ReviewMitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemia
Section snippets
Background
Steatosis is a common pathologic finding noted on liver biopsy characterized by excess fat accumulation within liver cells. This histologic abnormality is seen in a number of clinical settings which result in inadequate β-oxidation of fatty acids due to increased delivery, decreased secretion, or impaired metabolism of hepatic lipids (Table 1). While hepatic fat accumulation is classically associated with excess alcohol consumption, steatosis can be seen in those with minimal alcohol intake;
Association between NRTIs and mitochondrial dysfunction
NRTIs exert their antiviral effect via inhibition of reverse transcriptase, incorporation into the proviral transcript, and chain termination of the HIV viral genome. As a result of their structural similarity to endogenous nucleic acids, NRTIs may also affect cellular deoxyribonucleic acid (DNA) polymerases. While nuclear polymerases are minimally inhibited by NRTIs at physiologic concentrations, mitochondrial DNA polymerase γ appears much more susceptible to inhibition by nucleoside and
Mitochondria and lactic acid formation
Lactate is the product of glycolysis favored under anaerobic conditions or when mitochondrial oxidative function is impaired. It is produced by most metabolically active tissues at low levels and cleared predominantly by the liver and kidneys, where it is oxidized to pyruvate and used as a substrate for gluconeogenesis or the tricarboxylic acid cycle (Fig. 2). Blood levels of lactate are under tight homeostatic control, with additional uptake facilitated in tissues such as skeletal muscle and
Mitochondria and hepatic steatosis
Whereas fatty liver has been described as a common component of NRTI-associated lactic acidosis, the frequency of steatosis in HIV-infected individuals with mild hyperlactatemia or normal lactate values is unknown. Given the prevalence of NAFLD and NASH in the general population, it is reasonable to expect HIV-seropositive individuals may develop these disorders independently of antiretroviral therapy. Normally fat composes less than 5% of the liver parenchyma by weight; intrahepatic fat in
Diagnosis and treatment of hepatic steatosis and lactate elevations
As hepatic steatosis is often asymptomatic, diagnosis is frequently made during the evaluation of liver enzyme abnormalities in the general and HIV-infected populations. Elevation of alanine aminotransferase (ALT) levels up to 2–3 times the upper limit of normal is the most frequent lab abnormality encountered, although some patients may have normal hepatic enzymes. When present, symptoms are usually mild and non-specific including fatigue, lethargy, and occasional abdominal discomfort. Rarely,
Summary
The advent of HAART has brought substantial improvements in HIV-related morbidity and mortality, but toxicities of chronic antiretroviral therapy are creating new therapeutic challenges. Many of these toxicities are thought to reflect cumulative mitochondrial damage which is mediated primarily by NRTIs. The most serious manifestation of sustained injury to mitochondria is seen in patients with lactic acidosis and hepatic steatosis (Fig. 4). Although much remains to be learned about the
Acknowledgements
Funding in part provided through the Adult AIDS Clinical Trials Group, NIH/NIAIDS grant AI34853.
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