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
ï Failure to gain weight and height since 1
year
Negative history for:
ï Repeated fever/cough/cold
ï Vomiting/diarrhoea
ï Urinary complaints(polyuria/polydipsia)
ï Convulsion/behavior changes
ï Bony deformity
3. ï Born full term with birth weight â 3.2kg
ï Apparently normal for first 6 â 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 !!
ï Delayed motor milestones ( not able to stand or walk)
ï Only sib
ï 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 â 6.9kg, Height 70cm
( expected 11kg , 84 cm)
7. Investigations
ï Hb 9, TLC 6600, Platelet 3 lac
ï Urea 15, Creatinine 0.4
ï Bilirubin ( T/D/I) 1.6/0.8/0.8, SGPT 38
ï S Protein (T/A/G) 5.5/3.4/2.1
ï SAP 867
ï 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
ï Polycystic kidneys
ï Hydronephrosis
ï Pyelonephritis
ï Nephrotic syndrome
ï Storage disorders: GSD type I
Tyrosinemia
Amyloidosis
10. My suspected diagnosisâŠ.
ï ? Storage disorder with secondary
involvement of kidneys
ï ? Hematologic disorder involving
kidneys and liver
ï ? Polycystic kidneys
11. Further investigations
ï Hb 7.8, TLC 7400, Platelet 1.27lac
ï PS : hypochromic microcytic RBCs
ï Ca 8.29, Phosph 2.52, SAP 960
ï Blood gas: PH 7.38, PCO2 39, HCO3 23.6
ï Na 143.4, K 3.58, Cl 102.2
ï X ray wrist s/o rickets
ï ECHO Apical muscular VSD
12. Advised further Ix, but not ready to stay
Treatment given
ï Calcirol 1 sachet daily 10 d
ï Calcimax-P
ï Iron
ï Multivitamin
13. Follow up : ( 20 days)
Rickets was improvingâŠ
I was still suspecting
⊠?storage disorder
⊠? Hematologic disorder with secondary
renal
involvement
Gastroenterologist and hemato oncologistâs
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
ï Wilsonâs
ï GSD type-I
ï Galactosemia
ï Hereditary Fructose Intolerance
ï Tyrosinemia type I
16. Further Investigations
ï Urine for metabolic screen
Positive for reducing substance, fructose,
proteins.
ï TMS
Aminoacid profile s/o raised tyrosine level
Tyrosine trial I â 317.35”M
trial II â 330.36”M (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 ”mol/L <0.1 5.9
acetone
Tyrosine ”Mol/L 50-130 446.1
Phenylalanine ”Mol/L 40-120 74.16
Methionine ”Mol/L 20-50 426.23
Alpha feto ”gm/L <12 35,556
protein
Urine
Succinyl ”mol/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
ï Hepatomegaly with cirrhotic changes &
multiple siderotic nodules. No evidence of
mass leasion
ï Moderate splenomegaly
ï Moderately enlarged kidneys with
parenchymal disease
ï No evidence of lymphadenopathy or ascites
23. Treatment given
ï Diet low in tyrosine and phenylalanine
avoid milk/ dry fruit / high protein food
ï Tab NTBC (Nitisinone) 2mg daily after food bd
ï Syp Potassium citrate 4ml bd
ï 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 ”mol/L < 0.1 5.9 <0.1
acetone
Tyrosine ”Mol/L 50-130 446.1 501.25
Phenylalanine ”Mol/L 40-120 74.16 129.33
Methionine ”Mol/L 20-50 26.234 21.20
Alpha feto ”gm/L <12 35,556 3093
protein
Urine
Succinyl ”mol/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. ï Thus there is marked improvement in
biochemical profile related to tyrosine
metabolism.
ï However morphological changes in liver
appear quite severe, but hopefully should
improve if we believe the literature.
29. Tyrosinemia
ï Inborn error in the degradation of the
amino acid tyrosine.
ï Autosomal recessive.
ï Three types (type I, type II, type III).
30. TAT- tyrosine aminotransferase
Phenylalanin 4 HPPD - 4 OH phenylpyruvate
dioxygenase
FAH â 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
ï Deficiency of the enzyme
fumarylacetoacetate hydrolase (FAH).
ï Gene for FAH enzyme located on
chromosome 15
ï More than 30 mutation
ï Incidence is 1 in 100000 worldwide
32. Tyrosinemia type I
Phenylalanin
Tyrosine
Fumeryl acetoacetate Succinyl
acetoacetate
Enzyme
defect
succinyl acetone
inhibit
Fumerate
Acetoacetate ÎŽ ALA
porphobilinogen
36. Clinical presentation
ï Less than 6 months of age
Severe liver involvement with ascites, jaundice, GI
bleed
ï More than 6 months of age
Renal tubular dysfunctions with acidosis, failure to
thrive, rickets
hepatosplenomegaly
nephromegaly
peripheral neuropathy
37. Diagnosis
ï Increased succinylacetone concentration in the
blood and urine
ï Elevated plasma concentrations of tyrosine;
methionine, and phenylalanine
Definative diagnosis
ï FAH enzyme activity in skin fibroblasts
ï Mutation analysis of FAH gene
38. Treatment
Diet
Restriction of phenylalanin and
tyrosine
avoid milk and milk product, dry
fruits,
high protein food
ï allows control of acute crises
ï does not prevent progression of the
illness
41. Liver transplantation
Reserved for those children who
ï have severe liver failure at clinical presentation
and fail to respond to nitisinone therapy
ï have documented evidence of malignant
changes in hepatic tissue
42. Prognosis
ï Very good with NTBC
ï Reversal of morphological changes
ï Need for liver transplant may no
longer be there