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Story of two siblings with “Chubby Cheeks”

Story of two siblings with “Chubby Cheeks” . Dept. of Pediatric Gastroenterology SGPGIMS, Lucknow. Chubby cheeks – cute babies?. ALIVE. DIED !. ABG/ Blood sugar/ U. ketones / Lactate All normal ! Ammonia :119 (Normal:11-47). Exposure to fruit juices. GSD workup negative.

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Story of two siblings with “Chubby Cheeks”

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

  2. Chubby cheeks – cute babies? ALIVE DIED !

  3. ABG/ Blood sugar/ U. ketones/ Lactate All normal ! Ammonia :119 (Normal:11-47) Exposure to fruit juices GSD workup negative Affected SIB Liver biopsy: early cirrhosis macrovesicularsteatosis Acute encephalopathy Neonatal cholestasis Persisting: Doll like facies Organomegaly TB:7.4 DB:3.8 AST:321 ALT: 138 T. Prot:3.9 Alb: 2.0 ALP:1672 GGT:66 GAL1PUT & Epimerase normal Urine NGRS + AST/ALT: 253/180 T. Prot/ Alb: 4.0/1.8 ALP:1297 Resolved by 5mo Urine Succinylacetone normal High AFP Sep 2008 (3mo) Apr 2009 (10mo)

  4. 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

  5. Differential Diagnosis • Early cirrhosis • with steatosis • Neonatal cholestasis • No amylopectin inclusion bodies in liver biopsy GSD - IV Fanconi Bickel syndrome (GSD with RTA) • Neonatal cholestasis • No RTA /Rickets • Doll Like facies

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

  7. Fischers ratio (BCAA/ArAA) =2.18 Citrin deficiency <2.5 Caveat: Test done during asymptomatic phase, not during crisis!

  8. Lost to follow up Urine metabolic screen Sweat chloride Plasma Chitotriosidase Sphingomyelinase Beta-glucosidase Beta-galactosidase normal Persisting: Doll like facies Organomegaly Growth failure AST/ALT: 163/84 T. protein:5.9 Albumin: 2.9 ALP:913 GGT:138 CK: 24 Lipid profile: normal Apr 2009 (10mo) Jan 2012 (3 ½ yrs)

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

  10. Urine NGRS + GAL1PUT& Epimerase normal GSD workup negative High AFP Urine Succinylacetone normal Liver biopsy not possible - coagulopathy SGPGI H/O Transient neonatal cholestasis (not worked up anywhere) Bone Marrow : normal Failure to thrive Organomegaly Craving for protein rich food Aversion to carbohydrates/ juices TB/DB: 0.5/0.1 AST/ALT: 128/60 T. Prot/ Alb: 4.6/2.0 ALP:1505 GGT: 148 INR:1.6 TB/DB: 0.7/0.2 AST/ALT: 156/78 T. Prot/ Alb: 5.4/1.7 ALP:930 INR:1.8 Oct ‘08 (~3yrs) Jan ‘09

  11. Transient neonatal cholestasis Liver failure! Liver Transplant Urine for metabolic screen Sphingomyelinase Beta-glucosidase Beta-galactosidase normal DEATH Jaundice 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 INR:1.8 TB/DB: 2.0/1.3 AST/ALT: 121/77 T. Prot/ Alb: 4.5/1.5 ALP:684 GGT:88 INR: 2.3 TB/DB: 14.0/8.8 AST/ALT: 225/73 T. Prot/ Alb: 5.5/1.6 ALP:515 INR: 4.4 Jan ‘09 Dec ‘09 (~4yr) Apr ‘10 (4 ½ yr)

  12. SLC25A13 gene testing and mutational analysis not available

  13. Citrin deficiency Autosomal Recessive

  14. “Disease of East Asian Ancestry!” Pan-ethnic Carrier frequency of gene mutation China (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) Mol Genet Metab. 2009 Jan;96(1):44-9. Pediatr Res 2004 Oct;56(4):608-14

  15. Citrin deficiency Chubby faces Kobayashi et al Gene Reviews 2005

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

  17. Chubby Index = (1+2)/3 Chen HW, JPGN 47:187–192, 2008 Controls (n=13) Patients (n=5) • 13.3 • 1.336 • 1.00

  18. Can LFT predict? • Age: 93 days • DB:3.8 • TB:7.4 • AST:321 • ALT: 138 • ALP:1672 • GGT:66 Chen HW, JPGN 47:187–192, 2008 • 2.3 • 0.5

  19. Unexplained Hypoproteinemia! Feature of citrin def. Chen HW, JPGN 47:187–192, 2008

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

  21. Journal of Pediatric Gastroenterology and Nutrition Jun 2010 19 patients with Citrullinemia II 90% steatosis 79% fibrosis 21% diagnosed NAFLD Komatsu et al, J Hepatol 2008 Nov;49(5)) Fatty livers without obesity !BMI <20 High serum Pancreatic secretorytrypsin inhibitor (PSTI) >29ng/ml ……Pancreatitis (68%) !

  22. 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

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

  24. Diet peculiarities “My son hates rice and eats only fish!” “…. wants milk 24 x7 !!” (Seen in Citrullinemia Type II)

  25. 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

  26. Liver Transplant Recurrent encephalopathy Liver failure Hepatocellular Carcinoma (5-8%) Good outcome Auxillary Partial Orthotropic Kobayashi et al Gene Reviews 2005 Soo Kim, J Korean Surg Soc 2011;80:S51-54 Yazaki, Liver Transplantation, Vol 10, No 4 (April), 2004

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

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

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

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