Tyrosinemia is an autosomal recessive inborn error of tyrosine metabolism. Type I (hepatorenal tyrosinemia) is the most severe form, caused by deficiency of fumarylacetoacetate hydrolase (FAH), leading to accumulation of toxic metabolites (succinylacetone, fumarylacetoacetate, maleylacetoacetate) that cause progressive hepatic, renal, and neurologic damage. [1] Type II (oculocutaneous) and Type III (rare, neurologic) are less severe and do not involve liver disease. [2] Prevalence is approximately 1:100,000 live births, with higher incidence in certain founder populations (e.g., Saguenay–Lac-Saint-Jean region of Quebec: ~1:20,000). [3-4] Early detection via newborn screening and treatment with nitisinone (NTBC) combined with dietary restriction has resulted in >90% survival and dramatically improved outcomes. [1][5]
1. History
- Age of onset: Type I typically presents in the first 6 months of life (acute form) or later in the first year (chronic form) [1]
- Feeding difficulties: vomiting, diarrhea with high-protein foods, failure to thrive [2]
- Characteristic "boiled cabbage" or "rotten mushroom" odor [1]
- Jaundice, easy bruising/bleeding (especially nosebleeds) [2]
- Abdominal distension (most common presenting symptom in one cohort — 52.6%) [6]
- Neurologic crises: episodic abdominal pain, altered mental status, peripheral neuropathy, respiratory failure lasting 1–7 days [1-2]
- For known patients: assess nitisinone adherence, dietary compliance, recent illness/fasting [7]
- Type II: eye pain, photophobia, painful palmoplantar keratoderma [2]
- Type III: seizures, intermittent ataxia, intellectual disability [2]
2. Alarm Features
- Acute liver failure in an infant with profound coagulopathy but paradoxically normal or near-normal transaminases — classic red flag for HT1 [1][8]
- Neurologic crisis: acute-onset abdominal pain, progressive weakness (can mimic Guillain-Barré), respiratory failure requiring mechanical ventilation [1][7]
- Porphyria-like crisis from nitisinone non-adherence: abdominal pain, muscle weakness, hyponatremia (SIADH), seizures [7][9]
- GI bleeding, ascites, persistent hypoglycemia [1]
- Rising AFP or new hepatic nodules on surveillance (concern for hepatocellular carcinoma) [7][10]
- Gram-negative sepsis in association with acute liver failure in infancy [8]
3. Medications
- Nitisinone (NTBC / Orfadin): Mainstay of treatment for Type I
- Starting dose: 0.5 mg/kg PO twice daily; titrate based on succinylacetone levels; max 2 mg/kg/day [11]
- Target blood nitisinone concentration: 40–60 µmol/L [1]
- May switch to once-daily dosing in patients ≥5 years with undetectable succinylacetone after 4 weeks on stable dose [11]
- Side effects: transient thrombocytopenia, neutropenia, photophobia (from elevated tyrosine), corneal crystals [1][12]
- Do not adjust nitisinone dose to lower tyrosine — manage tyrosine with diet [11]
- Acute neurologic crisis: IV glucose, antihypertensives, analgesics, correction of hyponatremia, prompt nitisinone therapy; IV hemin has been used in porphyria-like crises [1][9]
- Supportive: vitamin D supplementation, phosphate replacement for rickets, antihypertensives for renal hypertension [1]
- Contraindicated: Avoid fasting (risk of hypoglycemia and metabolic decompensation) [1]
4. Diet
- Low-tyrosine, low-phenylalanine diet is mandatory alongside nitisinone [1][13]
- Target plasma tyrosine: 300–600 µmol/L (must remain <500 µmol/L to avoid ocular/dermatologic toxicity) [1][12]
- Target plasma phenylalanine: 20–80 µmol/L; if too low (<20 µmol/L), add protein from milk or foods [1]
- Specialized low-protein medical formula supplemented with tyrosine/phenylalanine-free amino acid mixtures [1]
- Some patients may use a simplified diet without strict protein calculation, per recent consensus [13]
- Frequent feeds and avoidance of prolonged fasting to prevent hypoglycemia [1]
- Inadequate dietary restriction leads to elevated tyrosine → corneal ulcers, keratitis, hyperkeratotic plaques, and potential neurocognitive effects [11-12]
5. Review of Systems
- GI: vomiting, diarrhea, abdominal pain, abdominal distension, GI bleeding
- Hepatic: jaundice, easy bruising, ascites
- Renal: polyuria, polydipsia (tubular dysfunction), bone pain (rickets)
- Neurologic: altered mental status, limb weakness/pain, paresthesias, respiratory difficulty
- Ophthalmologic: photophobia, eye pain, tearing (especially on nitisinone with poor dietary control)
- Musculoskeletal: bone pain, deformities (rickets)
- Growth: failure to thrive, poor weight gain
- Skin: palmoplantar keratoderma (Type II)
6. Collateral History and Family History
- Autosomal recessive inheritance — inquire about consanguinity, affected siblings, neonatal deaths of unknown cause [1][6]
- Ethnic background: higher prevalence in French-Canadian, Finnish, and Pakistani populations due to founder effects [4][14]
- Newborn screening results for the patient and siblings
- Prior sibling deaths from liver failure or undiagnosed metabolic disease [6]
- Parental understanding of and adherence to dietary restrictions and nitisinone therapy
7. Risk Factors
- Autosomal recessive inheritance (both parents carriers) [1]
- Consanguinity — reported in 87% of families in one cohort [6]
- Founder populations (Saguenay–Lac-Saint-Jean, Quebec; certain Scandinavian and Middle Eastern populations) [4][14]
- Absence of newborn screening or delayed screening [15]
- Late initiation of nitisinone (treatment started after 6 months increases HCC risk; after 1 year, OR 12.7 for HCC) [7][15]
- Non-adherence to nitisinone or dietary restrictions [7][10]
8. Differential Diagnosis
- Transient tyrosinemia of the newborn (elevated tyrosine, resolves spontaneously; no succinylacetone) [1-2]
- Tyrosinemia Type II (oculocutaneous; elevated tyrosine but no succinylacetone, no liver disease) [16]
- Tyrosinemia Type III (rare; moderate hypertyrosinemia, ataxia, seizures, no liver/skin/eye involvement) [16]
- Other causes of neonatal liver failure: galactosemia, neonatal hemochromatosis, mitochondrial hepatopathies, viral hepatitis, sepsis [1]
- Acute intermittent porphyria (neurologic crises mimic; distinguished by succinylacetone levels) [7]
- Homocystinuria (elevated methionine on NBS) [1]
- Wilson disease (older children with liver disease)
- Key distinguishing feature: succinylacetone is pathognomonic for Type I — its presence in blood or urine confirms the diagnosis [1]
9. Past Medical History
- Previous neurologic crises or hospitalizations
- History of liver disease, cirrhosis, hepatic nodules
- Renal tubular dysfunction, rickets, nephrocalcinosis
- Prior liver transplantation
- Developmental delays or neurocognitive deficits (reported even in treated patients) [7]
- Compliance history with nitisinone and dietary restrictions
- Ophthalmologic complications (corneal crystals, keratitis)
10. Physical Exam
- Vital signs: hypertension (renal involvement), tachypnea (metabolic acidosis or respiratory failure during crisis)
- General: failure to thrive, characteristic "cabbage-like" odor [1]
- Abdomen: hepatomegaly, splenomegaly, ascites, abdominal distension [6]
- Skin: jaundice, petechiae/ecchymoses (coagulopathy); palmoplantar keratoderma (Type II)
- Eyes: slit-lamp exam for corneal crystals/opacities (nitisinone-related if tyrosine elevated) [12]
- Musculoskeletal: rachitic rosary, widened wrists, bowing of legs (rickets) [1]
- Neurologic: peripheral neuropathy (decreased sensation, weakness), altered mental status during crises [1]
- Focused maneuvers: assess for asterixis (hepatic encephalopathy), deep tendon reflexes (neuropathy), respiratory effort
11. Lab Studies
- Pathognomonic: Elevated succinylacetone in blood and/or urine (must be specifically requested on urine organic acids) [1]
- Plasma amino acids: elevated tyrosine (can reach 800 µmol/L; normal <90), elevated methionine, elevated phenylalanine [1][3]
- Urine organic acids: elevated p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, p-hydroxyphenylacetate [1]
- AFP: markedly elevated (average ~160,000 ng/mL in symptomatic infants; normal <12 ng/mL after 3 months) [1]
- Coagulation: PT/PTT markedly prolonged, not corrected by vitamin K; factors II, VII, IX, XI, XII decreased; factors V and VIII preserved [1]
- Transaminases and bilirubin: paradoxically only modestly elevated despite severe liver disease [1][8]
- CBC: thrombocytopenia, neutropenia (can be transient on nitisinone) [1]
- Renal: BUN, creatinine, urine phosphate, calcium, protein-to-creatinine ratio (tubular dysfunction) [1]
- Urine δ-aminolevulinic acid (δ-ALA): elevated (secondary to succinylacetone inhibition of δ-ALA dehydratase) [1]
- Monitoring on treatment: succinylacetone (blood/urine), nitisinone blood level (target 40–60 µmol/L), tyrosine (<500 µmol/L), phenylalanine (20–80 µmol/L), AFP, LFTs, coagulation, CBC [1][13]
12. Imaging
- Abdominal ultrasound: first-line; hepatic focal lesions found in 47%, enlarged echogenic kidneys in 39–45% in one cohort [6]
- Abdominal MRI with contrast: gold standard for evaluating hepatic nodules/adenomas and assessing for HCC; recommended beginning at age 1 year and then annually or as clinically indicated [1]
- Kidney ultrasound: assess for nephrocalcinosis, enlarged kidneys [1][6]
- Wrist radiographs: evaluate for rickets (widened, frayed metaphyses) beginning at age 1 year [1]
- Surveillance imaging: 6-monthly to annual liver imaging for HCC screening in all patients, even on nitisinone [7]
13. Special Tests
- Newborn screening (NBS): succinylacetone on dried blood spot by tandem mass spectrometry (MS/MS) — pathognomonic first-tier test [1][17]
- Molecular testing: FAH gene sequencing for diagnostic confirmation [1][3]
- Erythrocyte PBG-synthase activity: decreased (inhibited by succinylacetone); used in some monitoring protocols [11]
- Slit-lamp ophthalmologic examination: baseline and regular follow-up for corneal tyrosine crystal deposition [12]
- Neuropsychological testing: recommended before school age and as indicated (neurocognitive deficits reported even in treated patients) [1]
14. ECG
- Hypertrophic cardiomyopathy has been reported in HT1, particularly in older children with chronic disease [7]
- ECG and echocardiography should be considered in patients presenting with chronic disease or cardiac symptoms
- Not routinely indicated in the acute ED setting unless hemodynamic instability or cardiac symptoms are present
15. Assessment
Tyrosinemia Type I is a metabolic emergency when presenting as acute liver failure in infancy. The hallmark clinical-laboratory dissociation — profound coagulopathy with near-normal transaminases — should raise immediate suspicion. [1][8] Neurologic crises can be life-threatening and mimic acute porphyria or Guillain-Barré syndrome. [7][9] Long-term complications include hepatocellular carcinoma (risk reduced but not eliminated by nitisinone, especially if treatment started after 6 months), chronic kidney disease, rickets, and neurocognitive deficits. [7][13] Types II and III have a relatively good prognosis with appropriate management. [2][18]
16. Treatment Plan
Initial stabilization (ED/acute setting):
- ABCs; IV access; correct coagulopathy with FFP if actively bleeding (vitamin K alone is ineffective) [1]
- IV dextrose-containing fluids to prevent/treat hypoglycemia; avoid fasting [1]
- For neurologic crisis: IV glucose (high-rate dextrose infusion), antihypertensives, analgesics, correct hyponatremia cautiously, initiate or resume nitisinone immediately [1][9]
- IV hemin may be considered for severe porphyria-like crises [9]
Definitive treatment:
- Nitisinone 0.5 mg/kg PO BID (start as soon as diagnosis confirmed or strongly suspected); titrate to undetectable succinylacetone; max 2 mg/kg/day [1][11]
- Low-tyrosine, low-phenylalanine diet with specialized amino acid formula [1]
- Succinylacetone should become undetectable within 24 hours of nitisinone initiation; failure to respond within 1 week suggests non-compliance, subtherapeutic dosing, or fulminant course [10]
Liver transplantation indications:
- Severe liver failure unresponsive to nitisinone [7][10]
- Development of hepatocellular carcinoma [7][10]
- Post-transplant: consider low-dose nitisinone (0.1 mg/kg/day) to prevent ongoing renal tubular/glomerular dysfunction from persistent succinylacetone [1]
17. Disposition
- Admit (often to PICU): acute liver failure, neurologic crisis, respiratory compromise, severe coagulopathy with bleeding, new diagnosis requiring stabilization and education [1]
- Admit for observation: positive NBS result with confirmatory workup pending; initiation of nitisinone therapy [1]
- Outpatient management: stable patients on established nitisinone therapy with good metabolic control
- Specialist consultation triggers: metabolic/biochemical genetics (always), hepatology, nephrology, neurology (for crises), transplant surgery (for liver failure or HCC), ophthalmology, developmental pediatrics [1]
18. Follow Up / Return Precautions
Surveillance schedule (on nitisinone): [1]
- Plasma tyrosine, phenylalanine, methionine, succinylacetone, nitisinone levels, AFP, CBC, LFTs, coagulation — per age-related recommendations (typically every 1–3 months initially, then every 3–6 months)
- Liver imaging (MRI with contrast): annually or as clinically indicated for HCC screening [1][7]
- Renal function (BUN, creatinine, urine studies): as clinically indicated [1]
- Ophthalmologic slit-lamp exam: at baseline and if symptomatic [12]
- Neuropsychological testing: before school age and as indicated [1]
- Developmental assessment at each visit [1]
Return precautions / patient counseling:
- Return immediately for: abdominal pain with weakness or altered mental status (neurologic crisis), new jaundice, bleeding, respiratory difficulty, seizures [1][7]
- Strict adherence to nitisinone — interruption can precipitate life-threatening porphyria-like crises [7]
- Maintain dietary restrictions; report photophobia, eye pain, or skin changes promptly [11-12]
- Avoid prolonged fasting; provide emergency protocol letters for local hospitals [1]
- Expected course with early treatment: >90% survival, normal growth, improved liver function, correction of renal tubular acidosis, improvement in rickets [1]
- Long-term risk of HCC persists even on treatment — lifelong surveillance required [7][13]
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