Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Mitochondrial Hepatopathies
A wide variety of mitochondrial disorders are associated with liver disease. Hepatocytes contain a high density of mitochondria because the liver, with its biosynthetic and detoxifying functions, is highly dependent on adenosine triphosphate. Defects in mitochondrial function can lead to impaired oxidative phosphorylation, 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 that affects nonmitochondrial proteins (see Chapter 105.4 ). Primary mitochondrial disorders can be caused by mutations affecting mitochondrial DNA (mtDNA) or by nuclear genes that encode mitochondrial proteins or cofactors (see Chapter 383 — Table 383.3 and Table 388.1 ). Specific patterns may be noted ( Table 388.2 ). 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 388.1
Genotypic Classification of Primary Mitochondrial Hepatopathies and Organ Involvement
From Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics, therapeutic approaches and outcomes, J Pediatr 163:942–948, 2013 (Table 2, p. 944).
| GENE | RESPIRATORY CHAIN COMPLEX | HEPATIC HISTOLOGY | OTHER ORGANS INVOLVED | CLINICAL FEATURES |
|---|---|---|---|---|
| Deletion | Multiple (Pearson) | Steatosis, fibrosis | Kidney, heart, CNS, muscle | Sideroblastic anemia, variable thrombocytopenia and neutropenia, persistent diarrhea |
| MPV17 | I, III, IV | Steatosis | CNS, muscle, gastrointestinal tract | Adult-onset multisystemic involvement: myopathy, ophthalmoplegia, severe constipation, parkinsonism |
| DGUOK | I, III, IV | Steatosis, fibrosis | Kidneys, CNS, muscle | Nystagmus, hypotonia, renal Fanconi syndrome, acidosis |
| MPV17 | I, III, IV | Steatosis, fibrosis | CNS, PNS | Hypotonia |
| SUCLG1 | I, III, IV | Steatosis | Kidneys, CNS, muscle | Myopathy, sensorineural hearing loss, respiratory failure |
| POLG1 | I, III, IV | Steatosis, fibrosis | CNS, muscle | Liver failure preceded by neurologic symptoms, intractable seizures, ataxia, psychomotor regression |
| C10orf2/Twinkle | I, III, IV | Steatosis | CNS, muscle | Infantile-onset spinocerebellar ataxia, loss of skills |
| BCS1L | III (GRACILE) | CNS ±, muscle ±, kidneys | Fanconi-type renal tubulopathy | |
| SCO1 | IV | Steatosis, fibrosis | Muscle | |
| TRMU | I, III, IV | Steatosis, fibrosis | Infantile liver failure with subsequent recovery | |
| EFG1 | I, III, IV | Steatosis | CNS | Severe, rapidly progressive encephalopathy |
| EFTu | I, III, IV | Unknown | CNS | Severe lactic acidosis, rapidly fatal encephalopathy |
CNS, central nervous system; GRACILE, growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death; PNS, peripheral nervous system.
Table 388.2
Hepatic Phenotypes of Mitochondrial Cytopathies
From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 5, Philadelphia, 2016, Elsevier (Box 71.2, p. 876).
|
Epidemiology
Mitochondrial respiratory chain disorders of all types affect 1 in 20,000 children younger than 16 yr of age; liver involvement has been reported in 10–20% of patients with respiratory chain defect. Primary mitochondrial disorders, including mtDNA depletion syndromes (MDSs), occur in 1 in 5,000 live births and are a known cause of acute liver failure in children <2 yr of age.
More than 200 pathogenic point mutations, deletions, insertions, and rearrangements that involve mtDNA and nuclear DNA and encodes mitochondrial proteins are identified. Mitochondrial genetics are unique because mitochondria are able to replicate, transcribe, and translate their mitochondrial-derived DNA independently. A typical hepatocyte contains approximately 1,000 copies of mtDNA. Oxidative phosphorylation (the process of adenosine triphosphate production) occurs in the respiratory chain located in the inner mitochondrial membrane and is divided into 5 multienzyme complexes: reduced nicotinamide adenine dinucleotide coenzyme Q reductase (complex I), succinate–coenzyme Q reductase (complex II), reduced coenzyme Q–cytochrome- c reductase (complex III), cytochrome- c oxidase (complex IV), and adenosine triphosphate synthase (complex V). The respiratory chain peptide components are encoded by both nuclear and mtDNA genes, hence mutations in either genome can result in disorders of oxidative phosphorylation. Thirteen essential polypeptides are synthesized from the small 16.5-kilobase circular double-stranded mtDNA. mtDNA also encodes the 24 transfer RNAs required for intramitochondrial protein synthesis, whereas nuclear genes encode more than 70 respiratory chain subunits and an array of enzymes and cofactors required to maintain mtDNA, including DNA polymerase-γ (POLG), thymidine kinase 2, and deoxyguanosine kinase.
The expression of mitochondrial disorders is complex, and epidemiologic studies are hampered by technical difficulties in collecting and processing the tissue specimens needed to make accurate diagnoses, the variability in clinical presentation, and the fact that most disorders display maternal inheritance with variable penetrance (see Chapter 97 ). mtDNA mutates 10 times more often than nuclear DNA due to a lack of introns, protective histones, and an effective repair system in mitochondria. Mitochondrial genetics also displays a threshold effect in that the type and severity of mutation required for clinical expression varies among people and organ systems; this is explained by the concept of heteroplasmy, in which cells and tissues harbor both normal and mutant mtDNA in various amounts because of random partitioning during cell division. Mutations, deletions, or duplications in either mitochondrial or nuclear genes can cause disease, and mutations in nuclear genes that control mtDNA replication, transcription, and translation may lead to MDS or to a translational disorder.
Clinical Manifestations
Defects in oxidative phosphorylation 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 complaints include vomiting, diarrhea, constipation, failure to thrive, and abdominal pain; certain mitochondrial disorders have characteristic gastrointestinal presentations. Pearson marrow-pancreas syndrome manifests with sideroblastic anemia and exocrine pancreatic insufficiency, whereas mitochondrial neurogastrointestinal encephalomyopathy manifests with chronic intestinal pseudo-obstruction and cachexia. Hepatic presentations range from chronic cholestasis, hepatomegaly, cirrhosis, and steatosis to fulminant hepatic failure and death. Patients with certain mitochondrial diseases may have normal or minimally elevated lactate levels even in the setting of a metabolic crisis. The lactate-to-pyruvate molar ratio (L:P) has been proposed as a screening test for mitochondrial disorders because it reflects the equilibrium between the product and substrate of the reaction catalyzed by lactase dehydrogenase. An L:P ≥ 25 has been considered to be highly suggestive of respiratory chain dysfunction; however, an elevated lactate or an elevated L:P can also represent secondary mitochondrial dysfunction occurring as a result of severe liver disease.
Primary Mitochondrial Hepatopathies
Neonatal Liver Failure
A common presentation of respiratory chain defects is severe liver failure manifested as jaundice, hypoglycemia, coagulopathy, renal dysfunction, and hyperammonemia, with onset within the first few weeks to months of life. Cytochrome- c oxidase (complex IV) is the most common deficiency in these infants, although complexes I and III and MDSs are also implicated (see Tables 388.1 and 383.3 ). The key biochemical features include a markedly elevated plasma lactate concentration, an elevated molar ratio of plasma lactate to pyruvate (L:P) (>25), and a raised ratio of β-hydroxybutyrate to acetoacetate (>4.0). Symptoms are nonspecific and include lethargy and vomiting. Most patients additionally have neurologic involvement that manifests 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 poor, and most patients die from liver failure or infection in the first few months of life.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here