Mitochondrial respiratory chain disorders and the liver

Abstract

Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood but they are probably under-diagnosed, partly due to under-recognition and partly due to the difficulty of investigation. It is particularly important to look for mitochondrial disorders if the liver disease presents with hypoglycaemia and lactic acidaemia or if it is accompanied by neurological, muscle or renal tubular abnormalities. Respiratory chain defects have been demonstrated in a number of patients who die of liver failure following severe epilepsy; this includes at least some cases of Alpers syndrome or 'progressive neuronal degeneration of childhood'. In mitochondrial liver disease, histology usually shows steatosis, often accompanied by fibrosis, cholestasis and loss of hepatocytes. Unless the clinical picture suggests a particular syndrome, such as Pearson syndrome, biochemical assays and histochemistry should be the initial investigations. Ideally, investigations should be carried out on liver as well as more standard tissues, such as muscle, since defects can be tissue-specific. Nuclear defects and nitDNA point mutations are probably responsible for many cases of mitochondrial liver disease but, as yet, the only identified molecular abnormalities are mtDNA rearrangements and mtDNA depletion. Treatment of mitochondrial liver disease is unsatisfactory. If the disease is confined to the liver, transplantation may be appropriate but in several patients transplantation has been followed by the appearance of disease in other organs, particularly the I brain.Mitochondria are subcellular organelles whose primary role is the oxidation of fuels to produce energy. This process is accomplished by a series of enzymes known as the mitochondrial respiratory chain. Mitochondria are the site of many other metabolic pathways but the term 'mitochondrial disease' is generally used to refer to those conditions associated with respiratory chain defects. Since the oxidation of fuels is important for almost all cells, defects of the mitochondrial respiratory chain can cause disease in any organ of the body. Liver disease is a relatively common problem in respiratory chain disorders that present during infancy. These genetic disorders are the sub,ject of the current review. Secondary defects of tlhe respiratory chain caused, for example, by drugs or toxins, can also lead to liver disease but these disorders are only considered briefly in the section on pathogenesis, where key references are giiven. Mitochondrial biochemistryMany oxidative reactions occur within mitochondria, including the D-oxidation pathway for fatty acids, the oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex and the oxidation of acetyl-CoA by the tricarboxylic acid cycle. These reactions all generate reduced cofactors, such as the reduced forms of flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). The mitochondrial respiratory chain couples the reoxidation of these cofactors to the for...

Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

“…These findings described below, together with the decrease of liver mitochondrial respiratory chain complex activity and of mtDNA copy number, have led to a wrong diagnosis of MRCD. Patient 1 had an oncocytic aspect of hepatocytes, a finding not reported so far in PFIC2 and described in MRCD (Morris 1999;Davit-Spraul et al 2010). Analysis of biliary bile acids performed at the time of liver transplantation has suggested PFIC2, biliary bile acid concentration being <1 mmol/L (Davit-Spraul et al 2010).…”

“…Recently, Molleston et al (2013) established a tiered approach to guide the evaluation of suspected mitochondrial disease. Clinical presentation of MRCD is heterogeneous and several organs may be affected including liver, brain, muscle, and/or kidney (Cormier-Daire et al 1997;Morris 1999). Isolated liver disease, observed in some cases, may represent an indication to liver transplantation, whereas multiorgan injury represents a contraindication (Dubern et al 2001).…”

Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats

“…[28] . Furthermore, FFAs not only promote hepatic lipotoxicity via a lysosomal pathway [29] but are also the most important source of reactive oxygen species (ROS) [30,31] . Some studies suggest that the excessive accumulation of saturated FFAs in liver cells directly induces mitochondrial dysfunction and oxidative stress [32] .…”

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

“…Respiratory chain defects are not rare and are known to cause early liver failure in infancy, 21 thereby leading to a change in fatty acid oxidation. 27 Changes to mitochondrial β-oxidation may result in accumulation of fatty acids in the cytosol, and this is typically represented by microvesicular steatosis.…”