EVALUATION OF THE CHILD WITH SUSPECTED MITOCHONDRIAL LIVER DISEASE

This review was developed by the Mitochondrial Liver Diseases Working Group of the Childhood Liver Disease Research and Education Network (ChiLDREN), supported by the National Institute of Digestive, Diabetes and Kidney Diseases, NIH, to guide evaluation of children with suspected mitochondrial liver disease. Data informing the evaluation guideline was supported by Medline searches of published English language literature and expert opinion from a committee of pediatric hepatologists and a mitochondrial metabolism specialist. Mitochondrial respiratory chain defects can affect any tissue, with the most energy-dependent organs being most vulnerable.(1) In general, clinical manifestations include multisystem involvement such as brain, muscle, heart, or kidney, with acute or chronic liver dysfunction, sometimes in the presence of lactic acidosis, a biomarker of limited sensitivity.(2, 3) Heterogeneous clinical presentations can be explained by the fact that the mitochondrial quantity and function are uniquely influenced by both nuclear and mitochondria DNA (mtDNA) or by the fact that cells in various tissues can contain different mixtures of normal and abnormal mitochondrial genomes (heteroplasmy). Most mitochondrial proteins and enzymes are coded by nuclear genes with Mendelian inheritance, while some respiratory chain subunits, ribosomal and transfer RNAs are encoded by mitochondrial genes that are maternally inherited.(4) Mutations, deletions, or duplications in either of these classes can cause disease, and mutations in nuclear genes that control mitochondrial DNA replication, transcription, and translation may lead to mtDNA depletion syndrome or to a translational disorder.(5-7) The respiratory chain, consisting of 5 multimeric complexes (I-V) in the mitochondrial inner membrane, generates energy as ATP via electron transport and oxidative phosphorylation (Figure 1). Defects in the respiratory chain enzymes or mitochondrial membrane transport proteins result in injury to energy-dependent organs, especially brain, retina, muscle, heart, and liver.(8) In addition, hepatic mitochondria oxidize fatty acids forming ketone bodies, an important source of energy for the brain in the fasting state. Fatty acid oxidation defects, an important group of primary bioenergetic defects, can present similarly with hepatopathy or encephalopathy, often with nonketotic hypoglycemia, acidosis and hyperammonemia, and are thus included in the differential diagnosis and should be simultaneously evaluated.(9) Figure 1 The respiratory chain, consisting of 5 multimeric complexes (I-V) in the mitochondrial inner membrane, generates energy as ATP via electron transport and oxidative phosphorylation. Establishing the diagnosis of primary mitochondrial bioenergetic defects in patients with liver disease requires a high index of suspicion in specific clinical scenarios. A tiered diagnostic evaluation is useful (Table 1). Although mitochondrial hepatopathies are a heterogeneous group of disorders, there are several general laboratory investigations in blood and urine which can reveal an altered redox status suggestive of respiratory-chain defects (lactate:pyruvate molar ratios and ketone body ratios). Specific laboratory tests are considered in those with unique clinical presentations as well, and either tissue analysis or genotyping is used to identify the etiology. Other typically involved organ systems should be evaluated when mitochondrial hepatopathy is suspected (Table 2). Several important management issues should be addressed during this evaluation process. These guidelines outline the evaluation of the infant or child with suspected mitochondrial hepatopathy. Two summary tables (Table 3 and ​and4)4) describing each genetic etiology follow; reference clinical laboratories for the genetic tests can be found on www.genetests.org Table 1 Tiered Approach to Evaluation of Suspected Mitochondrial Disease Table 2 Evaluation for Disease in Other Organ Systems Table 3 Genetic Etiologies of Mitochondrial Hepatopathies Presenting in Neonates or Infants Table 4 Genetic Etiologies of Mitochondrial Hepatopathies Presenting as Chronic Liver Disease or With Later Onset