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The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies
H Mandel1, C Hartman, D Berkowitz
1Metabolic Disease Unit, Rambam Medical Center, Israel.
Insights
Mitochondrial DNA depletion syndrome (MDS) causes liver failure in infants. Ultrastructural liver changes, including oncocyte-like mitochondria and steatosis, suggest this respiratory chain disorder.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Pediatric Pathology
Background:
- Mitochondrial respiratory chain disorders are a known cause of pediatric liver failure.
- Mitochondrial DNA depletion syndrome (MDS) is characterized by reduced mitochondrial DNA levels.
- The hepatic form of MDS presents with severe liver dysfunction in infants.
Purpose of the Study:
- To investigate the ultrastructural changes in liver tissue from infants with the hepatic form of MDS.
- To identify diagnostic histological patterns associated with MDS-related liver failure.
- To correlate ultrastructural findings with biochemical evidence of respiratory chain dysfunction.
Main Methods:
- Electron microscopy was used to examine liver biopsies from 10 infants with hepatic MDS.
- Biochemical assays assessed the activity of mitochondrial respiratory chain complexes.
- Southern blot analysis confirmed mitochondrial DNA depletion in liver tissue.
Main Results:
- Hepatocytes exhibited "oncocytic transformation" with abnormal mitochondria (size, shape, cristae, matrix) and microvesicular steatosis.
- Decreased activity of respiratory chain complexes I, III, and IV was observed in some patients.
- Mitochondrial DNA depletion was confirmed in 6 out of 10 patients.
Conclusions:
- The combined ultrastructural findings in hepatocytes present a diagnostic pattern suggestive of a respiratory chain disorder.
- These histological changes, particularly oncocytic transformation and steatosis, are key indicators of hepatic MDS.
- Diagnosis of hepatic MDS can be supported by recognizing these specific ultrastructural liver abnormalities in the appropriate clinical context.
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.
