430
Journal of the Royal Society of Medicine Volume 71 June 1978
Clinical aspects of viral hepatitis' Sheila Sherlock MD FRCP Department of Medicine, Royal Free Hospital, Pond Street, London NW3 2QG
Acute virus hepatitis has been related to a number of different causative agents. Type A hepatitis (formerly called infectious hepatitis) is related to an agent recently identified in the faeces of sufferers. Type B (formerly called serum hepatitis or post-transfusion hepatitis) is related to an antigen identified in blood and formerly called Australia antigen. Other viruses can cause hepatitis particularly in neonates, and these include herpes simplex, rubella and cytomegalovirus. After multiple transfusions, particularly in those having cardiac surgery, the Epstein-Barr virus and cytomegalovirus have been incriminated. There remains an acute virus hepatitis which clinically resembles type A or type B and which is presumably spread by blood. This is diagnosed by excluding type A and type B and has been designated non-A, non-B. Perhaps this type would have been better called type C or D. The clinical picture of acute viral hepatitis whether A, B or non-A, non-B is similar and has been described in text books (Sherlock 1975). Type B has received much attention because of the readily available diagnostic serum antigen (hepatitis B surface antigen, HBsAg). In general, type A and type B hepatitis run the same clinical course. Type B tends to be more severe. It also differs from type A in the acute stages, because of the occasional occurrence of a serumsickness-like syndrome; this was first described by Sir Robert Graves in 1843. It is marked by rashes, urticaria, macular papular or erythematous, arthralgia and angioneurotic oedema. This syndrome seems to be related to circulating immune complexes of HB,Ag, HB antibody and complement (Alpert et al. 1971). The joint and skin symptoms are indeed associated with depressed serum levels of the C3 component of complement. Arthritis may be particularly prominent even in the anicteric case. In type B hepatitis, the markers of infection appear at varying intervals in the plasma. The virion of type B hepatitis probably exists in the plasma as a large, complex particle known as the Dane particle. The surface of the particle represents excess viral protein. It is produced in the cytoplasm of the liver cell in excess and is responsible for the HB,Ag reaction used to identify sufferers from type B hepatitis and carriers both 'healthy' and with liver disease. The core of the Dane particle contains a double stranded DNA, a DNA polymerase and a core antigen. A core antibody appears in the serum. It also contains another antigen 'e', which is intimately associated with continued infectivity and on-going liver disease (Eleftheriou et al. 1975). The sequence of events in acute type B hepatitis has been well described by Melnick et al. (1976). About one month after exposure to hepatitis B infection, DNA polymerase appears in the serum. HBsAg appears at the same time; 'e' antigen may also be detected transiently. About six weeks after exposure, the serum transaminase levels rise. Clinical hepatitis develops about two months after exposure. Anticore antigen appears shortly after the transaminase rises. Antibody to HB,Ag only develops six months or more after exposure. Because of its late development and persistence, anti-HB.Ag has been used as a marker of recent hepatitis B 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 25 October 1977 0 1 41-0768/78/0071-0430/$O 1.00/0
,'.
The Royal Society of Medicine 1978
Journal of the Royal Society of Medicine Volume 71 June 1978
431
infection; 'e' antigen has usually disappeared by two months and antibody to it may or may not develop. There are limited observations on the development of anti-HBe and in particular the numbers of patients in whom it appears. Methods of determining 'e' antigen and 'e' antibody are at present insensitive and not generally available. There is a need for a commercially produced sensitive kit for their detection. Viral particles of hepatitis A appear in the faeces in the late incubation stage and disappear within a day or two of the development ofjaundice. This makes plain the lack of infectivity of patients with type A hepatitis once they become jaundiced. It is common clinical experience that such patients may be nursed in a general medical ward and cross-infection to other patients and staff is most unusual. Procedures are now available, alas not generally, for detection of antibody to hepatitis A virus and this allows specific diagnosis of this type (Moritsugu et al. 1976). Non-A, non-B hepatitis can only be diagnosed by exclusion of type A, type B and other viruses. It can be transmitted by blood (Meyers et al. 1977, Hoofnagle et al. 1977). Clinically, it resembles type A infection and tends to affect women of 35 years or older (Dienstag et al. 1977). The Fulminant Case This is a rare complication of viral hepatitis, type A, type B and non-A, non-B. The prognosis is very bad, survival being in the order of 20% of those reaching deep coma. It must therefore be recognized in the early stages (Figure 1). Clinical indications include a change in personality and young people may show aggressive behaviour and episodes of mania. If such changes develop, the grade of coma should be noted daily or even twice daily and recorded. Fetor hepatis may develop on the breath, vomiting is persistent and pyrexia sustained. Flapping lesion of the outstretched hands may be seen but can be transient. Jaundice deepens rapidly, although in the particularly fulminant case, death may ensue before icterus has had time to develop. The liver shrinks; the lower margin of the liver should be estimated daily by percussion and marked on the skin of the abdomen (Figure 1). Tendon reflexes become hyperactive.
[ THURSDAY
CONSCIOUSNESS
I ~~~~BP LEEG
v
WEDNESDAY ---v(,, TUESDAY MONDAY URINE /(
-
FLUID
l
OUTPUT 1. Clinical Figure daily check in patients with fulminant hepatitis
The best laboratory test of severity is the prothrombin time which remains greatly prolonged in spite of intramuscular vitamin K therapy. The serum aspartate transaminase level is not a good indication of severity for it may fall, even though the clinical condition is worsening. Hypoglycaemia and a low blood urea level should be noted. The mean frequency of the electroencephalogram slows. Death ensues a variable period after the onset, from cardiac or respiratory failure, cerebral oedema, septicaemia, renal failure, hypoglycaemia or pancreatitis or a combination of these
complications.
432
Journal of the Royal Society of Medicine Volume 71 June 1978
Chronic Hepatitis This has been well described following acute type B hepatitis. In any epidemic about 10% of sufferers do not clear HBSAg from the blood within six months. Disappearance of the hepatitis B antigen after this time is extremely rare. Such carrier patients may have normal liver function and liver biopsy can also be normal. Alternatively, they develop a chronic hepatitis of varying severity, progressing in some instances to cirrhosis and to primary liver cancer (Dudley et al. 1972). Acute type A hepatitis probably does not proceed to chronic hepatitis. The antigen is only transiently present in the stool. In the United States 60-70% of adults have antibody to it. Follow ups of epidemics of acute type A hepatitis, both large and small, have failed to reveal the development of a chronic or carrier state. Non-A, non-B hepatitis can be associated with a carrier hepatitis and chronic hepatitis has been described (Hoofnagle et al. 1977). References Alpert E, Isselbacher K J & Schur P H (1971) New England Journal of Medicine 285, 185 Dienstag J L, Alaama A, Mosley J W, Redeker A G & Purcell R H (1977) Annals ofInternal Medicine 87, 1 Dudley F J, Scheuer P J & Sherlock S (1972) Lancet ii, 1388 Eleftheriou N, Thomas H C, Heathcote J & Sherlock S (1975) Lancet ii, 1171 Hoofnagle J H, Gerety R J, Tabor E, Feinstone S M, Barker L F & Purcell R H (1977) Annals ofInternal Medicine 87, 14 Melnick J L, Dreesman G R & Hollinger F B (1976) Journal ofInfectious Diseases 133, 210 Meyers J D, Dienstag J L, Purcell R H, Thomas E D & Holmes K K (1977) Annals of Internal Medicine 87, 57 Moritsugu Y, Dienstag J L, Valdesuso J, Wong D C, Wagner J, Routenburg J A & Purcell R H (1976) Infections and Immunology 13, 898 Sherlock S (1975) In: Diseases of the Liver and Biliary System. 5th edn. Blackwells, Oxford; p 107
Journal of the Royal Society of Medicine Volume 71 June 1978
Clinical aspects of viral hepatitis' Sheila Sherlock MD FRCP Department of Medicine, Royal Free Hospital, Pond Street, London NW3 2QG
Acute virus hepatitis has been related to a number of different causative agents. Type A hepatitis (formerly called infectious hepatitis) is related to an agent recently identified in the faeces of sufferers. Type B (formerly called serum hepatitis or post-transfusion hepatitis) is related to an antigen identified in blood and formerly called Australia antigen. Other viruses can cause hepatitis particularly in neonates, and these include herpes simplex, rubella and cytomegalovirus. After multiple transfusions, particularly in those having cardiac surgery, the Epstein-Barr virus and cytomegalovirus have been incriminated. There remains an acute virus hepatitis which clinically resembles type A or type B and which is presumably spread by blood. This is diagnosed by excluding type A and type B and has been designated non-A, non-B. Perhaps this type would have been better called type C or D. The clinical picture of acute viral hepatitis whether A, B or non-A, non-B is similar and has been described in text books (Sherlock 1975). Type B has received much attention because of the readily available diagnostic serum antigen (hepatitis B surface antigen, HBsAg). In general, type A and type B hepatitis run the same clinical course. Type B tends to be more severe. It also differs from type A in the acute stages, because of the occasional occurrence of a serumsickness-like syndrome; this was first described by Sir Robert Graves in 1843. It is marked by rashes, urticaria, macular papular or erythematous, arthralgia and angioneurotic oedema. This syndrome seems to be related to circulating immune complexes of HB,Ag, HB antibody and complement (Alpert et al. 1971). The joint and skin symptoms are indeed associated with depressed serum levels of the C3 component of complement. Arthritis may be particularly prominent even in the anicteric case. In type B hepatitis, the markers of infection appear at varying intervals in the plasma. The virion of type B hepatitis probably exists in the plasma as a large, complex particle known as the Dane particle. The surface of the particle represents excess viral protein. It is produced in the cytoplasm of the liver cell in excess and is responsible for the HB,Ag reaction used to identify sufferers from type B hepatitis and carriers both 'healthy' and with liver disease. The core of the Dane particle contains a double stranded DNA, a DNA polymerase and a core antigen. A core antibody appears in the serum. It also contains another antigen 'e', which is intimately associated with continued infectivity and on-going liver disease (Eleftheriou et al. 1975). The sequence of events in acute type B hepatitis has been well described by Melnick et al. (1976). About one month after exposure to hepatitis B infection, DNA polymerase appears in the serum. HBsAg appears at the same time; 'e' antigen may also be detected transiently. About six weeks after exposure, the serum transaminase levels rise. Clinical hepatitis develops about two months after exposure. Anticore antigen appears shortly after the transaminase rises. Antibody to HB,Ag only develops six months or more after exposure. Because of its late development and persistence, anti-HB.Ag has been used as a marker of recent hepatitis B 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 25 October 1977 0 1 41-0768/78/0071-0430/$O 1.00/0
,'.
The Royal Society of Medicine 1978
Journal of the Royal Society of Medicine Volume 71 June 1978
431
infection; 'e' antigen has usually disappeared by two months and antibody to it may or may not develop. There are limited observations on the development of anti-HBe and in particular the numbers of patients in whom it appears. Methods of determining 'e' antigen and 'e' antibody are at present insensitive and not generally available. There is a need for a commercially produced sensitive kit for their detection. Viral particles of hepatitis A appear in the faeces in the late incubation stage and disappear within a day or two of the development ofjaundice. This makes plain the lack of infectivity of patients with type A hepatitis once they become jaundiced. It is common clinical experience that such patients may be nursed in a general medical ward and cross-infection to other patients and staff is most unusual. Procedures are now available, alas not generally, for detection of antibody to hepatitis A virus and this allows specific diagnosis of this type (Moritsugu et al. 1976). Non-A, non-B hepatitis can only be diagnosed by exclusion of type A, type B and other viruses. It can be transmitted by blood (Meyers et al. 1977, Hoofnagle et al. 1977). Clinically, it resembles type A infection and tends to affect women of 35 years or older (Dienstag et al. 1977). The Fulminant Case This is a rare complication of viral hepatitis, type A, type B and non-A, non-B. The prognosis is very bad, survival being in the order of 20% of those reaching deep coma. It must therefore be recognized in the early stages (Figure 1). Clinical indications include a change in personality and young people may show aggressive behaviour and episodes of mania. If such changes develop, the grade of coma should be noted daily or even twice daily and recorded. Fetor hepatis may develop on the breath, vomiting is persistent and pyrexia sustained. Flapping lesion of the outstretched hands may be seen but can be transient. Jaundice deepens rapidly, although in the particularly fulminant case, death may ensue before icterus has had time to develop. The liver shrinks; the lower margin of the liver should be estimated daily by percussion and marked on the skin of the abdomen (Figure 1). Tendon reflexes become hyperactive.
[ THURSDAY
CONSCIOUSNESS
I ~~~~BP LEEG
v
WEDNESDAY ---v(,, TUESDAY MONDAY URINE /(
-
FLUID
l
OUTPUT 1. Clinical Figure daily check in patients with fulminant hepatitis
The best laboratory test of severity is the prothrombin time which remains greatly prolonged in spite of intramuscular vitamin K therapy. The serum aspartate transaminase level is not a good indication of severity for it may fall, even though the clinical condition is worsening. Hypoglycaemia and a low blood urea level should be noted. The mean frequency of the electroencephalogram slows. Death ensues a variable period after the onset, from cardiac or respiratory failure, cerebral oedema, septicaemia, renal failure, hypoglycaemia or pancreatitis or a combination of these
complications.
432
Journal of the Royal Society of Medicine Volume 71 June 1978
Chronic Hepatitis This has been well described following acute type B hepatitis. In any epidemic about 10% of sufferers do not clear HBSAg from the blood within six months. Disappearance of the hepatitis B antigen after this time is extremely rare. Such carrier patients may have normal liver function and liver biopsy can also be normal. Alternatively, they develop a chronic hepatitis of varying severity, progressing in some instances to cirrhosis and to primary liver cancer (Dudley et al. 1972). Acute type A hepatitis probably does not proceed to chronic hepatitis. The antigen is only transiently present in the stool. In the United States 60-70% of adults have antibody to it. Follow ups of epidemics of acute type A hepatitis, both large and small, have failed to reveal the development of a chronic or carrier state. Non-A, non-B hepatitis can be associated with a carrier hepatitis and chronic hepatitis has been described (Hoofnagle et al. 1977). References Alpert E, Isselbacher K J & Schur P H (1971) New England Journal of Medicine 285, 185 Dienstag J L, Alaama A, Mosley J W, Redeker A G & Purcell R H (1977) Annals ofInternal Medicine 87, 1 Dudley F J, Scheuer P J & Sherlock S (1972) Lancet ii, 1388 Eleftheriou N, Thomas H C, Heathcote J & Sherlock S (1975) Lancet ii, 1171 Hoofnagle J H, Gerety R J, Tabor E, Feinstone S M, Barker L F & Purcell R H (1977) Annals ofInternal Medicine 87, 14 Melnick J L, Dreesman G R & Hollinger F B (1976) Journal ofInfectious Diseases 133, 210 Meyers J D, Dienstag J L, Purcell R H, Thomas E D & Holmes K K (1977) Annals of Internal Medicine 87, 57 Moritsugu Y, Dienstag J L, Valdesuso J, Wong D C, Wagner J, Routenburg J A & Purcell R H (1976) Infections and Immunology 13, 898 Sherlock S (1975) In: Diseases of the Liver and Biliary System. 5th edn. Blackwells, Oxford; p 107
