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Disorder of tyrosine metabolism
- 1. Disorder of tyrosine Metabolism Intern : 甄祉婷 Supervisor :Chief Dr 劉君恕 , Dr蔡昕霖 Resident : Dr.葉奕庭, Dr楊逸文
- 2. Introduction • Tyrosine : An aromatic amino acid Important in the synthesis of thyroid hormones , catecholamine & melanin • Several acquired and genetic disorders , Impaired catabolism of tyrosine Elevated plasma tyrosine concentrations
- 3. Tyrosine metabolism • Sites : Hepatocyte and renal proximal tubules • Catalyzed by 5 enzymatic reactions which yields -Acetoacetate (ketogenic) -Fumarate (glucogenic)
- 4. Autosomal recessive disorders • Deficiencies in specific enzymes in tyrosine catabolic pathway 1. Hereditary tyrosinemia (HT) Type 1 * 2. HT Type 2* 3. HT Type 3* 4. Alkaptonuria (AKU) * Results in elevated blood tyrosine levels
- 5. Hypertyrosinemia • Normal [Tyrosine] : 30-120 mm/L • Considered as elevated : > 200mm/L • Clinical manifestations typically do not become apparent until >500mm/L • To evaluate unexplained liver disease or neurologic abnormalities, such as seizures or developmental delay
- 6. Detection of hypertyrosinemia • Detected by quantitative measurement of plasma amino acids • Elevated urinary tyrosine in Renal Fanconi syndrome patients • HT types 1, 2, and 3 may be detected by expanded newborn metabolic screening
- 7. Genetic and acquired disorder Contributed to hypertyrosinemia • Inherited deficiencies of enzymes in the degradation pathway • Transient tyrosinemia of the newborn • Liver disease • Miscellaneous disorders including scurvy and hyperthyroidism
- 8. Evaluation of hypertyrosinemia • The most important diagnostic consideration : The presence or absence of liver disease ? • If liver disease is present, additional tests must be performed urgently to detect HT type 1 (a potentially lethal disorder that requires immediate treatment)
- 9. Hereditary tyrosinemia type 1 • a.k.a hepatorenal tyrosinemia, is the most severe disorder of tyrosine metabolism • 1 in 12,000
- 10. HT1 pathophysiology • HT1 is caused by deficiency of the last enzyme in the pathway of tyrosine catabolism FAH, Fumarylacetoacetate hydrolase • Fumarylacetoacetate (FAA), the substrate for FAH in the tyrosine pathway, accumulates in FAH-deficient hepatocytes and proximal renal tubular cells, resulting in liver and kidney damage
- 11. Fumarylacetoacetate (FAA) • Reacts with glutathione and sulfhydryl groups of proteins oxidative damage to cells -cell death -a profound perturbation of gene expression, especially in the liver Metabolic processes are impaired including gluconeogenesis, detoxification of ammonia synthesis of secreted proteins
- 12. Impaired protein synthesis • Impaired protein synthesis in FAH-deficient hepatocytes a marked reduction in TAT, tyrosine aminotransferase the first enzyme in tyrosine degradation, resulting in the elevated plasma tyrosine levels typical of the disorder
- 13. Tyrosine • itself is not toxic to the liver or kidney • Skin, eyes and brain : Dermatologic Ophthalmologic Possibly neurodevelopmental problems
- 14. • Why not we detect the amount of FAA in body fluids of HT1 patients ? Tentative Deduction : FAA has a short intracellular half life For diagnosis , we measured the principal metabolites of FAA -succinylacetoacetate (SAA) -succinylacetone (SA)
- 15. • Increased levels of these metabolites secondary biochemical alterations in HT1 Eg .1. SA is a potent inhibitor of the first step of heme biosynthesis SA inhibits aminolevulinate (ALA) dehydratase (porphobilinogen synthase) • result in neurologic symptoms of ALA dehydratase porphyria 2.Circulating SA may impair proximal ALA reabsorption in ALA excretion
- 17. HT1 genetics • autosomal recessive • human chromosome 15q23-q25, cloned, and sequenced -> FAH (fumarylacetoacetate hydrolase) • Saguenay-Lac-Saint-Jean region of Quebec – carrier rate : 1 in 20 to 25 – prevalence at birth : 1 in 1846
- 19. HT1 clinical features • severe progressive liver disease • renal tubular dysfunction – Fanconi syndrome with renal tubular acidosis, aminoaciduria, and hypophosphatemia (due to phosphate wasting) – rickets
- 20. HT1 clinical features- Liver • failure to thrive • Hepatomegaly • conjugated hyperbilirubinemia • AFP ↑ (cord blood) • Cirrhosis • Acute: Liver dysfunction commonly results in hypoglycemia and coagulation abnormalities • Chronic: mixed micronodular and macronodular cirrhosis. HCC in survivors, 37% untreated >2yrs
- 21. acute episodes of peripheral neuropathy (poorly-controlled HT1) • extensor hypertonia (75 percent) • vomiting or paralytic ileus (69 percent) • muscle weakness (29 percent) • self mutilation (8 percent)
- 22. Prognosis • Patients may die of 1. acute liver failure before the second year after birth 2. from chronic liver failure or hepatocellular carcinoma before the end of the second decade
- 23. HT1 laboratory diagnosis • measurement of urine organic acids • The presence of succinylacetone (SA) in urine • elevated plasma concentrations of tyrosine and methionine and excrete tyrosyl compounds in the urine
- 24. HT1 management • Dietary treatment: – ↓phenylalanine, tyrosine, methionine, and restriction of natural protein – production of SA-> chronic • Nitisinone : inhibits 4-OH phenylpyruvate dioxygenase (HPD) – 1991, 90 % improved – plasma amino acids, blood and urinary SA, liver function tests, complete blood count (CBC) and differential, and serum AFP (which increases further with hepatocellular carcinoma) – No response or HCC-> Liver transplantation • plasma tyrosine and AFP returned to normal, urinary SA decreased • Renal tubular function remains abnormal • Long term?
- 26. ACQUIRED TYROSINEMIA • most common • Transient tyrosinemia of the newborn – most common acquired cause – immaturity of 4-OH phenylpyruvate dioxygenase (HPD), 10% – Sx: lethargy, poor feeding, metabolic acidosis, and prolonged jaundice – Rx: ascorbic acid(cofactor of HPD) + decreased protein intake • Hepatocellular dysfunction – The tyrosine levels usually are <500 micromol/L – Sx: -
Editor's Notes
- p為染色體中之短臂，q為長臂
- Fail to thrive: don't gain weight as expected
- increased plasma tyrosine levels