Hepatitis C

by Dr. Andreas Lambrianides
General Surgeon
Hepatitis C virus (HCV) can and does cause acute hepatitis, but due to the mild nature or subclinical cause of this illness, most cases go unrecognized. Acute hepatitis C is symptomatic in only 25 - 35 percent of cases, with an incubation period of 6 - 10 weeks with a range of 3 - 20 weeks, and it is shortest after a large inoculum.

The clinical features include malaise, nausea; right upper quadrant pain, pale stools, dark urine and jaundice. These symptoms are usually mild but may be variable. Fulminant Hepatitis is rare with HCV but when it occurs is usually in immunosuppressed patients. Hepatocellular injury is invariable. Over 80% of acute HCV infected patients have a greater than 10- fold elevation of alanine aminotransferase (ALT) levels. The rise in ALT begins after four weeks and peaks at eight weeks. The rise usually precedes the onset of symptoms.

The most commonly used test for diagnosis of acute Hepatitis C is anti HCV antibodies which can be detected in 50 - 70% of patients at the onset of symptoms and in approximately 90% of patients 3 months after the onset of infection. With the current third generation anti HCV tests, antibodies do not become detectable before 7 - 8 weeks after inoculation.

The ideal test for early detection of infection with HCV is the HCV RNA polymerase chain reaction, which becomes detectable within one to two weeks after exposure. Acute self limiting Hepatitis C occurs in less than twenty percent of cases. The persistence of HCV RNA indicates the development of chronic hepatitis C. The single feature that distinguishes Hepatitis C from other hepatic viral infections is the tendency to become chronic, the term relating specifically to the duration of infection and not to the severity of the disease.

Globally the prevalence of chronic hepatitis C infection is estimated to be at 3 percent, with four million carriers in the USA and 5 million in Western Europe. In the USA, 0.5 percent of blood donors are anti HCV positive but 1.8 percent of the population is positive on random testing. A higher incident has been found in Africa. Up to 15 percent of the population in Egypt are anti HCV positive. With the availability of HCV screening serological tests after 1989, acute infection was found to be the cause of more than 80 percent of cases of post transfusion Hepatitis. After screening for HCV, the incidence of acute hepatitis which had reached a peak in the 1980s of 180 000 cases per year, fell to less than 30 000 by 1995. With current screening techniques the risk has now fallen to one in a hundred thousand units transfused or 0.001 %. A small risk of acquiring HCV from blood products remains because HCV antibodies take time to become positive after an individual is exposed to the virus. The use of more sensitive testing would reduce the risk even further. Currently the majority of hepatitis C infection occurs in patients with parenteral exposure from drug use and needle sharing and constitutes the major cause of transmission in the USA.

Risk factors associated with acute Hepatitis C include, injections associated with drug use 43%, sexual contact 15%, cocaine snorting 5% and occupation 4%. Cocaine snorting results in nasal ulceration and bleeding which serves as a source of HCV transmission. Sexual activity is a less frequent cause, (15 %) with hepatitis C as compared to 50% with hepatitis B.

Approx 25% of cases of Acute hepatitis C are jaundiced and the mortality rate is less than 1 %. The rate of subclinical infections is high and the onset of hepatitis C is more insidious as compared to hepatitis B. Approx 15 - 20 % of patients following infection with HCV will clear the virus. 80 - 85 % will develop chronic hepatitis C. Of all patients with Hepatitis C, 20 % will not develop significant liver damage and 60 - 65 % will develop liver disease after an average of 13 years. Of all the patients that develop liver disease, 20 - 25 % will develop cirrhosis after an average of twenty years. The most susceptible patients are those that are acquired HCV over the age of 40, male patients, those patients that consume large amounts of alcohol, failure to respond to interferon treatment, and those infected with a 1b genotype virus. Of all the cirrhotic patients, after an average of 15 - 25 years, 5 - 10 % will develop liver failure and 1 - 4 % will develop hepatocellular carcinoma (HCC).

The more significant clinical features of cirrhosis, include ascites, low levels of serum albumim, muscle wasting, hepatic encephalopathy, upper gastrointestinal bleeding from oesophageal or gastric varices, and hypersplenism. In patients with HCV cirrhosis, the annual risk of developing HCC is 1 - 6 %. In some retrospective studies an incidence of 1.4 % was found, while in some prospective studies the annual incidence was found to be 2.5 percent. HCC occurs more frequently in patients over 60 years of age and with Child's B/C Cirrhosis.

Chronic Hepatitis C is one of the major causes of cirrhosis in the USA and the most common indication for liver transplantation in adults. Chronic hepatitis C is also the major cause of HCC worldwide.

The aetiological agent for Hepatitis C was identified in 1989 using advanced molecular biology techniques. Molecular cloning, sequencing and analysis of the hepatitis C genome have enabled classification of the virus. Electron microscopic studies of virions purified from the serum of the HCV infected individuals have confirmed HCV to be an enveloped virus less than 80 nm in diameter, with a lipid envelope and strongly associated with the lipoprotein fraction of the serum. Each HCV particle contains a single RNA molecule of approximately 9500 nucleotides that contain a single gene. This encodes a polyprotein of 3008 - 3037 amino acids. The core and envelope proteins are structural proteins that form the viral particle, while the remainder, the non-structural proteins are required for virus replication. The structural proteins are derived from the
5 'end of the genome. The virus circulates in the blood as a population composed of a master sequence and a large number of minor variants. This occurs because of random mutations during viral replication and also the selection pressure exerted by the host's immune response. This mixed population of viral particle is referred to as quasispecies and is the basis of the variation found in the HCV genome. The virus is sub classified into 6 distinct genotypes.

The management of viral hepatitis involves general measures to reduce physical and psychosocial morbidity, anti viral therapy and interventions for complications.

Hepatitis A and B vaccinations should be offered to all patients with hepatitis C who do not have protective antibodies, to minimize the risk of decompensation of liver disease associated with a second hepatitis infection. No effective vaccine has yet been developed to protect contacts of those infected with hepatitis C. Immune serum globulin does not confer protection. There is much interest in dietary therapy, homeopathy, vitamins and other alternative therapies, and most patients are taking herbal remedies. There is no evidence that such measures affect the natural history of hepatitis and the patients are vulnerable to exploitation. In addition while most herbal remedies are safe, Chinese herbal medicines have occasionally being associated with severe hepatotoxicity.

Antiviral therapy is the only effective means at our disposal in the fight against hepatitis C. The short-term aim is to stop viral replication and to reduce liver cell inflammation and necrosis, so that progressive fibrosis does not occur. The long-term objective is to prolong survival by decreasing cirrhosis, liver failure and HCC.

Interferons are naturally occurring antiviral proteins that inhibit growth and replication by stimulating the host's immune response. The original report for the use of alpha interferon was in 1986.

The response to interferon at 12 weeks is an important point. Patients who fail to respond at that time are unlikely to respond to further treatment. The most promising new treatment is the combination of two antiviral drugs - Interferon and Ribavirin. Ribavirin is a Guanosine analogue, but is not effective if given alone. Results show a significant advantage for combination therapy as compared to interferon alone. In addition the effect of genotype is demonstrated: 65% of patients with genotype, 2 or 3 need only 6 months of combination therapy to attain viral clearance while 1 or 4 require a full 12 months treatment to achieve a 30 % SR rate.

Complications of interferon include systemic problems, neurological, psychological, cardiac, induction of autoimmunity, myelosuppression and susceptibility to infection.

Ribavirin complications include hematological problems, respiratory, dermatological and teratogenicity.

Although interferon has been shown to be effective in the treatment of chronic hepatitis C, recent trials indicate effectiveness for Acute Hepatitis C. At the end of 24 weeks therapy with interferon and a further 24 weeks follow up, 98 % had undetectable levels of Hepatitis C virus RNA in the serum and normal ALT levels. Early treatment of acute hepatitis C with interferon Alpha - 2b alone prevented the development of chronic HCV in almost all patients. This particular finding is important in health care workers with infection concerns due to needle stick or surgical injuries.

Available therapies for HCC include surgical resection, which is only suitable for small tumors and has carries a recurrent rate of 50 - 80% at 5 years.

Systemic chemotherapy has no proven benefit and liver transplantation is only suitable for small tumors in patients with portal hypertension and/or liver failure.

Embolisation may decrease the size of large tumors but does not increase survivor.

Discovering that a patient has hepatitis C is a shocking and traumatic experience for most patients. Many feel isolated just when strong support from family and friends is needed. When treatment is not successful, patients with hepatitis C often see themselves as having failed treatment when in fact treatment has failed them.