Mitochondrial Hepatopathies

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Chapter 353 Mitochondrial Hepatopathies

Hepatocytes are rich in mitochondria due to the energy required for the process of metabolism and are a target organ for disorders in mitochondrial function. Defects in mitochondrial function can lead to impaired oxidative phosphorylation (OXPHOS), increased generation of reactive oxygen species, impairment of other metabolic pathways, and activation of mechanisms of cellular death. Mitochondrial disorders can be divided into primary, in which the mitochondrial defect is the primary cause of the disorder, and secondary, in which mitochondrial function is affected by exogenous injury or a genetic mutation in a nonmitochondrial gene (Chapter 81.4). Primary mitochondrial disorders can be caused by mutations affecting mitochondrial DNA (mtDNA) or by nuclear genes that encode mitochondrial proteins or cofactors (Table 353-1). Secondary mitochondrial disorders include diseases with an uncertain etiology such as Reye syndrome; disorders caused by endogenous or exogenous toxins, drugs, or metals; and other conditions in which mitochondrial oxidative injury may be involved in the pathogenesis of liver injury.


DGUOK, deoxyguanosine kinase; MPV17; POLG, polymerase γ; CoA, coenzyme A; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide.

Adapted from Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics and pathogenesis, Hepatology 45:1555–1565, 2007.


More than 200 gene mutations that involve mtDNA and nuclear DNA that encodes mitochondrial proteins are identified. Mitochondrial genetics are unique because mitochondria are able to replicate, transcribe, and translate their mitochondrial derived DNA independently. The mitochondrial genome encodes 2 ribosomal RNAs, 22 transfer RNAs, and 13 proteins of complex I, III, IV, and V of the respiratory chain. OXPHOS (the process of adenosine triphosphate [ATP] production) occurs in the respiratory chain located in the inner mitochondrial membrane and is divided into 5 multienzyme complexes: reduced nicotinamide adenine dinucleotide (NADH) coenzyme Q (CoQ) reductase (complex I), succinate-CoQ reductase (complex II), reduced CoQ-cytochrome c reductase (complex III), cytochrome-c oxidase (complex IV), and ATP synthase (complex V). The polypeptides that form these complexes are transcribed from both mitochondrial and nuclear DNA; mutations in either genome can result in disorders of OXPHOS.

Expression of mitochondrial disorders is complex and epidemiologic studies are hampered by technical difficulties collecting and processing tissue specimens needed to make accurate diagnoses, the variability in clinical presentation, and the fact that most disorders display maternal inheritance with variable penetrance (Chapter 75). mtDNA mutates 10 times more frequently than nuclear DNA secondary to a lack of introns, protective histones, and an effective repair system in mitochondria. Mitochondrial genetics also display a threshold effect in that the type and severity of mutation required for clinical expression varies among people and organ systems. Despite this, it has been estimated that mitochondrial diseases have a prevalence of 11.5 cases per 100,000 populations. Treatments for mitochondrial hepatopathies are supportive. The role of liver transplantation is controversial given the multisystemic involvement.

Primary Mitochondrial Hepatopathies

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