Mitochondrial Hepatopathies

I. Overview

• Can present at any age
• Infants: acute liver failure (ALF)
• Older children: progressive chronic liver disease
• Multisystem involvement (CNS, cardiac, renal) raises suspicion
• Mitochondrial Depletion Syndromes (MDS):
  • Types: hepatocerebral, myopathic, encephalomyopathic
  • May affect one enzyme or multiple subunits of OXPHOS
  • Complex II (nDNA only) remains intact; Complexes I, III, IV often reduced (<40%)

II. Infant Presentation

• Poor feeding, hypotonia, lethargy, seizures
• Mild liver dysfunction progressing to failure in weeks/months
• Common cause: respiratory chain defects due to MDS
• Lab findings:
  • Lactate >2.5 mM
  • Lactate/pyruvate ratio >25
  • Ketotic hypoglycemia
  • ↑ PT, ± ↑ AST, ALT, bilirubin
• DGUOK deficiency mimics gestational alloimmune liver disease (hyperferritinemia)
• Histology:
  • Micro/macrovesicular steatosis
  • Canalicular cholestasis, bile duct thrombi
  • EM: abnormal mitochondrial size, number, cristae
• Outcome:
  • Poor prognosis; recurrent ALF possible
  • Neurological involvement common
  • Liver transplant often contraindicated

III. Older Children

Alpers-Huttenlocher Syndrome (POLG1)

• Bimodal onset: 3 mo–8 yrs and 17–24 yrs (80% before age 2)
• Neurological symptoms precede liver failure
• GERD, intractable vomiting
• ↓ Complex I, III, IV activity in liver/muscle
• MRI: cerebral volume loss
• ↓ Factor V, VII, albumin; ↑ INR
• Biopsy: microvesicular steatosis, portal fibrosis
• Valproic acid may worsen liver function

Pearson Syndrome (mtDNA deletion)

• 4,000–5,000 bp deletion in mtDNA
• Affects Complexes I, IV, V and 5 tRNAs
• Bone marrow: sideroblastic anemia, vacuolization
• Pancreas, liver: cirrhosis before age 4
• Adrenal insufficiency, Fanconi syndrome, diabetes
• Muscle typically spared
• Diagnosis: mtDNA deletion analysis

Navajo Neurohepatopathy (MPV17)

• Autosomal recessive; high incidence in Navajo children
• Sensorimotor neuropathy, hypotonia, areflexia, acral mutilation
• Three liver disease forms:
  • Infantile: fatal by age 2; jaundice, failure to thrive
  • Childhood: rapid liver failure (1–5 yrs)
  • Classical: progressive neurological symptoms with moderate liver disease
• Mutation in MPV17; affects Complexes I, III, IV

IV. Evaluation Strategy

Tier 1: Early Screening

• Lactate/pyruvate (best 1 hr post-feeding)
• Ammonia, α-fetoprotein, creatine phosphokinase
• Serum ketone bodies, acylcarnitine profile
• Serum-free and total carnitines
• Urine organic acids, urine/plasma ketone bodies
• Serum amino acids (alanine >600 μM)

Tier 2: Genetic Testing

• OXPHOS mutation panels via next-generation sequencing
• Survey for biallelic mutations in DGUOK, POLG1, MPV17
• If MELAS or Pearson suspected: mtDNA deletion/duplication assay

Tier 3: Tissue Evaluation

• Liver biopsy:
  • Light microscopy, EM, Oil Red O, iron stain
  • Frozen tissue for respiratory chain analysis and DNA quantification
• Skin biopsy: fibroblast culture
• Muscle biopsy: if neuromuscular symptoms present

Tier 4: Advanced Molecular Testing

• Targeted gene analysis for mtDNA depletion (e.g., SCO1, TWINKLE)
• Evaluate for FAO defects (e.g., ACAD9)