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