What is Tyrosinemia?

Tyrosinemia is an inborn or hereditary disorder involving a metabolic error that is associated with a severe liver disease during infancy. It hinders the natural ability of the body to effectively break down tyrosine, an amino acid.

Most inborn variants of Tyrosinemia are characterized by hypertyrosinemia; i.e. manufacturing of higher levels of tyrosine. If left untreated, the condition can be fatal.

Tyrosinemia Epidemiology

Tyrosinemia is a rare condition, occurring in almost 1 in every 100000 individuals. Type II of this disease affects less than one in every 250000 individuals. Type III is even rarer; with only a handful number of cases having been documented.

Tyrosinemia Types

There are 3 distinct types of this condition, and each of them is characterized by unique symptoms and factors of causation. The following are the different types of tyrosinemia.

Picture 1 – Tyrosinemia

  • Type I Tyrosinemia
  • Type II Tyrosinemia
  • Type III Tyrosinemia

Tyrosinemia Causes

The inheritance pattern for this disorder is autosomal recessive, which means that a child needs to inherit 2 defective genes, one from each parent in order to carry this disease. In cases where both parents carry the genetic mutation for the disease, there is a 1-in-4 risk for a child to develop Tyrosinemia.

Type I tyrosinemia is a type of genetic disorder caused by the deficiency of enzyme fumarylacetoacetate hydrolase (FAH) and p-hydroxyphenylpyruvic acid oxidase. The condition is also referred to as hepatorenal tyrosinemia, and is the most critical variant of tyrosinemia. The main function of the FAH gene is to regulate the production of the enzyme fumarylacetoacetase that is required to break down or metabolize amino acid tyrosine. The mutations of FAH gene leads to a deficiency of the enzyme fumarylacetoacetase, which then leads to a failure in breaking down tyrosine. Inheritance of the genetic mutation responsible for type I of the disorder occurs in autosomal recessive fashion. The symptoms of this condition are caused by the abnormal buildup of tyrosine and/or its metabolites in the various bodily organs. Metabolites are chemical substances that are formed as natural byproducts of a metabolic reaction. Fumarylacetoacetate, succinylacetone and maleylacetoacetate are normal byproducts of the metabolism of tyrosine. However, they may get abnormally elevated in children affected by Tyrosinemia type I.

Type II of tyrosinemia is also genetic and occurs due to mutations in tyrosine aminotransferase or TAT gene. This gene regulates production of the enzyme tyrosine aminotransferase found only in the liver cells or hepatocytes and is needed to break down tyrosine. The mutations of this gene lead to a deficiency of the tyrosine aminotransferase that result in failure to break down tyrosine. Like Type I, the genetic mutation linked with Type II is also inherited in autosomal recessive pattern.

Type III of Tyrosinemia is a very rare disorder that occurs due to a deficiency of enzyme 4-hydroxyphenylpyruvate dioxygenase that is encoded by the HPD gene.

Tyrosinemia Symptoms

The age of onset as well as the specific symptoms that are experienced may differ from one patient to another. The condition is mostly common in newborns who often exhibit it with a characteristic failure to thrive. The infants may also seem irritable and lethargic. They may also develop a few or all of the symptoms that are listed below:

  • Fever
  • Diarrhea
  • Jaundice
  • Vomiting
  • Bloody stools
  • Hepatomegaly
  • Swelling of legs and feet
  • Enlarged liver and spleen
  • Easy and frequent bruising
  • Difficulty in gaining weight
  • Abdominal swelling and bloating
  • Increased tendencies to bleed, especially nosebleeds

The common symptoms of this condition include kidney and liver disturbances as well as mental retardation.

Type I tyrosinemia is a progressive disease and additional symptoms generally develop over a certain time. These may include:

  • Enlarged spleen
  • Developmental delays
  • Cirrhosis or scarring of liver
  • Swelling of stomach caused by fluid retention
  • Hypoglycemia
  • Conjugated hyperbilirubinemia
  • Coagulation abnormalities
  • Elevated levels of AFP

Life-threatening complications will develop eventually in association with this type, including blood clotting deficiencies and kidney and/or liver failure. The risks of ascites and hemorrhage are increased, along with a greater propensity for hepatocellular carcinoma. The various additional symptoms that are generally associated with the Type I of this disorder include the following:

  • Aminoaciduria
  • Hypophosphatemia
  • Renal tubular acidosis
  • Dermatological manifestations
  • Cardiomyopathy or heart muscle disease
  • Peripheral neuropathy or damage to peripheral nervous system
  • Fanconi syndrome, which involves bone disease and high blood pressure secondary to the renal tubular dysfunction

Children with this type are more prone to develop liver cancer compared to the general population. The signs and symptoms associated with Type II may eventually affect the eyes, skin and the central nervous system. Common features include inflammations of the cornea or keratitis, mental retardation and palmoplantar hyperkeratosis (a condition that causes the skin on hands and feet to become reddened and thickened).

Tyrosinemia can be both acute and chronic, and the symptoms develop in a somewhat different manner in both cases. In case of acute tyrosinemia, the babies experience symptoms within a period of 1 month after birth. In a short period of time, the condition can grow severe and liver transplants may be required right away to manage the condition. Common features may include:

  • Melena
  • Epistaxis
  • Marked edema
  • Purpuric lesions
  • A distinctive, cabbage-like odor

In chronic variants, the symptoms progress slowly and take on less severe forms. In fact, they may not even be apparent until the adolescent years. In such instances, individuals usually develop a much less severe expression of the symptoms. These patients will also require liver transplant to survive, although they do not need to undergo an immediate surgery. In fact, they can be treated patiently for years if required prior to having a transplant surgery. Due to the inhibitory influence of succinylacetone on heme biosynthetic pathway, infants with the chronic form might develop polyneuropathy along with painful abdominal crises, much like in cases of acute intermittent porphyria.

Tyrosinemia Diagnosis

The diagnosis of Tyrosinemia is normally carried out by conducting urine and/or blood tests which help in detecting raised levels of tyrosine along with its metabolites. Liver biopsies may reveal decreased activities of the FAH enzyme in the liver tissue as well as reveal the status of overall liver functions. In case of Type II tyrosinemia, liver biopsies can reveal lower levels of the tyrosine aminotransferase enzyme. Lower serum albumin levels along with clotting factors are also frequently found in blood tests. The bilirubin levels might be increased to great levels and the blood transaminase levels may be mildly or moderately elevated. Quantitation of the plasma amino acids reveals selective increase in the methionine and tyrosine levels. Quantitation of the urinary amino acids shows increased excretion of all or most of the amino acids; i.e., generalized aminoaciduria. Imaging studies are usually not conducted unless there are signs of hepatocellular carcinoma or hepatoma.

Prenatal diagnosis can be conducted through amniocentesis, a process which involves obtaining a small quantity of amniotic fluid and then studying it for checking the levels of FAH or succinylacetone.

Tyrosinemia Differential Diagnosis

A number of health disorders show signs and symptoms similar to that of Tyrosinemia. Hence, while determining the diagnosis of this condition; it should be differentiated from such similar disorders in order to facilitate optimum treatment. The differential diagnoses for Tyrosinemia include diseases such as:

  • Hepatitis B
  • Iron Toxicity
  • Acetaminophen Toxicity
  • Fructose 1, 6-Diphosphatase Deficiency
  • Fructose Intolerance or Fructose 1-Phosphate Aldolase Deficiency
  • Galactosemia or Galactose-1-Phosphate Uridyltransferase Deficiency

Tyrosinemia Treatment

Tyrosinemia is mainly treated by medications, liver transplantation surgery and by adherence to a specific diet. Direct medical therapy needs to be carried out to manage coagulopathy and acute hepatic decompensation from the beginning. Replenishment of the depleted coagulation factors might become necessary to prevent exsanguination. Medications and diet help in curing Type I Tyrosinemia by preventing or reducing the formation and accumulation of tyrosine and its subsequent metabolites. Liver transplantation surgery helps to restore the normal activities of the fumarylacetoacetase enzyme.


In January, 2002, the FDA (U.S. Food and Drug Administration) has approved the use of the drug nitisinone (NTBC) presented as Orfadin for treatment of type I tyrosinemia. The drug helps in blocking tyrosine metabolism and reduces the accumulation of tyrosine and its group of metabolites within the body. It is used along with a diet that is low on protein.

Liver Transplant

Many children may require a liver transplant surgery to cure end-stage liver failure or to prevent the further development of a liver cancer. However, this procedure is opted for as a last resort for most of the cases due to the high risk or mortality or morbidity associated with it, the high cost, as well as the need for continued immunosuppressive therapy for preventing organ rejection.

The Type II Tyrosinemia needs to be detected early in order to avoid the progression of the disease towards mental retardation. Oral drugs derived from the vitamin A known as retinoids can be used to manage the skin conditions that are commonly associated with this disease.

Tyrosinemia Diet

Children having Chronic Tyrosinemia or Tyrosinemia Type I should be placed in a strict low-protein diet that is low on tyrosine, phenylalanine and methionine. A highly experienced and expert nutritionist working alongside a biochemical geneticist should oversee the nutritional requirements. Foods such as dairy products, meats, as well as other protein-rich foods like beans and nuts should be avoided. Although a strict attention to the nutrition along with an adequate mineral plus vitamin intake does not cure the disease, it still serves to manage the associated metabolic abnormalities as well as provide the impetus for normal growth and development.

Tyrosinemia Complications

The following complications may emerge from severe cases of Tyrosinemia:

Picture 2 – Tyrosinemia Image

  • Death
  • Seizures
  • Hepatoma
  • Liver damage
  • Hepatic cirrhosis
  • Abdominal crisis
  • Peripheral neuropathy
  • Hepatocellular carcinoma
  • Rickets that is secondary to RTA or renal tubular acidosis
  • Renal Fanconi syndrome, including renal tubular acidosis type II

Tyrosinemia Prognosis

If left untreated, patients can die of chronic hepatic failure before they reach the age of 2 years. In later-onset types, death can occur from hepatic tumor or hepatic failure during mid childhood. An early liver transplantation carries the usual complications and risks of major organ transplantations, such as the risks of rejection. Prognosis is better when the condition is detected and treated early. Although the experience with Orfadin is limited, it has been found to prevent progressive renal and liver disease along with aborting the fulminating clinical onset. Long-term results of treatment with this drug are not known. Not much is known about the Type II Tyrosinemia at present due to the small number of reported cases recorded in medical journals. A more definitive clinical picture along with new treatment options should emerge as more instances of this disease are identified.

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