Journal of Hepatology
Volume 43, Issue 2 , Pages 207-209, August 2005

Mitochondrial hepatopathies

  • Patrick F. Chinnery

      Affiliations

    • Department of Neurology, Mitochondrial Research Group, The Medical School, The University of Newcastle upon Tyne, Framlington Place, Newcastle upon NE2 4HH, UK
    • Corresponding Author InformationCorresponding author. Tel.: +44 191 222 8334; fax: +44 191 222 8553.
    • ,
  • Salvatore DiMauro

      Affiliations

    • Department of Neurology, Columbia University Medical Center, New York, NY, USA

published online 01 June 2005.

See Article, pages 333--341

Article Outline

 

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] 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 16.5Kb 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 [2], [3]. 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]. 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 [4], [5] or in a gene encoding an assembly factor for the complex [6], [7]. 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]. Multiple complex defects in children with liver involvement can be due to primary pathogenic point mutations [8] or single deletions of mtDNA [9], 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 [10], [11], [12]. Candidate gene studies a few years ago identified mutations in the thymidine kinase gene (TK2) in infants with mitochondrial depletion myopathy [13], and in the deoxyguanosine kinase gene (DGUOK) in infants with depletion and hepatocerebral syndrome [14]. 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] 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 [15], [16]. 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], with liver involvement in ∼1/5 [18], 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 [19], [20]. 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], although this is contentious [22]. Also of great interest, there is increasing evidence that mitochondrial mechanisms play an important role in common liver diseases, including viral hepatitis [23] and non-alcohol related steatohepatitis [24]. 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 1. Mitochondrial hepatopathies
GeneticMolecular defect
Single 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 therapy
Non-alcohol related steatohepatitis ?
Hepatitis B/C ?
Hepatocellular carcinoma?

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Acknowledgements 

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).

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References 

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PII: S0168-8278(05)00324-7

doi:10.1016/j.jhep.2005.05.012

Journal of Hepatology
Volume 43, Issue 2 , Pages 207-209, August 2005

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