|
|
|
Review
-
Hepatitis C Infection
|
Uzma
Khan, MD
OBJECTIVES
Review
hepatitis C infection including general information, microbiology,
pathophysiology, diagnostic considerations, as well as treatment
and prognosis.
GENERAL
INFORMATION
The
hepatitis C virus (HCV) is an RNA virus. It belongs to the
family Flaviviridae and genus Hepacivirus. It was initially
known as non-A, non-B hepatitis and was identified in 1989
as a separate genome consisting of 9500 nucleotides. RNA
viruses, such as hepatitis C virus, demonstrate high degrees
of heterogeneity because the polymerase enzymes of these
viruses lack proofreading ability and cannot correct copying
errors made during replication. Six major genotypes have
been identified, with genotype 1 being most common in the
United States. The importance of the different genotypes
comes into play in reference to interferon-based therapy.
The CDC reports that the incidence of acute hepatitis C
infection has actually fallen from 230,000/yr in the 1980s
to 36,000/yr currently. This decline is primarily related
to decreased infections in intravenous drug abusers. Three
million nine hundred thousand persons in the USA have antibodies
to HCV, an estimated 2.7 million of which are viremic. The
highest incidence of acute HCV infection occurs between
ages 20 to 39, mostly involving African-Americans and whites.
60 to 80 percent of those with acute hepatitis C infection
go on to develop chronic hepatitis C infection. Chronic
hepatitis C infection is the most common liver disease in
the USA and most common cause of liver transplantation,
accounting for 8,000 to 13,000 deaths annually. The highest
prevalence of chronic HCV occurs between ages 30 to 49,
mostly involving males and African-Americans. 20 to 30 percent
of those with chronic HCV infection develop cirrhosis, 1/3
of which go on to develop hepatocellular carcinoma.
The most common mode of transmission is parenteral, with
an estimated 60% of cases being transmitted this way. Decreased
transmission has been demonstrated from blood transfusions
since the advent of screening since 1990 and nucleic acid
testing since 1999. Risk factors for transmission in sequential
order are as follows: sex with an intravenous drug abuser,
having been in jail for greater than 3 days, religious scarification,
having been struck or cut with a bloody object, ear/body
piercing, and immunoglobulin injection. High risk groups
include health care workers, organ transplant recipients,
those who have sex with promiscuous heterosexual males or
homosexual males (with higher risk if the index case has
concomitant HIV), infants born to anti-HCV women (especially
if coinfected with HIV), hemodialysis patients.
The
pathogenesis is thought to occur via vigorous antibody and
cell-mediated immune response. Flavivirus is thought to
be directly cytopathic, though this has not been tested
in the case of HCV as the virus cannot be cultured. Rapid
turnover of plasma virus in infected patients accompanied
by weak CD4+ and CD8+ T-cell responses in acute infection
that fail to control viral replication contribute to persistent
hepatitis C infection. It has been suggested that the expression
of HCV core protein that binds to and represses p53 promoter
transcription is responsible for the development of hepatocellular
carcinoma due to intracellular reactive oxygen species from
mitochondrial injury.
Acute
HCV is responsible to 20% of acute hepatitis cases. The
majority of patients are asymptomatic. Those who are asymptomatic
have very mild courses, demonstrating malaise, fatigue,
right upper quadrant pain, and nausea. Less than 25% develop
jaundice. Fulminant hepatic failure due to acute HCV is
extremely rare. Most patients with chronic hepatitis C are
asymptomatic. The most common complaint in chronic hepatitis
C patients is fatigue, followed by nausea, anorexia, myalgia,
arthralgia, weakness, weight loss, and cognitive impairment.
There is no correlation between symptoms and serum aminotransferases
or liver histology, though symptoms do typically present
with the onset of hepatic cirrhosis. One-third of chronic
hepatitis C patients have normal alanine aminotransferase
(ALT). Some recent studies suggest that aspartate aminotransferase
(AST):ALT greater than or equal to 1 may correlate with
the development of cirrhosis, but nothing conclusive has
been found yet.
The
progression from chronic hepatitis C to cirrhosis occurs
over the course of about 20 years and is mostly silent.
Hepatomegaly and/or splenomegaly are not commonly found
in such patients. Lab testing may be helpful in identifying
patients with cirrhosis: 40% have elevated total bilirubin,
10% have hypoalbuminemia, and thrombocytopenia. 43% of patients
with chronic hepatitis C have elevated alpha fetoprotein,
and further imaging of the liver is suggested in such patients
to rule out hepatocellular carcinoma. Hepatic decompensation
presents most commonly as ascites in 48% of patients, followed
by variceal bleeding, encephalopathy, and jaundice. 5-year
survival for decompensated HCV-related cirrhosis is 51%.
In comparison, 3, 5, and 10-year survival rates for compensated
cirrhosis are 96, 91, and 79 percent, respectively; these
rates have not been affected by interferon therapy. Thirty
percent of patients with HCV develop hepatocellular carcinoma,
which suggests that cirrhosis alone is a major risk factor
for hepatocellular carcinoma. Accelerated disease progression
occurs with the following: cytokine transforming growth
factor B1, acquisition of HCV after age 40 to 55, questionable
environmental factors (as evidenced by increased complications
in Japan), HIV coinfection, high BMI and hepatic steatosis,
and alcohol intake, and HBV coinfection.
Extrahepatic
manifestations of chronic hepatitis C include many systems.
Hematologic disease includes essential mixed cryoglobulinemia,
monoclonal gammopathy, B-cell non-Hodgkin’s lymphoma.
Endocrine involvement has been manifested as an association
with diabetes mellitus, especially in those with hepatic
fibrosis, older age, obesity, and family history of diabetes.
HCV has been linked to insulin resistance as well. Hypothyroidism
is common in 2 to 13 percent of patients with HCV, especially
older women. Suggestion of autoimmune disease has been shown
in 40 to 65 percent of patients with HCV, as they are found
to have positive rheumatoid factor, anticardiolipin antibodies,
smooth muscle antibodies, or antithyroid antibodies in low
titers. Some have also demonstrated antibodies to liver/kidney
microsomes, which are seen in autoimmune hepatitis. Associations
with ITP and myasthenia gravis have been suggested, but
not proven. Ocular disease manifests as corneal ulcers,
uveitis, and scleritis. Retinal hemorrhages and cotton wool
spots have been reported with interferon therapy. The most
common renal diseases are membranoproliferative glomerulonephritis
and membranous nephropathy. Membranoproliferative glomerulonephritis
occurs due to anti-HCV and HCV RNA immune complex deposition
in glomeruli and is associated with essential mixed cryoglobulinemia.
Dermatologic disease includes porphyria cutanea tarda, leukocytoclastic
vasculitis (includes mononeuritis multiplex), and lichen
planus. Bone disease occurs in the form of hepatitis C-associated
osteosclerosis presenting with forearm and leg pain and
is extremely rare.
The
first biochemical evidence of HCV infection is HCV RNA in
serum or liver, which is detectable within days to eight
weeks after exposure. Serum aminotransferase elevations
are seen 6 to 12 weeks after exposure. Anti-HCV-ELISA tests
become positive eight weeks after exposure, but this test
does not differentiate between those who cleared the infection
from those who are chronically infected. Anti-HCV antibody
development may be delayed in patients with subclinical
infection. Serum aminotransferase fluctuation commonly occurs
after the acute infection, and its normalization does not
signify clearance of the infection. Persistent loss of HCV-RNA
demonstrates resolution of the infection and occurs in 15
percent of patients – no correlation with serum ALT.
Sreening recommendations following known exposure as follows:
HCV PCR testing immediately and at weeks 4 and 12, ELISA
antibody testing immediately and at week 12, serum transaminase
testing immediately and at weeks 4 and 12. Chronic hepatitis
C can be distinguished from acute hepatitis C based on the
timing of serologic markers.
Sustained virologic response has been demonstrated in 85%
with pegylated interferon therapy and ribavirin versus 80%
with pegylated interferon monotherapy. Treatment should
be initiated three months after development of symptoms
as spontaneous HCV clearance after acute infection occurs
within 12 weeks. Delaying treatment until after this time
does not seem to lower the likelihood of sustained virologic
response. Liver transplantation is the only therapy once
complications of cirrhosis have occurred. Recurrent HCV
infection of the graft invariably occurs in almost all patients.
REFERENCES
-
Alter, MJ. Epidemiology of hepatitis
C. Hepatology 1997; 26:62S.
-
Alter, MJ, Gerety, RJ, Smallwood, L, et al.
Sporadic non-A, non-B hepatitis: Frequency and epidemiology
in an urban United States population. J Infect Dis
1982; 145:886.
-
Centers for Disease Control and Prevention. Risk
of acquiring hepatitis C for health care workers and recommendations
for prophylaxis and follow-up after occupational exposure.
Hepatitis Surveillance Report No. 56, Atlanta 1995.
-
Chopra, Sanjiv. Clinical features and
natural history of hepatitis C virus infection. UpToDate
Online, version 13.1.
-
Goldman, Lee and Bennett, J. Claude. Cecil
Textbook of Medicine 21st edition. 2000. pp. 787-789.
-
Heintges, T, Wands, JR. Hepatitis C virus:
Epidemiology and Transmission. Hepatology 1997;
26:521.
-
Murphy, EL, Bryzman, SM, Glynn, SA, et al.
Risk factors for Hepatitis C virus infection in United
States blood donors. Hepatology 2000; 31:756.
-
Reinhard, Lorenz and Endres, Stefan.
Diagnosis and treatment of acute hepatitis C. UpToDate
Online, version 13.1.
-
http://www-micro.msb.le.ac.uk/3035/HCV.html
|
|
|
