Abstract
Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970. Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 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, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias.
Source Information
Department of Genetics, Hopital Sainte Justine, Montreal, PQ, Canada.
This article has been cited by other articles:
Nakamura, K., Tanaka, Y., Mitsubuchi, H., Endo, F. (2007). Animal Models of Tyrosinemia. J. Nutr. 137: 1556S-1560S [Abstract] [Full Text]
Burns, T. M., Ryan, M. M., Darras, B., Jones, H. R. Jr (2003). Current Therapeutic Strategies for Patients With Polyneuropathies Secondary to Inherited Metabolic Disorders. Mayo Clin Proc. 78: 858-868 [Abstract]
Evans, A. (2002). An Infant with Otitis Media and Abdominal Distension. CLIN PEDIATR 41: 537-541
Aponte, J. L., Sega, G. A., Hauser, L. J., Dhar, M. S., Withrow, C. M., Carpenter, D. A., Rinchik, E. M., Culiat, C. T., Johnson, D. K. (2001). Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1. Proc. Natl. Acad. Sci. USA 98: 641-645 [Abstract] [Full Text]
Mitchell, G. (1996). Bad guy makes good: Inhibition of 4-Hydroxyphenylpyruvate Dioxygenase by 2-(2-Nitro-4-trifluoromethyl benzoyl)-cyclohexane-1,3-dione and 2-(2-Chloro-4- methanesulfonylbenzoyl)-cyclohexane-1,3-dione Ellis MK, Whitfield AC, Gowans LA, Auton TR, McLean Provan W, Lock EA and Smith LL Toxicology and Applied Pharmacology, 1995; 133: 12-19. Hum Exp Toxicol 15: 179-181
Grompe, M., St.-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M. (1994). A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I. NEJM 331: 353-357 [Abstract] [Full Text]
Grompe, M, al-Dhalimy, M, Finegold, M, Ou, C N, Burlingame, T, Kennaway, N G, Soriano, P (1993). Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.. Genes Dev. 7: 2298-2307 [Abstract]
Bateman, R. L., Bhanumoorthy, P., Witte, J. F., McClard, R. W., Grompe, M., Timm, D. E. (2001). Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound Phosphorus-based Inhibitor. J. Biol. Chem. 276: 15284-15291 [Abstract] [Full Text]
Thursday, March 12, 2009
Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.
Abstract
Two Norwegian patients with chronic tyrosinemia type I showed > 50% residual fumarylacetoacetase activity in liver samples obtained during liver transplantation. The enzyme characteristics of both patients were comparable with those of a normal control. Immunohistochemistry on liver sections from these patients and from three other Norwegian tyrosinemia patients revealed a mosaicism of fumarylacetoacetase immunoreactivity corresponding completely or partly to some of the regenerating nodules. This appearance of enzyme protein is presumably induced by the disease process. The mechanism involved remains unclear and could be caused by a genetic alteration, regained translation of messenger RNA, or to enhanced stability of an abnormal enzyme.
Two Norwegian patients with chronic tyrosinemia type I showed > 50% residual fumarylacetoacetase activity in liver samples obtained during liver transplantation. The enzyme characteristics of both patients were comparable with those of a normal control. Immunohistochemistry on liver sections from these patients and from three other Norwegian tyrosinemia patients revealed a mosaicism of fumarylacetoacetase immunoreactivity corresponding completely or partly to some of the regenerating nodules. This appearance of enzyme protein is presumably induced by the disease process. The mechanism involved remains unclear and could be caused by a genetic alteration, regained translation of messenger RNA, or to enhanced stability of an abnormal enzyme.
Hereditary Tyrosinemia type I
Hereditary Tyrosinemia type I (HT1) is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), which functions in the last step of the tyrosine breakdown cascade. Tyrosinemic patients suffer from progressive liver failure during infancy, kidney damage and early development of hepatocellular carcinoma. The substrate of FAH, fumarylacetoacetate (FAA) is thought to be hepatotoxic and mutagenic.
HT-1 patients are currently treated with NTBC, a drug blocking tyrosine catabolism upstream of FAH, thereby preventing accumulation of the toxic metabolite FAA. Unfortunately patients still develop hepatocellular carcinoma (HCC), despite the NTBC treatment.
In our lab we have mice that are FAH-deficient and have a neonatal lethal phenotype that can be rescued by treating the pregnant and nursing female with NTBC. Withdrawing adult FAH-deficient mice from NTBC elicits the HT1 phenotype. Without treatment these mice die within 4-8 weeks. FAH-deficient mice receiving life-long treatment with 1 mg/kg NTBC per day do develop HCC after 8-15 months.
When treating FAH-deficient mice on NTBC with homogentisic acid FAA, a toxic metabolite, can accumulate again. These mice become very ill within 4 hours and will die of acute liver damage. When treating FAH-deficient mice that were withdrawn from NTBC for 15 days, with the same dose of HGA these mice survive this lethal dose of HGA. FAH-deficient mice withdrawn from NTBC seem to have developed a resistancy to cell death caused by HGA.
Failure of cell-death programs, for example as a result of resistance to HGA, may lead to accumulation of damaged cells and enhance the risk for cancer. The goal of this project is to investigate the different pathways leading to cell death in our mouse models.
Theses:
Marjanka Luijerink - Novel insights into the pathogenesis of Hereditary Tyrosinemia Type 1. 16 November 2004
Saskia Jacobs - Hereditary Tyrosinemia type 1 revisited. 1 November 2005
HT-1 patients are currently treated with NTBC, a drug blocking tyrosine catabolism upstream of FAH, thereby preventing accumulation of the toxic metabolite FAA. Unfortunately patients still develop hepatocellular carcinoma (HCC), despite the NTBC treatment.
In our lab we have mice that are FAH-deficient and have a neonatal lethal phenotype that can be rescued by treating the pregnant and nursing female with NTBC. Withdrawing adult FAH-deficient mice from NTBC elicits the HT1 phenotype. Without treatment these mice die within 4-8 weeks. FAH-deficient mice receiving life-long treatment with 1 mg/kg NTBC per day do develop HCC after 8-15 months.
When treating FAH-deficient mice on NTBC with homogentisic acid FAA, a toxic metabolite, can accumulate again. These mice become very ill within 4 hours and will die of acute liver damage. When treating FAH-deficient mice that were withdrawn from NTBC for 15 days, with the same dose of HGA these mice survive this lethal dose of HGA. FAH-deficient mice withdrawn from NTBC seem to have developed a resistancy to cell death caused by HGA.
Failure of cell-death programs, for example as a result of resistance to HGA, may lead to accumulation of damaged cells and enhance the risk for cancer. The goal of this project is to investigate the different pathways leading to cell death in our mouse models.
Theses:
Marjanka Luijerink - Novel insights into the pathogenesis of Hereditary Tyrosinemia Type 1. 16 November 2004
Saskia Jacobs - Hereditary Tyrosinemia type 1 revisited. 1 November 2005
Involvement of Endoplasmic Reticulum Stress in Hereditary Tyrosinemia Type I*
Anne Bergeron, Rossana Jorquera, Diana Orejuela, and Robert M. Tanguay1
From the Laboratory of Cell and Developmental Genetics, Department of Medicine, Centre de Recherche sur la Fonction, la Structure, et l'Ingénierie des Protéines, Pavillon Marchand, Université Laval, Ste-Foy, Québec G1K 7P4, Canada
Hereditary tyrosinemia type I (HTI) is the most severe disease of the tyrosine degradation pathway. HTI is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the enzyme responsible for the hydrolysis of fumarylacetoacetate (FAA). As a result, there is an accumulation of metabolites such as maleylacetoacetate, succinylacetone, and FAA. The latter was shown to display mutagenic, cytostatic, and apoptogenic activities and to cause chromosomal instability. Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum (ER) stress signaling. Treatment of V79 Chinese hamster lung cells with an apoptogenic dose of FAA (100 µM) causes an early induction of the ER resident chaperone GRP78/BiP and a simultaneous phosphorylation of the eIF2. FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12. Data obtained from fah–/– mice taken off the therapeutic 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione drug are similar. However, in this mouse model, there is also an increase in proteasome activity indicative of ER-associated degradation. This difference observed between the two models may be due to the fact that the murine model measures the effects of all metabolites accumulating in hereditary tyrosinemia type I as opposed to the cellular model that only measures the effects of exogenous FAA.
From the Laboratory of Cell and Developmental Genetics, Department of Medicine, Centre de Recherche sur la Fonction, la Structure, et l'Ingénierie des Protéines, Pavillon Marchand, Université Laval, Ste-Foy, Québec G1K 7P4, Canada
Hereditary tyrosinemia type I (HTI) is the most severe disease of the tyrosine degradation pathway. HTI is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the enzyme responsible for the hydrolysis of fumarylacetoacetate (FAA). As a result, there is an accumulation of metabolites such as maleylacetoacetate, succinylacetone, and FAA. The latter was shown to display mutagenic, cytostatic, and apoptogenic activities and to cause chromosomal instability. Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum (ER) stress signaling. Treatment of V79 Chinese hamster lung cells with an apoptogenic dose of FAA (100 µM) causes an early induction of the ER resident chaperone GRP78/BiP and a simultaneous phosphorylation of the eIF2. FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12. Data obtained from fah–/– mice taken off the therapeutic 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione drug are similar. However, in this mouse model, there is also an increase in proteasome activity indicative of ER-associated degradation. This difference observed between the two models may be due to the fact that the murine model measures the effects of all metabolites accumulating in hereditary tyrosinemia type I as opposed to the cellular model that only measures the effects of exogenous FAA.
What are "Orphan Drugs"?
What are "Orphan Drugs"?
Orphan products are drugs, biologics, or other therapeutics that treat diseases that affect fewer than 200,000 people in the United States.
What is the Orphan Drug Act of 1983?
The U.S. Orphan Drug Act (1983) gives incentives to pharmaceutical companies to develop drugs, biologics, or other therapeutics that will treat diseases that affect fewer than 200,000 people in the United States. The orphan drug law offers tax breaks and a seven-year exclusivity on product sales to induce companies to undertake the development and manufacturing of such product, which otherwise might not be profitable because of the small potential market. (Of the 5,000 diseases covered under the act, 47% affect fewer than 25,000 people.) The law has led to the introduction of over 200 valuable new products for the treatment of rare diseases.
Hereditary Tyrosinemia Type I FAQ's
• What is it? • Hereditary Tyrosinemia Type I
• General Questions • Technical Questions
• Administration & Dosage • Side Effects
What is Hereditary Tyrosinemia Type I?
Hereditary Tyrosinemia Type I is a rare genetic metabolic disorder characterized by lack of a liver enzyme called fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down a nutrient found in everyone's diet, tyrosine, leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with Hereditary Tyrosinemia Type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Hereditary Tyrosinemia Type I may progress to more serious complications such as severe liver disease. Hereditary Tyrosinemia type one is inherited as an autosomal recessive trait. Unless the patient receives a liver transplant or the drug Orfadin TM, the patient could die within the first year of life.
GENERAL (questions 1-10)
1. What is the indication?
Orfadin® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1
2. Contraindications?
None Known
3. Any Drug Interactions?
No drug-drug interaction studies have been conducted with nitisinone
4. What is the chemical designation for Orfadin® (nitisinone)?
2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione
or
C 14 H 10 F 3 NO 5
5. How does Orfadin® work?
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites Succinylacetone and Succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-Aminolevulinate, a neurotoxin responsible for the porphyric crisis characteristic of HT-1.
6. How were the clinical trials done?
An open-label study conducted by 96 investigators at 87 hospitals in 25 countries.
7. How quickly does Orfadin® work?
The median time to normalization was 0.3 months for the excretion of succinylacetone in urine and for porphobilinogen synthase (PBG) activity of erythrocytes. Plasma concentrations of succinylacetone normalized in a median time of 3.9 months
8. How does Orfadin® affect the overall survival of HT-1 patients?
Patients presenting with HT-1 under 2 months of age and treated with dietary restrictions alone had 2 and 4-year survival probabilities of 29% and 29%, respectively; HOWEVER- patients presenting with HT-1 under 2 months of age and treated with dietary restriction and nitisinone had 2 and 4-year survival probabilities of 88% and 88%, respectively in the study patients.
Additionally;
Patients historically presenting with HT-1 under 6 months of age and treated with dietary restriction alone had 2 and 4-year survival probabilities of 74% and 60%, respectively; HOWEVER- patients presenting with HT-1 under 6 months of age and treated with dietary restriction and ORFADIN® had 2 and 4 year survival probabilities of 94% and 94% respectively in the study patients.
9. What are the effects of Orfadin® treatment on the incidence of liver transplantation and death due to liver failure?
The long-term prognosis of patients treated with nitisinone wth regard to hepatic function is not yet known and long term studies are being conducted in Sweden.
The results of this clinical study suggest a market reduction (>75%) in the risk of early onset liver failure that characterizes the natural history of HT-1
10. How should Orfadin® be stored?
Store refrigerated, 2-8°C or 36-46°F
ADMINISTRATION AND DOSAGE (questions 11-18)
11. How is it dosed?
(Treatment should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1) The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1mg/kg/day divided for morning and evening administration.
12. Can it be taken with food?
Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal
13. How can it be given to infants and children too small to swallow a capsule?
For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use
14. What kind of diet should I prescribe for the child?
A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine
15. How and when do you adjust (titrate) the dosage?
Treatment should lead to normalized porphyrin metabolism. Succinylacetone should not be detectable in urine or plasma.
If the biochemical parameters (except plasma succinylacetone) are not normalized within one month… the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of nitisinone treatment.
16. What is the maximum recommended dose for all patients?
2 mg/kg/day
17. Are strict dietary restrictions enough?
Dietary restrictions of tyrosine and phenylalanine may improve liver and kidney function but does not prevent the progression of the disease.
18. Why is there a concern about patient taking Orfadin® needing to follow a strict dietary regimen?
Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone therefore, requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine
HEREDITARY TYROSINEMIA TYPE I (questions 19-23)
19. What are the clinical symptoms of hereditary tyrosinemia type 1?
• Progressive liver failure
• Increased risk of hepatocellular carcinoma
• Coagulopathy
• Painful neurologic crisis
• Renal tubule dysfunction resulting in rickets
20. What are the three types of hereditary tyrosinemia type 1?
Acute, subacute and chronic:
Most patients exhibit symptoms before 6 months of age with the acute form of the disease.
In the subacute form children present with symptoms between 6 and 12 months
Chronic form patients do not exhibit symptoms until after one year of age. These patients have a more gradual progression to liver failure but are at increased risk of developing hepatocellular carcinoma.
21. Who (or which form is) at risk for the painful porphyria-like neurologic crises?
Patients with all forms of the disease are at risk of painful porphyria-like neurologic crises, which occur in 5-20% of patients per year as apart of the natural history of the disorder
22. What is the upside of liver transplantation in HT-1 patient?
Liver transplant can correct most of the metabolic effects of the disorder except for the renal tubular dysfunction, which may be due to local production of toxic metabolites in the kidney
23. What is the downside of liver transplantation in HT-1 patient?
• availability
• cost
• a 5-25% retransplantation rate
• onerous drug regimen
TECHNICAL (questions 24-29)
24. Have pharmacokinetics/ drug metabolism studies been done in children?
No pharmacokinetics studies of nitisinone have been conducted in children or in HT-1 patients.
25. Are there concerns about using nitisinone in special populations?
The effects on the pharmacokinetics of nitisinone have not been studied in the following special populations:
• Geriatric: No studies/ no patients
• Gender: Not studied
• Race: Not studied
• Renal Insufficiency: Not studied
• Hepatic Dysfunction: Not studied
26. What is porphobilinogen synthase (PBG)?-
Porphobilinogen synthase (PBG) is one of the 8 requisite enzymes of heme biosynthesis. Abnormally elevated porphyrin levels and their precursors including PBG results in a group of disorders known as porphyrias. Deficiencies in PBG result in porphyria-like neurologic symptoms.
Porphobilinogen synthase is formed in the heme biosynthesis pathway by the conversion of aminolevulinic acid (ALA) into PBG. Succinylacetoacetone is a potent inhibitor of ALA thus a resulting in a deficiency of PBG.
27. How does Orfadin® affect porphyrin metabolism?
Porphyric crisis was observed in 0.3% cases per year. This compares to the incidence of 5-20% cases per year expected as part of the natural history of the disorder
28. What were the effects of Orfadin® on renal function?
At the one year visit, both urine excretion of amino acids and serum concentration of phosphate were within the reference range in studied patients
29. What is the significance of serum alpha-fetoprotein concentrations?
Increased alpha-fetoprotein may be a sign of inadequate treatment or may be indicative of hepatic malignancy.
SIDE EFFECTS (questions 30-35)
30. Are there Warnings for use of Orfadin®?
High Plasma Tyrosine Levels
Inadequate restriction of tyrosine and phenylalanine intake can result in elevations of plasma tyrosine. Plasma tyrosine levels should be kept below 500 μmol/L in order to avoid toxic effects. Toxic effects of elevate plasma tyrosine include:
Eyes
• corneal ulcers
• corneal opacities
• keratitis
• conjunctivitis
• eye pain
• photophobia
Skin
• painful hyperkeratotic plaques on the soles and palms
Nervous System
• various degrees of mental retardation
• developmental delay
Transient Thrombocytopenia and Leucopenia
3% of patients treated were observed to develop transient thrombocytopenia and leucopenia, while 1.5% developed both. Decreasing the dose, stopping treatment for observation were employed on various patients –all of whom normalized their platelet and white blood counts and continued on Orfadin®.
Platelet and white blood counts should be monitored regularly during treatment with Orfadin®
31. Are there Precautions for use of Orfadin®?
Ophthalmologic Care
• Slit-lamp examination of the eyes should be performed before initiation of nitisinone treatment
• Patients that become symptomatic need re-examination and measurement of plasma tyrosine concentration
• More restricted diet should be implemented if the plasma tyrosine level is above 500 μmol/L
• Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since HT-1 metaoblic defect may result in deterioration of the patient’s clinical condition
Risks of Porphyric Crises, Liver Failure and Hepatic Neoplasms
Patients were observed to suffer these afflictions during a median time of 22 months the clinical study as follows:
• Liver transplantation 13%
• Liver failure 7%
• Malignant hepatic neoplasms 5%
• Benign hepatic neoplasms 3%
• Porphyria 0.5%
Regular liver monitoring by imaging and laboratory tests including serum alpha-fetoprotein concentration is recommended
32. What about overdosage?
Accidental ingestion will result in elevated tyrosine levels, however, there is no information available on a specific treatment. Patients should be monitored for adverse events.
33. Are there any Drug/ Laboratory Test Interactions?
None Known
34. How about Carcinogenesis?
According to the Package Insert:
“Studies in animals have not been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not mutagenic in the Ames test. In a single dose-group study in rats given 100 mg/kg/day (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.”
35. What were the adverse reactions observed during the study?
1% or Greater:
Liver and Biliary System-hepatic neoplasm 8%, liver failure 7%
Visual System- conjunctivitis 2%, corneal opacity 2%, keratitis 2%, photophobia 2%, blephraritis 1%, eye pain 1% and cataracts 1%
Hemic and Lymphatic- thrombocytopenia 3%, leucopenia 3%, porphyria 1%, epistaxis 1%
Skin and Appendages-pruritis 1%, exfoliative dermatitis 1%, dry skin 1%, maculopapular rash 1%, alopecia 1%
Less than 1%:
Death
Nervous System- seizures, brain tumor, encephalopathy, headache, hyperkinesia
Cardiovascular-cyanosis
Digestive System- abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration
Liver and Biliary System-elevated hepatic enzymes, hepatic function disorder, liver enlargement
Metabolic and Nutritional-dehydration, hypoglycemia, thirst
Resistance Mechanism Disorders- Infection, septicemia, otitis
Respiratory-bronchitis, respiratory insufficiency
Musculoskeletal-pathologic fracture
Female Reproductive- amenorrhea
Psychiatric- nervousness, somnolence
Orphan products are drugs, biologics, or other therapeutics that treat diseases that affect fewer than 200,000 people in the United States.
What is the Orphan Drug Act of 1983?
The U.S. Orphan Drug Act (1983) gives incentives to pharmaceutical companies to develop drugs, biologics, or other therapeutics that will treat diseases that affect fewer than 200,000 people in the United States. The orphan drug law offers tax breaks and a seven-year exclusivity on product sales to induce companies to undertake the development and manufacturing of such product, which otherwise might not be profitable because of the small potential market. (Of the 5,000 diseases covered under the act, 47% affect fewer than 25,000 people.) The law has led to the introduction of over 200 valuable new products for the treatment of rare diseases.
Hereditary Tyrosinemia Type I FAQ's
• What is it? • Hereditary Tyrosinemia Type I
• General Questions • Technical Questions
• Administration & Dosage • Side Effects
What is Hereditary Tyrosinemia Type I?
Hereditary Tyrosinemia Type I is a rare genetic metabolic disorder characterized by lack of a liver enzyme called fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down a nutrient found in everyone's diet, tyrosine, leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with Hereditary Tyrosinemia Type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Hereditary Tyrosinemia Type I may progress to more serious complications such as severe liver disease. Hereditary Tyrosinemia type one is inherited as an autosomal recessive trait. Unless the patient receives a liver transplant or the drug Orfadin TM, the patient could die within the first year of life.
GENERAL (questions 1-10)
1. What is the indication?
Orfadin® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1
2. Contraindications?
None Known
3. Any Drug Interactions?
No drug-drug interaction studies have been conducted with nitisinone
4. What is the chemical designation for Orfadin® (nitisinone)?
2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione
or
C 14 H 10 F 3 NO 5
5. How does Orfadin® work?
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites Succinylacetone and Succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-Aminolevulinate, a neurotoxin responsible for the porphyric crisis characteristic of HT-1.
6. How were the clinical trials done?
An open-label study conducted by 96 investigators at 87 hospitals in 25 countries.
7. How quickly does Orfadin® work?
The median time to normalization was 0.3 months for the excretion of succinylacetone in urine and for porphobilinogen synthase (PBG) activity of erythrocytes. Plasma concentrations of succinylacetone normalized in a median time of 3.9 months
8. How does Orfadin® affect the overall survival of HT-1 patients?
Patients presenting with HT-1 under 2 months of age and treated with dietary restrictions alone had 2 and 4-year survival probabilities of 29% and 29%, respectively; HOWEVER- patients presenting with HT-1 under 2 months of age and treated with dietary restriction and nitisinone had 2 and 4-year survival probabilities of 88% and 88%, respectively in the study patients.
Additionally;
Patients historically presenting with HT-1 under 6 months of age and treated with dietary restriction alone had 2 and 4-year survival probabilities of 74% and 60%, respectively; HOWEVER- patients presenting with HT-1 under 6 months of age and treated with dietary restriction and ORFADIN® had 2 and 4 year survival probabilities of 94% and 94% respectively in the study patients.
9. What are the effects of Orfadin® treatment on the incidence of liver transplantation and death due to liver failure?
The long-term prognosis of patients treated with nitisinone wth regard to hepatic function is not yet known and long term studies are being conducted in Sweden.
The results of this clinical study suggest a market reduction (>75%) in the risk of early onset liver failure that characterizes the natural history of HT-1
10. How should Orfadin® be stored?
Store refrigerated, 2-8°C or 36-46°F
ADMINISTRATION AND DOSAGE (questions 11-18)
11. How is it dosed?
(Treatment should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1) The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1mg/kg/day divided for morning and evening administration.
12. Can it be taken with food?
Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal
13. How can it be given to infants and children too small to swallow a capsule?
For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use
14. What kind of diet should I prescribe for the child?
A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine
15. How and when do you adjust (titrate) the dosage?
Treatment should lead to normalized porphyrin metabolism. Succinylacetone should not be detectable in urine or plasma.
If the biochemical parameters (except plasma succinylacetone) are not normalized within one month… the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of nitisinone treatment.
16. What is the maximum recommended dose for all patients?
2 mg/kg/day
17. Are strict dietary restrictions enough?
Dietary restrictions of tyrosine and phenylalanine may improve liver and kidney function but does not prevent the progression of the disease.
18. Why is there a concern about patient taking Orfadin® needing to follow a strict dietary regimen?
Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone therefore, requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine
HEREDITARY TYROSINEMIA TYPE I (questions 19-23)
19. What are the clinical symptoms of hereditary tyrosinemia type 1?
• Progressive liver failure
• Increased risk of hepatocellular carcinoma
• Coagulopathy
• Painful neurologic crisis
• Renal tubule dysfunction resulting in rickets
20. What are the three types of hereditary tyrosinemia type 1?
Acute, subacute and chronic:
Most patients exhibit symptoms before 6 months of age with the acute form of the disease.
In the subacute form children present with symptoms between 6 and 12 months
Chronic form patients do not exhibit symptoms until after one year of age. These patients have a more gradual progression to liver failure but are at increased risk of developing hepatocellular carcinoma.
21. Who (or which form is) at risk for the painful porphyria-like neurologic crises?
Patients with all forms of the disease are at risk of painful porphyria-like neurologic crises, which occur in 5-20% of patients per year as apart of the natural history of the disorder
22. What is the upside of liver transplantation in HT-1 patient?
Liver transplant can correct most of the metabolic effects of the disorder except for the renal tubular dysfunction, which may be due to local production of toxic metabolites in the kidney
23. What is the downside of liver transplantation in HT-1 patient?
• availability
• cost
• a 5-25% retransplantation rate
• onerous drug regimen
TECHNICAL (questions 24-29)
24. Have pharmacokinetics/ drug metabolism studies been done in children?
No pharmacokinetics studies of nitisinone have been conducted in children or in HT-1 patients.
25. Are there concerns about using nitisinone in special populations?
The effects on the pharmacokinetics of nitisinone have not been studied in the following special populations:
• Geriatric: No studies/ no patients
• Gender: Not studied
• Race: Not studied
• Renal Insufficiency: Not studied
• Hepatic Dysfunction: Not studied
26. What is porphobilinogen synthase (PBG)?-
Porphobilinogen synthase (PBG) is one of the 8 requisite enzymes of heme biosynthesis. Abnormally elevated porphyrin levels and their precursors including PBG results in a group of disorders known as porphyrias. Deficiencies in PBG result in porphyria-like neurologic symptoms.
Porphobilinogen synthase is formed in the heme biosynthesis pathway by the conversion of aminolevulinic acid (ALA) into PBG. Succinylacetoacetone is a potent inhibitor of ALA thus a resulting in a deficiency of PBG.
27. How does Orfadin® affect porphyrin metabolism?
Porphyric crisis was observed in 0.3% cases per year. This compares to the incidence of 5-20% cases per year expected as part of the natural history of the disorder
28. What were the effects of Orfadin® on renal function?
At the one year visit, both urine excretion of amino acids and serum concentration of phosphate were within the reference range in studied patients
29. What is the significance of serum alpha-fetoprotein concentrations?
Increased alpha-fetoprotein may be a sign of inadequate treatment or may be indicative of hepatic malignancy.
SIDE EFFECTS (questions 30-35)
30. Are there Warnings for use of Orfadin®?
High Plasma Tyrosine Levels
Inadequate restriction of tyrosine and phenylalanine intake can result in elevations of plasma tyrosine. Plasma tyrosine levels should be kept below 500 μmol/L in order to avoid toxic effects. Toxic effects of elevate plasma tyrosine include:
Eyes
• corneal ulcers
• corneal opacities
• keratitis
• conjunctivitis
• eye pain
• photophobia
Skin
• painful hyperkeratotic plaques on the soles and palms
Nervous System
• various degrees of mental retardation
• developmental delay
Transient Thrombocytopenia and Leucopenia
3% of patients treated were observed to develop transient thrombocytopenia and leucopenia, while 1.5% developed both. Decreasing the dose, stopping treatment for observation were employed on various patients –all of whom normalized their platelet and white blood counts and continued on Orfadin®.
Platelet and white blood counts should be monitored regularly during treatment with Orfadin®
31. Are there Precautions for use of Orfadin®?
Ophthalmologic Care
• Slit-lamp examination of the eyes should be performed before initiation of nitisinone treatment
• Patients that become symptomatic need re-examination and measurement of plasma tyrosine concentration
• More restricted diet should be implemented if the plasma tyrosine level is above 500 μmol/L
• Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since HT-1 metaoblic defect may result in deterioration of the patient’s clinical condition
Risks of Porphyric Crises, Liver Failure and Hepatic Neoplasms
Patients were observed to suffer these afflictions during a median time of 22 months the clinical study as follows:
• Liver transplantation 13%
• Liver failure 7%
• Malignant hepatic neoplasms 5%
• Benign hepatic neoplasms 3%
• Porphyria 0.5%
Regular liver monitoring by imaging and laboratory tests including serum alpha-fetoprotein concentration is recommended
32. What about overdosage?
Accidental ingestion will result in elevated tyrosine levels, however, there is no information available on a specific treatment. Patients should be monitored for adverse events.
33. Are there any Drug/ Laboratory Test Interactions?
None Known
34. How about Carcinogenesis?
According to the Package Insert:
“Studies in animals have not been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not mutagenic in the Ames test. In a single dose-group study in rats given 100 mg/kg/day (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.”
35. What were the adverse reactions observed during the study?
1% or Greater:
Liver and Biliary System-hepatic neoplasm 8%, liver failure 7%
Visual System- conjunctivitis 2%, corneal opacity 2%, keratitis 2%, photophobia 2%, blephraritis 1%, eye pain 1% and cataracts 1%
Hemic and Lymphatic- thrombocytopenia 3%, leucopenia 3%, porphyria 1%, epistaxis 1%
Skin and Appendages-pruritis 1%, exfoliative dermatitis 1%, dry skin 1%, maculopapular rash 1%, alopecia 1%
Less than 1%:
Death
Nervous System- seizures, brain tumor, encephalopathy, headache, hyperkinesia
Cardiovascular-cyanosis
Digestive System- abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration
Liver and Biliary System-elevated hepatic enzymes, hepatic function disorder, liver enlargement
Metabolic and Nutritional-dehydration, hypoglycemia, thirst
Resistance Mechanism Disorders- Infection, septicemia, otitis
Respiratory-bronchitis, respiratory insufficiency
Musculoskeletal-pathologic fracture
Female Reproductive- amenorrhea
Psychiatric- nervousness, somnolence
Tyrosinemia, Hereditary
Important
It is possible that the main title of the report Tyrosinemia, Hereditary is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
Synonyms
Hepatorenal tyrosinemia
Hereditary tyrosinemia type 1
Fumarylacetoacetase deficiency
Congenital tyrosinosis
Disorder Subdivisions
Tyrosinemia type 1, acute form
Tyrosinemia type 1, chronic form
General Discussion
Tyrosinemia type I is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with tyrosinemia type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease. Tyrosinemia type one is inherited as an autosomal recessive trait.
It is possible that the main title of the report Tyrosinemia, Hereditary is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
Synonyms
Hepatorenal tyrosinemia
Hereditary tyrosinemia type 1
Fumarylacetoacetase deficiency
Congenital tyrosinosis
Disorder Subdivisions
Tyrosinemia type 1, acute form
Tyrosinemia type 1, chronic form
General Discussion
Tyrosinemia type I is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with tyrosinemia type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease. Tyrosinemia type one is inherited as an autosomal recessive trait.
Tyrosinemia
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
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
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.
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
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.
Hereditary Tyrosinemia Type I；HT-1
Preface:
Tyrosine is a non-essential amino acids the human body, the main sources include dietary intake and phenylalanine (phenylalanine) generated by metabolic intermediate product. When elevated plasma tyrosine may be referred to as high Tyrosinemia (hypertyrosinaemia; tyrosinaemia), its causes are likely to originate in the primary metabolic error, or by other causes of liver disease caused by cause. However because of high Tyrosinemia cause liver damage, but also much of the liver caused by continued high hair Tyrosinemia, the distinction between the two is not easy.
The basis of past studies indicate that high Tyrosinemia-related enzymes have at least three ways: tyrosine amino transferase (tyrosine aminotrasferase; TAT), ρ-hydroxy - phenyl - Coke grape acid oxidase (ρ - hydroxyphenylpyruvate dioxygenase; 4HPPD) and yanhusuo acetoacetic acid amide hydrolase (fumarylacetoacetate hydrolase; FAH), which, TAT will be the lack of eyes and skin caused by high Tyrosinemia, called Tyrosinemia type II ( Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of the soles of his feet to the palm of your hand horny albino disease (palmoplantar keratosis). 4HPPD will have much of a lack of abnormal metabolic products, including ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate coke, which is also known as the tyrosine hypercalciuria. The lack of FAH can cause liver and kidney lesions, called Tyrosinemia type I (Tyrosinaemia type I), also known as tyrosine disease (tyrosinosis), can be divided into two types of acute and chronic, is the the focus of articles.
Premature babies are often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), occasionally longer in full-term newborns can also be seen. This is probably the outstanding 4HPPD neonatal or temporary lack of sophisticated, high volume of phenylalanine and tyrosine intake, or caused by a lack of vitamin C. Such defects as babies grow, 4HPPD increasingly sophisticated and improved, taking vitamin C can also be passed and quickly corrected.
Etiology:
Hereditary Tyrosinemia type I is mainly due to caused by the lack of FAH. Tyrosine metabolism in the whole into fumarate (fumarate) and acetoacetic acid (acetoacetate) a total of five by the enzyme-catalyzed reaction steps:
A. formed by transglutaminase ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate).
B. three carbon containing branched-chain oxidation and simultaneously transfer and decarboxylation and the formation of uric acid (homogentisate).
C. will be oxidized into uric acid and maleic acid amide alone acetoacetic acid (maleylacetoacetate).
D. will be maleic acid acetoacetic acid amide single line into the role of heterogeneous yanhusuo acetoacetic acid amide (fumarylacetoacetate).
E. will yanhusuo acetoacetic acid amide hydrolase into yanhusuo acid and acetoacetic acid.
FAH participated in the fifth reaction. When the lack of FAH, the entire tyrosine metabolism will be hindered, making yanhusuo acetoacetic acid amide will be substantial accumulation of single-amide maleic acid acetoacetic acid may also be affected by the cumulative in the body, resulting in liver and kidney damage. These metabolites will be to restore (reduce) and go carboxylation (decarboxylate) into amber acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the examination of patients in vivo SA concentration, the diagnosis can be used as high an important basis for Tyrosinemia. In addition, because of metabolism of the suspension may also be caused by ρ-hydroxyphenyl pyruvic acid and its derivatives accumulated in the body.
Genetic model:
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH.
Classification (type):
1. Acute high Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Attack is usually at 1-6 months old when the sick are often loss of appetite, vomiting, diarrhea, abdominal distension and symptoms of low blood sugar, etc., and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction). Happen because of liver disease, the sick began to emerge rickets (rickets), symptoms such as hepatosplenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent porphyria pyrrole alveolar (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
2. Chronic Tyrosinemia:
The majority of chronic high Tyrosinemia in One of the children after the age of only developed symptoms. Growth retardation, gastrointestinal symptoms, sexual cirrhosis, multiple renal defects and rickets are clinical performance. Early in the disease may only be elevated tyrosine, while the later will show methionine (methionine) increased. Usually before the age of 10 at death, autopsies often visible liver tumor.
Diagnosis:
1. Antenatal check-up:
(1) such as the parents are known to cause high Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations.
(2) can also detect the concentration of SA in amniotic fluid to see if too high.
(3) pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
2. Blood tests:
Tyrosinemia is currently the most high credibility test are quantitative blood and urine of SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, the patient's liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
In addition to the concentration of SA can be used as high Tyrosinemia diagnostic tools, some biochemical aspects of detection may also apply to patients in general. For example: the concentration of serum tyrosine will increase, but the concentration of methionine was not significantly improved. Urine ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate concentration of coke will improve. When renal tubular damage, the Labor Department will show Fanconi Syndrome (Fanconi syndrome), which means in the urine has high levels of amino acids, glucose and phosphate. When the liver cell damage, and affect the generation of protein will also be some variety of chemical and biological performance, can be used as a basis for diagnosis. For example: vitamin K-dependent coagulation factors in acute illness is very high concentrations, while the chronic patients the concentration of the body is not normal. Vis-à-vis other liver enzyme activity, the patients in vivo γ-Glutamyltransferase activity will improve. α-fetoprotein concentrations in vivo in acute patients has increased significantly, but in chronic patients showed normal concentrations.
Treatment:
1.NTBC treatment (NTBC treament):
NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) are good 4HPPD inhibitor, can block ρ-hydroxyphenyl pyruvic acid into uric acid and reduce the emergence of SA , is the latest for the treatment of high Tyrosinemia method. According to the report show: sick every day at oral 0.6 mg / kg NTBC, apart from a ρ-hydroxyphenyl pyruvic acid and tyrosine concentrations will increase, other biochemical abnormalities will become normal, and clinical symptoms will be dramatically improved. NTBC can also be used for treatment of this and similar neurological pyrrole rhodopsin alveolar symptoms. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
2. Liver transplant (Liver Transplantation):
Handling stolen goods in liver transplant to treat the first type of high Tyrosinemia about 10 years of development time, because this type of patients will have severe liver damage, so when the recipient can have the provider of the liver the normal performance of the enzyme missing the phenomenon of patients will be improved, blood and urine in abnormal metabolites will disappear. Access to liver transplant patients can be normal after the diet, does not require special control of tyrosine and phenylalanine intake. In spite of this, the patient urine concentrations of SA and there will still be increased, presumably because of the problem caused by the kidneys. Liver transplant kidneys after long-term prognosis remains unclear.
3. Diet (Dietary treament):
Diet control are the first for the treatment of high Tyrosinemia method, the concept is to limit the tyrosine and phenylalanine intake so low that only the body can grow normally required. This food must come from a special formula, mainly the use of protein hydrolysates or without tyrosine and phenylalanine of the amino acid mixture, then add very small amounts of natural protein to supplement the appropriate tyrosine and phenylalanine. When a patient separately on tyrosine and phenylalanine intake daily to maintain at 15-20 mg / kg, the in vivo concentration of SA would be difficult to be detected. With diet control, due to renal tubular dysfunction resulting symptoms almost completely revert back to normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver tumor severely damaged or elections, such as needed by other methods such as the liver transplant to improve conditions.
4. Supportive treatment (Supportive treament):
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Tyrosine is a non-essential amino acids the human body, the main sources include dietary intake and phenylalanine (phenylalanine) generated by metabolic intermediate product. When elevated plasma tyrosine may be referred to as high Tyrosinemia (hypertyrosinaemia; tyrosinaemia), its causes are likely to originate in the primary metabolic error, or by other causes of liver disease caused by cause. However because of high Tyrosinemia cause liver damage, but also much of the liver caused by continued high hair Tyrosinemia, the distinction between the two is not easy.
The basis of past studies indicate that high Tyrosinemia-related enzymes have at least three ways: tyrosine amino transferase (tyrosine aminotrasferase; TAT), ρ-hydroxy - phenyl - Coke grape acid oxidase (ρ - hydroxyphenylpyruvate dioxygenase; 4HPPD) and yanhusuo acetoacetic acid amide hydrolase (fumarylacetoacetate hydrolase; FAH), which, TAT will be the lack of eyes and skin caused by high Tyrosinemia, called Tyrosinemia type II ( Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of the soles of his feet to the palm of your hand horny albino disease (palmoplantar keratosis). 4HPPD will have much of a lack of abnormal metabolic products, including ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate coke, which is also known as the tyrosine hypercalciuria. The lack of FAH can cause liver and kidney lesions, called Tyrosinemia type I (Tyrosinaemia type I), also known as tyrosine disease (tyrosinosis), can be divided into two types of acute and chronic, is the the focus of articles.
Premature babies are often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), occasionally longer in full-term newborns can also be seen. This is probably the outstanding 4HPPD neonatal or temporary lack of sophisticated, high volume of phenylalanine and tyrosine intake, or caused by a lack of vitamin C. Such defects as babies grow, 4HPPD increasingly sophisticated and improved, taking vitamin C can also be passed and quickly corrected.
Etiology:
Hereditary Tyrosinemia type I is mainly due to caused by the lack of FAH. Tyrosine metabolism in the whole into fumarate (fumarate) and acetoacetic acid (acetoacetate) a total of five by the enzyme-catalyzed reaction steps:
A. formed by transglutaminase ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate).
B. three carbon containing branched-chain oxidation and simultaneously transfer and decarboxylation and the formation of uric acid (homogentisate).
C. will be oxidized into uric acid and maleic acid amide alone acetoacetic acid (maleylacetoacetate).
D. will be maleic acid acetoacetic acid amide single line into the role of heterogeneous yanhusuo acetoacetic acid amide (fumarylacetoacetate).
E. will yanhusuo acetoacetic acid amide hydrolase into yanhusuo acid and acetoacetic acid.
FAH participated in the fifth reaction. When the lack of FAH, the entire tyrosine metabolism will be hindered, making yanhusuo acetoacetic acid amide will be substantial accumulation of single-amide maleic acid acetoacetic acid may also be affected by the cumulative in the body, resulting in liver and kidney damage. These metabolites will be to restore (reduce) and go carboxylation (decarboxylate) into amber acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the examination of patients in vivo SA concentration, the diagnosis can be used as high an important basis for Tyrosinemia. In addition, because of metabolism of the suspension may also be caused by ρ-hydroxyphenyl pyruvic acid and its derivatives accumulated in the body.
Genetic model:
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH.
Classification (type):
1. Acute high Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Attack is usually at 1-6 months old when the sick are often loss of appetite, vomiting, diarrhea, abdominal distension and symptoms of low blood sugar, etc., and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction). Happen because of liver disease, the sick began to emerge rickets (rickets), symptoms such as hepatosplenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent porphyria pyrrole alveolar (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
2. Chronic Tyrosinemia:
The majority of chronic high Tyrosinemia in One of the children after the age of only developed symptoms. Growth retardation, gastrointestinal symptoms, sexual cirrhosis, multiple renal defects and rickets are clinical performance. Early in the disease may only be elevated tyrosine, while the later will show methionine (methionine) increased. Usually before the age of 10 at death, autopsies often visible liver tumor.
Diagnosis:
1. Antenatal check-up:
(1) such as the parents are known to cause high Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations.
(2) can also detect the concentration of SA in amniotic fluid to see if too high.
(3) pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
2. Blood tests:
Tyrosinemia is currently the most high credibility test are quantitative blood and urine of SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, the patient's liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
In addition to the concentration of SA can be used as high Tyrosinemia diagnostic tools, some biochemical aspects of detection may also apply to patients in general. For example: the concentration of serum tyrosine will increase, but the concentration of methionine was not significantly improved. Urine ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate concentration of coke will improve. When renal tubular damage, the Labor Department will show Fanconi Syndrome (Fanconi syndrome), which means in the urine has high levels of amino acids, glucose and phosphate. When the liver cell damage, and affect the generation of protein will also be some variety of chemical and biological performance, can be used as a basis for diagnosis. For example: vitamin K-dependent coagulation factors in acute illness is very high concentrations, while the chronic patients the concentration of the body is not normal. Vis-à-vis other liver enzyme activity, the patients in vivo γ-Glutamyltransferase activity will improve. α-fetoprotein concentrations in vivo in acute patients has increased significantly, but in chronic patients showed normal concentrations.
Treatment:
1.NTBC treatment (NTBC treament):
NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) are good 4HPPD inhibitor, can block ρ-hydroxyphenyl pyruvic acid into uric acid and reduce the emergence of SA , is the latest for the treatment of high Tyrosinemia method. According to the report show: sick every day at oral 0.6 mg / kg NTBC, apart from a ρ-hydroxyphenyl pyruvic acid and tyrosine concentrations will increase, other biochemical abnormalities will become normal, and clinical symptoms will be dramatically improved. NTBC can also be used for treatment of this and similar neurological pyrrole rhodopsin alveolar symptoms. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
2. Liver transplant (Liver Transplantation):
Handling stolen goods in liver transplant to treat the first type of high Tyrosinemia about 10 years of development time, because this type of patients will have severe liver damage, so when the recipient can have the provider of the liver the normal performance of the enzyme missing the phenomenon of patients will be improved, blood and urine in abnormal metabolites will disappear. Access to liver transplant patients can be normal after the diet, does not require special control of tyrosine and phenylalanine intake. In spite of this, the patient urine concentrations of SA and there will still be increased, presumably because of the problem caused by the kidneys. Liver transplant kidneys after long-term prognosis remains unclear.
3. Diet (Dietary treament):
Diet control are the first for the treatment of high Tyrosinemia method, the concept is to limit the tyrosine and phenylalanine intake so low that only the body can grow normally required. This food must come from a special formula, mainly the use of protein hydrolysates or without tyrosine and phenylalanine of the amino acid mixture, then add very small amounts of natural protein to supplement the appropriate tyrosine and phenylalanine. When a patient separately on tyrosine and phenylalanine intake daily to maintain at 15-20 mg / kg, the in vivo concentration of SA would be difficult to be detected. With diet control, due to renal tubular dysfunction resulting symptoms almost completely revert back to normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver tumor severely damaged or elections, such as needed by other methods such as the liver transplant to improve conditions.
4. Supportive treatment (Supportive treament):
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Hereditary tyrosinemia
Tyrosine (Tyrosine) are a non-essential amino acids the human body, mainly from the dietary intake and phenylalanine (phenylalanine) metabolism. Caused by elevated plasma tyrosine may come from a number of diseases, including: the transient neonatal Tyrosinemia (Transient tyrosinemia of the newborn, TTN), hereditary Tyrosinemia Type I ( Hereditary tyrosinemia I), Tyrosinemia type II (tyrosinemia II; also known as Richner-Hanhart syndrome), Tyrosinemia type III (tyrosinemia III). Neonatal Tyrosinemia is temporary because of tyrosine metabolism caused by the enzyme is not yet mature enough, most of them occurred in premature infants, who will be with sophisticated enzymes has been improved, there will be no sequels. Tyrosinemia Type I and II clinical completely different type of patients have liver and kidney area of the main lesion; of patients with type II have toes, palms, soles of the feet over horny situation, will there is intellectual problem.
Tyrosinemia type I is mainly due to yanhusuo acetoacetic acid amide hydrolase enzymes (fumarylacetoacetate hydrolyase, FAH) caused by the lack of. FAH makes the lack of tyrosine metabolism have been hampered, leading to acetoacetic acid amide fumarate (fumarylacetoacetate) accumulation, can not be converted into fumarate (fumarate) and acetoacetic acid (acetoacetate). Substantial accumulation of acetoacetic acid amide fumarate into succinate acyl acetone (succinylacetone; SA), exist in the patient's plasma and urine. SA caused by the accumulation of liver injury; will inhibit omega-aminolevulinic acid (omega-ALA) hydrolase role, with the sort of acute porphyria (acute intermittent porphyria) of neurological symptoms.
Genetic model
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH. Tyrosinemia in the Americas and Europe to the incidence rate of one hundred thousandth 1/120000. Quebec, Canada and Norway, Finland, the incidence of higher, Quebec, the highest incidence of 1/1846, Norway and Finland for 1/60000.
Symptoms
Acute Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Usually a few weeks after birth to 6 months time attack, patients often have poor appetite, vomiting, diarrhea, abdominal distension and low blood sugar symptoms such as jaundice and ascites, who have a similar taste of cabbage; and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction), secondary rickets (rickets), liver symptoms such as splenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent? Pyronaridine alveolar rhodopsin (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
Chronic Tyrosinemia:
Tyrosinemia with acute symptoms, similar symptoms and incidence of late, the majority of patients after one year of age at onset. Rickets, liver and kidney barrier, high blood pressure, nervous system barriers to clinical symptoms, usually around the age of 10 may be found in the liver.
Diagnosis
Prenatal care:
Such as known prior to the one-child or both parents Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations. SA can also be detected in amniotic fluid concentrations are too high look.
Pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
Blood tests:
At present the most credible test Tyrosinemia quantitative blood and urine are in SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, patients with liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
Treatment
Food Control:
The use of low-protein diet and with no phenylalanine and tyrosine special formula to restrict these two amino acid intake to provide enough physical capacity required for normal growth. With diet control, due to renal tubular dysfunction resulting symptoms can be fully answered almost normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver severely damaged or have a tumor, the need to rely on other methods such as liver transplant, such as to improve the condition.
Liver transplant:
When the transplanted liver function, the patient's enzyme deficiency phenomenon would be improved, long-term effects than simply to better diet control. After liver transplantation can be a normal diet, no need for special restrictions. However, patients with urine testing is still out of SA, think are caused by the kidneys. After liver transplantation for renal prognosis of the long period of time remains unclear.
NTBC treatment:
2 - (2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione (NTBC) can block ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate) and transformed into uric acid (homogentisate), to reduce the emergence of SA. Studies have shown NTBC can improve on clinical symptoms and biochemical abnormalities. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
Supportive treatment:
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Tyrosinemia type I is mainly due to yanhusuo acetoacetic acid amide hydrolase enzymes (fumarylacetoacetate hydrolyase, FAH) caused by the lack of. FAH makes the lack of tyrosine metabolism have been hampered, leading to acetoacetic acid amide fumarate (fumarylacetoacetate) accumulation, can not be converted into fumarate (fumarate) and acetoacetic acid (acetoacetate). Substantial accumulation of acetoacetic acid amide fumarate into succinate acyl acetone (succinylacetone; SA), exist in the patient's plasma and urine. SA caused by the accumulation of liver injury; will inhibit omega-aminolevulinic acid (omega-ALA) hydrolase role, with the sort of acute porphyria (acute intermittent porphyria) of neurological symptoms.
Genetic model
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH. Tyrosinemia in the Americas and Europe to the incidence rate of one hundred thousandth 1/120000. Quebec, Canada and Norway, Finland, the incidence of higher, Quebec, the highest incidence of 1/1846, Norway and Finland for 1/60000.
Symptoms
Acute Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Usually a few weeks after birth to 6 months time attack, patients often have poor appetite, vomiting, diarrhea, abdominal distension and low blood sugar symptoms such as jaundice and ascites, who have a similar taste of cabbage; and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction), secondary rickets (rickets), liver symptoms such as splenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent? Pyronaridine alveolar rhodopsin (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
Chronic Tyrosinemia:
Tyrosinemia with acute symptoms, similar symptoms and incidence of late, the majority of patients after one year of age at onset. Rickets, liver and kidney barrier, high blood pressure, nervous system barriers to clinical symptoms, usually around the age of 10 may be found in the liver.
Diagnosis
Prenatal care:
Such as known prior to the one-child or both parents Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations. SA can also be detected in amniotic fluid concentrations are too high look.
Pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
Blood tests:
At present the most credible test Tyrosinemia quantitative blood and urine are in SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, patients with liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
Treatment
Food Control:
The use of low-protein diet and with no phenylalanine and tyrosine special formula to restrict these two amino acid intake to provide enough physical capacity required for normal growth. With diet control, due to renal tubular dysfunction resulting symptoms can be fully answered almost normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver severely damaged or have a tumor, the need to rely on other methods such as liver transplant, such as to improve the condition.
Liver transplant:
When the transplanted liver function, the patient's enzyme deficiency phenomenon would be improved, long-term effects than simply to better diet control. After liver transplantation can be a normal diet, no need for special restrictions. However, patients with urine testing is still out of SA, think are caused by the kidneys. After liver transplantation for renal prognosis of the long period of time remains unclear.
NTBC treatment:
2 - (2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione (NTBC) can block ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate) and transformed into uric acid (homogentisate), to reduce the emergence of SA. Studies have shown NTBC can improve on clinical symptoms and biochemical abnormalities. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
Supportive treatment:
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Subscribe to:
Posts (Atom)