AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

The biochemical basis for tyrosinemia I remained enigmatic until the late 1970s, when researchers described a compound called succinylacetone found in the urine of infants with the condition. Succinylacetone was ultimately determined to be the decarboxylation product of succinyl acetoacetate, a compound derived from the tyrosine catabolic intermediate fumarylacetoacetate. Investigators inferred that the enzymatic defect might reside in deficiency of fumarylacetoacetase, which mediates production of fumaric acid and acetoacetate. This inference was later proven correct; succinyl acetoacetate accumulated because of this defect. Decarboxylation produced succinylacetone, which was then excreted in the urine.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Failure to thrive may precede the appearance of more dramatic findings. 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Halothane anesthesia
Giant cell hepatitis
Other causes of acute hepatic failure

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Normocytic anemia and leukocytosis are characteristically present. Although the prothrombin time is increased, thrombocytosis may be present.
• Serum bilirubin and transaminase levels are uniformly increased and the cholesterol level is low, signifying hepatocellular damage.
• The alpha-fetoprotein level is increased, mirroring an increase seen in cord blood of newborns examined prospectively, even in the presence of tyrosine and methionine levels that are within the reference range.
  
  
  • Evidence suggests that hepatic damage does occur in utero; therefore, the clinical presentation of infantile tyrosinemia I actually represents the point at which liver damage has become so severe that hepatic decompensation occurs.
  • Increased plasma levels of tyrosine and methionine may simply indicate that this point has been reached.
  • Recent evidence suggests that, after the initiation of NTBC treatment, alpha-fetoprotein levels that rise, slowly decrease, or never normalize are all strongly associated with the subsequent development of hepatocarcinoma.²
• Urinalysis may reveal alkaline pH, glucosuria, and proteinuria.
• Urine chemistry reveals phosphaturia, glucosuria, and increased δ-aminolevulinic acid concentrations.
• Quantitation of plasma amino acids in an early stage shows selective increases of tyrosine and methionine levels. As hepatic failure progresses, levels of most of the other amino acids become elevated.
• Quantitation of urinary amino acids shows generally increased excretion of most or all amino acids (generalized aminoaciduria).

Imaging Studies

• Imaging studies do not aid in diagnosis, except in cases of suspected hepatoma or hepatocellular carcinoma.

Other Tests

• Urinary succinylacetone is the biochemical marker substance, and its presence is diagnostic for tyrosinemia I.
• Proper collection and handling of the sample is of critical importance.

Procedures

• No specific diagnostic procedures are indicated.

Histologic Findings

Active inflammation with fatty infiltration in the liver is evident. Lobular regeneration is present and ultimately results in nodular cirrhosis. Changes consistent with hepatoma may also be seen. The kidney shows tubular swelling and formation of nodules, similar to that seen in the liver.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Most patients are so ill at the time of presentation that inpatient treatment is mandatory.
• Direct medical therapy is aimed at the acute hepatic decompensation and coagulopathy from the outset. Replenishment of depleted coagulation factors may be essential to prevent exsanguination.
• Nutritional treatment should be designed to minimize the phenylalanine-tyrosine load to only essential requirements.

Surgical Care

• If the critically ill child can be sufficiently stabilized by medical means, surgery has no role.
• Liver transplantation is the treatment of last resort (eg, the development of severe cirrhosis or hepatic tumor.)

Consultations

• Biochemical geneticist
• Hepatologist or gastroenterologist
• Hematologist

Diet

• All children should be prescribed a low-phenylalanine low-tyrosine diet designed to meet their needs for growth without providing excesses of these amino acids.
• Only a highly experienced nutritionist working with a biochemical geneticist can properly oversee the nutritional regimen.

Activity

Normal childhood activity does not need to be restricted.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Tyrosine degradation inhibitor

In addition to dietary treatment, some advise the use of NTBC, a highly potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase. NTBC prevents the formation of fumarylacetoacetate from tyrosine. Results from an international study initiated in 1992 resulted in the US Food and Drug Administration (FDA) approving the drug in January 2002.

An open-label study of 207 patients (aged 0-21.7 y; median age, 9 mo) showed a dramatic improvement in overall survival for patients younger than 2 months who presented with hereditary tyrosinemia type I and who were treated with nitisinone and dietary restriction, as compared with historical control subjects (29% vs 88% survival probabilities at 2 and 4 y).³

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Intercurrent illness may precipitate subsequent crises based on diminished intake, causing muscle protein catabolism with release of phenylalanine and tyrosine for energy.
• Such crises require admission for treatment.

Further Outpatient Care

• Patients must be under the regular care of a biochemical geneticist and an experienced nutritionist.
• Because of the low-phenylalanine, low-tyrosine diet, frequent quantitation of plasma amino acid levels is required. Adjustment is based on these results and on parameters of physical growth.

In/Out Patient Meds

• In addition to dietary treatment, some advise use of NTBC, which prevents the formation of fumarylacetoacetate from tyrosine.
• NTBC is available only in an international study protocol.
• Close monitoring of patients taking NTBC is essential, according to protocol requirements.

Transfer

• Immediately transfer any patient suspected of having tyrosinemia I to a major academic medical center, clinical status permitting.

Deterrence/Prevention

• Aside from treatment with NTBC, no other deterrents of disease onset are known.

Complications

• Hepatic cirrhosis
• Renal Fanconi syndrome, including renal tubular acidosis type II
• Rickets secondary to renal tubular acidosis (RTA)
• Peripheral neuropathy
• Abdominal crisis
• Seizures
• Hepatoma or hepatocellular carcinoma

Prognosis

• Without treatment, patients die from chronic hepatic failure by age 2 years. In the later-onset type, death from hepatic failure or hepatic tumor may occur in mid childhood.
• Early liver transplantation poses the usual risks and complications of any major organ transplantation, including the risk of rejection.
• Although experience with NTBC is limited, the drug appears to be effective in preventing progressive liver and renal disease and in aborting the fulminant clinical onset. The long-term results of NTBC therapy are uncertain.

Patient Education

• Teach family members how to help the patient adhere to dietary restrictions and medication schedules.
• Emphasize the importance of regular follow-up care with a biochemical geneticist.
• Family members should understand that hepatic malignancy might develop despite all therapy. Medical follow-up care is imperative.
• Prenatal diagnosis is possible for future pregnancies.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider and diagnose the disorder before death because succinylacetone is extremely labile and cannot be used in postmortem diagnosis
• Failure to direct appropriate diagnostic attention to the development of hepatic malignancies

Special Concerns

• NTBC is available only in an international study protocol; therefore, its availability may be delayed.
• Experience of NTBC in young infants before clinical onset and knowledge of the long-term consequences of its use in others are extremely limited.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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21. Luijerink MC, Jacobs SM, van Beurden EA, et al. Extensive changes in liver gene expression induced by hereditary tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). J Hepatol. Dec 2003;39(6):901-9. [Medline].
22. Magera MJ, Gunawardena ND, Hahn SH, et al. Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I. Mol Genet Metab. May 2006;88(1):16-21. [Medline].
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Article Last Updated: Jul 11, 2007