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Liver Disease in the Ashkenazi-Jewish Lipoamide Dehydrogenase Deficiency

1997; Lippincott Williams & Wilkins; Volume: 24; Issue: 5 Linguagem: Inglês

10.1097/00005176-199705000-00019

1536-4801

Iris Aptowitzer, Ann Saada, Joseph Faber, David Kleid, Orly Elpeleg,

Mitochondrial Function and Pathology

Inborn errors of mitochondrial enzymes may affect the liver, especially during metabolic decompensation episodes. Fatty infiltration is common in most fatty acid oxidation defects, portal fibrosis is seen in some of the urea cycle disorders, and patients with mtDNA depletion may present with liver failure (1-3). Other defects of oxidative phosphorylation in which liver involvement has been reported are complex III or complex IV (cytochrome c oxidase) deficiency and mtDNA deletion (Pearson's syndrome) (4). To the best of our knowledge, prominent liver involvement has never been reported in patients with pyruvate dehydrogenase complex (PDHc) deficiency. We describe a boy with PDHc defect due to deficiency of one of its subunits, lipoamide dehydrogenase (LAD), that manifested solely in severe hepatocellular disease. CASE REPORT A 2-year-old boy was admitted to our institution because of vomiting of 10 days' duration. He was the fifth of six children born to Ashkenazi-Jewish, unrelated parents. His four sisters were reported healthy, but his 4-year-old brother had suffered from repeated vomiting episodes since early infancy. The patient was born at term following a normal pregnancy and delivery and was breast-fed until 7 months of age. He also was reported to suffer from short vomiting episodes that were induced by intercurrent infections. Mild hepatomegaly was noted by his family doctor during some of these episodes. On admission, weight was 11.4 kg (10th percentile) and length was 87 cm (50th percentile). The patient was pale and his consciousness was depressed, but he responded to painful stimuli. Heart rate was 135/min, respiratory rate was 24/min, and temperature was 36.6°C. Aphthoustomatitis was noted, and the liver was palpable 7 cm below the right costal margin with a span of 11 cm. The rest of the examination was normal. Laboratory investigation revealed leukocytosis (17,000/mm3) with a normal differential count, markedly elevated liver transaminases (AST-8813 U/L and ALT-9859 U/L), and coagulopathy with INR 2.68. Plasma electrolytes, urea, creatinine, bilirubin, alkaline phosphatase, γ-GTP, ammonia, creatine phosphokinase, and blood gases were all normal. Serology of HAV, HBV, CMV, EBV were negative. Treatment with intravenous fluids, hexacapron, vitamin K, and cryoprecipitate was initiated with favorable response. When the boy was discharged 5 days later, his physical examination was unremarkable apart from slight hepatomegaly. Neurological examination was normal, and psychomotor development was appropriate for his age. Liver transaminases had decreased markedly (AST-111 U/L and ALT-583 U/L), and coagulation functions were normal. The patient was readmitted 1 month later because of recurrent vomiting. Physical examination revealed pallor, lethargy, sleepiness, and hepatomegaly. The liver was palpable 3 cm below the right costal margin. A compensated metabolic acidosis (pH 7.29, pCO2-34, HCO3-10) was noted in addition to mild elevation of liver transaminases and marked coagulopathy. Plasma lactate was 7.6 mM (normal, <2.1mM), lactate/pyruvate ratio was normal, total carnitine was reduced to 15.4 μM (normal, 30-60 μM), and all amino acids were near or below the lower normal range except for alanine, which was elevated (677 μM; control, 148-475 μM). In urine, the excretion of lactate was moderately increased. Excretion of fumaric, glutaric, and α-ketoglutaric acids was mildly elevated. The patient was treated with intravenous fluids, but plasma lactate remained high (peak value, 16 mM). Mitochondrial respiratory chain defect was suspected. Therapy with Na dichloroacetate, thiamine, and carnitine was initiated, leading to normalization of plasma lactate within 3 days. An open-muscle biopsy of the left quadriceps muscle was performed under general anesthesia. Muscle pathology, including histochemical staining and electron-microscopic examination, was normal. In muscle homogenate, the activity of PDHc (5) was reduced to 0.9 nmol/min/mg protein (control, 5.7 ± 1.5 nmol/min/mg protein; n = 8), the activity of α-ketoglutarate dehydrogenase complex (6) was reduced to 0.69 nmol/min/mg protein (control, 3.70 ± 1.56 nmol/min/mg protein; n = 6), the activity of LAD (7) was reduced to 10 nmol/min/mg protein (control, 121 ± 9 nmol/min/mg protein; n = 11), whereas the activity of the pyruvate decarboxylase subunit of PDHc was within the normal range (5). In isolated mitochondria, the activity of the five respiratory chain complexes was normal (8-12). The oxidation of pyruvate and malate as indicated by the O2 uptake by the isolated mitochondria (13) was reduced to 59% of the control mean (n = 17). The activity of LAD in fibroblasts was reduced to 12% of the control mean (n = 4). Western blot analysis (14) revealed reduction of LAD protein in muscle to 60% of the control (n = 6), whereas the other subunits of the PDHc were present in normal amounts. Consent for liver biopsy was not given. Postoperatively, the boy's clinical course was complicated by an E. coli and staphylococcal sepsis with adult respiratory distress syndrome, disseminated intravascular coagulation, and acute tubular necrosis. The patient expired on the 18th day of hospitalization. It is of note that plasma lactate remained at near-normal value throughout this period. DISCUSSION This patient presented at 2 years with hepatocellular disease mimicking infectious anicteric hepatitis. Inborn error of metabolism was not suspected during his first admission because of normal values of blood gases, glucose, and ammonia. Lactic acid level was determined only when compensated metabolic acidosis was noted during the second admission. The finding of lactic acidemia prompted an investigation of pyruvate metabolism and the mitochondrial respiratory chain. The reduced activity of LAD in two tissues-muscle and fibroblasts-suggested that LAD deficiency was the primary enzymatic defect in this patient. PDHc is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. It is composed of three catalytic subunits, two regulatory proteins, and a stabilizing protein. LAD is the third catalytic subunit (E3) and participates in the reoxidation of the dihydrolipoyl moiety, which is bound to the transacetylase subunit (E2) of the complex. LAD is also a component of two other α-keto acid dehydrogenase complexes, α-ketoglutarate- and branched-chain keto acid-dehydrogenase complexes. Thus, deficiency of LAD results in extensive metabolic disturbances, including lactic acidemia, Krebs cycle dysfunction, and impaired branched-chain amino acid degradation. A small number of patients with LAD deficiency have been reported (15-19). All patients presented during the first weeks of life with progressive neurological deterioration and lactic acidemia and died in early childhood. Liver involvement was not reported in some cases, whereas slight liver enlargement with mild elevation of liver transaminases was described in others. We have recently identified LAD deficiency in several Ashkenazi-Jewish families. The age of onset and clinical course were alike for all patients within the same family but differed among the families. Three phenotypes could be distinguished: (a) neonatal presentation with marked metabolic acidosis, prominent liver involvement during vomiting episodes, and residual neurological damage in the form of mild to moderate muscle hypotonia with normal cognitive development (14,20); (b) early childhood presentation, with prominent liver disease during metabolic decompensation episodes, and normal neurological examination 21, present case); (c) postpubertal presentation, with metabolic decompensation episodes characterized by vomiting, marked rhabdomyolysis, and minimal liver involvement (22). Thus, in contrast to the previously described patients, the liver is the main organ involved in most of our patients while the brain is largely spared. The pattern of the liver involvement is distinctive, including marked elevation of liver transaminases, prolongation of the prothrombin time, and near normal bilirubin, alkaline phosphatase, and γ-GTP. Typically, all abnormalities return to normal levels within 4-6 days. Jewish LAD deficiency is a heterogenous entity. In addition to the clinical variability and despite similar residual LAD activity, our patient is the only one who has had a level of protein as high as 60% of the control. The amount of the LAD protein in the Jewish patients who presented in the neonatal period is <25% of the control. This suggests that the disease-causing mutations of our patient are different from those of the others. We have recently reported that more than one mutation is involved in Jewish LAD deficiency-the two patients of the first phenotype were found to be compound heterozygotous for a deleterious frame-shift mutation and for another, as yet unidentified, mutation (14). We conclude that LAD deficiency may present in early childhood, simulating anicteric viral hepatitis, without any metabolic abnormalities detected by routine screening. Attention should be paid to extremely elevated transaminase levels that normalize rapidly, especially in anicteric hepatitis. We recommend that plasma lactic acid level, along with plasma amino acids and urinary organic acids, be analyzed in similar patients, as well as those who present with recurrent vomiting episodes of unknown ethiology. Acknowledgment: This work was supported in part by the Israeli Ministry of Health, grant no. 3272-95, and by the Mirsky Foundation. The authors thank C. Belaishe and E. Chen for expert technical assistance.