Recent advances in our understanding of the structure and function of mitochondria have led to the recognition that inherited and acquired
mitochondrial dysfunction may be responsible for diseases affecting the liver and other organ systems. Mitochondrial health may also determine hepatocyte survival in other hepatic disorders not directly related to the mitochondrion. Primary mitochondrial hepatopathies are conditions in which there are inherited defects in structure or function of the mitochondria, most of which involve the respiratory chain and oxidative phosphorylation,
fatty acid oxidation, the
urea cycle, and other pathways confined to mitochondria. Maternally inherited mutations or deletions of the mitochondrial genome, or putative nuclear gene mutations encoding electron transport
proteins, cause defective electron transport, oxidative stress, impaired oxidative phosphorylation, and other metabolic derangements that lead to
hepatic failure or chronic
liver dysfunction in affected children. The
mitochondrial DNA (
mtDNA) depletion syndrome, which similarly leads to
liver failure and neurologic abnormalities, is caused by a putative nuclear gene that controls
mtDNA replication or stability. Other proven or suspected primary mitochondrial hepatopathies include
Pearson's marrow-pancreas syndrome,
Alpers disease, mitochondrial neurogastrointestinal encephalomyopathy syndrome, and
Navajo neuropathy. Secondary mitochondrial hepatopathies are conditions in which the mitochondria are major targets during liver injury from another cause, such as
metal overload, certain drugs and toxins, alcoholic liver injury, and conditions of
oxidant stress. Diagnosis of
mitochondrial dysfunction may be difficult with currently available tools, however, elevated blood
lactate:
pyruvate ratios or arterial
ketone body ratios with characteristic liver histology are initial tests. Measuring respiratory chain
enzyme activities,
mtDNA levels, and searching for
mtDNA mutations and deletions are more specific tests. Treatment of these disorders is currently empirical, involving agents that may improve the redox status of mitochondria, promote electron flow, or act as mitochondrial
antioxidants.
Liver transplantation has occasionally been successful in patients who lack other systemic involvement.