What is tyrosinemia type 1?

Tyrosinemia type I is a metabolic disease caused by mutations – or genetic changes – in the FAH gene. If left untreated, it usually leads to acute liver disease, limited kidney function with growth disorders, rickets (a disease of the growing bone caused by a vitamin D deficiency), and neurological crises by the age of 1. Without adequate treatment, the progression of the disease is fatal within the first ten years of life. If treated with nitisinone and if a diet low in tyrosine is maintained, however, the survival rate is over 90%.

How is tyrosinemia type 1 diagnosed?

Suspected Diagnosis

Tyrosinemia type I is suspected with presentation of the following:

  • Elevated tyrosine level during newborn screening

  • Severe liver disease in early infancy

  • Signs of kidney disease, rickets, and/or neurological crises in children > 6 months old

Laboratory Chemical Diagnostics

  • Increased concentrations of specific metabolic products in the blood and urine

  • Disturbed coagulation values as a sign of liver function disorder due to untreated tyrosinemia type I

Genetic Diagnostics

The diagnosis of “tyrosinemia type I” is confirmed by detection of a mutation – or genetic change – in the FAH gene.

What is the risk of cancer?

As a rule, it is necessary to differentiate between patients who have been treated early on and adequately and those who have not received any treatment.

Children with untreated tyrosinemia type I have a much higher risk of liver cancer (hepatocellular carcinoma). In children who have received adequate treatment (i.e. children for whom nitisinone therapy has been begun before the age of 2), the risk of a hepatocellular carcinoma is < 5% by the age of 10.

In addition to the increased risk of cancer, there may also be other clinical manifestations as part of tyrosinemia type I. Here as well, it is necessary to differentiate between treated and untreated cases of the disease.

Untreated Tyrosinemia Type I

Children with tyrosinemia type I not detected in newborn screening are generally discovered during early infancy through severe liver complications or later during the first year of life due to liver function disorder, kidney complications, a growth disorder, and rickets. If left untreated, tyrosinemia type I results in death within the first ten years of life.

  • Liver complications:
    If not diagnosed and/or treated, tyrosinemia type I typically results in acute liver failure within the first 6 months of life. From the outset, the liver is unable to produce any more coagulation factors, with the clinical result of a blood coagulation disorder with increased or prolonged episodes of bleeding. Other liver values (transaminase and bilirubin) are usually only slightly elevated, representing an unusual clinical picture that in turn distinguishes tyrosinemia type I from other severe liver diseases.

  • Kidney complications:
    Kidney complications in untreated children do not usually become evident until after the age of 6 months, when they manifest in the form of limited renal tubule function. This leads to increased excretion of amino acids and to phosphate loss, which can cause both rickets as well as the defective excretion of acids via the kidneys.

  • Neurological crises:
    In untreated children, repeated neurological crises can occur. They manifest with symptoms such as behavioral changes, abdominal pain, damage to the peripheral nerves, and breathing disorders, which may even require ventilation.

Treated Tyrosinemia Type I

The combination of nitisinone therapy and a tyrosine-reduced diet leads to a survival rate > 90%, normal growth, improved liver function, the prevention of cirrhosis, improved kidney function, and prevention of rickets.

  • Neurological crises:
    These have only been observed in patients following prolonged interruption of treatment.

  • Liver complications:
    Acute liver failure usually improves within the first week after nitisinone therapy is started.

What causes tyrosinemia type I?

Tyrosinemia type I is caused by mutations – or genetic changes – in the FAH gene. This gene encodes for the FAH protein, which is required in the last step of breaking down the amino acid tyrosine.

Now if the FAH gene is altered, the FAH protein will not be produced properly and will no longer be able to perform its normal function. This leads to the improper breakdown of tyrosine, causing various metabolic products to accumulate. This in turn results in damage to the liver, kidneys, and nerves.

Tyrosinemia type I is found in around one in 100,000-120,000 people. It occurs much more frequently in Scandinavia, Finland, and Quebec (Canada). It can be passed on by parents to their children, as an autosomal-recessive disease.

Is there a treatment?

Nitisinone therapy should be started right after the diagnosis is made. In addition, it is also necessary to maintain a low-tyrosine diet once the diagnosis has been made.

If there is a lack of response to nitisinone or if there are malignant changes in the liver, a liver transplant may be worth considering.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Due to the increased risk of a hepatocellular carcinoma, the following surveillance examinations should be carried out:

  • Monthly determination of AFP levels (alpha-fetoprotein) for the first 6 months of life

  • After the age of 6 months, determination of AFP every 6 months

  • An ultrasound or MRI of the liver is an option for basic diagnostics.

Self-Care and Support

What should I pay special attention to?

Particularly important for patients with tyrosinemia type I is uninterrupted nitisone therapy and consistently maintaining a low-tyrosine diet.

You should consult a doctor as soon as increased or prolonged episodes of bleeding, increased sleepiness, or sucking difficulties occur. However, non-specific symptoms such as abdominal pain should be noted and reported to a doctor as well. You should likewise go to a doctor if new anomalies or complaints develop.

Support Groups and Additional Information