story of two siblings with “chubby cheeks”
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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?