Tyrosinemia Type 1 on Infant Metabolic Screening
Tyrosinemia type 1 (HT-1) is an autosomal recessive disorder of tyrosine metabolism caused by fumarylacetoacetate hydrolase (FAH) deficiency, resulting in hepatic failure, renal dysfunction, neurologic complications, and long-term risk of hepatocellular carcinoma—blood succinylacetone (SA) is the primary and specific screening marker, not tyrosine. 1
Screening Methodology
Blood succinylacetone should be used as the primary marker to detect HT-1 through newborn screening (NBS), with 100% consensus agreement among experts. 1
Why Succinylacetone, Not Tyrosine
- Tyrosine as a primary marker is NOT recommended because it is neither sensitive nor specific for HT-1 1
- Approximately 28% of HT-1 patients may be missed if screening relies on elevated tyrosine alone, as many infants with HT-1 have normal tyrosine levels at the time of blood collection (typically <48 hours of life) 1
- Elevated tyrosine is commonly seen in benign transient hypertyrosinemia of newborns, prematurity, total parenteral nutrition use, and other liver diseases—making it non-specific 1
- Succinylacetone is pathognomonic for HT-1, providing both sensitivity and specificity 2, 3
Critical Pitfall
Some NBS programs use a "second-tier" approach, measuring SA only when tyrosine exceeds a cutoff (e.g., >150 μmol/L)—this strategy is explicitly not recommended as it will miss patients with normal tyrosine levels 1
Confirmatory Testing After Positive Screen
Infants with elevated tyrosine and/or SA on NBS should be seen immediately at a metabolic center for urgent evaluation. 1
Initial Diagnostic Workup
The most important confirmatory test is blood or urine succinylacetone level. 1
If high suspicion for HT-1 exists, obtain simultaneously at first visit: 1
- Plasma amino acids (PAA) to differentiate HT-1 from tyrosinemia types II and III
- Liver function tests: PT, INR, PTT, ALT/AST
- α-fetoprotein (AFP)
- Complete blood count with platelet count
- Renal function: bicarbonate, BUN, creatinine, calcium, phosphate
- Urinalysis
Diagnostic Confirmation
- Documentation of normal plasma SA levels is mandatory before excluding HT-1 1
- Consider alternative diagnoses if SA is negative: liver disease from other causes, prematurity, mitochondrial depletion syndrome 1
- Genetic testing can identify FAH gene mutations (chromosome 15q23, approximately 100 known mutations) 1, 4
Immediate Management Upon Diagnosis
Once HT-1 is confirmed, NTBC (nitisinone) and dietary therapy should be initiated immediately. 1, 5
NTBC Therapy
- Starting dose: 0.3-0.5 mg/kg twice daily (can increase to 1 mg/kg twice daily based on response) 5
- Administer at least one hour before or two hours after meals 5
- For patients unable to swallow capsules, contents may be suspended in water, formula, or applesauce immediately before use 5
Dietary Management
- Restrict phenylalanine and tyrosine intake 5, 6
- Monitor for hypophenylalaninemia, which may impair neurocognitive development in young infants 6
- Consider phenylalanine supplementation (20-30 mg/kg/day) if consistently low blood phenylalanine concentrations occur during the first months of life 6
Critical Action: Sibling Testing
If a child is diagnosed with HT-1, siblings must be tested immediately for SA to initiate treatment if affected. 1
Long-Term Monitoring Protocol
First Year of Life 1
Monitor every 6 months:
- Blood succinylacetone (or urine if blood unavailable)
- Blood NTBC concentration
- Plasma amino acids
- Serum AFP (any increase requires immediate imaging)
- CBC
- PT, PTT, ALT/AST (until normalized)
After First Year 1
Continue every 6 months:
- Blood succinylacetone
- Blood NTBC concentration
- Plasma amino acids
- Serum AFP
Yearly monitoring:
- Liver imaging (CT/MRI with contrast or ultrasound)—wait 1 week post-NTBC initiation to avoid anesthetic-induced porphyric crisis
- CBC, PT, PTT, ALT/AST
- Renal function tests
- Developmental/neuropsychology assessment before school age
- Ophthalmology slit-lamp examination if symptomatic
Clinical Outcomes with Early Treatment
When identified presymptomatically through NBS and treated immediately with NTBC and diet, the majority of affected infants remain asymptomatic. 1
Survival Data
- Patients presenting <2 months of age treated with NTBC and diet: 88% survival at 2 and 4 years (compared to 29% with diet alone historically) 5
- Patients presenting 2-6 months of age treated with NTBC and diet: 94% survival at 2 and 4 years (compared to 60-74% with diet alone historically) 5
Complications Prevented
- Porphyria-like crises reduced to 0.3% of cases per year (from 5-20% expected without NTBC) 5
- Renal tubular dysfunction improves, with median urinary α-1-microglobulin decreasing significantly within one year of treatment 5
- Liver transplantation often avoided with early intervention 1
Common Pitfalls to Avoid
- Never rely on tyrosine alone for screening—this misses approximately 28% of cases 1
- Never delay treatment while awaiting genetic confirmation—clinical and biochemical diagnosis is sufficient to start therapy 1, 4
- Never forget to screen siblings of diagnosed patients 1
- Do not assume normal NBS excludes HT-1 if clinical suspicion exists—false negatives can occur with tyrosine-based screening 3
- Monitor phenylalanine levels closely in young infants to prevent hypophenylalaninemia-related neurocognitive impairment 6