Tyrosinemia

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),[1] 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.

The biochemical basis for tyrosinemia I remained enigmatic until the late 1970s, when researchers described a compound called succinylacetone (SAA) found in the urine of infants with the condition. The normal catabolic pathway, which moves tyrosine to 4-hydroxyphenylpyruvic acid, then to homogentisic acid, the ring then being cleaved to produce maleylacetoacetate (MAA) and fumarylacetoacetate (FAA), is interrupted at the next step, which would normally produce fumarate and acetoacetate. The therapeutic agent 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) interrupts the pathway after formation of 4-OH-phenylpyruvic acid. Absent this agent, with the accumulation of FAA, there is conversion to succinylacetoacetate, and spontaneous decarboxylation results in production of SAA, which is a metabolic dead-end. See the image below.

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 in both liver and kidney. This inference was later proven correct; succinyl acetoacetate accumulated because of this defect. Decarboxylation produced succinylacetone, which was then excreted in the urine, its source both hepatic and renal.

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 pharmacological 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.

Data have suggested that fumarylacetoacetate itself induces mitotic abnormalities and instability in the genome.[2] 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. A 2013 report[3] indicates that fumarylacetocetate, but not succinylacetone, inhibits DNA glycosylases, which are instrumental in removing mutagenic base substitutions in the gene. Such data more firmly establish an etiologic relationship between the pathway intermediates and the mutational events they cause.

A new animal model, a rabbit knockout of fumarylacetoacetate hydrolase (FAH), which is the deficient enzyme in the affected human, has been reported; the authors state that the model is a faithful reproduction of the human disease and offers great potential for further study.[4]  In recent years, attention has turned toward use of the CRISPR/Cas9 technique to engineer normal cells from affected ones, with an intent to "genetically engineer" affected infants as a replacement for liver transplantation.[5]   

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 have less than a 5% risk of developing hepatocarcinoma.

A 2014 report indicated rapid reversal with NTBC treatment (within 48 hours) of phosphaturia and continuing improvement in other parameters of renal tubular dysfunction over the ensuing 2 weeks of the study.[6] 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, although data so far indicate there are no ill effects.[7] On the other hand, long-term neurocognition studies indicate that treated children with a frequently elevated serum tyrosine significantly lag behind their siblings.[8, 9, 10, 11]

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.[12] 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. Absence of normal enzyme function 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. To date, 95 causative mutations have been described.[13]

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.

In all initially diagnosed cases, including those discovered in early infancy, prognosis should be regarded as guarded. However, in the very young infant, early institution of NTBC treatment promises a far better eventual outcome than in those patients treated later. As with most inherited metabolic disorders with long-term survival, it is becoming apparent that appropriate maintenance of therapy becomes very difficult in the adolescent period.[14]

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.

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.

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 95 distinct mutations have been reported, with no clear relationship between genotype and phenotype.

Normocytic anemia and leukocytosis are characteristically present in tyrosinemia. 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. Evidence suggests that, after the initiation of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) treatment, alpha-fetoprotein levels that rise, slowly decrease, or never normalize are all strongly associated with the subsequent development of hepatocarcinoma.[15]

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 do not aid in diagnosis, except in cases of suspected hepatoma or hepatocellular carcinoma. Plain films of wrists and knees may be of help in diagnosis of rickets, secondary to the renal tubular acidosis component of the Fanconi syndrome.

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.

Neonatal screening programs in many areas are capable of detecting succinylacetone in submitted blood samples.

Molecular diagnosis is available and can detect the 4 most common mutations, which account for more than 95% of cases. This technique also enables prenatal diagnosis.[16]

No other specific diagnostic procedures are indicated.

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.

Since the development of screening methods for succinylacetone, with the ensuing application to newborn screening, many patients are being detected prior to clinical decompensation, thus enabling initiation of treatment with nitisinone (NTBC), which has become the medical therapy of choice after extensive, worldwide experience.[17] Additional experience with NTBC therapy has shown a direct correlation between age of initiation and subsequent clinical course.

It is possible to use a submitted blood spot for monitoring succinylacetone levels periodically, in order to adjust NTBC and dietary therapies.[18]

Most patients with tyrosinemia who are not diagnosed at birth 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. After stabilization, nitisinone should be started.

Nutritional treatment should be designed to minimize the phenylalanine-tyrosine load to only essential requirements.

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).[19]

Prior to the introduction of medications for the treatment of tyrosinemia, liver transplantation was the only effective treatment. Nitisinone (Orfadin) was the first drug approved to treat hereditary tyrosinemia type I, along with dietary restriction of tyrosine and phenylalanine. Orfadin has been available in capsule form since January 2009 in oral suspension form since April 2016. The tablet formulation of nitisinone (Nityr) was FDA-approved in July 2017. Unlike Orfadin capsules, which require refrigeration, Nityr may be stored at room temperature. For patients who are unable to swallow the tablet, Nityr may be dissolved to make an oral liquid or crushed and mixed in applesauce.

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).[20]  A more recent study has shown very positive long-term theraputic and safety assessments.[21]  Nitisinone must be used in conjunction with diet restriction of the amino acids tyrosine and phenylalanine. Treatment with nitisinone and dietary management should begin as soon as possible after the diagnosis is confirmed. There is recent evidence that tyrosine tolerance tends to increase slightly with age, although this dos not remove the need for close monitoring.[22]

Consider obtaining consultations from the following specialists:

• Biochemical geneticist

• Hepatologist or gastroenterologist

• Hematologist

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.

Normal childhood activity does not need to be restricted.

In addition to dietary treatment, appropriate medical therapy involves the use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a highly potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase.

Class Summary

The clinical manifestations of tyrosinemia stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts on tyrosine metabolism upstream of the defect to prevent the production of these metabolites.

Nitisinone (Nityr, Orfadin)

Adjunct to dietary restrictions to treat hereditary tyrosinemia type-1. Highly potent reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. Prevents formation of catabolic intermediates from tyrosine (ie, maleylacetoacetate, fumarylacetoacetate) that are converted to toxic metabolites (ie, succinylacetone, succinyl acetoacetate) and that are responsible for observed liver and kidney toxicity.

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.

Intercurrent illness in tyrosinemia 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.

In addition to dietary treatment, the standard of care now requires use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which prevents the formation of fumarylacetoacetate from tyrosine.[23]

Close monitoring of patients taking NTBC is essential, according to protocol requirements.

Subsequent, long-term experience with NTBC (nitisinone) has shown this agent to be very effective in both the acute phase of the disease, as well as in prevention of hepatic cellular carcinoma. In addition, children with initial renal tubular dysfunction show complete remission after long-term treatment with NTBC.[24, 25]

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

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

Potential complications include the following:

• 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

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.

Experience with NTBC has become more extensive; the drug appears to be effective in preventing progressive liver and renal disease and in aborting the fulminant clinical onset if started prior to age 1 month, a key reason for advocacy of adding this disorder to newborn screening panels in many places. The long-term results of NTBC therapy are emerging, and while early treatment appears very effective in eliminating cirrhosis and/or hepatomas, development in many affected children has been reported to be slower than normal.[26]

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.