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Tomoko Yamaguchi, Kenji Ihara, Takayuki Matsumoto, Yasushi Tsutsumi, Akihiko Nomura, Shouichi Ohga, Toshiro Hara, Inflammatory Bowel Disease-Like Colitis in Glycogen Storage Disease Type 1b, Inflammatory Bowel Diseases, Volume 7, Issue 2, 1 May 2001, Pages 128–132, https://doi.org/10.1097/00054725-200105000-00008
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Summary
Chronic inflammatory bowel disease (IBD)-like colitis is occasionally associated with glycogen storage disease-type 1b (GSD-1b). We describe a 17-year old boy with GSD-1b who developed an IBD-like colitis. Roentgenography and colonoscopy showed the lead-pipe appearance of the colon and circumferential ulcers. Histopathologic examination revealed nonspecific inflammation without granulomatous lesions. High-dose granulocyte-colony stimulating factor (G-CSF) and sulfasalazine led to the resolution of the colitis, although neutropenia continued. Besides this case, 10 published cases of GSD-1b and IBD-like colitis were reviewed. All cases had severe neutropenia and/or neutrophil dysfunction. The mean onset of bowel disease was 12.3 years of age. Seven cases required surgical treatment. All five patients with G-CSF/GM-CSF therapy showed clinical remission. These findings suggest that IBD-like colitis is a grave complication of GSD-1b and that recurrent enteric infections due to neutrophil deficiency may contribute to the development of this bowel disease.
Introduction
Glycogen storage disease (GSD) type-1b (MIM #232220) is an inherited metabolic disorder in which glucose-6-phosphate cannot be converted to glucose due to the deficiency of the microsomal transport system for glucose-6-phosphate in the liver (1,2). Hypoglycemia, hepatomegaly, and growth failure are the common clinical symptoms of GSD type 1, while neutropenia and neutrophil dysfunction are restricted to type-1b (3). GSD-1b patients often complain of oral aphtha and perianal abscess. On the other hand, inflammatory bowel disease (IBD)-like colitis develops as an occasional complication in the gastrointestinal (GI) tract (4,–10). IBD-like colitis is mostly indistinguishable from Crohn’s disease (CD). Neutropenia and defective neutrophil functions may account for the condition, although the precise mechanism remains elusive. Recently, granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) have been applied to GSD-1b patients, and the cases with IBD-like colitis are successfully managed with this therapy (9,10). We report a case of GSD-1b with CD-like colitis. This bowel disease responded to high-dose G-CSF therapy and salazosulfapyridine (SASP), despite the presence of neutropenia. The pathogenesis of this unique complication is discussed with a review of the literature.
Case Report
A 16-year-old boy was hospitalized with fever and diarrhea. The patient had been diagnosed as GSD-1b by typical clinical findings and defective enzyme activity at 4 months of age (11,12). Genetic analysis of glycose-6-phosphate translocase gene (G6PT1) revealed that he was a compound heterozygote of a missense mutation from tryptophan to cysteine at amino acid position 118, and an A to C transversion at intron 1 at −2 splicing acceptor site of intron 1. There was no family history of IBD. This patient carried no associated human leukocyte antigen loci with CD, ulcerative colitis (UC), and Behçet’s disease. Despite the frequent oral intake of carbohydrate-rich milk in the daytime and continuous nasogastric infusion at night, hypoglycemic attacks often occurred. Alpha-glucosidase inhibitor (Voglibose) (0.1 mg p.o. before every meal), which inhibits the dissolution of polysaccharides, had controlled hypoglycemia for these 3 years (13). G-CSF (5 μg/kg s.c., four times a week) therapy was started at 10 years of age. The frequency of severe bacterial infections was reduced, while absolute neutrophil count (ANC) still ranged from 200 to 800 cells/μL.
On admission, the boy, who had dwarfism (height: 150 cm, −3.6 SD, weight: 47.7 kg, +18%), presented with multiple oral ulcers and a tender abdomen. Liver was palpated 6 cm, and spleen tip was palpable below the costal margin. Peripheral blood count showed white blood cells at 1.74 × 103/μL (ANC 530/μL), Hb 11.4 g/dl, and platelets at 226 × 103/μL. The C-reactive protein level was 3.2 mg/dl. Erythrocyte sedimentation rate was 80 mm/hr. Blood chemistries were unremarkable. Serum immunoglobulin levels and mitogen responses were normal. Watery stool contained occult blood. Stool culture was negative for pathogenic bacteria. Mantoux skin test was also negative. Computed tomography revealed hepatosplenomegaly. Tc-scintigram accumulated to the spleen. Barium meal examination and esophagogastroduodenoscopy showed no abnormality. Contrast barium enema exhibited lead-pipe appearance of the entire colon with a narrowing segment at the splenic flexure (Fig. 1). Colonoscopy showed the disappearance of haustra, distorted vascular transparency, and circumferential ulcers (Fig. 2). Histological examination revealed nonspecific chronic inflammation without granulomatous lesions (Fig. 3). The polymerase chain reaction (PCR) study of biopsy specimens was negative for Mycobacterium species. These findings favored the diagnosis of CD-like colitis. High-dose G-CSF (250 μg, daily s.c.) therapy, oral SASP, and intravenous hyperalimentation lead to a clinical improvement after 2 months of hospitalization, whereas the increase of ANC was unsatisfactory. Since then, G-CSF, SASP, and dietary therapy to avoid sources of roughage have been continued. Reevaluation by colonoscopy and X-ray examination 1 year after admission disclosed an improvement of the colitis, although neutropenia and occasional enteric infections remained.
During the prolonged G-CSF therapy, ANC did not rise to the levels as expected. Bone marrow (BM) study showed myeloid hyperplasia without maturation arrest, whereas colony formation of BM progenitors in vitro was diminished. Epinephrine (0.2 mg, s.c.) provocation test did not increase circulating neutrophils, while corticosteroid (100 mg, s.c.) elicited a slight increase of ANC (from 300 to 800 cells/μl). Within 4 hours after an injection of G-CSF (250 μg, s.c.), ANC increased to 1,500 cells/μl, remained level for at least 12 hours, and returned to the preinjection level within the next 12 hours. Expression of G-CSF receptor was normal. There was no apparent recovery of neutrophil functions including superoxide production (<40% of normal) or chemotaxis to bacterial factor (∼66% of normal) during high-dose G-CSF therapy. Phagocytic activity and spontaneous apoptosis of neutrophils were not impaired during the therapy. Antigranulocyte antibody (Ab) and anti-G-CSF Ab were not detected. The refractory neutropenia seemed to be attributable to the limited mobilization and the defective maturation in BM, and otherwise peripheral consumption.
Literature Review
Eleven patients with GSD-1b who manifested IBD-like colitis are reviewed in Table 1 (4,–10,14). The onset of bowel disease was 12.3 ± 5.4 (mean + SD) years of age, ranging from 5 to 21 years old. Male to female ratio was 7 to 4. Affected lesions extended the length of the entire GI tract from the oral cavity to the anus. The most predominant site was the terminal ileum and the colon. Histopathology indicated three cases of CD or CD-like disease, and six of nonspecific inflammation. ANC was less than 1,000 cells/μL in all cases specified. Neutrophil functions were depressed in all seven cases examined. Surgical interventions including ileocolectomy, colectomy, and gastrostomy were instituted for seven patients. One patient received splenectomy, which failed to improve neutropenia. All five patients with G-CSF/GM-CSF therapy exhibited the clinical remission of IBD-like colitis. However, neutrophil functions did not necessarily recover during the G-CSF/GM-CSF therapy.
a O, Oral cavity; E, Esophagus; I, Ileum; Ce, Cecum; C, Colon; R, Rectum; A, Anus.
b C, Constriction; I, irregularity of mucosa; U, ulceration; F, fistula; P, pseudopolyp; T, thumb printing; Co, cobblestone appearance.
c Cr, Crohn’s like inflammation; NI, nonspecific inflammation.
d D, Defective.
e Me, Metronidazole; ED, elementary diet; Sa, Salicylic acid; St, Steroid; Su, Sulfasalazine; O, Olsalazine.
ND, not described; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor.
a O, Oral cavity; E, Esophagus; I, Ileum; Ce, Cecum; C, Colon; R, Rectum; A, Anus.
b C, Constriction; I, irregularity of mucosa; U, ulceration; F, fistula; P, pseudopolyp; T, thumb printing; Co, cobblestone appearance.
c Cr, Crohn’s like inflammation; NI, nonspecific inflammation.
d D, Defective.
e Me, Metronidazole; ED, elementary diet; Sa, Salicylic acid; St, Steroid; Su, Sulfasalazine; O, Olsalazine.
ND, not described; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor.
Discussion
As is with cyclic neutropenia, chronic granulomatous disease, Chediak-Higashi syndrome, and acute leukemia (15,–18), the IBD-like condition in GSD-1b seems to be attributable to neutropenia or neutrophil dysfunction, because all patients with GSD-1b exhibited neutropenia, and most of them have chemotactic defects of neutrophils and diminished activity of respiratory burst in phagocytes (19,20). Recently, human gene G6PT1 was identified, and patients with GSD I non-a from various ethnic groups had mutations in this gene (12). We previously reported that the G6PT1 gene was highly expressed in hematopoietic progenitor cells (21), therefore, the mutations of the G6PT1 gene in patients may cause diminishment of various functions of hematological cells and thereby introduce IBD-like colitis. In the present review, severe neutropenia and/or neutrophil dysfunction were found in all cases examined. Although most patients suffered from recurrent infections since infancy, bowel symptoms appeared during adolescence or soon thereafter. It is speculated that neutrophil deficiency leads to chronic low-grade infections of the gut, which may increase the predisposition to mucosal and bowel inflammation (14). In this setting, the development of IBD-like colitis may depend on the management of clinical and subclinical gastrointestinal infections, where persistent stimulation of microbes exists. Continuous infusion of carbohydrate-rich milk may disturb the intestinal flora and allow for optimal growth conditions for pathogenic microorganisms. Cornstarch or alpha-glucosidase inhibitor therapy may increase the aberrant stimulation to the intestine. In addition, G6PT1 gene was also expressed in the colon or intestine in relatively high levels (about one-half to one-third of hematopoietic progenitor cells) (21). It is possible that the G6PT enzyme in endothelial cells of the GI tract functions to protect against various bacteria or agents, and that the deficiency of the enzyme contributes to the development or progression of IBD-like colitis.
It is noteworthy that all five patients undergoing G-CSF/GM-CSF therapy recovered from their bowel disease, even though the neutrophil deficiency remained. Two refractory case reports, Hoover’s (9) and ours, showed splenomegaly and frequent GI infections. Both patients required G-CSF to maintain the ANC between 200 and 700 cells/μl. In Hoover’s study, ANC did not increase after splenectomy, while in our study, refractory neutropenia might be partly due to limited mobilization from the BM pool. Ambruso et al. (20) reported that 6 of 16 GSD-1b patients showed maturation arrest and 11 of 16 demonstrated myeloid hyperplasia in the BM study. Neutropenia of GSD-1b seems to stem from the defective maturation or mobilization, and splenomegaly might result from frequent bacterial infections. During G-CSF therapy, bacterial infection was appreciably controlled even though superoxide production and chemotactic activity of neutrophils did not apparently being normal, as described above. In addition, G-CSF administration induced sufficient increase of peripheral neutrophils with rapid decrease in ANC in our case, which suggested the peripheral consumption of neutrophils. Taken together, infection control in the gut rather than complete normalization of neutrophil function may be essential for the improvement of IBD-like colitis. Additionally, it is suggested that G-CSF therapy also may be effective for CD, UC, or IBD-like colitis when patients show neutropenia or neutrophil dysfunction.
Pathogenesis of other IBD including UC and CD involves multiple genetic and environmental factors. The genetic contribution of the G6PT1 gene to IBD is less unlikely, because the G6PT1 gene is not located on the chromosome loci for IBD, i.e., the linkage studies have identified several susceptible loci for IBD on chromosomes 1, 3, 4, 5, 6, 7, 10, 12, 14, 16, 17, 22, and X (22,23), while the human G6PT1 gene was mapped to chromosome 11q23.3 (24). However, further studies by candidate gene association will give us more information about the contribution of G6PT to the pathogenesis of IBD.
Acknowledgment
This work was supported in part by a grant-in-aid from the Ministry of Education, Science and Culture of Japan.
References
- glycogen storage disease
- inflammation
- neutropenia
- colonoscopy
- inflammatory bowel disease
- ulcer
- granulocyte colony-stimulating factor
- granulocyte-macrophage colony-stimulating factor
- colitis
- glycogen
- recombinant granulocyte-macrophage colony-stimulating factors
- granuloma
- intestinal diseases
- neutrophils
- sulfasalazine
- surgical procedures, operative
- infections
- colon
- histopathology tests
- disease remission