Tyrosinaemia Type 1

Tyrosinaemia type 1 is an autosomal recessive disorder of tyrosine breakdown caused by deficiency of fumarylacetoacetate hydrolase. It leads to accumulation of toxic metabolites, especially succinylacetone, causing liver failure, renal tubular dysfunction, porphyria like neurological crises and hepatocellular carcinoma.

Incidence is about 1 in 100 000 live births worldwide. It is much higher in some regions, for example about 1 in 1800 in a founder population of Quebec.

Clinical forms are acute infantile liver failure (onset before 6 months), subacute (6 to 12 months) with coagulopathy, rickets and failure to thrive, and chronic forms with rickets, cirrhosis and carcinoma.

Pathophysiology.

The enzyme block in the final step of the tyrosine route leads to accumulation of maleylacetoacetate and fumarylacetoacetate, which convert to succinylacetone.

Succinylacetone inhibits delta aminolevulinic acid dehydratase (causing neurological crises with raised delta aminolevulinic acid), damages hepatocytes and renal tubules, and is mutagenic.

• Acute liver failure: coagulopathy out of proportion to modestly raised transaminases, hypoglycaemia, jaundice, ascites and hepatomegaly.
• Renal tubular dysfunction with phosphaturia, glycosuria, aminoaciduria and hypophosphataemic rickets.
• Neurological crises: severe pain, hypertension, vomiting, paralysis and respiratory failure.
• Distinctive cabbage like odour in some cases.
• Cirrhosis and hepatocellular carcinoma in untreated or late treated disease.

Red flags.

• Coagulopathy not responsive to vitamin K with normal or modest transaminases.
• Very high alpha fetoprotein.
• Unexplained rickets with renal tubular dysfunction.

• Succinylacetone in blood or urine is diagnostic and is the basis of newborn screening. Plasma tyrosine may be normal or modestly raised in early disease.
• Plasma amino acids (tyrosine, methionine, phenylalanine raised), urine delta aminolevulinic acid, alpha fetoprotein (markedly raised), INR, liver function, glucose, phosphate, alkaline phosphatase and urinary amino acids.
• Molecular testing of FAH confirms the diagnosis.
• Abdominal ultrasound and MRI for nodules.

Differential diagnosis. Galactosaemia, neonatal haemochromatosis, mitochondrial hepatopathy, fatty acid oxidation defects, hereditary fructose intolerance, viral hepatitis, acute porphyria and other causes of liver failure.

Disease modifying treatment.

• Nitisinone 1 mg/kg/day orally in 1 or 2 doses, started as soon as the diagnosis is made. Increase to a maximum of 2 mg/kg/day if succinylacetone remains detectable. In acute liver failure, start at 1 to 2 mg/kg/day.
• Phenylalanine and tyrosine restricted diet with a tyrosine- and phenylalanine free amino acid formula. Aim for plasma tyrosine 200 to 400 micromol/L, and avoid levels over 500 micromol/L, which risk corneal and skin lesions.
• Aim for undetectable succinylacetone.

Acute illness.

• IV glucose 10% to maintain glucose over 3.5 mmol/L, vitamin K 1 mg IV, fresh frozen plasma 10 to 15 mL/kg for bleeding, and avoidance of fasting.
• Treat neurological crises with nitisinone, IV glucose and haem arginate under specialist direction.

Monitoring. Succinylacetone, tyrosine and phenylalanine every 3 to 6 months, alpha fetoprotein, liver ultrasound or MRI every 6 months, platelets and neutrophils, and slit lamp examination each year.

Referral and escalation. Refer to a metabolic centre and a liver transplant centre. Liver transplant is indicated for acute liver failure not responding to nitisinone, or for hepatocellular carcinoma or rising alpha fetoprotein with a suspicious nodule.