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BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I Ilaria.

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Presentation on theme: "BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I Ilaria."— Presentation transcript:

1 BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I Ilaria Giulini Neri Department of Pediatrics San Paolo Hospital University of Milan International meeting glycogen storage diseases associations 2-3 October, Milan

2 Glycogen storage disease type I (GSD I) Disorder of glucose homeostasis (glycogenolysis/gluconeogenesis) Disorder of glucose homeostasis (glycogenolysis/gluconeogenesis) Incidence: 1/ Incidence: 1/ Autosomal recessive transmission Autosomal recessive transmission Type Ia glucose-6-phosphatase deficiency Type Ia glucose-6-phosphatase deficiency Type Ib glucose-6-phosphatase translocase Type Ib glucose-6-phosphatase translocase

3 Clinical and biochemical features of GSD I Metabolic derangements: fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia Several long term complications: short stature, liver adenoma, renal damage, osteoporosis, polycistic ovaries. Type Ib: neutropenia and neutrophil dysfunction Accumulation of glycogen in liver, kidney, and intestine

4 Bone 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) MD in adolescence/adult patients: diminished bone mass accretion during childhood or historical differences in treatment? (Rake et al., J Inherit Met Dis, 2003) BMD in adolescence/adult patients: diminished bone mass accretion during childhood or historical differences in treatment? (Rake et al., J Inherit Met Dis, 2003) N J Inherit Met Dis, 2004) No correlation between BMD and markers of bone turnover (Cabrera-Abreu et al., J Inherit Met Dis, 2004)

5 Bone 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 resistance Chronic lactic acidosis: 1. 1.increase of mobilization and release of bone alkaline salts (calcium phosphate and carbonate) in response to a acid load to mantain acid-base balance 2. 2.loss of calcium and phosphate with urine hypercalciuria and reduced tubular reabsorption of phosphate 3. 3.high activity of osteoclasts, reduced of osteoblasts

6 Bone matrix loss in GSD/pathophysiology Endogenous glucocorticoid excess, altered levels of GH and IGF-1 seems to reduce collagen content in bone and matrix synthesis Abnormal pubertal growth spurt with sex hormone secretory dysfunction (important role in bone formation and adequate peack bone mass, especially during puberty) Decreased calcium absorption

7 Bone 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) D ecreased physical activity (chronic disease) ?

8 AIM OF THE STUDY To study prevalence of osteopenia and osteoporosis To determine plasmatic levels of 25(OH)D and to research a correlation with bone mineral density (BMD) To evaluate correlation between metabolic balance and bone markers BONE METABOLISM AND VITAMIN D ROLE IN PATIENTS WITH GSD I

9 Why vitamin D? Important role in calcium homeostasis and bone metabolism Vitamin D insufficiency osteoporosis (not rickets or osteomalacia) as a result of calcium malabsorption Vitamin 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) BACKGROUND

10 Why 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) BACKGROUND

11 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. Vitamin D/skin production

12 Vitamin D/food content Modified by Zittermann, Vitamin D in preventive medicine: are we ignoring the evidence?British Journal of Nutrition (2003) 1UI = 0,025 µg/die

13 American Academy of Pediatrics (2008): 400 IU per day to prevent ricket and vitamin D deficiency in children and adolescents Institute of Medicine (1997): -200 IU per day for adults up to 50 years of age -400 IU per day for adults between age 51 and IU per day for those aged 70 years and over. In absence of adequate sun exposure: UI/day (20-25μg/day). Vitamin D/recommended adequate intake

14 Daily recommended amount of calcium and vitamin D (L.A.R.N.)

15 Serum concentrations of 25(OH)D levels are low in patients with inflammatory bowel diseases such as ulcerative colitis and Crohns disease (Jahnsen et al. 2002). Moreover, supplementation with vitamin D or calcitriol significantly ameliorated symptoms (Cantorna et al. 2000). Vitamin D/inflammatory bowel disease

16 In GSD type I: Dietary restrictions Metabolic derangements Intestinal malabsorption The current guidelines for GSD I do not recommend evaluation of vitamin D as part of routine follow up Banugaria et al., Mol Genet Met, 2009: Hypovitaminosis D in glycogen storage disease type I

17 PATIENTS and METHODS PATIENTS: n = 13 n = 13 Ia/Ib = 6/7 Ia/Ib = 6/7 M/F = 8/5 M/F = 8/5 Median age: 22 y, 7 mo Median age: 22 y, 7 mo Range = 8 – 30 y Range = 8 – 30 yMETHODS: Every 4 – 6 months: 1.Clinicalevaluation 1.Clinical evaluation 2.Nutritional evaluation 3.Laboratory analysis 4.DXA scans

18 RESULTS and DISCUSSION Bone mineral density (BMD) Reduced BMD in 69% of patients

19 BMD in GSD Ia/Ib RESULTS and DISCUSSION

20 BMD and markers of bone turnover RESULTS and DISCUSSION

21 BMD and metabolic control RESULTS and DISCUSSION

22 Vitamin D status RESULTS and DISCUSSION Low 25(OH)D in 69% of patients

23 Vitamin D and BMD RESULTS and DISCUSSION pz^ : taking supplements

24 Correlation between bone disease and metabolic control High prevalence of low 25(OH)D levels Low 25(OH)D levels despite supplementationCONCLUSIONS

25 Correction of low 25(OH)D concentration - 1 Some or all of the following: 1. encouragement of safe, moderate exposure of skin to ultraviolet light 2. appropriate increases in food fortification with vitamin D 3. provision of higher doses of vitamin D in supplements Banugaria et al., Hypovitaminosis D in glycogen storage disease type I. Mol Genet Met, 2009

26 Correction of low 25(OH)D concentration ,000 IU for adult patients (4,000 IU daily for children) of vitamin D 2 once weekly for 8 weeks. - Maintenance dose = 1000 IU vitamin D daily or, alternatively, 50,000 IU vitamin D every other week Holick et al., Vitamin D deficiency. N Engl J Med 357, (2007).

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28 Thanks for your attention!


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