Saudi Journal of Gastroenterology
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Year : 1996  |  Volume : 2  |  Issue : 1  |  Page : 39-43
Fulminant hepatic failure in children

Department of Pediatrics, Yale University, School of Medicine, New Haven, CT, USA

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Fulminant hepatic failure is a clinical syndrome resulting from massive necrosis or severe func­tional impairment of hepatocytes. This paper reviews the etiology, pathogenesis and management of this condition. Orthotopic liver transplantation may achieve very high survival rates (50-70%).

How to cite this article:
Suchy FJ. Fulminant hepatic failure in children. Saudi J Gastroenterol 1996;2:39-43

How to cite this URL:
Suchy FJ. Fulminant hepatic failure in children. Saudi J Gastroenterol [serial online] 1996 [cited 2022 Jan 17];2:39-43. Available from:

Fulminant hepatic failure is a clinical syndrome resulting from massive necrosis or severe functional impairment of hepatocytes. The synthetic, excretory and detoxifying functions of the liver are all severely impaired, with hepatic encephalopathy being the essential diagnostic criteria. According to strictly­defined criteria, the illness should evolve over a period of less than eight weeks from the onset of the liver disease and precludes pre- existing liver disease in any form. There are a number of limitations to this narrow definition of fulminant hepatic failure, which are particularly highlighted in pediatric patients. For example, infants may present with hepatic failure in the perinatal period associated with the prenatal onset of liver disease, which may even evolve to cir­rhosis before birth. This pattern may be observed in neonates with several inborn errors of metabolism including tyrosinemia, neonatal iron storage disease, and inborn errors of bile acid synthesis. Congenital viral infection may also become manifest as hepatic failure. In older children fulminant Wilson's disease may also present in children who were previously asymptomatic, but a piori have significant pre-exist­ing liver disease. The time frame over which, loss of hepatic function occurs may also present problems. In some cases of non-A, nob-B, non-C hepatitis, the onset of encephalopathy may occur later, often from eight-28 weeks after the onset of jaundice [1] .

   Etiology Top

Fulminant hepatic failure [Table - 1] is most com­monly observed as a result of viral hepatitis. It can occur as a complication of viral hepatitis A, B, D, or E. Cases of hepatic failure, secondary to hepatitis C are not common, particularly in children. Hepatic failure may occur in adolescents who have combined infections with hepatitis B and D. Mutations in the precore region of hepatitis B virus DNA, have been associated with severe hepatitis and fulminant liver failure. This occurs more frequently in neonates born to mothers who are hepatitis Be antigen nega­tive. Hepatitis B may also be responsible for some cases of fulminant liver disease in the absence of the usual serologic markers of hepatitis B infection. Hepatitis B virus DNA can be detected in the liver of these patients. In the United States, a yet uniden­tified viral agent accounts for the majority of what has been termed fulminant non-A, non-B hepatitis in children. The illness is characterized by the lack of the usual parenteral risk factors identified for hepatitis B or C. The disease occurs sporadically. A number of other viral agents can also produce ful­minant hepatitis in children, often as part of a more generalized, severe, systemic illness. Barr-Epstein virus, adenodirus, herpes simplex virus, enteroviruses, cvtomegalovirus, and varicella zoster infections have all been implicated.

Hepatotoxic drugs and chemicals may also cause fulminant hepatic failure in children. Predictable hepatic injury may follow the ingestion of an over­dose of acetaminophen, exposure to chlorinated hydrocarbons, and the ingestion of the Amanita species of mushrooms. Idiosyncratic damage may follow the use of drugs including isoniazid, sodium valporate, and halothane. Drug-related injury may be the second most common cause of fulminant liver disease in children. An exhaustive history of expo­sure to prescription and nonprescription drugs and toxins in the home should be taken in every patient.

Hepatic failure may also result from ischemia and hypoxia. Hepatic vascular occlusion, congestive heart failure, cyanotic congenital heart disease, obstructive lesions of the aorta, and circulatory shock may all be associated with hepatic failure.

Inherited, metabolic disorders may also produce hepatic failure. Wilson's disease, galactosemia, hereditary fructose intolerance, hereditary tyrosinemia, neonatal iron storage disease, disorders of the beta oxidation of fatty acids, and deficiencies of mitochondrial electron transport, may all result in hepatic failure. In some of these cases, selected aspects of liver function might be disproportionately affected. For example, impaired synthetic function and hyperammonia may be more prominent in the beta oxidation effects, early in the course of the ill­ness. In born errors of bile acid metabolism have also been associated with hepatic failure in the neonate [2],[3],[4],[5],[6] .

   Pathology Top

Patchy or confluent, massive necrosis of hepato­cytes is commonly found on liver biopsy or in the liver, removed at autopsy or at the time of transplan­tation. Collapse of the reticulin framework of the liver may occur as a result of multilobular or bridging necrosis. Little or no regeneration of hepatocytes is typical. Centrilobular necoris may be characteristic of certain forms of liver injury, particularly with acetaminophen intoxication or with circulatory shock. Microvesicular fatty change of hepatocytes may be the predominant lesion, rather than liver cell necrosis. This occurs in defects of the beta oxidation of fatty acids and in Reye's syndrome. The absence of cell necrosis in these disorders implies a failure of organelle function. In inborn errors of metabolism such as galactosemia and hereditary fructose intoler­ance, there may be spotty hepatocyte necrosis com­bined with macrovesicular fat accumulation within hepatocytes. Pseudocinar arrangement of hepato­cytes may also be found in these disorders [2],[3],[4],[5],[6] .

   Pathogenesis Top

The pathogenesis of fulminant hepatic failure remains poorly understood. Impaired regenera­tion of the liver following massive destruction of liver cells is likely to be a critical determinant. The mechanisms that underlie the poor regenerative response in these cases is not well defined. Mas­sive destruction of hepatocytes may represent a direct cytotoxic effect of a viral agent or a hyperimmune response to viral antigens. Indeed, in over a third of patients with hepatitis B, induced hepatic failure serum may be negative for hepatitis B surface antigen within a few days of presentation, and there is often no detectable hepatitis B DNA in serum. In inborn errors of metabolism, the accumulation of potentially hepatotoxic metabolites may be involved in cellu­lar injury. Oxidative damage may be of impor­tance in disorders such as Wilson's disease or neonatal iron storage disease. Formation of hepatotoxic metabolites that bind covalently to cellular macromolecules is involved in the injury produced by acetaminophen and isoniazid. Depletion of intracellular glutathione which is essential for detoxification of reactive metabolites is involved in the pathogenesis of hepatic injury. A number of other factors have been proposed as contributing to alteration in hepatocellular func­tion including altered perfusion, endotoxemia, and impaired hepatic reticuloenthelial function.

The pathogenesis of hepatic encephalopathy remains an area of controversy and continued investigation. Increased serum levels of ammonia do not entirely explain altered cerebral function in that, levels of ammonia may be normal or only slightly elevated even when patients are deeply comatose. False neurotransmitters, amines, increased gamma aminobutyric acid receptor activity, or increased circulating levels of endogenous benzodiazapin-like substances have been proposed. Increased absorption of these potential neurotoxins and decreased hepatic clearance may be involved in producing encephalopathy [2],[3],[4],[5],[6] .

   Clinical Manifestation Top

The child with fulminant hepatic failure usually has been previously healthy and has no known risk factors for liver disease, such as exposure to hepatitis. or use of blood products. Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting, and abdominal pain are commonly observed. In patients with severe acute liver disease, there should be careful observa­tion for features of hepatic encephalopathy, which initially, may be characterized by minor disturbances of consciousness or motor function [Table - 2]. Early stages of encephalopathy may be particularly dif­ficult to detect in infants. Irritability, poor feeding, and a change in the sleep rhythm may be the only findings in infants. In older children, asterixis may be demonstrated. The patient may become somnolent and confused or combative on arousal and eventu­ally, may become responsive only to painful stimuli. Progression can occur over the course of a few days or even weeks to deeper stages of coma in which extensor responses and decerebrate and decorticate posturing appear. Respiration may be increased early but respiratory failure may occur on evolution to stage IV coma. A rapid decrease in liver size with­out clinical improvement is an ominous sign. Bleed­ing from the gastrointestinal tract as a result of severe coagulopathy and ascites are common findings. The neurologic dysfunction associated with higher grades of coma are thought to be related to the development of cerebral edema which is related to both cytotoxic and vasogenic factors [2],[3],[4],[5],[6] .

   Laboratory Findings Top

Serum aminotransferase levels are often markedly elevated; serum direct and indirect bilirubin levels are variably increased. Although extremely high levels of serum aminotransferase activity are often found, the peak level does not correlate well with the severity of illness. In metabolic disorders, liver fail­ure may be present with only modest elevation in their activity. Serum aminotransferase activities may actually decrease as the patient deteriorates, (the process of liver necrosis has released most of the available sources for the enzymes). A coagulopathy is always present with prolongation of the prothrom­bin time which does not improve after the parenteral administration of vitamin K. Hypoglycemia can occur particularly in infants. A number of electrolyte disturbances are common, including hyperkalemia, hyponatremia, a metabolic acidosis or respiratory alkalosis. Although renal function may be impaired as a result of tubular injury or hypovolemia, a func­tional form of renal failure, so- called hepatorenal syndrome, can occur in patients with liver failure and correlates with a very poor outcome [2],[3],[4],[5],[6] .

   Treatment Top

The treatment of fulminant hepatic involves primarily, supportive care. There is no proven therapy which is known to reverse hepatocyte injury or to promote regeneration of hepatocytes. Patients with fulminant hepatic failure, with higher stages of coma, should be treated in the set­ting of an intensive care unit where monitoring of vital functions is possible [2],[3],[4],[5],[6] . Numerous compli­cations can also he identified and promptly treated [Table - 3]. In patients who are significantly disoriented or in coma, endotracheal intubation may be required to prevent aspiration, to reduce cerebral edema by hyperventilation, and to facili­tate aspiration of secretions. Mechanical ventila­tion and the administration of oxygen are often required in more severely- affected patients. Elec­trolyte and glucose-containing solutions should be administered intravenously to maintain urine out­put, to correct electrolyte abnormalities, and to prevent hypoglycemia. Hyponatremia is com­monly found, but is usually dilutional and not a reflection of sodium depletion. Parenteral infu­sion of calcium, phosphorous, and magnesium is often required. Intravenous administration of vitamin K should be given in an attempt to correct coagulopathy. Disseminated intravascular coagu­lation may he present in these patients as a result of liver failure as well as from infection. Infusion of factor concentrates or platelets may be neces­sary. In principle, clinical bleeding should be treated with factor replacement rather than treat­ing laboratory abnormalities. Patients can rapidly become fluid overloaded with infusions of large amounts of fresh frozen plasma. Plasmapheresis may be useful for temporary correction of coagulopathy without resulting in volume over­load. Hypovolemia should be avoided and treated with judicious infusion of fluids and blood prod­ucts through a centrally-placed line. Prophylactic administration of H; receptor blockers is usually advised because of the high risk for developing gastrointestinal bleeding. Renal dysfunction com­monly occurs from dehydration, from acute tubu­lar recrosis, from the initial toxic insult and from hepatorenal syndrome. Infection commonly occurs and is often responsible for the demise of these patients. At least 50 % of patients experi­ence serious infection including septicemia, pneumonia, peritonitis, and urinary tract infec­tions. Gram positive and gram negative organisms, as well as fungal infections can occur.

Cerebral edema is an extremely-serious compli­cation that responds poorly to measures usually used to treat this complication in other disorders. Corticosteroid administration is of no value. Hyperventilation may actually worsen oxygen availability to the brain, but osmotic diuresis may be useful in maintaining cerebral perfusion pres­sure. The placement of an intracranial pressure monitor may he useful in guiding treatment.

Gastrointestinal hemorrhage, infection, seda­tives, electrolyte balance, and hypovolemia. may precipitate or exacerbate hepatic encephalopathy and should be prevented and aggressively treated. Protein intake should be restricted or limited. The gut should he purged with several enemas and lac­tulose administered, in a dose sufficient to pro­duce several acidic loose bowel movements daily. Lactulose may also be administered as a retention enema up to four times per day. Lactulose, a nonabsorbable disaccharide, is metabolized to organic acids by the colonic flora. It is thought to lower blood ammonia by decreasing microbial ammonia synthesis and by trapping of ammonia in the acidic colonic contents. The nonabsorbable antibiotic neomycin may be given orally or rec­tally to decrease enteric bacteria which produce ammonia.

A variety of approaches have been used to assist the liver in removing toxins which may cause encephalopathy [Table - 4]. Plasmapheresis or perfusion of the patient's plasma through an anion­exchange resin or a column of charcoal has been used in several studies. In uncontrolled studies, the patients may experience some clinical improvement but these treatments, when analyzed in controlled trials, did not improve sur­vival. There are a number of liver-assist devices under evaluation consisting of matrices of cul­tured hepatocytes. These devices are being used to support patients until regeneration of the patient's liver occurs, or to serve as a bridge until a suitable organ donor can be found. Orthotopic liver transplantation is life-saving in patients who reach advanced stages of coma. Patients with ful­minant hepatic failure demonstrate lower rates of patient and graft survival, following orthotopic liver transplantation than patients with nonful­minant disease. This probably relates to the fact that these patients are more likely to be on life­support, including mechanical ventilation and vasopressors, than patients with more chronic liver disease. They are also more likely to receive an organ from an incompatible blood group­matched donor. Reduced-sized allografts and liv­ing related donor transplantation have been addi­tional advances in the treatment of infants with hepatic failure [7],[8] .

   Prognosis Top

The prognosis varies and depends on the etiol­ogy of the hepatic injury and stage of encephalopathy [9] . With intensive medical therapy, rates of survival of over 50 % can be achieved in liver failure complicating acetaminophen overdose and some patients with fulminant hepatitis A or B infection. In contrast, children with non-A, non-B, non-C hepatitis or the acute form of Wilson's disease rarely recover without liver transplantation. In patients who progress to stage IV coma, the prognosis is extremely poor. Complications of liver failure including sepsis, hemorrhage, or renal failure increase the mortality. Several recent studies which have included some children have defined some features which define prognosis. Jaundice for more than seven days prior to the onset of encephalopathy and a prothrombin time of over 50 sec can be expected in patients with poor prog­nosis. Patients who are fortunate enough to recover with only supportive care do not usually develop cirrhosis or chronic liver disease. It has recently been recognized that aplastic anemia may complicate fulminant non- A, non-B, non-C hepatitis.

   References Top

1.O'Grady JG, Schalm SW. Williams R. Acute hepatic failure: redefining the syndromes. Lancet 1993:342:273-5.  Back to cited text no. 1    
2.Sherlock S. Fulminant hepatic failure. Advances in Internal Medicine 1993;38:245-67.  Back to cited text no. 2  [PUBMED]  
3.Riegler JL. Lake JR. Med Clin North Am 1993;77:1057-­83.  Back to cited text no. 3    
4.Whitington PF. Fulminant hepatic failure in children. In Liver Disease in Children. FJ Suchy (ed), Mosby, Philadephia 1994.pp. 180-213.  Back to cited text no. 4    
5.Lee WM. Acute liver failure. N Engl J Med 1993:329:1862-972.  Back to cited text no. 5    
6.Hoofnagle JH. Carithers RL. Shapiro C. Ascher N. Ful­minant hepatic failure: summary of a workshop. Hepatology 1995:21:240-52.  Back to cited text no. 6    
7.Caraceni P. Van Thiel DH. Acute hepatic failure. Lan­cet 1995;345:163-9.  Back to cited text no. 7    
8.Ascher NL. Lake JR. Emond JC, Roberts JP. Liver transplantation for fulminant hepatic failure. Arch Surg 1993;128:677-82.  Back to cited text no. 8    
9.O'Grady JG. Alexander GJM. Hayllar KM. Williams R. Early indicators of prognosis in fulminant hepatic fail­ure. Gastroenterology 1989;97:4439-45.  Back to cited text no. 9    

Correspondence Address:
Frederick J Suchy
Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520
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Source of Support: None, Conflict of Interest: None

PMID: 19864840

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