Tirosinemia

There are 3 main inborn errors of tyrosine metabolism called:

• Tyrosinaemia I or hereditary infantile tyrosinaemia

• Tyrosinaemia II or Richner-Hanhart syndrome

• Tyrosinaemia III

This article is almost exclusively about type I. There are other conditions in which tyrosine levels may be elevated in infancy, due to delayed development of enzymes but as these are transient and usually benign they will not be considered here.

Epidemiologia

• Tyrosinaemia I is much more common than type II.

• Type III is very rare.

The incidence of type I is about 1 in 100,000 births. It is inherited as an autosomal recessive. Incidence and clinical pattern shows no sex difference. It is more common in a region of Quebec province in Canada; the incidence is very high, and the incidence of carriers of one specific mutation is 1 in 14 adults.¹

Presentazione

Most infants present within the first 2 or 3 months of life. A minority present later with a slower form that produces rachitismo and more gradual development of cirrosi.

Sintomi

• Insufficiente crescita is the first feature.

• Vomiting and diarrhoea come next, rapidly progressing to bloody stool, lethargy, and jaundice. A distinctive cabbage-like odour is characteristic.

• The chronic form presents at about 1 year old with failure to thrive and delayed walking, possibly due to rickets.

Segni

• Hepatomegaly is present in the first 3 months of life.

• The acute onset may be dramatic, with hepatomegaly, jaundice, epistaxis, melaena, purpuric lesions, marked oedema, and the distinctive cabbage-like odour.

• The more chronic form may cause polyneuropathy and painful abdominal crises, rather like acute intermittent porfiria. There is an abnormality of haem production.

• If they survive, they may have hepatic nodules due to carcinoma epatocellulare (HCC) with possible metastases or cirrhosis.

• This disease includes the Fanconi syndrome that is renal tubular disorder which occurs in a number of metabolic disorders. Polyuria causes polydypsia. There is loss of water, calcium, potassium, magnesium, and other substances in the body. It often leads to bone disease and stunted growth.

Diagnosi differenziale

• Fructose 1-6-diphosphatase deficiency

• Fructose 1-phosphate aldolase deficiency (fructose intolerance)

• Galactose 1-phosphate uridyltransferase deficiency (galactosemia)

• Epatite B

• Poisoning from iron or paracetamol

• Altre cause di acute hepatic failure

Indagini

• There is a normocytic anaemia and leukocytosis. Prothrombin time is elevated but platelets may be high.

• Serum bilirubin and transaminases are raised with low cholesterol - signifying hepatocellular damage.

• Il alpha-fetoprotein level is raised.

• Urine analysis may show alkaline pH, glycosuria, and proteinuria.

• Urine chemistry shows raised phosphate, glycosuria, and increased d-aminolevulinic acid.

• Plasma amino acid assay in an early stage shows selective increases of tyrosine and methionine. As insufficienza epatica progresses, most other amino acids become elevated.

• Urinary succinylacetone is the biochemical marker substance, and its presence is diagnostic for tyrosinaemia I. Proper collection and handling of the sample is of critical importance.

Histology shows active inflammation with fatty infiltration in the liver. Lobular regeneration is present, resulting ultimately in nodular cirrhosis. Changes of hepatoma also may be seen. The kidney shows tubular swelling and formation of nodules, similar to that seen in the liver.

Malattie associate

• Tyrosinaemia II has a different clinical presentation. There are herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation and growth retardation. The biochemical and enzyme defect is different from type I.

• Tyrosinaemia III is an extremely rare cause of intermittent ataxia, without hepato-renal involvement or skin lesions. There is normal psychomotor development and mild mental retardation.

Gestione

Misure generali

Phenylalanine and tyrosine dietary intake should be restricted to the minimum requirement.

Farmacologico

• Treatment of hepatic failure and coagulation deficiencies is required.

• Nitisinone (or NTBC- 2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione) may be used as an adjunct to dietary restrictions:
  

  • This is a highly potent reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. This prevents formation of catabolic intermediates from tyrosine that are converted to toxic metabolites and are responsible for the liver and kidney damage. Although approved in the USA by the FDA in 2002, it is only available as part of a study protocol.

  • In patients whose treatment with NTBC is started early in life, 1% of hepatocellular carcinomas have occurred during the first year of treatment. No further cases of HCC have occurred among these patients, who have been followed for up to 9 years.²

Chirurgico

Trapianto di fegato is the treatment of last resort. This may be when either severe cirrhosis or hepatic tumours have developed.³

Complicazioni

• Hepatic cirrhosis

• Renal Fanconi syndrome (including renal tubular acidosis type II)

• Rickets secondary to renal tubular acidosis (RTA) and loss of phosphate

• Neuropatia periferica

• Abdominal crisis (like porphyria)

• Convulsioni

• Hepatoma or hepatocellular carcinoma.

Prognosi

Without treatment, death occurs from hepatic failure by age 2 years. In the later-onset variety, death may occur in mid childhood, either from hepatic failure or from hepatic tumour. Early liver transplantation carries the usual risks and complications of any major organ transplant procedure, including risk of rejection. Although experience is limited, NTBC appears to be effective in preventing the progressive liver and renal disease and in aborting fulminant clinical onset. The long-term results of NTBC therapy are uncertain.⁴

Prevenzione

Pre-natal diagnosis is available.⁵