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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31829ef67a
Invited Reviews

Evaluation of the Child With Suspected Mitochondrial Liver Disease

Molleston, Jean P.*; Sokol, Ronald J.; Karnsakul, Wikrom; Miethke, Alexander§; Horslen, Simon||; Magee, John C.; Romero, René#; Squires, Robert H.**; Van Hove, Johan L.K.††; for the Childhood Liver Disease Research Education Network (ChiLDREN)

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In the article that published in the September 2013 issue on page 269, a drug name was changed in error. The sentence on page 275 should read instead: “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 AZT), chloramphenicol, quinolones, and linezolid (48).”

Journal of Pediatric Gastroenterology and Nutrition. 59(3):340, September 2014.

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Author Information

*Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine, Indianapolis, IN

Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO

Department of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD

§Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

||Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA

Section of Transplant Surgery, University of Michigan Medical School, Ann Arbor, MI

#Pediatrics, Hepatology, and Liver Transplantation, Emory University School of Medicine, Atlanta, GA

**Division of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Pittsburgh, PA

††Department of Pediatrics, Section of Genetics, University of Colorado, School of Medicine, Aurora, CO.

Address correspondence and reprint requests to Jean P. Molleston, MD, Riley Hospital for Children, Indianapolis, IN 46202 (e-mail:

Received 8 March, 2013

Accepted 29 May, 2013

Supported by NIH Grants: Indiana University School of Medicine, U01DK084536; University of Colorado Denver/Children's Hospital Colorado, U01 DK062453; Johns Hopkins University School of Medicine, U01 DK062503; Cincinnati Children's Hospital Medical Center, U01 DK062497; Seattle Children's Hospital, U01 DK084575; University of Michigan Medical School, U01 DK062456; University of Pittsburgh School of Medicine, U01 DK062466; Emory University School of Medicine, U01 DK084585.

The authors report no conflicts of interest.

This review was developed by the Mitochondrial Liver Diseases Working Group of the Childhood Liver Disease Research and Education Network, supported by the National Institute of Digestive, Diabetes and Kidney Diseases, National Institutes of Health, to guide evaluation of children with suspected mitochondrial liver disease. Data informing the evaluation guideline were 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, whereas some respiratory chain subunits, ribosomal RNAs, 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 adenosine triphosphate via electron transport and oxidative phosphorylation (Fig. 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
Figure 1
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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 that 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 patients 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 (Tables 3 and 4) describing each genetic etiology follow. Reference clinical laboratories for the genetic tests can be found at

TABLE 1-a  Tiered ap...
TABLE 1-a Tiered ap...
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Table 2
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Table 3
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Table 4
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TABLE 1-b  Tiered ap...
TABLE 1-b Tiered ap...
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Mitochondrial liver disease can present acutely in a child with no history of hepatic dysfunction, or with chronic liver and central nervous system (CNS) disease. Fulminant or acute liver failure is 1 important presentation of mitochondrial disease (41). Especially in a young child or in one with preexisting or disproportionate CNS involvement, mitochondrial disease is in the differential diagnosis of acute liver failure. More important, if liver transplant is being considered, careful attention must be paid to potential extrahepatic manifestations of mitochondrial dysfunction. Another clinical presentation is chronic liver disease, manifested by elevated aminotransferases, hepatomegaly, cholestasis, cirrhosis, and especially steatohepatitis; these may be accompanied by other indicators of mitochondrial disease, including hypoglycemia or lactic acidosis. Third, liver disease accompanied by chronic neuromuscular disease or disease in other organ systems may be a sign of mitochondrial disease.

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A wide array of tests that are useful in establishing the diagnosis of mitochondrial hepatopathies is available. These tests range from simple, inexpensive, easily available screening tests to extremely expensive, widely ranging genetic studies. In the child who is suspected of having a mitochondrial disease, a tiered approach to diagnostic testing is recommended. Early screening tests (tier 1) may provide clues to abnormalities in energy metabolism, and results of these tests may guide subsequent confirmatory testing to establish a molecular diagnosis. Genotyping is available clinically for the more common mitochondrial diseases (tier 2); the clinical scenario or results of screening tests can inform the choice of genetic tests. For example, a panel screening for specific gene mutations in DGUOK, POLG1, and MPV17 responsible for infantile liver failure with lactic acidosis and mitochondrial DNA depletion is readily available and may be useful early in evaluation (see Table 3). The diagnostic role of next-generation sequencing (NGS), which is now allowing sequencing of >100 genes involved in mitochondrial diseases with a single blood test and at relatively low cost (42), or even whole exome or genome sequencing, will become increasingly important and will eventually replace genotyping single genes or small panels of genes in tier 2; however, the identification of multiple gene variants of uncertain significance will require detailed clinical and biochemical confirmation for interpretation. Tissue may also be needed to make a specific biochemical diagnosis, particularly if the liver is the major or sole affected organ (tier 3; Fig. 2). Occasionally, diagnostic findings will only be revealed in liver tissue rather than in blood, muscle, or skin fibroblasts. When further clarification is needed, genotyping for less common disease-causing genes may be required (tier 4); however, the use of NGS earlier on in the evaluation process in the future (in tier 2) may obviate the need for this step in the evaluation paradigm. At present, the diagnostic yield of NGS of all mitochondrial genes is high in patients with well-characterized mitochondrial disease, in particular with biochemical evidence of mitochondrial enzymatic dysfunction (42), but is low in patients with only a clinical suspicion (43). Biochemical studies evaluating the structure and function of mitochondrial subunits in the affected tissue can be performed as needed, specifically to determine whether new genetic variants have a functional effect (Fig. 3). Thus, a combination of biochemical and molecular studies may be needed to confirm the pathologic nature of new gene variants to be described in the future. Table 1 outlines a tiered approach to diagnostic evaluation.

Figure 2
Figure 2
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Figure 3
Figure 3
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Tables 3 and 4 catalog known mitochondrial hepatopathies and briefly describe the mutation, defect, clinical description, and diagnostic testing. The typical hepatic presentation, ranging from hepatic failure to cholestasis to steatohepatitis to cirrhosis, is briefly outlined; neurologic symptoms and other systems involved are briefly reviewed and references are provided. The disorders are separated into those with a neonatal or an infantile presentation (Table 3) and those with later or more chronic onset (Table 4). There is, however, overlap between these 2, and new diseases and presentations are recognized frequently.

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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.

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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.

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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.

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The authors thank Vicki Haviland-Wilhite for expert secretarial assistance and Marisa Friederich, PhD, for technical assistance.

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DGUOK; genetics; inborn errors of metabolism; liver disease; liver failure; mitochondrial disease; mitochondrial hepatopathy; MPV17; POLG

© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,


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