The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

Abstract

Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS. (HEPATOLOGY 2001;34:776-784.)The mitochondrial respiratory chain is a highly organized system involved in the ATP-generating, oxidative phosphorylation (OXPHOS) process. It is composed of 5 enzymatic complexes, which include more than 100 proteins. Thirteen of the polypeptides are encoded by mitochondrial DNA (mtDNA) whereas the remaining subunits by the nuclear genome.

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

“…20 It is also interesting to note that the magnitude of mtDNA depression was similar in adipose tissue of patients suffering from HIV-associated lipoatrophy 14 and in hepatic tissue of inherited mtDNA replication defects with liver failure. 21 Our investigations do not demonstrate a clear relationship between mtDNA depletion in hepatic tissue and an increase in serum lactate, but it is important to note that lactate levels were normal in virtually all patients. In contrast to previous reports, 22 there was no lactate elevation in individuals receiving stavudine compared with zidovudine, although lactate was somewhat higher with D drug treatment in our study.…”

Mutations in theMPV17 gene are responsible for rapidly progressive liver failure in infancy

“…6 At the histological level, all 4 of our cases exhibited similar features, including swollen granular hepatocytes, microvesicular steatosis, and focal pericellular and periportal fibrosis. Taken together, these findings are not specific and have been previously observed in other forms of mtDNA depletion due to molecular defects in other nuclear genes such as DGUOK 13 and POLG (Alpers syndrome). 14 The ultrastructure of MPV17-deficient mitochondria is characterized by dilated and distorted cristae and by central accumulation of the matrix, which displaces the cristae toward the periphery of the organelle and causes enlargement in some instances to an extreme degree.…”

Treatment with Lactose (Galactose)-Restricted and Medium-Chain Triglyceride-Supplemented Formula for Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency

“…Microvesicular fatty changes are a characteristic feature of Reye syndrome or hepatic mitochondrial DNA depletion syndrome (Becroft 1966;Mandel et al 2001), suggesting a low energy state of the liver. The pathogenesis of citrin deficiency is likely an energy shortage of the liver due to impaired glycolysis.…”