1. Tyrosine metabolism disorders are caused by defects in the catabolic pathway that breaks down tyrosine, leading to elevated tyrosine levels in the blood and other issues. 2. Hereditary tyrosinemia type 1 is caused by a defect in the final enzyme in the pathway and results in liver and kidney damage if left untreated. 3. Treatment for hereditary tyrosinemia type 1 involves dietary restrictions and medication to reduce toxic metabolite buildup and prevent associated complications like liver failure and cancer.

1. 酪胺酸代謝異常疾病
Intern : 甄祉婷
Supervisor: Chief Dr. 劉君恕 , Dr. 蔡昕霖
Resident: Dr.葉奕廷, Dr.楊逸文
台北榮總兒童外科
2016/10/20

2. 簡介
• 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. 酪胺酸的代謝
• Sites : Hepatocyte and renal proximal tubules
• Catalyzed by 5 enzymatic reactions which yields
-Acetoacetate (ketogenic)
-Fumarate (glucogenic)

4. 自體隱性遺傳疾病
• 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. 高酪胺酸血症
• 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. 高酪胺酸血症之診斷
• 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. 造成高酪胺酸血症之原因
• Inherited deficiencies of enzymes in the
degradation pathway
• Transient tyrosinemia of the newborn
• Liver disease
• Miscellaneous disorders including scurvy and
hyperthyroidism

8. 如何評估高酪胺酸血症
• 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. 遺傳性高酪胺酸血症（HT1）
• a.k.a hepatorenal tyrosinemia, is the most
severe disorder of tyrosine metabolism
• 1 in 12,000

10. HT1之病生理學
• 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. 蛋白質合成障礙
• 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. 酪胺酸
• 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

16. HT1之遺傳學
• 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

18. HT1之臨床特徵
• severe progressive liver disease
• renal tubular dysfunction
– Fanconi syndrome with renal tubular acidosis,
aminoaciduria, and hypophosphatemia (due to
phosphate wasting)
– rickets

19. HT1之臨床特徵：肝臟
• 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

20. HT1控制不良所產生之
急性周邊神經病變
• extensor hypertonia (75 percent)
• vomiting or paralytic ileus (69 percent)
• muscle weakness (29 percent)
• self mutilation (8 percent)

21. 預後
• 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

22. HT1之實驗室診斷
• 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

23. HT1之治療
• 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?

25. 後天性之高酪胺酸血症
• 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: -

26. 參考資料
• “Disorders of tyrosine metabolism” on
UptoDate, accessed on 2016/10/20