Ingestion of raw clams and oysters from polluted waters has caused epidemics. Steaming the clams may not kill the virus, for the temperature achieved inside the clams is not sufficiently high. Contamination during preparation has resulted in transmission via other foods, including sandwiches, orange juice, potato salad and meat. Clinical course The hepatitis is usually mild, particularly in children where it is frequently sub-clinical or passed off as gas- troenteritis. The disease is more serious and prolonged in adults. Needle liver biopsy in patients with acute type A hepati- tis shows a particularly florid portal zone lesion with expansion, marked cellular infiltration and erosion of the limiting plate. Cholestasis is marked. It is therefore surprising that hepatitis A infection never leads to ongoing chronic hepatitis or cirrhosis. Fibrin ring granu- lomas are described [16]. Cholestatic hepatitis A affects adults [7]. The jaundice lasts 42–110 days and itching is severe. Serum IgM anti- HAV is positive. The prognosis is excellent. Acase can be made for cutting short the jaundice and relieving the itching by a short course of prednisolone 30mg reducing to zero over about 3 weeks. The nephrotic syndrome has been reported with immune complex, mesangial, proliferative glomeru- lonephritis [25]. Hepatitis A may trigger chronic autoimmune hepatitis type 1 in genetically predisposed individuals [19]. This may be related to defects in T-cell suppressor-inducer cells. Relapsing hepatitis A. Occasionally after 30–90 days the patient relapses. The serum transaminase levels have never returned to normal. The relapse resembles the original attack clinically and biochemically and virus A is found in the stools [18]. The relapse may last several months but recovery eventually ensues [6]. Rarely, the relapse can be associated with arthritis, vasculitis and cryoglobulinaemia [4]. Prognosis This is excellent and recovery is usually full. Mortality in large epidemics is less than one per 1000 and HAV ac- counts for less than 1% of cases of fulminant viral hepatitis. In older people, however, the disease has considerable morbidity, mortality and treatment costs [1]. In non- hospitalized adults, the symptoms lasts about 34 days with 33 days’ work loss. In a hospitalized patient, symptom duration is longer (68 days) with 33 days’ work loss. Chronicity does not develop. Follow-up of large epidemics in World War I [3] showed no long-term sequelae. Prevention The virus is excreted in the faeces for as long as 2 weeks before the appearance of jaundice. The anicteric patient may excrete the virus for a similar period. The virus is therefore disseminated before the diagnosis is made. For this reason, isolation of patients and contacts cannot be expected to influence significantly the spread of hepatitis. HAV is relatively resistant to inactivation by heat, ether or acid, but it is inactivated by formalin 1 in 4000 at 37°C for 72h, chlorine 1p.p.m. for 30min and by microwaving. Immune serum globulin (ISG) prophylaxis Efficacy depends on the antibody content and hence the source of the plasma. ISG is being largely replaced by vaccine; however, vaccine takes 1–2 weeks to achieve adequate antibody levels. Immunoglobulin is still used in those acutely exposed, such as household contacts. It is ineffective in the control of hepatitis A in hyperen- demic areas or for interrupting community-wide or common-source outbreaks. Anti-ISG must be given within 2 weeks of exposure and the protection lasts 4–6 months. ISG may be given with the first dose of vaccine but the resultant HAV anti- body titres will be reduced [24]. Hepatitis A vaccines (table 16.3) Viral particles are inactivated with formaldehyde. The vaccine is safe and immunogenic [21, 22]. The only side- effect is mild soreness of the arm. A single 1-ml dose of vaccine is followed by a booster 6–12 months later. The single dose gives rapid protection within 15 days which lasts for 1 year. If followed by the booster, 95% serocon- version ensues with long-lasting protection [17]. Prevac- cination serum testing for HAV antibody is necessary only in those born after 1945, living in countries with low prevalence and who, presumably, have had a small chance of contracting the disease (fig. 16.12). Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses 275 Table 16.3. Hepatitis A vaccine Formol inactivated 2 doses, initial and 6–12 months booster Indications travellers occupational exposure epidemics ?mass immunization in children ?chronic liver disease (HCV) In one dose the formol-inactivated vaccine was shown to be highly protective in children in a Jewish commu- nity in New York [22]. In a large study of children in Thailand, two doses protected against HAV for at least 1 year [10]. Live attenuated HAV vaccine This has been prepared from HAV in cell culture. It is inexpensive and has been widely used in developing countries such as China. Given subcutaneously, it seems safe and effective [15]. Indications for HAV vaccine (table 16.3) HAV vaccine is indicated for travellers to areas where hygiene is at risk. Unvaccinated, three to six visitors per 1000 per month will develop HAV. Children and staff in day-care units and their parents, and nurses, particularly working in intensive care units, should be vaccinated. Global control will require early mass immunization in childhood (routine aged 2, catch-up aged about 10) [12, 13]. Eventually, vaccination will be combined with other paediatric vaccines. Such worldwide vaccination is a long way off being achieved. Food handlers and sewage workers are candidates for vaccination. The military should be vaccinated, particu- larly if they are going to areas where hygiene is poor. Promiscuous, homosexual males should be vaccinated. HAV infection has a harmful effect on patients with chronic liver disease, especially HCV [20]. The HAV vaccine is effective in such patients [11]. It should pro- bably be given to those with non-end-stage disease although there may be economic constraints. HAV anti- body testing should be done as the patient is likely to have been previously exposed to HAV. References 1 Berge JJ, Drennan DP, Jacobs RJ et al. The cost of hepatitis A infections in American adolescents and adults in 1997. Hepa- tology 2000; 31: 469. 2 Center for Disease Control. Prevention of hepatitis through active or passive immunization, recommendations of the Advisory Committee of Immunization Practices (ACIP). MMWR 1999; 48: 1. 3 Cullinan ER, King RC, Rivers JS. The prognosis of infective hepatitis. A preliminary account of a long-term follow-up. Br. Med. J. 1958; i: 1315. 4 Dan M, Yaniv R. Cholestatic hepatitis, cutaneous vasculitis and vascular deposits of immunoglobulin M and comple- ment associated with hepatitis A virus infection. Am. J. Med. 1990; 89: 103. 5 Feinstone SM, Kapikian AZ, Purcell RH. Hepatitis A: detec- tion by immune electron microscopy of a virus-like antigen associated with acute illness. Science 1973; 182: 1026. 6 Glikson M, Galun E, Oren R et al. Relapsing hepatitis A. Review of 14 cases and literature survey. Medicine (Balti- more) 1992; 71: 14. 7 Gordon SG, Reddy KR, Schiff L et al. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann. Intern. Med. 1984; 101: 635. 8 Hollinger FB, Khan NC, Oefinger PE. Post-transfusion hepatitis type A. JAMA 1983; 250: 2313. 9 Hutin YJF, Pool V, Cramer EH et al. Amultistate, food-borne outbreak of hepatitis. N. Engl. J. Med. 1999; 340: 595. 10 Innis BL, Snitbhan R, Kunasol P et al. Protection against hepatitis Aby an inactivated vaccine. JAMA 1994; 271: 1328. 11 Keeffe EB, Iwarson S, McMahon BJ et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology 1998; 27: 881. 12 Koff RS. Hepatitis A. Lancet 1998; 341: 1643. 13 Koff RS. The case for routine childhood vaccination against hepatitis A. N. Engl. J. Med. 1999; 340: 644. 14 Mannuccio PM, Godvin S, Gringeri A et al. Transmission of hepatitis A to patients with haemophilia by factor VIII con- centrates treated with organic solvent and detergent to inac- tivate viruses. Ann. Intern. Med. 1994; 120: 1. 15 Mao JS, Chai SA, Xic RY et al. Further evaluation of the safety and protective efficacy of live attenuated hepatitis A vaccine (H-2 strain). Vaccine 1997; 15: 944. 16 Ponz E, Garcia-Pagán JC, Bruguera M et al. Hepatic fibrin- ring granulomas in a patient with hepatitis A. Gastroenterol- ogy 1991; 100: 268. 17 Sjögren MH, Hoke CH, Binn LN et al. Immunogenicity of an inactivated hepatitis Avaccine. Ann. Intern. Med. 1991;114: 470. 18 Sjögren MH, Tanno H, Fay O et al. Hepatitis A virus in stool during clinical relapse. Ann. Intern. Med. 1987; 106: 221. 19 Vento S, Garofano T, Di Perri G et al. Identification of hepati- tis A virus as a trigger for autoimmune chronic hepatitis type I in susceptible individuals. Lancet 1991; 337: 1183. 20 Vento S, Garafano T, Renzini C et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N. Engl. J. Med. 1998; 338: 286. 21 Werzberger A, Kuter R, Nalin D. Six years follow-up after hepatitis A vaccination. N. Engl. J. Med. 1998; 338: 1160. 22 Werzberger A, Mensch B, Kuter B et al. Acontrolled trial of a formalin-inactivated hepatitis Avaccine in healthy children. N. Engl. J. Med. 1992; 327: 453. 23 Yotsuyanagi H, Koike K, Yasuda K et al. Prolonged fecal excretion of hepatitis Avirus in adult patients with hepatitis A virus as determined by polymerase chain reaction. Hepatology 1996; 24: 10. 24 Zaaijer HL, Leentvaar-Kuijpers A, Rotman H et al. Hepatitis Aantibody titres after infection and immunization: implica- tions for passive and active immunization. J. Med. Virol. 1993; 40: 22. 25 Zikos D, Grewal KS, Craig K et al. Nephrotic syndrome and acute renal failure associated with hepatitis A viral infec- tion. Am. J. Gastroenterol. 1995; 90: 295. Hepatitis E virus This accounts for sporadic and major epidemics of viral hepatitis in developing countries [2]. Many large epi- demics of hepatitis believed to be due to HAV have now been identified as caused by HEV. The disease is enteri- cally transmitted, usually by sewage-contaminated water. 276 Chapter 16 Hepatitis E is a 32–34-nm RNA virus, unenveloped and with three open reading frames (ORFs). It resembles calciviruses but has not been classified and has been placed in a new group called herpesviridae. It is a cyto- pathic virus causing minimal immunological injury. HEV is excreted in the bile which is a rich source of virus. Low faecal excretion accounts for the rare exam- ples of secondary spread. Nucleotide viral sequences have been obtained from isolates from Burma [13], Mexico [16], Pakistan and China [9]. There are marked variations in the nucleotide sequence of HEV strains isolated from all over the world. Isolation of virus is difficult from stools, and low faecal excretion probably accounts for low secondary spread [11]. Immunity probably wains and longevity of protec- tive antibody is uncertain. Clinical features In general, hepatitis E resembles hepatitis A. It affects young adults and is rare in children [3]. It has a self- limited course. Human volunteer studies have given an incubation period of 22–46 days for blood and 34–46 days for faeces [5]. The onset is abrupt. The majority of clinical cases are jaundiced and there are no extra- hepatic features. Chronicity does not develop. Epidemic. Infection comes from drinking water conta- minated by leakage of sewage. Monsoon seasons are at high risk for epidemics. The mortality rate is high: 1–2%, and up to 10–20% in pregnant women. Death is due to fulminant liver failure. Sporadic HEV. This is a common cause of acute viral hepatitis in endemic areas. It presents with moderate or severe symptoms, including acute liver failure, sub- acute liver failure and prolonged cholestatic hepatitis [1]. Mortality is 45% for fulminant or sub-acute liver failure. Unlike epidemic HEV, the mortality is not high in pregnant women [8]. Diagnostic tests Serum IgG and IgM antibodies are measured by ELISA assay using recombinant antigens and synthetic pep- tides prepared from cloned HEV [6]. HEV RNA can be detected by RT-PCR [12]. IgM HEV can be detected within 10–12 days of acute illness and has disappeared in the majority by 6 months. Anti-HEV IgG appears at about 10–12 days of illness and remains positive for long periods. Viraemia is transient and the HEV PCR is usually negative by 3 weeks. Positive antibody tests have been reported from almost all parts of the developing world. They include Egyptian children [7], Kashmiris [8], Taiwanese [17] and migrant workers in Qatar [14]. Sufferers diagnosed in Western countries have usually been visitors to developing areas [4, 15]. Nucleotide analysis can be used to confirm the source. Infection is very unusual in the West, although antibody has been found in Italian intravenous drug users and in American blood donors [10]. Liver biopsy This shows cholestasis, pseudo-glandular formations, ballooning of hepatocytes and very prominent zone 1 infiltrates containing polymorphs (fig. 16.13). Massive and sub-massive necrosis is seen in fulminant cases and bridging necrosis is the prominent feature of sub-acute hepatitis. Even after 5–10 years of follow-up cirrhosis is not seen. Prevention This is by clean water, better sanitation and hygiene edu- cation. A vaccine may prove possible, as there is a common genotype. References 1 Acharya SK, Dasarathy S, Kumer TLet al. Fulminant hepati- tis in a tropical population, clinical course, aetiology and early predictors of outcome. Hepatology 1996; 23: 1443. 2 Aggarwal R, Naik SR. Epidemiology of hepatitis E past, present and future. Top. Gastroenterol. 1997; 18: 19. 3 Arankalle VA, Tsarev SA, Chadha MS et al. Age-specific prevalences of antibodies to hepatitis A and E viruses in Pune, India, 1982 and 1992. J. Infect. Dis. 1995; 171: 447. 4 Buisson Y, Coursaget P, Bercion R et al. Hepatitis E virus infection in soldiers sent to endemic regions. Lancet 1994; 344: 1165. 5 Chauhan A, Jameel S, Dilawari JB et al. Hepatitis E virus transmission to a volunteer. Lancet 1993; 341: 149. Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses 277 Fig. 16.13. Liver biopsy from a pregnant Arab girl suffering from acute hepatitis E showing cholestasis, pseudo-glandular formations, ballooning degeneration of hepatocytes and very prominent portal zone cellular infiltrates. She recovered. (H & E,¥100.) 6 DeGuzman LJ, Pitrak DL, Dawson GJ et al. Diagnosis of acute hepatitis E infection using enzyme immunoassay. Dig. Dis. Sci. 1994; 39: 1691. 7 Goldsmith R, Yarbough PO, Reyes GR et al. Enzyme-linked immunosorbent assay for diagnosis of acute sporadic hepatitis E in Egyptian children. Lancet 1992; 339: 328. 8 Khuroo MS, Rustgi VK, Dawson GJ et al. Spectrum of hepatitis E virus infection in India. J. Med. Virol. 1994; 43: 281. 9 Krawczynski K. Hepatitis E. Hepatology 1993; 17: 932. 10 Lok ASF, Soldevila-Pico C. Epidemiology and serologic diagnosis of hepatitis E. J. Hepatol. 1994; 20: 567. 11 Nanda SK, Ansari IH, Acharya SK et al. Protracted viremia during acute sporadic hepatitis E virus infection. Gastroen- terology 1995; 108: 225. 12 Ray R, Aggarwal R, Salunke PN et al. Hepatitis E virus genome in stools of hepatitis patients during large epidemic in North India. Lancet 1991; 338: 783. 13 Reyes GR, Purdy MA, Jungsuh PK et al. Isolation of a cDNA from the virus responsible for enterically transmitted non- A, non-B hepatitis. Science 1990; 247: 1335. 14 Shidrawi RG, Skidmore SJ, Coleman JC et al. Hepatitis E — an important cause of important non-A, non-B hepatitis among migrant workers in Qatar. J. Med. Virol. 1994; 43: 412. 15 Skidmore SJ, Yarbrough PO, Gabor KA et al. Imported hepatitis E in UK. Lancet 1991; 337: 1541. 16 Velázquez O, Stetler HC, Avila C et al. Epidemic transmis- sion of enterically transmitted non-A, non-B hepatitis in Mexico, 1986–87. JAMA 1990; 263: 3281. 17 Wu J-C, Sheen JJ, Chiang T-Yet al. The impact of travelling to endemic areas on the spread of hepatitis E virus infection: epidemiological and molecular analysis. Hepatology 1998; 27: 1415. Hepatitis G virus The aetiology of some liver disease in man remains unknown. Twenty-five per cent of cases of fulminant hepatitis have an unknown origin; 17.5% of cirrhosis remains cryptogenic. In 60% of post-transfusion hepati- tis, the cause is never found. Two ‘new’ viruses have been found, but their relation to human liver disease remains uncertain. HGV was cloned from a patient with chronic hepatitis whose plasma had transmitted hepatitis to tamarin monkeys [6]. It is a member of the flaviviridae family and has 25% homology with HCV [5]. It is found in 1–2% of blood donors in the USA. Risk factors are similar to those for hepatitis C. Its presence in liver tissue is probably due to serum contamination [7]. It is doubtful whether it is a hepatotrophic virus. Persistent infection is common, but does not lead to chronic liver disease [2]. It does not play a major role in idiopathic fulminant hepatic failure [8] or in chronic liver disease in man [3]. It is prevalent in liver transplant recipients, but does not have a long-term harmful effect on the graft [4]. It does not worsen the course of concurrent HCV infection [1]. HGV does not seem to be a serious human pathogen. References 1 Alter HJ, Nakatsuji Y, Melpolder J et al. The incidence of transfusion associated hepatitis G virus infection and its rela- tion to liver disease. N. Engl. J. Med. 1997; 336: 747. 2 Alter MJ, Gallagher M, Morris TT et al. Acute non A-E hepati- tis in the United States and the role of hepatitis G virus infec- tion. N. Engl. J. Med. 1997; 336: 741. 3 Guilera M, Satz JC, Lopez-Labrador FX et al. Hepatitis G virus infection in chronic liver disease. Gut 1998; 42: 107. 4 Haagsma EB, Cuypers HTM, Gouw AS et al. High prevalence of hepatitis G virus after liver transplantation without appar- ent influence on long-term graft function. J. Hepatol. 1997; 26: 921. 5 Leary TP, Muerhoff AS, Simon SJN et al. Sequence and genomic organization of GBV-C: a novel member of the fla- viviridae associated with human non-A-E hepatitis. J. Med. Virol. 1996; 48: 60. 6 Linnen J, Wages J Jr, Zhang-Keek ZY et al. Molecular cloning and disease association of hepatitis G virus: a transfusion- transmissable agent. Science 1996; 271: 505. 7 Pessoa MG, Terbault NA, Detmer J et al. Quantification of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic. Hepatology 1998; 27: 877. 8 Satz JC, Sans M, Mas Aet al. Hepatitis G virus infection in ful- minant hepatic failure. Gut 1997; 41: 696. Hepatitis TT virus In 1997, this virus was described in a Japanese patient (initials, TT) with non-A-G post-transfusion hepatitis [3]. It is an unenveloped single-stranded DNA virus of the circoviridiae family. It is found in the blood of about 1% of US blood donors [1]. The prevalence depends on methodology, particularly the sets of primers used for PCR [2]. It is not a causative agent for hepatitis. It is common in patients with acute and chronic liver disease, but is of no identifiable clinical significance [1, 4]. With such a high carriage rate in healthy individuals [4], it is unlikely to be a significant cause of liver disease. References 1 Charlton M, Adjel P, Poterucha J et al. TT-virus in North American blood donors, patients with fulminant hepatic failure and cryptogenic cirrhosis. Hepatology 1998; 28: 839. 2 Mizokami M, Albrecht JK, Kato T et al. TT virus infection in patients with chronic hepatitis C virus infection — effect of primers, prevalence and clinical significance. J. Hepatol. 2000; 32: 339. 3 Nishikawa T, Okamoto H, Konishi K et al. A novel DNA virus (TTV) associated with elevated transaminase levels in post- transfusion hepatitis of unknown aetiology. Biochem. Bio. Phys. Res. Comm. 1997; 241: 92. 4 Parquet M, Del C, Yatsuhashi H, Koga M et al. Prevalence and clinical characteristics of TT virus (TTV) in patients with spo- radic acute hepatitis of unknown aetiology. J. Hepatol. 1999; 31: 985. 278 Chapter 16 Yellow fever This acute infection is due to a group B arbovirus trans- mitted to man by the bite of infected mosquitoes [3]. The virus cycle is a direct human one in urban yellow fever, or may involve wild monkeys in the jungle variety. The two endemic regions are South America and equatorial Africa. Pathology In humans, the liver histology shows predominantly mid-zonal acidophilic hepato-cellular necroses (Coun- cilman bodies). Ceroid is abundant and inflammation scanty. Under electron microscopy viral particles are absent. The acidophilic bodies are composed of round cytoplasmic masses densely packed with organelles, fat vacuoles, ceroid pigment and residual bodies [2]. Appearance differs from acidophilic bodies found in other liver diseases. Inflammation is absent. Intra- nuclear inclusions (Torres bodies) are diagnostic. With recovery, regeneration is complete without chronicity. Clinical features Following an incubation period of 3–6 days, onset is sudden with fever, chills, headache, backache, pros- tration and vomiting, often of altered blood. The blood pressure falls, haemorrhages become widespread, jaundice and albuminuria are conspicuous and there is a relative bradycardia. Delirium proceeds to coma and death may occur within 9 days. With recovery, the tem- perature becomes normal and convalescence progresses rapidly. There are no sequelae and life-long immunity follows. The majority of infections are probably milder, with no detectable jaundice and only a few constitu- tional symptoms. Diagnosis Laboratory confirmation is by demonstrating specific IgM antibodies to yellow fever virus. Yellow fever antigen may be detected in formalin-fixed, paraffin- embedded tissue cut from blocks made as long as 8 years before [1]. Prothrombin deficiency parallels the severity of the liver lesion. The serum cholesterol and glucose levels fall in the fatal case. Serum transaminases are increased rela- tive to severity. Treatment There is no specific treatment. Death results principally from renal damage. The hepatic lesion is self-limited and short-lived and does not demand special treatment. Prevention consists of vaccination at least 10 days before arrival in an endemic area and by control of mosquitoes. References 1 Hall WC, Crowell TP, Watts DM et al. Demonstration of yellow fever and dengue antigens in formalin-fixed, paraffin- embedded human liver by immunohistochemical analysis. Am. J. Trop. Med. Hyg. 1991; 45: 408. 2 Vieira WT, Gayotto LC, Dé Lima CP et al. Histopathology of the human liver in yellow fever with special emphasis on the diagnostic role of the Councilman body. Histopathology 1983; 7: 195. 3 World Health Organization. Present status of yellow fever: memorandum from a PAHO meeting. Bull. WHO 1986; 64: 511. Infectious mononucleosis (Epstein–Barr virus) This is due to human herpes virus IV (EBV), which excites a generalized reticulo-endothelial reaction [2]. Primary infection in children is usually asymptomatic. In adolescents and young people, it causes a hepatitis which may mimic HAV, HBV or HCV hepatitis. Presen- tation, particularly in adults, may be as fever with right, upper quadrant, abdominal discomfort. Pharyngitis and lymphadenopathy may be absent. It can cause fulminant hepatitis in elderly people [3]. It may be a trigger for autoimmune hepatitis in susceptible people [5]. In the immunosuppressed, whether congenital or recipients of solid organ or bone marrow transplants, or sufferers from AIDS, EBV infection may be associated with lym- phoproliferative disorders. This is especially so in chil- dren having liver transplants (Chapter 38) [4]. Hepatic histology The changes are seen within 5 days and reach their peak between the 10th and 30th days. The sinusoids and portal tracts are infiltrated with large, mononuclear cells (fig. 16.14). Polymorphonuclear leucocytes and lymphocytes increase, and the Kupffer cells proliferate. The appearances may resemble leukaemia. The lesions resemble those of early A, B or C viral hepatitis. The architecture of the liver is preserved. Zone 3 focal necroses may be randomly distributed. There is no surrounding cellular reaction. Later binucleate liver cells and mitoses are conspicu- ous. The regeneration is out of proportion to cell necro- sis. After clinical recovery, abnormal cells disappear, although this may take as long as 8 months. Chronic hepatitis and cirrhosis are not sequelae. Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses 279 Clinical features Occasionally jaundice can be deep [1]. It is not due to large glands in the porta hepatis. Persistent infection is a cause of chronic ill health. Immune responses determine the clinical and patho- logical expression. Using monoclonal antibodies, direct hepatic viral infection has been shown. Diagnosis The serum albumin level may be slightly decreased and the serum globulin value slightly elevated. Hyperbilirubinaemia is present in about one-half of patients. Serum transaminase values are raised to about 20 times the normal in 80% of patients. Values are usually less than those found in the early stages of an acute virus A, B or C hepatitis. In about one-third the serum alkaline phosphatase value is increased, often more so than that of bilirubin. The monospot reaction is positive. The disease is diag- nosed conclusively by an increase in serum IgM anti- bodies against EBV capsid antigens. In the immunosuppressed, particularly with post- transplant lymphoproliferative disease, EBV proteins may be shown by immunofluorescence on liver biopsy material. PCR is used for DNA in situ hybridization in blood and tissues [2]. Distinction from viral hepatitis (table 16.4) Although the diagnosis of viral hepatitis from infectious mononucleosis is usually easy, in an occasional patient with mild anicteric hepatitis or severe mononucleosis this may be impossible. 280 Chapter 16 Fig. 16.14. Infectious mononucleosis. The sinusoids and portal tracts (P) are filled with mononuclear cells. One small local necrosis (N) is seen in the upper right-hand corner. H, central hepatic vein. (Best’s carmine,¥70.) Table 16.4. Comparison of infectious mononucleosis and viral hepatitis Infectious mononucleosis Viral hepatitis Epidemic history Suggestive Suggestive Onset Fever ++ Anorexia -+ Sore throat +- Rash + Rare Pruritus -+ Physical signs Lymphadenopathy ++ ± Jaundice Mild, transient Well developed, persisting Liver Enlarged; not Enlarged and usually tender tender Spleen Enlarged and tender Enlarged but not tender Pale stools -+ Dark urine ±++ Peripheral blood Leucocytes Usually increased; Decreased, with characteristic cells relative lymphocytosis Monospot Positive Negative IgM EBV Present Absent HBsAg Negative Positive, type B IgM anti-HAV Negative Positive, type A Liver biopsy Diffuse mononuclear Zone 3 ‘spotty’ infiltration; focal necrosis; necroses mononuclear infiltration References 1 Fuhrman SA, Gill R, Horwitz CA et al. Marked hyperbiliru- binemia in infectious mononucleosis. Arch. Intern. Med. 1987; 147: 850. 2 Markin RS. Manifestations of Epstein–Barr virus-associated disorders in liver. Liver 1994; 14: 1. 3 Papatheodoridis GV, Delladetsima JK, Kavallierou L et al. Fulminant hepatitis due to Epstein–Barr virus infection. J. Hepatol. 1995; 23: 348. 4 Smets F, Bodeus M, Goubau P et al. Characteristics of Epstein–Barr virus primary infection in paediatric liver transplant recipients. J. Hepatol. 2000; 32: 100. 5 Vento S, Guella L, Mirandola F et al. Epstein–Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995; 346: 608. Other viruses All viruses may affect the liver in common with other organs. The histological changes are usually non- specific, consisting of fatty change, or focal necrosis and lymphocytic infiltration of the portal zones. Biochemical tests are usually unchanged or show mild rises in transaminases. Occasionally, the patient may be frankly icteric when the picture of type A, B or C hepatitis is closely simulated. The upsurge of AIDS has increased the prevalence of hepatitis due to various unusual viruses. These fre- quently prove fatal (Chapter 29). They are also important in those receiving large doses of immunosuppressive drugs, such as liver and bone marrow recipients, or patients with reticulosis. They are seen in neonates (Chapter 26) and may follow a blood transfusion. Cytomegalovirus In neonates, cytomegalovirus is usually inapparent. Confirmed disease in early infancy is rare. Sometimes, however, in association with the respiratory distress syn- drome, cytomegalovirus may cause a devastating fatal pneumonitis. In adults, the clinical picture can be very diverse. Cytomegalovirus can cause a disease strongly resem- bling EBV-related mononucleosis. Patients usually lack pharyngitis and posterior cervical lymphadeno- pathy. Serum transaminase and alkaline phosphatase levels are increased and atypical lymphocytes are found in the peripheral blood. The monospot test is usually negative. The picture may simulate type A, B or C hepatitis, having a similar onset but with failure of the pyrexia to subside with the onset of jaundice. Icterus lasts 2–3 weeks and even up to 3 months. Occasionally, massive hepatic necrosis may be fatal. Granulomatous hepatitis can develop in a previously normal adult with prolonged unexplained fever and without lymphadenopathy [1]. In these patients, liver biopsy shows non-caseating granulomas. The immuno- suppressed show characteristic inclusions. Cholangitis, papillary stenosis and sclerosing cholan- gitis can accompany cytomegalovirus infections in patients with AIDS (Chapter 29). Cytomegalovirus infection is a rare cause of post- transfusion hepatitis. Cytomegalovirus may cause disseminated disease, of which hepatitis is only a part, in the immunosuppressed, such as those with leukaemia. Cytomegalovirus hepatitis is a real problem in adult and paediatric recipients of kidneys and, particularly, liver transplants [4]. The infection is usually a primary one, rather than reactivation, and the donor is cytomegalovirus antibody positive (Chapter 29). Diagnosis is by isolation of virus from urine or saliva. Complement-fixing antibodies rise and cytomegalovirus IgM antibodies can be found. The virus cannot usually be shown in liver biopsy but direct hepatic involvement has been confirmed by demonstrating nuclear and cyto- plasmic inclusions in hepatocytes [9]. Herpes simplex Human herpes virus types I and II affect all humans at some time during their lives. In infants, herpes hepatitis may be part of generalized herpetic disease. In adults, disseminated herpes simplex is very rare. It can affect those with underlying diseases, e.g. ulcerative colitis [10], with AIDS, those receiving immunosuppres- sive treatment or having organ transplants. Fulminant hepatic failure can also affect the previously normal and immunocompetent [3]. It may complicate genital herpes [8] and be seen in pregnancy [5]. Herpetic mucocutaneous lesions are usually absent. The onset is with fever, prostration, marked elevation of transaminases and leucopenia. Jaundice is absent. Fulminant liver failure with fatal coagulopathy can develop. Liver biopsy shows patchy areas of coagulative necro- sis with surrounding hepatocytes containing viral inclu- sions (fig. 16.15) [3]. The virus can be shown by electron microscopy. It can be cultured from the liver and, using immunoperoxidase staining, may be shown in affected hepatocytes. Acyclovir or gancyclovir is curative. Miscellaneous Coxsackie virus B may cause hepatitis in the adult. Cox- sackie virus, group A, type IV, has been isolated from the plasma of a child with hepatitis, and complement-fixing antibodies appeared in the serum during convalescence. Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses 281 Varicella and varicella-zoster may be complicated by hepatitis in both normal and immunologically compro- mised individuals [6]. In children, the picture must be distinguished from Reye’s syndrome [6]. Measles is affecting an older age group. Eighty per cent of adult sufferers have liver involvement; 5% becoming jaundiced [2]. It is most frequent in the seriously ill. Resolution is complete. Rubella can be associated with serum transaminase elevations and may be mistakenly diagnosed as hepatitis C [11]. Paramyxoma viruses. Severe sporadic hepatitis with histologically large syncytial giant hepatocytes may be related to the paramyxoma viruses [7]. Virological con- firmation and classification is awaited. References 1 Clarke J, Craig RM, Saffro R et al. Cytomegalovirus granulo- matous hepatitis. Am. J. Med. 1979; 66: 264. 2 Gavish D, Kleinman Y, Morag Aet al. Hepatitis and jaundice associated with measles in young adults. Arch. Intern. Med. 1983; 13: 674. 3 Goodman ZD, Ishak KG, Sesterhenn IA et al. Herpes simplex hepatitis in apparently immunocompetent adults. Am. J. Clin. Pathol. 1986; 85: 694. 4 King SM, Petric M, Superina R et al. Cytomegalovirus infec- tions in paediatric liver transplantation. Am. J. Dis. Child. 1990; 144: 1307. 5 Klein NA, Mabie WC, Shaver DC et al. Herpes simplex virus hepatitis in pregnancy. Two patients successfully treated with acyclovir. Gastroenterology 1991; 100: 239. 6 Myers MG. Hepatic cellular injury during varicella. Arch. Dis. Child. 1982; 57: 317. 7 Phillips MJ, Blendis LM, Poucell S et al. Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral fea- tures. N. Engl. J. Med. 1991; 324: 455. 8 Rubin MH, Ward DM, Painter J. Fulminant hepatic failure caused by genital herpes in a healthy person. JAMA 1985; 253: 1299. 9 Sacks SL, Freeman HJ. Cytomegalovirus hepatitis: evidence for direct hepatic viral infection using monoclonal anti- bodies. Gastroenterology 1984; 86: 346. 10 Shlien RD, Meyers S, Lee JAet al. Fulminant herpes simplex hepatitis in a patient with ulcerative colitis. Gut 1988; 29: 257. 11 Zeldis JB, Miller JG, Dienstag JL. Hepatitis in an adult with rubella. Am. J. Med. 1985; 79: 515. Hepatitis due to exotic viruses These very dangerous viruses have the liver as the primary target [2]. They include Marburg, Lassa and Ebola viruses. They are becoming increasingly impor- tant as man encroaches into underdeveloped areas, as ecology changes and as a source of infection to medical or laboratory staff dealing with patients or their blood. Lassa fever is due to an arenavirus transmitted from rodents to man or from man to man. It is largely found in West Africa. The case fatality rate is 36–67%. Diagnosis is made by demonstrating virus in the blood during the first few days and by IgM antibodies from the fifth day. It has been successfully treated with ribavirin [3]. The liver shows eosinophilic necrosis of individual hepatocytes with little inflammation. Bridging necrosis is usual. Marburg virus disease is due to an RNA virus trans- mitted by Vervet monkeys. In 1967, an outbreak of this disease occurred in persons in contact with monkeys in experimental institutes in Germany [4]. Further patients have been reported from South Africa and Kenya [5]. After an incubation period of 4–7 days the patients present with headache, pyrexia, vomiting, a characteris- tic rash, a haemorrhagic diathesis and central nervous system involvement. Serum transaminase levels are very high. Liver pathology shows single-cell acidophilic necrosis and Kupffer cell hyperactivity. This is followed by eccen- tric and radial extension of the necrosis, cytoplasmic inclusions and portal zone cellularity. Steatosis is noted in the severely affected. The virus can persist in the body for 2–3 months after initial infection. 282 Chapter 16 Fig. 16.15. Herpes virus II hepatitis. An area of coagulative necrosis can be seen (arrow). Adjacent liver cells were shown to have nuclear viral inclusions. (H & E,¥100.) Ebola virus infection resembles Marburg in clinical course, hepatic histology and electron microscopy [1]. It has been reported from Zaïre and the Sudan and has been transmitted to biologists working with it. Treatment There is no specific treatment for these exotic virus infections. Symptomatic measures are used and very strict precautions are necessary to avoid spread to contacts. References 1 Ellis DS, Simpson DIH, Francis DP et al. Ultra-structure of Ebola virus particles in human liver. J. Clin. Pathol. 1978; 31: 201. 2 Howard CR, Ellis DS, Simpson DIH. Exotic viruses and the liver. Semin. Liver Dis. 1984; 4: 361. 3 McCormick JB, King IJ, Webb PA et al. Lassa fever. Effective therapy with ribavirin. N. Engl. J. Med. 1986; 314: 20. 4 Martini GA, Knauff HG, Schmidt HA et al. Uber eine bisher unbekannte von Affen eingeschleppte Infektions-krankheit: Marburg-Virus-Krankheit. Dtsch. Med. Wschr. 1968; 57: 559. 5 Smith DH, Johnson BK, Isaacson M. Marburg-virus disease in Kenya. Lancet 1982; i: 816. Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses 283 [...]... 5 0 1 05 1 95 1 (a) 2 85 3 75 4 65 555 6 45 7 35 2 Number of infections 20 (b) 15 10 5 0 293 1 05 1 95 2 85 3 75 4 65 555 6 45 Time after first injection (days) 7 35 Fig 17.12 Efficacy of hepatitis B vaccine Results of a doubleblind trial of the efficacy of hepatitis B vaccine in 1083 homosexual men Distribution of infections in recipients of (a) placebo and (b) vaccine over 7 35 days Arrows show time of first and second... of serum IgG anti-HDV (anti-delta) Co-infection is diagnosed by finding serum IgM antiHDV in the presence of high-titre IgM anti-HBc These markers appear at 1 week, and IgM anti-HDV is gone by 5 6 weeks but may last for up to 12 weeks [1] When serum IgM anti-HDV disappears, serum IgG anti-HDV is found There may be a window period between the disappearance of one and the detection of the other Loss of. .. 18.1) [26] The viral genome is composed of a 5 non-coding region, a long open reading frame encoding a polyprotein precursor of about 3000 amino acids, and a 3¢ non-coding region The 5 non-coding region is highly conserved Because of this and the crucial role played in the translation of the viral polyprotein, the 5 non-coding region has become a target for the development of nucleic acid-based antiviral... DNA Then the viral DNA integrates with host DNA and the host DNA polymerase transcribes for the virus ORF-X Fig 17.4 Organization of the genome of HBV showing the four open reading frames (ORF), polymerase (P), surface antigen (S), core antigen and X, and the pre-S1 and pre-S2 regions hepatocyte receptors This effect may be important in the development of chronic hepatitis B (pre-S2 is similar) The. .. prevalence of chronic hepatitis C is estimated to average 3% (ranging from 0.1 to 5% in different countries) There are some 1 75 million chronic HCV carriers throughout the world, of which an estimated 2 million are in the USA and 5 million in Western Europe HCV accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepato-cellular... response The long-term protection depends on the antibody response, which is 85 100% in healthy young subjects Anti-HBs should be measured 1–3 months after completion of the basic course of vaccine Non-responders have peak anti-HBs levels of < 10 iu/l and lack protection Low responders have peak anti-HBs levels of 10–100 iu/l and generally lack detectable anti-HBs levels within about 5 7 years They may... to be treated The virus for hepatitis B is a small encapsulated DNA virus (fig 17.2) The core is formed in the nucleus and the surface particles in the cytoplasm The core contains a DNA polymerase DNA structure is doublestranded and circular with a single-stranded gap of 600–2100 nucleotides The DNA polymerase reaction appears to repair the gap The core contains a core antigen, and another antigen called... intimate, often sexual, contact The carrier rate of HBsAg varies worldwide from 0.1 to 0.2% in Britain, the USA and Scandinavia, to more than 3% in Greece and southern Italy and even up to 10– 15% in Africa and the Far East If anti-HBs is measured, the rate of exposure to hepatitis B in any community is much higher Carriage of HBsAg is even higher in some isolated communities: 45% in Alaskan Eskimos [47] and. .. remains the main mode of transmission; but this route of transmission is diminishing due to a heightened awareness of the risk of needle sharing and, in some countries, the availability of needle-exchange programmes However, a huge backlog of infected patients continue to progress towards cirrhosis and hepato-cellular carcinoma The cost of investigating and treating these patients remains and continues... 2 85 286 Chapter 17 Nucleus Cell membrane Host DNA polymerase Host DNA Viral DNA Dane particle Viral DNA polymerase Integration of viral DNA into host DNA Transcription by host polymerase Sub-types of HBsAg pre S1 pre- -S2 L (-) F-S OR S(+) ORF HBsAg -C DR RF -P 1 DR2 O HBcAg pr e- C DNA polymerase HBeAg Fig 17.3 The hepatitis B virion enters the hepatocyte and the core reaches the nucleus At first the . 7 35 Number of infections 0 20 15 10 5 1 2 1 05 1 95 2 85 3 75 4 65 Time after first injection (days) 55 5 6 45 7 35 Fig. 17.12. Efficacy of hepatitis B vaccine. Results of a double- blind trial of the efficacy of. infectious and their sexual contacts should be vaccinated and Hepatitis B Virus and Hepatitis Delta Virus 293 Number of infections 0 30 25 20 15 10 5 1 2 (a) (b) 1 05 1 95 2 85 3 75 4 65 555 6 45 7 35 Number. DNAand the host DNApolymerase transcribes for the virus. L (-) S(+) DR1 DR2 pre-S1 pre-S2 ORF-S ORF-P DNA polymerase pre-C HBcAg HBeAg ORF-C ORF-X HBsAg Fig. 17.4. Organization of the genome of