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• W2050766142 abstract "Glycogen storage disease type 1b (GSD 1b) results from a defect in the microsomal membrane translocase system for glucose-6-phosphate. Glycogen storage disease type 1a (GSD 1a) differs from GSD 1b in that it results from a defect in the enzyme glucose-6-phosphatase (1,2). This defect associated with GSD 1b inhibits the hydrolysis of glucose-6-phosphate by the microsome for transport into the lumen of the endoplasmic reticulum of hepatocytes (1). Features associated with GSD 1b, as in GSD 1a, include hypoglycemia, hepatomegaly, growth failure, lactic acidosis, hyperuricemia, and hyperlipidemia. Recurrent infection secondary to neutropenia and neutrophil dysfunction is a distinctive feature of GSD type 1b (3). Impaired neutrophil chemotaxis, mobilization, decreased superoxide production, and maturational arrest at various stages of myeloid development all contribute to the abnormal neutrophil function observed in this condition (3–5). Other associations include Crohn-like enteritis (6,7), oral and anal ulcerations (4), esophagitis (7), and iron deficiency anemia (5). Neutropenia and neutrophil dysfunction are probable causes of Crohn-like enteritis in GSD 1b. Crohn-like enteritis also has been reported in patients with neutropenia and other diseases characterized by neutrophil dysfunction, such as chronic granulomatous disease (8,9). Treatment with granulocyte colony-stimulating factor (G-CSF) improves neutropenia, neutrophil function, and Crohn-like enteritis in patients with GSD 1b (5,10,11). The purpose of this report is to increase awareness that hypoglycemia may be a sign of Crohn-like enteritis in patients with GSD 1b who have responded previously to G-CSF. Furthermore, as a consequence of G-CSF therapy, splenomegaly developed in the patient described in this case report. Splenectomy was performed to treat this side effect. CASE REPORT The patient, a 9-year-old girl, originally presented at 3 months of age with failure to thrive and marked hepatomegaly. At the time of examination, the patient was found to have an absolute granulocyte count (AGC) of 0.300 × 109/L, a platelet count of 554 × 109/L, hemoglobin concentration of 92 g/L; lactic acidosis (pH = 7.25, lactate 11.7 mmol/L), ketonuria, a triglyceride concentration of 9.0 mmol/L (normal 0.5–1.5); and a urate concentration of 99 mmol/L (normal 140–380 mmol/L). Ultrasonography showed a homogeneously enlarged liver and slightly enlarged kidneys bilaterally. Postprandial plasma glucose concentrations ranged from 5.5 mmol/L to 6.7 mmol/L but decreased to 1.1 mmol/L or lower within 2 to 3 hours. The patient began frequent daytime feeds with Prosobee (Mead-Johnson Nutritionals, Ottawa, Ontario, Canada) and Polycose (Ross, Saint-Laurrent, Quebec, Canada), which provided 10 mg glucose · kg−1 · min−1 during the day, and a continuous nasogastric infusion of a similar formulation, which yielded 6 mg · kg−1 · min−1 during the night. Liver biopsy performed at 4.5 months of age led to a diagnosis of glycogen storage disease type 1 with periodic acid Schiff-positive material that was diastase labile, indicating glycogen in the cytoplasm. Recurrently documented instances of neutropenia with recurrent infections during the next 12 months led to the identification of GSD 1b in the patient. Treatment with G-CSF was initiated at 22 months of age because of agranulocytosis, aphthous ulcers, and acute inflammation around the gastrostomy tube site of the patient. Clinical improvement was noted within 10 days, and AGC increased to 3.6x109/L. The patient remained well while G-CSF was administered. The G-CSF dose was adjusted in response to symptoms suggestive of neutrophil dysfunction, including recurrent mouth ulcers, intermittent perianal inflammation, gastrostomy tube site inflammation, or neutropenia (AGC < 1.0x109/L). The development of splenomegaly secondary to G-CSF also became a limiting factor to the G-CSF dosing regimen of the patient. The patient had not experienced severe hypoglycemia (glucose concentration < 2.5 mmol/L) for 9 years, except for two accidental interruptions of the continuous nighttime infusion caused by gastrostomy tube disconnections. At 9 years of age, hypoglycemia occurred in the early morning, despite continuous nighttime nasogastric administration of 6.9 mg glucose · kg−1 · min−1. Two of these events were associated with seizures, and both responded to treatment with 10% intravenous dextrose. Concurrently, the patient was receiving ongoing treatment with G-CSF (10.4 μg · kg−1 · min−1 every three of four days). During the previous 2 months, the following symptoms had developed: watery stools, worsening flatus, nighttime stools, chronic aphthous ulcers, anal fissures, and weight loss. She also was unresponsive to antibiotic therapy for bowel decontamination. Several days before admission, a sore throat, a cough, a recurrent low-grade fever, and joint pains developed in the patient. At the time of admission to a peripheral hospital, her temperature was 39.6°C. She had vomited her continuous nighttime feed twice, and her blood sugar concentration was 1.0 mmol/L. She was treated with intravenous glucose, was stabilized, and was transferred. At the time of examination, she seemed pale and tired, with a temperature of 39.6°C. Her heart rate was 100 beats per minute, and her respiratory rate was 23 breaths per minute. She had three mouth ulcers. Pulmonary examination was clear. Abdominal examination revealed a soft, nontender abdomen with active bowel sounds. Her liver extended 5 cm below the right costal margin in the midclavicular line, and her spleen extended 8 cm below the left costal margin in the midclavicular line. The gastrostomy tube site was healthy. Blood, urine, and stool cultures were studied. The complete blood count with differential showed a white blood cell count of 1.3 × 109/L, an AGC of 0.800 × 109/L, a hemoglobin concentration of 78 g/L, and a platelet count of 94x109/L. The rest of the blood evaluation showed an erythrocyte sedimentation rate of 64 mm/h, normal electrolytes, and the following concentrations: glucose, 6.0 mmol/L; urea, 1.6 mmol/L; creatinine, 36 μmol/L; albumin, 28 g/L; total protein, 63 g/L; aspartate transaminase, 27 IU/L; alanine transaminase, 17 IU/L; lactate, 1.0 mmol/L; uric acid, 242 μmol/L; serum triglyceride, 1.01 mmol/L (range, 0.34–1.13). Urinalysis yielded normal results. The patient was treated with broad-spectrum antibiotics and, to prevent further hypoglycemia, continuous total parenteral nutrition (10% dextrose infusion providing 6.9 mg · kg−1 · min−1). The fever resolved after 5 days, and the patient remained clinically stable, with normal blood sugar ranging from 3.6–6.8 mmol/L. All blood and stool cultures were sterile after 5 days. Upper endoscopy showed small gastric erosions adjacent to the gastrostomy tube. Colonoscopy showed discrete ulcers with edema and loss of vascular pattern in the transverse colon and the terminal ileum. Histologic findings from the samples taken in the duodenum showed mild villous blunting (Fig. 1A.), and in the colon, mild edema, focal crypt abscess formation, and an ulcer with fibrous exudate containing neutrophils were noted (Fig. 1B.).FIG. 1.: A: Histology of duodenal biopsy showing mild villus blunting. B: Colonic biopsy showing a focal crypt abscess with neutrophil infiltration and fibrous exudates.Figure 1: ContinuedThe dose of G-CSF was increased from 10.4 μg/kg to 11.5 μg/kg, and the dosing frequency was increased to daily. The mouth ulcers, anal ulcer, and fissures of the patient resolved, and her stool pattern returned to normal. Her regular feeding pattern was restarted without any further episodes of hypoglycemia. Her white blood cell count increased to 3.1 × 109/L, and her AGC increased to 1.83 × 109/L. Other laboratory observations that improved included hemoglobin (101 g/L) and platelet count (117 × 109/L). The patient remained well with a higher dose of G-CSF, without any symptoms of Crohn-like enteritis. However, after 6 weeks of this higher dose of G-CSF, she had worsening splenomegaly, a recognized side effect of G-CSF therapy in children (12). Splenomegaly is not a feature of GSD 1b (13). The patient's splenomegaly caused considerable discomfort with movement, preventing the patient from participating in physical activities and causing an antalgic gait. Edema developed in the left leg because of partial occlusion of the lymphatics. Thrombocytopenia and anemia also developed. Attempts to decrease the dose of G-CSF lead to recurrences of neutropenia, infection, mouth sores, and diarrhea without any change in spleen size. After discussion with the patient and her family, a splenectomy was performed on May 3, 1999, without complications. The patient developed Howell Jolly bodies secondary to the splenectomy. Platelet count improved from 89 × 109/L to 315 × 109/L and hemoglobin concentration improved from 83 g/L to 104 g/L. The patient's diarrhea resolved, and her serum glucose concentration remained greater than 3.6 g/L during administration of a lower dose of G-CSF (7.3 μ · kg−1 · min−1). The splenectomy has been very beneficial for this patient. DISCUSSION The sudden onset of fever and hypoglycemia associated with seizures, which developed after many years of uninterrupted metabolic stability, was unusual. None of this child's previous febrile illnesses or infections caused hypoglycemic seizures. Nighttime hypoglycemia probably was not caused by decreased nutritional intake because overnight supplementation with nasogastric infusion remained constant throughout this period. In addition to hypoglycemia, the patient's weight loss, hypoalbuminemia, chronic diarrhea, and decreased intestinal transit probably resulted from intestinal injury secondary to neutropenia and neutrophil dysfunction. This injury was manifested by focal partial villus atrophy and a Crohn-like mucosal inflammation that involved the duodenum, terminal ileum, cecum, and colon. This contributed to hypoglycemia through malabsorption, increased intestinal losses, and increased energy requirements. Neutropenia associated with GSD 1b and complicated by hypersplenism, which limited her G-CSF dosing, probably contributed to the previous failure of bowel decontamination by means of antibiotics to improve her gastrointestinal symptoms. Most reports of Crohn-like enteritis in patients with GSD 1b describe abdominal pain and anorexia (6,7) or diarrhea (5,10), whereas only one report notes hypoglycemia despite continuous enteral supplementation (10). The current patient did not report abdominal pain or cramping. Her hypoglycemia warranted further investigation and revealed Crohn-like enteritis and a concurrent low neutrophil count, which subsequently responded to an increased dose and frequency of G-CSF therapy. The other patient in the literature with underwent orthotopic liver transplantation. Therefore, the hypoglycemic improvement of that patient cannot be attributed solely to G-CSF therapy improving the Crohn-like enteritis. We hypothesize that G-CSF improved the patient's ability to combat inflammation in the bowel through increased neutrophil counts and improved function. Decreased bowel inflammation would allow for slower transit times, causing absorption of nutrients and possibly helping the partial villus blunting to return to normal. This would allow improved absorption of carbohydrates and would decrease the likelihood of hypoglycemia. Bowel decontamination with antibiotics would have a similar effect by decreasing bacterial stimulation of inflammation. Inflammation caused by bowel contamination has been observed in an interleukin-10 knockout mouse model (14). This may provide a partial explanation for intestinal inflammation observed in patients with neutrophil dysfunction. It also may explain why our patient usually responds to antibiotic therapy. The intestinal tract has a limited repertoire of response to injury. Therefore, similar manifestations may be common to more than one cause. Patients with GSD 1b are immunosuppressed, with increased risk of infection secondary to neutrophil dysfunction and neutropenia. Previous attempts to treat these patients with immunosuppressive agents have been unsuccessful (5,10) and are relatively contraindicated because of the increased risk of infection. Treatment with an increased dose and frequency of G-CSF produced a resolution of our child's diarrhea, hypoglycemic episodes, and oral and anal ulcers. Because of ongoing neutropenia, neutrophil dysfunction, and related symptoms, it was necessary to continue G-CSF therapy (11). Correction of neutropenia and Crohnlike enteritis with G-CSF is well-documented in GSD 1b literature (5,10,11). The exact mechanism by which G-CSF improves Crohn-like enteritis in GSD 1b is unclear. Previous in vitro studies have shown that G-CSF enhances or primes neutrophil oxygen-dependent and -independent microbicidal functions in response to cellular activation (15,16,17). In a recent article, it was shown that neutrophils in patients with GSD1b are unable to increase intracellular glucose. This limits their ability to generate reduced nicotinamide adenine dinucleotide phosphate from the hexose-monophosphate shunt as an energy source for such metabolic activities as respiratory bursts (18). In addition, G-CSF may inhibit neutrophil apoptosis (17,19). As a result, it is possible that G-CSF administration overcomes neutrophil dysfunction associated with GSD 1b (3). However, this still needs to be established in vivo. Clinically, the current patient still requires intermittent therapy with metronidazole to treat diarrhea and anal fissures despite adequate neutrophil counts, indicating that G-CSF does not overcome the neutrophil dysfunction seen in such patients. In addition, the side effects of G-CSF therapy, such as splenomegaly, have not been well-documented in this patient population. Splenomegaly is not a feature of GSD 1b (4). A review of the literature showed one 18-year-old patient with GSD 1b, who was treated with G-CSF and underwent splenectomy because of G-CSF induced splenomegaly (11). Crohn-like enteritis was not a feature of the disease of this patient. We also know of two patients with GSD 1b who underwent splenectomy for splenomegaly, but neither has been reported in the literature. Another report documents two patients with neutropenia and splenomegaly secondary to G-CSF therapy who have undergone splenectomy with good results (12). Hypoglycemia in a previously metabolically stable patient with GSD 1b may be a symptom of Crohn-like enteritis associated with this disease. Further investigation to evaluate the underlying cause of this hypoglycemia is warranted, especially if the patient has other symptoms suggestive of inflammatory bowel disease. Hypoglycemia may respond to treatment of Crohn-like intestinal inflammation with a higher dose or frequency of G-CSF. To our knowledge, this is the first reported patient with developed Crohn-like enteritis while undergoing G-CSF maintenance therapy. Heightened suspicion must be maintained for the association of these conditions with such patients, even while they are receiving therapy. Furthermore, splenomegaly secondary to G-CSF therapy was observed and was managed successfully by splenectomy." @default.
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• W2050766142 title "Crohn-like Enteritis Presenting as Hypoglycemia in a Patient With Glycogen Storage Disease Type 1b, Treated With Granulocyte Colony-stimulating Factor and Splenectomy" @default.
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