a case of nephromegaly
TRANSCRIPT
Case Presentation A case of Nephromegaly
Dr Nilam ThakerPediatric NephrologistAhmedabad
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
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
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)
Systemic Examination
P/A Bilateral enlarged palpable
kidneys Hepatomegaly 4 cm, firm
Splenomegaly 2 cm CVS systolic murmur
RS, CNS unremarkable
Clinical impression
Failure to thrive AnemiaRickets Bilateral nephromegalyHepatosplenomegaly? CHD
InvestigationsHb 9, TLC 6600, Platelet 3 lacUrea 15, Creatinine 0.4Bilirubin ( T/D/I) 1.6/0.8/0.8,
SGPT 38S Protein (T/A/G) 5.5/3.4/2.1SAP 867Urine routine normal
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
D/D of Bilateral enlarged kidneys
Polycystic kidneysHydronephrosisPyelonephritisNephrotic syndromeStorage disorders: GSD type I Tyrosinemia Amyloidosis
My suspected diagnosis….
? Storage disorder with secondary involvement of kidneys
? Hematologic disorder involving kidneys and liver
? Polycystic kidneys
Further investigationsHb 7.8, TLC 7400, Platelet 1.27lacPS : hypochromic microcytic RBCsCa 8.29, Phosph 2.52, SAP 960
Blood gas: PH 7.38, PCO2 39, HCO3 23.6Na 143.4, K 3.58, Cl 102.2
X ray wrist s/o ricketsECHO Apical muscular VSD
Advised further Ix, but not ready to stay
Treatment given Calcirol 1 sachet daily 10 dCalcimax-PIronMultivitamin
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.
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?
Conditions with liver & kidney involvement
Wilson’sGSD type-IGalactosemiaHereditary Fructose IntoleranceTyrosinemia type I
Further InvestigationsUrine 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)
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
Further Ix 30/11/11
Blood Unit Ref range
Succinyl acetone
µmol/L <0.1 5.9
Tyrosine µMol/L 50-130 446.1
Phenylalanine µMol/L 40-120 74.16
Methionine µMol/L 20-50 426.23
Alpha feto protein
µgm/L <12 35,556
Urine
Succinyl acetone
µmol/mmol creatinine
0-2 314.88
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
Tests 30/11/11 Normal range
calcium 8.5 mg/dl 8.1-10.4
Phosphorous 1.3 mg/dl 4-7
Sodium 145 135-145
Potassium 2.6 3.5-5.3
Chloride 132 96-109
HCO3 16 22-26
Creatinine 0.3 0.3-0.7
Urine phosphate 9.98mg/dl
FEP 27 s/o TRP 73 ( N 85-95%)
phosphate TmP GFR 1.3 ( N 2.9-4.6) leak
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
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 bdSyp Joulie solution 2.5 ml qds
Advised to come for follow up after one month
Came after 4 monthsBlood Unit Ref range 30/11/11 3/4/12
Succinyl acetone
µmol/L < 0.1 5.9 <0.1
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 protein
µgm/L <12 35,556 3093
Urine
Succinyl acetone
µmol/mmol creatinine
0-2 314.88 0.08
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 phosphatase
1175 IU/L 321 Up to 390
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
Tests 30/11/11 3/4/11 Normal range
calcium 8.5 mg/dl 9.1 8.1-10.4
Phosphorous 1.3 mg/dl 8.6 4-7
Sodium 145 128 135-145
Potassium 2.6 5.3 3.5-5.3
Chloride 132 98 96-109
HCO3 16 13 22-26
Creatinine 0.3 0.3 0.3-0.7
Treatment modified
Joulie solution stoppedPotassium citrate decreasedTab sodamint addedTab NTBC continued
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.
Tyrosinemia
Inborn error in the degradation of the amino acid tyrosine.
Autosomal recessive.Three types (type I, type II, type
III).
Phenylalanin
Tyrosine
TAT
4 hydroxy phenyl pyruvate
4HPPD
Homogentisate
Maleylacetoacetate
Fumeryl acetoacetate
FAH
Fumerate
Acetoacetate
Tyrosinemia II
Tyrosinemia III
Tyrosinemia I
TAT- tyrosine aminotransferase4 HPPD - 4 OH phenylpyruvate
dioxygenaseFAH – fumeryl acetoacetate
hydrolase
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
Tyrosinemia type I
Phenylalanin
Tyrosine
Fumeryl acetoacetate Succinyl acetoacetate
succinyl
acetone inhibit Fumerate Acetoacetate δ ALA
porphobilinogen
Enzymedefect
Pathophysiology
Fumarylacetoacetate and maleylacetoacetate :
alkylating agents
hepatorenal damage
mutagenic properties
hepatocellular carcinoma
Succinylacetone
inhibits tubular transport of glucose aminoacids Phosphate inhibits porphobilinogen synthase
accumulation of -aminolevulinate
acute porphyria-like neurological symptoms
Liver: severe liver disease with coagulopathy
cirrhosis hepatocellular carcinomaKidneys: tubular dysfunction
aminoaciduria, glucosuria, acidosis phosphaturia --- rickets
Nervous system: acute peripheral neuropathy
painful paraesthesias neurologic crisis
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
Diagnosis Increased succinylacetone concentration in
the blood and urine
Elevated plasma concentrations of tyrosine; methionine, and phenylalanine
Definative diagnosisFAH enzyme activity in skin fibroblasts
Mutation analysis of FAH gene
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
NTBC: ( Nitisinone)2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
Inhibition of 4-hydroxyphenylpyruvate
dioxygenase.
Effect : abolition of the production of the metabolites responsible for the pathogenesis of the disease
Dose: 0.5 to 2 mg/kg/d
http://www.childrenshospital.org/newenglandconsortium/NBS/descriptions/images/tyro3.gif
Liver transplantation
Reserved for those children whohave severe liver failure at clinical
presentation and fail to respond to nitisinone therapy
have documented evidence of malignant changes in hepatic tissue
Prognosis
Very good with NTBCReversal of morphological
changesNeed for liver transplant may no
longer be there
Thank You