Tyrosinemia

Background

  • Tyrosinemia refers to a group of inherited disorders of tyrosine metabolism.
  • Tyrosinemia type 1 (HT1) is the most severe and EM-relevant form, caused by deficiency of fumarylacetoacetate hydrolase (FAH), leading to accumulation of toxic metabolites that cause acute liver failure, Fanconi syndrome, porphyria-like neurologic crises, and hepatocellular carcinoma.[1] Emergency physicians may encounter HT1 patients presenting with fulminant hepatic failure in infancy, unexplained coagulopathy, neurologic crises mimicking porphyria or Guillain-Barré syndrome, or metabolic decompensation from missed nitisinone doses.[2]
  • Autosomal recessive; incidence ~1 in 100,000 births worldwide; much higher in Saguenay-Lac-Saint-Jean region of Quebec (1 in 1,850)[1]
  • Three types exist; type 1 is the focus of this page as it is by far the most EM-relevant:
Type Enzyme deficiency Key features
Type 1 (hepatorenal) Fumarylacetoacetate hydrolase (FAH) Liver failure, Fanconi syndrome, neurologic crises, HCC risk; life-threatening
Type 2 (oculocutaneous) Tyrosine aminotransferase Painful palmoplantar keratosis, herpetiform corneal ulcers; no liver disease
Type 3 4-hydroxyphenylpyruvate dioxygenase Mild; intellectual disability; extremely rare

Mechanism of toxicity (Type 1)

  • FAH deficiency → accumulation of fumarylacetoacetate (FAA), maleylacetoacetate (MAA), and succinylacetone (SA) — all are directly cytotoxic[1]
  • SA is a mitochondrial toxin → proximal tubule dysfunction → Fanconi syndrome
  • SA inhibits porphobilinogen synthase (δ-aminolevulinic acid dehydratase) → accumulation of δ-aminolevulinic acid (δ-ALA) → porphyria-like neurologic crises (identical mechanism to lead poisoning and acute intermittent porphyria)[2]
  • FAA/MAA cause direct hepatocellular damage → cirrhosis, liver failure, hepatocellular carcinoma
  • Nitisinone (NTBC) blocks the pathway upstream of FAH, preventing formation of all toxic metabolites — this transforms HT1 from a fatal disease into a manageable chronic condition[3]

Clinical features

Presentations the EM physician will encounter

Acute liver failure (infants <6 months) — the classic presentation

  • Often the first presentation of undiagnosed HT1
  • Jaundice, hepatomegaly
  • Severe coagulopathy (disproportionate to degree of jaundice — INR may be markedly elevated with only mild transaminase elevation; this pattern is characteristic)[1]
  • Ascites
  • Hypoglycemia
  • Bleeding (GI hemorrhage, oozing from venipuncture sites)
  • Sepsis (increased susceptibility)
  • Boiled cabbage odor to urine/sweat (from methionine accumulation; classic but not always present)[2]
  • Failure to thrive, vomiting, diarrhea, fever
  • May progress rapidly to multiorgan failure and death

Porphyria-like neurologic crisis — the most dangerous acute emergency

  • Occurs in untreated patients or patients who stop or miss nitisinone doses[4]
  • Episodic, lasting 1-7 days; often triggered by intercurrent infection
  • Severe abdominal pain (may mimic acute abdomen/surgical emergency)
  • Painful paresthesias, peripheral neuropathy (ascending; may mimic Guillain-Barré syndrome)
  • Progressive muscle weakness including respiratory muscles → respiratory failure requiring mechanical ventilation[1]
  • Self-injurious behavior (in response to extreme pain)
  • Seizures
  • Hypertension (often marked)
  • Hyponatremia (SIADH-like)
  • Altered mental status, irritability, agitation
  • Can be fatal from respiratory arrest if unrecognized
  • Mechanism identical to acute porphyria: elevated δ-ALA from SA inhibition of porphobilinogen synthase

Chronic/subacute presentation (>6 months)

  • Hepatosplenomegaly, failure to thrive
  • Fanconi syndrome: polyuria, polydipsia, metabolic acidosis, hypophosphatemia, hypokalemia, glycosuria, aminoaciduria
  • Rickets (from phosphate wasting + impaired vitamin D activation)
  • Progressive chronic kidney disease
  • Hypertrophic cardiomyopathy (reported in up to 30%)[2]

Known HT1 patient with metabolic decompensation

  • Missed nitisinone doses → rapid reaccumulation of toxic metabolites → acute liver dysfunction, neurologic crisis, or both[4]
  • Intercurrent illness → catabolic state → increased tyrosine turnover → metabolic decompensation
  • Noncompliance (especially in adolescents)

Differential diagnosis

Infant with acute liver failure and coagulopathy

Porphyria-like neurologic crisis

Fanconi syndrome (other causes)

Evaluation

EM workup

  • Hepatic function panel: AST/ALT may be only mildly elevated despite severe synthetic dysfunction (a characteristic discrepancy); bilirubin elevated
  • Coagulation studies: INR/PT markedly elevated — often the most striking lab abnormality; disproportionate to transaminases[1]
  • Blood glucose: hypoglycemia (hepatic failure)
  • BMP: hypokalemia, hypophosphatemia, low bicarbonate (Fanconi/RTA), hyponatremia (in neurologic crises)
  • CBC: anemia, thrombocytopenia (from liver failure/hypersplenism)
  • AFP (alpha-fetoprotein): markedly elevated (often >100,000 ng/mL) — this is a key diagnostic clue; AFP in HT1 is among the highest of any condition[1]
  • Ammonia: elevated in severe hepatic failure
  • Lactate: elevated if tissue hypoperfusion or metabolic crisis
  • ABG/VBG: metabolic acidosis (from Fanconi syndrome and/or hepatic failure)
  • Urinalysis: glycosuria (normal glucose), aminoaciduria, phosphaturia (Fanconi pattern)
  • ECG/echocardiography: if cardiomyopathy suspected

Diagnostic confirmation (arrange via specialist; not ED tests)

  • Urine/blood succinylacetone: pathognomonic for HT1; the definitive screening marker[1]
  • Elevated plasma tyrosine, methionine, phenylalanine
  • Elevated urinary δ-aminolevulinic acid (during neurologic crises)
  • FAH gene mutation analysis (confirmatory)

When to suspect HT1 in the ED

  • Infant with liver failure + coagulopathy out of proportion to transaminases + very high AFP
  • Infant/child with Fanconi syndrome + liver disease (most causes of Fanconi syndrome spare the liver; HT1 affects both)
  • Child with porphyria-like crisis (abdominal pain + neuropathy + hypertension + hyponatremia) — porphyria is extremely rare in children; consider HT1
  • Boiled cabbage odor
  • Known HT1 patient who has missed nitisinone doses and presents with acute symptoms

Management

Acute liver failure

  • Manage per standard Acute liver failure protocols:
    • IV fluids, correct hypoglycemia (D10W infusion)
    • FFP, cryoprecipitate, vitamin K for coagulopathy/active bleeding
    • Treat/prevent Hepatic encephalopathy (lactulose, rifaximin)
    • Broad-spectrum antibiotics if sepsis suspected
    • Monitor ammonia, electrolytes, glucose frequently
  • Start nitisinone (NTBC) immediately if HT1 is suspected or confirmed — do not wait for confirmatory testing[3]
    • Dose: 1-2 mg/kg/day orally (can be given via NG tube)
    • May show clinical improvement within hours to days
    • If liver fails to respond to nitisinone within 1 week → liver transplant referral[5]
  • Early contact with metabolic/hepatology center — these patients may need emergent liver transplant

Neurologic crisis

  • Restart or increase nitisinone immediately if doses were missed — this is the definitive treatment[4]
  • Monitor respiratory function closely — progressive neuropathy can cause respiratory failure requiring intubation and mechanical ventilation[1]
  • Pain management: opioids may be required for severe pain; avoid hepatotoxic agents
  • Seizure management: benzodiazepines first-line
  • Hypertension management: may require antihypertensives
  • Correct hyponatremia carefully (risk of osmotic demyelination with rapid correction)
  • Glucose infusion (10% dextrose) — high-calorie IV fluids reduce protein catabolism and tyrosine turnover
  • Do NOT give hemin (used in acute porphyria) — not indicated and not effective in HT1 neurologic crises; the mechanism involves δ-ALA accumulation from SA, not a deficiency in heme synthesis pathway

Fanconi syndrome management

  • Potassium, phosphate, bicarbonate supplementation (see Fanconi syndrome)
  • IV fluids for dehydration
  • Vitamin D (calcitriol)

Medication safety

  • Do NOT discontinue nitisinone — interruption can precipitate life-threatening liver failure or neurologic crisis within days to weeks[4]
  • If the patient cannot take oral nitisinone (vomiting, intubation), contact the metabolic team immediately for guidance
  • Avoid hepatotoxic medications (acetaminophen, hepatically metabolized drugs) in patients with liver disease
  • Maintain low-tyrosine/low-phenylalanine diet — if the patient is NPO, provide IV dextrose to reduce catabolism; consult metabolic dietitian

Disposition

  • Acute liver failure: ICU admission; early contact with liver transplant center and metabolic specialist
  • Neurologic crisis: ICU admission (risk of respiratory failure); continuous monitoring; restart nitisinone
  • New diagnosis suspected (infant with liver failure + high AFP + coagulopathy): admit; start nitisinone while awaiting confirmatory tests; metabolic/genetics and hepatology consultation
  • Known HT1 patient with intercurrent illness: low threshold for admission; monitor liver function, electrolytes, glucose; ensure nitisinone is continued; IV dextrose to reduce catabolism
  • Stable known HT1 patient with mild illness: may consider discharge with close metabolic team follow-up if PO tolerant, nitisinone continued, and caregiver reliable
  • Notify the patient's metabolic specialist of all ED visits

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Tyrosinemia Type I. GeneReviews. NCBI. 2025.
  2. ↑ 2.0 2.1 2.2 2.3 Tyrosinemia. Medscape. 2025.
  3. ↑ 3.0 3.1 de Laet C, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;8:8. doi:10.1186/1750-1172-8-8
  4. ↑ 4.0 4.1 4.2 4.3 Tyrosinemia Type I and Reversible Neurogenic Crisis After a One-Month Interruption of Nitisinone. J Pediatr Res. 2018.
  5. ↑ Tyrosinemia type 1. Orphanet. 2024.
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