Chapter 353 Mitochondrial Hepatopathies
Hepatocytes are rich in mitochondria due to the energy required for the process of metabolism and are a target organ for disorders in mitochondrial function. Defects in mitochondrial function can lead to impaired oxidative phosphorylation (OXPHOS), increased generation of reactive oxygen species, impairment of other metabolic pathways, and activation of mechanisms of cellular death. Mitochondrial disorders can be divided into primary, in which the mitochondrial defect is the primary cause of the disorder, and secondary, in which mitochondrial function is affected by exogenous injury or a genetic mutation in a nonmitochondrial gene (Chapter 81.4). Primary mitochondrial disorders can be caused by mutations affecting mitochondrial DNA (mtDNA) or by nuclear genes that encode mitochondrial proteins or cofactors (Table 353-1). Secondary mitochondrial disorders include diseases with an uncertain etiology such as Reye syndrome; disorders caused by endogenous or exogenous toxins, drugs, or metals; and other conditions in which mitochondrial oxidative injury may be involved in the pathogenesis of liver injury.
Table 353-1 PRIMARY MITOCHONDRIAL HEPATOPATHIES
DGUOK, deoxyguanosine kinase; MPV17; POLG, polymerase γ; CoA, coenzyme A; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide.
Adapted from Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics and pathogenesis, Hepatology 45:1555–1565, 2007.
More than 200 gene mutations that involve mtDNA and nuclear DNA that encodes mitochondrial proteins are identified. Mitochondrial genetics are unique because mitochondria are able to replicate, transcribe, and translate their mitochondrial derived DNA independently. The mitochondrial genome encodes 2 ribosomal RNAs, 22 transfer RNAs, and 13 proteins of complex I, III, IV, and V of the respiratory chain. OXPHOS (the process of adenosine triphosphate [ATP] production) occurs in the respiratory chain located in the inner mitochondrial membrane and is divided into 5 multienzyme complexes: reduced nicotinamide adenine dinucleotide (NADH) coenzyme Q (CoQ) reductase (complex I), succinate-CoQ reductase (complex II), reduced CoQ-cytochrome c reductase (complex III), cytochrome-c oxidase (complex IV), and ATP synthase (complex V). The polypeptides that form these complexes are transcribed from both mitochondrial and nuclear DNA; mutations in either genome can result in disorders of OXPHOS.
Expression of mitochondrial disorders is complex and epidemiologic studies are hampered by technical difficulties collecting and processing tissue specimens needed to make accurate diagnoses, the variability in clinical presentation, and the fact that most disorders display maternal inheritance with variable penetrance (Chapter 75). mtDNA mutates 10 times more frequently than nuclear DNA secondary to a lack of introns, protective histones, and an effective repair system in mitochondria. Mitochondrial genetics also display a threshold effect in that the type and severity of mutation required for clinical expression varies among people and organ systems. Despite this, it has been estimated that mitochondrial diseases have a prevalence of 11.5 cases per 100,000 populations. Treatments for mitochondrial hepatopathies are supportive. The role of liver transplantation is controversial given the multisystemic involvement.
Defects in OXPHOS can affect any tissue to a variable degree, with the most energy-dependent organs being the most vulnerable. One should consider the diagnosis of a mitochondrial disorder in a patient of any age who presents with progressive, multisystem involvement that cannot be explained by a specific diagnosis. Gastrointestinal (GI) complaints include vomiting, diarrhea, constipation, failure to thrive (FTT), and abdominal pain; certain mitochondrial disorders have characteristic GI presentations. Pearson marrow-pancreas syndrome manifests with sideroblastic anemia and exocrine pancreatic insufficiency, whereas mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) manifests with chronic intestinal pseudo-obstruction and cachexia. Hepatic presentations range from chronic cholestasis, hepatomegaly, or steatosis to fulminant hepatic failure and death.
A common presentation of respiratory chain defects is severe liver failure in the 1st few months of life, characterized by lactic acidosis, jaundice, hypoglycemia, renal dysfunction, and hyperammonemia. Symptoms are nonspecific and include lethargy and vomiting. Most patients additionally have neurologic involvement manifested as a weak suck, recurrent apnea, or myoclonic epilepsy. Liver biopsy shows predominantly microvesicular steatosis, cholestasis, bile duct proliferation, glycogen depletion, and iron overload. With standard therapy, the prognosis is very poor, and most patients die from liver failure or infection in the 1st few months of life. Cytochrome-c oxidase (Complex IV), a nuclear encoded gene, is the most common deficiency in these infants although complex I and III have also been implicated (see Table 353-1).
Alpers syndrome (Alpers-Huttenlocher syndrome or Alpers hepatopathic poliodystrophy) also manifest from infancy up to 8 yr of age with seizures, hypotonia, feeding difficulties, psychomotor regression, and ataxia. Patients typically develop hepatomegaly and jaundice and have a slower progression to liver failure than those with cytochrome-c oxidase deficiency. The disease is inherited in an autosomal recessive fashion; mutations in the catalytic subunit of the nuclear gene mtDNA polymerase-γA (POLG) have been identified in multiple families with Alpers syndrome, leading to the advent of molecular diagnosis for Alpers syndrome.
Mitochondrial DNA depletion syndrome (MDS) is characterized by a tissue-specific reduction in mtDNA copy number, leading to deficiencies in complexes I, III, IV, and V. MDS manifests with phenotypic heterogeneity, and multisystem and localized disease forms include myopathic, hepatocerebral, and liver-restricted presentations.
Infants with the hepatocerebral form present in the neonatal period with progressive liver failure, neurologic abnormalities, hypoglycemia, and lactic acidosis. Death usually occurs by 1 yr of age. Spontaneous recovery has been reported in 1 patient with liver-restricted disease. Inheritance is autosomal recessive and mutations in the deoxyguanosine kinase (dGK) gene have been identified in many patients with hepatocerebral MDS. dGK is a nuclear gene whose protein product phosphorylates deoxyguanosine to deoxyguanosine monophosphate, confirming the importance of nucleotide pool homeostasis in mtDNA stability and maintenance. Thymidine kinase 2 (TK2) is also involved in deoxynucleotide phosphorylation and has been implicated in the myopathic form; no known genetic defect has been identified in liver-restricted MDS. Multiple other genes including DGUOK, POLG, and MPV17 have been implicated in hepatocerebral MDS.
Liver biopsies of patients with MDS show microvesicular steatosis, cholestasis, focal cytoplasmic biliary necrosis, and cytosiderosis in hepatocytes and sinusoidal cells. Ultrastructural changes are characteristic with oncocytic transformation of mitochondria, which is characterized by mitochondria with sparse cristae, granular matrix, and dense or vesicular inclusions. Diagnosis is established by demonstration of a low ratio of mtDNA (<10%) to nuclear DNA in affected tissues and/or genetic testing. Importantly, the sequence of the mitochondrial genome is normal.
Navajo neurohepatopathy (NNH) is an autosomal recessive sensorimotor neuropathy with progressive liver disease found only in Navajo Indians of the southwestern United States. The incidence is 1/1,600 live births. Diagnostic criteria have been defined and include sensory neuropathy; motor neuropathy; corneal anesthesia; liver disease; metabolic or infectious complications including FTT, short stature, delayed puberty, or systemic infection; and evidence of central nervous system (CNS) demyelination on radiographic imaging. A definite case requires 4 of these criteria or 3 with a sibling previously diagnosed with NNH. A founder effect is possible with the identification of a homozygous R50Q mutation in the MPV17 gene in 6 patients with NNH from 5 different families. Interestingly, this is the same gene implicated in MDS (see earlier), demonstrating that NNH may be a specific type of MDS found only in Navajo Indians.
NNH has been divided into 3 phenotypic variations based on age of presentation and clinical findings. Different presentations have been noted within single families. First, classic NNH appears in infancy with severe progressive neurologic deterioration manifesting clinically as weakness, hypotonia, loss of sensation with accompanying acral mutilation and corneal ulcerations, and poor growth. Liver disease, present in the majority of patients, is secondary and variable and includes asymptomatic elevations of liver function tests, Reye syndrome–like episodes, hepatocellular carcinoma, or cirrhosis. γ-Glutamyl transpeptidase (GGT) levels tend to be higher than in other forms of NNH. Liver biopsy might show chronic portal tract inflammation and cirrhosis, but it shows less cholestasis, hepatocyte ballooning, and giant cell transformation than other forms of NNH.
Infantile NNH manifests between the ages of 1 and 6 mo with jaundice and failure to thrive and progresses to liver failure and death by 2 yr of age. Patients have hepatomegaly with moderate elevations in aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT), and GGT. Liver biopsy demonstrates pseudo-acinar formation, multinucleate giant cells, portal and lobular inflammation, canalicular cholestasis, and microvesicular steatosis. Progressive neurologic symptoms are not usually noticed at presentation but do develop later.
Childhood NNH manifests from age 1-5 yr with the acute onset of fulminant hepatic failure that leads to death within months. Most patients also have evidence of neuropathy at presentation. Liver biopsies are similar to those in infantile NNH, except significant hepatocyte ballooning and necrosis, bile duct proliferation, and cirrhosis are also seen.
Nerve biopsy in all types might show reduction of large- and small-caliber myelinated nerve fibers and degeneration and regeneration of unmyelinated nerve fibers. There is no effective treatment for any of the forms of NNH, and neurologic symptoms often preclude liver transplantation. The identical MPV17 mutation is seen in patients with both the infantile and classic form of NNH highlighting the clinical heterogeneity of NNH.
Secondary mitochondrial hepatopathies are caused by a hepatotoxic metal, drug, toxin, or endogenous metabolite. In the past, the most common secondary mitochondrial hepatopathy was Reye syndrome, the prevalence of which peaked in the 1970s and had a mortality rate of >40%. Even though mortality has not changed, the prevalence has decreased from >500 cases in 1980 to ∼35 cases per yr since. It is precipitated in a genetically susceptible person by the interaction of a viral infection (influenza, varicella) and salicylate use. Clinically, it is characterized by a preceding viral illness that appears to be resolving and the acute onset of vomiting and encephalopathy (Table 353-2). Neurologic symptoms can rapidly progress to seizures, coma, and death. Liver dysfunction is invariably present when vomiting develops, with coagulopathy and elevated serum levels of AST, ALT, and ammonia. Importantly, patients remain anicteric and serum bilirubin levels are normal. Liver biopsies show microvesicular steatosis without evidence of liver inflammation or necrosis. Death is usually secondary to increased intracranial pressures and herniation. Patients who survive have full recovery of liver function but should be carefully screened for fatty-acid oxidation and fatty-acid transport defects (Table 353-3).
Table 353-3 DISEASES THAT PRESENT A CLINICAL OR PATHOLOGIC PICTURE RESEMBLING REYE SYNDROME
CoA, coenzyme A.
Acquired abnormalities of mitochondrial function can be caused by several drugs and toxins, including valproic acid, cyanide, amiodarone, chloramphenicol, iron, antimycin A, the emetic toxin of Bacillus cereus, and nucleoside analogs. Valproic acid is a branched fatty acid that can be metabolized into the mitochondrial toxin 4-envalproic acid. Children with underlying respiratory chain defects appear more sensitive to the toxic effects of this drug and valproic acid has been reported to precipitate liver failure in patients with Alpers syndrome and cytochrome-c oxidase deficiency. Nucleoside analogs directly inhibit mitochondrial respiratory chain complexes. Fialuridine, used to treat hepatitis B infection, can produce fatal lactic acidosis and liver failure. The mechanism of mitochondrial injury involves the direct incorporation of fialuridine into mtDNA, replacing thymidine and thereby directly inhibiting DNA transcription, which leads to acquired mtDNA depletion syndrome. The reverse transcriptase inhibitors zidovudine, didanosine, stavudine, and zalcitabine used to treat HIV-infected patients inhibit DNA polymerase-γ of mitochondria and can block elongation of mtDNA, leading to mtDNA depletion. Other conditions that can lead to mitochondrial oxidative stress include cholestasis, nonalcoholic steatohepatitis, α1-antitrypsin deficiency, and Wilson disease.
There is no effective therapy for most patients with mitochondrial hepatopathies; neurologic involvement often precludes orthotopic liver transplantation. Several drug mixtures that include antioxidants, vitamins, cofactors, and electron acceptors have been proposed, but no randomized, controlled trials have been completed to evaluate these drug combinations. Therefore, current treatment strategies are supportive.
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