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Rickets Microchapters |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
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Rickets Microchapters |
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Diagnosis |
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|
Treatment |
|
Case Studies |
|
MAH On the Web |
|
American Roentgen Ray Society Images of MAH |
Overview
Rickets is a bony disease due to decreased mineralization of growth plate, associated with abnormal serum calcium and phosphate level[1]. This leads to softening of bones.Rickets is more common in children especially in developing countries due to malnutrition and famines. It can also occur in adults and similar presentation in adults is termed as osteomalacia. The origin of the word "rickets" is unknown. The Greek derived word "rachitis" (meaning "inflammation of the spine") was later adopted as the scientific term for rickets, due chiefly to the words' similarity in sound.
Historical Perspective
Classification
There are 3 types of rickets
- Nutritional Rickets (due to deficiency of Vit D, calcium, and phosphorous)
- Vitamin D dependent rickets (due to defective metabolism of vitamin D)
- Vitamin D resistant rickets (hypophosphatemic rickets due renal phosphate wasting)
Pathophysiology
Physiology
Rickets is decreased mineralization of the growth plate and is associated with abnormal serum calcium and phosphate level. Viatmin D, Fibroblast growth factor 23 (FGF23) and Parathyroiad hormone (PTH) play role in calcium and phosphate homeostasis. Low phosphate level is common pathway in growth plate abnormalities both in calciopenic and phophopenic forms of ricket [2]. Further explained below in pathogeneisis.
Vitamin D Vitamin D in its prohormone forms ergocalciferol (vit D2) from yeasts and fungi and cholecalciferol (vit D3) as produced by UV irradiation in human skin from 7-dehydrocholestrol. Vitamin D undergoes hydyroxylation at 25 position in liver with help of 25-hydroxylase enzyme and hydroxylation at 1 position with help of 1-''a''-hydroxlase(encoded by CYP271B)in kidneys. This 25 and 1 hydroxylation activates vitamin D and activated form of vitamin D is 1,25(OH)2D. This 1,25(OH)2D acts on intestine and increases calcium and phosphate absorption and also acts on bone to increase bone resorption. Metabolic inactivation of 1,25(OH)2D and 25(OH)D occurs in kidneys and intestine by hydroxylation at 24 position with help of enzyme 24-hydroxylase (encoded by CYP24A1) [3]. If there is nutritional deficiency of vitamin D or resistance to action of vitamin D (Vitamin D dependent rickets type 1,2), leads to low serum calcium and phosphate level. This causes increased production of PTH from parathyroid glands. PTH acts on kidneys to increase 1-a-Hydroxylase and calcium absorption and decrease renal phosphate reabsorption leading to hypophosphatemia. Hypophosphatemia is central to development of rickets.
Fibroblast Growth Factor 23 (FGF23) FGF23 is a phosphaturic hormone produced by osteocytes. FGF23 decreases the renal threshold of phosphate reabsorption by decreasing the sodium dependent phosphate transport protein 2A and 2C (NPT2A and NPT2C) on the apical surfaces of proximal renal tubular cells[4]. So when the level of FGF23 is high, circulating phosphate level will be low in serum. In addition, FGF23 decreases the level of 1,25(OH)2D in blood by increasing the expression of CYP24A1 (inducer of 24-hydroxlase) and down regulating the expression of CYP27B1 (inducer of 1-a-hydroxlase enzyme). The relative deficiency of 1,25(OH)2D decreases serum phosphate level, as normally 1,25(OH)2D increases intestinal phosphate absorption through sodium dependent phosphate transport protein 2B (NPT2B) [5].
Pathogenesis
Growth plate (physis) is present between epiphysis and metaphysis. There is maturation of chondrcytes (cartilage cells) progressively occurs from epiphysis to metaphysis. Thickness of growth plate is depending on two opposing factors, proliferation and hypertrophy of chondrocytes, on one hand, and vascular invasion of growth plate followed by mineralization of physis followed by conversion into primary bone spongiosa, on other hand [6]. Hypertrophic chondrocytes undergo apoptosis and these apoptotic cells and replaced by mineralized bone matrix by vascular invasion [6]. Apoptosis of hypertrophic chondrocytes is induced by extracellualar phosphate via phosphorylation of mitogen-activated-protein-kinase (MAPK) pathway intermediates and downstream inhibition of caspase-9-dependent mitochondrial apoptotic pathway [2]. The decrease in ambient phosphate level impaired the apoptosis of hypertrophic chondrocytes. The ligand 1,25(OH)2D and its receptors also plays a role in this pathway [7]. When there is no apoptosis of hypertrophic chondrocytes, growth plate thickens and becomes disorganized. Chondrocytes lose their columnar orientation [8] with expansion of hypertrophic zone. In the metaphysis, mineralization defect leads to accumulation of osteod [9].
Causes
Causes of Nutritional Rickets
- Vitamin D deficeincy[10]
- Lack of supplementation for breast feeding infants
- Darker skin color
- poor sunlight exposure
- Poor vit D intake of lactating mothers[11]
- High latitude
- full boding clothing
- restricted intake
- 25-hydroxylase deficiency (also known as vitamin-D dependent rickets type 1B)[12]
- 1-a-hydroxylase deficincy (also known as vitamin-D dependent rickets type 1A)owing to renal disease or mutation in CYP27B1
- Hereditory 1,25(OH)2D resistant rickets due to mutation in VDR (vitamin-D dependent rickets type 2)[13] or due to overexpression of vitamin D response element(VDRE)-binding ribonucleoprotein (vitamin D dependent rickets type 2b)
- Calcium deficiency
- poverty
- malnutrition
- intake of competing Oxalate and phosphate intake
- extensive breast feeding without complementary calcium containing supplements(extensive breast feeding could be partially protective if no other calcium containing foods source available)[14]
Genetics
Associated Conditions
Gross Pathology
There is change in structure of bone with increase in diameters of physis and metaphysis. Bone strength is compromised which is compensated by increase in bone size but overall bone is weak and bowing of bones occurs.
Microscopic Pathology
Impaired apotosis and mineralization of hypertrophic chondrocytes leads to increase in longitudinal thickness of bone, loss of columnar arrangement of chondrocytes and osteod matrix accumulation in hypertrophic zone between growth plate and metaphysis.[15]
References
- ↑ Shore RM, Chesney RW (2013). "Rickets: Part I." Pediatr Radiol. 43 (2): 140–51. doi:10.1007/s00247-012-2532-x. PMID 23208530.
- ↑ 2.0 2.1 Sabbagh Y, Carpenter TO, Demay MB (2005). "Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes". Proc Natl Acad Sci U S A. 102 (27): 9637–42. doi:10.1073/pnas.0502249102. PMC 1172249. PMID 15976027.
- ↑ Bikle DD (2014). "Vitamin D metabolism, mechanism of action, and clinical applications". Chem Biol. 21 (3): 319–29. doi:10.1016/j.chembiol.2013.12.016. PMC 3968073. PMID 24529992.
- ↑ Tenenhouse HS, Werner A, Biber J, Ma S, Martel J, Roy S; et al. (1994). "Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization". J Clin Invest. 93 (2): 671–6. doi:10.1172/JCI117019. PMC 293897. PMID 8113402.
- ↑ Sabbagh Y, O'Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C; et al. (2009). "Intestinal npt2b plays a major role in phosphate absorption and homeostasis". J Am Soc Nephrol. 20 (11): 2348–58. doi:10.1681/ASN.2009050559. PMC 2799172. PMID 19729436.
- ↑ 6.0 6.1 Pitt MJ (1991). "Rickets and osteomalacia are still around". Radiol Clin North Am. 29 (1): 97–118. PMID 1985332.
- ↑ Miedlich SU, Zhu ED, Sabbagh Y, Demay MB (2010). "The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice". Endocrinology. 151 (10): 4607–12. doi:10.1210/en.2010-0354. PMC 2946147. PMID 20685875.
- ↑ Lacey DL, Huffer WE (1982). "Studies on the pathogenesis of avian rickets. I. Changes in epiphyseal and metaphyseal vessels in hypocalcemic and hypophosphatemic rickets". Am J Pathol. 109 (3): 288–301. PMC 1916114. PMID 7180943.
- ↑ Rauch F (2003). "The rachitic bone". Endocr Dev. 6: 69–79. doi:10.1159/000072770. PMID 12964426.
- ↑ Unuvar T, Buyukgebiz A (2010). "Nutritional rickets and vitamin D deficiency in infants, children and adolescents". Pediatr Endocrinol Rev. 7 (3): 283–91. PMID 20526242.
- ↑ Bodnar LM, Catov JM, Roberts JM, Simhan HN (2007) Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates. J Nutr 137 (11):2437-42. DOI:10.1093/jn/137.11.2437 PMID: 17951482
- ↑ Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA (2015). "CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency". J Clin Endocrinol Metab. 100 (7): E1005–13. doi:10.1210/jc.2015-1746. PMC 4490307. PMID 25942481.
- ↑ Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF; et al. (2008). "Vitamin D and human health: lessons from vitamin D receptor null mice". Endocr Rev. 29 (6): 726–76. doi:10.1210/er.2008-0004. PMC 2583388. PMID 18694980.
- ↑ Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K; et al. (2016). "Global Consensus Recommendations on Prevention and Management of Nutritional Rickets". J Clin Endocrinol Metab. 101 (2): 394–415. doi:10.1210/jc.2015-2175. PMC 4880117. PMID 26745253.
- ↑ Shapiro IM, Boyde A (1987). "Mineralization of normal and rachitic chick growth cartilage: vascular canals, cartilage calcification and osteogenesis". Scanning Microsc. 1 (2): 599–606. PMID 3616560.