INTRODUCTION — Tyrosine is an aromatic amino acid important in the synthesis of thyroid hormones, catecholamines, and melanin. Impaired catabolism of tyrosine is a feature of several acquired and genetic disorders that may result in elevated plasma tyrosine concentrations .
TYROSINE METABOLISM — Tyrosine degradation is catalyzed by a series of five enzymatic reactions that yield acetoacetate, which is ketogenic, and the Krebs cycle intermediate fumarate, which is glucogenic (figure 1). The hepatocyte and renal proximal tubules are the only two cell types that express the complete pathway and contain sufficient quantities of all enzymes required for tyrosine catabolism.
Four autosomal-recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic pathway: hereditary tyrosinemia (HT) types 1, 2, and 3 and alkaptonuria (AKU). Each disorder is assigned a number on the Online Mendelian Inheritance in Man (OMIM) website. Except for AKU, these disorders result in elevated blood tyrosine levels.
Hypertyrosinemia — Normal plasma tyrosine concentrations are 30 to 120 micromol/L. Values >200 micromol/L are considered elevated. However, clinical manifestations typically do not become apparent until plasma levels exceed 500 micromol/L.
Hypertyrosinemia is detected by quantitative measurement of plasma amino acids. This test usually is performed to evaluate otherwise unexplained liver disease or neurologic abnormalities, such as seizures or developmental delay. Hypertyrosinemia also may be detected on a plasma specimen obtained to investigate elevated urinary tyrosine, seen in the renal Fanconi syndrome (which is manifested by impaired proximal tubular function). HT types 1, 2, and 3 may be detected by expanded newborn metabolic screening available in most states.
Hypertyrosinemia is caused by a variety of genetic and acquired disorders (table 1). They include:
●Inherited deficiencies of enzymes in the degradation pathway
●Transient tyrosinemia of the newborn
●Miscellaneous disorders including scurvy and hyperthyroidism
The most important diagnostic consideration in the evaluation of hypertyrosinemia is the presence or absence of liver disease. If liver disease is present, additional tests must be performed urgently to detect HT type 1, a potentially lethal disorder that requires immediate treatment.
HEREDITARY TYROSINEMIA TYPE 1 — Hereditary tyrosinemia type 1 (HT1; MIM# 276700), also known as hepatorenal tyrosinemia, is the most severe disorder of tyrosine metabolism. HT1 occurs in 1 in 12,000 to 1 in 100,000 individuals of Northern European descent [2,3].
HT1 pathophysiology — HT1 is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in the pathway of tyrosine catabolism (figure 1) . Fumarylacetoacetate (FAA), the substrate for FAH in the tyrosine pathway, accumulates in FAH-deficient hepatocytes and proximal renal tubular cells, resulting in liver and kidney damage.
FAA causes oxidative damage to cells by reacting with glutathione and sulfhydryl groups of proteins. FAA is also mutagenic , although it is not known whether it causes direct or indirect damage to DNA. The mutagenicity of FAA is thought to be the cause of the high rate of hepatocellular carcinoma in HT1.
The oxidative and DNA damage caused by FAA leads to either cell death or a profound perturbation of gene expression, especially in the liver [6,7]. As a result, many metabolic processes, including gluconeogenesis, detoxification of ammonia, and synthesis of secreted proteins, are impaired. Impaired gene expression in FAH-deficient hepatocytes leads to a marked reduction in tyrosine aminotransferase (TAT), the first enzyme in tyrosine degradation, resulting in the elevated plasma tyrosine levels typical of the disorder. Tyrosine itself is not toxic to the liver or kidney but causes dermatologic, ophthalmologic, and possibly neurodevelopmental problems.
FAA has a short intracellular half-life and thus is not found in body fluids of HT1 patients. The principal metabolites of FAA, succinylacetoacetate (SAA) and succinylacetone (SA), are released into the circulation and can be measured for diagnosis.
Increased levels of these metabolites can lead to secondary biochemical alterations in HT1. As an example, SA is a potent inhibitor of aminolevulinate (ALA) dehydratase (porphobilinogen synthase), the first step of heme biosynthesis [4,8,9]. This can result in ALA dehydratase porphyria with neurologic symptoms . Circulating SA also may impair proximal ALA reabsorption, which contributes to the increase in ALA excretion . (See "ALA dehydratase porphyria".)
HT1 genetics — The mode of inheritance for HT1 is autosomal recessive. The gene encoding FAH is located on human chromosome 15q23-q25 .
HT1 occurs more commonly in some ethnic groups, most notably in the Saguenay-Lac-Saint-Jean region of Quebec, Canada. In that population, the carrier rate and prevalence at birth were estimated at 1 in 20 to 25 inhabitants and 1 in 1846 livebirths, respectively [13,14]. A splice mutation was identified in the FAH gene in all patients from Saguenay-Lac-Saint-Jean and in 28 percent of patients from other regions . A stop mutation is common in Finnish patients .
HT1 clinical features — HT1 is characterized by severe, progressive liver disease and renal tubular dysfunction. The latter typically is manifest as the Fanconi syndrome with renal tubular acidosis, aminoaciduria, and hypophosphatemia (due to phosphate wasting) . Features of rickets often are present in untreated patients.
Patients not diagnosed by newborn screening typically present in early infancy with failure to thrive and hepatomegaly. Some develop conjugated hyperbilirubinemia. An often marked elevation in serum alpha fetoprotein (AFP) is common in HT1. Studies in newborns have shown that cord blood AFP is elevated at a time when tyrosine levels are still normal . This observation suggests that the liver disease begins prenatally, as does the common finding of nodularity or cirrhosis in affected neonates. (See "Causes of cholestasis in neonates and young infants".)
Progression of the liver disease can be chronic or acute, with rapid deterioration and early death . Liver dysfunction commonly results in hypoglycemia and coagulation abnormalities. Serum aminotransferase levels typically are only mildly elevated and often disproportionately low compared with the marked degree of coagulopathy. Complications of liver failure, including jaundice, ascites, and hemorrhage, often develop.
The chronic form consists of a mixed micronodular and macronodular cirrhosis. The risk of developing hepatocellular carcinoma is high in untreated survivors, occurring in as many as 37 percent of untreated patients older than two years of age [18,19]. Cancer formation is thought to be caused by the mutagenicity of FAA.
Both the acute and chronic forms can occur in affected siblings or other patients with identical genotypes . Intrafamilial variability in the severity of HT1 may be caused in part by somatic mosaicism. Immunohistologic analysis of liver in some patients shows FAH enzyme activity in some regenerating nodules . In these areas of regeneration, one of the mutant alleles has reverted spontaneously to the normal genotype. Reversion to the normal allele in some individuals may be associated with milder liver disease, but the risk for liver cancer remains .
Severe neurologic manifestations are common in poorly controlled HT1 and contribute to morbidity and mortality. In one study of 48 children with tyrosinemia identified with neonatal screening, neurologic crises resembling the crises of the neuropathic porphyrias occurred in 20 (42 percent) . These acute episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis. Between crises, most patients regained normal function. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. Intellectual disability is not a feature.
Approximately 30 percent of patients display cardiomyopathy at the time of diagnosis, with interventricular septal hypertrophy being the most common finding. This disease manifestation is reversible with nitisinone therapy [23,24].
If untreated, patients with HT1 have a significantly shortened lifespan. Patients may die of acute liver failure before the second year after birth or from chronic liver failure or hepatocellular carcinoma before the end of the second decade.
HT1 laboratory diagnosis — The most important diagnostic test for HT1 is the measurement of SA either in urine or in blood. Many newborn screening programs perform sensitive SA measurements on dried blood spots and confirmatory testing. Elevation of SA is pathognomonic for the disorder. Molecular testing for disease-causing mutations is available through multiple laboratories, but treatment should not be delayed until molecular confirmation is available. Affected patients usually also have elevated plasma concentrations of AFP, tyrosine, and methionine and excrete tyrosyl compounds in the urine.
Newborn screening for HT1 is available in regions with high prevalence, including Quebec, and in all states in the United States. Tandem mass spectrometry can reliably detect diagnostic quantities of SA . (See "Newborn screening".)
HT1 management — Detailed recommendations for the management of patients with HT1 have been published . Therapy consists of a combination of treatment with nitisinone and dietary restriction of protein. Nitisinone increases blood tyrosine levels, and restriction of protein intake is needed to prevent the side effects of elevated blood tyrosine levels. Many patients on the combination of nitisinone therapy and protein restriction develop low blood phenylalanine levels, which is linked to neurodevelopmental problems [26,27]. Phenylalanine supplementation is used in these patients to achieve normal blood levels .
Nitisinone — The medical treatment of choice is nitisinone, formerly known as NTBC, which inhibits 4-OH phenylpyruvate dioxygenase (HPD), an early step in the tyrosine degradation pathway . This treatment reduces metabolic flow through the pathway and limits formation of the toxic compounds FAA and SA (figure 1). Nitisinone should be started as early as possible (ie, immediately after diagnosis of HT1 by blood or urine measurement of SA).
Efficacy — Since the first nitisinone trial in 1991, over 90 percent of treated patients have improved clinically [29-32]. Treatment started at an early age reduces the risk of early development of hepatocellular carcinoma , although longer follow-up is needed to determine if the effect persists throughout life. Therapy with nitisinone also decreases the need for orthotopic liver transplantation (OLT), particularly when started in early infancy . In addition, kidney function is preserved in patients treated with nitisinone who undergo OLT. (See 'Liver transplantation' below.)
The long-term risk of developing neurologic problems on nitisinone therapy is unknown. This is a concern because neurologic complications develop in some patients with inherited HPD deficiency, the same enzyme affected by nitisinone [34,35]. A study of long-term outcomes of nitisinone treatment in France showed cognitive impairment in 35 percent of patients . A subsequent Dutch study demonstrated that some patients experience cognitive decline over time despite nitisinone treatment and despite dietary control of tyrosine levels . Other studies have documented a higher incidence of behavioral problems, even in patients treated from early infancy . It is not known whether this phenotype is related to elevated tyrosine, phenylalanine deficiency, or caused by other factors. However, low phenylalanine levels are of particular concern in this regard .
Dosing — A typical starting dose of nitisinone is 1 mg/kg per day, divided into a morning and evening dose and given orally. Once-daily dosing was approved by the US Food and Drug Administration (FDA) in 2020. Because nitisinone increases plasma tyrosine levels, patients should have a protein-restricted diet that is low in phenylalanine and tyrosine. The dietary protein intake is varied to keep the plasma tyrosine level 200 to 600 micromol/L .
If the biochemical parameters (except plasma SA) have not normalized within one month of starting therapy (see 'Monitoring' below), the dose should be increased to 1.5 mg/kg/day. The dose of nitisinone should be adjusted to completely suppress excretion of SA. However, it may take as long as three months for complete suppression of SA to occur. A dose of 2 mg/kg/day may be needed, especially in infants. However, this dose should be considered maximal. A general target for blood level of nitisinone is 40 to 60 micromol/L. In older individuals, therapeutic blood levels of nitisinone can often be achieved with doses <1 mg/kg/day. Monitoring of the nitisinone blood levels is recommended for dose adjustment and also to check therapy compliance.
Monitoring — Metabolic monitoring includes the measurement of plasma amino acids (especially tyrosine and phenylalanine), blood or urinary SA, liver and kidney function tests, complete blood count (CBC) with differential, nitisinone levels, and serum AFP (which increases further with hepatocellular carcinoma). Metabolic monitoring is performed monthly for the first year, then every three months until age five years and every six months thereafter. Detailed recommendations for monitoring developed by expert consensus were published in 2017 . The CBC is monitored because some patients develop hematologic abnormalities , especially leukopenia and thrombocytopenia. Serum AFP can take many months to normalize after nitisinone therapy is started. It is important to monitor the trend of the decline, which should be continuously downward. If AFP levels off in a range above normal or begins to increase, an evaluation of possible hepatocarcinoma should be initiated. In one study, AFP levels did not normalize in approximately one-third of patients, even after one year of nitisinone treatment .
Ophthalmologic examination and hepatic imaging (magnetic resonance imaging is preferred) should be performed annually.
Some patients treated with nitisinone have reduced levels of blood phenylalanine levels, raising concerns about negative effects on growth and neurologic development from lack of this essential amino acid . The clinical significance of this observation is unclear, but supplementation of phenylalanine in the diet is suggested when two independent measurements show phenylalanine levels of <30 micromoles/L .
Liver transplantation — OLT is performed in patients with persistent liver failure who do not respond to nitisinone therapy or have hepatic malignancy [39-41]. In one series of eight patients transplanted at a median age of 64 months, plasma tyrosine and AFP returned to normal, urinary SA decreased, and, if present, hypertrophic cardiomyopathy resolved . Renal tubular function remains abnormal in many transplanted patients, and careful monitoring of kidney function is therefore recommended . Plasma and urinary SA levels are not completely normalized after transplantation , but the clinical significance of this finding is unknown. OLT is not predicted to prevent the accumulation of mutagenic and toxic FAA in renal tubules. More extensive long-term studies are needed to determine whether renal pathology (progressive tubular disease or renal cancer) can be prevented by OLT in the absence of nitisinone treatment.
HEREDITARY TYROSINEMIA TYPE 2 — Hereditary tyrosinemia type 2 (HT2; MIM# 276600), also known as oculocutaneous tyrosinemia or Richner-Hanhart syndrome, is characterized by early development of eye and skin abnormalities.
HT2 pathophysiology — HT2 is caused by deficiency of tyrosine aminotransferase (TAT), the first enzyme in the tyrosine degradation pathway (figure 1). As a result, plasma tyrosine and its metabolites are elevated. These elevated levels are thought to be responsible for the clinical manifestations of the disorder. In animal models, a diet high in tyrosine can induce the ocular findings of HT2 .
HT2 clinical features — The ophthalmologic and dermatologic features of HT2 usually become apparent in the first year after birth, although some patients present as adults. The characteristic ocular findings are corneal ulcers or dendritic keratitis (table 2). These result in photophobia, pain, excessive lacrimation, and redness.
The skin lesions consist of painful hyperkeratotic plaques, primarily on the palms and soles. Plaques also may develop on elbows, knees, and ankles. Some patients have erythematous papular lesions.
Approximately 50 percent of patients with HT2 have intellectual disability . However, it is unclear whether the neurologic problems are due to elevated tyrosine or caused by other factors such as consanguinity. Unlike hereditary tyrosinemia type 1 (HT1), the liver and kidney are not affected in this disorder. As a result, liver function tests, the plasma creatinine concentration, and acid-base balance are normal.
HT2 laboratory diagnosis — HT2 should be suspected if patients present with typical signs or if elevated tyrosine levels are detected on newborn metabolic screening. The plasma tyrosine concentration in this disorder typically is >1000 micromol/L, substantially higher than in other forms of tyrosinemia. The urine contains large amounts of tyrosine metabolites (eg, 4-hydroxyphenylacetate, 4-hydroxyphenylactate, and 4-hydroxyphenylpyruvate).
Measurement of urine organic acids and serum alpha fetoprotein (AFP) should be performed to exclude a mild form of HT1. The diagnosis is confirmed by detection of mutations in the TAT gene .
HT2 management — Management of HT2 consists of a diet low in tyrosine and phenylalanine. Plasma tyrosine levels should be kept below 500 micromol/L. This approach usually results in resolution of the skin and eye lesions. Early dietary intervention may prevent cognitive impairment .
HEREDITARY TYROSINEMIA TYPE 3 — Hereditary tyrosinemia type 3 (HT3; MIM# 276710) is a rare, autosomal-recessive disorder caused by deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), the second step in the tyrosine catabolism pathway (figure 1) [35,47]. Numerous mutations have been identified in the HPD gene on chromosome 12q24 . Most affected patients have neurologic dysfunction, including ataxia, seizures, and mild psychomotor retardation, but no other systemic involvement (table 2). The majority of reported cases have intellectual disability, but a causative relationship between HPD deficiency and neurologic problems has not been conclusively demonstrated. Ascertainment bias may account for the apparent correlation. Patients with normal psychomotor development have been reported .
The diagnosis is confirmed by detection of mutations in the HPD gene. Prenatal detection is available using this technique.
Plasma tyrosine levels are elevated in this disorder but typically remain below 500 micromol/L and therefore usually do not cause corneal ulcers or hyperkeratosis. Treatment consists of a diet low in tyrosine and phenylalanine, although whether this diet can prevent or reverse the neurologic symptoms is uncertain.
ALKAPTONURIA — Alkaptonuria (AKU; MIM# 203500) is an autosomal-recessive disorder that results from deficient activity of homogentisic acid dioxygenase (HGD), the third enzyme in tyrosine degradation . The description of AKU by Garrod in 1902 led to recognition of the concept of a single enzyme deficiency resulting in lifelong disease . The gene encoding HGD is located on chromosome 3q21-q23 and mutations identified in patients with AKU [52,53].
Clinical features — HGD deficiency results in elevated levels of homogentisic acid (HGA), which polymerizes, forming a pigment that is deposited in connective tissue throughout the body (ochronosis) (picture 1). Affected patients usually are asymptomatic in childhood.
In affected babies, urine in a diaper may darken and can turn almost black after several hours (black nappies). During the third decade, deposits of the brownish or bluish pigment become apparent, typically first in the ear cartilage and sclerae. Pigment is also deposited in the large joints and the spine, especially the lumbosacral region. Calcification of multiple intervertebral discs is a characteristic radiographic finding. The development of ochronotic arthritis results in limitation of motion and often complete ankylosis, resembling rheumatoid arthritis or osteoarthritis (table 2). Axillary and inguinal areas may have a brownish discoloration . Perspiration can stain clothing in affected patients.
The natural history of AKU was evaluated in a study of 58 patients, ages 4 to 80 years . Arthropathy was common, and one-half of the patients had replacement of one knee, hip, or shoulder before 55 years of age. Kidney stones developed in 16 patients (27 percent) at a mean age of 64 years. The mean ages for detection of cardiac valve involvement and coronary artery calcification were 54 and 59 years, respectively. In another series, aortic valve disease was common in patients over 40 years of age .
Diagnosis — The disorder is characterized by the excretion of urine that appears normal when fresh but turns dark brown or black if left standing or after alkalinization. The dark color is caused by oxidation of HGA, and AKU has also been called black urine disease. Cloth diapers that are washed in alkaline solutions will have dark-brown staining.
Although the discoloration of urine in AKU is apparent in infancy, the diagnosis usually is made in adults during routine urinalysis or investigation of arthritis . In the natural history study cited above, AKU was diagnosed before one year of age in 12 of 58 patients (21 percent) . In the remaining patients, the mean age at diagnosis was 29 years.
Levels of HGA are increased in blood, urine, and tissue samples. The diagnosis is confirmed by quantitative measurement of HGA in urine and mutation analysis of the HGD gene. Tyrosine levels are normal.
Management — There are no approved treatments for AKU. However, nitisinone, which inhibits the second enzyme in the tyrosine catabolic pathway, decreased urinary and blood HGA levels by >95 percent in several studies [57,58]. Complete blockage of tyrosine degradation is not necessary to achieve this reduction, and the typical dose of 2 to 10 mg/day in adults is significantly lower than that used in hereditary tyrosinemia type 1 (HT1). However, no clinical benefits (hip total range of motion and other measures of musculoskeletal function) were demonstrated in a randomized trial of nitisinone in patients with AKU who already had significant arthritis . Some improvement in clinical severity scores after 48 months of therapy was noted in a randomized clinical trial . In addition, significant reductions in ochronotic pigmentation in the eye and ears were documented after several years of therapy . It is unknown whether early treatment prior to the development of musculoskeletal symptoms would be beneficial . Dietary restriction of tyrosine and phenylalanine reduce the excretion of HGA, although the clinical effect is limited . Arthropathy is not reversible with this approach, although diet may prevent further progression. Ascorbic acid, which inhibits the enzyme that catalyses the oxidation of HGA to the polymer with affinity for collagen, is given, but its efficacy has not been demonstrated for ochronosis .
ACQUIRED TYROSINEMIA — The most common causes of elevated plasma tyrosine levels are acquired rather than inherited (table 1).
Transient tyrosinemia of the newborn — Transient tyrosinemia of the newborn is the most common acquired cause of increased plasma tyrosine levels [1,64]. The etiology of this disorder is immaturity of 4-OH phenylpyruvate dioxygenase (HPD), which is involved in an early step of tyrosine degradation (figure 1). Transient immaturity of this enzyme, the gene for which is mutated in hereditary tyrosinemia type 3 (HT3), occurs in approximately 10 percent of preterm infants and some term infants. Tyrosine levels are measured in most newborn screening programs, and this condition will cause an abnormal newborn screening result. Testing for hereditary tyrosinemia type 1 (HT1) and hepatic injury should be done in all cases of elevated tyrosine. If succinylacetone (SA) is absent and liver functions are normal, tyrosine levels should be monitored longitudinally. In transient tyrosinemia, levels should normalize within a few weeks. If this does not occur, an evaluation for hereditary tyrosinemia type 2 (HT2) and HT3 should be initiated.
This disorder rarely is a problem with modern neonatal management. In the past, affected patients could develop lethargy, poor feeding, metabolic acidosis, and prolonged jaundice. Symptoms responded rapidly to ascorbic acid, a cofactor of HPD, and decreased protein intake.
Hepatocellular dysfunction — Hepatocellular dysfunction of any etiology can result in elevated plasma tyrosine levels and excretion of increased amounts of tyrosine metabolites in urine. The tyrosine levels usually are <500 micromol/L. As a result, symptoms of hypertyrosinemia are not seen. However, the association can cause diagnostic confusion in a child who presents with unexplained liver disease in whom elevated plasma tyrosine could reflect HT1.
●Four autosomal-recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic pathway: hereditary tyrosinemia (HT) types 1, 2, and 3 and alkaptonuria (AKU) (figure 1). Except for AKU, these disorders result in elevated blood tyrosine levels (table 2). (See 'Tyrosine metabolism' above.)
●HT1 (hepatorenal tyrosinemia) is characterized by severe, progressive liver disease and renal tubular dysfunction (table 2). Most patients present in early infancy with failure to thrive and hepatomegaly. Nitisinone is the medical treatment of choice. (See 'Hereditary tyrosinemia type 1' above.)
●HT2 (oculocutaneous tyrosinemia) is characterized by early development of eye and skin abnormalities that usually become apparent in the first year of life (table 2). HT2 should be suspected in patients with typical signs or elevated tyrosine levels on newborn metabolic screening. Management consists of a diet low in tyrosine and phenylalanine. (See 'Hereditary tyrosinemia type 2' above.)
●HT3 is a rare disorder. Affected patients often have neurologic dysfunction (ataxia, seizures, mild psychomotor retardation) but no other systemic involvement (table 2). Treatment consists of a diet low in tyrosine and phenylalanine. (See 'Hereditary tyrosinemia type 3' above.)
●AKU should be suspected in patients whose urine appears normal when fresh but turns dark brown or black if left standing after alkalinization. Patients with AKU usually are asymptomatic in childhood. During the third decade, deposits of brownish or bluish pigment become apparent in the ear cartilage and sclerae (picture 1). Tyrosine levels are normal. No approved therapy is available. Dietary restriction of tyrosine and phenylalanine reduce the excretion of homogentisic acid (HGA), although the clinical effect is limited. Clinical trials with nitisinone are ongoing and have shown promise. (See 'Alkaptonuria' above.)
●Transient tyrosinemia of the newborn is the most common acquired cause of hypertyrosinemia. It is caused by immaturity of 4-OH phenylpyruvate dioxygenase (HPD) (figure 1) and occurs in approximately 10 percent of preterm infants and in some term infants. (See 'Transient tyrosinemia of the newborn' above.)
●Hepatocellular dysfunction of any etiology can result in elevated plasma tyrosine levels and excretion of increased amounts of tyrosine metabolites in urine. The tyrosine levels usually are <500 micromol/L. (See 'Hepatocellular dysfunction' above.)