Acute Infectious Hepatitis with Fulminant Hepatic Failure – A Study of 289 Cases
Deshpande, R.S., M.B., B.S., D.P.H. Medical Superintendent In-charge, Kasturba Hospital for Infectious Diseases, Sane Guruji Marg, Bombay, India
Serum enzyme levels are markedly elevated and prothrombin time is markedly prolonged. SGOT and SGPT–transaminase levels are more frequently elevated. Serum activity of these enzymes is helpful in detecting the presence or absence of hepatocellular disease in a jaundiced patient. SGOT greatly increases in the serum of patients in the acute phase of viral hepatitis. SGPT also increases in similar circumstances. However, depth of jaundice and height of SGOT and/or SGPT levels are unreliable. They may even fall as the patient’s condition worsens.
Cerebrospinal fluid shows normal number of cells and increased protein. Glutamic acid is often increased and also glutamine. Ammonia content is often raised but is poorly correlated with blood. Electroencephalogram may be helpful.
Present Day Status of the Therapy of Fulminant Hepatic Failure
The therapy of acute fulminant hepatocellular failure demands prompt care and attention. Mortality in fulminant hepatic failure is very high, 81% in the first 318 patients who reported to the Fulminant Hepatic Failure Surveillance Study (FHF Surveillance Study, 1969)17.
Zacharias et al (1967)50 successfully treated 3 cases of hepatic coma due to infective hepatitis out of 11 cases. Sundaravalli and Raju (1973)42 studied 35 children with hepatic coma due to infectious hepatitis. 10 had exchange transfusions out of which 3 survived and out of the remaining 25 cases 3 survived. Thus in all 6 children survived out of 35 children.
Jones et al (1967)23 had no survivals in 7 cases. Trey and Davidson (1970)46 had a poor survival rate of only 17.6% in those with stage IV coma, but 66% in those with the stage II encephalopathy.
Saunders et al (1970)37 Brit. med. Bull. (Vol. 28, No. 2, 1972)6 in Cape Town have published results of one of the largest series of cases among their own patients. Their study showed that out of 47 patients 7 recovered consciousness of which only 4 survived. Of 20 patients treated conservatively 4 (20%) survived. This is to be compared to 10 (21%) survivors of the 47 patients treated by exchange transfusion. Some of the initial enthusiasm for this procedure has waned, for, the published long-term results are depressing.
The collected results of the Fulminant Hepatic Failure Surveillance Study (Trey and Davidson, 1970)46 also need careful scrutiny. Of 101 patients in whom no special procedure was undertaken, 10% survived whilst the survival in 166 patients treated with exchange transfusion was 24%. However, the preliminary results of the first randomly allocated and controlled trial of exchange transfusion in fulminant hepatitis carried out in Los Angeles showed a higher mortality in the treated group (A.G. Redekar and colleagues)36. Among 60 patients with fulminant hepatitis there was no significant difference between the survival rate of the patients treated conservatively and the patients treated by corticosteroids and/or exchange transfusion and/or cross circulation and/or hyperbaric oxygen (Benhamou, Rueff and Sicot, 1972)3.
Exchange transfusion may be used to remove toxic substances from the blood and in particular those that are protein bound and so not dialysable (Trey et al., 1966)45. Patients who have been treated with exchange transfusion have a survival rate of approximately 20%.
A recent controlled trial by Redekar and Yamahiro (1973)35 showed that exchange blood transfusion has failed to maintain its popularity as it showed no benefit. The prognosis is very poor if deep coma is reached, the mortality rate being 90%.
Corticosteroids should not be given routinely. Although they probably have some effect on the healing of the liver, they should be reserved for the patient with prolonged cholestasis or one who seems to be passing into the subacute stage with persistent jaundice and high serum globulin and transaminase values. In chronic cases, which received corticosteroids, it is possible that this treatment may have helped to perpetuate the disease although this has not been proved. It certainly did not prevent the development of chronic sequelae. (Sherlock, 1973,38 Ducci and Katz, 1952,13 Bernard et al, 1964,4 Blum et al, 1969,7 Cachin et al, 1963 A & B9,10).
The outlook of therapy in comatose patients is so poor that a case could be made for corticosteroid therapy. Favourable results have been reported but more usually reported are the failures. Periotoneal dialysis and haemodialysis are certainly useful in the treatment of the uraemic stage. Liver perfusion and hepatic transplantation have also been used experimentally. Hyperbaric oxygen therapy, coenzyme administration, haemodialysis, peritoneal dialysis, exchange transfusion and cross circulation treatment, extracorporeal liver perfusion have been tried.
The aim is to support the failing liver cells till spontaneous regeneration takes place. Major emphasis has to be placed on restitution of hepatic function. Attempts have been made to rectify the metabolic derangements, combat infection and hypoglycaemia, while anticipating restoration of normal liver function by spontaneous regeneration of liver cells. The very rapid onset of coma suggests a metabolic origin rather than structural change and in keeping with this there is equally rapid reversal. Treatment must be adapted to the problem of the individual patient. Results at the same time are depressing and encouraging. Precipitating factors like gastrointestinal haemorrhage or fall in blood pressure, or acute infection in operation should be taken care of.
Bed rest reduces functional demands on the liver. In acute cases it is advisable while the disease is active. In subacute and chronic hepatocellular failure bed rest is continued while improvement is maintained. In static cases after 4 to 5 weeks, the patients may be allowed moderate activity.
Such supportive therapy, which requires intensive medical and nursing care as well as the full range of biochemical and haematological services, is based on the detailed monitoring of almost every organ and system in the body. In the management of these patients, temperature, blood pressure and pulse must be observed 4-hourly. There should be a fluid intake and output chart and if possible daily weighing, daily estimation of haemoglobin and haematocrit level and occult blood in stools. Daily assessment of hepatic size, daily handwriting chart, daily tests of simple arithmetic and ability to copy a five-pointed star with matches. 4-hourly grading, if necessary, of neuropsychiatric status, daily examination of lungs for evidence of infection or oedema and if facilities permit daily serum bilirubin, sodium, potassium, chloride, bicarbonate and urea levels to assess electrolyte equilibrium. All sedatives are contraindicated if the patient is manic or violent. Treatment of precipitant factors like haemorrhage, infection, alcoholism, electrolyte imbalance, minor operations and management of possible harmful effects or over-dosage of morphine or hypnotics is necessary. Bowels should be emptied of nitrogen containing material, by enema or magnesium sulphate purge. Stop nitrogen containing drugs ammonium chloride, urea, stop diuretics and maintain correct caloric, fluid and electrolyte levels. Ensure at least one free bowel movement daily.
The principles in the management are withdrawal of protein, emptying the bowel by enema and neomycin therapy, as these are the standard measures used in the treatment of presumed cerebral intoxication and to reduce bacterial growth in the colon.
At the early stage of anorexia and nausea no benefit accrues from rigid insistence upon a low fat diet. When appetite returns a high protein diet may hasten recovery. In the early stages all dietary protein should be stopped. 1600 calories should be supplied daily as glucose drinks, 20% solution through gastric drip. Alternatively 10% Levulose may be used. Protein has to be completely eliminated from the diet until the protein is alert. In a patient with an episode of coma normal protein intake may soon be restored. In chronic cases protein restriction is needed to control mental symptoms. During recovery, protein is added as 20 g increments on alternate days. The limits of tolerance are usually 40-60 g per day. Exacerbation of symptoms is treated by rest and abstention from proteins. In acute cases, a few days to a few weeks deprivation of protein does not prove harmful and in the chronic group when dietary protein is to be restricted for many months, clinical malnutrition is not seen. In patients with liver disease, nitrogen equilibrium seems to be maintained on severely reduced intake of protein. The risk of temporary restriction is preferable to the hazards of nitrogen toxicity. Vitamins, high carbohydrate diet and dietary supplements are useful.
Scrupulous attention has to be paid to establishing and maintaining the electrolyte and acid base balance. Hypoglycaemia is especially dangerous. The patients have reduced liver glycogen stores and have decreased capacity for hepatic glucogenesis. Hypokalaemia is frequently encountered in patients with fulminant hepatic necrosis (Felig et al, 1970)14.
In case renal failure develops more concentrated solution can be infused with a large vein pump. If symptoms worsen, the regime for the treatment of acute neurological complications should be adopted. Cardio-vascular and respiratory symptoms must receive attention. Surgical exclusion of the colon for the by-passing of colonic toxins, in chronic neuropsychiatric states, needs to be considered.
Neomycin 1 g 4-hourly by mouth may be given for a week. Oral dose of 3-8 g per day or enemata of 1-2 g of Neomycin in 100-200 cc of normal saline may be given.
Cerebrospinal fluid shows normal number of cells and increased protein. Glutamic acid is often increased and also glutamine. Ammonia content is often raised but is poorly correlated with blood. Electroencephalogram may be helpful.
Present Day Status of the Therapy of Fulminant Hepatic Failure
The therapy of acute fulminant hepatocellular failure demands prompt care and attention. Mortality in fulminant hepatic failure is very high, 81% in the first 318 patients who reported to the Fulminant Hepatic Failure Surveillance Study (FHF Surveillance Study, 1969)17.
Zacharias et al (1967)50 successfully treated 3 cases of hepatic coma due to infective hepatitis out of 11 cases. Sundaravalli and Raju (1973)42 studied 35 children with hepatic coma due to infectious hepatitis. 10 had exchange transfusions out of which 3 survived and out of the remaining 25 cases 3 survived. Thus in all 6 children survived out of 35 children.
Jones et al (1967)23 had no survivals in 7 cases. Trey and Davidson (1970)46 had a poor survival rate of only 17.6% in those with stage IV coma, but 66% in those with the stage II encephalopathy.
Saunders et al (1970)37 Brit. med. Bull. (Vol. 28, No. 2, 1972)6 in Cape Town have published results of one of the largest series of cases among their own patients. Their study showed that out of 47 patients 7 recovered consciousness of which only 4 survived. Of 20 patients treated conservatively 4 (20%) survived. This is to be compared to 10 (21%) survivors of the 47 patients treated by exchange transfusion. Some of the initial enthusiasm for this procedure has waned, for, the published long-term results are depressing.
The collected results of the Fulminant Hepatic Failure Surveillance Study (Trey and Davidson, 1970)46 also need careful scrutiny. Of 101 patients in whom no special procedure was undertaken, 10% survived whilst the survival in 166 patients treated with exchange transfusion was 24%. However, the preliminary results of the first randomly allocated and controlled trial of exchange transfusion in fulminant hepatitis carried out in Los Angeles showed a higher mortality in the treated group (A.G. Redekar and colleagues)36. Among 60 patients with fulminant hepatitis there was no significant difference between the survival rate of the patients treated conservatively and the patients treated by corticosteroids and/or exchange transfusion and/or cross circulation and/or hyperbaric oxygen (Benhamou, Rueff and Sicot, 1972)3.
Exchange transfusion may be used to remove toxic substances from the blood and in particular those that are protein bound and so not dialysable (Trey et al., 1966)45. Patients who have been treated with exchange transfusion have a survival rate of approximately 20%.
Corticosteroids should not be given routinely. Although they probably have some effect on the healing of the liver, they should be reserved for the patient with prolonged cholestasis or one who seems to be passing into the subacute stage with persistent jaundice and high serum globulin and transaminase values. In chronic cases, which received corticosteroids, it is possible that this treatment may have helped to perpetuate the disease although this has not been proved. It certainly did not prevent the development of chronic sequelae. (Sherlock, 1973,38 Ducci and Katz, 1952,13 Bernard et al, 1964,4 Blum et al, 1969,7 Cachin et al, 1963 A & B9,10).
The outlook of therapy in comatose patients is so poor that a case could be made for corticosteroid therapy. Favourable results have been reported but more usually reported are the failures. Periotoneal dialysis and haemodialysis are certainly useful in the treatment of the uraemic stage. Liver perfusion and hepatic transplantation have also been used experimentally. Hyperbaric oxygen therapy, coenzyme administration, haemodialysis, peritoneal dialysis, exchange transfusion and cross circulation treatment, extracorporeal liver perfusion have been tried.
The aim is to support the failing liver cells till spontaneous regeneration takes place. Major emphasis has to be placed on restitution of hepatic function. Attempts have been made to rectify the metabolic derangements, combat infection and hypoglycaemia, while anticipating restoration of normal liver function by spontaneous regeneration of liver cells. The very rapid onset of coma suggests a metabolic origin rather than structural change and in keeping with this there is equally rapid reversal. Treatment must be adapted to the problem of the individual patient. Results at the same time are depressing and encouraging. Precipitating factors like gastrointestinal haemorrhage or fall in blood pressure, or acute infection in operation should be taken care of.
Bed rest reduces functional demands on the liver. In acute cases it is advisable while the disease is active. In subacute and chronic hepatocellular failure bed rest is continued while improvement is maintained. In static cases after 4 to 5 weeks, the patients may be allowed moderate activity.
Such supportive therapy, which requires intensive medical and nursing care as well as the full range of biochemical and haematological services, is based on the detailed monitoring of almost every organ and system in the body. In the management of these patients, temperature, blood pressure and pulse must be observed 4-hourly. There should be a fluid intake and output chart and if possible daily weighing, daily estimation of haemoglobin and haematocrit level and occult blood in stools. Daily assessment of hepatic size, daily handwriting chart, daily tests of simple arithmetic and ability to copy a five-pointed star with matches. 4-hourly grading, if necessary, of neuropsychiatric status, daily examination of lungs for evidence of infection or oedema and if facilities permit daily serum bilirubin, sodium, potassium, chloride, bicarbonate and urea levels to assess electrolyte equilibrium. All sedatives are contraindicated if the patient is manic or violent. Treatment of precipitant factors like haemorrhage, infection, alcoholism, electrolyte imbalance, minor operations and management of possible harmful effects or over-dosage of morphine or hypnotics is necessary. Bowels should be emptied of nitrogen containing material, by enema or magnesium sulphate purge. Stop nitrogen containing drugs ammonium chloride, urea, stop diuretics and maintain correct caloric, fluid and electrolyte levels. Ensure at least one free bowel movement daily.
The principles in the management are withdrawal of protein, emptying the bowel by enema and neomycin therapy, as these are the standard measures used in the treatment of presumed cerebral intoxication and to reduce bacterial growth in the colon.
At the early stage of anorexia and nausea no benefit accrues from rigid insistence upon a low fat diet. When appetite returns a high protein diet may hasten recovery. In the early stages all dietary protein should be stopped. 1600 calories should be supplied daily as glucose drinks, 20% solution through gastric drip. Alternatively 10% Levulose may be used. Protein has to be completely eliminated from the diet until the protein is alert. In a patient with an episode of coma normal protein intake may soon be restored. In chronic cases protein restriction is needed to control mental symptoms. During recovery, protein is added as 20 g increments on alternate days. The limits of tolerance are usually 40-60 g per day. Exacerbation of symptoms is treated by rest and abstention from proteins. In acute cases, a few days to a few weeks deprivation of protein does not prove harmful and in the chronic group when dietary protein is to be restricted for many months, clinical malnutrition is not seen. In patients with liver disease, nitrogen equilibrium seems to be maintained on severely reduced intake of protein. The risk of temporary restriction is preferable to the hazards of nitrogen toxicity. Vitamins, high carbohydrate diet and dietary supplements are useful.
Scrupulous attention has to be paid to establishing and maintaining the electrolyte and acid base balance. Hypoglycaemia is especially dangerous. The patients have reduced liver glycogen stores and have decreased capacity for hepatic glucogenesis. Hypokalaemia is frequently encountered in patients with fulminant hepatic necrosis (Felig et al, 1970)14.
In case renal failure develops more concentrated solution can be infused with a large vein pump. If symptoms worsen, the regime for the treatment of acute neurological complications should be adopted. Cardio-vascular and respiratory symptoms must receive attention. Surgical exclusion of the colon for the by-passing of colonic toxins, in chronic neuropsychiatric states, needs to be considered.
Neomycin 1 g 4-hourly by mouth may be given for a week. Oral dose of 3-8 g per day or enemata of 1-2 g of Neomycin in 100-200 cc of normal saline may be given.
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