Viral Hepatitis Update

Spencer Wilson, MD

Acute viral hepatitis has been defined as a systemic viral infection in which there is hepatocellular necrosis and inflammation. There are characteristic clinical, biochemical, immuno-serologic, and morphologic features. There are five major viruses: Hepatitis A virus (HAV), hepatitis B virus (HBV), Hepatitis C virus (HCV), hepatitis D virus (delta Virus, HDV), and Hepatitis E virus (enterically transmitted, epidemic non-A, non-B hepatitis, HEV). Chronic viral hepatitis is a necro-inflammatory disorder of the liver initiated by viruses and persisting for longer than six months. It occurs in association with HBV, HCV, and delta virus infection. In contrast, patients with acute hepatitis A and hepatitis E virus infection have no propensity whatsoever to develop a chronic carrier state or chronic liver disease. Hepatitis A The hepatitis A virus (HAV) is a 27 nm RNA virus classified as an enterovirus and belonging to the picornovirus family The nucleic acid of HAV is single-stranded RNA and. to date, only a Single serotype has been identified. The virus is stable for several months at 40cbut can be inactivated by exposure to heat to 100BC for five minutes. The virus can be transmitted to chimpanzees and marmosets and has been recently grown in tissue culture. Susceptibility to HAV infection increases linearly with age and bears an inverse correlation to socioeconomic status. In major metropolitan centers in the United States, 50% of persons 50 years of age or older have detectable antibody to HAV. HAV is spread predominantly by the fecal-oral route via contaminated food and water. Overcrowding, poor hygiene, and poor sanitation favor the spread of this infection. A chronic viremic or fecal carrier state does not occur. Hence, patients are only transiently infectious. Viremia and fecal shedding occur over a short and finite period of time lasting several days to a few weeks. Transmission occurs via serial spread from one infected individual to another susceptible individual. Parenteral transmission of hepatitis A infection is extremely rare. Intravenous drug users, dialysis patients, transfusion recipients, and health care workers are not at increased risk of infection. Acquisition of HAV secondary to frequent oral-anal sexual contact has been documented in homosexual men. The diagnosis is accomplished by testing the serum for antibody to hepatitis A. The IgM antibody appears during the acute phase and is detected by immune adherence hemagglutination, as well as by radioimmunoassay and usually disappears within 4 to 12 weeks. Persistent anti-HAV IgG antibody, is then detectable and confers homologous immunity. Fecal shedding of the hepatitis A virus occurs in the early phase of the illness. HAV is detected in stool during the first week of infection in 50% of patients, during the second week in 25% of patients, and in the third and fourth weeks only rarely. In the United States, HAV is responsible for 25% of sporadic cases of hepatitis. In most persons, the disorder is mild, self-limited, and anicteric. Constitutional symptoms of fever, malaise, and anorexia are common and an abrupt onset is characteristic. If the patient develops jaundice, the urine may darken and the stool may lighten a few days before the onset of jaundice. When jaundice begins, the other symptoms usually subside. Tender hepatomegaly is common. Splenomegaly and lymphadenopathy are present in less than a third of patients.

Hepatitis A has an incubation period is 15 to 50 days. The virus is present in the blood stream for a short final period of time. The viremic phase is very short lived. It is shed in the stool for a short period of time. The majority of individuals do not develop jaundice. The ratio of anicteric hepatitis to jaundice is 20 to 1. Patients recover by in large. There are 2 antibodies, which are the IgM and the IgG. The way to make the diagnosis of acute hepatitis A is to look at a single sample of serum and if it is positive for IgM Anti-HV your patient with acute hepatitis has acute hepatitis A infection. IgG antibody appears during the convalescence phase, and confers life long immunity. There are 3 variants of hepatitis A virus infection which are cholestatic hepatitis, relapsing, and fulminant. Fulminant occurs rarely but can lead to fatalities and the only treatment in that setting is to do a liver transplant. Cholestatic hepatitis occurs more often in middle-aged or elderly individuals. They can have bilirubins in excess of 20 or 30 mg/dL. They develop marked pruritus. We can do an IgM antibody and make the diagnosis of acute hepatitis A. The patient has a bilirubin of 30, so we can get an ultrasound and make sure the bile ducts are not dilated and make the diagnosis of hepatitis A infection. This is the one time to consider a short course of corticosteroids. Prednisone, 30 or 40 mg, for week and then taper it, will significantly truncate or abrogate the illness. Relapsing hepatitis A occurs in about 10% of patients with hepatitis A infection. If you see patient who you make the diagnosis of hepatitis A and then 3 weeks later they call you as they seem to be recovering, but they call you and say Im feeling sick again. You check the ALT and it is 1200 IU, they may complain of arthralgia, arthritis, and immune complex mediated phenomenon may be present. That is relapsing hepatitis A, and it is worth knowing that because you can save them unnecessary testing like ERCP, ultrasounds, and CAT scans. In these 2 variants of cholestatic and relapsing hepatitis A infection, it is worth using corticosteroids if the patient is very symptomatic. They all recover and it never leads to chronic hepatitis. If it does lead to chronic hepatitis a year later the patient has abnormal LFTs and they are they complaining of symptoms that are probably autoimmune chronic hepatitis. Hepatitis A has triggered that. On rare occasions you can see chronic liver disease develop. With classic autoimmune they respond beautifully to steroids. They usually have a positive ANA. They have hypergammaglobulinemia. Vaccine is now available and it has wonderful vigorous antibody response up to 1000 fold compared to immune serum globulin. It will confer protection for 10 to 20 years as opposed to Gamma globulin which can confers protection for 4 to 6 months. Vaccine should be given to people who travel frequently to parts of the world where hepatitis A is endemic, to people who work with non-human primates like a zoo or a laboratory, to gay men with multiple sex partners, and also to military personnel who might be called upon to go to a part of the world where hepatitis A is endemic. It is also recommended for patients with severe chronic liver disease like hemochromatosis with cirrhosis, Wilsons, or hepatitis B or C. If they were to get hepatitis A they have a much higher mortality. We should look for hepatitis A antibody in our patients with severe chronic liver disease because if it is negative, they should get the vaccine. That is a recent recommendation.

The jaundice generally disappears six to eight weeks after onset and most patients have full clinical and biochemical recovery by six months. The disease is more severe in adults. In the United States, severe cases of clinical hepatitis A are being increasingly recognized. As a consequence of improved sanitation and hygiene practices, many individuals are not exposed to the virus during early childhood. Adult patients may develop severe and debilitating hepatitis A infection. There are three unusual variants of hepatitis A infection-cholestatic hepatitis, relapsing hepatitis, and fulminant hepatitis. In patients with cholestatic hepatitis, serum bilirubin levels may exceed 25 mg/dL. These patients eventually recover, although it may take several weeks to a few months for full recovery. A short course of corticosteroids can significantly abrogate the illness. Relapsing hepatitis is seen in 10% of patients. During a relapse, the ALT level may exceed 1000 IU/L, and fecal excretion of HAV may recur. Although patients can have a protracted course, complete recovery is the rule, and there is no propensity for the chronic carrier state. Fulminant HAV infection is rare and the estimated case mortality rate is about 0.1% among patients hospitalized with this illness. Characteristic laboratory findings include moderate to marked elevations in the serum ALT and AST values. The peak transaminase values range from 400 to several thousand international units, and the rise in the levels of these enzymes often precedes the elevation in serum bilirubin concentration. Leukopenia is a routine finding, and atypical lymphocytosis is common. The presence of leukocytosis is suggestive of fulminant disease or coexisting infection. Prevention HAV infection can be effectively curtailed by measures emphasizing good sanitation and personal hygiene. Patients are most contagious in the early phase of the illness before the definitive diagnosis is established. Passive immunization with regular immune serum globulin is 80-98% effective in preventing HAV infection. Recommendations for Immune Globulin Prophylaxis of Hepatitis A Immunization mL kg body weight IM Post exposure (close personal contacts household and sexual) Institutional contacts (prisons. facilities for mentally retarded daycare centers) Exposure to nonhuman primates preexposure Travelers (susceptible) to tropical and developing countries Dose

Hepatitis B surface antigen is a spherical particle about 22 nm in size. This is extra core material was not incorporated during the assembly of the virus during its replication within the liver. The actual virus is 42-nm donut shape particle called the Dane particle. It contains a core surface antigen, core antigen, e antigen, DNA polymerase, and DNA. Then 3 antigen antibodies systems related to hepatitis B are surface antigens, core antigen, and e antigen. The corresponding antibodies are surface antibody, core antibody, and e antibody. In a typical patient with acute hepatitis B, less than 1% get full hepatitis B. 95 to 98% go into complete recovery. Only about 2% that go on are chronically infected. Remember for hepatitis A it is zero and for hepatitis C, it is an astounding 70 to 80% that go on to become chronically infected. In B it is about 2 to 5 %. These patients develop chronic hepatitis cirrhosis that can eventuate later into primary hepatocellular carcinoma. In every part of the world where hepatitis B is endemic, 20 to 30% of patients with chronic hepatitis B, do not have underlying cirrhosis. In contrast, that is very rare with hepatitis C. I have yet to see a patient with hepatitis C with a hepatoma who did not have underlying cirrhosis. This is important for screening ramifications. I do not screen for hepatoma in a patient with hepatitis C, unless they have cirrhosis. I will screen for hepatoma in a patient with hepatitis B if they are from a part of the world where hepatitis B is endemic, vertical transmission from the mother, family history of hepatoma, and, even in the absence of cirrhosis and abnormal liver function tests, those individuals should be screened. The most important determinant of who is going to become chronically infected after getting acute hepatitis B is age of acquisition of acute hepatitis B. If you get it as an adult it is only 2%. If you get it as a newborn it is 90%. If you get it as a young child, it is about 50 to 70%. Hence, the importance of screening all pregnant women for chronic hepatitis B infection and the universal vaccination. The catch up program is important, and we are in the midst of it right now in adolescence in our country who didnt get vaccinated years ago, but who are now becoming sexually active, using drugs, and are in situations in which they are at risk of getting chronic hepatitis B infections. Global vaccination is the answer to this problem. What are the epidemiologic features of hepatitis B? There is a high prevalence around the world. There is a large human carrier reservoir where about 350 million worldwide, which is mind boggling 5% of the entire human population are chronically infected with hepatitis B virus. There are various modes of transmissions. In 1941 there was a yellow fever vaccine given to army recruits in our country and one lot was contaminated with hepatitis B. It led to about 49,000 cases of hepatitis B infection. What should we do when we see somebody with chronic hepatitis B? When you see somebody with chronic hepatitis B Id like you to address the following 5 questions with them. What is their stage of liver disease? Are these healthy asymptomatic chronic carriers? Do they have chronic hepatitis? Do they have cirrhosis? If they have cirrhosis, do they have varices? Should we put them on prophylactic beta-blocker therapy to prevent the first variceal bleed? It is made on the basis of biochemistry testing and if necessary on liver biopsy. 2) Are they candidates for interferon treatment? They have to fulfill certain criteria. They have to be replicative. They have to be e antigen positive. They have to have abnormal liver function tests. They have to have an elevated ALT. We dont treat people who have normal ALT and AST. The chronic carriers dont respond to interferon. There should be no contraindications to treatment. They shouldnt have decompensated liver disease. They shouldnt be cirrhotics with ascites. They shouldnt be depressed. They should have cytopenia, low bleed count, low white count. What is the candidacy for interferon treatment? What is the risk of liver cancer? If this is a patient from a part of the world where hepatitis B is endemic and there is a strong family history of hepatoma then that is a high risk. If this is a person who was born and bred in the United States and they

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0.02 0.05 every 4 months 0.02 or 0.05 every 5 months during prolonged stay

An inactivated hepatitis A vaccine is available. The immune response occurs in 95.8% of patients after the first dose and in 99.8% of patients after the second dose. The antibody response is 50 to 100-fold greater than with immune serum globulin. Vaccination is appropriate for military personnel, employees of child care centers, international travelers, food handlers, prisoners, and health care workers. Hepatitis B There are three antigen-antibody systems related to hepatitis B Hepatitis B surface

antigen (HBsAg); hepatitis B core antigen (HBcAg) and e antigen (HBeAg); and their corresponding antibodies Hepatitis B surface antigen (HBsAg): A unique feature of HBV infection is that concentrations of viral antigen and viral particles in the blood may reach 500g/mL and 5-10 trillion particles/mL respectively. HBsAg exceeds Dane particles by a factor of 103 to 106 in the circulation. Blood that is positive for HBsAg connotes one of three possibilities: 1) the subject is incubating HBV infection: 2) active HBV infection is present: 3) a chronic carrier state is in existence Anti-HBs is a neutralizing body detected in secretions and excretions. Its appearance together with that of core antibody (Anti-HBc) signals recovery from hepatitis B and the development of subsequent immunity. Anti-HBs is the only antibody that appears in persons who have been administered the vaccine which consists of purified hepatitis B surface antigen. Among hospital personnel, prior to vaccination, the antibody is most prevalent in surgeons, pediatricians, and pathologists, and those with close contact with blood products and tissues. Hepatitis B core antigen (HBcAg): The second antigen-antibody system is hepatitis B core antigen (HBcAg) and core antibody (anti-HBc) HBcAg is present in the nucleus of infected hepatocytes. Testing for core antigen is not a routine aid for diagnosing HBV infection. In contrast in patients with acute hepatitis B, core antibody can be detected in serum before ant-HBs, which generally appears about four months after the acute illness. High titer IgM, anti-HBc is the only serological marker present during the so-called gap or "window" period, which refers to a period of time when the patient has acute infection, but tests for HBsAg and antiHBs are negative. Hepatitis B e antigen (HBeAg): There is the e antigen and e antibody (anti-HBe) system. Hepatitis B e antigen appears early, transiently, and universally in the serum of patients with acute HBV infection. Therefore, the mere presence of this antigen does not correlate with severity or with chronicity. However, persistence of this antigen for greater than 12 weeks suggests a high likelihood of the development of a chronic carrier state. In addition, in chronic carriers, e antigen positively correlates with infectivity (both horizontal and vertical transmission). Horizontal transmission refers to contamination through accidental contact such as splashing of mucous membranes or needle sticks. Vertical transmission which has been the major mode of transmission in many parts of the world, refers to transmission from mother to newborn, and may occur either when the mother is an asymptomatic carrier or when she has the misfortune of developing acute hepatitis B virus infection during pregnancy. In the later instance, the risk of transmitting HBV to the newborn is greatest if the infection develops during the third trimester of within two months of delivery. The incubation period is 50-180 days. HBsAg generally disappears by 20 weeks. During the "window" period, which may last four weeks or longer, the only serological marker of hepatitis B is anti-HBc. It is present in high titer and is of the IgM class. HbeAg often disappears and anti-HBe appears during recovery. It is estimated that there are 300 million chronic carriers of HBsAg. This is 5% of the entire world population. In past studies, serological markers of hepatitis B were present in 70% of gay men and 25% of patients with Down's syndrome, lepromatous leprosy, polyarteritis nodosa, and chronic renal failure receiving dialysis as well a needle-using drug addicts, were chronic carriers of HBsAg. Modes of transmission are varied and range from tattoos and acupunctures to sports such as orienteering, which is common in Scandinavia. The prevalence of HBsAg is

happen to get hepatitis B as an adult and there is no other family member, they are healthy, they are asymptomatic, they have normal liver function tests, then hepatoma is very unlikely. I have yet to see a hepatoma in such a patient. I dont even screen them for hepatoma. What is their serologic status? If appropriate the ones who need to should get the vaccine. If somebody has chronic hepatitis B and drinks moderate amounts of alcohol they are more likely to get hepatoma and more likely to get it a decade earlier then their colleagues with the same disease who dont drink alcohol. The indications for treatment are biochemical evidence of ongoing hepatitis, elevated ALT, serologic evidence of viral replication, e antigen should be positive, they should have compensated liver disease, which means they can be cirrhotics, decent albumins, no ascites, and no encephalopathy. Those patients you can treat with interferon. If they have decompensated liver disease and you treat with interferon, interferon can induce a flare and that flare can be fatal in a patient with decompensated liver disease. Youve got to exclude other causes of liver dysfunction. If the patient has chronic hepatitis B and abnormal LFTs, it doesnt mean that it is necessarily chronic hepatitis B as a cause of the abnormal liver profile. That patient could have hemochromatosis, taking niacin, or could have many other reasons for having chronic liver disease, so we need to do a biopsy and a work-up before you say this is chronic hepatitis B infection. The patients most likely to respond to interferon are those with high pretreatment serum ALT, low serum HBDNA, active hepatitis, recent acquisition, negative for delta, and negative for HIV. If they have had chronic hepatitis B for 5 or 10 years, they are more likely to respond then if they have had it for 30 or 40 years. They should be negative for delta and HIV. If the biopsy shows active hepatitis then they are more likely to respond. The higher the pre-treatment ALT value, the better the response. The single most important determinant predictor is the pre-treatment ALT. The higher the pretreatment ALT is the better the response is. If the ALT is less than 2 times the upper limit of normal the response is 3%. If it is 2 to 3 times the upper limit of normal it is 33%. If it is more than 3 times the upper limit of normal it is 66%. In the laboratory the high normal value is 40. If the pre-treatment ALT is 150-200, then that is good and they have about a two-thirds chance of responding to interferon. If the ALT value is 60, it is not worth treating with interferon. It is expensive. It has side effects and it is not likely to work. Then if they have a flare, which is defined as a doubling of the pre-treatment ALT, exceeding 200 international units, then they are more likely to respond. What we really need to do at that point is to continue the interferon to congratulate the patient and to monitor them carefully, but tell them they are likely to respond. They actually have a better chance of responding than if they have no flare. What does interferon result in? It results in durable loss of HBV and e antigen, durable loss of surface antigen, sustained normalization of ALT, and a documented decrease in liver inflammation, so virochemical, virologic, and histologic response are all achieved in chronic hepatitis B with interferon treatment. Contraindications are decompensated liver disease, significant neuropsychiatric disease, and depression. We do treat patients with mild depression. You can put them on anti-depressants and you need to follow them carefully with a psychiatrist. If they have an underlying autoimmune disorder like rheumatoid arthritis, psoriasis, ITP, Crohns, lupus, you have to be concerned because interferon has a proclivity to produce autoantibodies and you can exacerbate the underlying disease. One has to be very cautious. It is not an absolute contraindication, but I forewarn those patients that if they develop symptoms related to their underlying autoimmune disease, then we often will stop the medication. Lamivudine or 3TC is being investigated actively in the treatment of chronic hepatitis B, and it appears to be very promising. It inhibits DNA synthesis by terminating the provirus DNA chain. Lamivudine doesnt appear to cause lactic acidosis, hepatic failure, renal failure, or pancreatitis. There are some mild constitutional symptoms and mild laboratory abnormalities. Im using this drug in conjunction with interferon or without interferon if interferon is

highest in parts of southeast Asia and sub-Saharan Africa. About 1% of patients seeking medical attention will have fulminant hepatitis, while 90-95% recover completely. Two to five percent of patients with acute hepatitis B will become chronic carriers, a state defined as the persistence of hepatitis B surface antigenemia for longer than 6 months. Some carriers develop chronic hepatitis or cirrhosis and a significant number succumb to primary hepatocellular carcinoma. The latter is especially true if the infection was acquired during early childhood or infancy. Sequelae of hepatitis B virus infection Acute Hepatitis B 1% 9 Death 90% 9 Complete Recovery 2-5% 9 Chronic Carder 9 Chronic Hepatitis 9 Cirrhosis
9 Primary Hepatocellular Carcinoma

not an option. If they have severe cytopenia or a history of depression or a very low platelet count we are having very good success with this drug. It is not FDA approved yet for hepatitis B.

There is a strong association between chronic hepatitis B virus infection and primary hepatocellular carcinoma The worldwide prevalence of primary hepatocellular carcinoma is similar to that for the prevalence of hepatitis B surface antigenemia. Infection as attested to by the presence of anti-HBs, anti-HBc, or both of these antibodies. Therefore, the presence of the chronic carrier state of hepatitis B infection confers an extremely high risk for the development of primary hepatocellular carcinoma On a worldwide basis, primary hepatocellular carcinoma is the most common malignant visceral neoplasm. The hepatitis B vaccine holds great promise in eradicating of significantly curtailing HBV infection on a worldwide basis has been hailed as the first "anti-cancer vaccine". Synthetic yeast-derived vaccines have been licensed for use. Interferon at a dose of 5 million units daily for four to six months results in loss of hepatitis B virus DNA and hepatitis B e antigen in 30-50% of patients. Aminotransferase levels normalize in 40% of patients. Hepatitis B surface antigen is lost initially in approximately 15%. Most patients who seroconvert from e antigen to e antibody will also likely become negative for HBsAg with the passage of time. The success rate of interferon treatment is predicated on a number of variables Factors that predict a favorable response are listed in Table 2. Table 2: Factors That Predict a Favorable Response to Interferon Therapy in Patients with Chronic Hepatitis B Virus Infection 1. High aminotransferase levels. 2. HBV DNA level less than 200 pg per mL

3. Active histology. 4. Acquisition of chronic hepatitis B virus infection in adulthood. 5. Negative HIV serology 6. Negative HDV serology Interferon-related adverse effects are common and include fever, flu-like illness, irritability, depression, malaise, and alopecia. Careful monitoring of the hematological indices (WBC count, platelet count) is necessary, and patients with low platelet counts (less than 50,000 - 75,000) are not suitable candidates. However, the majority of patients are able to tolerate treatment and discontinuation of the drug because of intolerable side-effects is necessary in less than 5% of treated patients. Remissions in chronic hepatitis B induced by alfa interferon are durable in most patients, and remissions are followed by loss of HBsAg and evidence of residual viral infection. Lamivudine, a nucleoside antagonist appears to be a promising agent against hepatitis B virus in initial pilot studies. Hepatitis D (Delta Agent) The hepatitis D virus (HDV) is an infectious RNA agent. Biological expression of this agent in man requires the concomitant obligatory association of hepatitis B surface antigenemia. HDV can cause both acute and chronic hepatitis. Clinically, HDV hepatitis may be indistinguishable from other forms of acute and chronic viral hepatitis, although on average, it is more severe. The mortality of icteric acute HDV hepatitis ranges from 2-20% (the mortality for HBV is approximately 1%). Likewise, chronic delta hepatitis tends to be more severe than chronic HBV and HCV infection. Approximately 75% of patients with chronic delta hepatitis have been found to develop cirrhosis and complications of portal hypertension as contrasted with a 25% incidence of such complications in patients with chronic HBV infection. In some patients with chronic delta hepatitis infection, the disease is rapidly progressive and cirrhosis develops within a few years of onset of infection. The prevalence of delta hepatitis infection in chronic hepatic B carriers with primary hepatocellular carcinoma is low. It has been suggested that since delta is almost invariably pathogenic it leads to the dire complications of cirrhosis and portal hypertension, eventuating in death or receipt of a liver transplant before the requisite period of time necessary for cancer of the liver to develop has elapsed. Acute HDV occurs in two forms coinfection and superinfection. Coinfection refers to the simultaneous introduction of HBV and delta infection into the host. It is generally benign, although on occasion it is fulminant. Simultaneous acute HBV and HDV progresses to chronic liver disease in less than 5% of patients. In patients with coinfection, the HBsAg is positive, the IgM anti-HBc is positive and IgM antiHDV is positive in low titer. The pattern of elevation in serum aminotransferase levels is often biphasic. In contrast to coinfection, superinfection with delta often results in severe and fulminant disease and a high frequency of progression to chronic disease in those surviving. Chronic active hepatitis is found in 90% of patients and simultaneous post-necrotic cirrhosis is present in approximately 50% of such patients. Most cases of chronic delta hepatitis probably arise from superinfection. The serological course is characterized by presence of hepatitis B surface antigenemia, positive IgG antiHBc, and the presence of IgM anti-HDV. This antibody is often present in high titer

(greater than 1 in 100) and sustained in contrast to the short-lived anti-HDV that is present in low tier in patients with coinfection. The diagnosis of delta infection can be made by testing the serum for anti-HDV, assaying for HDV RNA in the serum, and by performing immunoperoxidase staining for hepatitis D virus antigen in liver tissue specimens. New assays, such as molecular hybridization for HDV RNA should simplify the diagnosis of HDV in the future. HDV infection should be suspected and appropriate serological testing performed in patients with severe acute hepatitis B virus infection, patients with severe chronic hepatitis B virus infection, and in chronic hepatitis B surface antigen carriers who develop on exacerbation of their liver disease. The epidemiology of delta infection can be summarized as follows: A. Endemic delta virus infection is common in the mid-east and the Mediterranean High prevalence rates have been documented in Korea, South America. and Romania In contrast prevalence rates of HDV are low in the United States, South Africa. North Africa, Northern Europe, and China. B. HDV as a disease afflicting certain high risk populations-notably intravenous drug "addicts" and hemophiliacs. HDV is supposedly rare in gay men and health-care workers, although a number of fulminant cases of delta infection among gay men have been described in recent years
In delta virus there are about 300 million B carriers and about 20 million delta carriers now. You should think of delta when you see fulminant hepatitis B infection. Up to 70% can have delta. Patients lining up for a liver transplant in Pittsburgh were found to be delta positive. The one time we dont find delta with increased frequency is in patients with chronic hepatitis B and hepatoma. That at first glance appears as a paradox. How come? The answer or the hypothesis is that delta is so bad for the patients that it kills the patient from complications of end stage liver disease, hypertension, or they get referred for a liver transplant before the required incubation of 20 or 30 or 50 years for hepatoma development. In 3 different parts of the world where people have looked at the prevalence of delta in patients with chronic hepatitis B and hepatoma it is actually very low. Delta occurs in 2 cases adds core infection or super infection. Core infection is simultaneous delta and B. You might say a double peak in ALT. That could be a clue, my patients have delta as well. Super infection is the patient with chronic hepatitis B who is doing well, and then out of the blue decompensates. They start with encephalopathy, ascites, and one of the possibilities is delta. What are the other possibilities? Hepatoma, portal vein thrombosis, spontaneous reactivation, seroconversion from e antigen to e antibody as a flare, and delta, which is about 4 or 5 reasons why a patient with chronic hepatitis B who is doing well suddenly decompensates. Super infection is often fatal. It can be very severe.

Since delta hepatitis infection is inextricably linked to type B hepatitis, prevention of delta hepatitis can be achieved by preventing hepatitis B virus infection. The widespread use of the HBV vaccines should result in the curtailment of this virulent pathogen. There is no proven therapy for delta hepatitis. Corticosteroids are not beneficial in this disease. Although interferon appears to inhibit hepatitis D virus replication, and may result in improvement in serum aminotransferase levels during active therapy, discontinuation of therapy with alpha-interferon is almost always followed by a significant clinical relapse. Hepatic transplantation has been performed in some patients. Hepatitis C Frequency and Sequelae of Post-Transfusion Hepatitis C Virus Infection 3 million people transfused each year in the United States 9 150,000 - 300,000 develop acute hepatitis C 9 75,000 - 150,000 develop chronic hepatitis C 9 15,000 - 30,000 develop cirrhosis 9

Number developing primary hepatocellular carcinoma unknown The characteristic clinical features of hepatitis C, can be summarized as follows: 1) It has an incubation period of 2-22 weeks; and ultra-short incubation period of 4 days to 4 weeks has been reported in hemophiliacs 2) The acute disease is clinically indistinguishable from acute hepatitis A or hepatitis B virus infection 3). In the United States, it accounts for a significant percentage (20%) of sporadic acute viral hepatitis 4). One of the characteristic features of chronic hepatitis C hepatitis is the cyclical pattern of transaminase elevations. The hepatitis C virus is in the togavirus family. It is enveloped, sensitive to lipid solvents, and 50-60 nm in diameter. It contains a linear, single-stranded RNA and bears no genomic homology to hepatitis B virus, hepatitis D virus, or retroviruses. Hepatitis C virus is a major cause of acute and chronic hepatitis. It can also lead to cirrhosis and may be an important factor in the development of primary hepatocellular carcinoma. The putative role of chronic hepatitis C infection in primary hepatocellular carcinoma is predicated on a number of observations, including the following: 1) HBV-negative primary hepatocellular carcinoma appears to be on the rise in Japan. 2) A third of hepatitis B surface antigen-negative hepatocellular carcinoma patients have a previous history of receipt of blood transfusions. 3) HBV-negative primary hepatocellular carcinoma patients have been shown in some studies to lack HBV DNA. 4) There are anecdotal case reports of acute hepatitis C progressing to chronic hepatitis C, eventuating in cirrhosis and, over a 10-20 year period, culminating in primary hepatocellular carcinoma. 5) Some investigators have noted liver cell dysplasia in a significant proportion of patients with chronic hepatitis C. The hepatitis C virus antibody test is used to detect both acute and chronic HCV infection. It takes on average three months for the antibody test to become positive and, on occasion, may take up to a year for the antibody test to become positive in patients with acute HCV infection. In contrast, in approximately 80-90% of patients with chronic hepatitis C, the hepatitis C virus antibody test will be positive. The prevalence of hepatitis C virus antibody in male homosexuals is relatively 1ow (5%). A recent study has suggested that household and sexual contacts of chronic HCV-infected patients do not appear to have HCV infection. Based on these observations, it has been suggested that sexual transmission of HCV is most inefficient. The major factors in community-acquired HCV infection include blood transfusions, intravenous drug abuse, and inapparent percutaneous exposure. Vertical transmission (mother-to-infant transmission) appears to be uncommon. It is possible that HCV infection is more likely to be transmitted if the mother also has HIV infection. With the current availability of the HCV antibody, and the use of autologous blood, it is estimated that in 1996, post-transfusion hepatitis will occur in 1% or less of recipients.
Hepatitis C. Weve made some inroads into our understanding of the life cycle of hepatitis C. Hemophiliacs and IV users, unfortunately, have a very high prevalence. Newly started IV drug addicts within the first 6 months 50% will seroconvert. They will become positive for hepatitis C antibody. At the end of a year 75% are positive. Normal blood donors are 1%. You will notice that I dont have one group who is usually at high risk for hepatitis on this slide and that is gay men. Prior to the advent of the B vaccine 25% of gay men were positive for hepatitis B surface antigen. Another 50% had core antibody or surface antibody or both. Three-quarters were infected and onethird is currently infected with viremia. If you look at the prevalence of hepatitis C antibody in gay men with multiple sexual partners then it is 5%. If you look at people in a sexually transmitted disease clinic then it is 5%. If you look at female prostitutes then it is 5%. It is not 20% or 30%. We think sexual transmission does occur, but is rare. I have more than 500 patients and one of my fellows looked at all the family members. We have 3 instances of family members being positive. That is all. With chronic hepatitis C, looking at semen and saliva for HCV RNA by PCR, none of the samples were positive. We think sexual transmission can occur, but it is very rare. The figure of 5% is good. I tell my patients not to share toothbrushes, razor blades, and nail clippers. If they have had a relationship for 20 years and the spouse is negative then there is no need to change it. If you are starting a new relationship and they are very concerned then the male partner should wear a condom. I do urge that family members be screened. The next time you go see your internist or pediatrician get it tested. You can hug, kiss, and share cotton candy or popcorn because that is not the way you are going to transmit hepatitis C. Vertical transmission is the question that gets asked often. If the titer was very high, more than a million than half, the newborns of these mothers shown in close circles came down with hepatitis C. If it was less than a million it was 0%. That is probably true that the titer has some correlation with infectivity. We need further studies to validate this. The figure that you can tell your patient who wants to conceive and says what is the chance of transmitting this to my newborn is 5 to 10%. That 5 to 10% for sexual and 5% for vertical. There is 5% to needle stick. Somebody from the hospital, physician or employee, calls in a panic saying they just got stuck by a needle and the patient has hepatitis C and what is going to happen to me. Instead of telling them you have a 5% chance of coming out with hepatitis C. I tell them you have a 95% chance of not getting hepatitis C. We will do a PCR test in 2 weeks and then in 2 months and if that is negative then forget about it. If it is positive there is now sufficient data that a short course of interferon will truncate or decrease the chance, so I would treat those patients with interferon for 6 months to a year. That 5% is good for sexual transmission, vertical transmission, and horizontal transmission. It is also perfectly appropriate for mothers to breast-feed. There is no proof whatsoever that breast-feeding leads to transmission of hepatitis C. Two additional risk factors in men not women are share snorting devices, and they put the cocaine on a dollar bill and they use a straw and they pass it around. There is a high incidence of hepatitis in the patients and there fellow snorters and that are how they are probably transmitting hepatitis C. Ive seen at least 6 patients in the last 6 months where the only risk factor appears to be cocaine snorting. That blue solution in barber shops that says kills germs, watch out for that. That solution and a drop of serum form patients with hepatitis C and a week later it was positive for hepatitis C. Dentists, barbers, cocaine snorting, ear piercing are many different ways of getting hepatitis C. A few important things about hepatitis C are no correlation between LFTs and liver biopsy findings, so you can have completely normal or minimal elevations in ALT and AST and have severe disease. Asymptomatic patients with normal LFTs can have substantial liver injury. Fulminant hepatitis due to hepatitis C has been documented in our country for the first time. It is rare, but here are cases reported in the literature of fulminant hepatitis C. There are just a handful of cases reported by Dmitri and colleagues from Europe where hepatoma has developed in the absence of cirrhosis. New infections per year is probably closer to 50,000, so the figure has

Table 4 Hepatitis C Virus Seroepidemiological Studies Prevalence of Hepatitis C Virus Antibody Positivity Post-transfusions chronic HCV Sporadic chronic HCV Acute. self-limited post-transfusion HCV Multiply-transfuse hemophiliacs 60-90% 50-75% 20-50% 75%

Intravenous drug users/addicts Prisoners Dialysis patients Health care workers

75% 20% 10% 1%

Previous studies have shown that both corticosteroids and acyclovir therapy are ineffective in chronic hepatitis C. Alpha-interferon, at a dose of 3 million units administered subcutaneously three times a week, is beneficial. Approximately 40% of patients treated with 3 million units of recombinant alpha-interferon subcutaneously will normalize serum ALT levels at the end of six months. An additional proportion of patients will show improvement, but not normalization of serum ALT levels. Relapse remains a common. although not universal, problem following discontinuation of interferon therapy. Factors Predicting a Favorable Response to Interferon are Listed in Table 5. Chronic Hepatitis C Predictors of Response to Interferon Clinical Variables Absence of Cirrhosis Shorter Duration Younger Patients Lack of Iron Overload Virologic Variables HCV Genotype HCV RNA Levels HCV. Ag Staining

dropped. Once you all become chronically infected progression to chronic hepatitis occurs in 70 to 80% of cases. It is the most frequent cause of chronic hepatitis in our country. It is a number one indication for liver transplantation in adult liver transplant centers in our country. One-third of the cases is done for chronic hepatitis C. Some of these patients clearly have alcohol as a contributing factor. Progression to cirrhosis occurs in about 20 to 50% of cases. It is that natural history that still needs to be defined. We at centers see the patients with sick liver disease, cirrhosis, and liver cancer. In my experience with several hundred patients all of who have been subjected to a liver biopsy 25% are cirrhotic the first time I see them. Under the age of 45, 19% are cirrhotic. There are cases of acute hepatitis progressing to cirrhosis to liver cancer hepatoma. Development in chimpanzees and epidemiologic surveys in non-B non-alcoholic patients with liver cancer, hep C antibodies were present in the majority of these patients. The only approved treatment is interferon and at the moment 50% responds to 3 million units subcutaneously for 6 months. We are now going to 12-month treatment. Predictors of response are being investigated and unfortunately there is a very high relapse rate. More than half the people who respond will relapse. Here are some characteristics of predictors of response are younger the patient, women. Ideal body weight is more likely to respond. Mild disease is more likely to respond than cirrhosis. Increased hepatic iron content is more likely to respond. Genome types other than non-A, non-B unfortunately 70% of the genotypes in our country are non-A and non-B. Genotypes other than non-A and non-B we have a 3 fold or 4 fold increase sustained response to interferon compared to genotype non-a and non-B. What happens with interferon is you can get flu-like symptoms, bone marrow suppression, mental status changes, befuddlement, short fuse-irritability, and depression, which one has to be very concerned about. The one side effect that may be permanent is thyroid abnormalities, which occur in 1 to 4%. Then some miscellaneous side effects are hair loss, which occurs late is mild and reversible. Rarely one can have severe and bizarre nightmares. Ive had 2 patients of whom I had to stop the interferon because of bizarre nightmares. One patient had Hodgkins disease many years ago and got transfused and now at the age of 38 he has bad chronic hepatitis C with lots of fibrosis and inflammatory disease. On biopsy he is in the 300 range. Mild disease is defined histologically. If you have a patient with abnormal liver function test and you confirm that they are viremic and do a biopsy. Lets say you did it and you saw a little bit of inflammation. The patients will turn to you and say what is going to happen me. I give them a printed sheet that goes as follows; you may go on like this and die at the age of 100 years of boredom, or the disease will progress, or we treat you with interferon and you respond, or we treat you with interferon and at the end of 3 months we give up. 3 months is a good cut off. If they have mild disease, but they have a lot of stability in their life. If they are not drinking, getting a divorce, I say lets treat with interferon. You are most likely to respond and in 3 months we will know. If in the next 3 months you happen to be in the 5 % category with intolerable side effects, we will stop. It is a very good way to approach this phenomenon. You really have to make an individual decision and you cant have generalizations about this. Ribavirin is very exciting. This is a purine nucleus analog. It is not approved. We are studying it nave patients and in patients with relapses and nonresponders. There is a suggestion that response is not dependent on the viral load. It appears safe and the one side effect is hemolytic anemia. Patients can drop the hemoglobins as much as 3 or 4 grams. We have to select out patients carefully. If it is a 68-year-old diabetic with coronary artery disease and they have chronic hepatitis C, forget it. Select you patients carefully and monitor the hematocrit. If they have relapsed and they responded biochemical and virologically to interferon, their success rate with interferon Ribavirin is going to be about 60%. We are talking about a cure. Where as if they were nonresponders it is probably going to be 10 to 20%. It will likely get approval by the FDA in the next year or so.

Recent studies have established a key role for HCV in the pathogenesis of at least some cases of essential mixed cryoglobulinemia (EMC). EMC is a multisystem syndrome more common in women. Characteristic features include purpura, arthritis, neuropathy, vasculitis, and glomerulonephritis. HCV RNA has been noted to be present not only in the serum, but also in cryoprecipitates from patients with EMC. In addition, the disappearance of cryoglobulinemia, with successful alfa interferon therapy, strengthens the case of the role of this virus in the pathogenesis of this syndrome. Hepatitis C also has been reported to be an important pathogenetic factor of the liver disease present in patients with porphyria cutanea tarda. Hepatitis E Hepatitis E (HEV), also called enterically-transmitted or epidemic non-A, non-B hepatitis, is a form of vital hepatitis that is serologically unrelated to hepatitis A or hepatitis B. The etiologic agent is a spherical, single-stranded, RNA virus. 32-34 nm in diameter. Recent molecular studies suggest that the HEV genome is a positive single-stranded RNA. HEV is similar to calciviruses. The hepatic necrosis seen with HEV is felt to be immunologically mediated and not a direct cytopathic effect. HEV has been responsible for large water-borne epidemics in the Indian subcontinent, in Central and Southeast Asia, Africa, and Mexico. A large waterborne outbreak occurred in Delhi in the winter of 1955-1956. Heavy rains led to flooding of the Yamuna River. Recession of the flood waters led to backup of a large open drain and subsequent contamination of the water supply. Despite chlorination of the water, almost 30,000 people were afflicted with icteric disease. Since then, similar attacks in which thousands of individuals have been affected have been described. Transmission has occurred secondary to contaminated water.

The majority of sporadic cases of acute hepatitis in endemic areas are also due to HEV. The salient epidemiologic and clinical features of HEV are summarized in Table 6. Sporadic cases have been described in western countries in visitors who have traveled to areas of the world that are endemic for HEV. A serological test for the diagnosis of HEV is available in the Centers for Disease Control's Hepatitis Branch in Atlanta. Gamma globulin lots prepared in the United States do not confer protection against HEV. It is not clear whether Gamma globulin prepared from pooled sera of individuals in endemic areas is effective in preventing HEV infection. The best way to protect against acquisition of this form of viral hepatitis is to avoid potentially contaminated food or water. Table 6: Epidemiologic and Clinical Features of Hepatitis E Virus (HEV) Epidemiologic Features: Responsible for large outbreaks (hundreds to several thousand) in developing countries Major cause of sporadic, acute hepatitis in endemic regions Rare sporadic cases reported among travelers visiting endemic regions

Vaccine or immunity in hepatitis C is not effective. Even worse, you can take a patient and the sera and give it to a chimp and produce hepatitis. The chimp recovers and takes the same sera 6 months later and give it to the same chimp you get a second bout of hepatitis C.

Clinical Features: Route of transmission: fecal-oral Incubation period: 2-9 weeks Highest attack rate: 15-40 year age group Case fatality rate: 10-20% in pregnant women Chronic carrier state: none Does not lead in chronic liver disease. Efficacy of gamma globulin lots prepared from pooled sera of individuals in endemic areas in preventing HEV unknown. Vaccine is not available

Hepatitis G Virus Recently two presumed hepatitis agents, designated hepatitis G virus (HGV) and hepatitis (HGBV-C) have been described. The hepatitis G virus is a novel Flavivirus, which is closely related, if not identical, to the hepatitis GBV virus type C. Molecular characterization of these agents has shown them to be virtually identical isolates of the same virus. The initial source form which hepatitis G virus was cloned, was, from a patient with chronic hepatitis, whose plasma transmitted hepatitis to tamarins. HGBV was so designated because it was originally derived from a surgeon (whose initials were GB), in whom acute hepatitis developed in the 1960's. His plasma caused hepatitis in tamarins. Subsequently, three different HGBV agents were cloned and designated hepatitis GB virus Currently, hepatitis G virus (HGV) can be diagnosed by detecting hepatitis G virus RNA by PCR. HGV has a global distribution, with a high prevalence in the U.S. donor population.

It is present in 1.7% of eligible blood donors, 1.5% of donors with ALT levels in excess of 45 IU/L and 1.6% of the donor population thus far tested. An important question regarding HGV infection is whether it causes acute liver injury and whether it is responsible for some cases of chronic liver disease. HGV RNA has been detected in patients with acute Non A to Non E viral hepatitis, in patients with chronic hepatitis of presumed viral etiology, in patients with cryptogenic cirrhosis and in Some patients with primary hepatocellular carcinoma HGV is also present in patients on maintenance hemodialysis. In a recent study, it was detected in 3.1% of patients on hemodialysis as compared with 0.9% of healthy blood donors. Preliminary evidence suggests that HGV is present in approximately 40-50% of patients with fulminant hepatitis of unclear etiology. It is unclear why hepatitis G virus is present in such a high proportion of such patients when, at best, it produces only a mild, acute hepatitis in patients with acute vital hepatitis of Non A to Non E etiology. In patients with acute post-transfusion hepatitis, in whom the presence of hepatitis G virus can be documented, the plasma ALT peak and the peak titers of the virus in the plasma are discordant. Persistent viremia continues for several years, the finding that 75% of individuals positive for HGV RNA have normal liver function tests and the finding of several patients with both chronic hepatitis C viral infection and chronic hepatitis B viral infection, who appear to have co-infection with HGV. When such individuals are treated with Interferon, there appears to be a decrease in HGV RNA titers. The exact role of the hepatitis G virus in producing disease in humans remains unclear at the moment. There are no prospective studies that have documented histologically, the progression from acute hepatitis G virus infection through various stages of chronic liver disease, such as: chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. At the moment, in patients with chronic Non A to Non E hepatitis, or cryptogenic cirrhosis, there is no proof that, if present, hepatitis G virus is the cause of the disease, or merely an innocent bystander.
Hepatitis E is only seen in people traveling from parts of the world where it is endemic or visitors to those parts of the world. Large outbreaks involving tens of thousands. There was an outbreak in China a few years ago with 123,000 cases of jaundice that all turned out be hepatitis E. Sporadic cases also occur. Fecal is a route of infection. High attack rate in 15 to 40-year age group. There is low secondary attack rate amongst exposed household members in contrast to hepatitis A where it is rampant in susceptible household members. The most important significance is that in pregnant women in the 3rd trimester it has an infection rate of 20%. There is no proof that Gamma globulin can protect against hepatitis A. Please forewarn your patients who want to travel to those parts of the world if they are in their late second trimester or third trimester they should not go. If they do they really need to be careful about the water supply. There is no proof that Gamma globulin confers protection.

Hepatitis G virus appeared in January 26, 1996. We find hepatitis G virus in patients with unexplained acute hepatitis presumed viral. There is unexplained chronic hepatitis, unexplained cirrhosis, hepatoma, and aplastic anemia. However, there is no proof that G causes liver disease. G often coexists with C. It is present in 1.7% of the US donor population. In these 26 abstracts there was no difference in LFTs, liver biopsy, response to interferon, recurrence after liver transplantation, and so on. It is a virus that we can probably forget about. We dont think it is a hepatatrophic or hepatitis virus.