Story of two siblings with Chubby Cheeks Dept

Story of two siblings with “Chubby Cheeks” Dept. of Pediatric Gastroenterology SGPGIMS, Lucknow

Chubby cheeks – cute babies? ALIVE DIED !

GSD workup negativ e Neonatal cholestasi s Liver biopsy: early cirrhosis macrovesicu lar steatosis TB: 7. 4 DB: 3. 8 Urine AST: 321 NGRS ALT: + 138 T. Resolv High Prot: 3. 9 ed by AFP Alb: 2. 0 5 mo ALP: 16 72 Sep 2008 (3 mo) (10 mo) Exposure to fruit juices Affected SIB GAL 1 PUT & Epimerase normal Urine Succinylaceton e normal ABG/ Blood sugar/ U. ketones/ Lactate All normal ! Ammonia : 119 (Normal: 11 -47) Acute encephalopat Persisting: hy Doll like facies Organomega ly AST/ALT: 253/180 T. Prot/ Alb: 4. 0/1. 8 ALP: 1297 Apr 2009

Differential Diagnosis üUrine NGRS+ Hereditary Fructose üGalactosemia ruled Intolerance out üFruit juices- acute ×Neonatal cholestasis symptoms ×No GI symptoms ×Doll like facies ×Cirrhosis before fructose exposure ×Fructose provocation- no hypoglycemia / hyperlactatemia

Differential Diagnosis üEarly cirrhosis with steatosis üDoll Like facies GSD - IV Fanconi Bickel syndrome (GSD with RTA) ×Neonatal cholestasis ×No amylopectin inclusion bodies in liver biopsy ×Neonatal cholestasis ×No RTA /Rickets

Doll Like facies… What is it ? Transient neonatal cholestasis Affected sib with downhill course Hyperammonemia (encephalopathy) Steatosis & cirrhosis on biopsy Doll like facies Citrin deficiency

Fischers ratio (BCAA/Ar. AA) =2. 18 Citrin deficiency <2. 5 Caveat: Test done during asymptomatic phase, not during crisis!

Lost to follow up Urine metabolic screen Sweat chloride Plasma Chitotriosidase Sphingomyelinase Beta-glucosidase Beta-galactosidase Apr 2009 (10 mo) yrs) norma l AST/ALT: 163/84 T. protein: 5. 9 Albumin: 2. 9 ALP: 913 GGT: 138 CK: 24 Lipid profile: normal Persisting: Doll like facies Organomeg aly Growth failure Jan 2012 (3 ½

Preference to protein rich foods, loves milk –

Urine NGRS + GSD workup negativ e High AFP GAL 1 PUT& Epimerase normal Urine Succinylacetone normal Liver biopsy not possible H/O coagulopathy Transient Bone Marrow : neonatal normal Failure to cholestasis thrive (not worked Craving for protein rich Organomega food Aversion to up ly anywhere) TB/DB: 0. 5/0. 1 carbohydrates/ juices SGP GI AST/ALT: 128/60 T. Prot/ Alb: 4. 6/2. 0 ALP: 1505 GGT: 148 Oct ‘ 08 (~3 yrs) INR: 1. 6 TB/DB: 0. 7/0. 2 AST/ALT: 156/78 T. Prot/ Alb: 5. 4/1. 7 ALP: 930 Jan ‘ 09 INR: 1. 8

Transient neonatal cholestasis Liver failure! Urine for metabolic screen Sphingomyelinase Beta-glucosidase Beta-galactosidase Recurrent encephalopathy Off and on ascites TB/DB: 0. 7/0. 2 AST/ALT: 156/78 T. Prot/ Alb: 5. 4/1. 7 ALP: 930 Jan ‘ 09 INR: 1. 8 norma l ic d n au J e TB/DB: 2. 0/1. 3 AST/ALT: 121/77 T. Prot/ Alb: 4. 5/1. 5 ALP: 684 Dec ‘ 09 (~4 yr) GGT: 88 Liver Transpla nt D E A T H TB/DB: 14. 0/8. 8 AST/ALT: 225/73 T. Prot/ Alb: 5. 5/1. 6 ALP: 515 Apr ‘ 10 (4 ½ yr) INR: 4. 4

SLC 25 A 13 gene testing and mutational analysis not available

Citrin deficiency Autosomal Recessive

Pan-ethnic “Disease of East Asian Ancestry!” Carrier frequency of gene mutation China (1/79) Taiwan (1/98) Korea (1/50) Japan (1/69) Frequency of homozygous mutation for SLC 25 A 13 gene : 1: 20, 000 -34, 000 (East Asia) Mol Genet Metab. 2009 Jan; 96(1): 44 -9. Pediatr Res 2004 Oct; 56(4): 608 -14

Citrin deficiency Chubby faces Kobayashi et al Gene Reviews 2005

Recovery ALF Citrulline CLD mia Type II Chinese NICCD cohort (n=26) 21 (81%) 5 (19%) by 1 yr age : 4 died, 1 LT Retrospective Japanese series (n=75) 45 NICCD 30 new born screening 2 (4. 5%) 1 (2. 2%) by by 1 yr 16 yrs Japanese NICCD cohort (n=5) 4 recovered by 1 yr 1 LT by 2 yr Malaysian NICCD cohort (n=11) 10 (91%) recovery by 22 mo 1 (9%) died Chinese CLD (unknown - - - Song et al , Zhonghua Er Ke Za Zhi 2009 Aug; 47(8): 624 -7. - et al Zhonghua- Xue Za Zhi. 2010 - Apr; 27(2): 180 -5 21 Xing Ohura et al J Inherit Metab Dis 2007 Apr; 30(2): 139 -44 patients

Chubby Index = (1+2)/3 Chen HW, JPGN 47: 187– 192, 2008 Controls (n=13) (n=5) Patients ü 13. 3 ü 1. 336 ü 1. 00

Can LFT predict? Age: 93 days üDB: 3. 8 üTB: 7. 4 AST: 321 ALT: 138 üALP: 1672 GGT: 66 Chen HW, JPGN 47: 187– 192, 20 ü 2. 3 ü 0. 5

Younger Sib Total Protein/ Albumin Sep 08: 3. 9 / 2. 0 Jan 09: Unexplained Hypoproteinemi a! 4. 3 / 2. 1 Total Protein/ April 09: 4. 0 / 1. 8 Albumin Oct 08 Jan 09 Dec 09 Elder Total Protein/ Jan 12: 5. 9 / 2. 9 sib Albumin AST 128 156 121 ALT 60 78 77 AST/ALT 2. 1 2. 0 1. 57 ALP 1505 930 684 T. Protein 4. 6 5. 4 4. 5 Albumin 2. 0 1. 7 1. 5 Feature of citrin Chen def. HW, JPGN 47: 187– 192, 20 Apr 10 225 97 2. 3 505 5. 5 1. 6

Histopathology changes Steatosis (2/3) Neonatal Hepatitis like Fibrosis. Cirrhosis >50% Citrin deficiency (Taiwan series) NASH NAFLD May persist into 6% Neonatal cholestasis (Chinese series) 12% Idiopathic neonatal hepatitis (Japanese series) Liver failure

Journal of Pediatric Gastroenterology and Nutrition Jun 2010 21% diagnosed NAFLD 19 patients with Citrullinemia II 90% steatosis 79% fibrosis Komatsu et al, J Hepatol 2008 Nov; 49(5)) Fatty livers without obesity ! BMI <20 High serum Pancreatic secretory trypsin inhibitor (PSTI) >29 ng/ml

Diagnosis Citrulline level high 60 -73% : NICCD Japanese series 90%: new born screening Chen HW et al, JPGN 47: 187– 192, 2008 Kobayashi et al Gene Reviews 2005 Tazawa et al, Mol Genetic Metabol 2004; 83(3): 213 -9

Caveats in diagnosis Literature from Chinese/Japanese articles Natural History is unclear Misdiagnosis as Galactosemia and Tyrosinemia (increase galactose and tyrosine in blood, Urine GCMS: galactosuria) Plasma amino acids Various nonspecific v. Inconsistently and varied metabolites elevation v. New born screen ineffective Gene mutation v. Normal during asymptomatic phase, GI bleed, high protein not widely intake

Diet peculiarities Urea Cycle defects Protein aversion “My son hates rice and eats only fish!” “…. wants milk 24 x 7 !!” (Seen in Citrullinemia Type II) Citrin deficiency Protein craving Carbohydrate aversion

Diet recommendations Protein : 15 -20% Fat : 50% Carbohydrates: 30 -35% Milk : Protein (20%) Fat (50%) Carb (30%) Avoid High carbohydrate / Fructose Glycerol for brain edema

Liver Transplant Recurrent encephalopathy Liver failure Hepatocellular Carcinoma (5 -8%) Good outcome Auxillary Partial Orthotrop ic Kobayashi et al Gene Reviews 2005 Soo Kim, J Korean Surg Soc 2011; 80: S 51 -5 Yazaki, Liver Transplantation, Vol 10, No 4 (April), 2

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

Lipids 1)compensate for energy 2) FA inhibit hepatic glycolysis Urea Cycle for ureagenesis Protein intake More availability of aspartate through aspargine and pyruvate from alanine Chubby cheeks Citrate –malate shuttle activated: Increase of Glycerol 3 phosphate + breakdown of citrate (Acetyl Co. A +OAA) Hypoproteinemia (subclinical edema)

Unexplained concepts • Why majority outgrow the disease? • Any additional factors for progression to CLD/ALF ? • Postulation for protein craving?