Mitochondrial Hepatopathies

Abstract

Content available: Author Interview and Audio Recording Answer questions and earn CME Mitochondria play critical roles in energy, calcium, iron, and reduction/oxidation homeostasis, as well as regulation of apoptosis. They are the only organelle that contains its own circular genomes (mitochondrial DNA [mtDNA]). Maternally inherited mtDNA houses 37 genes encoding mitochondrial transfer RNAs (tRNAs), ribosomal RNA, and 13 proteins that exclusively function as subunits of the oxidative-phosphorylation machinery. Additional proteins critical to mitochondrial structure and function are encoded by the nuclear genome. Mitochondrial disorders include defects in oxidative-phosphorylation complexes, mtDNA maintenance, and mtDNA transcription and translation and can result from mitochondrial or nuclear mutations and yield disease involving virtually every organ system, including the liver. Mitochondrial hepatopathies are heterogenous and individually rare, but collectively they comprise an important cause of early liver failure. In two studies of infants with acute liver failure, about 20% of cases were attributable to mitochondrial pathology.1, 2 Mitochondrial liver disease may manifest as liver failure (acute, chronic, or recurrent), cholestasis, liver fibrosis, or elevated transaminases (Table 1). Presentation is typically pediatric. A mitochondrial etiology is especially likely in cases with multisystem involvement but is also associated with isolated hepatopathy. Low birth weight and intrauterine growth restriction have been associated.3, 4 Lactic acidosis and hypoglycemia are common biochemical features5, 6 and could lead to the misdiagnosis of other conditions, such as glycogen storage disease type I.6 Mitochondrial depletion syndromes (MDSs) feature decreased mtDNA copy number secondary to defects in mtDNA replication. MDSs may present with infantile hepatocerebral syndrome with acute or chronic liver failure. Mortality is high. Hepatocellular carcinoma is a complication in survivors (DGUOK and MPV17).4, 5 Affected infants typically present with growth failure, feeding difficulty, developmental delay, and hypotonia. Although brain involvement is usually prominent, in rare cases DGUOK may cause isolated liver failure. In POLG disease, brain involvement may not be immediately apparent, but developmental regression and epilepsia partialis continua are inevitable. Valproate triggers fulminant liver failure in MDS7 and is contraindicated. Pediatric valproate-induced liver failure should be assumed to be MDS. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) secondary to thymidine phosphorylase deficiency is an adolescent-onset MDS that may have cirrhosis, as well as gastrointestinal dysmotility, peripheral neuropathy, and asymptomatic leukoencephalopathy.8 Single large-scale mtDNA deletions cause a spectrum of phenotypes, including Pearson syndrome, a severe disease characterized by sideroblastic anemia and exocrine pancreatic insufficiency. More than 33% of patients have liver involvement (hepatomegaly, cholestasis, and/or progressive liver failure). Kearns-Sayre syndrome develops in childhood in survivors. Point mutations in mtDNA almost never cause liver disease.9 Mitochondrial translation disorders are also characterized by early-onset liver failure with frequent neurological manifestations. Early diagnosis and management are critical because recovery is possible with appropriate medical support, for example, acute infantile liver failure caused by mutations in TRMU.6 Mitochondrial hepatopathy is also associated with deficiency of individual oxidative-phosphorylation complexes, for example, BCS1L mutations cause infantile cholestasis with liver iron overload and multisystemic features.4 Diagnostic work-up for suspected mitochondrial hepatopathy includes full phenotyping, biochemical studies, functional studies, and genetic confirmation.10 Cardiac, neuromuscular, retinal, or auditory involvement may raise suspicion for mitochondrial disease generally, but specific features may be diagnostic. Peripheral neuropathy (MPV17), pili torti (BCS1L), rotary nystagmus (DGUOK), and sideroblastic anemia (mtDNA deletion) can be observed (Fig. 1). Biochemical laboratory testing, including amino acids, organic acids, and lactate/pyruvate and acylcarnitine profiles, are not sensitive but can strongly increase suspicion for mitochondrial disease. Pathological examination of liver tissue plays a key role in confirming a clinical suspicion of mitochondrial hepatopathy and directing future testing (Fig. 2). Light microscopic findings are variable and depend on genetic lesion, patient age, and disease severity at time of biopsy. Classical findings beyond early infancy include nonzonal mixed (macrovesicular and microvesicular) steatosis, variable fibrosis, and presence of oncocytic hepatocytes with granular, hypereosinophilic cytoplasm. Electron microscopy shows this oncocytic change reflects proliferation of structurally abnormal mitochondria, characterized by lack of cristae, tubular cristae, and/or electron-dense matrix granules. The light microscopic differential diagnosis includes other metabolic disorders, Wilson disease, and secondary mitochondrial dysfunction as a result of drug toxicity; ultrastructural changes, including mitochondrial proliferation, are more specific for primary mitochondrial disorders. Mitochondrial hepatopathy is also a significant causative factor for congenital liver failure, where the histological picture may be of neonatal (giant cell) hepatitis, or even so-called neonatal hemochromatosis: hepatic parenchymal collapse with massive ductular proliferation, cholestasis, and evidence of siderosis both in liver and extrahepatic tissues. In such cases, classic histological and ultrastructural features may be absent; ancillary testing of rapidly procured postmortem tissue is required to establish the diagnosis. The differential diagnosis in these cases includes gestational alloimmune liver disease, congenital infection, or other metabolic disorders. Acquiring tissue samples enables functional mitochondrial testing. Electron transport enzymology is sensitive for BCS1L (complex III) and SCO1 (complex IV) deficiency. BN-PAGE can suggest mitochondrial translation defects; mtDNA quantification is the diagnostic gold standard for MDS diagnosis. Functional testing is most sensitively performed on liver tissue. Because there is a high degree of phenotype overlap, whole-exome sequencing is often the most effective way to reach a definitive diagnosis. Analysis of mtDNA to rule out deletion is also warranted. Evidence-based management guidelines for mitochondrial hepatopathies are lacking, and curative treatments are unavailable. Supportive measures led by a multidisciplinary team are the mainstay of therapy. Early introduction of enteral feeding optimizes mitochondrial function and minimizes lactic acidosis. Feeding tube placement may be required to ensure adequate nutritional support for patients. Avoidance of fasting and/or frequent feedings can prevent hypoglycemia. Specific therapies are indicated for some diagnoses: branched-chain amino acid restriction and riboflavin supplementation for dihydrolipoamide dehydrogenase (DLD) deficiency, and cysteine supplementation for TRMU deficiency.6 Liver transplantation for mitochondrial hepatopathy is controversial. Good outcomes have been reported in patients with mild MPV17 and DGUOK without neurological involvement.3, 5 However, posttransplant disease worsening has been observed in patients with MDS with any neurological involvement, especially in POLG. Generally, liver transplant is not contraindicated, but risks and benefits should be carefully evaluated. Posttransplant management is challenging because some immunomodulators are mitotoxic. Hematopoietic stem cell transplant has resulted in clinical improvement in some patients with MNGIE.8 Mitochondrial dysfunction is associated with impaired redox homeostasis and glutathione depletion. N-acetylcysteine may ameliorate oxidative stress and is a potential therapy for mitochondrial hepatopathies.6 Gene therapy has shown experimental success for several monogenic liver disorders. The liver is amenable to gene therapy: it is easily targeted by adeno-associated virus vectors and is a lifelong replicating tissue.11 Therefore, it holds future promise as a therapeutic option for mitochondrial hepatopathies. Mitochondrial hepatopathies are an important cause of infantile/pediatric liver failure. They should be suspected in patients with neonatal-onset liver dysfunction, steatosis, fulminant or acute disease, or in individuals with neuromuscular or multiorgan involvement. 1. What are clinical features that should increase suspicion for underlying mitochondrial hepatopathy? Mitochondrial hepatopathy should be suspected in cases of neonatal-onset liver dysfunction, steatosis, fulminant, or acute disease, or in individuals with neuromuscular or multiorgan involvement. 2. How are mitochondrial hepatopathies diagnosed? Diagnosis of mitochondrial hepatopathies is multifaceted and includes biochemical and genetic testing, pathological examination of liver tissue, and functional mitochondrial enzymology. 3. How are mitochondrial hepatopathies treated? Treatment for mitochondrial hepatopathy is largely supportive. N-acetylcysteine may be helpful. Mitochondrial hepatopathy is not an absolute contraindication for consideration of transplantation.

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