JIMD Reports DOI 10.1007/8904_2015_452
RESEARCH REPORT
High Incidence of Serologic Markers of Inflammatory Bowel Disease in Asymptomatic Patients with Glycogen Storage Disease Type Ia Nicole T. Lawrence • Tayoot Chengsupanimit • Laurie M. Brown • David A. Weinstein
Received: 05 March 2015 / Revised: 09 April 2015 / Accepted: 23 April 2015 # SSIEM and Springer-Verlag Berlin Heidelberg 2015
Abstract Most patients with glycogen storage disease (GSD) type Ib show features related to inflammatory bowel disease (IBD). The development of IBD seems to be associated with the defect of neutrophil function in GSD Ib. Patients with GSD Ia were not recognized to have similar gastrointestinal complaints until recently and are not associated with a neutrophil defect. Fifty consecutive GSD Ia inpatients over the age of 2 years without a diagnosis of IBD were screened using serologic and genetic markers via the Prometheus IBD sgi Diagnostic test. Eleven patients were tested positive for IBD (22%), with five fitting the pattern for Crohn’s disease, five for ulcerative colitis, and one with nonspecific IBD. Only 2 out of the 11 patients had any gastrointestinal complaints. No pattern could be distinguished from individual inflammatory markers, genetics, inflammation antibodies, age, complications, or metabolic control. Of note, 9 out of 11 patients testing positive were female. Patients with GSD Ia were found to have a higher rate of serologically indicated IBD when compared with the general population. While these subjects will need to be followed to determine if these serologic markers correlate with clinical disease, this study supports that IBD may be more common in the GSD Ia population. Further
Communicated by: Gerard T. Berry, M.D. Competing interests: None declared N.T. Lawrence Division of Pediatric Gastroenterology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA
T. Chengsupanimit : L.M. Brown : D.A. Weinstein (*) Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610-0296, USA e-mail: [email protected]
studies are warranted to explain the relationship between IBD and GSD I since it may provide clues regarding the pathogenesis of IBD development in the general population.
Background Glycogen storage disease type Ia (GSD Ia; OMIM 232200) is an autosomal recessive disorder of glycogen metabolism that affects approximately 1 in 100,000 live births (Chen 2001). Mutations of the genes that encode glucose-6phosphatase (subtype Ia) and glucose-6-phosphate translocase (subtype Ib) have been isolated (Lei et al. 1993, 1995). Diagnosis is suspected in infants with fasting hypoglycemia, lactic acidosis, hyperlipidemia, and hepatomegaly. Other complications include hepatic adenomas, growth retardation, osteoporosis, and nephropathy. GSD Ib is similar to GSD Ia with the added features of neutropenia and phagocyte dysfunction (Gitzelmann and Bosshard 1993). Without immediate recognition of symptoms and appropriate treatment, GSD can be fatal in infancy. Fortunately, much success has been achieved in the management of GSD as blood glucose levels can be sustained with cornstarch and overnight nasogastric feeds (Wolfsdorf and Crigler 1997, 1999). However, the improved mortality rates have been offset by an increase in morbidity as patients reach older ages. Roe et al. (1986) first described an association between inflammatory bowel disease (IBD) and GSD Ib. Since that time, there have been continued investigations on the causal relationship of these two conditions (Melis et al. 2003). Historically, neutropenia has been used to explain the almost universal development of GSD enterocolitis in patients with GSD Ib. Surprisingly, treatment with granulocyte colony-stimulating factor has led to an improvement of
JIMD Reports
the symptoms of IBD, but has not resulted in the resolution of the disease (Visser et al. 2002). It is published that up to 77% of GSD Ib patients have serologically, histologically, and clinically confirmed IBD (Visser et al. 2000). A prospective study of 19 asymptomatic patients with GSD Ib also found that 89% of the subjects had elevated antiCBir1 concentrations and serologic studies consistent with IBD (Davis et al. 2010). Until recently, there have been no definitive connections made between IBD and other types of GSD. We have recently found a cohort of GSD Ia patients that are endoscopically and/or histologically confirmed to have either enteritis or colitis, two of which had characteristics of Crohn’s disease (CD) and three with disease most consistent with ulcerative colitis (UC) (Lawrence et al. 2014). As mentioned previously, IBD in patients with GSD Ib is typically attributed to functional deficiency in neutrophils. However to date, GSD Ia is rarely associated with a quantitative or qualitative defect of neutrophils. The aim of this study was to determine if there is a genetic or serologic predisposition of patients with GSD Ia to develop IBD.
were used to analyze the continuous data. Frequency tables were used to summarize categorical data.
Results Out of 50 total participants in the study, 11 tested positive for IBD. Five had a pattern consistent with Crohn’s disease, five had a pattern consistent with ulcerative colitis, and one had nonspecific IBD. Our prevalence rate is thus 22% within this cohort. Of note, 9 out of 11 patients testing positive for IBD were female. Sex and panel result were not independent (w2 ¼ 11.22, p ¼ 0.007). For all other individual variables (age, antibody assays, genetics/genotype, inflammatory markers), either no pattern was discovered or there was no significant difference between patients testing positive for IBD and patients testing negative for IBD (Fig. 1, Table 1). The same patients testing positive do not seem to show a higher complication rate or less optimal metabolic control than the patients testing negative.
Discussion Methods Blood samples were obtained from 50 consecutive inpatients with GSD Ia who qualified for the study and did not already have a diagnosis of IBD at UF Health Shands Hospital between January 2014 and October 2014. Informed consent was obtained from all participants to confirm they understood how their sample would be used in an IBD panel. Study protocols conformed to ethical guidelines and was approved by the University of Florida Institutional Review Board (IRB201300312). This is an observational, nonrandomized prevalence study of patients diagnosed with GSD Ia who did not manifest symptoms of IBD. The Prometheus IBD sgi Diagnostic test (Prometheus Laboratories, San Diego, CA) was used to predict and differentiate IBD based on an algorithm combining serologic, genetic, and inflammatory markers. The serologic markers include antibodies against yeast (ASCA-IgA and –IgG), antibodies against bacteria (Anti-OmpC, Anti-CBir1, Anti-Fla-X, and Anti-A4-Fla2), and autoantibodies (ANCA, pANCA, and DNase-sensitive ANCA). Genetic markers include ATG16L1, NKX2-3, STAT3, and ECM1. These are associated with autophagy, cell type specification and differentiation, signal transduction, and the extracellular matrix, respectively. Inflammatory markers include ICAM-1, VCAM-1, VEGF, CRP, and SAA. To ensure appropriate statistical power, 50 patients were recruited as the total cohort. Means and standard deviations
The management of GSD has markedly improved over the past 40 years. While survival was rare prior to the 1970s, most patients with GSD Ia and Ib are now doing well into adulthood (Rake et al. 2002; Visser et al. 2000). With aging, long-term complications have been appreciated, including the development of hepatic adenomas (Beegle et al. 2015), hepatocellular carcinomas (Limmer et al. 1988), osteoporosis (Minarich et al. 2012), and hepcidininduced anemia (Wang et al. 2012). IBD may be a
Fig. 1 Inflammatory bowel disease (IBD) panel result of patients by age
Inflammation
Genetics
G;G
4.8 4.8 5.0 >100.0 77.7 >100.0 18.6
C;C A;A A;G 0.47 0.52 812 0.3 2.2
x
Diagnosis
ECM1 (rs3737240) NKX2-3 (rs10883365) STAT3 (rs744166) ICAM-1 (mg/mL) VCAM-1 (mg/mL) VEGF (pg/mL) CRP (mg/L) SAA (mg/L)
13
Age (year)
Serology
F
Sex
CD UC Inconclusive for CD vs. UC ASCA-IgA ELISA (EU/mL) ASCA IgG ELISA (EU/mL) Anti-OmpC IgA ELISA (EU/mL) Anti-CBir1 IgG ELISA (EU/mL) Anti-A4-Fla2 IgG ELISA (EU/mL) Anti-FlaX IgG ELISA (EU/mL) AutoAntibody ELISA (EU/mL) IFA perinuclear pattern detected DNAse sensitive ATG16L1 (rs2241880)
1
Patient
C;C A;A A;A 0.43 0.53 244 0.4 1.1
A;A
x
RESEARCH REPORT
High Incidence of Serologic Markers of Inflammatory Bowel Disease in Asymptomatic Patients with Glycogen Storage Disease Type Ia Nicole T. Lawrence • Tayoot Chengsupanimit • Laurie M. Brown • David A. Weinstein
Received: 05 March 2015 / Revised: 09 April 2015 / Accepted: 23 April 2015 # SSIEM and Springer-Verlag Berlin Heidelberg 2015
Abstract Most patients with glycogen storage disease (GSD) type Ib show features related to inflammatory bowel disease (IBD). The development of IBD seems to be associated with the defect of neutrophil function in GSD Ib. Patients with GSD Ia were not recognized to have similar gastrointestinal complaints until recently and are not associated with a neutrophil defect. Fifty consecutive GSD Ia inpatients over the age of 2 years without a diagnosis of IBD were screened using serologic and genetic markers via the Prometheus IBD sgi Diagnostic test. Eleven patients were tested positive for IBD (22%), with five fitting the pattern for Crohn’s disease, five for ulcerative colitis, and one with nonspecific IBD. Only 2 out of the 11 patients had any gastrointestinal complaints. No pattern could be distinguished from individual inflammatory markers, genetics, inflammation antibodies, age, complications, or metabolic control. Of note, 9 out of 11 patients testing positive were female. Patients with GSD Ia were found to have a higher rate of serologically indicated IBD when compared with the general population. While these subjects will need to be followed to determine if these serologic markers correlate with clinical disease, this study supports that IBD may be more common in the GSD Ia population. Further
Communicated by: Gerard T. Berry, M.D. Competing interests: None declared N.T. Lawrence Division of Pediatric Gastroenterology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA
T. Chengsupanimit : L.M. Brown : D.A. Weinstein (*) Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610-0296, USA e-mail: [email protected]
studies are warranted to explain the relationship between IBD and GSD I since it may provide clues regarding the pathogenesis of IBD development in the general population.
Background Glycogen storage disease type Ia (GSD Ia; OMIM 232200) is an autosomal recessive disorder of glycogen metabolism that affects approximately 1 in 100,000 live births (Chen 2001). Mutations of the genes that encode glucose-6phosphatase (subtype Ia) and glucose-6-phosphate translocase (subtype Ib) have been isolated (Lei et al. 1993, 1995). Diagnosis is suspected in infants with fasting hypoglycemia, lactic acidosis, hyperlipidemia, and hepatomegaly. Other complications include hepatic adenomas, growth retardation, osteoporosis, and nephropathy. GSD Ib is similar to GSD Ia with the added features of neutropenia and phagocyte dysfunction (Gitzelmann and Bosshard 1993). Without immediate recognition of symptoms and appropriate treatment, GSD can be fatal in infancy. Fortunately, much success has been achieved in the management of GSD as blood glucose levels can be sustained with cornstarch and overnight nasogastric feeds (Wolfsdorf and Crigler 1997, 1999). However, the improved mortality rates have been offset by an increase in morbidity as patients reach older ages. Roe et al. (1986) first described an association between inflammatory bowel disease (IBD) and GSD Ib. Since that time, there have been continued investigations on the causal relationship of these two conditions (Melis et al. 2003). Historically, neutropenia has been used to explain the almost universal development of GSD enterocolitis in patients with GSD Ib. Surprisingly, treatment with granulocyte colony-stimulating factor has led to an improvement of
JIMD Reports
the symptoms of IBD, but has not resulted in the resolution of the disease (Visser et al. 2002). It is published that up to 77% of GSD Ib patients have serologically, histologically, and clinically confirmed IBD (Visser et al. 2000). A prospective study of 19 asymptomatic patients with GSD Ib also found that 89% of the subjects had elevated antiCBir1 concentrations and serologic studies consistent with IBD (Davis et al. 2010). Until recently, there have been no definitive connections made between IBD and other types of GSD. We have recently found a cohort of GSD Ia patients that are endoscopically and/or histologically confirmed to have either enteritis or colitis, two of which had characteristics of Crohn’s disease (CD) and three with disease most consistent with ulcerative colitis (UC) (Lawrence et al. 2014). As mentioned previously, IBD in patients with GSD Ib is typically attributed to functional deficiency in neutrophils. However to date, GSD Ia is rarely associated with a quantitative or qualitative defect of neutrophils. The aim of this study was to determine if there is a genetic or serologic predisposition of patients with GSD Ia to develop IBD.
were used to analyze the continuous data. Frequency tables were used to summarize categorical data.
Results Out of 50 total participants in the study, 11 tested positive for IBD. Five had a pattern consistent with Crohn’s disease, five had a pattern consistent with ulcerative colitis, and one had nonspecific IBD. Our prevalence rate is thus 22% within this cohort. Of note, 9 out of 11 patients testing positive for IBD were female. Sex and panel result were not independent (w2 ¼ 11.22, p ¼ 0.007). For all other individual variables (age, antibody assays, genetics/genotype, inflammatory markers), either no pattern was discovered or there was no significant difference between patients testing positive for IBD and patients testing negative for IBD (Fig. 1, Table 1). The same patients testing positive do not seem to show a higher complication rate or less optimal metabolic control than the patients testing negative.
Discussion Methods Blood samples were obtained from 50 consecutive inpatients with GSD Ia who qualified for the study and did not already have a diagnosis of IBD at UF Health Shands Hospital between January 2014 and October 2014. Informed consent was obtained from all participants to confirm they understood how their sample would be used in an IBD panel. Study protocols conformed to ethical guidelines and was approved by the University of Florida Institutional Review Board (IRB201300312). This is an observational, nonrandomized prevalence study of patients diagnosed with GSD Ia who did not manifest symptoms of IBD. The Prometheus IBD sgi Diagnostic test (Prometheus Laboratories, San Diego, CA) was used to predict and differentiate IBD based on an algorithm combining serologic, genetic, and inflammatory markers. The serologic markers include antibodies against yeast (ASCA-IgA and –IgG), antibodies against bacteria (Anti-OmpC, Anti-CBir1, Anti-Fla-X, and Anti-A4-Fla2), and autoantibodies (ANCA, pANCA, and DNase-sensitive ANCA). Genetic markers include ATG16L1, NKX2-3, STAT3, and ECM1. These are associated with autophagy, cell type specification and differentiation, signal transduction, and the extracellular matrix, respectively. Inflammatory markers include ICAM-1, VCAM-1, VEGF, CRP, and SAA. To ensure appropriate statistical power, 50 patients were recruited as the total cohort. Means and standard deviations
The management of GSD has markedly improved over the past 40 years. While survival was rare prior to the 1970s, most patients with GSD Ia and Ib are now doing well into adulthood (Rake et al. 2002; Visser et al. 2000). With aging, long-term complications have been appreciated, including the development of hepatic adenomas (Beegle et al. 2015), hepatocellular carcinomas (Limmer et al. 1988), osteoporosis (Minarich et al. 2012), and hepcidininduced anemia (Wang et al. 2012). IBD may be a
Fig. 1 Inflammatory bowel disease (IBD) panel result of patients by age
Inflammation
Genetics
G;G
4.8 4.8 5.0 >100.0 77.7 >100.0 18.6
C;C A;A A;G 0.47 0.52 812 0.3 2.2
x
Diagnosis
ECM1 (rs3737240) NKX2-3 (rs10883365) STAT3 (rs744166) ICAM-1 (mg/mL) VCAM-1 (mg/mL) VEGF (pg/mL) CRP (mg/L) SAA (mg/L)
13
Age (year)
Serology
F
Sex
CD UC Inconclusive for CD vs. UC ASCA-IgA ELISA (EU/mL) ASCA IgG ELISA (EU/mL) Anti-OmpC IgA ELISA (EU/mL) Anti-CBir1 IgG ELISA (EU/mL) Anti-A4-Fla2 IgG ELISA (EU/mL) Anti-FlaX IgG ELISA (EU/mL) AutoAntibody ELISA (EU/mL) IFA perinuclear pattern detected DNAse sensitive ATG16L1 (rs2241880)
1
Patient
C;C A;A A;A 0.43 0.53 244 0.4 1.1
A;A
x
