FEATURE PAEDIATRICS
ETIOLOGY Viral hepatitis remains the main cause of fulminant hepatic failure in children. FHF can occur as a complication of viral hepatitis A, B, C, D, or E. Cases of 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 FHF. This occurs more frequently in neonates born to mothers who are hepatitis B e antigen negative. A number of viral agents can also produce fulminant hepatitis in children, often as part of a generalized, severe, systemic illness. Hepatitis A virus infection is a recognized cause of FHF. Diagnosis is made by the presence of anti- HAV IgM in the child’s serum. Epstein- Barr virus, adenovirus, herpes simplex virus, enteroviruses, cytomegalovirus, and varicella zoster infections have all been implicated. Exposure to drugs and toxins remains the second most common cause of FHF in children. An exhaustive history of exposure to prescription and nonprescription drugs and toxins in the home should be taken in every patient. Predictable hepatic injury may follow the ingestion of an overdose of acetaminophen which is reported to cause direct hepatotoxicity and hepatocellular necrosis. Other toxins include exposure to chlorinated hydrocarbons and the ingestion of the Amanita species of mushrooms or salicylates. Idiosyncratic damage may follow the use of drugs including isoniazid, sodium valporate, and halothane. FHF may also result from ischemia, hypoxia and circulatory shock as may occur in severe birth asphyxia, sepsis, congestive heart failure, hepatic vascular occlusion, congestive heart failure, cyanotic congenital heart disease, or obstructive lesions of the aorta. Inherited, metabolic disorders may also produce FHF mainly in young infants, but may still be found in all ages. Wilson’s disease, galactosemia, Budd-Chiari syndrome, 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. Autoimmune hepatitis can present as FHF with most of the affected patients having liver/kidney microsomal antibodies. Inborn errors of bile acid metabolism have also been associated with hepatic failure in the neonate (see table 1).
PATHOLOGY The liver biopsy shows patchy or confluent, massive hepatocyte necrosis associated with collapse of the reticulin framework. There may be little or no regeneration of hepatocytes Centrilobular necrosis is the characteristic feature of acetaminophen intoxication or with circulatory shock. Fatty change of hepatocytes may be the predominant lesion, rather than liver cell necrosis. Galactosemia, hereditary fructose intolerance and other inborn errors of metabolism are characterized by patchy hepatocyte necrosis combined with fat accumulation in the hepatocytes.
PATHOGENESIS The pathogenesis of FHF remains poorly understood. Little do we know about the key factors that lead to the rapid massive liver necrosis. Future research is required to further understand the mechanisms that underlie the poor regenerative response, the cascade of events leading to hepatocyte necrosis, the mechanism behind the depletion of intracellular glutathione, which is essential for detoxification of reactive metabolites, and why these events influence some few exposed individuals and not many others. Table 2 illustrates the most common causes of FHF and related pathogenesis. Ammonia currently is thought to
be the main pathophysiological agent resulting in encephalopathy, which occurs in 100% of patients with FHF. Alteration of permeability of blood brain
Table 2
Causative factor Viral infection
Inborn errors of metabolism
Neonatal iron storage disease
Pathogenesis
Direct cytotoxic effect of a viral agent Hyperimmune response to viral antigens
Accumulation of potentially hepatotoxic metabolite
Wilson’s disease Oxidative damage
Depletion of intracellular glutathione which is essential for detoxification of reactive metabolites
Acetaminophen Formation of reactive intermediary products of paracetamol metabolism. These bind to intracellular proteins and interfere with cellular metabolism
Isoniazid, Sodium Valproate, and Halothane
Generation of free radicals leading to degradation of the membrane phosphorlipid.6
Results in
Massive destruction of hepatocytes
sharing of pairs of electrons between atoms
Electrons sharing between atoms (bind covalently)
Impaired hepatic reticulo- endothelial function.
Massive destruction of hepatocytes
Idiosyncratic damage inducing cell necrosis
barrier allows entry of toxic metabolites into the brain and thus contributes to cerebral edema, representing a major cause of death (32%).Other metabolic factors that have been implicated in the pathogenesis behind unexplained altered cerebral functions when increased serum levels of ammonia do not entirely explain why the patient is deeply comatosed include butyrate, amines, valerate, octinoate and increased circulating levels of endogenous
Table 1 Categorizing the most common causes of FHF in infants and children
Infection Hepatitis A,B,C,D and E EBV, CMV, Adenovirus, Herpes virus Drugs, chemicals and poisons Paracetamol Halothane Izoniazide Thio-uracil
Carbon tetrachloride Amantia Phalloides Metabolic Fructosemia Tyrosinemia Wilson’s disease Neonatal iron storage disease Vascular (Ischemic) Budd-Chiari Syndrome Acute circulatory failure Gram negative septicemia with septic shock Heat stroke Miscellaneous Metastatic infiltrates
Arab Health Show Issue
2012 137
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