This case presentation describes a 20 month old female patient who presented with failure to thrive, anemia, rickets, hepatosplenomegaly, and bilateral nephromegaly. Initial workup found elevated tyrosine levels and further testing confirmed a diagnosis of Tyrosinemia type 1. The patient was started on a low tyrosine/phenylalanine diet and NTBC treatment. Follow up showed improvement in biochemical markers and symptoms, though liver damage remained severe. The case discusses the pathophysiology, presentation, diagnosis and management of Tyrosinemia type 1.
2. Female / 20 months 20/9/11
Failure to gain weight and height since 1
year
Negative history for:
Repeated fever/cough/cold
Vomiting/diarrhoea
Urinary complaints(polyuria/polydipsia)
Convulsion/behavior changes
Bony deformity
3. Born full term with birth weight – 3.2kg
Apparently normal for first 6 – 8 months, had an
episode of diarrhoea lasted for 4-5 days at 8 months
followed by failure to thrive.
She was given AKT for 6 months outside !!
Delayed motor milestones ( not able to stand or walk)
Only sib
No significant family history
4. General Examination
Vitals stable, BP 92/48
Pallor present,
Features of rickets present
(wrist widening, open AF, rickety
rosary)
Weight – 6.9kg, Height 70cm
( expected 11kg , 84 cm)
7. Investigations
Hb 9, TLC 6600, Platelet 3 lac
Urea 15, Creatinine 0.4
Bilirubin ( T/D/I) 1.6/0.8/0.8, SGPT 38
S Protein (T/A/G) 5.5/3.4/2.1
SAP 867
Urine routine normal
8. Investigation
USG Abdomen:
Kidneys- RK 93 X 44, LK 98X 44 both enlarged
increased echogenicity, normal CMD. No stone,
HDN, cysts or focal lesion
Liver- enlarged with diffusely altered echotexture,
no focal mass lesion; CBD,PV- N
Spleen- enlarged with normal echotexture
9. D/D of Bilateral enlarged kidneys
Polycystic kidneys
Hydronephrosis
Pyelonephritis
Nephrotic syndrome
Storage disorders: GSD type I
Tyrosinemia
Amyloidosis
10. My suspected diagnosis….
? Storage disorder with secondary
involvement of kidneys
? Hematologic disorder involving
kidneys and liver
? Polycystic kidneys
11. Further investigations
Hb 7.8, TLC 7400, Platelet 1.27lac
PS : hypochromic microcytic RBCs
Ca 8.29, Phosph 2.52, SAP 960
Blood gas: PH 7.38, PCO2 39, HCO3 23.6
Na 143.4, K 3.58, Cl 102.2
X ray wrist s/o rickets
ECHO Apical muscular VSD
12. Advised further Ix, but not ready to stay
Treatment given
Calcirol 1 sachet daily 10 d
Calcimax-P
Iron
Multivitamin
13. Follow up : ( 20 days)
Rickets was improving…
I was still suspecting
◦ ?storage disorder
◦ ? Hematologic disorder with secondary
renal
involvement
Gastroenterologist and hemato oncologist’s
opinion taken.
14. Summary of proceedings so far
We have a case who presented
◦ with renal complaints,
◦ and then during the work-up found to have liver
involvement which was not advanced on
presentation
Differential
diagnosis?
Further work-up?
15. Conditions with liver & kidney involvement
Wilson’s
GSD type-I
Galactosemia
Hereditary Fructose Intolerance
Tyrosinemia type I
16. Further Investigations
Urine for metabolic screen
Positive for reducing substance, fructose,
proteins.
TMS
Aminoacid profile s/o raised tyrosine level
Tyrosine trial I – 317.35µM
trial II – 330.36µM (normal 20-275)
17. Confirmation
Succinyl acetone study from urine by GC-MS
study
Urine GC-MS:
Significant elevation of succinyl acetone
4 hydroxy phenyl pyruvate
4 hydroxy phenyl lactate
S/O Tyrosinemia type-I
18. Further Ix 30/11/11
Blood Unit Ref range
Succinyl µmol/L <0.1 5.9
acetone
Tyrosine µMol/L 50-130 446.1
Phenylalanine µMol/L 40-120 74.16
Methionine µMol/L 20-50 426.23
Alpha feto µgm/L <12 35,556
protein
Urine
Succinyl µmol/mmol 0-2 314.88
acetone creatinine
19. Tests 30/11/11 Normal value
Total Bilirubin 1.6 mg/dl 0-1
Direct Bilirubin 0.5 mg/dl 0-0.6
Indirect Bilirubin 1.1 mg/dl 0-0.4
SGOT 90 IU/L 15-45
SGPT 53 IU/L 10-40
GGTP 200U/L 8-78
Alkaline phosphatase 1175 IU/L Up to 390
Total protein 4.7 gm% 6.3-8.6
Albumin 2.9 gm% 3.7-5.6
Globulin 1.8 gm% 1.5-3.5
A:G Ratio 1.61 0.9-2
22. MRI Abdomen
Hepatomegaly with cirrhotic changes &
multiple siderotic nodules. No evidence of
mass leasion
Moderate splenomegaly
Moderately enlarged kidneys with
parenchymal disease
No evidence of lymphadenopathy or ascites
23. Treatment given
Diet low in tyrosine and phenylalanine
avoid milk/ dry fruit / high protein food
Tab NTBC (Nitisinone) 2mg daily after food bd
Syp Potassium citrate 4ml bd
Syp Joulie solution 2.5 ml qds
Advised to come for follow up after
one month
24. Came after 4 months
Blood Unit Ref range 30/11/11 3/4/12
Succinyl µmol/L < 0.1 5.9 <0.1
acetone
Tyrosine µMol/L 50-130 446.1 501.25
Phenylalanine µMol/L 40-120 74.16 129.33
Methionine µMol/L 20-50 26.234 21.20
Alpha feto µgm/L <12 35,556 3093
protein
Urine
Succinyl µmol/mmol 0-2 314.88 0.08
acetone creatinine
25. Tests 30/11/11 3/4/12 Normal value
Total Bilirubin 1.6 mg/dl 1.2 0-1
Direct Bilirubin 0.5 mg/dl 0.7 0-0.6
Indirect Bilirubin 1.1 mg/dl 0.5 0-0.4
SGOT 90 IU/L 64 15-45
SGPT 53 IU/L 74 10-40
GGTP 200U/L 350 8-78
Alkaline 1175 IU/L 321 Up to 390
phosphatase
Total protein 4.7 gm% 6.1 6.3-8.6
Albumin 2.9 gm% 4 3.7-5.6
Globulin 1.8 gm% 2.1 1.5-3.5
A:G Ratio 1.61 1.9 0.9-2
28. Thus there is marked improvement in
biochemical profile related to tyrosine
metabolism.
However morphological changes in liver
appear quite severe, but hopefully should
improve if we believe the literature.
29. Tyrosinemia
Inborn error in the degradation of the
amino acid tyrosine.
Autosomal recessive.
Three types (type I, type II, type III).
30. TAT- tyrosine aminotransferase
Phenylalanin 4 HPPD - 4 OH phenylpyruvate
dioxygenase
FAH – fumeryl acetoacetate hydrolase
Tyrosine
TAT Tyrosinemia II
4 hydroxy phenyl pyruvate
4HPPD Tyrosinemia
III
Homogentisate
Maleylacetoacetate
Fumeryl acetoacetate
FAH
Tyrosinemia I
Fumerate
Acetoacetate
31. Tyrosinemia type I
Deficiency of the enzyme
fumarylacetoacetate hydrolase (FAH).
Gene for FAH enzyme located on
chromosome 15
More than 30 mutation
Incidence is 1 in 100000 worldwide
32. Tyrosinemia type I
Phenylalanin
Tyrosine
Fumeryl acetoacetate Succinyl
acetoacetate
Enzyme
defect
succinyl acetone
inhibit
Fumerate
Acetoacetate δ ALA
porphobilinogen
36. Clinical presentation
Less than 6 months of age
Severe liver involvement with ascites, jaundice, GI
bleed
More than 6 months of age
Renal tubular dysfunctions with acidosis, failure to
thrive, rickets
hepatosplenomegaly
nephromegaly
peripheral neuropathy
37. Diagnosis
Increased succinylacetone concentration in the
blood and urine
Elevated plasma concentrations of tyrosine;
methionine, and phenylalanine
Definative diagnosis
FAH enzyme activity in skin fibroblasts
Mutation analysis of FAH gene
38. Treatment
Diet
Restriction of phenylalanin and
tyrosine
avoid milk and milk product, dry
fruits,
high protein food
allows control of acute crises
does not prevent progression of the
illness
41. Liver transplantation
Reserved for those children who
have severe liver failure at clinical presentation
and fail to respond to nitisinone therapy
have documented evidence of malignant
changes in hepatic tissue
42. Prognosis
Very good with NTBC
Reversal of morphological changes
Need for liver transplant may no
longer be there