Generalised Mitochondrial Cytopathy Is an Absolute Contraindication to Orthotopic Liver Transplant in Childhood

This article is accompanied by an editorial. Please see: Romero R. The difficulty with rapid communication: fulminant hepatic failure in infancy.J Pediatr Gastroenterol Nutr 1998:26:472-474. Acute liver failure in infancy may related to sepsis, viral infections, adverse drug events, or many varied metabolic aetiologies. Recently a number of infants have been described with fulminant hepatic failure (FHF) as a manifestation of mitochondrial cytopathy (MC), but all have had concomitant neuromuscular involvement of neonatal onset(1-4). Mitochondrial cytopathies are increasingly recognised in childhood. They have symptoms and appearance of multisystem diseases and are caused by inborn errors of one or more of the complexes of the respiratory chain(5-8). Oxidative phosphorylation is present in the central nervous system and muscles, but many other organs and tissues are highly dependent on mitochondrial energy supply(9)-leading to the wide range of clinical manifestations ascribed to MC. Orthotopic liver transplantation (OLT) has been performed for FHF of different aetiologies in infancy and childhood with success(10). There is only one report of successful OLT for MC limited to the liver (11), and no child diagnosed with generalised MC has had a successful transplantation. We describe two patients who had FHF alone and who underwent liver transplantation. CASE REPORTS Patient 1 A male infant born to nonconsanguinous white parents was admitted at 4.5 months with poor feeding, irritability, and jaundice. Developmental progress was thought to be normal. He was vomiting, with hepatomegaly, ascites, and hepatic encephalopathy grade 1. Initial laboratory results revealed bilirubin 216 μmol/l (conjugated fraction, 162 μmol/l); aspartate aminotransferase 567 U/l (normal, 15-60 U/l); alanine aminotransferase 292 U/l (normal, 0-35 U/l); alkaline phosphatase 655 U/l (normal, 100-350 U/l); albumin 31 g/l(normal, 33-47 g/l); prothrombin time 35 seconds (control 13 sec); blood sugar 4 mmol/l on 4 g/kg per day intravenous glucose intake. Blood ammonia,α1 antitrypsin level and phenotype, galactose-1-phosphate uridyl transferase, urinary succinylacetone, and genetic testing for hereditary fructose intolerance all produced normal or negative findings. Results of screening for viral infections including hepatitis A, B, and C were negative. Plasma and urinary amino acid and organic acid concentrations were compatible with FHF, as was serum ferritin-520 μmol/l (normal, 18-300 μmol/l). Lactate pre- and postglucose load of 1.5 g/kg were 1.8 and 2.5 mmol/l, respectively (normal, < 2.5 mmol/l). Echocardiographic and cranial ultrasound findings were normal, as were those of abdominal ultrasound, except for a homogeneously enlarged liver. Neither liver biopsy nor lumbar puncture for cerebrospinal fluid (CSF) examination were attempted, because of marked coagulopathy. Electroencephalography tracing revealed mild, generalised encephalopathy. The clinical course was characterised by rapidly progressive hepatic failure, despite maximal medical support, and OLT of segments two and three from a CMV -ve O group-matched liver was performed. The excised liver revealed microvesicular steatosis. He had an uneventful posttransplant course with good graft function until postoperative day 15, when a marked decline in neurologic function was observed. He had a glazed expression, no person or object recognition, no purposeful movements, and was very irritable. Cranial computed tomographic scan showed generalised atrophy but no focal abnormality. Examination of the CSF revealed a high lactate level of 4 mmol/l (normal,<2.5 mmol/l). Examination of a muscle biopsy specimen by electron microscope revealed a partial reduction in the activity of Complex I of the mitochondrial respiratory chain, swollen mitochondria (Fig. 1), and the presence of ragged red fibres on histologic study. A diagnosis of generalised MC was made. Relentless neurologic and developmental decline occurred, despite a normally functioning graft, and the patient died at 8.5 months of respiratory infection. Autopsy results revealed astrocytic hyperplasia in the brain, compatible with MC. Patient 2 A male child born to nonconsanguinous white parents was admitted at 4.5 months of age with diarrhoea, vomiting, weight loss, dark urine, and pale stools. Developmental progress seemed normal. During the next 2 weeks, worsening liver synthetic function and grade 2 hepatic encephalopathy was noted. On examination, jaundice, palmar erythema, ascites, and a firm, irregular hepatomegaly were found. Findings in initial laboratory investigations were as follows: albumin 28 g/l; prothrombin time 23 seconds(control 13); alanine aminotransferase 1287 U/l; aspartate aminotransferase 611 U/l; bilirubin 355 μmol/l; glucose 1.4 mmol/l with lactate 2 mmol/l and bicarbonate 23 mmol/l. Blood ammonia, α1 antitrypsin level and phenotype, galactose-1-phosphouridyltransferase, urinary succinylacetone, and genetic testing for hereditary fructose intolerance all yielded normal or negative results; the rate of tubular reabsorption of phosphate was normal. Results of screening for viral infections including hepatitis A, B, and C were negative. Plasma and urinary amino acid and organic acid concentrations were compatible with FHF, as was serum ferritin 873 μmol/l (normal, 18-300μmol/l); abdominal ultrasound, echocardiogram, and cranial ultrasound were all normal; and gastroduodenoscopy showed early submucosal varices and mild portal gastropathy. Medical therapy for FHF was attempted; however, deterioration occurred with uncorrectable coagulopathy, and OLT of segments two and three from a CMV -ve, group-matched donor was performed when the patient was 6 months of age. Examination of the excised liver revealed microvesicular steatosis. After extubation on postoperative day 2, he remained flaccid and markedly hypotonic. An electroencephalogram showed polyspike activity, and despite treatment with phenytoin, a left upper limb focal seizure developed associated with electroencephalographic evidence of a right-sided focus. Subsequent respiratory muscle weakness and generalised hypotonia associated with recurrent focal seizures precipitated CSF examination and a muscle biopsy to exclude MC. Cerebral spinal fluid protein was 1.3 g/l, and CSF lactate was 4.1 mmol/l. Electron microscopic examination of a muscle biopsy specimen revealed mitochondrial swelling(Fig. 1) and a general decrease in respiratory chain enzyme activity. At 10 months of age, developmental regression was manifest, and neurologic deterioration with a decreasing level of consciousness and loss of visual fixation occurred. Despite a normally functioning liver transplant, the patient died of respiratory failure at 10.5 months. DISCUSSION Both patients had progressive acute liver failure without evidence of a multisystem condition (e.g., hypotonia, developmental delay, seizures, hyperlactataemia, or renal or cardiac abnormalities). Pretransplant CSF lactate and liver or muscle biopsy were not attempted because of marked coagulopathy. Involvement of tissues other than the liver (i.e., skeletal muscle and neurologic) became apparent subsequent to OLT, at which point a diagnosis of generalised MC was made, based on a raised CSF lactate level, abnormal skeletal mitochondria seen by electron microscope, and abnormal respiratory chain enzyme analysis. There was partial reduction in Complex I activity in patient 1 and generalised decrease of enzyme activity in patient 2(Fig. 2). In each patient, the graft continued to function normally until death. Fatal neonatal or infant hepatic insufficiency with hyperlactataemia is not rare and is seen in a number of conditions, including galactosaemia,α1 antitrypsin deficiency, defects of fatty acid oxidation, tyrosinaemia type 1, neonatal haemochromatosis, and urea cycle defects(12). Defects of the respiratory chain in infancy usually affect muscle, with variable involvement of other systems-e.g., renal, cardiac, or CNS. Multisystem disorders have been associated with abnormalities of Complex I(13), Complex III (14,15), or in combination (16)(Fig. 2). However, recently, a number of infants have been described with FHF as a manifestation of MC, but all have had concomitant neuromuscular involvement of neonatal onset, hyperlactataemia, or Fanconi syndrome(1-4,15). Mitochondrial DNA depletion has been documented in two patients with infant-onset liver failure as part of a multisystem disease (1,17). None of these patients underwent OLT, and they all died in terminal liver failure. Mitochondrial cytopathy involving only the liver has been successfully treated with OLT in one reported case (11). Variable tissue expression (e.g., lack of muscle involvement and consequent absence of hyperlactataemia [17]) may result in an initial appearance of generalised MC as liver disease alone, as was true in our cases, and a high index of suspicion is necessary for identification of these patients. To exclude generalised MC-based liver disease, we suggest a diagnostic protocol, as described in Table 1. The most important investigations are CSF lactate, liver biopsy, and muscle biopsy for ultrastructural mitochondrial changes and analysis of respiratory chain enzyme activity. These procedures require vigorous correction of coagulopathy. The aim of the protocol is therefore to recognise extrahepatic MC, in that the hepatic involvement is correctable by OLT. We have used this protocol effectively in four subsequent infants with FHF. Generalised MC was excluded in three, allowing OLT to proceed followed by full neurologic recovery with no evidence of systemic disease up to 18 months after surgery. The fourth patient was diagnosed with generalised MC after examination of a muscle biopsy specimen, and OLT was contraindicated. He developed asymmetric myoclonus followed by neurologic deterioration and died 17 days after admission. In conclusion, we suggest that FHF in infancy may be the sole symptom of generalised MC and that a low threshold for investigation to exclude this important group of disorders be adopted, in that OLT is an ineffective treatment for the generalised form of MC. Acknowledgment: The authors thank Dr. Faro Raafat and members of the histology department for histologic and electron microscopic studies.FIG. 1: . Transmission electromicrograph of muscle: normal(A), patient 1 (B), and patient 2 (C). The patient samples show the marked swelling and abnormal shape of the mitochondria (arrows: magnification, ×12,000).FIG. 2: . Enzyme complexes and coenzymes involved in the respiratory chain.