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• W2036996801 abstract "Orthotopic Liver Transplantation for Mitochondrial Respiratory Chain Disorders: A Study of Five Children. Transplantation 2001; 71: 633 Dubern B, Broue P, Dubuisson C, Cormier-Daire V, Habes D, Chardot C, Devictor D, Munnich A, and Bernard O. During the last two decades, mitochondrial respiratory chain disorders have been recognized to cause acute and chronic liver failure, usually associated with variable involvement of other organs (1). Over the same period of time, liver transplantation has become an accepted treatment option for end-stage liver disease, with only a few definite contraindications, such as extrahepatic disseminated malignancy or multiorgan failure. The number of patients awaiting liver transplantation is on a continuous increase, despite attempts at enlarging the donor pool by surgical innovations including living related donation. It is therefore important to have a judicious approach to transplantation for conditions where the long-term outcome is poor or unknown. These would include mitochondrial respiratory chain disorders. In this issue of Transplantation Dubern et al. (2) report their experience of orthotopic liver transplantation in five children affected by this condition. The outcome is variable toward survival and progression of the disease in other organs, but of the three survivors, only one appears to have no obvious extrahepatic involvement. Mitochondria constitute about one-fifth of the cytoplasmic volume of the liver cells. They have a dual membrane framework: an outer membrane that holds a highly folded inner membrane, matrix, and genome. These organelles act as powerhouse for the cells by conserving the energy from oxidation of substrates through the work of enzymes called the mitochondrial respiratory chain (3). The energy is conserved as an electrochemical proton gradient across the inner membrane, although the matrix contains enzymes of the fatty acid oxidation, tricarboxylic acid cycle, urea cycle, and other metabolic pathways (Fig. 1). Most of the enzymes are coded for by nuclear DNA. In addition to nuclear DNA, mitochondria are unique in possessing a separate genome called mitochondrial DNA (mtDNA) derived from the unfertilized ovum. As sperm contains almost no mitochondria, the mtDNA inheritance is exclusively maternal (3,4). In humans, mtDNA is a circular double-stranded molecule, 16,569 base pairs long, encoding for 2 ribosomal RNAs and 22 transfer RNAs. It also encodes for 13 proteins involved in the respiratory chain complex, of which 7 subunits belong to complex I, 1 to complex III, 3 to complex IV, and 2 to complex V. Nuclear DNA is responsible for the encoding of the remaining subunits and of all the other mitochondrial proteins. Mutations in both mtDNA and nuclear DNA can affect the mitochondrial function. Compared with nuclear DNA, mtDNA has a higher rate of mutation, lacks protective histones, has an ineffective gene repair system and is constantly exposed to reactive oxygen species produced by oxidative phosphorylation. There are 2–10 copies of mtDNA in each mitochondria and every hepatocyte contains several mitochondria making it possible for both normal and mutated mtDNA to coexist in the same cell, a condition called heteroplasmy that allows the persistence of lethal mutations. During cell division the mitochondria segregate randomly, thus changing the ratio of normal to mutated mtDNA in daughter cells, the phenotype of which is determined by the relative proportion of the normal to the mutated mtDNA. The threshold of mutated mtDNA needed to produce a deleterious phenotype varies among individuals and among organs. For example, to cause muscle disease, transfer RNA point mutations must affect >85–90% of mtDNA (3). Similar calculations for mitochondrial hepatopathies are not yet available. Figure 1: Schematic structure of a mitochondrion, with the electron transport chain in the inset. nDNA, Nuclear DNA; mtDNA, mitochondrial DNA; TCA, tricarboxylic acid; FAO, fatty acid oxidation; c, complex; UQ, ubiquinone; Cyt C, cytochrome C.Several mechanisms account for the phenotype of mitochondrial disorders, such as lack of energy production for cellular metabolism, inhibition of β-oxidation of fats, increased production of reactive oxygen species, loss of mitochondrial calcium, and increase in mitochondrial membrane permeability. These mechanisms lead to the steatosis, cell death, and fibrosis seen in primary mitochondrial hepatopathies, and are also involved in mitochondrial injury secondary to drugs (valproic acid, salicylates, antiviral drugs such as FIAU, AZT, and DDI etc.), toxins (cyanide, ethanol, and bacterial toxins) or iron and copper overload (5). Clinical features and molecular defects of hepatic mitochondrial respiratory chain disorders are summarized in Table 1. The unique feature of heteroplasmy accounts for the diversity of the clinical syndrome. The liver disease varies from mild elevation of liver enzymes to end stage liver disease. Similarly the severity of disease is variable in other organ systems. Organs with a high cell turnover, as bone marrow, liver, and intestine, tend to improve with time, as cells with lesser degree of heteroplasmy tend to have selective survival advantage over cells that have a higher number of abnormal mitochondria, although organs with little or no cell replication, such as brain or muscle, deteriorate progressively. Table 1: Hepatic mitochondrial respiratory chain disordersAlthough liver histology is not specific, micro- and macrovesicular steatoses are consistent features in mitochondrial disorders. A varying degree of fibrosis is observed in the majority of patients, and biliary features such as canalicular cholestasis, bile plugs, and bile duct proliferation are not uncommon. Depending on the clinical presentation, there is a variable degree of hepatocellular necrosis. Electron microscopy shows abnormalities of the mitochondrial membrane, a very dense matrix, and at times inclusions. These changes are not uniform, with adjacent cells showing no abnormalities. The follow-up of the four survivors after liver transplant for mitochondrial disorders reported in the literature, including the patient from Dubern et al. (2) is still too short to predict their long-term outcome. However, transplant appears to be an option for patients with isolated liver involvement. A high degree of suspicion while investigating children with liver disease to search for mitochondrial respiratory chain disorders is essential. In addition to the scheme outlined by Dubern et al. (2) we do perform muscle biopsy, bone marrow aspirate, cerebrospinal fluid examination, and liver biopsy under a single anesthesia, after correcting the coagulopathy with fresh frozen plasma or exchange transfusion. Liver and muscle biopsies, transported in liquid nitrogen, are promptly processed for quantitative assessment of the respiratory chain enzyme complexes. If the investigations suggest neurological or muscular involvement liver transplantation should not be attempted, as the natural history of the disease in these organs is one of progressive worsening. This approach should select the small number of patients with isolated liver involvement, likely to benefit from a transplant, without using indiscriminately the scarce donor organ pool." @default.
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• W2036996801 title "LIVER TRANSPLANTATION FOR MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS: TO BE OR NOT TO BE?" @default.
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