Fatal neonatal liver failure and mitochondrial cytopathy (oxidative phosphorylation deficiency): A light and electron microscopic study of the liver

Abstract

Mitochondrial cytopathies are multisystemic disorders of extremely variable expression due to a deficiency in oxidative phosphorylation. Cases have recently been reported in which fatal liver failure with neonatal onset was the major clinical and biochemical syndrome. In this series we reviewed the liver histology of 10 such patients who died in the first weeks of life (from 3 days to 6 mo). In six cases the diagnosis was confirmed by study of the mitochondrial respiratory chain in the muscle, liver or both; in the other four, appropriate tests were not available for diagnosis but symptoms were identical and all other diagnoses were ruled out. In all 10 cases we noted significant steatosis, mostly microvesicular; widespread hepatocytic, canalicular and bile duct cholestasis with bile thrombi and cholangiolar proliferation; and different degrees of hepatosiderosis and glycogen depletion. Fibrosis took varying forms: perisinusoidal, periportal with the formation of septa, even precirrhosis. In the two cases of infants who died, one at 5 and one 6 mo, micronodular cirrhosis was also present. Mitochondria, either densely or loosely packed, were abnormal-pleiomorphic with few or no cristae and a granular fluffy matrix. Dense, large granules were seen in two cases. The association of neonatal liver failure and hyperlactacidemia should lead to immediate examination of the respiratory chain. The expression of this mitochondrial cytopathy can be lethal, associated with severe liver damage due to the deficiency in oxidative phosphorylation.

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

“…Such ultrastructural abnormalities are not specific for MDS because they have been previously reported in other patients with respiratory chain disorders. 17 On the other hand, the detection of these ultrastructural features in patients who display early progressive liver failure, neurological abnormalities, lactic acidosis, hypoglycemia, and elevated plasma ␣-fetoprotein levels, should direct the clinician to the diagnosis of the hepatic form of MDS, to be confirmed by evaluation of mtDNA content. The prominent increase in the number of mitochondria, designated as "oncocytic change" or "oncocytic transformation" has been previously associated with a number of other conditions, normal or pathological.…”

“…The normal biochemical findings in muscle tissue of patients with hepatic MDS and the ethical difficulty to obtain a sufficiently large liver sample for complete enzymatic and molecular work-up, may lead to a significant under-diagnosis of this condition. It can be assumed that some of the previously reported infants 17,38 who died of undiagnosed liver failure and OXPHOS dysfunction may have suffered from hepatic MDS. The present description of the ultrastructural findings in a large cohort of patients can increase the diagnosis rate of hepatic MDS.…”

Mitochondrial respiratory chain disorders and the liver

“…Some patients dying of liver failure have shown no histological abnormalities except steatosis (29). In general, however, progression of the liver disease is associated with other changes.…”

Steatosis of indeterminate cause in a pediatric group: is it a primary mitochondrial hepatopathy?

“…14 The major features are a higher rate in male children, with serum alanine aminotransferase (ALT) levels that are usually higher than serum aspartate aminotransferase (AST) levels, and with hypertriglyceridemia and vague abdominal pain (which is usually the main reason for seeking clinical evaluation). [14][15][16] According to Mandel et al 17 and Bioulac-Sage et al, 18 childhood microvesicular steatosis may be associated with mitochondrial abnormalities relating to increased numbers of organelles. 18,19 There is also a correlation with respiratory chain defects and consequently impaired oxidative phosphorylation.…”

“…[14][15][16] According to Mandel et al 17 and Bioulac-Sage et al, 18 childhood microvesicular steatosis may be associated with mitochondrial abnormalities relating to increased numbers of organelles. 18,19 There is also a correlation with respiratory chain defects and consequently impaired oxidative phosphorylation. 20,21 When this type of abnormality occurs, transfer of electrons to oxygen molecules generates reactive oxygen species, thus producing superoxide anions and hydrogen peroxide.…”