Dr. Sherman is a Hepatologist practicing in Toronto, Canada. This paper has been submitted as a contribution to the Canadian Hepatitis Education Council.
There are numerous consequences of hepatitis C viral (HCV) infections in some instances, as a result of a paucity of data, this review will be confined to the physical consequences of HCV infection as they pertain to the infected individual. Psychologic and financial implications of HCV infections will not be discussed nor will the consequences to family members, friends, colleagues, employers and the economy in general. Wherever possible, only data derived from studies or observations in which the diagnosis of HCV has been established serologically will be utilized. Due to the wide geographic distribution of the 20 different genetic variants (HCV genotypes) and the strong probability that the natural history of HCV infections are genotype-dependent, studies from North America and to a lesser extent, Europe, will be highlighted.
What are the Consequences of Acute HCV Infections?
The absence of specific clinical, serologic and/or histologic markers for acute HCV infections has complicated attempts to describe the various features of acute HCV. This shortcoming is compounded by the fact that exacerbations of underlying chronic HCV and additional hepatic infections / insults superimposed on chronic HCV can mimic essentially all aspects of acute HCV infections. Thus, much of the published data describing features of acute HCV are limited to blood transfusion studies wherein patients with no underlying liver disease were prospectively monitored for symptoms and signs of acute hepatic injury. Whether these findings can be extrapolated to cases of acute HCV infection derived from exposure to lower innoculum sizes such as those associated with parenteral drug abuse, needle stick exposures, or sporadic cases has yet to be determined.
Symptoms and Signs
Most chronic HCV carriers are asymptomatic. When symptoms are present, the most common are fatigue (70%), abdominal pain/discomfort (20%), anorexia (15%) and weight loss(5%). The majority of chronic HCV carriers have hepatomegaly (70%) while some have an enlarged, palpable spleen (20%). Palmar erythema, spider nevi, etc. are no more or less common than is seen in other causes of chronic liver disease.
The mean incubation period from HCV exposure to development of symptoms or signs of acute liver injury is approximately 6 to 8 weeks (range 2-26). 1 In general, patients tend to be asymptomatic or have non-specific complaints similar to those associated with acute hepatitis A/B infections such as mild anorexia, nausea, fever, chills, general malaise, fatigue, right upper quadrant discomfort, and in more severe cases darkening of the urine and pale stool. Hepatomegaly and to lesser extent, splenomegaly are common. Only 25% of acute HCV cases develop jaundice. 1
When tested monthly for 6 months or every other month for a year, as many as 80% of patients with chronic HCV infections will have abnormal aminotransferase values. As in acute HCV, the ALT/AST is > 1 unless cirrhosis has developed at which time the ratio can be reversed. A characteristic feature of chronic HCV is the fluctuation in aminotransferase values seen in approximately 50% of cases. In the remaining 50% of patients aminotransferase values are relatively stable. Whether fluctuations in the former group represent effects of mutations in the virus on the liver, or episodic immune responsiveness by the host remains unclear. Also unclear is the issue of whether aminotransferase values correlate with the severity of liver disease and specifically, histologic findings. In general, ALT values have not been found correlate well with histologic features of disease however, AST values may be more useful in that regard.
The natural history of the 20% of patients with positive diagnostic tests for HCV (including HCV-RNA positivity) and persistently normal liver enzymes is unclear. While some clearly progress to more advanced disease, in others infections appear to remain quiescent in a state somewhat resembling that of the “carrier” seen in patients with chronic HBV infections. Liver enzyme abnormalities associated with acute HCV infections typically reflect a hepatocellular injury pattern with a predominance of aminotransferase (ALT/AST) abnormalities relative to serum alkaline phosphatase and gamma glutamyl transferase levels. 1 In almost all cases the ALT/AST ratio is greater than 1. The propensity of HCV to involve bile duct epithelial cells can result in a significant cholestatic component. However, pure cholestasis (elevated alkaline phosphatase and GGT with normal ALT/AST values) has not be described. Unlike acute HAV/HBV, biochemical abnormalities often fluctuate in severity and may normalize rapidly only to become abnormal again within days, weeks or months. Reasons for such fluctuations are not known, but rapid mutations and/or simultaneous infection with various subspecies of HCV may be involved.
Liver biopsies for acute HCV should be confined to low risk patients who have unexplained clinical/biochemical features of acute hepatitis. In high risk patients suspected of having acute HCV infections, liver biopsies should be delayed until a chronic carrier state (disease persisting beyond 6 months) has been documented. Histologic features of acute HCV infection are similar to those described with other forms of acute viral hepatitis. The most helpful distinguishing features are bile duct injury (present in two thirds of acute HCV infections) and lymphoid aggregates (present in one third of cases).2
Extrahepatic features of acute HCV infection are uncommon. Rare instances of arthritis, serum sickness, and aplastic anemia have been described but serologic confirmation of the diagnosis in these cases has been lacking.6
Progression to Chronic Liver Disease
Whereas past reports suggested that 50% of parenterally acquired and 5 to 15% of non-parenterally acquired HCV infections progressed to chronic liver disease, more recent studies employing sensitive assays for HCV indicate that about 80% of patients will remain infected with this virus beyond a 6 month period.5-6 Indeed, the possibility has been raised that chronic HCV infections may occur in all infected individuals.5 A reason(s) for the high propensity to develop a chronic carrier state in this disease remains to be determined. Viral mutations and spontaneous downregulation of viral replication may allow the virus to evade the host’s immune responses. Alternatively, certain components of the immune response may be inadequate. For example, neutralizing antibodies in acute HCV tend to be weak and transient, and endogenous interferon production appears to be attenuated. Neither in the acute phase nor thereafter, is viral RNA integrated into the host genome.
Despite an encouraging early report that liver failure in patients with chronic HCV is uncommon, the relatively short follow up, advancing age of the patients and the results of more recent studies suggest that such is not the case. Indeed, a recent study from California reported that after a mean follow up of 4 years, 5% of chronic HCV carriers died of liver failure(Tong MJ. N Engl J Med 1995;123:330-37).
Although the precise cause of death was not reported, 80% of the patients in that study had thrombocytopenia, 40% ascites, 20% hepatitic encephalopathy. These results support the discouraging findings of an earlier European study which reported rates of progression to liver failure in the 10 to 20% range (Alter HJ.AASLD Postgraduate Course, 1994;pp 225-46). However, it should be noted that not all patients (perhaps only 50%) with HCV-induced cirrhosis progress to liver failure and that 2 to 10% of patients will undergo spontaneous resolutions prior to or following the onset of cirrhosis.
Whether acute HCV infections cause fulminant hepatic failure remains unclear. Studies in North America and Europe have largely failed to identify HCV-RNA in either sera or liver tissue from these patients.3 Conversely, Japanese and Taiwanese investigators have identified HCV infections in the 20 to 60% of fulminant hepatic failure cases in their countries.4 The fact that viral load tends to be higher in patients with fulminant hepatic failure, combined with data suggesting that viral load correlates with genotyping raises the possibility that genotype variability is in part responsible for this discrepancy in findings.5 Nonetheless, a specific HCV-genotype has yet to be implicated as a major cause of fulminant hepatic failure. High viral loads in fulminant hepatic failure raise the possibility that the disease in these patients results from a direct cytopathic effect of the virus rather than immune-mediated mechanisms as is the case in HBV-induced fulminant hepatic failure.
If clotting parameters permit or the transjugular biopsy route is available, patients with chronic HCV infections should be biopsied in order to document the extent of disease, the likelihood of progression to cirrhosis and in rare instances, to exclude the presence and/or establish the contribution of co-existing liver diseases. In addition to the typical features of chronic hepatitis seen with most viral and non viral causes of chronic liver disease, there are three useful characteristic, but not diagnostic features of chronic HCV infections; steatosis (present in 30-70%), lymphoid aggregates (45-80%), and bile duct damage (20-90%).2 When employing the traditional classification for chronic viral hepatitis, the percent of patients with non-specific changes, chronic persistent hepatitis, chronic active hepatitis, and cirrhosis varies considerably depending whether the data were derived from population-versus clinic-versus hospital-based studies, the timing of the biopsies (early versus late disease), geographical considerations, the nature of the study population (haemophiliacs versus nonemophiliacs, immune compromised versus immune competent hosts) and the presence or absence of confounding variables such as non-alcoholic hepato-steatonecrosis, alcohol consumption, co-existing HBV infections, etc. In one large population-based study (Spanish Red Cross blood donors) 45% of chronic HCV carriers had histologic features of chronic active hepatitis, 25% normal or non-specific changes, 20% chronic persistent hepatitis and 10% cirrhosis.12 Similar findings have recently been described in Canada.11
Perhaps more important than the results of cross-sectional studies is the question of the natural history of the histologic findings. Specifically, do patients with a certain level of histologic activity remain relatively stable, progress to more severe disease, or regress to a more benign histologic pattern? The limited data that pertains to this issue is derived from Japanese studies in which after 10 years of follow up, 50% of patients with chronic persistent hepatitis had histologic evidence of chronic active hepatitis, 60% of patients with mild chronic active hepatitis developed severe chronic active hepatitis or cirrhosis and 75% of patients with moderate or severe chronic active hepatitis progressed to cirrhosis.13 Other Japanese investigators have reported that chronic persistent hepatitis rarely progresses to chronic active hepatitis and only 25% of chronic active hepatitis cases evolve to cirrhosis.14 Accurate data from North America where genotype variability and the absence of co-existing HBV infection may be relevant, are lacking. Nonetheless, clinical impressions from North American investigators has led to the assumption that about 10% of all chronic HCV carriers progress to cirrhosis every 10 years beginning approximately 20 years after onset of the infection. Those who progress more rapidly than others (cirrhosis within 5-10 years of infection) tend to have genotypes 1A or 1B, high viral loads, and a history of concomitant alcohol abuse or an immune compromised state.15
Risk of this complication of chronic HCV infection appears to vary according to the geographic distribution of the study population. In Alaska where hepatocellular carcinoma is common, serologic evidence of HCV infection is rare (less than 5%), whereas in Spain, 75% of patients with hepatocellular carcinoma are seropositive for HCV disease.18-19 A strong association between hepatocellular carcinoma and HCV has also been reported in other southern European countries and Japan.20 Prospective studies to document the true incidence of hepatocellular carcinoma in well defined transfusion-related cases are presently ongoing. Unfortunately, the duration of follow up in these studies remains less than the 25 to 30 years period in which the appearance of hepatocellular carcinomas would be predicted. Nonetheless, cross-sectional data indicates that approximately 5 to 10% of chronic HCV carriers have hepatocellular carcinoma and by extrapolation, 50% of HCV carriers with cirrhosis will develop hepatocellular carcinoma.20 Hepatocellular carcinoma has also been described in HCV infected individuals without cirrhosis but such reports are rare.21 The precise relationship between HCV and hepatocellular carcinoma has yet to be defined. While a direct causative role may ultimately be identified, an indirect or mere association between HCV and hepatocellular carcinoma is also possible. In favour of the latter possibility is the fact that HCV causes cirrhosis which itself can be considered a pre-cancerous lesion. Similarly, many alcoholics have serologic evidence of HCV infections and alcohol-induced liver disease, particularly following prolonged abstinence which may be associated with the development of hepatocellular carcinoma.22 HBV infections commonly co-exist in HCV carriers (in one South African study, 75% of HCV carriers with hepatocellular carcinoma were found to have serologic evidence of a previous HBV infection) and therefore, the contribution of co-existing HBV to hepatocellular carcinoma development in these cases must be considered.23 Finally, while HCV-RNA is present in the sera, liver and tumors of the majority of HCV infected individuals with hepatocellular carcinoma, as mentioned earlier, the RNA in these instances is located within the cell but outside the cellular DNA where tumor suppressor and promoter genes are located.24
Although numerous reports exist of extrahepatic complications of chronic HCV disease, clinically relevant problems tend to be uncommon and in small uncontrolled trials, responsive to management of the underlying HCV infection.25 Those entities in which an association has been established include vasculitic syndromes (essential mixed cryoglobulinemia and cutaneous vasculitis) and membranoproliferative glomerulonephritis.26 Less well established associations include porphyria cutanea tarda, Sjogren’s syndrome, lichen planus, Mooren corneal ulcerations and perhaps, pulminary fibrosis and rheumatoid arthritis.
Like the virus itself, our understanding of the natural history and consequences of HCV infections is constantly changing. Whereas in the late 1970’s, chronic HCV was generally considered a benign condition, presently we assume that at least 20 to 30% of chronic HCV carriers are in danger of developing and succumbing to complications of cirrhosis or hepatocellular carcinoma. Hopefully, this less optimistic impression reflects the large amount of data derived from tertiary care centres serving patients with more active and/or advance disease. Perhaps as more population-based data is developed, the pendulum will swing back towards the impression of a more favourable outcome.
Finally, it is hoped that the development of new, effective antiviral agents will significantly alter the natural history and consequences of this disease.
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