CITRIN DEFICIENCY

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

2. Chubby cheeks – cute babies?

3. GSD
workup
negative
Exposure to
fruit juices
Affected SIB
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)

4. Differential Diagnosis
Hereditary Fructose
Intolerance

5. Differential Diagnosis
GSD - IV
Fanconi
Bickel
syndrome
(GSD with RTA)

6. 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

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
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 protein rich foods, loves milk – parents reluctant!

10. Urine NGRS
+
GSD
workup
negative
High
AFP
H/O Transient
neonatal
cholestasis
(not worked 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 neonatal cholestasis
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 testing and
mutational analysis not available

13. Citrin deficiency
Autosomal
Recessive

14. 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. Recovery
ALF
Citrullinemia CLD
Type II
Chinese NICCD
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)
Neonatal Hepatitis 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 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) >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)
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
“My son 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
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

29. 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 CoA +OAA)
Hypoproteinemia (subclinical edema)

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