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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Semin Liver Dis. Author manuscript; available in PMC 2014 January 10.
Published in final edited form as:
PMCID: PMC3888320

Liver Disease in Mitochondrial Disorders

Way S. Lee, M.D.1,2 and Ronald J. Sokol, M.D.2


Liver involvement, a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period, may manifest as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. There are usually significant neuromuscular symptoms, multisystem involvement, and lactic acidemia. The liver disease is usually progressive and eventually fatal. Current medical therapy of mitochondrial hepatopathies is largely ineffective, and the prognosis is usually poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease that does not respond to transplantation. Several specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA) have been identified in recent years. Prospective, longitudinal multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases.

Keywords: Mitochondrial hepatopathies, genetics, pathogenesis

Mitochondria are double-membrane intracellular organelles containing a soluble matrix and their own unique genome.1 They are the main source of the high-energy phosphate molecule adenosine triphosphate (ATP), which is essential for all active intracellular processes.1 Structural and functional alterations of mitochondria are increasingly being recognized in the pathogenesis of a group of diseases, including involvement of the central and peripheral nervous systems, skeletal muscle, bone marrow, the endocrine and exocrine pancreas, kidney, myocardium, and intestines.13 Because the metabolically active liver requires continuous synthesis of ATP, hepatocytes contain a relatively high density of mitochondria compared with other cells. Disorders affecting mitochondrial oxidative phosphorylation (OXPHOS) and hepatocellular metabolism directly influence fatty acid oxidation, resulting in impaired bile flow and steatosis, cell death, and fibrogenesis.1,46 Mitochondrial hepatopathies present clinically primarily in early childhood; however, secondary disorders present at any age. Significant recent advances have occurred in our understanding of mitochondrial hepatopathies, including identification of the molecular basis of many disorders. This review will describe recent development in primary mitochondrial hepatopathies, including the genetics, management, and the future directions for research.


ATP is produced by the respiratory chain on the inner mitochondrial membrane by OXPHOS (Fig. 1).1 In this process, reduced cofactors (reduced nicotinamide adenine dinucleotide [NADH], reduced flavin adenine dinucleo-tide [FADH2], and electron transfer flavoprotein [ETF]) generated from the intermediary metabolism of carbohydrates, proteins, and lipids donate electrons to complexes I and II and ubiquinone, which then flow down an electrochemical gradient to complexes III, cytochrome c, and finally to complex IV, resulting in the active translocation of protons (H+) out of the mitochondrial matrix into the intermembrane space, which establishes an electrochemical gradient. At complex V, protons flow back into the mitochondrial matrix, and the released energy is used to synthesize ATP.1,2

Figure 1
The respiratory chain protein complexes and oxidative phosphorylation of the mitochondria. Reducing equivalents derived from glycolysis, fatty acid oxidation, and the tricarboxylic acid cycle are converted into ATP through a system of electron carriers ...

A unique feature of mitochondria in mammalian cells is the presence of a distinct genome, mitochondrial DNA (mtDNA), which is independent from that of the nucleus.4 A typical hepatocyte contains ~1000 copies of mtDNA. Both nuclear and mtDNA genes encode for respiratory chain peptide components. Thirteen essential polypeptides are synthesized from the small 16.5-kb, circular double-stranded mtDNA. In contrast, nuclear genes encode more than 70 respiratory chain subunits and an array of enzymes and cofactors required to maintain mtDNA.1,3 These genes include DNA polymerase-γ (POLG), thymidine kinase 2 (TK2), and deoxyguanosine kinase (DGUOK).3 mtDNA also encodes the 24 transfer RNAs (t-RNAs) required for intramitochondrial protein synthesis.1

An important feature of mitochondria is that virtually all mtDNA is derived from the unfertilized oocyte.4 Most researchers believe that virtually no paternal mtDNA from the sperm survives entry into the fertilized ovum at the point of conception, the embryo thus developing with maternal mtDNA alone. Possible explanations for this phenomenon include suppression of paternal mtDNA, or dilution beyond the limits of detection and to levels at which its contribution would in any case be irrelevant.7,8 This maternal inheritance in mtDNA disorders is important for genetic counseling.


Recent studies have shown that mitochondrial respiratory chain disorders of all types affect 1 in 20,000 children under 16 years of age.9 In a population-based study of the prevalence of mitochondrial encephalomyopathies in Sweden, liver involvement was noted in 20% of the cases studied.10 In another study of 1041 children from a tertiary referral center, 22 (10%) of the 234 patients with respiratory chain defects had liver dysfunction, and 10 patients had the onset of liver disease in the neonatal period.11 Given the heterogeneity of the features and difficulties with establishing these diagnoses, these figures are likely to be underestimates of the true prevalence of these disorders.


A striking feature of mitochondrial disorders is their clinical heterogeneity, ranging from single-organ involvement to severe multi-system disease.1113 Hepatic manifestations of mitochondrial disorders range from hepatic steatosis, cholestasis, and chronic liver disease with insidious onset to neonatal liver failure, frequently associated with neuromuscular symptoms.2 Sokol and Treem2 have proposed a classification scheme for mitochondrial hepatopathies (Table 1), which includes primary disorders, in which the mitochondrial defect is the primary cause of the liver disorder, and secondary disorders, in which a secondary insult to mitochondria is caused by either a genetic defect that affects nonmitochondrial proteins or by an acquired (exogenous) injury to mitochondria.4 Leonard and Shapiro14 have further divided primary mitochondrial diseases into those caused by mutations affecting mtDNA genes (class 1a) and those caused by mutations in nuclear genes that encode mitochondrial respiratory chain proteins or cofactors (class 1b).

Table 1
Classification of Mitochondrial Hepatopathies


The clinical presentation of mitochondrial hepatopathies is heterogeneous, including neonatal acute liver failure, lactic acidosis, cholestasis, or chronic liver failure (Tables 2 and and33).

Table 2
Clinical and Laboratory Features of Primary Mitochondrial Hepatopathies
Table 3
Respiratory Chain Complex-Involved and Molecular Causes of Mitochondrial Hepatopathies

Neonatal Liver Failure

Mitochondrial hepatopathies involving respiratory chain defects frequently present as acute liver failure with onset within the first weeks to months of life. Associated features include lethargy, hypotonia, vomiting, poor suck, and seizures.11,12 In others, after an initial normal course, a viral infection or some other undefined inciting event triggers hepatic and, sometimes, neurologic deterioration.11 Most infants also have severe neurologic involvement developing in infancy with a weak cry, recurrent apnea, and myoclonic epilepsy.11,12 Cormier-Daire et al observed the following major clinical features, namely (1) onset in the first week of life, (2) transient hypoglycemia, (3) neurologic involvement with severe hypotonia, myoclonus epilepsy, psychomotor retardation, (4) early liver failure, and (5) a rapidly fatal course.11

Key biochemical manifestations include a markedly elevated plasma lactate concentration, an elevated molar ratio of plasma lactate to pyruvate (> 20 and frequently > 30 mol/mol), and a raised β-hydroxybutyrate and arterial ketone body ratio of β-hydroxybutyrate to acetoacetate (> 2.0 mol/mol).5 Respiratory chain complex analysis of liver or muscle generally shows low activity of complex I, III, or IV. The course of the illness is usually rapidly progressive. In most of these infants, liver failure progresses to death within weeks to months after presentation, although occasional infants have recovered or have had successful liver transplantation.

A recent study suggests that antenatal manifestations are common in infants with respiratory chain disorders.15 Low birth weight (< 3rd percentile for gestational age) was noted in 23% of cases and another 7% had other associated anomalies, including polyhydramnios, hypertrophic cardiomyopathy, cardiac rhythm abnormalities, hydronephrosis, and ventricular septal defects.15

Mitochondrial DNA Depletion Syndrome

Mitochondrial DNA depletion syndrome (MDS) is defined as a reduction in mtDNA copy number in different tissues leading to insufficient synthesis of respiratory chain complexes I, III, IV, and V.3,16 There are two clinical phenotypes of MDS, a myopathic and a hepatocerebral form, with considerable phenotypic heterogeneity within both forms.17 Patients with the hepatocerebral form present within the first weeks of life with hepatomegaly and progressive liver failure leading to death a few months later.5,6,17 Presenting symptoms include vomiting, severe gastroesophageal reflux, failure to thrive, or developmental delay.

Neurologic abnormalities include hypotonia, Leigh syndrome, nystagmus, psychomotor delay, pyramidal signs, seizures, and cataracts.5,6 The nystagmus is usually multidirectional, and there may be hypo- or areflexia.6 Other clinical features include cardiomegaly, amyotrophia, and renal tubulopathy.6 Biochemically, lactic acidosis, hypoglycemia, moderately raised serum alanine aminotransferase and aspartate aminotransferase, coagulopathy, and elevated total and conjugated bilirubin are common.5,6 Liver histology is characterized by macro- and microvesicular steatosis, hepatocytic and canalicular cholestasis, fibrosis, and iron deposition in hepatocytes and sinusoidal cells (Fig. 2).6

Figure 2
(A) Photomicrograph of liver biopsy from a 3-month-old child with POLG mutations and mitochondrial DNA depletion syndrome, showing microvesicular steatosis, cholestasis with bile pigment in canaliculi (arrows), and ballooning degeneration of hepatocytes ...

There is considerable overlap between the clinical and laboratory features of MDS and the neonatal liver failure form of respiratory chain disease. The major difference between the two conditions is the demonstration in MDS of low ratio (< 10%) of the normal amount of mtDNA relative to nuclear DNA in affected tissues, with a normal mtDNA genome sequence (Table 3).6 Another difference is as compared with the neonatal liver failure of respiratory chain disease, the progression of liver failure in MDS is usually less rapid, with the course of illness lasting for a few months.6

Alpers-Huttenlocher Syndrome (Delayed-Onset Liver Disease)

Typically, the onset of symptoms in Alpers-Huttenlocher syndrome occurs between 2 months and 8 years of life and is characterized by hepatomegaly, jaundice, and progressive coagulopathy and hypoglycemia.18 In most of these children, liver failure is preceded by the development of hypotonia, feeding difficulties, symptoms of gastroesophageal reflux or intractable vomiting, failure to thrive, and ataxia followed by the onset of refractory partial motor epilepsy or multifocal myoclonus.1820 Multiple anticonvulsants are usually necessary to control the seizures. The use of valproic acid may exacerbate the deficiency of respiratory chain enzyme activity and precipitate liver failure.19 The generally accepted diagnostic criteria of this condition are (1) presence of refractory, mixed type seizures that include a focal component, (2) episodic psychomotor regression that is often triggered by intercurrent infections, and (3) hepatopathy with or without acute liver failure.21

Progressive neurologic deterioration may ensue rapidly. In other children, the neurologic features are less severe or of somewhat later onset. There may be elevated blood or cerebrospinal fluid (CSF) lactate and pyruvate levels, characteristic electroencephalogram findings (high-amplitude slow activity with polyspikes),19 asymmetric abnormal visual-evoked responses,19 and low-density areas or atrophy in the occipital or temporal lobes on computed tomography (CT) scanning of the brain.22 In some patients, NADH oxidoreductase (complex I) deficiency has been found in liver or muscle mitochondria.11,23

Pearson's Syndrome

Pearson's marrow-pancreas syndrome was first described in 1979 in 4 children with neonatal-onset severe macrocytic anemia, variable neutropenia and thrombocytopenia, vacuolization of marrow precursors, and ringed sideroblasts in the bone marrow.24 The clinical features involve the hematopoietic system, exocrine pancreas, liver, and kidneys. Pancreatic insufficiency due to extensive pancreatic fibrosis and acinar atrophy usually causes diarrhea and fat malabsorption later in infancy or early childhood. Partial villous atrophy of the small intestine was also noted.

The liver involvement is manifested as hepatomegaly, hepatic steatosis, hemosiderosis, and cirrhosis. Liver failure and death in some cases has been reported before the age of 4 years.25,26 Other clinical manifestations of Pearson syndrome include renal tubular disease (Fanconi's syndrome), patchy erythematous skin lesions, and photosensitivity, diabetes mellitus, hydrops fetalis, and the late development of visual impairment, tremor, ataxia, proximal muscle weakness, external ophthalmoplegia, and a pigmentary retinopathy.27 Deletions of mtDNA segments are reported in most patients. In general, there is no effective therapy available for Pearson's syndrome apart from symptomatic treatment with red cell transfusions or carbohydrate restriction.

Villous Atrophy Syndrome

This rare disease was first described by Cormier-Daire et al28 in two unrelated children with severe anorexia, vomiting, chronic diarrhea, and villus atrophy in the first year of life. Intestinal biopsy in both cases showed partial villous atrophy with eosinophilic infiltration. Both patients needed a period of parenteral nutrition because of persistence of diarrhea not responding to enteral nutrition. Significant neurodevelopment delay was noted in one of the patients. Other features included severe renal insufficiency and involvement of the pyramidal tract of the central nervous system (CNS). Hepatic involvement was characterized by mild elevation of aminotransferases, hepatomegaly, and steatosis. Diarrhea, vomiting, and lactic acidosis worsened with high dextrose intravenous infusions or enteral nutrition. Diarrhea improved and even resolved completely by 5 years of age in association with normalization of intestinal biopsies. Subsequent course of the disease was complicated by retinitis pigmentosa, cerebellar ataxia, sensor-ineural deafness, and proximal muscle weakness with eventual death late in the first decade of life. Respiratory-chain enzyme assays were normal in circulating lymphocytes; however, complex III deficiency was demonstrated in skeletal muscle.

Navajo Neurohepatopathy

Navajo neurohepatopathy (NNH) is a sensorimotor neuropathy with progressive liver disease that has been reported in full-blooded Navajo children.13 This disorder was initially termed Navajo neuropathy because of the development of weakness, hypotonia, areflexia, loss of sensation in the extremities, acral mutilation, corneal ulceration, poor growth, short stature, and serious systemic infections.13,29 Cerebral magnetic resonance imaging shows the presence of progressive white matter lesions, and peripheral nerve biopsies show severe loss of myelinated fibers.13,29 Subsequently, it was shown that liver involvement was an important clinical feature and a common cause of death.13 Reye-like syndrome episodes, cholestasis, cirrhosis, or liver failure may occur in infancy or childhood. There are three clinical presentations of NNH, including an infantile presentation, with failure to thrive and jaundice progressing to hepatic failure and death within the first 2 years of life, with or without neurologic findings; a childhood form presenting between 1 and 5 years of age with rapid development of liver failure within 6 months of presentation; and the classic form in which progressive neurologic findings dominate although liver dysfunction (and even cirrhosis) was present in all patients. Liver histology demonstrates portal fibrosis or micronodular cirrhosis, macrovesicular and microvesicular steatosis, pseudoacinar formation, multinucleated giant cells, cholestasis, and periportal inflammation.13 The liver involvement is progressive with liver failure developing within months to years in most patients. There is no effective treatment to date for affected children.13


When to Suspect Mitochondrial Hepatopathies?

Diagnosis of mitochondrial respiratory chain disorders in patients with liver disease requires a high index of suspicion. Clinical events that should suggest these disorders include (1) association of neuromuscular symptoms with liver dysfunction, (2) multisystem involvement in a patient with acute or chronic liver disease, (3) rapidly progressive course of liver disease, and (4) presence of lactic acidosis, hepatic steatosis, or ketonemia.2 Table 4 shows screening tests available for respiratory chain defects. Lactic acidemia is a well-known feature of mitochondrial disorders, including mitochondrial hepatopathies.30 The pathogenesis of lactic acidemia lies in the fact that all cells use glucose and produce pyruvate by glycolysis.31 The pyruvate is then reduced by NADH to lactate, if the mode of metabolism is preferentially glycolytic or if there is a problem reoxidizing NADH.3,30 Reoxidation of NADH generated by pyruvate dehydrogenase complex is performed by respiratory chain complex within mitochondria.30

Table 4
Screening Tests for Respiratory Chain Defects

Lactic acidemia is a constant presenting feature in some, intermittent in others, and may be absent in yet other mitochondrial disorders.30 The majority of respiratory chain defects presents with a raised blood and CSF lactate associated with a raised lactate to pyruvate ratio, indicating altered cellular redox state.30 Lactic acidemia is prominent in neonatal liver failure, MDS, and villous atrophy syndrome but generally not present in Navajo neurohepatopathy and Alpers-Huttenlocher syndrome (Table 3). More specifically, Robinson30 points out that moderate lactic acidemia (defined as serum lactate level between 2 and 5 mmol/L) is noted in MDS caused by mutations of the genes DGUOK, TK2, and POLG, and severe lactic acidemia (serum lactate more than 5 mmol/L) is a relatively constant feature in BCS1L mutations affecting complex III.30

Measurement of Mitochondrial Respiration

One sensitive method of documenting altered mitochondrial function is the direct measurement of mitochondrial respiration. Analysis of oxygen consumption in fresh mitochondrial-enriched fractions of tissues (liver, muscle, lymphocytes, fibroblasts) can be performed by polarographic studies in the presence of a series of respiratory substrates to define the site of the respiratory impairment.2 For example, patients with complex I deficiency (NADH oxidoreductase) will show impaired mitochondrial oxygen consumption stimulated by NADH substrates, such as glutamate and malate, and those with complex II (succinate oxidoreductase) deficiency will have improved respiration with FADH substrates, such as succinate.2 These tests require isolation of mitochondria from fresh tissue, which is not available at most centers.

Enzymatic Activity of Respiratory Chain Complexes

Alternatively, direct measurement of the enzymatic activity of each of the complexes of the mitochondrial respiratory chain can be measured in frozen tissues. Samples of liver, kidney, myocardium, skin, or other tissues must be frozen immediately at the bedside or in the operating room and stored at –80°C. Measurement of respiratory chain enzyme activities can be performed spectrophotometrically using specific electron acceptors and donors.32

Histopathologic Investigations

All forms of mitochondrial hepatopathies show abnormal hepatic histopathologic features, which include micro-and macrovesicular steatosis, cholestasis, hepatocellular degeneration and swelling, lobular inflammation, portal fibrosis, and eventually cirrhosis. Pseudoacinar formation is noted to be prominent in NNH,13 and hemosiderosis of the liver is noted in Pearson's syndrome25,26 and MDS.17


More than 200 pathogenic point mutations, deletions, insertions, and rearrangements have been identified since the first mtDNA mutations were reported in 1988, and are more likely to be associated with neuromuscular disorders than hepatic.33 On the contrary, it is now clear that most mitochondrial diseases with primary involvement of the liver are caused by nuclear, rather than mtDNA mutations (Table 3).

Neonatal Liver Failure

Low hepatic activity of respiratory chain complexes IV, I, III, and occasionally of complex II, either in isolation or in combination, has been found in infants with this presentation.11,34,35 Among these, deficiency of complex IV (cytochrome c oxidase; COX) is the most common cause. COX is the terminal enzyme of the mitochondrial respiratory chain that catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen (Fig. 1).36 This exergonic reaction is coupled with COX-mediated proton translocation from matrix to cytosol.36 The mammalian COX is a hetero-oligomer composed of 13 subunits. The 3 largest subunits forming the catalytic core of the enzyme are encoded by mtDNA, whereas the remaining 10 subunits involved in the assembly and regulation of the enzyme are encoded by nuclear DNA.36


In one affected family with predominately hepatic failure in infancy, lactic acidosis and neurodevelopmental delays, mutations in the COX assembly nuclear gene SCO1 have been associated with COX deficiency.37 The SCO1 gene, located at chromosome 17p13.1, is believed to encode a protein functioning as a copper chaperone that transfers copper from Cox17p, a copper-binding protein of the cytosol and mitochondrial intermembrane space, to the mitochondrial COX subunit II.38 Mutation analysis of affected patients in a family showed compound heterozygosity for the SCO1 gene.37 A mutated allele inherited from the father showed a 2-bp frameshift deletion (ΔGA; nt 363–364) resulting in both a premature stop codon and a highly unstable mRNA. The maternally inherited mutation (C520T) changed a highly conserved proline into a leucine in the protein (P174L).37 This proline, adjacent to the CxxxC copper-binding domain of SCO1, is likely to play a crucial role in the tridimensional structure of the domain.


Respiratory complex III (ubiquinol–cytochrome c reductase complex) catalyzes the electron transfer from coenzyme Q to cytochrome c. BCS1L is a nuclear gene encoding proteins involved in the assembly of respiratory complex III. A mutation in BCS1L has been found to be associated with mitochondrial neonatal liver failure.39 De Lonlay et al39 reported deficient activity of complex III of the respiratory chain in liver, fibroblasts, or muscle in affected infants with hepatic failure, lactic acidosis, renal tubulopathy, and variable degrees of encephalopathy. Three mutations in BCS1L were demonstrated in three affected families.39 Subsequently, de Meirleir et al40 confirmed that mutations in BCS1L were associated with fatal complex III deficiency and liver failure in two siblings. These included a missense mutation R45C and a nonsense mutation R56X, both located in the exon 1 of BCS1L gene.40 It is likely that mutations in BCS1L will be responsible for a substantial portion of infants who present with neonatal liver failure and lactic acidosis. It should be noted, however, that not all patients with neonatal liver failure will have a positive identification of a mutation.39 Other genetic causes are likely to be identified in the future.

mtDNA Depletion Syndrome

The mtDNA processing enzyme activities are dependent on several factors, including deoxyribonucleotide (dNTP) concentrations within the mitochondria, availability of ATP, and several metal cofactors.41 Imbalance of any of these cofactors or enzymes could affect mtDNA stability. The mtDNA pool is maintained by either import of cytosolic dNTPs through dedicated transporters or by salvaging deoxynucleosides within the mitochondria. The mitochondrial deoxynucleoside salvage pathway is regulated by nuclear-encoded enzymes, including deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2).42,43 Human dGK phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine, and deoxyuridine. Imbalance of this mitochondrial dNTP pool has been proposed to be responsible for both the hepatocerebral and myopathic forms of MDS.44 In 2001, mutations in two genes involved in this pathway were identified in patients with MDS: DGUOK in the hepatocerebral form and TK2 in the myopathic form.44,45


Mandel et al,44 using homozygosity mapping in three consanguineous kindreds affected with hepatocerebral MDS, mapped this disease to chromosome 2p13, which encompasses the gene DGUOK encoding dGK. A single-nucleotide deletion (204delA) within the coding region of DGUOK was identified.45 Reduction of enzymatic activities of mitochondrial respiratory chain complexes containing mtDNA encoded subunits (complexes I, III, and IV, but not complex II, which is solely encoded by nuclear genes) was demonstrated in the liver but not in muscle, showing the tissue-specific nature of this disorder. However, Salviati et al46 screened the frequency of DGUOK mutations in 21 patients with hepatocerebral MDS and noted that DGUOK mutations were present in only 14%, suggesting this was not the only gene responsible for MDS in the liver.46 No genotype-phenotype correlation was demonstrated.

In recent years, 2 other nuclear genes have been identified as additional causes of the hepatocerebral form of MDS. Mutations in DNA polymerase-γ (POLG), the mitochondrial polymerase that is encoded by a nuclear gene, have now been described in infants with MDS as well as older children with Alpers-Huttenlocher disease.47,48 Most of the cases with MDS in early childhood are associated with at least one mutation in the linker region of POLG and one in the polymerase domain. More recently, Spinazzola et al49 have employed an integrative genomics approach to discover mutations in the nuclear gene MPV17 in three families affected by the hepatocerebral form of MDS. This gene encodes an inner mitochondrial membrane protein of uncertain function.

Alpers-Huttenlocher Syndrome

Mutations in POLG have recently been shown to be the primary genetic cause of Alpers-Huttenlocher syndrome.50,51 DNA polymerase-γ (pol-γ) is essential for mtDNA replication and repair,52 is comprised of a 140-kDa catalytic (α) subunit that contains DNA polymerase, 3′-5′ exonuclease, and dRP lyase activities, and a 55-kDa accessory (β) subunit that functions as a processivity and DNA binding factor.52 Deficiency in mitochondrial pol-γ activity and mtDNA depletion was first reported in a patient with Alpers-Huttenlocher syndrome by Naviaux et al in 1999.53 Subsequently, Naviaux et al50 reported that in two unrelated pedigrees with Alpers-Huttenlocher syndrome, each affected child was found to harbor a homozygous mutations in exon 17 of POLG that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in pol-γ, within the linker region of the protein.50 Subsequently, other reports have confirmed that the Ala467Thr substitution in pol-γ was the most common although not exclusive, mutation in Alpers-Huttenlocher syndrome.47,48

Molecular diagnosis is now possible in the majority of Alpers-Huttenlocher syndrome patients.51 Nyugen et al51 sequenced the POLG locus in 15 sequential probands with the clinical features of Alpers-Huttenlocher syndrome and noted that POLG DNA testing accurately diagnosed 87% of cases. Five new POLG amino acid substitutions (F749S, R852C, T914P, L966R, L1173fsX) were reported. The most common mutation was the Ala467Thr substitution described above, which accounted for ~40% of the alleles and was present in 65% of the patients.51 All patients with Alpers-Huttenlocher syndrome had either Ala467Thr or the W748S substitution in the linker region. Mutations in POLG have also been associated with another severe form of hepatocerebral syndrome, autosomal dominant or recessive progressive external ophthalmoplegia, neuropathy, ataxia, hypogonadism, migraine, hearing loss, muscle weakness, parkinsonism, and psychiatric symptoms.48,50,54

Navajo Neurohepatopathy and MPV17 Gene Mutation

Vu et al55 first demonstrated mtDNA depletion in liver tissue of two patients with NNH, suggesting that a nuclear gene might be responsible for this autosomal recessive disease. A genome-wide scan, performed using 400 DNA microsatellite markers demonstrated mapping of the disease to chromosome 2p24.1.55MPV17, the gene associated with MDS, was recently mapped to this region. The MPV17 product is involved in mtDNA maintenance and in the regulation of OXPHOS49 and is localized to the inner mitochondrial membrane.49 Sequencing of MPV17 in 6 NNH patients from 5 families in 2006 demonstrated the same homozygous disease-causing R50Q mutations in exon 2 in all patients, confirming a founder effect in this disease.56 Thus, it is now clear that NNH is indeed a form of mtDNA depletion with a unique clinical presentation in Navajos. Molecular diagnosis, which is now available in CLIA-approved clinical laboratories, may now play a role in differentiating this cause of neonatal liver disease from other causes in Navajo children.

Pearson's Syndrome

The association of Pearson's syndrome and a specific deletion in mtDNA was first reported in 1990 by Rotig et al.57 It is now established that mtDNA rearrangements are present in all patients with this rare disease with large (4000–5000 base-pair) deletions predominating in three quarters of reported cases.25,58,59 The most common deletion is located between nt 8488 and nt 13,460.60 The proteins affected by this deletion included respiratory chain enzymes (complex I is the most severely affected), 2 subunits of complex V, 1 subunit of complex IV, and 5 t-RNA genes. Other mtDNA deletions of differing lengths are associated with clusters of the characteristic clinical manifestations.57,59 Rotig et al57 reported a 5-year-old boy with sideroblastic anemia, persistent diarrhea, lactic acidosis, and liver failure with a 3.1-kb deletion (nt 6074–9179). In contrast, Jacobs et al59 described a patient with anemia and diarrhea but no pancreatic or hepatic involvement with a 3.4-kb deletion (nt 6097–9541). Heteroplasmy of mtDNA in different tissues may explain these discrepant findings.

More recently, Muraki et al61 described a child with classic features of Pearson's syndrome. Initial analysis for mtDNA deletions or duplications on bone marrow at 1 year of age, and a repeat analysis on the muscle at 5 years of age, did not show any duplication. An analysis after the death of the child at 7 years of age showed mtDNA duplications in the kidneys, heart, and bone marrow. The authors concluded that mtDNA duplications are present in many tissues but may fluctuate in the bone marrow.61

Villous Atrophy Syndrome

Villous atrophy syndrome has been recognized as a mtDNA rearrangement defect.28 A complex III deficiency was found in muscle of affected patients. Southern blot analysis showed evidence of heteroplasmic mtDNA rearrangements that involved deletion and deletion-duplication.28 Two different mutations were described in the 2 children reported.28 In one patient, a deletion spanning 3380 base pairs encompassed 3 genes for complex I and 3 transfer ribonuclease genes. The deletion in the second patient was larger.


Treatment of acute liver failure and progressive liver disease in the mitochondrial hepatopathies include medical therapies and liver transplantation. Current medical therapies (Table 5) involved the use of various vitamins, cofactors, respiratory substrates, or antioxidant compounds with the aim of mitigating, postponing, or circumventing the damage to the respiratory chain.2,62 Unfortunately, none of these therapies has been proved to be effective in the majority of patients.63 Clinical management of individuals with the respiratory chain disorders is thus largely supportive with the aims of providing prognostic information and genetic counseling.

Table 5
Proposed Pharmacologic Treatments for Respiratory Chain Disorders

Based on the understanding of the enzymatic and biochemical derangements, several treatment strategies have been proposed for mitochondrial disorders, though none have been proved to be effective.63,64 Several different pharmacologic treatments and nutritional supplements have been used in individuals with mitochondrial disorders with varying degree of success. These include antioxidants (vitamin E, vitamin C),65,66 electron acceptor and cofactors (coenzyme Q10, idebenone, thiamine, riboflavin, menadione),6773 and agents to specifically treat lactic acidosis (dichloroacetate).74 Other agents proposed include succinate, which donates electron directly to complex II75; carnitine, which can correct secondary carnitine deficiency76; and creatine monohydrate, which enhances muscle phosphocreatine.77 Other supportive treatments may also include infusion of sodium bicarbonate for acute metabolic acidosis, transfusion for anemia and thrombocytopenia, and exogenous pancreatic enzymes for pancreatic insufficiency.2

A recent Cochrane analysis concluded that there is no clear evidence to suggest the benefit of any medical therapies in mitochondrial disorders.63 However, it should be noted that most of the therapeutic trials reported were conducted primarily in the myopathic forms of mitochondrial disorders.63 There is little reported experience on medical therapies in mitochondrial hepatopathies.


The role of liver transplantation (LT) in mitochondrial hepatopathies is complicated because of the multisystemic nature of this disorder and the observation that involvement of other organ systems may not become evident until after liver transplantation.79,80 Summarizing the reported experience, survival appears to be less than 50%.7982 Clearly the presence of significant neuro-muscular or cardiovascular involvement at the time of LT evaluation is an absolute contraindication to LT as a therapeutic option, inasmuch as extrahepatic clinical disease continues to progress to death after transplantation.79,80 It also appears that significant intestinal symptomatology (and hence presumed intestinal involvement) predicts a poor prognosis after LT.79 Finally, and most worrisome, unrecognized neurologic involvement prior to transplantation may progress rapidly after transplantation.80 Thus, the absence of extrahepatic features of mitochondrial disease at the time of LT does not guarantee a good outcome even if the transplant is successful.

There have been, however, patients who have had successful LT with no development of posttransplant extrahepatic manifestations. Thus, a careful and thorough pretransplant evaluation of potentially affected organ systems (kidneys, heart, muscle, intestinal tract, central nervous system, and pancreas) is mandatory. To exclude mitochondrial hepatopathies in patients with neonatal acute liver failure, Thomson et al80 proposed a protocol of investigations that includes blood (plasma lactate, postprandial 3-OH-butyrate, free fatty acid/ketones body ratio), liver and muscle biopsies, CSF lactate, tubular reabsorption of phosphate, fasting urine osmolality, echocardiogram, electroretinogram, and cranial CT scan. However, performing such evaluation is particularly challenging in patients presenting with acute liver failure and associated acute neurologic decompensation in whom a decision about LT needs to be made urgently, sometimes before diagnostic testing can be completed. Therefore, improved diagnostic techniques and predictive biomarkers to assist with selecting the best candidates for LT are certainly needed.


Despite elucidation of the genetic etiology of mitochondrial hepatopathies in recent years, there remains much to be learned about these disorders. The overall frequency and full clinical spectrum of hepatic involvement and natural history need to be defined. Diagnostic evaluation now involves genotyping the likely involved genes; however, more rapid and predictable diagnostic techniques (e.g., needle liver and muscle biopsy analysis of respiratory chain enzymes) still need to be developed and made widely accessible. Genotypephenotype correlations and the relationship of geno-type to response to liver transplantation await prospective large-scale studies. There are also undoubtedly other genetic causes that will be identified in coming years. A feasible and effective treatment is, at present, not available and the precise role of liver transplantation needs to be better defined. Finally, the role of polymorphisms in genes causing these disorders as potential modifiers in other disorders of the liver may identify new targets for therapeutic approaches. The Cholestatic Liver Disease Consortium, a National Institutes of Health funded, multicentered Rare Disease Clinical Research Consortium,83 is attempting to address many of these questions.


Way S. Lee was a visiting Fulbright Scholar from the Department of Pediatrics, University of Malaya Medical Centre, Kuala Lumpur, Malaysia, to the Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The University of Colorado School of Medicine, and The Children's Hospital, Denver, Colorado. This work was supported in part by grants from the National Institutes of Health (MOI RR00069, ROI DK038446, UOIDK062453, U54DK078377) and the Fulbright Scholarship.


acute fatty liver of pregnancy
adenosine triphosphate
cytochrome bc synthesis 1L
central nervous system
cytochrome c oxidase
cerebrospinal fluid
computed tomography
deoxyguanosine kinase
deoxyguanosine kinase gene
deoxy-ribose phosphate
electron transfer flavoprotein
reduced flavin adenine dinucleotide
long-chain 3-hydroxyacyl CoA dehydrogenase
liver transplantation
mitochondrial DNA depletion syndrome
mitochondrial inner membrane protein gene
magnetic resonance imaging
mitochondrial DNA
reduced nicotinamide adenine dinucleotide
Navajo neurohepatopathy
oxidative phosphorylation
DNA polymerase-γ gene
DNA polymerase-γ
suppressor of cytochrome oxidase deficiency 1
thymidine kinase 2
thymidine kinase 2 gene
thymidine phosphorylase
D-α-tocopheryl polyethylene glycol-1000 succinate
transfer RNA


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