Case PresentationA case of Nephromegaly Dr Nilam Thaker Pediatric Nephrologist Ahmedabad
Female / 20 months 20/9/11 Failure to gain weight and height since 1 yearNegative 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 ExaminationVitals stable, BP 92/48Pallor present,Features of rickets present(wrist widening, open AF, rickety rosary)Weight – 6.9kg, Height 70cm ( expected 11kg , 84 cm)
Clinical impressionFailure to thriveAnemiaRicketsBilateral nephromegalyHepatosplenomegaly? CHD
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
InvestigationUSG Abdomen:Kidneys- RK 93 X 44, LK 98X 44 both enlarged increased echogenicity, normal CMD. No stone, HDN, cysts or focal lesionLiver- enlarged with diffusely altered echotexture, no focal mass lesion; CBD,PV- NSpleen- enlarged with normal echotexture
D/D of Bilateral enlarged kidneys Polycystic kidneys Hydronephrosis Pyelonephritis Nephrotic syndrome Storage 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 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
Advised further Ix, but not ready to stayTreatment given Calcirol 1 sachet daily 10 d Calcimax-P Iron Multivitamin
Follow up : ( 20 days)Rickets was improving…I was still suspecting ◦ ?storage disorder ◦ ? Hematologic disorder with secondary renal involvementGastroenterologist and hemato oncologist’s opinion taken.
Summary of proceedings so farWe 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’s GSD type-I Galactosemia Hereditary Fructose Intolerance Tyrosinemia type I
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)
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 lactateS/O Tyrosinemia type-I
Further Ix 30/11/11Blood Unit Ref rangeSuccinyl µmol/L <0.1 5.9acetoneTyrosine µMol/L 50-130 446.1Phenylalanine µMol/L 40-120 74.16Methionine µMol/L 20-50 426.23Alpha feto µgm/L <12 35,556proteinUrineSuccinyl µmol/mmol 0-2 314.88acetone creatinine
Tests 30/11/11 Normal valueTotal Bilirubin 1.6 mg/dl 0-1Direct Bilirubin 0.5 mg/dl 0-0.6Indirect Bilirubin 1.1 mg/dl 0-0.4SGOT 90 IU/L 15-45SGPT 53 IU/L 10-40GGTP 200U/L 8-78Alkaline phosphatase 1175 IU/L Up to 390Total protein 4.7 gm% 6.3-8.6Albumin 2.9 gm% 3.7-5.6Globulin 1.8 gm% 1.5-3.5A:G Ratio 1.61 0.9-2
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 bd Syp Joulie solution 2.5 ml qdsAdvised to come for follow up afterone month
Came after 4 monthsBlood Unit Ref range 30/11/11 3/4/12Succinyl µmol/L < 0.1 5.9 <0.1acetoneTyrosine µMol/L 50-130 446.1 501.25Phenylalanine µMol/L 40-120 74.16 129.33Methionine µMol/L 20-50 26.234 21.20Alpha feto µgm/L <12 35,556 3093proteinUrineSuccinyl µmol/mmol 0-2 314.88 0.08acetone creatinine
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).
TAT- tyrosine aminotransferase Phenylalanin 4 HPPD - 4 OH phenylpyruvate dioxygenase FAH – fumeryl acetoacetate hydrolase Tyrosine TAT Tyrosinemia II 4 hydroxy phenyl pyruvate4HPPD Tyrosinemia III Homogentisate Maleylacetoacetate Fumeryl acetoacetate FAH Tyrosinemia I Fumerate Acetoacetate
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 Succinylacetoacetate Enzyme defect succinyl acetone inhibit Fumerate Acetoacetate δ ALAporphobilinogen
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 phenylalanineDefinative diagnosis FAH enzyme activity in skin fibroblasts Mutation analysis of FAH gene
TreatmentDiet 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
Liver transplantationReserved 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
Prognosis Very good with NTBC Reversal of morphological changes Need for liver transplant may no longer be there