As part of the evaluation for mitochondrial hepatopathies, a systematic approach also needs to be instituted to search for involvement of other affected organ systems (Table 2). This takes on particular significance when liver failure occurs in a child with suspected mitochondrial disease because the decision to consider liver transplantation is especially challenging. Because mitochondrial disease usually involves multiple organ systems and is generally progressive in other organs even following liver transplantation, there are many uncertainties regarding liver transplantation. Possible posttransplant appearance of new progressive symptoms in organs uninvolved before liver transplantation also needs to be considered (44–47). Establishing criteria for liver transplantation in mitochondrial hepatopathies is beyond the scope of this article; however, in the evaluation for transplantation, meticulous evaluation for disease in other organ systems is paramount, especially because results of testing for specific disorders can be delayed by weeks. Evaluation of the CNS is critical. Besides a careful neurologic examination, magnetic resonance imaging of the brain is done to evaluate for Leigh disease, cerebellar atrophy, leukodystrophy, and cerebral atrophy. Magnetic resonance spectroscopy can be especially helpful, but blood lactate >3 mmol/L may affect interpretation. Evaluation can also include electroencephalography and cerebrospinal fluid examination (see above). To evaluate for cardiomyopathy, electocardiogram and echocardiogram should be done. A detailed ophthalmologic examination may reveal ophthalmoplegia in DGUOK deficiency, retinopathy in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or respiratory chain defects, corneal abrasions in MPV17, or optic atrophy in POLG disease. Serum electrolytes, serum and urine phosphorus and creatinine, urine amino acids, urinalysis, and urine protein are measured to evaluate renal function because abnormal tubular function may suggest a defect in BCS1L. Because diabetes mellitus and even adrenal insufficiency can be seen in mitochondrial disorders, HbA1c and morning cortisol level should be considered. Pancreatic insufficiency is seen in some mitochondrial diseases and may be detected by measuring fecal pancreatic elastase. Hearing screening should be performed.
The child with mitochondrial disease can be vulnerable to metabolic perturbations such as hypoglycemia or acidosis; close monitoring is important. It is important to discontinue or avoid medications that may exacerbate hepatopathy or impair mitochondrial function or mtDNA translation or transcription, including sodium valproate, tetracycline, and macrolide antibiotics, reverse transcriptase inhibitors (particularly azathioprine), chloramphenicol, quinolones, and linezolid (48). Use of Ringer lactate intravenous solution should be avoided because the liver may not be able to metabolize lactate; propofol should be avoided during anesthesia or sedated procedures because the drug can interfere with mitochondrial function (49). The goal is to maintain anabolism using a balanced intake of fat and carbohydrates with at least 75% of normal energy intake while avoiding unbalanced intakes (eg, glucose only at high intravenous rate) or fasting for >12 hours (50). In patients with preexisting lactic acidosis, lactate levels should be monitored around procedures to avoid excessive lactic acidosis.
Mitochondrial disease can present from infancy to adulthood with varying degrees of hepatic and extrahepatic involvement. In the last decade, there has been a rapid expansion of newly recognized mitochondrial diseases and their molecular bases. Available technology to aid in diagnosis has improved substantially. Nonetheless, diagnosis of suspected mitochondrial disease in children is complicated; a systematic clinical, biochemical, and molecular approach can aid in making a timely, accurate, and cost-effective diagnosis.
The authors thank Vicki Haviland-Wilhite for expert secretarial assistance and Marisa Friederich, PhD, for technical assistance.
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