Mitochondrial hepatopathy: Respiratory chain disorders- ‘breathing in and out of the liver’

Table 1 Various mitochondrial primary respiratory chain disorders

Disorder	Mutation/defective gene	Location of defect	Affected proteins/consequence
Neonatal liver failure: (1) Complex I deficiency; (2) Complex III deficiency; (3) Complex IV deficiency; and (4) Multiple complex deficiencies	ACAD9; BCS1L; SCO1	nuDNA	Respective complexes deficiency as per name
Delayed onset liver failure: Alper’s Huttenlocher syndrome	POLG mutation	nuDNA	Defective mtDNA polymerase; mtDNA depletion
MtDNA depletion syndrome	DGUOK; TK-2; MPV 17; POLG	All nuDNA	Decreased deoxyribonucleotide concentrations within mitochondria
Mitochondrial neuro-gastrointestinal encephalomyelopathy	TYMP	nuDNA	Markedly low levels of thymidine phosphorylase activity
Pearson marrow pancreas syndrome	4000-5000 bp deletions in mtDNA; tRNA gene of mtDNA	Both mtDNA	Complex I, IV, V
Navajo neurohepatopathy	MPV 17 mutations	nuDNA	mtDNA depletion
Villous atrophy with hepatic involvement	Rearrangement defect/deletion-duplications in mtDNA	mtDNA	Complex III deficiency

nuDNA: Nuclear DNA; mtDNA: Mitochondrial DNA.

Table 2 Gastrointestinal manifestations of mitochondrial respiratory chain defects

Site	Manifestation
Oral cavity and esophagus	Sicca syndrome; Dry mouth; Dysphagia
Stomach	Vomiting; Reflux; Pseudo-obstruction
Small bowel and large bowel	Pseudo-obstruction; Diarrhea; Megacolon; Constipation
Extra-luminal/miscellaneous	Poor appetite; Pancreatitis; Pancreatic cysts

Table 3 Stepwise evaluation of mitochondrial hepatopathies (respiratory chain disorder/non- respiratory chain disorders)

Steps	Description	Additional action
Level-1 (body fluids)	Basic: CBC, INR, AFP, CPK, NH3, sugars, phosphorous, urine ketones. Advanced: Lactate: Pyruvate (1 h post feeds); Ketone Body ratio, 3OH-butyrate: Acetoacetate; Serum acylcarnitine profile; Urine organic acidogram; Serum aminoacidogram; 3 Methyl Glutaconic acid in serum/urine; CSF lactate: Pyruvate, CSF alanine, protein; Plasma thymidine (MNGIE); Leucocyte CoQ levels	Parallel level-1: Evaluate other involved systems: CNS: MRI/MR-Spectroscopy, EEG; Eye: Fundus evaluation, clinical evaluation for ophthalmoplegias; Hearing screen; Heart: 2D-Echo, ECG; Renal: urine electrolytes, proteins, amino acids; Muscle: Muscle biopsy (Level-1 in case of primary muscle involvement, level-3 otherwise); Endocrine: HbA1c, 8 AM cortisol; Pancreas: Fecal elastase
Level-2 (genetics)	Common genes genotyping: POLG-1; DGUOK; MPV-17; SUCLG-1; TRMU; C10ORF2/Twinkle; CPT-1; mtDNA point mutations	Alternative level-2: Next generation sequencing/clinical exome sequencing for simultaneous evaluation of all mitochondrial DNA and nuclear DNA
Level-3 (invasive)	Tissue diagnosis: (1) Liver biopsy: Light microscopy including oil red O stain for steatosis; Electron microscopy for structural mitochondrial alterations; Frozen tissue analysis for respiratory chain enzymes, DNA quantification. (2) Muscle biopsy: Frozen tissue analysis as above; Blue native page analysis. (3) Skin biopsy: Same as muscle biopsy	Key points to note during level-3 evaluation: Biopsy specimens for electron microscopy need to be preserved in glutaraldehyde and not formalin; It is possible that one invasive test may not give a clue and one has to proceed for an additional invasive test. This is usually because of heteroplasmy. Often liver biopsy molecular analysis provides a final definitive answer; Combination of level-1, level-2 and level-3 studies are sometimes needed to provide comprehensive management and for prognostication

2D Echo: Two-dimensional echocardiography; AFP: Alpha-fetoprotein; CBC: Complete blood count; CNS: Central nervous system; CoQ: Coenzyme Q; CPK: Creatine phosphokinase; CSF: Cerebrospinal fluid; EEG: Electroencephalogram; HbA1c: Glycosylated hemoglobin; INR: International normalized ratio; MRI: Magnetic resonance imaging; NH3: Serum ammonia levels; POLG: DNA polymerase subunit gamma; RCD: Respiratory chain disorders.

Table 4 Biochemical differentiation between various metabolic hepatopathies (respiratory chain disorder vs non respiratory chain disorder comparison)

	Acidosis	Urine ketones	Blood sugar	Serum lactate	Serum ammonia
RCD	++	++	Normal	++++	±
FAOD	++	Nil (non-ketotic)	Low (hypoglycemia)	+	+
OA	+++ (persistent)	++/+++	Low/normal/high	Normal	++
UCD	Normal	Normal	Normal	Normal	++++

FAOD: Fatty acid oxidation defects; OA: Organic acidemias; RCD: Respiratory chain defects; UCD: Urea cycle defects.

Table 5 Management during evaluation in acute phase

Following thumb rules while attending to a patient with suspected mitochondrial disorder
Monitor closely for hypoglycemia and acidosis
Avoid lactated ringer’s solution for fluid administration: Worsens acidosis
Bicarbonate infusions as 1st line of defense
Avoid propofol for sedation/anesthesia
Avoid fasting > 12 h; avoid high rate glucose only infusions
Avoid drugs that are toxic to mitochondria: Chloramphenicol, valproate, aminoglycosides, phenytoin, carbamazapine, phenobarbital, statins, linezolid
Avoid drugs precipitating hepatopathy/liver dysfunction

Table 6 Pharmacotherapy used for mitochondrial diseases

Drug	Pediatric dose	Remark
Coenzyme Q: (1) Ubiquinol form; (2) Ubiquinone form	2-8 mg/kg/d in BD dosing; 10-30 mg/kg/d BD dosing	Preferably had after meals; Most effective and most used therapy; Free radical scavenger; Bypasses complex I
Idebenone	5 mg/kg/d	Synthetic form of CoQ; Penetrates blood-brain barrier
L-carnitine	10-100 mg/kg/d IV or oral divided 3 times/d	Avoid in long chain FAO-Ds: May lead to cardiac arrhythmias
Creatine	0.1 g/kg PO, OD	Used for repletion of muscle phosphocreatine levels
L-arginine	500 mg/kg IV per day for 1-3 d followed by 150-300 mg/kg oral daily in BD dosing	Used for acute stroke; Watch for hypotension while infusion; Evidence is anecdotal
Thiamine	100 mg/d	Cofactor of PDH; useful for thiamine responsive PDH deficiency; Helpful in leigh disease
Riboflavin	50-400 mg/d	Give at night time before sleep; Shown to be useful in ACAD9 mutations; Flavin precursor for complex I & II
Vitamin C	5 mg/kg/d OD	Antioxidant; Artificial electron acceptor
Vitamin E	Variable dosing, up to 25 IU/kg/d OD (avoid > 400 IU/d)	Absorption better when taken with meals
Dichloroacetate	25-50 mg/kg/d	Improves lactic acidosis

BD: Twice daily; CoQ: Coenzyme Q; FAO-D: Fatty acid oxidation defects; IV: Intravenous; PDH: Pyruvate dehydrogenase; PO: Per oral; OD: Once daily.