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

16. Reference
• https://www.uptodate.com/contents/disorder
s-of-tyrosine-
metabolism?source=search_result&search=tyr
osinemia&selectedTitle=1~25#H5

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: -