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CITRIN DEFICIENCY
- 1. Story of twosiblings with “Chubby Cheeks” Dept. of Pediatric Gastroenterology SGPGIMS, Lucknow
- 2. Chubby cheeks –cute babies?
- 3. GSD workup negative Exposure to fruit juices AffectedSIB Neonatal cholestasis TB:7.4 DB:3.8 AST:321 ALT: 138 T. Prot:3.9 Alb: 2.0 ALP:1672 GGT:66 Resolved by 5mo Sep 2008 (3mo) Acute encephalopathy Liver biopsy: early cirrhosis macrovesicular steatosis Urine NGRS + High AFP ABG/ Blood sugar/ U. ketones/ Lactate All normal ! Ammonia :119 (Normal:11-47) GAL1PUT & Epimerase normal Persisting: Doll like facies Organomegaly AST/ALT: 253/180 T. Prot/ Alb: 4.0/1.8 ALP:1297 Urine Succinylacetone normal Apr 2009 (10mo)
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- 5. Differential Diagnosis GSD -IV Fanconi Bickel syndrome (GSD with RTA)
- 6. Doll Like facies… Whatis it ? Transient neonatal cholestasis Affected sib with downhill course Hyperammonemia (encephalopathy) Steatosis & cirrhosis on biopsy Doll like facies Citrin deficiency
- 7. Fischers ratio (BCAA/ArAA) =2.18 Citrin deficiency <2.5 Caveat: Testdone during asymptomatic phase, not during crisis!
- 8. Lost to followup Urine metabolic screen Sweat chloride Plasma Chitotriosidase Sphingomyelinase Beta-glucosidase Beta-galactosidase Apr 2009 (10mo) normal AST/ALT: 163/84 T. protein:5.9 Albumin: 2.9 ALP:913 GGT:138 CK: 24 Lipid profile: normal Persisting: Doll like facies Organomegaly Growth failure Jan 2012 (3 ½ yrs)
- 9. Preference to proteinrich foods, loves milk – parents reluctant!
- 10. Urine NGRS + GSD workup negative High AFP H/O Transient neonatal cholestasis (notworked up anywhere) SGPGI GAL1PUT& Epimerase normal Urine Succinylacetone normal Liver biopsy not possible - coagulopathy Bone Marrow : normal Failure to thrive Organomegaly TB/DB: 0.5/0.1 AST/ALT: 128/60 T. Prot/ Alb: 4.6/2.0 ALP:1505 GGT: 148 INR:1.6 Oct ‘08 (~3yrs) Craving for protein rich food Aversion to carbohydrates/ juices TB/DB: 0.7/0.2 AST/ALT: 156/78 T. Prot/ Alb: 5.4/1.7 ALP:930 INR:1.8 Jan ‘09
- 11. Liver failure! Transient neonatalcholestasis Urine for metabolic screen Sphingomyelinase Beta-glucosidase Beta-galactosidase normal Liver Transplant D E A T H 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 testingand mutational analysis not available
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- 14. Carrier frequency ofgene 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 Kobayashiet al Gene Reviews 2005
- 16. Recovery ALF Citrullinemia CLD Type II ChineseNICCD cohort (n=26) 21 (81%) by 1 5 (19%) : yr age 4 died, 1 LT - - Retrospective Japanese series (n=75) 45 NICCD 30 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):180-5 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. Younger Sib Total Protein/Albumin Sep 08: Total Protein/ Albumin Jan 09: Total Protein/ Albumin April 09: Total Protein/ Albumin Jan 12: Unexplained Hypoproteinemia! 3.9 / 2.0 4.3 / 2.1 4.0 / 1.8 5.9 / 2.9 Feature of citrin def. Chen HW, JPGN 47:187–192, 2008 Elder sib Oct 08 Jan 09 Dec 09 Apr 10 AST ALT AST/ALT 128 60 156 78 225 97 2.1 2.0 121 77 1.57 ALP T.Protein Albumin 1505 4.6 2.0 930 5.4 1.7 684 4.5 1.5 2.3 505 5.5 1.6
- 20. Histopathology changes Steatosis (2/3) NeonatalHepatitis like FibrosisCirrhosis >50% Citrin deficiency (Taiwan series) NASH NAFLD May persist into adulthood 6% Neonatal cholestasis (Chinese series) 12% Idiopathic neonatal hepatitis (Japanese series) Liver failure
- 21. Journal of PediatricGastroenterology 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) >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 Literaturefrom Chinese/Japanese articles Natural History is unclear Misdiagnosis as Galactosemia and Tyrosinemia (increase galactose and tyrosine in blood, galactosuria) Plasma amino acids Inconsistently and varied elevation New born screen ineffective Normal during asymptomatic phase, GI bleed, high protein intake Urine GCMS: Various nonspecific metabolites
- 24. Diet peculiarities Urea Cycle defects Protein aversion “Myson hates rice and eats only fish!” “…. wants milk 24 x7 !!” (Seen in Citrullinemia Type II) Protein craving Citrin deficiency Carbohydrate aversion
- 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 Liverfailure 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 glittersis not GOLD! All Chubby cheeks are not GSD! THANK YOU
- 29. Lipids 1)compensate for energy 2) FAinhibit 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 CoA +OAA) Hypoproteinemia (subclinical edema)
- 30. Unexplained concepts • Whymajority outgrow the disease? • Any additional factors for progression to CLD/ALF ? • Postulation for protein craving?