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. 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.
• Autosomal recessive; incidence ~1 in 100,000 births worldwide; much higher in Saguenay-Lac-Saint-Jean region of Quebec (1 in 1,850)
• 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
• 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)
• 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

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)
• 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)
• 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
• 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
• 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%)

Known HT1 patient with metabolic decompensation

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

Differential diagnosis

Infant with acute liver failure and coagulopathy

• Neonatal hepatitis (other causes)
• Galactosemia
• Hereditary fructose intolerance
• Neonatal hemochromatosis
• Gestational alloimmune liver disease
• Viral hepatitis (HSV, enterovirus, adenovirus)
• Sepsis
• Biliary atresia
• Acetaminophen toxicity

Porphyria-like neurologic crisis

• Acute intermittent porphyria
• Lead poisoning
• Guillain-Barré syndrome
• Abdominal pain (peds) (surgical causes)
• Intussusception

Fanconi syndrome (other causes)

• Cystinosis (most common inherited cause)
• Drug-induced (tenofovir, ifosfamide, valproic acid)
• Wilson disease

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
• 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
• 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
• 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
  • 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
• 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
• Monitor respiratory function closely — progressive neuropathy can cause respiratory failure requiring intubation and mechanical ventilation
• 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
• 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

• Fanconi syndrome
• Acute liver failure
• Acute intermittent porphyria
• Lead poisoning
• Cystinosis
• Galactosemia
• Wilson disease
• Hepatocellular carcinoma
• Guillain-Barré syndrome

External Links

• GeneReviews — Tyrosinemia Type I
• Medscape — Tyrosinemia
• Orphanet J Rare Dis — Recommendations for the management of tyrosinaemia type 1 (2013)
• NORD — Tyrosinemia Type 1
• Orphanet — Tyrosinemia type 1