Mitochondrial Abnormalities in HCV and HCV/HIV Coinfection

This small Irish study found 11 of 14 (78%) of patients with non-alcoholic steato-hepatitis (NASH) had abnormal mitochondrial DNA. Since NRTIs, used for treating HIV, may cause mitochondrial damage, these findings may raise a potential concern. It's been suggested by studies that mitochondrial toxicity from NRTIs may be associated with lipodystrophy. If mitochondria damage in HCV only occurs in liver cells, than lipodystrophy may or may not be affected. Could damaged mitochindria in liver cells affect lipodystrophy? I don't think we know but I think it might. The mitochondria in the coinfected person's liver cells may get hit twice-- by NRTIs and HCV. I guess we don't know if NRTIs can cause mitochondrial damage in the liver cells. Bear in mind, it's also been suggested that you may need to reach a certain threshold level of mitochondrial damage to incur a real and certain negative affect. But I don't think we know yet what that threshold level is. And, other factors can cause mitochondrial damage, such as genetic and environmental factors.

     Bohan Alan, ST VINCENTS Hosp, Dublin Ireland; Olivia Droogan, BEAUMONT Hosp, Dublin Ireland; Niamh Nolan, ST VINCENT'S Hosp, Dublin Ireland; Philip Mayne, TEMPLE STREET CHILDREN'S Hosp, Dublin Ireland; John Bonham, SHEFFIELD CHILDREN'S Hosp, Sheffield United Kingdom; Paul Thornton, Acad Hosp, Philadelphia, PA; Michael A Farrell, BEAUMONT Hosp, Dublin Ireland; John E Hegarty, St Vincent's Univ Hosp, Dublin Ireland

Non-alcoholic steatohepatitis (NASH) is a diagnosis based on histological criteria in patients who consume minimal quantities of alcohol. Traditionally associated with diabetes, obesity and female gender, it is a well-described condition, the pathogenesis of which is unknown. Abnormalities of mitochondrial DNA (mtDNA) and fatty acid metabolism have been observed in alcohol, drug related and inherited metabolic disorder related fatty liver damage and may play a role in the pathogenesis of NASH. The aim of this study was to assess the prevalence of mitochondrial genetic abnormality and fatty acid -oxidation deficiency in a group of 14 patients who fulfilled histological criteria for NASH and 24 controls.

The study group, with a mean age 44.1 (range 29-60) years, was non-obese (BMI<32), non-diabetic, did not consume alcohol and had no known aetiological associations with hepatic steatosis. Twenty-four controls, with a mean age of 44.5 (range 31-61) included 8 normal donor, 8 obesity related steatosis and 8 non-fatty chronic HCV liver biopsies. Using standard DNA extraction, polymerase chain reaction (PCR) and gel electrophoretic techniques it was found that eleven of fourteen (78.6%) NASH biopsies expressed abnormal mtDNA. Ten (71.4%) expressed a 4977-bp mtDNA gene deletion, compared to none of eight normal, none of eight obese (BMI>35) and none of 8 HCV liver biopsy specimens. One patient with NASH expressed the MERRF 8344 mutation. In total, 11(78.5%) of patients with NASH and none of the controls expressed abnormal mtDNA. Using spectrophotometric assay techniques, carnitine levels were within the normal range in all patients while analysis of fatty acid -oxidation did not indicate functional deficiency of intramitochondrial enzymes. The pathogenesis of NASH is incompletely understood, but histological similarity to other forms of mitochondrial related fatty liver disease and the detection of mitochondrial DNA abnormalities in some patients with NASH would suggest that genetic and/or acquired mitochondrial dysfunction play a role in the development of this condition.