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Hepatitis C: The Clinical Spectrum of Disease
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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