Metabolic Liver Disease Overview

Question 1

Inborn Errors of Metabolism

Answer 1

2nd most common cause of neonatal liver diseases and need for liver transplants.
Sometimes can be fatal if untreated. Sometimes family planning is impacted.

Question 2

Metabolic pathway:Z

Answer 2

Normal: A + B -enzyme/cofactor >C.
Abnormal lack of enzyme/cofactor can lead to build up of substrate (could be toxic: example urea cycle with hyperammonemia).
OR can lead to loss of product (decreased glucose in GSD).
Or a substrate can be metabolized via alternative pathway: (increased succinyacetone in tyrosinemia).

Question 3

When to suspect metabolic disease

Answer 3

• acute neurological deterioration/loss of developmental milestones
• liver dysfunction with hypoglycemia.
• non-ketotic hypoglycemia
• lactic acidosis or increased NH3.
• rental tubular disease
• ALF
• Fam hx.
• Fatty liver or cirrhosis in childhood

Question 4

Screening for metabolic liver disease

Answer 4

• Serum: glucose, ammonia, blood gas, uric acid, electrolytes, lactate:pyruvate ratio, ketones bodies, 3- OHB:AcAc ratio).
  Specialized tests: urine organic acids and amino acids, serum AA and FFA, carnitine, free carnitine, serum acylcarnitine.
• Urine: ketone bodies, reducing substances, sulfites, pH
• Exam: cataracts, strabismus, hypotonia, odor, dysmorphic features, retinitis

Question 5

Mitochondrial Cytopathies

Answer 5

occurs in 1:5,000 live births (combined).
Most commonly affected organ systems: CNS, Muscle/Heart, GI/Liver.

Question 6

Mitochondrial Hepatopathies Primary

Answer 6

Primary disorders: mitochondria are primary targets of gene mutation: critical mitochondrial protein.
- mtDNA mutations or deletions. (rare)
- nuclear gene mutations (usual)

Question 7

Mitochondrial Hepatopathies Secondary:

Answer 7

Secondary disorders: mitochondria are key targets of endogenous toxin (other metabolic diseases) or exogenous mitochondrial toxin (ex: drugs/metals).

Question 8

4 presentations of mitochondrial hepatopathies

Answer 8

1. Neonatal liver failure with lactic acidosis (which worsens when you give IV dextrose).
2. Neurologic or multisystem presentations with liver involvement: fatty liver, elevated LFTs, systemic failure.
3. Alpers Disease: 6-36 months: loss of developmental milestones, vomiting/GERD, intractable seizures, deterioration on valproate -> liver failure.
4. Cirrhosis/fatty liver.

Question 9

Nuclear genes and mitochondria

Answer 9

Mitochondrial diseases are almost always caused by AR mutations in NUCLEAR genes, not mitochondrial gene mutations.

Question 10

mtDNA Depletion Syndrome

Answer 10

-abnormally low amounts of mt DNA relative to normal levels of nuclear DNA > impaired synthesis of mt DNA.
This leads to impairment of respiratory chain (Complex I, III, IV), increased oxidative stress and ATP depletion
3 different types:
- Hepatocerebral.
- Myopathic
- Encephalomyopathic

Question 11

3 genes which cause mt depletion syndrome

Answer 11

• ## dGUOK Deficiency.-

Question 12

dGUOK deficiency

Answer 12

• MCC of mtDNA depletion
• neonatal liver failure, lactic acidosis, hypoglycemia, renal Fanconi’s, nystagmus, DD, hypotonia.
• increased ferritin, AFP, transferring saturation: can be mistaken for neonatal hemochromatosis.
  -spontaneous survival if limited Neuro symptoms.
• risk of hepatocellular carcinoma in survivors.
• enzyme involved in nucleotide salvage pathway in mitochondria

Question 13

POLG1 Deficiency

Answer 13

Causes Alpers-Huttenlocher syndrome and cases of neonatal liver failure (milder disease in adults)
- Intractable seizures common (worsens with valproate).
- May have NORMAL lactate and pyruvate.
- Liver transplant contra-indicated in most patients because of systemic involvement.

Question 14

MPV17 Deficiency

Answer 14

Inner mitochondrial membrane protein.
- Navajo Neruohepatopathy:
- peripheral neuropathy, leukoencephalopathy, aural mutilation, weakness, corneal abrasions and blindness, liver involvement.
-neonatal cholestasis, ALF or fatty cirrhosis or neurologic (sensory and motor neuropathy predominate),
Non-Navajo neonatal liver failure.

Question 15

Sequential evaluation

Answer 15

1. Lactate, pyruvate, NH3, acyl carnitine, CNS imaging (MRS)
2. Consider muscle or liver biopsy for mt DNA depletion, respiratory chain enzyme analysis. Histology and electron microscopy.
3. Genotyping: nuclear: POLG, MPV17, DGUOK.

Question 16

Treatment

Answer 16

ALF: balance of IV dextrose (limited) and lipids, correct acidosis, treat hyperammonemia, possible transplant.
Chronic disease: MCT oil, cornstarch for hypoglycemia.

Question 17

Mito toxic drugs to avoid

Answer 17

valproic acid, propofol, ringer’s lactate. Amiodarone, biguanides, haloperidol, linezoid, chloramphenicol, doxorubicin, aspirin, AZT

Question 18

Liver transplant considerations

Answer 18

• liver transplant only ok if disease is limited to the liver (other organs must be fully evaluated).
• DGUOK: can transplant in patients with no neurological findings.
  Contraindicated in POLG and MPV17.
  Inform family that other organ failure (CNS, PNS, cardiac, muscle) may appear after liver transplant.