A 34-year-old man with type 1 diabetes mellitus comes to the office due to achy pain in the shoulders, elbows, and thighs over the past several months. The patient was diagnosed with diabetes 15 years ago and has had difficulty adequately controlling it. He currently takes multiple daily injections of insulin. Vital signs are within normal limits. Physical examination shows mild pedal edema. Serum creatinine is 2.2 mg/dL, up from 1.6 mg/dL six months ago. Additional laboratory results show low serum calcium and elevated parathyroid hormone levels. Inhibition of which of the following enzymatic steps is most likely responsible for this patient's current symptoms?

Question

A 34-year-old man with type 1 diabetes mellitus comes to the office due to achy pain in the shoulders, elbows, and thighs over the past several months.  The patient was diagnosed with diabetes 15 years ago and has had difficulty adequately controlling it.  He currently takes multiple daily injections of insulin.  Vital signs are within normal limits.  Physical examination shows mild pedal edema.  Serum creatinine is 2.2 mg/dL, up from 1.6 mg/dL six months ago.  Additional laboratory results show low serum calcium and elevated parathyroid hormone levels.  Inhibition of which of the following enzymatic steps is most likely responsible for this patient's current symptoms?

Quizplus · Accepted Answer

11ec160b_3d05_bc6c_9249_570193b54d16_MD0001_00 Synthesis of vitamin D begins in the skin with the conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) by ultraviolet light. Cholecalciferol is subsequently converted to 25-hydroxyvitamin D (the primary body store of vitamin D) by 25-hydroxylase in the liver. Finally, 25-hydroxyvitamin D is filtered by renal glomeruli (with vitamin D-binding protein) and delivered to proximal tubule cells, where 1-alpha-hydroxylase converts it to 1,25-dihydroxyvitamin D, the physiologically active form. The activity of 1-alpha-hydroxylase is upregulated by parathyroid hormone (PTH) and inhibited by fibroblast growth factor 23 (FGF23), a peptide secreted by osteocytes in response to high levels of 1,25-dihydroxyvitamin D. Chronic kidney disease (CKD) results in impaired conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D due to the following factors: FGF23 levels increase early in CKD, causing direct inhibition of 1-alpha-hydroxylase Reduced glomerular filtration limits the delivery of 25-hydroxyvitamin D to proximal tubule cells Reduced functional renal mass limits production of 1-alpha-hydroxylase Inadequate production of 1,25-dihydroxyvitamin D causes reduced intestinal absorption of calcium. This, along with increased phosphate retention (due to impaired glomerular and tubular function), leads to a compensatory increase in parathyroid hormone secretion (secondary hyperparathyroidism). Chronically increased PTH levels have a deleterious effect on bone metabolism (renal osteodystrophy), and can cause weakness, bone and muscle pain, defective bone mineralization, and an increased risk of fractures. (Choice A) The initial step in vitamin D synthesis is driven by ultraviolet exposure in the skin. Factors that can lead to vitamin D deficiency include inadequate sunlight exposure (eg, institutionalized elders, living at extreme latitudes), use of high-grade sunblock, nocturnal occupations, and heavily pigmented skin. (Choice B) 25-Hydroxyvitamin D deficiency due to inadequate 25-hydroxylase activity can be seen in patients with liver disease, but is uncommon and primarily seen in those with advanced cirrhosis. (Choices D and E) Vitamin D-24-hydroxylase converts 25- and 1,25-dihydroxyvitamin D into inactive 24-hydroxylated metabolites; it functions to degrade excess levels of vitamin D. Although it is expressed predominantly in the kidneys and may be impaired in chronic kidney disease, loss of this enzyme would lead to higher 1,25-dihydroxyvitamin D levels and so would reduce, rather than worsen, the patient's symptoms. Educational objective: In chronic kidney disease, conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is impaired. In addition, failure of glomerular and tubular function results in phosphate retention and hypocalcemia. This leads to a compensatory rise in parathyroid hormone (secondary hyperparathyroidism) that can present with weakness, muscle and joint pain, defective bone mineralization, and increased fracture risk. __________ References: Impaired vitamin D metabolism in CKD. (http://www.ncbi.nlm.nih.gov/pubmed/23465502)

A 34-Year-Old Man with Type 1 Diabetes Mellitus Comes to the Office