Presentation on theme: "Department of Pediatrics San Paolo Hospital University of Milan"— Presentation transcript:
1Department of Pediatrics San Paolo Hospital University of Milan International meetingglycogen storage diseases associations2-3 October, MilanBONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE IIlaria Giulini NeriDepartment of PediatricsSan Paolo Hospital University of Milan
2Glycogen storage disease type I (GSD I) Disorder of glucose homeostasis (glycogenolysis/gluconeogenesis)Incidence: 1/Autosomal recessive transmissionType Ia glucose-6-phosphatase deficiencyType Ib glucose-6-phosphatase translocase
3Clinical and biochemical features of GSD I Accumulation of glycogen in liver, kidney, and intestineMetabolic derangements: fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemiaType Ib: neutropenia and neutrophil dysfunctionSeveral long term complications: short stature, liver adenoma, renal damage, osteoporosis, polycistic ovaries.
4Bone matrix loss in GSD/literature data Histopathological study: osteoporosis, no osteomalacia (Soejima et al., Pediatr Pathol, 1985)Radiographic study: osteopenia, retarded bone maturation, fractures, nonspecific skeletal abnormalities (Miller et al., AM J Roentgenol, 1979)BMC in prepubertal patients (Lee et al., Eur J Pediatr 1995)Association with reduced muscle force and metabolic control (Schwan et al., J Pediatr 2002)BMD in adolescence/adult patients: diminished bone mass accretion during childhood or historical differences in treatment? (Rake et al., J Inherit Met Dis, 2003)No correlation between BMD and markers of bone turnover (Cabrera-Abreu et al., J Inherit Met Dis, 2004)
5Bone matrix loss in GSD/pathophysiology Restrictive diet (dairy products, other sources of sucrose, fructose, galactose need to be avoided)Hypoglycaemia and low insulin values lead to a low non-enzymatic glycosilation of bone matrix proteins impaired bone resistanceChronic lactic acidosis:increase of mobilization and release of bone alkaline salts (calcium phosphate and carbonate) in response to a acid load to mantain acid-base balanceloss of calcium and phosphate with urine hypercalciuria and reduced tubular reabsorption of phosphatehigh activity of osteoclasts, reduced of osteoblasts
6Bone matrix loss in GSD/pathophysiology Endogenous glucocorticoid excess, altered levels of GH and IGF-1 seems to reduce collagen content in bone and matrix synthesisAbnormal pubertal growth spurt with sex hormone secretory dysfunction (important role in bone formation and adequate peack bone mass, especially during puberty)Decreased calcium absorption
7Bone matrix loss in GSD/pathophysiology Hypotrophic muscles and decreased muscle function (result of reduced whole-body protein synthesis and of increased proteinolysis due to increased gluconeogenesis, especially in poor metabolic control)Decreased physical activity (chronic disease) ?
8BONE METABOLISM AND VITAMIN D ROLE AIM OF THE STUDYBONE METABOLISM AND VITAMIN D ROLEIN PATIENTS WITH GSD ITo study prevalence of osteopenia and osteoporosisTo evaluate correlation between metabolic balance and bone markersTo determine plasmatic levels of 25(OH)D and to research a correlation with bone mineral density (BMD)
9background Why vitamin D? Important role in calcium homeostasis and bone metabolismVitamin D insufficiency osteoporosis (not rickets or osteomalacia) as a result of calcium malabsorptionVitamin D deficiency proximal muscle weakness (receptor for vitamin D (VDR) is expressed in human muscle tissue, and VDR activation may promote de novo protein synthesis in muscle)
10backgroundWhy vitamin D?Serum 25(OH)D is the correct functional indicator of vitamin D status; reference values according to Holick, M. F. Vitamin D deficiency. N Engl J Med (2007).The increment in serum 25(OH)D produced by an oral dose of vitamin D is greater at low basal levels than at higher values.Safe upper limit: 2000UI(=50 ug)/day (Food and Nutrition Board)
11Vitamin D/skin production Sun exposure could be sufficient to cover requests (UVB exposure for min generates UI vit D3/24 h).Problems: winter months, sunscreen, sun- protective clothing, low outdoor activities, northern latitudes, dark skin pigmentation, reduced skin synthesis in older people.
12Vitamin D/food content 1UI = 0,025 µg/dieModified by Zittermann, Vitamin D in preventive medicine: are we ignoring the evidence?British Journal of Nutrition (2003)
13Vitamin D/recommended adequate intake American Academy of Pediatrics (2008):400 IU per day to prevent ricket and vitamin D deficiency in children and adolescentsInstitute of Medicine (1997):200 IU per day for adults up to 50 years of age400 IU per day for adults between age 51 and 70600 IU per day for those aged 70 years and over.In absence of adequate sun exposure:UI/day (20-25μg/day).
14Daily recommended amount of calcium and vitamin D (L.A.R.N.)
15Vitamin D/inflammatory bowel disease Serum concentrations of 25(OH)D levels are low in patients with inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease (Jahnsen et al. 2002).Moreover, supplementation with vitamin D or calcitriol significantly ameliorated symptoms (Cantorna et al. 2000).
16In GSD type I: Dietary restrictions Metabolic derangements Intestinal malabsorptionThe current guidelines for GSD I do not recommend evaluation of vitamin D as part of routine follow upBanugaria et al., Mol Genet Met, 2009: “Hypovitaminosis D in glycogen storage disease type I”
20BMD and markers of bone turnover RESULTS and DISCUSSIONBMD and markers of bone turnover
21BMD and metabolic control RESULTS and DISCUSSIONBMD and metabolic control
22RESULTS and DISCUSSION Vitamin D statusLow 25(OH)D in 69% of patients
23RESULTS and DISCUSSION Vitamin D and BMDpz^ : taking supplements
24Correlation between bone disease and metabolic control CONCLUSIONSCorrelation between bone disease and metabolic controlHigh prevalence of low 25(OH)D levelsLow 25(OH)D levels despite supplementation
25Correction of low 25(OH)D concentration - 1 Some or all of the following:encouragement of safe, moderate exposure of skin to ultraviolet lightappropriate increases in food fortification with vitamin Dprovision of higher doses of vitamin D in supplementsBanugaria et al., Hypovitaminosis D in glycogen storage disease type I. Mol Genet Met, 2009
26Correction of low 25(OH)D concentration - 2 50,000 IU for adult patients (4,000 IU daily for children) of vitamin D2 once weekly for 8 weeks.Maintenance dose = 1000 IU vitamin D daily or, alternatively, 50,000 IU vitamin D every other weekHolick et al., Vitamin D deficiency. N Engl J Med 357, (2007).