Acute and chronic hepatitis

Mini-symposium

Liver and metabolism

Acute and chronic hepatitis

G. Mieli-Vergani Hepatitis A l

ing and persisting HAV infection have been occasionally reported. In acute hepatitis A, transaminases are elevated 3-4 days before the onset of jaundice, returning to normal in 2-3 weeks but sometimes as late as 6 months. The bilirubin rises after the transaminases. Minor coagulation defects are common, but if more serious or persistent they suggest evolution to fulminant hepatitis or an underlying chronic liver disease. Haemolysis and severe cholestasis may occur in patients with haemolytic disorders. Diagnosis is made by detecting IgM antibody to the HAV. This appears 3-7 weeks after infection and usually persists for 1-4 months, occasionally for more than one year.

The virus The hepatitis A virus (HAV) is a small unenveloped symmetrical RNA virus similar to picornavirus. It causes infectious hepatitis. HAV appears in the stools during the prodromal phase, which begins 2-6 weeks after oral inoculation, and is detectable for up to 2 weeks after the onset of clinical hepatitis. This represents the period of infectivity.

Prevalence HAV infection occurs worldwide. Because it is frequently asymptomatic, its incidence is unknown. Data on prevalence of past infection are available by measuring serum IgG to HAV. Infection is linked to poor general hygiene and to low socio-economic status. Epidemics and sporadic cases in developed countries are due to contamination of food or water. HAV is increasingly found amongst high risk groups, such as drug abusers. Epidemics may arise in day care centres and in neonatal intensive care units, where transmission occurs through blood products.

Pathogenesis of #ver damage Liver damage probably results from a direct cytopathic effect of HAV and from host immune reactions to virus-infected hepatocytes.

Treatment and prophylaxis Treatment is supportive. Control and prevention depends on comprehensive sanitation. Passive immunisation with normal human immunoglobulin protects against clinical hepatitis for about 3 months. Inactivated and attenuated vaccines have been developed in laboratory animals. Vaccines for humans will be commercially available soon.

Clinical feattcres and laboratory findings HAV usually causes a minor illness. Probably fewer than 5% of cases are recognised clinically. The most serious complication is fulminant hepatitis. It affects 0.14%-0.35% of symptomatic patients, the incidence increasing with increasing age. Survival is about 65%. HAV does not provoke a chronic hepatitis. Relaps-

Hepatitis B 2'3 The virus

Giorgina Mieli-Vergani MD, PhD Senior Lecturer in Paediatric tlepatology, Dept of Child Health, King's College School of Medicineand Dentistry,Denmark Hill, LondonSE5 8RX, UK. Correspondenceand requests for offprintsto GM-V. Current Paediatrics (1991) 1, 212-215

. . . . . . . . . . . ~...... u~: l.,a

212

The hepatitis B virus (HBV) is a double stranded DNA virus replicating by reverse transcriptase. The complete infective form of HBV is a 42 run spherical particle called Dane particle. It has an inner nucleo-

ACUTE AND CHRONIC HEPATITIS

Prevalence

capsid core 27 nm in diameter, the hepatitis B core (HBc) and an outer lipoprotein coat comprising the hepatitis B surface antigen (HBsAg). The nucleotide sequence of the viral genome has been fully characterised. Three different forms of HBsAg are detected in the sera of infected patients: Dane particles, spherical 22 nm HBsAg particles and filamentous HBsAg with a diameter of 22 nm. A further antigen called 'e' (HbeAg) is coded for by the viral genome. HBVspecific DNA and DNA polymerase are detected in sera containing Dane particles. Recovery from infection is accompanied by the production of specific antibodies: anti-HBc, anti-HBe, anti-HBs. Markers of HBV infection and their meaning are listed in Table 1.

Table

213

There are 200-300 million carriers of HBV in the world, 20-30% of whom will die of cirrhosis or tumour. In hyperendemic areas (e.g. South-East Asia or Africa), 80-90% of the population is infected during childhood and 15-20% are chronic carriers. Age of infection varies: up to 30% of children are infected during the first year of life in South-East Asia, but only 5% in some parts of Africa. In areas of low endemicity (e.g. Northern Europe), < 10% of the adults have been infected and < 1% are carriers. Infection and carrier rates in countries of intermediate endemicity (e.g. Mediterranean countries, Middle East, Latin America) vary between 30-90°/0 and 2-15% respectively. In areas of low endemicity infection commonly occurs through sexual contact or drug abuse.

Significance of serological markers of hepatitis B

Clinical features and laboratoryfindings

Dane particle HBsAg HBeAg IgM anti-HBc IgG anti-HBc Anti-HBs HB V-DNA polymerase HBV-DNA

Full virus High infectivity Acute or chronic HBV infection Infectivity? Active viral replication High infectivity High titre: acute hepatitis Low titre: chronic infection Past exposure to HBV or continuous infection if associated with HBsAg positivity Immunity to HBV Active viral replication High infectivity Active viral replication High infectivity

The incubation period is 2-6 months. Infection may be subclinical in about 50% of cases. Biochemical and serologic features of an acute, uncomplicated hepatitis B are shown in Figure 1. Less than 1%0 of symptomatic patients progress to fulminant hepatitis. About 60% die, unless transplanted. Children usually acquire HBV infection from their mothers at birth or later through family contacts. A mother can infect her baby because she develops acute hepatitis during the third trimester of pregnancy, at the time or soon after delivery, or because

I jaundice I /

I HBsAg I H BeAg

,--.-~.

-,,

[ anti- HBs

I •

! lanti.HB.

I

f

I anti-HBc IgM. f

7,

Ianti-HBc 19G J

AST

.

% "%,%

.................. B

i

I

0

1

months

I

I

2

3

,

4

,

5

,

6

D

II

years

exposure Fig. 1--Sequential appearance and disappearance of hepatitis B antigens and antibodies during an acute uncomplicated hepatitis. HBsAg: hepatitis B surface antigen Anti-HBs: antibody to hepatitis B surface antigen HBeAg: hepatitis B e antigen Anti-HBe: antibody to hepatitis B e antigen Anti-HBc: antibody to core antigen AST: aspartate aminotransferase

214 C U R R E N T PAEDIATRICS she is an asymptomatic chronic carrier. The age of infection is inversely correlated with the risk of becoming a chronic carrier. Persistent carrier state occurs in 70-90% ofinfections in infancy and declines to 6-10% of infections occurring after the 6th year of life. Mother's HBeAg positivity indicates high infectivity: > 90% of infants born to HBsAg/HBeAg positive mothers are infected, 80-90% of them becoming chronic carriers. In contrast, the risk of chronic neonatal infection in infants born to HBeAg negative virus-infected mothers is about 10%. However, acute and even fulminant hepatitis may develop in infants born to HBsAg positive mothers who are HBeAg negative and anti-HBe positive. HBV infected male infants have the highest risk of developing aggressive liver disease, cirrhosis and cancer.

Pathogenesis of liver damage HBV is not directly cytopathic. Destruction of infected liver cells is mediated by cytotoxic T lymphocytes reacting with viral antigens expressed on the hepatocyte membrane. In addition, patients with hepatitis B produce antibodies to part of the hepatocyte cell membrane called 'liver specific protein' (LSP). Antibody-dependent non-T cell mediated cytotoxicity directed to LSP on autologous hepatocytes from patients with chronic HBV infection was shown in vitro. Progression to chronic infection may be due to a genetic or acquired deficiency in interferon production. HBsAg-specific T suppressor cells may also play a role in the maintenance of non-responsiveness to HBsAg in chronic HBV carriers.

Treatment and prophylaxis Plasma derived and recombinant vaccines against HBV are available. Perinatal infection is best prevented by combining passive and active immunisation at birth, but the cost of specific immunoglobulin (Slg) is prohibitive in many parts of the world. HBV vaccination needs to be tailored to the different countries. In highly endemic areas, universal immunisation of newborns with HBV vaccine, without screening of pregnant women or use of HBV SIg, should be adopted. In endemic areas where the infection occurs mainly during childhood, HBV vaccine should be incorporated into the current immunisation program. In areas of low endemicity, all pregnant women should be screened for HBsAg and all newborns of HBsAg.positive mothers, whether HBeAg positive or not, should be immunised with SIg and HBV vaccine. Protective immunity after HBV vaccine is obtained in between 86-93% of babies. Infants who become infected despite vaccination have acquired HBV in utero or are non-responders. Some may be infected by virus escape mutants. A titre of anti-HBsAg above 10 U/I is protective.

The duration of protection after vaccination is unknown. Chronic HBV infection has been treated with several antiviral drugs. Lymphoblastoid or recombinant alpha-interferons are the best option with up to 50% chance of long-term inhibition of HBV replication in patients who acquire the infection in adulthood. Results in paediatric age are less encouraging and controversial, particularly for children who have acquired the infection at birth. Hepatitis C 5

The virus The hepatitis C virus (HCV) is an enveloped singlestranded RNA virus, related to flaviviruses. HCV has been isolated, cloned and sequenced recently. It is the predominant agent responsible for post transfusion non-A, non-B hepatitis. It may also account for sporadic cases.

Pre valence The prevalence o f H C V infectioh is unknown. Various serological tests to detect specific antibody have been developed and used for diagnostic purposes and for screening of blood and blood products. Although a positive anti-HCV test in screened transfusion blood is sufficient reason to discard the specimen, the significance of anti-HCV in patients remains uncertain. Recent surveys of populations at risk for developing HCV infection have documented a substantial prevalence of anti-HCV positivity, and have suggested a relationship between exposure to HCV and chronic liver disease, hepatocellular carcinoma, and, possibly, autoimmune chronicactive hepatitis. In healthy volunteers and community based surveys, the prevalence of anti-HCV is 0.6-1.4%. The meaning of anti-HCV positivity and the role of HCV in determining acute and chronic liver disease will be clarified when more sensitive and specific tests to detect viral antigens and specific antibody are commercially available.

Clinical features The incubation following blood transfusion is about 2 months. It can be much shorter after administration of coagulation factors. It is not clear whether two different non-A, non-B viruses are involved or whether both diseases are due to HCV, the different incubation periods depending on the size of the inoculum. Post transfusion hepatitis is usually a mild disease. Many cases are asymptomatic. Jaundice affects only about 10% of cases. There may be a single peak of transaminase followed by recovery or fluctuation of liver enzymes over many months. There is a high rate of progression to chronic hepatitis and cirrhosis. The mechanism of liver damage is unknown.

ACUTE AND CHRONIC HEPATITIS

Treatment and prophylaxis Recombinant interferon alpha induces biochemical and histological decrease in disease activity in chronic HCV infection. Relapse after cessation of therapy, however, is common, affecting 50-80% of the responding patients. Screening of blood donors for anti-HCV antibody should decrease post-transfusion hepatitis. No vaccination is available. Hepatitis D 4 Tile virus

The hepatitis D virus (HDV) is a single-stranded circular RNA virus requiring HBV helper function for propagation in hepatocytes. It is an important cause of acute and severe chronic liver damage in many countries.

Prevalence HDV is distributed worldwide, but tends to cause infection in localised epidemics involving HBV carriers. HDV infection is endemic in the Middle East, Southern Europe and some areas of Africa and South America. In non-endemic areas HDV infection is found more frequently in haemophiliacs and drug abusers. In endemic areas HDV infection is disseminated by close contact, as indicated by family clustering of cases, but vertical transmission from mother to infant is unusual.

Clinical features, pathogenesis of liver damage and treatnlent HDV infection may be acquired simultaneously with HBV or may affect a chronic HBV carrier. Simultaneous infection causes acute hepatitis. In HBV carriers, HDV superinfection may cause a severe or fulminant hepatitis. Asymptomatic HBV carriers with little liver damage may develop severe chronic hepatitis and cirrhosis following HDV superinfection. Diagnosis is made by finding HDV in serum or liver and by detecting specific antibody. HDV is probably directly cytopathic. There is no known treatment. Interferon does not achieve sustained suppression of

215

HDV replication. HBV vaccination should prevent and limit HDV spread. Hepatitis

E6

The virus Hepatitis E virus (HEV) is a non-enveloped singlestranded R N A virus, similar to the caliciviruses. It is 32-34 nm in diameter and appears in the stools of patients affected by a form of enterically transmitted non-A, non-B hepatitis. There are no comercially available tests for antigen or antibody detection. Enterically transmitted non-A, non-B hepatitis is probably caused not only by HEV but also by other as yet unidentified viruses. HEV is an important cause of large epidemics of acute hepatitis'in the subcontinent of India, Central and South East Asia, Middle East, parts of Africa, parts of North America, Mexico and Soviet Union.

Clinical features The incubation period is about 40 days. The highest attack rate is in subjects aged 15-49 yearS. Symptoms and biochemical results are similar to those of hepatitis A. The illness is generally short and mild. Cases of fulminant hepatitis are reported, especially in pregnant women, with a mortality of 10-20%. The pathogenesis of liver damage is unknown. HEV may be directly cytopathic. No treatment or prophylaxis are available. References 1. Forbes A, Williams R. Changing epidemiology and clinical aspects of hepatitis A. Brit Med Bull 1990; 46: 303-318. 2. Maynard JE, Kane MA, Alter M J, Hadler SC. Control of hepatitis B by immunization: global perspective. In: Zuckerman A J, ed. Viral hepatitis and liver disease. New York: Alan R Liss, 1988: pp 967-969. 3. Alexander GJM. Immunology of hepatitis B virus infection. Brit Med Bull 1990; 46: 354-367. 4. Monjardino JP, Saldanha JA. Delta hepatitis. The disease and the virus. Brit Med Bull 1990; 46: 399-407. 5. Choo QL, Weiner A J, Overby LR, Kuo G, Houghton M, Bradley DW. Hepatitis C virus: the major causative agent of viral non-A, non-B hepatitis. Brit Med Bull 1990; 46: 423-441. 6. Bradley DW. Enterically-transmitted non-A, non-B hepatitis. Brit Med Bull 1990; 46: 442-461.