ACUTE VİRAL HEPATİTİS

Acute viral hepatitis is a common and serious disease caused by several viral agents ad marked by necrosis and inflammation of the liver. The first reference to epidemic jaundice has been ascribed to Hippocrates. The earliest record in Western Europe is in a letter written in 751 AD by Pope Zacharias to St. Boniface, Archbishop of Mainz. Since then there have been numerous accounts of epidemics, particularly during wars. Hepatitis was a problem in the Franco-Prussian War, the American Civil War and World War I. In the World War II huge epidemics occurred, particularly in the Middle East and Italy.
There are many varieties (table1.1). Hepatitis A is a self-limited, faecal-spread disease. Hepatitis B is a parenterally transmitted disease that often becomes chronic. Hepatitis D is parenterally spread and affects only those with hepatitis B infection. Hepatitis C is a parenterally spread disease with a high chronicity rate. Hepatitis E is enterically spread, usually via water, and causes a self-limited hepatitis in under developed countries. There will undoubtedly be other members of the hepatitis alphabet.

VIRUS A (HAV) HEPATITIS

Hepatitis A accounts for 20-25% of clinical hepatitis in the developed world. It is due to a small, 27 nm cubically symmetrical RNA picorna virus. It has four capsid proteins referred to as VP1 and VP4. Only a single serotype has been identified. However, the genome has been cloned and characterised and a number of minor differences have been identified among isolates from different parts of the world.

Epidemiology

The disese occurs sporadically or in epidemic form and has an incubation time of 15-50 days. It is usually spread by the faecal- oral route. Parenteral transmission is extremely rare, but can follow transfusion of blood from a donor who is in the incubation stage of the disease.
Age 5-14 group most affected and adults are often infected by spread from the children.
Spread is related to overcrowding, poor hygiene and poor sanitation. With an improved standard of living the prevalence is decreasing worldwide.
Explosive water-borne and food-borne epidemics are described. Use of human sewage for soil fertilisation can result in frozen-fruit-related epidemics.
Ingestion of raw clams and oysters from polluted waters is known to have caused four epidemics. Steaming 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 subclinical or passed off as gastroenteritis. The disease is more serious and prolonged in adults.
The rare fulminant course may be related to the dose of virus or impaired antibody responsiveness.
Cholestatic hepatitis A affects adults. The jaundice lasts 42-110 days and itching is severe. Serum IgM anti-HAV is positive. The prognosis is excellent. A case can made for cutting short the jaundice and relieving the itching by a short course of prednidolone 30 mg reducing to zero over about 3 weeks.
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. The relapse may last several months but recovery eventually ensues.
Rarely, the relapse can be associated with arthritis, vasculitis and cryoglobulinaemia.


Prognosis

This is excellent, and recovery is usually full. Mortality in large epidemics is less than 1 per 1000 and virus A accounts for less than 1% of cases fulminant viral hepatitis. The average adult with icretic hepatitis can anticipate 6 weeks of illness and this will rarely exceed 3 months.
Chronicity does not develop. Follow-ups of large epidemics in World War 1 showed no long-term sequelae. Viral carriage is transient in faeces. Antibodies develop and the patient becomes immune.

Prevention

The virus is excreted in the faces for as long as two weeks before the appearance of jaundice. The anicretic patient may excrete the virus for a similar period. The virus is therefore disseminated before the diagnosis is made. For this reason, isolation of the patients and contacts cannot be expected to influence significantly the spread of hepatitis.
Virus A is relatively resistant to inactivation by heat, ether or acid, but it is inactivated by formalin 1 in 4000 at 37°C for 72 hours, chlorine 1 p.p.m. for 30 minutes and by microwawing.

Immune Serum Globulin Prophylaxis

The use of immune serum globulin (ISG) for travellers can be reduced if preliminary testing for anti-HAV is done. The applies particularly to those who are likely to have antibody, those over 40 years old, frequent travellers, those born in HAV-endemic areas and those with a history of jaundice.
ISG should be given to close personal contacts of sufferers.
When a common source of infection is identified, for instance food or water, ISG should be given to all those exposed. This particularly applies to epidemics in schools, hospitals, prisons and other institutions.

Hepatitis A Vaccines (fig. 1.1)

A live, attenuated vaccine has been prepared from hepatitis A growing in fetal monkey kidney cell cultures. It is cheap, effective and can be given orally.
Inactivated vaccines have been prepared from cultures of virus A adapted on human fibroblasts and inactivated by formol.
A recombinant vaccine has been prepared, using the viral protein (VP1) of the virus.
Finally, a synthetic vaccine is being considered.
Now available, hepatitis A vaccines will replace immune globulin for travellers and for the military proceeding abroad. Children in nursey schools, homosexuals and workers handling faeces will also be candidates.

VIRUS B (HBV) HEPATITIS

In 1965, Blumberg and colleagues in Philadelphia found an antibody in two multiply-transfused haemophiliac patients which reacted with an antigen in a single serum in their panel which came from an Australian Aborigine. Later the antigen was found in patients with viral hepatitis. Because of its discovery in an aboriginal serum the antigen was called Australia antigen. In 1977, Blumberg was awarded the Nobel Prize for his discovery. Australia antigen is now known to be the surface of the hepatitis B virion and is termed hepatitis B surface antigen. (HBsAg)
The virion of hepatitis B (Dane particle) consists of surface and core. The core is formed in hepatocyte nucleus and the surface particles are made in the cytoplasm.

Serological Diagnosis (table 1.2)

HbsAh appears in the blood about six weeks after infection and has disappeared by three months. Persistence for more then six months implies a carrier state.
MARKER
SIGNIFICANCE
Hepatitis A
IgM anti-HAV
IgG anti-HAV

Acute hepatitis A
Immune to hepatitis A
Hepatitis B
HBsAg
IgM anti-HBc
IgG anti-HBc
Anti-HBs
HbeAg

Anti-Hbe
HBV DNA

Acute or chronic hepatitis B carriage
Acute hepatitis B (high titre)
Chronic hepatitis B (low titre)
Immune to hepatitis B
Acute hepatitis B. Persistence means continued infectious state
Convalescene or continued infectious state
Continued infectious state
Delta
IgM anti-delta
IgG anti-delta


Acute or chronic infection with delta agent
Chronic delta infection (high titre with+ve IgM anti-delta)
Past delta infection (low titre with –ve IgM anti-delta)



Live attenuated
Synthetic
peptides
Recombinant
capsid
VP1 protein in
yeast
Inactivated Anti-HBs appears late, some three months after the onset, and persists. Anti-HBs levels are rarely high and 10-15% of patients with acute type B hepatitis never develop the antibody. Anti-HBs accounts for recovery and immunity. In the past, HBsAg and HbsAb were believed to be mutually exclusive. However, as many as one-third of carriers of HBsAg also have HbsAb. The mechanism is uncertain, but it has been attributed to simultaneous infection with different sub-types.
HBeAg correlates with ongoing viral synthesis and infectivity. It is transiently present during the acute attack. It is present for a shorter time than HBsAg. Persistence for more than ten weeks strongly suggests the development of chronicity.
Anti-HBe is a marker of relatively low infectivity. The appearance of anti-HBe is strong evidence that the patient will recover completely.
HBcAg cannot be detected in circulating blood, but its antibody (anti-HBc) can. High titres of IgM anti-HBc mark present acute virus hepatitis. This antibody is detected after HBsAg has been cleared from the serum. This is true of 5-6% of cases with acute hepatitis B and is encountered particularly in fulminant hepatitis. It is also useful in determining whether an acute attack of hepatitis is due to virus B or to superinfection with another virus. Persistence of IgM anti-HBc implies ongoing virus B-related chronic disease, usually chronic active hepatitis. Lower titres of IgG anti-HBc with anti-HBs mark hepatitis B infection in the remote past. Higher titres of IgG anti-HBc without anti-HBs indicate persistence of viral infection.
HBV DNA is the most sensitive index of viral replication. This can now be assessed by the southern blot technique. It can be present in anti-HBe positive sera when it indicates severe ongoing disease.
A sensitive and rapid method exists for detecting HBV DNA by polymerase chain reaction (PCR). Even one viral genome can be detected. Using PCR, HBV DNA can be found in serum and liver after the loss of HBsAg, particularly in those receiving antiviral treatment. HBV DNA in serum detected by PCR is a good marker of the level of viraemia, can be correlated with serum transaminase levels and parallels the presence of HBsAg in serum.

Epidemiology

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, United States 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, and 85% in Australian Aborigines.
In high-carriage-rate areas infection is acquired by passage from the mother to the neonate. The infection is usually not via the umbilical vein, but from the mother at the time of birth during close contact afterwards.
In high epidemic areas such as Africa, Greece and Hong Kong, the transmission is in childhood and is probably horizontal through kissing and shared utensils, such as tooth brushes and razors. Contact in pre-school day care centres is possible. Sexual contacts in the family are at risk.
Blood transfusion continues to cause hepatitis B in countries where donor blood is not screened for HBsAg.

Clinical Course

The course may be anicretic. The high carriage rate of serum markers in those who give no history of acute hepatitis B suggests that subclinical episodes must be extremely frequent. The non-icretic case is more liable to become chronic than the icretic one.
The usual clinical attack diagnosed in the adult tends to be more severe than for virus A or non-A, non-B (C) infections. The overall picture is, however, similar. The self-limited, benign icretic disease usually lasts less than 4 months. Jaundice rarely exceeds 4 weeks. Occasionally, a prolonged benign course is marked by increased serum transaminase values for more than 100 days. Relapses are rare. Cholestatic hepatitis with prolonged deep jaundice is unusual.
There may be features suggesting immune complex disease. This is shown in the prodromal period by a serum sickness-like syndrome. This develops about a week before jaundice. It can be associated with an icretic or an anicretic attack. The syndrome has also been described with chronic hepatitis B. Fever is usual. The skin lesion is urticarial, and rarely, in children, a papular acrodermatits. The arthropathy is symmetrical, non-migratory and affects small joints. Serum rheumatoid factor is negative. It is usually transitory but can persist. These events can be related to circulating immune complexes.
A fulminant course of hepatitis B in the first four weeks is related to an enhanced immune response with more rapid clesring of virus. Antibodies to surface and ‘e’ antigen increase, and multiplication of virus ceases. In fulminant hepatitis B, the surface antigen may be low titre or undetectable. The diagnosis may be made only by finding serum IgM anti-HBc.
Subacute hepatic necrosis is marked by increasing severe diseases evolving over one to three months.
Chronic hepatitis can develop insidiously.

Extra-hepatic associations

These conditions are often associated with circulating immune complexes containing HBsAg. The accompanying liver disease is usually mild and at the most a chronic persistent hepatitis.
Acute and chronic type B hepatitis can develop in patients with agammaglobulinaemia.
Polyarteritis. This involves largely medium and small arteries and appears early in the course of the disease.
Glomerulonephritis. This has been associated with hepatitis B infection, largely in children. Liver disease is minimal. The patients are usually HBeAg positive. Immune complexes of HBsAg and HbsAb, HBcAg and anti-HBc or HBeAg and anti-HBe are found in glomerular and papillary basement membranes.
Polymyalgia rheumatica has been connected with hepatitis B infection.
Essential mixed cryoglobulinaemia. A patient with peripheral neuropathy and cryoglobulinaemia showed a cryoprecipitate with a high concentration of HBsAg.
The Guillain-Barré syndrome has been reported with HBsAg-containing immune complexes in serum and cerebrospinal fluid.
Myocarditis may have an immune complex basis.

Hepatitis B carriers

There are an estimated 300 million hepatitis B carriers in the world.
The dilemma of a person, such as a hospital worker, carrying the antigen and coming from an area where it is prevalent is a very difficult one. Hospital staff who develop HBsAg-positive hepatitis and clear the antigen from the blood are immune to type B hepatitis. If they become carriers, the position is difficult. The extent of the infectivity of surgeons, dentists or indeed any hospital worker to patients and casual contacts has not been established but cannot be very great.
‘Healthy’ carriers may show changes may show changes on liver biopsy ranging from non-specific minimal abnormalities through to chronic active hepatitis and cirrhosis.

Chronic organic sequelae

Exposure to HBV can have different results. Some are immune and have no clinical attack; they presumably have anti-HBs. In others, an acute attack develops varying from anicretic to fulminant. Previously normal persons usually clear the antigen from the serum within about 4-6 weeks from the onset of symptoms. Chronic liver disease is associated with persistent antigenaemia. In general, the more florid and acute the original attack the less likely are chronic sequelae.
If the patient survives a fulmanant attack of viral hepatitis, ultimate recovery is complete without the development of chronic disease.
Chronicity is more likely in those with immunological incompetence such as neonates, homosexuals, sufferers from AIDS, leukaemia and cancer, renal failure or those receiving immunosuppressive treatment.

Prevention

HEPATITIS B IMMUNOGLOBULİN (HBIG)

HBIG is a special hyperimmune serum globulin with a high antibody titre. It is effective for passive immunization against hepatitis B if given prophylactically or within hours of infection. Hepatitis vaccine should always be given with HBIG, particularly if the subject is at risk of re-infection. It is indicated for sexual contacts of acute sufferers, babies born HBsAg-positive mothers, and victims of parenteral exposure (needle stick) to HBsAg-positive blood.

HEPATITIS B VACCINES

Vaccines are prepared from the uninfectious outer surface of the virus (HBsAg).
The plasma-derived vaccine comes from plasma of hepatitis carriers. It is highly effective in preventing hepatitis B in high risk groups. It is completely safe. The only side-effects are an occasional sore arm and pyrexia, probably due to the alum preservative.
Hepatitis B vaccines are effective in preventing hepatitis B in promiscuous homosexuals, haemodialysis patients, Down’s syndrome and other mentally retarded patients., health care workers, babies born to HBsAg-positive mothers, in children in Africa and susceptibles in Alaska.
In healthy individuals the recombinant vaccine is given in a dose of 10 mg (1ml) intramuscularly at 0,1 month and a booster at 6 months. This induces sufficient antibody response in 94% of individuals.
The vaccine is usually given intramuscularly into the arm. Intradermal administration is effective although antibody titres are not so high as with the intramuscular route.
Pre-testing. Vaccination is unnecessary if the person has a positive HBs or HBcAb.
Duration of protection. This is uncertain. Protection outlasts detectable antibody. Further vaccine should be considered at 5-7 years after the initial course, particularly if the subject is still exposed to hepatitis B.

Antibody response

The long-term protection depends on the antibody response which is 85-95% in healthy young subjects. Anti-HBs should be measured 1-3 months after completion of the basic course of vaccine.
Failure to develop adequate antibodies may be related to freezing the vaccine or giving it into the buttock rather than the deltoid region.
A poor antibody response is seen in the aged and in the immunocompromised including HIV-positive persons. They should be given doses of 20 mg.
Approximately 5-10% of normal persons have absent or poor antibody responses. Some may respond to a booster.


Indications (table 1.3)

The need for vaccination depends on the chance of that person being exposed to hepatitis B. Vaccination is mandatory for health care staff in close contact with hepatitis B patients, particularly those working on renal dialysis units, liver units, haemophilia and oncology units, genitourinary departments treating homosexuals or those working in homes for the mentally retarded. Surgeons and dentists and their assistants, medical students and laboratory workers regularly exposed to blood and also candidates. The vaccine should be given to medical personnel proceeding overseas to areas where the prevalence of hepatitis B is high.

Table 1.3. Indications for hepatitis vaccination
Surgical and dental staff including medical students
Hospital and laboratory staff in contact with blood
Patients and staff in departments of oncology and haematology, kidney, mental subnormality and liver disease
Mental subnormality
Accidental exposure to HBsAg +ve blood
Close family and sexual contacts of HBsAg +ve carriers
Babies born to HBsAg +ve mothers.
Children as part of EPI programme
Drug abusers
Homosexually active men
Travellers to high-risk areas

Acute sufferers from hepatitis B are highly infectious and their sexual contacts should be vaccinated and given hyperimmune-globulin. Sexual and family contacts of hepatitis B carriers should also, if at all possible, be vaccinated after their antibody status has been determined.