Tyrosinimea
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Here is a detailed overview of Tyrosinemia:
Tyrosinemia
Tyrosinemia refers to a group of inborn errors of metabolism caused by defective degradation of the amino acid tyrosine. There are three distinct types, each caused by a different enzymatic defect.
Tyrosine Degradation Pathway
Phenylalanine -> Tyrosine -> 4-hydroxyphenylpyruvate -> Homogentisate -> Maleylacetoacetate -> Fumarylacetoacetate -> Fumarate + Acetoacetate (via FAH)
Type I - Hepatorenal Tyrosinemia (Most Severe)
Enzyme Defect
Fumarylacetoacetate hydrolase (FAH) - the terminal enzyme in tyrosine catabolism. Gene: FAH (autosomal recessive).
Epidemiology
- Incidence ~1:100,000 worldwide
- Very high frequency in Saguenay-Lac Saint-Jean region of Quebec, Canada (1:1,800 due to founder effect)
Pathophysiology
- Fumarylacetoacetate and maleylacetoacetate accumulate and are hepatotoxic
- Succinylacetone accumulates - this is the pathognomonic marker
- Succinylacetone inhibits delta-aminolevulinate dehydratase (ALA dehydratase), causing buildup of 5-aminolevulinic acid (ALA), producing porphyria-like neurologic crises
Clinical Features
Acute presentation (< 6 months):
- Acute liver failure
- Coagulopathy, hypoglycemia, hypoalbuminemia
- Only mildly elevated transaminases (disproportionately low for degree of liver failure - a clue!)
- Neonatal cholestasis
Chronic presentation (> 6 months):
- Failure to thrive
- Hepatomegaly, cirrhosis
- Renal tubular dysfunction - Fanconi syndrome: glycosuria, proteinuria, aminoaciduria, hyperphosphaturia
- Hypophosphatemic rickets
- Very elevated alpha-fetoprotein (AFP) for age
Neurologic crises (porphyria-like):
- Painful paresthesias
- Autonomic dysfunction
- Progressive paralysis and respiratory depression
- Can be fatal
Cardiac:
- Cardiomyopathy in ~30% of newly diagnosed patients (interventricular septal hypertrophy most common); typically resolves with treatment
Malignancy:
- Very high risk for hepatocellular carcinoma (HCC) - can occur as young as 2 years of age in untreated patients
Liver Histology
- Macrovesicular steatosis
- Pseudoacinar rosette formation of hepatocytes (may contain bile plugs)
- Hemosiderosis
- Hepatocyte necrosis and apoptosis
- Fine diffuse fibrosis progressing to micronodular cirrhosis
- Regenerative nodules and HCC
Diagnosis
- Urine succinylacetone - pathognomonic; gold standard. Succinylacetone is NOT elevated in other causes of hypertyrosinemia
- Elevated plasma tyrosine (nonspecific - also elevated in TYR2, TYR3, liver disease, prematurity)
- Elevated AFP (markedly high)
- FAH enzyme activity in red blood cells (research labs)
- Newborn screening: succinylacetone is the primary marker (tyrosine alone is unreliable in the newborn period)
Treatment
- NTBC (nitisinone) - inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the enzyme upstream of FAH. This blocks production of succinylacetone, which becomes undetectable in urine almost immediately. This is now first-line treatment.
- Dietary restriction of phenylalanine and tyrosine (precursors) - diet alone does not prevent liver decompensation or cirrhosis but benefits the kidneys
- Liver transplantation - indicated for patients progressing to liver failure despite NTBC, or for those who develop HCC. Reverses hepatic metabolic abnormalities and prevents neurologic disease.
- Monitoring: plasma amino acids (diet adequacy), serial AFP (HCC surveillance), urine succinylacetone (NTBC response)
Type II - Oculocutaneous Tyrosinemia (Richner-Hanhart Syndrome)
Enzyme Defect
Hepatic tyrosine aminotransferase (TAT) - the first step in tyrosine catabolism. Gene: TAT (autosomal recessive).
Clinical Features (triad)
- Ocular: Lacrimation, photophobia, corneal erosions, neovascularization, and opacification (from crystalline tyrosine deposits). Usually begins in the 1st-2nd year.
- Skin: Painful palmar and plantar hyperkeratosis on weight-bearing areas, tracking along dermatoglyphs; bullae possible. May not appear until the 2nd decade.
- Neurologic: Mild to moderate intellectual disability in >50% of patients; self-mutilation, language defects, incoordination
Key Point
- Serum tyrosine is markedly elevated (>0.18 mM)
- In any child with palmoplantar keratoderma + photophobia/tearing, think TYR2
Diagnosis
- Elevated serum and urine tyrosine
- No succinylacetone (distinguishes from TYR1)
Treatment
- Low-tyrosine, low-phenylalanine diet (improves/prevents eye and skin lesions; may not reverse established intellectual disability)
- Oral retinoids for skin lesions
- Must be started early to prevent neurologic damage
Type III - Tyrosinemia (HPD Deficiency)
Enzyme Defect
4-Hydroxyphenylpyruvate dioxygenase (HPD). Gene: HPD (autosomal recessive).
Clinical Features
- Rarest form
- Primarily neurologic: intellectual disability, seizures, ataxia
- Mild hypertyrosinemia
- No liver or eye involvement
Summary Comparison Table
| Feature | Type I (TYR1) | Type II (TYR2) | Type III (TYR3) |
|---|---|---|---|
| Enzyme defect | FAH | TAT | HPD |
| Gene | FAH | TAT | HPD |
| Diagnostic marker | Succinylacetone (urine) | Elevated serum tyrosine | Elevated serum tyrosine |
| Liver disease | Severe (cirrhosis, HCC) | None | None |
| Renal (Fanconi) | Yes | No | No |
| Eye findings | No | Yes (corneal erosions) | No |
| Skin | No | Yes (palmoplantar keratosis) | No |
| Neurology | Porphyria-like crises | Mild intellectual disability | Intellectual disability, seizures |
| Key treatment | NTBC + diet ± liver Tx | Low-Tyr/Phe diet | Low-Tyr/Phe diet |
Key High-Yield Points
- TYR1 causes disproportionately low transaminases for the degree of liver dysfunction - a classic exam point
- Succinylacetone in urine = diagnostic for TYR1 (not elevated in other causes of hypertyrosinemia)
- NTBC works by blocking upstream of the enzyme defect, preventing accumulation of toxic intermediates
- HCC can occur at age 2 - regular AFP monitoring is mandatory in TYR1
- Porphyria-like neurologic crises in TYR1 are due to ALA accumulation from succinylacetone-mediated inhibition of ALA dehydratase
Sources: Yamada's Textbook of Gastroenterology, 7th ed. | Tietz Textbook of Laboratory Medicine, 7th ed. | Adams and Victor's Principles of Neurology, 12th ed. | Andrews' Diseases of the Skin, Clinical Dermatology
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Tyrosinemia
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The PDF includes:
- Title banner with a professional blue header
- Tyrosine catabolism pathway summary box
- Type I (TYR1) - full coverage: pathophysiology, clinical features (acute/chronic), liver histology, diagnosis table, treatment
- Type II (TYR2) - Richner-Hanhart syndrome triad table, diagnosis, treatment
- Type III (TYR3) - enzyme defect and features
- 3-type comparison table side by side
- 10 high-yield exam points formatted for quick review
- Source references from 6 authoritative textbooks
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