Mitochondrial Hepatopathies: Disorders of Fatty Acid Oxidation and the Respiratory Chain

Pathophysiology

The first step in fatty acid metabolism is lipolysis in response to fasting, resulting in circulating free fatty acids (FFAs). FFAs are then transported across the plasma membrane by specific FFA transporters and are activated to coenzyme A (CoA) esters in the cytosol by acyl-CoA synthetases before entry into the mitochondria through the carnitine cycle for further metabolism. Long-chain acyl-CoA esters must first be conjugated to carnitine before active transport across the mitochondrial membrane and, once in the mitochondria, then are freed as acyl-CoA esters in the mitochondrial matrix, where the four step cycle of β-oxidation occurs. The carnitine cycle results in return of the freed carnitine moiety to the cytoplasmic pool. Carnitine itself is transported into cells by a dedicated transporter. Approximately half of the carnitine stores in the body are synthesized endogenously, and half are obtained by the diet. It tends to be low in pregnant women, and therefore newborns, but is sufficiently supplied in breast milk and newborn formulas to replenish levels in babies. Low carnitine levels in blood imply increased losses, usually urinary. Defects have been recognized in each of these steps.

β-Oxidation in the mitochondrial matrix is a four-step, cyclical process whereby fatty acids are sequentially shortened, with release of a molecule of acetyl-CoA with each cycle. The first two cycles of β-oxidation of long-chain fatty acids take place at the inner mitochondrial membrane using very-long-chain acyl-CoA dehydrogenase (VLCAD) and the associated mitochondrial trifunctional protein (MTP). This complex contains the other three enzymes needed to complete a cycle, including long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD). Reducing equivalents are generated from two of the reactions of FAO, which are shuttled to the electron transport chain by electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH).

Medium- and short-chain fatty acids can cross the mitochondrial membrane independent of carnitine or long-chain transporters, which provides the rationale for the use of medium-chain triglyceride (MCT) in long-chain defects. Whether of dietary origin or a product of β-oxidation, these are then oxidized within the mitochondrial matrix by length-specific enzymes.

Within the liver, acetyl-CoA is used for ketone body production or as a substrate for the tricarboxylic acid (TCA) cycle. Once lipolysis occurs, there should be accompanying ketone production. Hence, finding significant FFAs with a disproportionally low 3-OH butyrate level in the context of fasting is a useful diagnostic clue. Defects at any stage in the FAO pathway will result in local failure of energy production, inadequate ketone body production, and hypoglycemia. Hypoglycemia results from both reduced hepatic glucose production through gluconeogenesis and increased peripheral consumption. ^, When β-oxidation is defective, abnormal and potentially toxic metabolites may accumulate.

Depending on the site of the block, differing acylcarnitines will accumulate proximally, and their pattern detection in blood and urine can help to localize the defect. Similarly, differing urinary organic acid profiles may help to characterize the site of the block. FFA may undergo ω-oxidation in microsomes, thereby producing dicarboxylic acids. Some of these metabolic signatures may be manifest only at the time of metabolic instability, whereas in some defects they can be persistent.

Clinical Features and Diagnosis

The clinical presentation of FAOD is dependent on the enzyme defect and age of the patient. ^, The most common presentation in infancy and early childhood is hypoketotic hypoglycemia and encephalopathy, with or without hyperammonemia, and can be seen in both long- and medium-chain disorders. Lactate is often mildly elevated in long-chain defects. Symptoms may be provoked by fasting or intercurrent infection. The first 24 to 48 hours postnatally can be particularly dangerous in breastfeeding mothers until an adequate mild supply is established. Hepatomegaly, elevated transaminases, and modest hyperammonemia occur in more than 80% of cases, with cholestasis in up to one-third. True acute liver failure (ALF) is uncommon but has been described in most of the long-chain defects. Prior to access to adequate diagnostic techniques, patients were often classified as having Reye syndrome and represented as many as 15% to 25% of sudden unexpected deaths. Rhabdomyolysis can occur at any age but is more common in older children, adolescents, and adults. In these patients, muscle cramps and pain may herald the onset of a full episode or rhabdomyolysis or be isolated without evidence of muscle breakdown. Cardiac symptoms include cardiomyopathy and arrhythmias and can occur at any age. Neurologic symptoms other than hypoglycemic encephalopathy or seizures are uncommon. A retinopathy is unique to LCHAD deficiency. A summary of clinical and biochemical features is shown in Table 71.1 .

A fascinating aspect of this group of disorders is the association with maternal illness during pregnancy. This association was first noted when a mother with acute fatty liver of pregnancy (AFLP) delivered an infant with LCHAD deficiency. However, it has become clear that this association is not limited to fetal LCHAD deficiency but may occur in a mother carrying a fetus with any FAOD. The maternal illness may be part of a spectrum ranging from AFLP to the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. The mechanism of this process is unclear but presumably results from limited ability of the heterozygote maternal liver to detoxify metabolites produced by the fetus in combination with the metabolic stress of pregnancy. Efforts to detect metabolic abnormalities in maternal blood during affected pregnancies have been largely uninformative, but recently long-chain hydroxyacyl carnitine species were detected in a carrier of LCHAD deficiency at 31 weeks of pregnancy during AFLP, supporting the concept of metabolic intoxication. The incidence of AFLP in pregnancies where the fetus has an FAOD is significant, but the converse is not true. At most, FAOD account for 20% of AFLP and probably less. Given the implications for the child and future pregnancies, it is still crucial that all children born after pregnancy affected by AFLP are systemically screened for FAOD and, if necessary, prospectively treated until results are available.

All of the disorders of FAO can be identified by newborn screening, although late-onset variants may be normal. With the advent of newborn screening, a broader category of milder and even asymptomatic phenotypes is increasingly recognized. ^, Carriers are typically asymptomatic (although occasional reports of expressing heterozygotes appear infrequently in the literature), and thus carrier testing is typically through molecular analysis once a gene defect is identified in an affected child.