Portal de Periódicos da CAPES

Mitochondrial hepatopathies

2005; Elsevier BV; Volume: 43; Issue: 2 Linguagem: Inglês

10.1016/j.jhep.2005.05.012

1600-0641

Patrick F. Chinnery, Salvatore DiMauro,

Pediatric Hepatobiliary Diseases and Treatments

Mitochondria are double-membrane intracellular organelles and the main source of the high-energy phosphate molecule adenosine triphosphate (ATP), which is essential for all active intracellular processes. The biosynthetic and detoxifying properties of the liver are highly dependent upon ATP, so it comes as no surprise that hepatocytes are packed with mitochondria, and disorders of mitochondrial function cause liver disease. The key questions for the hepatologist are: how do mitochondrial hepatopathies present clinically? What are their pathological features? How should they be managed? And, finally, how common are they? In this issue of the Journal, Labarthe and colleagues [[1]Labarthe F. Dobbelaere D. Devisme L. De Muret A. Jardel C. Taanman J.-W. et al.Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency.J Hepatol. 2005; 43: 333-341Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] address some of these issues, providing a definitive clinical, biochemical, and morphological description of one of these disorders. ATP is synthesised by the respiratory chain on the inner mitochondrial membrane. Reduced co-factors (NADH and FADH2) generated from the intermediary metabolism of carbohydrates, proteins, and fats donate electrons to complexes I and II, and these flow down to an electrochemical gradient to complexes III and IV, in the process pumping protons (H+) out of the mitochondrial matrix into the inter-membrane space. The resulting mitochondrial membrane potential is harnessed by complex V to synthesise ATP. This process is called oxidative phosphorylation (OXPHOS). The respiratory chain is controlled by two genomes. Thirteen essential polypeptides (structural subunits) are synthesised from small 16.5 Kb circles of double stranded DNA contained within the mitochondria themselves (mtDNA). MtDNA also codes for the 24 RNAs required for intra-mitochondrial protein synthesis. However, it is estimated that human mitochondria contain well over 1000 different proteins, of which many are either directly or indirectly involved in supporting the respiratory chain. These include over 70 nuclear-encoded respiratory chain subunits, and an array of enzymes and co-factors required to maintain mitochondrial DNA, and to enable intra-mitochondrial transcription and translation. These factors are critically important in maintaining normal liver function. Hepatic involvement in primary (i.e. genetic) mitochondrial disorders rarely presents in adult life, but is a common feature in childhood respiratory chain disease, particularly in the neonatal period [2Morris A.A. Mitochondrial respiratory chain disorders and the liver.Liver. 1999; 19: 357-368Crossref PubMed Scopus (61) Google Scholar, 3Cormier-Daire V. Chretien D. Rustin P. et al.Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation.J Pediatr. 1997; 130: 817-822Abstract Full Text PDF PubMed Scopus (83) Google Scholar]. It is, generally, thought that liver complications are a late feature of a multi-system disorder, such as Leigh syndrome. Typically, infants present with developmental delay, central nervous system involvement (encephalopathy and seizures), hypotonia, and myopathy. Renal tubulopathy, anaemia, cardiac, or gastrointestinal features are also frequently seen. Early symptoms of hepatic involvement tend to be masked by other organ involvement, but include failure to thrive, vomiting and feeding difficulties [[2]Morris A.A. Mitochondrial respiratory chain disorders and the liver.Liver. 1999; 19: 357-368Crossref PubMed Scopus (61) Google Scholar]. Hypoglycaemia is one clue, along with mild to moderate hepatomegaly. Elevated liver transaminase levels often provide the first evidence of liver involvement, but rarely rise above 10 times the upper limit of normal. In some infants, the liver dysfunction may spontaneously reverse or remain stable, but in some there is rapid progression to cholestasis, coagulopathy, and ascites. Pathologically, the only feature may be steatosis, but this can progress to fibrosis, cholestasis and widespread hepatocellular necrosis. Biochemical studies reveal single or multiple respiratory chain complex defects, which may be restricted to the liver and remain undetectable in skeletal muscle or skin fibroblasts. Patients with an OXPHOS defect affecting a single respiratory chain complex may have a mutation in a gene encoding a subunit of that complex [4Ugalde C. Triepels R.H. Coenen M.J. et al.Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene.Ann Neurol. 2003; 54: 665-669Crossref PubMed Scopus (97) Google Scholar, 5Uusimaa J. Finnila S. Vainionpaa L. et al.A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child with Alpers-Huttenlocher-like disease.Pediatrics. 2003; 111: e262-e268Crossref PubMed Scopus (31) Google Scholar] or in a gene encoding an assembly factor for the complex [6de Lonlay P. Valnot I. Barrientos A. et al.A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.Nat Genet. 2001; 29: 57-60Crossref PubMed Scopus (266) Google Scholar, 7Valnot I. Osmond S. Gigarel N. et al.Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.Am J Hum Genet. 2000; 67: 1104-1109Abstract Full Text Full Text PDF PubMed Google Scholar]. For example, SCO1 is involved in the assembly of complex IV (cytochrome c oxidase), and mutations in SCO1 may present with hepatic failure and encephalopathy [[7]Valnot I. Osmond S. Gigarel N. et al.Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.Am J Hum Genet. 2000; 67: 1104-1109Abstract Full Text Full Text PDF PubMed Google Scholar]. Multiple complex defects in children with liver involvement can be due to primary pathogenic point mutations [[8]Vallance H.D. Jeven G. Wallace D.C. Brown M.D. A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation.Pediatr Cardiol. 2004; 25: 538-540Crossref PubMed Scopus (61) Google Scholar] or single deletions of mtDNA [[9]McDonald D.G. McMenamin J.B. Farrell M.A. Droogan O. Green A.J. Familial childhood onset neuropathy and cirrhosis with the 4977bp mitochondrial DNA deletion.Am J Med Genet. 2002; 111: 191-194Crossref PubMed Scopus (20) Google Scholar], but are more often associated with dramatically reduced amounts of mtDNA in affected tissues. Recent work has identified the primary molecular defects in a significant proportion of the 'mtDNA depletion syndromes'. Within the last year, compound heterozygous mutations in the mitochondrial DNA polymerase γ gene (POLG1) have been found in a large proportion of cases of Alpers syndrome (also called the Alper-Huttenlocher syndrome), which presents with refractory seizures, psychomotor regression, cortical blindness and liver disease with micronodular cirrhosis [10Naviaux R.K. Nguyen K.V. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.Ann Neurol. 2004; 55: 706-712Crossref PubMed Scopus (366) Google Scholar, 11Ferrari G. Lamantea E. Donati A. et al.Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA.Brain. 2005; 128: 723-731Crossref PubMed Scopus (262) Google Scholar, 12Davidzon G, Mancuso M, Ferraris S, et al. POLG mutations and Alpers syndrome. Ann Neurol in press.Google Scholar]. Candidate gene studies a few years ago identified mutations in the thymidine kinase gene (TK2) in infants with mitochondrial depletion myopathy [[13]Saada A. Shaag A. Mandel H. Nevo Y. Eriksson S. Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.Nat Genet. 2001; 29: 342-344Crossref PubMed Scopus (497) Google Scholar], and in the deoxyguanosine kinase gene (DGUOK) in infants with depletion and hepatocerebral syndrome [[14]Mandel H. Szargel R. Labay V. et al.The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.Nat Genet. 2001; 29: 337-341Crossref PubMed Scopus (469) Google Scholar]. Both TK2 and DGOUK regulate intra-mitochondrial nucleoside pools, thus enabling the normal continual synthesis of mtDNA. The current paper by Lebarthe and colleagues [[1]Labarthe F. Dobbelaere D. Devisme L. De Muret A. Jardel C. Taanman J.-W. et al.Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency.J Hepatol. 2005; 43: 333-341Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] provides a definitive description of the hepatology associated with DGUOK mutations. Labarthe et al. studied seven cases with hepatocerebral syndrome and mtDNA depletion. They confirm the early presentation in the immediate postnatal period with elevated blood lactate levels, hypoglycaemia and hyperammonaemia in some cases, leading to rapidly progressive liver failure with cholestasis, ascites, and a coagulopathy which was fatal within the first few months of life. However, in their cases, the neurological features were overshadowed by the hepatic picture, and brain imaging was unhelpful. Skeletal muscle, the cornerstone of investigation for most suspected mitochondrial disorders, was normal. The liver histology revealed multifocal hepatocellular damage, with steatosis, cholestasis and fibrosis—but none of the patients had portal hypertension. The diagnosis was confirmed by enzymatic analysis of respiratory chain complexes and by measuring mtDNA levels in the liver. This led to the identification of a novel four base pair insertion in the DGOUK gene, which reduced the steady-state levels of DGUOK mRNA. Although impaired enzyme activity would be expected, this could not be confirmed using one assay of DGUOK activity. This paper demonstrates the importance of studying affected tissues whenever possible, because the biochemical defect may no be apparent in unaffected tissues. This may seem obvious—but conventional diagnostic approaches focus on less invasive techniques, particularly in neonates, such as cultured skin fibroblasts or skeletal muscle. This work has important implications for clinical management. Unfortunately, at present we can only offer supportive care, although there have been recent successes with liver transplantation for liver-specific mitochondrial diseases [15Dubern B. Broue P. Dubuisson C. et al.Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children.Transplantation. 2001; 71: 633-637Crossref PubMed Scopus (46) Google Scholar, 16Salviati L. Sacconi S. Mancuso M. et al.Mitochondrial DNA depletion and dGK gene mutations.Ann Neurol. 2002; 52: 311-317Crossref PubMed Scopus (142) Google Scholar]. However, identifying the underlying molecular defect facilitates genetic counselling and prenatal diagnosis, thereby preventing disease in future offspring. How common are these disorders? Recent studies have shown that mitochondrial respiratory chain disease affects ∼1 in 20,000 children under 16 [[17]Skladal D. Halliday J. Thorburn D.R. Minimum birth prevalence of mitochondrial respiratory chain disorders in children.Brain. 2003; 126: 1905-1912Crossref PubMed Scopus (369) Google Scholar], with liver involvement in ∼1/5 [[18]Darin N. Oldfors A. Moslemi A.R. Holme E. Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities.Ann Neurol. 2001; 49: 377-383Crossref PubMed Scopus (275) Google Scholar], but given the difficulties with diagnosis, these figures are likely to be an under-estimate. Perhaps more important in epidemiological terms are the acquired mitochondrial hepatopathies seen in patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs). Fatal hepatopathy with lactic acidosis and mtDNA depletion is a well recognised complication of NRTI therapy, although it is less common with new-generation drug combinations [19Lewis W. Day B.J. Copeland W.C. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective.Nat Rev Drug Discov. 2003; 2: 812-822Crossref PubMed Scopus (429) Google Scholar, 20Nunez M. Soriano V. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management.Drug Saf. 2005; 28: 53-66Crossref PubMed Scopus (98) Google Scholar]. It may be possible to prevent irreversible liver damage by detecting the lactic acidosis and mtDNA depletion before the liver failure becomes clinically manifest [[21]Montaner J.S. Cote H.C. Harris M. et al.Mitochondrial toxicity in the era of HAART: evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy.J Acquir Immune Defic Syndr. 2003; 34: S85-S90Crossref PubMed Scopus (61) Google Scholar], although this is contentious [[22]Chiappini F. Teicher E. Saffroy R. et al.Prospective evaluation of blood concentration of mitochondrial DNA as a marker of toxicity in 157 consecutively recruited untreated or HAART-treated HIV-positive patients.Lab Invest. 2004; 84: 908-914Crossref PubMed Scopus (51) Google Scholar]. Also of great interest, there is increasing evidence that mitochondrial mechanisms play an important role in common liver diseases, including viral hepatitis [[23]Wheelhouse N.M. Lai P.B. Wigmore S.J. Ross J.A. Harrison D.J. Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver.Br J Cancer. 2005; 92: 1268-1272Crossref PubMed Scopus (42) Google Scholar] and non-alcohol related steatohepatitis [[24]Fromenty B. Robin M.A. Igoudjil A. Mansouri A. Pessayre D. The ins and outs of mitochondrial dysfunction in NASH.Diabetes Metab. 2004; 30: 121-138Abstract Full Text PDF PubMed Scopus (228) Google Scholar]. The work by Lebarthe and colleagues reminds us of the histopathological features shared by some genetically determined and acquired mitochondrial hepatopathies, suggesting that further studies in both areas may be mutually beneficial, and hopefully lead us towards a definitive treatment for these disorders (Table 1).Table 1Mitochondrial hepatopathiesGeneticMolecular defectSingle respiratory chain complex defectsStructural subunit genes (e.g. MTND6)Complex assembly factor genes (e.g. BCS1L, SCO1)Multiple complex defectsMtDNA mutation (deletion or point mutation)Thymidine kinase 2 (TK2)Deoxyguanosine kinase (DGUOK)Polymerase γ (POLG1)AcquiredNucleoside analogue retroviral therapyNon-alcohol related steatohepatitis ?Hepatitis B/C ?Hepatocellular carcinoma? Open table in a new tab PFC is a Wellcome Trust Senior Fellow in Clinical Science. SDM is supported by NIH grants NS11766, and HD32062, a grant from the Muscular Dystrophy Association, and by the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF).