid factors bind with anti-HCV immunoglobulin G (IgG) or to the IgG-HCV immune complex leading to a deposition of circulating immune complexes in small- or medium-sized blood vessels ultimately resulting in essential MC, MPGN, MPGN and leukocytoclastic vasculitis. (17-18)

The exact nature of the relationship between MC and progressive liver disease remains unclear. It has been hypothesized that the association between cirrhosis and MC may be due to the association of cryoglobulin with longstanding HCV infection and older age. (10) However, fibrosis progression rate is clearly shown to be related to duration of infection rather than MC. (19) Furthermore, Siagris et al reported no significant correlation of duration of infection or older age with prevalence of MC in HCV-infected patients. (10) Hence, it is still not clear from the findings that the development of MC is cause or effect of progressive liver fibrosis or cirrhosis in chronic HCV infection. Further prospective longitudinal studies with histologic evaluation of liver biopsies comparing chronic HCV patients with or without cryoglobulinemia are warranted to clarify molecular and clinical relationship between MC and liver fibrosis.

Various neurologic manifestations have been reported in patients with chronic hepatitis C. (20-21) The most common peripheral neurologic deficit is mononeuropathy multiplex, which is clearly related to cryoglobulinemia, vasculitis, and thrombosis. (20-21) Other neurologic disorders associated with HCV include acute inflammatory syndromes, such as encephalitis, and encephalomyelitis. It has been postulated that, since HCV belongs to a family of Flaviviridae, which is characterized by neurotropism, it has the ability to invade the nervous system. HCV RNA is seen in affected brain tissue or cerebrospinal fluid (22-24) of patients with certain acute inflammatory central nervous system syndromes. Negative-strand HCV was identified in brain tissue of two patients with post-transplantation recurrent HCV and three of six autopsied patients with chronic HCV infection. (25-26) These findings support the idea that HCV may cause neurologic deficits or symptoms directly by invading and replicating in the nervous system. However, due to lack of suitable methodologies for in situ detection, it is unclear whether HCV has the same abilities of infection of the nervous system as its class. As of yet, the pathogenesis of nervous system involvement remains unclear because it can be attributed to in situ HCV replication, toxicity of HCV-encoded proteins, or immune-mediated antiviral response. Further basic virologic and clinical studies will be necessary to fully understand the viral interaction with the nervous system and the resulting neurologic symptoms.

Type II diabetes mellitus (DM) has been implicated as an important endocrine manifestation of chronic HCV. (27-30) Even though there is no formal proof for the infectious disease model for type II DM, it has been hypothesized that HCV mediates type II DM in genetically susceptible individuals. Thuluvath et al provided support for both racial and environmental factors for infectious disease model for the development of DM in chronic HCV. (31) They reported an increased prevalence of type II DM in black patients with HCV compared with controls matched for race, severity of liver disease, and body mass index. This finding is significant since both HCV infection and black race have been reported as independent risk factors for type II DM. (32-33) It has been noted that HCV-positive diabetics have beta-islet cell dysfunction with decreased C-peptide levels and limited acute insulin responses. (11,32) In addition, an improvement of glucose metabolism have been observed after antiviral therapy in patients with chronic HCV even though there is no animal or in vitro models to test the hypothesis that HCV directly damage beta islet cells or disturbs their synthetic function. (11) Therefore, further genetic, animal model, tissue culture media, and mechanistic studies are needed to determine the role of HCV on glucose metabolism and pancreatic disease that leads to type II DM. In addition, prospective longitudinal studies are needed in chronic HCV patients on antiviral therapy to determine whether DM is a reversible process in patients who clear HCV infection.

In conclusion, HCV may lead to various extrahepatic manifestations. The majority of extrahepatic manifestations can be explained in terms of an immune-mediated syndrome related to MC even though the exact mechanism by which HCV may result in MC is still not clear. Furthermore, MC is associated with increased fibrosis and cirrhosis. Hence, early treatment of HCV infection in patients with MC may decrease the rate of fibrosis and may prevent cirrhosis including its complications. Mechanisms of other extrahepatic manifestations such as neurologic manifestations and DM related to chronic HCV are unclear and necessitate further research to clarify pathophysiology and clinical course of extrahepatic manifestations of chronic HCV.

References

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The employees of the Southern Medical Journal wish to extend our heartfelt sympathies to the victims of Hurricane Katrina and Hurricane Rita.

We would also like to thank the members of the medical profession who assisted in the relief efforts throughout the Gulf Coast. Your professionalism, courage and tenacity have been an inspiration. Your compassion has reminded us of the true meaning of the avocation to which we have devoted our lives.

The purpose of human life is to show compassion and the will to help
others.
--Albert Schweitzer

Smruti R. Mohanty, MD

From the Center for Liver Diseases, Department of Medicine, Section of Gastroenterology, the University of Chicago, Chicago, IL.

Reprint Requests to Smruti R. Mohanty, MD, Assistant Professor of Medicine, Center for Liver Diseases, Department of Medicine, Section of Gastroenterology, the University of Chicago, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637. Email: [e-mail]

Accepted April 19, 2005