Story of two siblings with “Chubby Cheeks”

Dept. of Pediatric GastroenterologySGPGIMS, Lucknow

Chubby cheeks – cute babies?

DIED !ALIVE

Sep 2008 (3mo) Apr 2009 (10mo)

Neonatal cholestasis

Resolved by 5mo

Liver biopsy: early cirrhosis macrovesicular

steatosis

GSD workup negative

Urine NGRS

+

GAL1PUT &Epimerase

normal

High AFP

Urine Succinylacetone

normal

Exposure to fruit juices

Acute encephalopathy

Persisting:Doll like faciesOrganomegalyTB:7.4

DB:3.8AST:321ALT: 138T. Prot:3.9Alb: 2.0ALP:1672GGT:66

AST/ALT: 253/180T. Prot/ Alb: 4.0/1.8ALP:1297

Affected SIB

ABG/ Blood sugar/

U. ketones/ Lactate All normal !

Ammonia :119 (Normal:11-47)

Differential Diagnosis

Urine NGRS+Galactosemia ruled out

Fruit juices- acute symptoms

Hereditary Fructose Intolerance

×Neonatal cholestasis×No GI symptoms×Doll like facies×Cirrhosis before fructose exposure×Fructose provocation- no hypoglycemia / hyperlactatemia

Differential Diagnosis

Early cirrhosis

with steatosisGSD - IV

×Neonatal cholestasis×No amylopectin inclusion bodies in liver biopsy

Doll Like facies

Fanconi Bickel

syndrome(GSD with RTA)

×Neonatal cholestasis×No RTA /Rickets

Doll Like facies…What is it ?

Citrin deficiency

Transient neonatal cholestasis

Doll like facies

Affected sib with downhill

courseHyperammonemia(encephalopathy)

Steatosis &cirrhosis on

biopsy

Fischers ratio(BCAA/ArAA)

=2.18

Citrin deficiency <2.5

Caveat:Test done during

asymptomatic phase, not during

crisis!

Apr 2009 (10mo) Jan 2012 (3 ½ yrs)

Urine metabolic screen Sweat chloridePlasma Chitotriosidase SphingomyelinaseBeta-glucosidaseBeta-galactosidase

Lost to follow up

normal

Persisting:Doll like faciesOrganomegalyGrowth failure

AST/ALT: 163/84T. protein:5.9Albumin: 2.9ALP:913GGT:138CK: 24Lipid profile: normal

Preference to protein rich foods, loves milk – parents reluctant!

Oct ‘08 (~3yrs) Jan ‘09

TB/DB: 0.5/0.1AST/ALT: 128/60T. Prot/ Alb: 4.6/2.0ALP:1505GGT: 148INR:1.6

TB/DB: 0.7/0.2AST/ALT: 156/78T. Prot/ Alb: 5.4/1.7ALP:930INR:1.8

H/O Transient neonatal cholestasis(not worked upanywhere)

Failure to thriveOrganomegaly

Urine NGRS+

GAL1PUT& Epimerasenormal

High AFP

Urine Succinylacetone normal

GSD workup negative

Liver biopsy not possible - coagulopathy

Bone Marrow : normal

Craving for protein rich food Aversion to carbohydrates/ juices

SGPGI

Jan ‘09 Dec ‘09 (~4yr) Apr ‘10 (4 ½ yr)

TB/DB: 0.7/0.2AST/ALT: 156/78T. Prot/ Alb: 5.4/1.7ALP:930 INR:1.8

TB/DB: 2.0/1.3AST/ALT: 121/77T. Prot/ Alb: 4.5/1.5ALP:684 GGT:88INR: 2.3

TB/DB: 14.0/8.8AST/ALT: 225/73T. Prot/ Alb: 5.5/1.6ALP:515INR: 4.4

Transient neonatal cholestasis Liver failure!

Recurrent encephalopathy

Jaundice

Off and on ascites

DEATH

Urine for metabolic screen Sphingomyelinase Beta-glucosidase Beta-galactosidase

normal

Liver Transplant

SLC25A13 gene testing and mutational analysis not available

Citrin deficiency

Autosomal Recessive

Carrier frequency of gene mutationChina (1/79) Taiwan (1/98)Korea (1/50) Japan (1/69)

Frequency of homozygous mutation for SLC25A13 gene :1:20,000-34,000 (East Asia)

Pediatr Res 2004 Oct;56(4):608-14

“Disease of East Asian Ancestry!”Pan-ethnic

Mol Genet Metab. 2009 Jan;96(1):44-9.

Citrin deficiency

Chubby facesKobayashi et al Gene Reviews 2005

Recovery ALF Citrullinemia Type II

CLD

Chinese NICCD cohort (n=26)

21 (81%) by 1 yr age

5 (19%) : 4 died, 1 LT

- -

Retrospective Japanese series (n=75)

45 NICCD30 new born screening

2 (4.5%) by 1yr

1 (2.2%) by 16yrs

-

Japanese NICCD cohort (n=5)

4 recovered by 1yr

1 LT by 2yr

- -

Malaysian NICCD cohort (n=11)

10 (91%) recovery by 22mo

1 (9%) died

Chinese CLD (unknown etiology) cases (n=44)

- - - 21 patients(~50%) (20families) Mutation+

Song et al ,Zhonghua Er Ke Za Zhi 2009 Aug;47(8):624-7. Xing et al Zhonghua Xue Za Zhi.2010 Apr;27(2):180-5Ohura et al J Inherit Metab Dis 2007 Apr;30(2):139-44

Chubby Index = (1+2)/3

13.31.3361.00

Controls (n=13) Patients (n=5)

Chen HW, JPGN 47:187–192, 2008

Can LFT predict?Age: 93 daysDB:3.8TB:7.4 AST:321 ALT: 138ALP:1672 GGT:66

0.5

2.3

Chen HW, JPGN 47:187–192, 2008

Younger Sib Total Protein/ Albumin Sep 08: 3.9 / 2.0Total Protein/ Albumin Jan 09: 4.3 / 2.1Total Protein/ Albumin April 09: 4.0 / 1.8Total Protein/ Albumin

Jan 12: 5.9 / 2.9

Elder sib Oct 08 Jan 09 Dec 09 Apr 10AST 128 156 121 225ALT 60 78 77 97AST/ALT 2.1 2.0 1.57 2.3ALP 1505 930 684 505T.Protein 4.6 5.4 4.5 5.5Albumin 2.0 1.7 1.5 1.6

Unexplained Hypoproteinemia!

Feature of citrin def.Chen HW, JPGN 47:187–192, 2008

Histopathology changes

Steatosis (2/3) Neonatal Hepatitis like Fibrosis- Cirrhosis

NASHNAFLD

May persist into adulthood

Liver failure

6% Neonatal cholestasis (Chinese series)

12% Idiopathic neonatal hepatitis (Japanese series)

>50% Citrin deficiency(Taiwan series)

Journal of Pediatric Gastroenterology and Nutrition Jun 2010

19 patients with Citrullinemia II

21% diagnosed

NAFLD

90% steatosis79% fibrosis

Fatty livers without obesity ! BMI <20 High serum Pancreatic secretory trypsin inhibitor (PSTI) >29ng/ml

……Pancreatitis (68%) !

Komatsu et al, J Hepatol 2008 Nov;49(5))

Diagnosis

Chen HW et al, JPGN 47:187–192, 2008Kobayashi et al Gene Reviews 2005

Citrulline level high

60-73% : NICCD Japanese series

90%: new born screening

Tazawa et al, Mol Genetic Metabol 2004;83(3):213-9

Caveats in diagnosis

Literature from Chinese/Japanese articlesNatural History is unclear

Plasma amino acidsInconsistently and varied elevationNew born screen ineffectiveNormal during asymptomatic phase, GI bleed, high protein intake

Misdiagnosis as Galactosemia and Tyrosinemia(increase galactose and tyrosine in blood, galactosuria)

Urine GCMS: Various nonspecific

metabolites

Gene mutation not widely available

Diet peculiaritiesUrea Cycle defects

Protein aversion

Citrin deficiencyProtein cravingCarbohydrate aversion

“…. wants milk 24 x7 !!”(Seen in Citrullinemia Type II)

“My son hates rice and eats

only fish!”

Diet recommendations

Protein : 15-20% Fat : 50%

Carbohydrates: 30-35%

Avoid High carbohydrate / Fructose

Glycerol for brain edema

Milk : Protein (20%) Fat (50%) Carb (30%)

Liver Transplant

Recurrent encephalopathyLiver failure

Hepatocellular Carcinoma (5-8%)

Good outcomeKobayashi et al Gene Reviews 2005

Auxillary Partial

Orthotropic

Yazaki, Liver Transplantation, Vol 10, No 4 (April), 2004Soo Kim, J Korean Surg Soc 2011;80:S51-54

THANK YOU

All that glitters is not GOLD!All Chubby cheeks are not GSD!

Urea Cycle for ureagenesis

Lipids 1)compensate for

energy2) FA inhibit hepatic

glycolysis

Protein intakeMore availability of aspartate through aspargine and pyruvate from alanine

Chubby cheeksCitrate –malate shuttle activated: Increase of Glycerol 3 phosphate + breakdown of citrate

(Acetyl CoA +OAA)Hypoproteinemia (subclinical edema)

Unexplained concepts

• Why majority outgrow the disease?• Any additional factors for progression to

CLD/ALF ?• Postulation for protein craving?