Liver Transplantation for Acute Liver Failure in Children

Etiology of Pediatric Acute Liver Failure

The Pediatric Acute Liver Failure (PALF) Study Group, a multicenter and multinational consortium, suggested the following definition: (1) no known evidence of chronic liver disease, (2) biochemical evidence of liver injury, and (3) hepatic-based coagulopathy defined by international normalized ratio (INR) over 1.5 not corrected by vitamin K administration in the presence of hepatic encephalopathy (HE) or INR over 2.0 regardless of the presence of HE.

The etiology of PALF is age dependent ( Table 36.1 ). In infants younger than 3 months, metabolic, infectious, and gestational alloimmune liver disease are the common causes. Galactosemia, tyrosinemia type 1, and mitochondrial disorders are the common etiology of metabolic disease in infants and young children. Herpes simplex virus (HSV) is an important treatable cause in infants and children. In older children, drug toxicity, viruses, metabolic diseases, and autoimmune hepatitis are the main causes. The etiology remains indeterminate in 30% to 50% of the patients, partly because of the lack of proper diagnostic evaluation. About 10% of indeterminate PALF patients can develop bone marrow failure, and some progress to aplastic anemia, even after successful liver transplantation (LT).

Diagnostic Procedures Necessary to Prepare for Liver Transplantation

Diagnostic evaluations must be extensive to evaluate the etiology of PALF ( Table 36.2 ). Early establishment of the etiology provides the predictor of outcomes and identifies conditions that are treatable without LT or contraindicated for LT. Potentially treatable diseases are HSV infection, gestational alloimmune liver disease, acute acetaminophen toxicity, autoimmune hepatitis, and Wilson disease. Gestational alloimmune liver disease is confirmed by demonstration of extrahepatic iron deposits by a buccal salivary gland biopsy or magnetic resonance imaging (MRI). Autoimmune hepatitis presenting with PALF is mostly of type 2, with positive anti–liver kidney microsome antibodies. Coombs-negative hemolytic anemia, a high bilirubin-to-alkaline phosphatase ratio, and renal failure are characteristic features of ALF attributed to Wilson disease. An elevated ratio of lactate to pyruvate is a sensitive but nonspecific marker of mitochondrial disorders, and it is important to rule out neuromuscular involvement. Brain MRI, cerebral spinal fluid analysis, muscle enzymes, muscle biopsy for mitochondrial and respiratory chain analysis, echocardiogram, and assessment of renal tubular function are important to exclude systemic disease. Hepatocerebral mitochondrial DNA depletion syndromes are autosomal recessive diseases caused by mutations in DGUOK , MPV17 , and POLG . A next-generation sequencing panel for candidate genes may be the best diagnostic strategy to identify these disorders. Recognition of hemophagocytic lymphohistiocytosis (HLH) as a cause of PALF is important because LT is not curative.

The role of liver biopsy in PALF is controversial. Severe coagulopathy makes percutaneous liver biopsy high risk, and sampling error is possible. Liver histology does not increase the diagnostic yield and may not differentiate autoimmune PALF from indeterminate PALF. In contrast, liver biopsy can be safely performed by the transjugular approach, and histological findings may guide diagnosis and therapy.

Clinical tools to predict irreversible brain injury are lacking. Neuroimaging is frequently normal until late in the course of neurological injury. Brain-computerized tomography or MRI was abnormal in only 13% of PALF patients and was not associated with outcome. Brain imaging may be used to exclude other causes of decline in mental status, such as intracranial hemorrhage. Children with electroencephalogram abnormalities, including slowing and epileptiform discharges on admission to the pediatric intensive care unit (PICU), were more likely to require LT or die.