Complications
May manifest as recurrent epistaxis, ecchymoses, or oozing after dental surgery or other surgical treatments and is caused by impaired platelet function. Reduced platelet adhesiveness, abnormal platelet aggregation, and impaired release of adenosine diphosphate in response to collagen and epinephrine have been observed. These platelet defects are secondary to the systemic metabolic abnormalities of this disease and are corrected by improving patients' metabolic state.
Nephromegaly is a characteristic feature. Proximal tubular dysfunction (glucosuria, phosphaturia, potassium wasting, and generalized aminoaciduria) is reversible when biochemical control of the disease improves.[37] Some patients also have hypocitraturia and hypercalciuria, which predisposes to nephrocalcinosis and renal calculi.[38]
Albuminuria may be observed in adolescents. Young adults may have more severe renal injury with proteinuria, hypertension, and decreased creatinine clearance due to focal segmental glomerulosclerosis and interstitial fibrosis, which ultimately lead to end-stage renal disease. Therapy instituted at or before 1 year of age that maintains optimal metabolic control may delay, prevent, or slow the progression of renal disease.[39] Treatment with ACE inhibitors decreases glomerular filtration rate in patients with glomerular hyperfiltration.[40]
Development of hepatic adenomas is a common complication that occurs in the majority of adult patients, usually appearing in the second and third decades of life (prepubertal lesions are uncommon). Adenomas may undergo malignant degeneration or hemorrhage.
Ultrasonography is the preferred method of screening for hepatic adenomas. MRI provides greater definition when malignancy is suspected because of a change in appearance from a small, well-circumscribed lesion to one that is larger and poorly marginated. Serum alpha-fetoprotein levels are normal in patients with adenomas, but have been elevated in some cases of hepatocellular carcinoma.[41][42]
An unremitting iron-resistant anemia occurs in association with large hepatic adenomas, which express hepcidin, a peptide that inhibits intestinal absorption of iron and macrophage recycling of iron. Resection of hepatic adenomas results in rapid correction of the anemia.[43]
Radiographic studies have shown osteopenia and pathologic studies have shown pure osteoporosis, without evidence of abnormalities in calcium, phosphate, parathyroid, or vitamin D metabolism. Bone mineral content is decreased compared with normal children of the same age. Endocrine and metabolic disturbances, including lactic acidosis, elevated cortisol levels, resistance to growth hormone, and delayed pubertal development may all account for these observations of decreased bone mineralization.
Strict adherence to an optimal dietary regimen can ensure normal growth and musculoskeletal development. This includes adequate intake (via supplementation) of calcium and vitamin D.[44]
Most patients with GSD Ib have either constant or cyclic neutropenia, the severity of which ranges from mild to complete agranulocytosis and is associated with recurrent bacterial infections. The cause of neutropenia and neutrophil dysfunction in GSD Ib has been associated with accumulating 1,5-anhydroglucitol-6-phosphate and, as a result, may be targeted by SGLT2 inhibitors.[29][30][31]
Patients frequently develop an inflammatory bowel disease resembling Crohn disease, which is responsive to treatment with granulocyte colony stimulating factor.[47] Children with GSD Ib are prone to oral complications, including recurrent mucosal ulceration, gingivitis, and rapidly progressive periodontal disease.
Although hypoglycemia becomes less severe with increasing age, inadequate therapy causes pronounced impairment of growth and delayed puberty. However, patients grow and develop normally when continuous glucose therapy is started early in life and long-term metabolic control is maintained.
Menstrual irregularities and hirsutism are uncommon and may reflect patients' poor metabolic control rather than be a complication of the disease per se. However, ultrasonography studies in all types of hepatic GSDs demonstrate a high prevalence of morphologically polycystic ovaries (even in prepubertal children). The clinical significance of this is still unclear. Normal pregnancies have been reported in women with GSD Ia.[45] There have been a small number of cases of successful pregnancies in women with GSD Ib.[46] Pregnancy presents special metabolic risks to the mother and fetus requiring expert management throughout the pregnancy and delivery.
Pulmonary hypertension has been described presenting in the second or third decade of life and leading to premature death from heart failure.
Patients with GSD Ib have an increased prevalence of thyroid autoimmunity and primary hypothyroidism.[48] Screening is recommended.
Arterial dysfunction (increased intima-media thickness and abnormal radial artery reactivity) has been observed in young adults with GSD I and may be attributable to dyslipidemia.[49]
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