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

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 syndro me (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed pro gressive liver failure, neurological abnormalities, hypoglycemia, and lacti c acidosis that warranted investigation of respiratory chain disorder in li ver tissue, specifically expressing the disease. Decreased activity of resp iratory 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 f illed with mitochondria having aspects of "oncocytic transformation," assoc iated with numerous changes in shape, size, cristae, and matrix. The change s were virtually identical in all specimens. In many hepatocytes, microvesi cular steatosis was the salient feature. Additional findings included chole stasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosideros is in hepatocytes and sinusoidal cells. In some hepatocytes the damage appe ared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are n ot specific, when taken together, they show a diagnostic pattern highly sug gestive of a respiratory chain disorder. In the appropriate clinical contex t, these findings can direct the clinician towards the diagnosis of hepatic MDS.