At a Glance

Tyrosinemia (also known as Tyrosinemia type 1, Hereditary Tyrosinemia, or Hepatorenal Tyrosinemia) is an inherited disorder of metabolism of the essential amino acid tyrosine due to a defect in fumarylacetoacetate hydrolase (FAH). Tyrosine (TYR) is present in all protein containing foods, and individuals with Tyrosinemia will have elevated levels of TYR. Urine may have a cabbage-like smell.

Tyrosinemia type 1 is inherited in an autosomal recessive manner, meaning the individual has inherited two abnormal copies of the FAH gene (each gene contains a mutation). Both parents of an individual with Tyrosinemia are carriers and do not manifest any symptoms of disease.

Tyrosinemia type 1 will typically manifest if untreated in infants with severe liver involvement or possibly with both liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. When untreated, children may have repeated neurological crises with poor feeding, vomiting, changes in mental status, and abdominal pain that may be unrecognized initially. These neurologic crises may last 1-7 days and may be severe enough to cause peripheral neuropathy and/or respiratory failure requiring mechanical ventilation. Renal Fanconi syndrome is an important feature that may initially be mild but may progress and lead to significant concerns with aminoaciduria, renal tubular acidosis, and glycosuria. Progressive liver failure, neurologic crisis, or hepatocellular carcinoma may lead to death if untreated before 10 years of age.

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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Tyrosinemia can be diagnosed through measurement of TYR in plasma amino acid analysis. Many infants are found to have elevations of TYR or methionine on newborn screening.

Succinylacetone should be present in urine organic acid analysis and is confirmatory for Tyrosinemia type 1. If succinylacetone is not present, then Tyrosinemia type 1 has been ruled out as the cause of elevated TYR levels. Succinylacetone may not be as easily detected in un-oximated organic acid protocols, and, if in question, the biochemical genetics laboratory director should be contacted for discussion.

Additional testing should be performed to assess liver dysfunction (e.g., aspartate transaminase (AST) and alanine aminotransferase (ALT)) and synthetic function (e.g., prealbumin, albumin, prothrombin time (PT), and partial thromboplastin time (PTT)). Screening should closely monitor electrolytes, renal function, glomerular filtration rate, and vitamin D status.

Detection of hepatic nodules and adenomas should include serial measurement of alpha-fetoprotein and liver structure through CT or MRI. Plasma carnitine levels should be measured, as they are often decreased because of Renal Fanconi syndrome.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The most common cause of TYR elevations (usually mild and often elevated together with methionine) is liver disease, usually acquired forms. Repeat TYR analysis following overnight fast should be performed, and other diagnostic testing should be done to determine if acquired or other forms of inherited liver disease are present. Causes of acquired liver disease may include forms of viral hepatitis, bacterial infection, acetaminophen or other drug overdose, herbal medicines, or mushroom poisoning. Causes of inherited liver disease include galactosemia, hereditary fructose intolerance, lysosomal storage disease, urea cycle disorders, mitochondrial DNA depletion disorders, Niemann-Pick type C disease, and congenital disorders of glycosylation.

Clinical interpretation of elevations of TYR is essential. It is often not possible to determine the significance of elevations of TYR without clinical information and additional follow-up diagnostic testing as reviewed above.

Elevations of TYR can also be seen after infusion of total parenteral nutrition (TPN, often with many other nonspecific elevations of other amino acids included in the TPN bag) or because of Tyrosinemia type 2 or 3, transient neonatal tyrosinemia (due to prematurity of the neonatal liver enzymes, often with the presence of 4-hydroxy-phenyllactic acid and 4-hydroxy-phenylpyruvic acid and no succinylacetone on urine organic acids), and hyperthyroidism.

Newborn screening results must be closely examined as false positives are common and follow-up plasma amino acid analysis and often urine organic acids are necessary. Most commonly elevations of TYR on the newborn screen will be due to prematurity of the infant liver, co-existing liver disease, or the infant receiving TPN.

Low TYR levels are seen in phenylketonuria, disorders of biopterin synthesis, and hypothyroidism.

What Lab Results Are Absolutely Confirmatory?

Confirmation of Tyrosinemia type 1 can be done through DNA sequencing of the FAH gene. Sequencing will pick up more than 95% of mutations. Targeted sequencing of known familial mutations or mutations common to the Ashkenzi Jewish or French-Canadian populations should be considered first.

Direct enzyme analysis of a liver biopsy sample is not readily available, except in research settings.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

TYR levels should be monitored to measure treatment effect. Patients should be started on nitisinone (also known as Orfadin® or NTBC, 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione)), which blocks parahydroxyphenylpyruvic acid dioxygenase, the second step in the TYR degradation pathway. This drug then prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone but will lead to increased blood TYR levels. Restriction of dietary TYR is required to prevent development of TYR crystals in the cornea which may occur if levels a greater than 600 mol/L. Ongoing clinical management with close monitoring of dietary protein is important to ensure adequate growth and development.

Liver transplantation is now only needed in children who have severe liver failure at presentation, have failed to respond to NTBC therapy, or have developed hepatic malignant changes.

With early and prompt treatment, there is a greater than 90% survival rate with normal growth, improved liver function, and prevention of cirrhosis. Other complications, including osteoporosis and Fanconi syndrome with renal tubular acidosis, may also be avoided. The effect of NTBC on reversing long-term renal disease and other long-term neuropsychological function, learning, and cognitive deficits are not yet fully known.

Tyrosinemia type 2 and type 3 also exist. Tyrosinemia type 2 is known as Oculocutaneous Tyrosinemia or Richner-Hanhart syndrome. This disorder is due to an autosomal recessive deficiency of TYR aminotransferase, the first step in TYR catabolism. Individuals classically have ocular, skin, and neurological disease. Eye disease includes photophobia due to bilateral corneal ulcerations that may progress to severe scarring, glaucoma, and visual loss. Skin lesions include pressure ulcers or blisters in the palms and soles then progressing to hyperkeratotic plaques. Neurological disease includes normal development to severe seizures, self-mutilation, and mental impairment. This disorder will typically respond well to a phenylalanine/TYR restricted diet.

Tyrosinemia type 3 is a rare disorder with only limited understanding of its full clinical pattern. It is due to an autosomal recessive defect in 4-hydroxypheylpyruvate dioxygenase—also the site of inhibition of NTBC. Symptoms may include developmental delay, ataxia, microcephaly, and seizures, whereas other individuals have been identified by newborn screening without any clinical symptoms. A low phenylalanine/TYR diet should be considered if signs of neurological impairment are present.