Key Points

• Rare autosomal recessive disorder due to fumarylacetoacetate hydrolase (FAH) deficiency (Hereditary Tyrosinemia Type I).
• Accumulation of toxic metabolites (fumarylacetoacetate, succinylacetone) leads to progressive liver and renal injury and risk of hepatocellular carcinoma.
• Presents in infancy with acute liver failure, coagulopathy, and tubular renal dysfunction; untreated survival <1 year.
• Diagnosis by elevated plasma tyrosine and succinylacetone levels, molecular testing, and newborn screening.
• Treatment includes nitisinone (NTBC), low-tyrosine/low-phenylalanine diet, and liver transplantation for advanced disease.

Introduction

Hereditary Tyrosinemia Type I (HT-1), also called acute hypertyrosinemia, is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the final enzyme in the tyrosine catabolic pathway. Accumulation of upstream metabolites such as fumarylacetoacetate and succinylacetone causes multi-organ toxicity, primarily affecting the liver, kidneys, and peripheral nerves.

Epidemiology

• Incidence: Approximately 1 in 100,000–120,000 live births; higher in certain populations (e.g., Quebec, Finland).
• Onset: Infancy to early childhood; acute form presents within the first months of life, chronic form after age 2 years.
• No significant gender predilection.

Pathophysiology

1. FAH deficiency blocks the conversion of fumarylacetoacetate to fumarate and acetoacetate.
2. Toxic metabolites (fumarylacetoacetate, succinylacetone) accumulate in hepatocytes and renal tubular cells.
3. Cellular damage via oxidative stress and DNA alkylation leads to liver necrosis, cirrhosis, and renal tubular dysfunction.
4. Succinylacetone inhibits δ-aminolevulinic acid dehydratase, causing porphyria-like neurological crises.

Clinical Presentation

Acute Infantile Form (Type I)

• Onset: 1–6 months of age.
• Hepatic: Acute liver failure, jaundice, coagulopathy, hypoglycemia, hepatomegaly.
• Renal: Fanconi syndrome (polyuria, polydipsia, rickets).
• Systemic: Failure to thrive, vomiting, ascites.
• Neurologic: Peripheral neuropathy, episodes of porphyria-like crisis with abdominal pain, neuropathic pain.

Chronic Form (Type I)

• Onset: After age 2 years.
• Milder hepatic dysfunction with cirrhosis and risk of hepatocellular carcinoma.
• Persistent renal tubular damage and growth retardation.

Diagnostic Evaluation

• Newborn screening: Succinylacetone in dried blood spots.
• Plasma amino acids: Elevated tyrosine, methionine.
• Succinylacetone measured in urine/plasma (specific marker).
• Liver function tests: Transaminase elevation, direct hyperbilirubinemia, prolonged PT/INR.
• Renal studies: Aminoaciduria, glycosuria, phosphaturia consistent with Fanconi syndrome.
• Molecular genetic testing: FAH gene mutations.

Differential Diagnosis

• Other neonatal liver failure causes (galactosemia, tyrosinemia Type II, viral hepatitis).
• Wilson disease (later onset).
• Organic acidemias (e.g., propionic acidemia).
• Porphyria (acute neurologic crises).

Management

Nitisinone (NTBC)

• Mechanism: Inhibits 4-hydroxyphenylpyruvate dioxygenase, preventing downstream toxic metabolite formation.
• Dose: 1–2 mg/kg/day; adjust to maintain undetectable succinylacetone.
• Monitor for elevated tyrosine levels requiring dietary adjustment.

Dietary Therapy

• Low-tyrosine, low-phenylalanine diet with specialized medical formulas.
• Regular monitoring of plasma amino acids and nutritional status.

Liver Transplantation

• Indications: Acute liver failure, progressive cirrhosis, or risk of hepatocellular carcinoma despite therapy.
• Curative for hepatic manifestations; renal damage may persist.

Nursing Considerations

• Monitor growth parameters, liver and renal function tests, and coagulation profiles.
• Educate caregivers on NTBC dosing, adherence, and dietary restrictions.
• Assess for signs of hypoglycemia, bleeding, and rickets.
• Coordinate multidisciplinary care: nutritionists, hepatologists, nephrologists, and genetic counselors.

Prognosis

• With NTBC and dietary management, 2-year survival >90% and reduced risk of liver cancer.
• Lifelong treatment required; adherence critical to prevent complications.

Patient Education

• Emphasize strict adherence to medication and dietary regimen.
• Recognize signs of acute crisis (abdominal pain, neuropathy, coagulopathy).
• Importance of regular follow-up and laboratory monitoring.
• Genetic counseling for families regarding recurrence risk.

References

1. Grompe M, Lindblad B, Tupa N, et al. Treatment of hereditary tyrosinemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. N Engl J Med. 1994;330(21):1553–1558.
2. de Laet C, Dionisi-Vici C, Leonard JV, et al. Recommendations for the management of tyrosinaemia type I – European network and society for the study of inborn errors of metabolism (SSIEM) guidelines. J Inherit Metab Dis. 2013;36(4):697–709.
3. Morrow G, Tanguay RM. Tyrosinemia type I: Pathogenesis, diagnosis, and treatment. J Pediatr Gastroenterol Nutr. 2014;58(2):165–172.
4. Lindblad B, Lindstedt S. The role of succinylacetone in hereditary tyrosinemia. Acta Paediatr Scand. 1984;73(3):351–355.