ABSTRACT
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 phospho-rylation, 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
en-cephalomyopathy 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.
KEY WORDS
oxidative phosphorylation - respiratory chain - genetic defects - free radicals -
childhood liver disease
