Hypertyrosinemia – Causes, Symptoms and Treatment

What is Hypertyrosinemia?

Hypertyrosinemia refers to a condition in which the level of the amino acid tyrosine in the blood is persistently elevated. Tyrosine is a non-essential amino acid synthesized by the body from the essential amino acid phenylalanine. It serves as a building block for important neurotransmitters and hormones such as dopamine, adrenaline, and thyroid hormones. When the breakdown of tyrosine is impaired, the substance accumulates in the blood, tissues, and organs, potentially causing significant damage.

Causes

Hypertyrosinemia is classified into several types based on its underlying cause:

• Tyrosinemia Type I (Hepatorenal Tyrosinemia): The most common and severe form, caused by a deficiency of the enzyme fumarylacetoacetase (FAH), which is required in the final step of tyrosine degradation. Toxic intermediates accumulate and primarily damage the liver and kidneys.
• Tyrosinemia Type II (Richner-Hanhart Syndrome): Caused by a deficiency of the enzyme tyrosine aminotransferase (TAT). It mainly affects the eyes and skin, and may also impair intellectual development.
• Tyrosinemia Type III: A rare form caused by deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which can lead to neurological abnormalities.
• Transient Neonatal Hypertyrosinemia: A temporary form commonly seen in premature infants and newborns due to immature liver function and high dietary protein intake. It usually resolves spontaneously.
• Acquired Hypertyrosinemia: Can occur in severe liver disease, as the liver plays a central role in tyrosine metabolism.

All inherited forms follow an autosomal recessive pattern of inheritance, meaning both parents must carry a mutated gene for the child to be affected.

Symptoms

Symptoms vary depending on the type of the disorder:

Tyrosinemia Type I

• Acute or chronic liver failure, often presenting in infancy
• Coagulation disorders due to liver damage
• Kidney dysfunction (renal tubular acidosis)
• Growth retardation and failure to thrive
• Increased risk of liver cancer (hepatocellular carcinoma)
• Neurological crises with severe pain and episodes of paralysis

Tyrosinemia Type II

• Painful corneal clouding and extreme light sensitivity of the eyes
• Painful thickening of the skin, especially on the palms and soles (hyperkeratosis)
• Possible intellectual disability

Tyrosinemia Type III

• Neurological symptoms such as balance disorders and developmental delays

Diagnosis

Diagnosis is established through a range of investigations:

• Newborn Screening: In many countries, Tyrosinemia Type I is included in the expanded newborn screening program using tandem mass spectrometry (MS/MS). The key marker is succinylacetone, a characteristic toxic metabolite detected in dried blood spots.
• Plasma Amino Acid Analysis: Measurement of elevated tyrosine concentrations in the blood.
• Urine Analysis: Detection of succinylacetone and other organic acids in the urine.
• Enzyme Activity Assay: Measurement of the activity of the deficient enzyme in blood or tissue samples.
• Molecular Genetic Testing: Identification of the causative gene mutation for confirmation and family counseling.
• Imaging: Ultrasound and MRI of the liver to assess organ damage.

Treatment

Treatment depends on the type of hypertyrosinemia:

Pharmacological Therapy (Type I)

The most important treatment for Tyrosinemia Type I is nitisinone (NTBC). It inhibits the enzyme HPPD, thereby preventing the formation of toxic metabolic intermediates. Nitisinone has fundamentally improved the prognosis of the disease and significantly reduced the need for liver transplantation.

Dietary Therapy

All types require a diet restricted in tyrosine and phenylalanine, since phenylalanine is converted to tyrosine in the body. Special amino acid formulas free of tyrosine and phenylalanine ensure adequate protein intake. The diet must be followed strictly and lifelong.

Liver Transplantation

In Type I, when nitisinone is insufficient or a hepatocellular carcinoma has developed, a liver transplantation may be necessary. It corrects the metabolic defect in the liver, though not in other organs.

Transient Neonatal Hypertyrosinemia

This form typically requires no specific treatment. Adjusting the diet (reducing protein intake) and, if needed, supplementing with vitamin C, which supports tyrosine catabolism, is usually sufficient.

Prognosis

The prognosis strongly depends on the type and timing of diagnosis. When Tyrosinemia Type I is detected early and treated consistently with nitisinone, patients can achieve a largely normal life expectancy and quality of life. Lifelong regular liver monitoring is required due to the ongoing risk of hepatocellular carcinoma.

References

1. Schlune A, Thimm E, Herebian D, Mayatepek E. - Tyrosinaemias. In: Hoffmann GF, Zschocke J, Nyhan WL (eds): Inherited Metabolic Diseases. Springer, Berlin, 2017.
2. van Spronsen FJ et al. - Tyrosinaemia type I: recommendations for diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):191. PubMed PMID: 29191206.
3. Chinsky JM et al. - Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group update. Genet Med. 2017;19(12). PubMed PMID: 28771251.