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Hepatitis C: The Clinical Spectrum of Disease
About Dr Zahid
Yasin Hashmi
The hepatitis C virus (HCV) is an important cause of both acute and chronic
hepatitis. As with all diseases, the clinical course and outcome of hepatitis C
are variable - there is no single natural history of disease, but rather a broad
clinical spectrum of disease presentations and outcomes. In the United States,
hepatitis C represents approximately 20 percent of cases of acute hepatitis. The
mean incubation period to onset of symptoms is 7 weeks; the range is 3-20 weeks.
However, long before onset of symptoms, markers of virus appear in the serum:
HCV RNA is detectable within 1-3 weeks of exposure and rises rapidly to levels
of 106-108 genomes per ml. After several weeks, serum alanine aminotransferase
levels (ALT) begin to rise and shortly thereafter clinical symptoms appear. The
severity of the acute illness is variable; virtually all infected patients have
a transient elevation in ALT with peak levels greater than tenfold elevated. Yet
only a third of patients develop jaundice or symptoms: in the remainder, the
disease is anicteric and subclinical. If clinically apparent, the illness
generally lasts 2-12 weeks. Acute hepatitis C can result in fulminant hepatitis,
but this is quite rare. In cases of acute, self-limited disease, HCV RNA becomes
undetectable within a few weeks of onset of symptoms and aminotransferase levels
return to normal. Unfortunately, the majority of patients with acute hepatitis C
develop chronic infection; symptoms of acute hepatitis resolve, but ALT levels
remain elevated and HCV RNA persists. Indeed, a propensity to chronicity is the
most distinguishing characteristic of HCV infection, occurring in at least 85
percent of patients with acute HCV infection. The factors that lead to
chronicity in hepatitis C are not well defined. The quasispecies nature of HCV
and the tendency of the envelope gene of the virus to mutate rapidly may be key
factors, the virus constantly escaping immune recognition by mutations in the
antigenic epitopes to which any neutralizing antibody is made. The role of
cellular immunity to HCV antigens in explaining why 15 percent of patients clear
HCV infection while the majority do not may also be important.
Not all patients who continue to be viremic continue to have raised ALT levels.
In most surveys, approximately one-third of patients with chronic HCV infection
have persistently normal serum ALT levels, and in others ALT levels are only
intermittently abnormal. These patients have been referred to as "healthy
HCV carriers," but this term is misleading and should be avoided. Liver
biopsies in patients with chronic HCV infection with normal ALT levels reveal
histological evidence of chronic hepatitis in virtually all patients. Perhaps
more appropriate is to say that these patients have mild or subclinical chronic
hepatitis C: their prognosis may be excellent.
The majority of patients with chronic HCV infection have raised ALT levels,
which can fluctuate widely over time. There is not a very good correlation
between the height of the ALT levels and disease severity as judged
histologically. Long-term followup studies, however, suggest that most patients
with progressive liver disease who develop cirrhosis have prominent ALT
elevations; these can, however, be intermittent.
A smaller proportion of patients with chronic HCV infection have clinical
symptoms or signs of liver disease. Symptoms in chronic hepatitis C tend to be
nonspecific, mild, and intermittent. The most frequent symptom is fatigue,
variably described as lethargy, malaise, lack of energy or stamina, and easy
fatigability. Often, it is a challenge to determine whether the fatigue is
attributable to the liver disease rather than to something else - depression,
anxiety over the illness, aging, sleep disturbance, or another medical
condition. Other, less frequent symptoms are nausea, poor appetite, muscle
aches, arthralgias, feverishness, weakness, and weigh loss. Symptoms are rarely
incapacitating, but they can cause a decrease in the quality of life. In
general, patients with higher ALT levels and more severe disease histologically
are more likely to have symptoms, but marked exceptions exist. Because the
symptoms are nonspecific, it is hard to define what percentage of patients with
chronic HCV infection are symptomatic; but it is probably less than 20 percent.
These are the patients, however, who are most likely to present to a physician
for diagnosis and management.
Chronic hepatitis C, whether or not symptoms are present, can lead to cirrhosis
and end-stage liver disease. Cirrhosis can develop rapidly, within 1-2 years of
exposure, or slowly, within 2-3 decades. In studies with 10-20 years of followup,
cirrhosis develops in 20-30 percent of patients. It is unclear whether the
remaining patients will eventually develop cirrhosis or not. Thus, chronic
hepatitis C probably does not have one typical course; there are probably
multiple typical courses, from rapidly progressive to slowly progressive to
nonprogressive.
Once cirrhosis develops, the symptoms of end-stage liver disease can appear,
such as marked fatigue, muscle weakness and wasting, fluid retention, easy
bruisability, upper intestinal hemorrhage, jaundice, dark urine, and itching.
Nevertheless, some patients with cirrhosis remain asymptomatic of liver disease
until they have major complications of cirrhosis, such as variceal hemorrhage or
ascites or they die of an unrelated cause. Hepatitis C ranks with alcoholic
liver disease as the most common cause of cirrhosis and the major indication for
liver transplantation in the United States. Liver transplantation is the only
means of restoring health to patients with end-stage liver disease due to HCV.
Recurrent infection of the new graft occurs in almost all patients, but in many
cases the recurrent infection is mild. Long-term studies are needed to assess at
what rate recurrent hepatitis C leads to recurrence of cirrhosis. At present,
long-term survival after liver transplantation for hepatitis C is similar to
that for other diagnoses, averaging 65 percent after 5 years.
In many areas of the world, chronic hepatitis C is a major cause of
hepatocellular carcinoma (HCC). This tumour occurs largely in patients with
long-standing disease, and the majority have cirrhosis. Therapies for HCC are
unsatisfactory and focus must be on prevention of development of cirrhosis and
early detection of liver cancer.
The spectrum of hepatitis C also includes several nonhepatic manifestations,
including arthritis, keratoconjunctivitis sicca, lichen planus,
glomerulonephritis, and essential mixed cryoglobulinemia (EMC). EMC is a
syndrome marked by varying combinations of fatigue, muscle and joint aches,
arthritis, skin rash (hives, purpura, or vasculitis), neuropathy, and
glomerulonephritis. Cryoglobulins are found in serum composed of immune
complexes of HCV and anti-HCV, immunoglobulins, rheumatoid factor, and
complement. Hepatitis C appears to be the most common cause of EMC, a fact that
was not appreciated before the availability of serological tests for HCV.
Cryoglobulins are detectable in up to one-third of patients with chronic
hepatitis C, but the clinical syndrome of EMC occurs in only 1-2 percent of
patients. This syndrome can be severe, incapacitating, and even fatal.
Resolution of the hepatitis C is followed by resolution of the EMC.
Glomerulonephritis can also occur with hepatitis C; it usually represents the
renal involvement of HCV-related EMC. Overall, this syndrome might best be
called HCV-related systemic vasculitis.
A final clinical manifestation of chronic hepatitis C is porphyria cutanea tarda
(PCT). This form of porphyria is found in several forms of chronic liver disease
often in association with iron overload. In some parts of the world, hepatitis C
is the major underlying cause of PCT. Like other forms, HCV-related PCT can be
treated with phlebotomy to deplete the excess iron stores that exacerbate the
porphyria.
Thus, there is a wide clinical spectrum to acute and chronic hepatitis C. Simple
and reliable systems to stage and grade the severity of chronic hepatitis C are
needed. Histological systems such as the histology activity index (HAI) have
been developed to categorize chronic hepatitis C for use in clinical studies of
natural history and therapy. A possible system which mixes clinical symptoms,
serum biochemical tests, and liver histology would be as follows:
Disease activity:
Mild (ALT normal or <2 times upper limit)
Moderate (ALT 2-5 times upper limit)
Severe (ALT >5 times upper limit)
Cirrhosis: Present or absent
Symptoms: Present or absent
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