eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Tyrosinemia

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Contributor Information and Disclosures

Updated: Sep 1, 2009

Introduction

Background

Elevated blood tyrosine levels are associated with several clinical entities. The term tyrosinemia was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was chosen at a time when specific enzymatic diagnosis was unavailable, leaving a clinical description that has not been duplicated in the 50 years since its publication.

Transient tyrosinemia is believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and spontaneously disappears with no sequelae. Transient tyrosinemia is not categorized as an inborn error of metabolism because it is not caused by a genetic mutation.

Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbagelike) odor, renal tubular dysfunction (Fanconi syndrome), and survival of less than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Some patients have a later onset, usually before age 6 months, with a somewhat protracted course.

For many years, the diagnosis was based on the observation that plasma tyrosine and methionine levels were significantly elevated. Postmortem examination revealed that both the liver and the kidney had a highly unusual pattern of nodular cirrhosis, the histopathologic hallmark of the disease. In the early 1970s, researchers discovered that most severe liver diseases caused such findings regardless of etiology, and, in the late 1970s, the biochemical and enzymatic causes of the disease were reported.

Tyrosinemia II is a disease with a clinical presentation distinctly different from that described above. This presentation includes herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation. The biochemical and enzymatic basis for the disease bears no relationship to that of tyrosinemia I, and tyrosinemia II is not discussed further in this article.

Tyrosinemia III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions, and is also not discussed further in this article.

Pathophysiology

Although many aspects of the biochemical toxicity of this compound are known, the cellular basis for the multiorgan dysfunction found at the clinical level is unclear. In the kidney, succinylacetone has been demonstrated to be a mitochondrial toxin that inhibits substrate-level phosphorylation by means of the Krebs cycle. This compound also causes dysfunction of membrane transport in normal rat kidneys, altering membrane fluidity and possibly disrupting normal structure. It can cause renal tubular dysfunction in normal rat kidneys, mimicking human Fanconi syndrome, for which no other animal model is available. Beyond its effects on the kidney, succinylacetone is a potent inhibitor of δ-aminolevulinic acid dehydratase, the enzyme that mediates formation of porphobilinogen, the cyclic precursor of porphyrins in the heme biosynthetic sequence. Succinylacetone-related alterations in heme biosynthesis of normal rat liver and kidney have been demonstrated.

Recent data have suggested that fumarylacetoacetate itself induces mitotic abnormalities and instability in the genome.¹ Research in murine animal models has indicated that this metabolite initiates apoptosis of hepatic and renal tubular cells. Taken together, these data form the basis for a unifying hypothesis regarding the development of hepatocellular carcinoma in children with hereditary tyrosinemia.

The effective therapeutic use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in tyrosinemia does not normalize hepatic collagen metabolism, leaving the already fibrosed liver vulnerable to further structural damage. However, data regarding the hepatic response to NTBC are conflicting.

One group reported reversibility of cirrhotic nodules in a patient receiving NTBC treatment, whereas another group reported that the drug did little to suppress gene expression of other genes responsible for ongoing hepatic damage in a murine model. Longer-term experience with NTBC has provided more encouraging results, suggesting that children with the disease who receive NTBC prior to age 2 years of age have less than a 5% risk of developing hepatocarcinoma. In addition, corneal opacities due to deposition of tyrosine crystals in the tissues caused by long-term treatment with NTBC have been reported. Tyrosine levels rise because of the enzymatic block created in the p -hydroxyphenylpyruvic acid dioxygenase. A tendency for precipitation is noted because tyrosine is relatively insoluble compared with other amino acids. The potential long-term effects of precipitation in tissues other than the cornea remain unknown.

In patients with tyrosinemia who have undergone orthoptic liver transplantation, urinary excretion of succinylacetone dramatically decreases, although excretion generally persists at levels lower than those observed before transplantation. This persistence can be attributed to ongoing production of the compound by kidneys, which remain genetically affected by the enzyme defect. The generalized toxic effect on mitochondria, membranes, and heme biosynthesis can logically be assumed to be at the root of the pathologic observations of nodular cirrhosis.

Increased urinary excretion of δ-aminolevulinic acid can be attributed to inhibition of the heme biosynthetic pathway. A similar mechanism can account for the seizures commonly observed in patients; this mechanism is based on the demonstration of fumarylacetoacetase in the normal human brain. Genetic absence of the enzyme could then be assumed to induce cellular accumulation of succinylacetone and to facilitate its toxic effects on the neuron.

Frequency

United States

The estimated incidence is 1 case per 100,000 live births.

International

In some areas of North America, notably a region of Quebec province, the incidence is extraordinarily high, and the estimated incidence of carriers of a specific mutation is 1 in 14 adults.

Mortality/Morbidity

Affected infants often have a fulminant onset, with a rapid development of hepatic cirrhosis and failure. The onset of hepatic failure places the infant at risk for a serious coagulopathy. Survivors of the neonatal episode are at significant risk of hepatocellular carcinoma. In one series in which combined medical and surgical techniques were used, the mortality rate was reduced to less than 15%.

Sex

Tyrosinemia I is an autosomal recessive disorder; therefore, the sex distribution is equal. The severity of onset and the subsequent course does not differ between the sexes.

Age

The disease is present from conception because it is caused by genetic mutation. Most infants present within the first 2-3 months of life; far fewer infants present later with a chronic form, which frequently manifests initially as rickets and slowly developing hepatic cirrhosis.

Clinical

History

• Failure to thrive may precede the appearance of more dramatic findings in tyrosinemia. Patients with such findings often have a history of diminished nutritional intake and anorexia.
• The patient then develops vomiting and diarrhea, which rapidly progress to bloody stool, lethargy, and jaundice. At this stage, a distinctive cabbagelike odor may be appreciated.
• At approximately age 1 year, infants with the chronic form may have failure to thrive and delayed walking, which may indicate rickets.
• Because the disease is autosomal recessive, the family pedigree typically does not reveal previously affected individuals. However, a French-Canadian ancestry should raise suspicion because of the extraordinarily high incidence of heterozygotes in the adult population of this lineage.

Physical

• Clinical suspicion should be extremely high in infants with failure to thrive and hepatomegaly in the first 3 months of life.
• The acute onset may be dramatic, with hepatomegaly, jaundice, epistaxis, melena, purpuric lesions, marked edema, and the distinctive cabbagelike odor.
• Because of the inhibitory effects of succinylacetone on the heme biosynthetic pathway, infants with the chronic form may develop polyneuropathy and painful abdominal crises, as seen in acute intermittent porphyria.
• Survivors may have hepatic nodules and cirrhosis; the nodules may indicate hepatocellular carcinoma. Distant metastases can occur.

Causes

• The sole explanation for tyrosinemia I is genetic mutation in homozygous form. Heterozygote individuals are entirely unaffected.
• The gene is mapped to band 15q23-q25, and approximately 30 distinct mutations have been reported, with no clear relationship between genotype and phenotype.

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