Hepatitis B: the disease

Hepatitis B: the disease S. Sherlock Hepatitis B virus (HBV) is carried by .~ 300 million people in the world. The natural history oJ" the disease in an individual patient depends on the method by which the infection was acquired, whether perinatal, in childhood, as a result of drug abuse, or in the course of health care work. Other important factors determining the course of the disease include an individual's sex and immunological status. Geographic factors also contribute. Changing lifestyles and the use of prophylactic hepatitis B vaccination affect the prevalence in various groups in the community. The clinical course of the disease, possible complications, and a recent classification system for chronic HBsAg carriers are discussed. Keywords:Hepatitis B; serum markers; epidemiology; chronic hepatitis; clinical course

Introduction Carried by an estimated 300 million persons globally, hepatitis B virus (HBV) is the major cause of liver disease world-wide. The diseases associated with HBV infection not only give rise to much human suffering but place an intolerable burden on public health services, particularly in those countries least able to afford them.

Nature of the virus The causative virion consists of an envelope and a nucleocapsid. Hepatitis B surface antigen (HBsAg), located in the viral envelope, was formerly called Australia antigen. Immunogenic but not infectious, it is the basis of hepatitis B vaccines. The nucleocapsid contains a DNA polymerase and a circular, double-stranded DNA molecule. This core carries two important antigenic determinants: the hepatitis B core antigen (HBcAg) and the hepatitis B e antigen (HBeAg), a protein subunit of the core. The doublestranded DNA genome of HBV has been cloned and sequenced. The S gene has been found to code for the protein of the viral envelope (i.e. HBsAgt. In addition, the presence of a pre-S region (pre-Sl and pre-S2 regions) precedes the gene coding for HBsAg: it may be concerned with the ability of the HBV to interact with a host hepatocyte. The C gene encodes the core protein (i.e. HBcAg), while the putative DNA polymerase-encoding P gene overlaps the S gene. A fourth reading frame less well understood is designated X. The genomic organization of the hepatitis B virion and its domains are shown in Figure I. HBV is one of a group of animal viruses known as the hepadnaviridae; similar hepatotropic viruses leading to persistent viral infection are known to affect woodchucks, ground squirrels and Peking ducks.

Markers of HBV infection Ongoing viral replication is indicated by the presence of any serological markers of the virion core. Hence, serum HBeAg correlates with ongoing viral synthesis and infectivity. Antibodies to HBeAg (anti-HBe) are, by Department of Surgery, Royal Free Hospital School of Medicine, London NW3 2QG, UK 0264-410X]90/S10006-04 ~ 1990 Butterworth & Co. (Publishers) Ltd $6

Vaccine, Vol. 8, Supplement 1990

contrast, markers of relatively low infectivity and appear in the integrated stage of infection. The presence of IgM antibodies to HBcAg (anti-HBc) implies the existence of ongoing HBV-related chronic liver disease. Lower titres of IgG anti-HBc with antibodies to HBsAg (anti-HBs) mark hepatitis B infection in the remote past, whereas higher titres of IgG anti-HBc without anti-HBs indicate persistence of viral infection. Serum hepatitis B viral DNA (HBV DNA) is the most sensitive index of viral replication. It can be present in anti-HBe-positive serum. Routine testing for serum HBV DNA will undoubtedly replace tests for HBeAg I

Epidem!ology The disease is transmitted parenterally or by intimate, often sexual, contact. The carrier rate of HBsAg varies world-wide from 0.1 to 0.2% in Britain, the US and Scandinavia, to > 3% in Greece and Southern Italy and to as much as 10 to 15% in Africa and the Far East 2. In some isolated communities the HBsAg carriage rate is remarkably high: 45% in Alaskan Eskimos 3 and 85% in Australian Aborigines. In high-carriage-rate areas, infection is probably acquired by passage from mother to neonate, either at

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ii ,IL/J

/ ;

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Figure 1 The structure and organization of the HBV genome

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Hepatitis B: the disease: S. Sherlock Table 1 Overall incidence and disease transmission patterns of hepatitis B in the US, 1982-1987 Overall incidence (%) Risk factor/Group Male homosexuals Intravenous drug abusers

Heterosexual exposure Health care workers

Transfusion Dialysis Mentally subnormal No source

1982-1985

1985-1987

21 15 18 5 2 1 1 36

9 27 24 1

32

Overall incidence of hepatitis B was constant with 13 cases per 100000 population; adapted from Ref. 4

infection may precipitate a fulminant course; this may either be hepatitis A, delta virus, or non-A, non-B hepatitis. The occurrence of subacute hepatic necrosis is marked by increasingly severe disease evolving over 1 to 3 months. Approximately 10% of patients contracting hepatitis B as adults and 98% of those infected as neonates will not clear HBsAg from the serum within 6 months. Such patients become carriers and this state is likely to persist. Males are six times more likely to become carriers than females. Chronic hepatitis

Immunopathogenesis the time of birth or during subsequent close maternal contact. In other geographical areas, the disease tends to be transmitted during childhood, especially in the family circle. Social behaviour related to sexual promiscuity or drug addiction plays a signifcant role in HBV infection. The rate at which homosexuals contract hepatitis B is related to the duration of homosexual activity, number of sexual partners and to anal sexual contact. Although the prevalence of hepatitis B in homosexuals in the US is currently waning due to fear of contracting AIDS infection and to changing lifestyles, it seems to be on the rise among drug abusers (Table •)4. In all countries throughout the world, the incidence of hepatitis B is particularly high among persons whose occupation or illness bring them into contact with infected blood or blood products. Thus, blood transfusion may cause hepatitis B in countries where donor blood is not screened for HBsAg. Hospital staff in contact with patients, and especially patients' blood, usually have a higher infection rate than those persons in the general community. Opportunities for parenteral infection include the use of medical and dental instruments, ear piercing and manicures, prophylactic inoculations, subcutaneous injections, acupuncture and tattooing. Parenteral drug abusers develop hepatitis B when sharing unsterile needles and syringes with fellow addicts.

Clinical course

The course of the disease may be subclinical and anicteric (Figure 2). Indeed, the high carriage rate of serum markers of HBV infection in persons without a history of an acute HBV attack suggests that subclinical cases must be extremely frequent. The anicteric case is more likely to become chronic than the icteric one. Although the usual clinical attack of hepatitis B tends to be more severe than for virus A or non-A, non-B infections, the overall clinical picture is similar. The icteric disease usually lasts < 4 months and jaundice is rarely > 4 weeks. Cholestatic hepatitis is unusual. A serum-sickness-like syndrome can complicate the prodromal period. A fulminant course in the first 4 weeks may be related to an enhanced immune response with more rapid clearing of virus; titres of HBsAg may be low or undetectable. The diagnosis may be made only by finding serum IgM anti-HBc titres. Another viral hepatitis

Progression to chronic hepatitis depends on a combination of continuing viral replication in the liver and the background of the patient, in particular the immunological status. The virus is not directly cytopathic, and lysis of infected hepatocytes with progression to chronicity depends on the immune response of the host 5. Various mechanisms have been postulated to explain why lysis of infected hepatocytes sometimes fails to occur: increased suppressor T-cell function, a defect in cytotoxic (K) lymphocytes, or blocking antibodies on the cell membrane 6. Cytotoxic T cells recognize viral antigen on the infected hepatocyte only in the context of HLA class I antigen 7. Failure of lysis could be due to an inability to display either HLA class I antigen or viral antigen. In the neonatally acquired disease, perpetuation may be related to maternal anti-HBc blocking expression of viral core antigens on the hepatocyte membrane. Some patients with adult-acquired disease show a reduced capacity to produce ct and ~ interferons with resultant defective expression of HLA class I antigens on the hepatocyte membrane.

Aetiology During the phase of active viral replication, the patient's serum is positive for HBeAg and HBV DNA. The patient is highly infectious and there is rapid progress of hepatic inflammation. After a variable period, often of several years, HBeAg and HBV DNA disappear from the blood and are replaced by anti-HBe. The viral genome has then become an integral part of the patient's genome so that viral

Recovery

Fulminonf ? %~'Clinical / 25%

"--.

/

Subclinicol 65%

Acute

19o% ~

HEPATITIS B 10% Chronic

Cirrhosis/

?20*/.

I"~olthy' corrier

.?so*/.

~"-& ConcerA / ? " Fltlu~ 2 The natural history of hepatitis B infection in adults

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Hepatitis B: the disease: S. Sherlock

Table 2 Classification of chronic HBV Type

Parameter Viral replication (HBeAg, HBV DNA, HBcAg in nuclei) Inflammation

I

II

III

+ ve

ve

- ve

+ ve

+ ve

- ve

Antivirals < 10%

? Steroids 2(~ 30%

Prognosis

(transaminases increased) Management 5-year mortality

Nil Very low

Adapted from Ref. 14

HBeAg DNA-positive

HBeAg DNA- negative

Trons!minase increase

Tronsominoss decrsose

Lobulor hepatitis Bridging necrosis

CPH or inactive cirrhosis

Rgure 3 Events occurring when patient seroconverts from HBeAg/HBV DNA-positive to HBeAg/HBV DNA-negative

genes are transcribed along with those of the host (Figure 3). Clones of integrated cells form the basis of malignant transformation, particularly into hepatocellular carcinoma 8. The patient now shows serum anti-HBe, but some viral replication may be continuing as shown by the presence of HBV DNA and/or HBcAg in hepatocyte nuclei 9.

Clinical

course

The clinical spectrum of chronic hepatitis may follow an unresolved acute hepatitis B infection, usually of the mild and 'grumbling' type. Following this, elevated serum transaminases are found to fluctuate with intermittent jaundice. The patient may be virtually symptom-free with only biochemical evidence of continued activity; sometimes, the patient may simply complain of fatigue. The diagnosis is frequently made at the time of blood donation or during routine blood screening. Chronic hepatitis is often a silent disease; symptoms do not correlate with the severity of liver damage. In about one half of cases, the clinical presentation is as an established chronic liver disease with jaundice, ascites, or portal hypertension. The patient usually gives no history of a previous acute attack of hepatitis B.

Clinical relapse This is marked by increasing fatigue, usually accompanied by rises in serum transaminase values. Relapse may be related to seroconversion from an HBeAgpositive to an HBeAg-negative state (Figure 3). Liver biopsy shows an acute lobular-type hepatitis which ultimately subsides; serum transaminase values fall. Seroconversion may be spontaneous in 10 to 15% of patients per annum or it may follow antiviral treatment. HBV DNA can remain positive even when anti-HBe has developed ~o. Spontaneous reactivation from HBeAg-negative to HBeAg-positive has also been described 11'1z. The liver disease becomes more active and may be fatal. Reactivation can follow cancer chemotherapy, organ transplantation, or administration of immunosuppressants

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to HBeAg-positive patients. The patient may also be superinfected with delta virus. This accelerates the progress of the chronic hepatitis. Finally, any deterioration in a hepatitis B carrier should raise the possibility of hepatocellular carcinoma.

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1990

The clinical course varies considerably. Many patients remain in a stable compensated state. This is particularly so when hepatic histology shows only a mild, chronic active hepatitis. Such patients with or without therapy may go into remission, the histological picture being that of chronic persistent hepatitis. The prognosis is proportional to the severity of the underlying liver disease. Women generally exhibit less severe disease than men. The presence of ascites, vascular spiders, or presentation at > 40 years of age are bad signs. A 7-year follow-up of patients with chronic hepatitis B showed that one-third had improved, one-third were unchanged and one-third had worsened. Patients with chronic hepatitis or cirrhosis, especially males, and those >45 years of age, should be screened regularly so that hepatocellular carcinoma may be diagnosed when surgical resection is still possible. Serum ~-fetoprotein should be measured and ultrasound examination performed at 6-month intervals.

Classification of chronic hepatitis Classification has hitherto been made based on hepatic histology as determined by percutaneous liver biopsy. Chronic persistent hepatitis is a milder form of the disease with a good prognosis; chronic active hepatitis has a worse prognosis and severe chronic active hepatitis with bridging necrosis is particularly bad. While this classification system has been helpful, difficulties in interpretation arise due to small biopsy size and sampling error with different histological appearances in various parts of the biopsy. At the 1988 World Congress of Gastroenterology in Rome, a classification system (Table 2) was proposed based on the presence of viral replication (serum HBeAg and HBV DNA-positive with HBcAg detectable in hepatocellular nuclei) and hepatocellular necrosis (altered serum transaminases) ~3 Three types of chronic hepatitis were recognized and related to clinical management and prognosis. It now remains to be seen whether this simple, practical working classification proves to be useful when applied to large numbers of patients.

References 1

Sherlock, S. In: Chronic Hepatitis in Diseases of the Liver and Biliary System 8th Edn, Blackwell Scientific Publications, 1989, pp. 339-371

2

London, W.T. and Blumberg, B.S. Comments on the role of epidemiology in the investigation of hepatitis B virus. Epidemiol.

Rev. 1985, 7, 59 3

4

McMahon, B.J., Rhoades, E.R., Heyward, W.L. et al. A comprehensive programme to reduce the incidence of hepatitis B virus infection and its sequelae in Alaskan natives. Lancet 1987, U, 1134 Centers for Disease Control. Changing patterns of groups at high risk for hepatitis S in the United States. Morbid. Mortal. Week. Rep.

1988, 27, 429 5

Dudley, F.J., Scheuer, P.J. and Sherlock, S. Natural history of

hepatitis associated antigen-positive chronic liver disease. Lancet 6

1972, II, 1388 Thomas, H.C. and Lok, A.S.F. The immunopathology of autoimmune and hepatitis B virus-induced chronic hepatitis. Semin Liver Dis. 1984, 4, 36

Hepatitis B: the disease: S. Sher/ock 7 Chu, C-M., Shyu, WE., Kyo, K-W. et al. HLA class I antigen display on heptocytss in chronic hepatitis B virus infection: its role in the pathogeneeis of chronic type B hepatitis. Hepatology1987, 7,1311 8 Popper, H., Shafritz, D.A. and Hoofnagle, J.H. Relation of the hepatitis B virus carrier state to hepato-cellular caminoma. Hepatology 1987, 7, 764 9 Hoofnagle, J.H., Shafritz, D.A. and Popper, H. Chronic type B hepatitis and the 'healthy' HBsAg carrier state. Hepatology 1987, 7, 758 10 Bonino, F., Rosina, F., Rizzetto, M. et al. Chronic hepatitis in HBsAg

carriers with serum HBV-DNA and anti-HBe. Gastroenterology 1986, gO, 1268 11 Fattovich, G., Rugge, M., Pontisso, P. et al. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986, 6, 167 12 Davis, G.L., Hoofnagle, J.H. and Waggoner, J.G. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 1984,86,230 13 Working Party on Chronic Hepatitis B. Proceedings International Congress of Gastroenterology, Rome, Italy, 1988

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