539178
research-article2014
NCPXXX10.1177/0884533614539178Nutrition in Clinical Practice X(X)Bharadwaj et al
Clinical Research
Prevalence and Predictors of Vitamin D Deficiency and Response to Oral Supplementation in Patients Receiving Long-Term Home Parenteral Nutrition
Nutrition in Clinical Practice Volume 29 Number 5 October 2014 681–685 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614539178 ncp.sagepub.com hosted at online.sagepub.com
Shishira Bharadwaj, MD1; Tushar D. Gohel, MD1; Omer J. Deen, MD2; Kathleen L. Coughlin, MS, RD, LD, CNSC1; Mandy L. Corrigan, MPH, RD, LD, CNSC1; Jill Fisher, RD, LD, CNSC1; Rocio Lopez, MS1; Abdullah Shatnawei, MD1; and Donald F. Kirby, MD, FACP, FACN, AGAF, CNSC, CPNS1
Abstract Previous studies have suggested a high prevalence of vitamin D deficiency in patients receiving long-term home parenteral nutrition (HPN). The aim of this study was to determine the prevalence and predictors of vitamin D deficiency in long-term HPN patients. Methods: A retrospective, institutional review board–approved study was performed on all adult patients followed by the Cleveland Clinic HPN program receiving HPN therapy >6 months between 1989 and 2013 with a 25-(OH) D3 level reported. Patients were categorized by serum vitamin D status as follows: sufficient, insufficient, and deficient with respective 25-(OH) D3 levels of ≥30 ng/mL, 20–30 ng/mL, and 6 months), assess the response to oral vitamin D therapy, and explore the predictors of vitamin D deficiency.
Materials and Methods Patients The Cleveland Clinic Institutional Review Board approved this historical cohort study. A retrospective chart review of eligible adults (>18 years) enrolled in the Cleveland Clinic HPN database for a minimum of 6 months was conducted. Electronic medical records (HPN database and Epic) were reviewed to extract demographic information and clinical variables.
Patient Groups Eligible patients were categorized by mean serum vitamin D status as follows: (1) vitamin D sufficient, 25-(OH) D3 > 30 ng/ mL; (2) insufficient, 25-(OH) D3 = 20–30 ng/mL; and (3) deficient, 25-(OH) D3 < 20 ng/mL.
Inclusion and Exclusion Criteria Adult patients followed by the Home Nutrition Support Service at the Cleveland Clinic between 1989 and 2013 who required HPN for >6 months were included. Patients were excluded if serum vitamin D levels were not recorded in the HPN database.
Protocol Seventy-nine of 467 patients who received HPN >6 months met eligibility criteria. Demographic and clinical variables,
Nutrition in Clinical Practice 29(5) including age, sex, body mass index (BMI), HPN indication, comorbidities that affect vitamin D homeostasis (inflammatory bowel disease [IBD], celiac disease, liver disease, renal disease, osteoporosis, hypothyroidism), and medications (steroids, bisphosphonates, hydrochlorothiazide, furosemide, heparin, levothyroxine, and oral vitamin D) during the study period, were extracted from electronic medical records. All patients received routine intravenous (IV) multivitamin supplementation, which included 200 IU of vitamin D3 (cholecalciferol). Oral supplementation (50,000 IU) was prescribed for patients identified to have vitamin D level 200 cm Portion of bowel removed Ileum Jejunum Proximal colon Distal colon Entire colon Intestinal transplant
Value 26 (32.9) 23.8 ± 5.2 52.0 ± 12.7 39.2 8 (10.1) 29 (36.7) 9 (11.4) 11 (13.9) 10 (12.7) 9 (11.4) 3 (3.8) 14 (17.7) 2 (2.5) 26 (32.9) 3 (3.8) 9 (11.4) 8 (10.1) 1 (1.3) 8 (10.1) 2 (2.5) 3 (3.8) 4 (5.1) 10 (12.7) 18 (28.6) 6 (9.5) 17 (27.0) 22 (34.9) 22 (27.8) 10 (12.6) 12 (15.1) 6 (7.5) 47 (59.4) 3 (3.7)
Table 2. Vitamin D Deficiency and Prescription in 79 Patients. Characteristic Vitamin D prescription Amount prescribed 50,000 IU once weekly 50,000 IU twice weekly 50,000 IU thrice weekly Vitamin D level, mean ± SD, ng/mL Average vitamin D deficiency degree Sufficient vitamin D Insufficient vitamin D Deficient vitamin D Supplement used any time during the 3 months prior to serum vitamin D level Supplement used any time during the 6 months prior to serum vitamin D level
Value 65 (82.3) 34 (43.0) 44 (55.7) 24 (30.4) 24.5 ± 12.7 20 (25.3) 24 (30.4) 35 (44.3) 10 (12.7) 20 (25.3)
Values are presented as number (%) unless otherwise indicated. IU, International Units.
24 (30.4%) had doses 3 times per week. A total of 79 patients were categorized into deficient (35 [44.3%]), insufficient (24 [30.4%]), and sufficient (20 [25.3%]) groups based on the serum vitamin D levels.
Univariate Comparison of Clinical and Demographic Variables On univariable analysis, younger age, no history of bisphosphonate use, absence of a jejunum, and lack of oral vitamin D supplementation were associated with a higher likelihood of having vitamin D deficiency. For every 5-year increase in the age at the time of measurement, the odds of having deficiency decreased by 10% (P = .043). In addition, patients taking bisphosphonates had a 54% lower likelihood of having deficiency (P = .011). Patients who had their jejunum removed had a 6-fold higher likelihood of vitamin D deficiency. Also, those who had taken supplements any time during the previous 3 and 6 months had a 59% and 45% lower likelihood of having deficiency, respectively (P = .001, P = .032).
Values are presented as number (%) unless otherwise indicated. HPN, home parenteral nutrition; IBD, inflammatory bowel disease.
Multivariate Analysis of Variables Predicting Vitamin D Deficiency in HPN Patients
of small bowel removed if known, and medications (steroids, bisphosphonates, hydrochlorothiazide, furosemide, heparin, levothyroxine, and oral vitamin D supplementation) during the study period. Patients had between 1 and 29 measurements of vitamin D levels done during their HPN therapy, with a median of 4 laboratory measurements per patient (Table 2). Sixty-five (82.3%) patients had at least 1 prescription of oral vitamin D supplementation (50,000 IU) during this time; 34 (43.0%) had once-weekly doses, 44 (55.7%) had twice-weekly doses, and
Table 3 presents the results of the multivariable analysis. Oral vitamin D supplementation, absence of a jejunum, age, and ischemia were kept in the final model. After adjusting for all variables in the model, patients who had taken supplements any time during the previous 3 months had 30% lower odds of having vitamin D deficiency (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.52–0.93; P = .016). In addition, absence of a jejunum was associated with a 5-fold increase in the likelihood of having deficiency after adjusting for all variables in the model (OR, 5.3; 95% CI, 1.9–15.1; P = .002).
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Nutrition in Clinical Practice 29(5)
Table 3. Multivariable Analysis of Factors Predicting Vitamin D Deficiency in Patients Receiving Long-Term Home Parenteral Nutrition. Characteristic Supplement used any time during the previous 3 months prior to serum vitamin D level History of jejunal resection Age at vitamin D measurement (5-year increase) Ischemia
OR (95% CI)
P Value
0.70 (0.52–0.93)
.016a
5.3 (1.9–15.1) 0.98 (0.96–1.00)
.002a .093
0.57 (0.32–1.01)
.055
CI, confidence interval; OR, odds ratio. a Statistically significant.
Discussion Our study was designed to investigate the risk factors for vitamin D deficiency in patients receiving long-term HPN. In our retrospective study, most patients were vitamin D deficient. Two variables were associated with a higher risk of vitamin D deficiency: absence of a jejunum and lack of vitamin D supplementation. Of particular interest, only a minority of patients reached sufficient levels despite receiving supplementation. Recent research has led to enormous rebirth in interest in vitamin D due to its new role as a prohormone.21 There is controversy as to the optimal vitamin D plasma concentration. Most experts agree that serum vitamin D levels ranging from 20–30 ng/mL are required to prevent rickets and osteomalacia.22 However, recent research has shown that >30 ng/mL may be required to protect against malignancy and infectious, inflammatory, and autoimmune diseases.7,8,23 HPN is a life-sustaining therapy for patients with intestinal failure.24 Patients who require long-term HPN are particularly at risk for deficiency due to risk factors such as lack of exposure to sunlight, suboptimal vitamin D intake, advanced age, and diseases or medication that influence vitamin D metabolism.16 The prevalence of vitamin D deficiency in such patients ranges from 60%–80%.16 In a small study (n = 35) involving New England HPN patients, the prevalence rate of vitamin D deficiency was 77%.25 Another study from Canada found 65% of HPN patients to have vitamin D deficiency.26 Despite supplementation (both with daily injectable and oral), most remained in the insufficient range. Patients requiring HPN therapy may receive a daily multivitamin injection that contains 200 IU (5 µg) of vitamin D. Unfortunately, there has been a nationwide shortage of adult multivitamin injections.19 Also, independent vitamin D parenteral preparations are not available in the United States. Our study further supports the above findings since only a minority of our patients were in the sufficient range. In our present study, absence of a jejunum was associated with a 5-fold increase in the likelihood of vitamin D deficiency, which suggests that such patients may require alternate
methods of vitamin D supplementation. Although our study did not show bowel length to co-relate with serum vitamin D levels, we believe it to be one of the predictors of serum vitamin D levels. However, our study was limited by sample size, and data on bowel length were not available for every patient. Restoration of optimal vitamin D status in such patients with oral vitamin D supplementation or use of alternate routes such as exposure to sunlight or a UV-emitting device may be essential in such patients. A recent study by Kumar and Raman16 found oral supplementation to be ineffective in this population, especially in patients with SBS. However, 1 patient who was an ardent sun tanner had sufficient vitamin D status throughout the study period. Koutkia et al20 found UV radiation to be effective in a patients with Crohn’s disease who had SBS. Although only case reports have been published in the HPN population, exposure to sunlight and UV radiation has been better studied in non-HPN individuals.27 From our study, we believe that in high-risk patients, especially those without a jejunum and patients who are deficient despite receiving oral supplementation, exposure to sunlight or a UV-emitting device could be an effective alternative to be considered. However, the American Academy of Dermatology does not support the use of UV radiation from both the sun and tanning devices since there is no scientifically validated, safe threshold level that allows for maximal vitamin D synthesis without increasing skin cancer risk.28 Although there is no general consensus, Thompson and Duerksen26 recommend to routinely start patients on 1000 IU of vitamin D per day and then increase to 50,000 IU/wk if this fails to normalize vitamin D status. Pittas and Saltzman29 recommend 50,000 IU/wk for 12 weeks in patients below 30 ng/ mL. Vitamin D toxicity has never been reported in HPN patients. Hence, higher oral doses to achieve sufficient levels may be necessary, especially considering many HPN patients have significant malabsorption, including fat malabsorption. Alternatively, future studies must be designed to explore whether a water-micellized form of multivitamins, as used in children with cystic fibrosis, would result in better serum vitamin D levels in patients receiving HPN.30 Our study may have several clinical implications, including identification of high-risk subgroups in the HPN patient population that may require closer monitoring of vitamin D levels, as well as higher oral supplementation or different formulations (either IV or intramuscular) for restoration of optimal vitamin D levels. Also, patients without a jejunum may require a different modality such as a UV-emitting device to maintain optimal vitamin D levels, albeit with an increased risk of skin cancer, which will require dermatologic oversight. There are several limitations to our study. In this retrospective study, we were unable to assess compliance of patients taking oral vitamin D supplements. Second, HPN macronutrient content was not included in this study. However, we assumed that macronutrients, including lipids in HPN, would not affect the metabolism of oral vitamin D supplementation.
Bharadwaj et al Third, considering the retrospective nature of the study, we could not fully preclude bias caused by the selection of patients. Therefore, the findings of the study may be due to chance or type I error. In addition, including only 79 of the 467 patients receiving HPN could have further added to selection bias. The reason for the above is, periodic serum vitamin D level measurements in this patient population have become a recent norm in our institution. Fourth, the study might have incurred referral bias because the Cleveland Clinic is a tertiary care center. Fifth, due to the retrospective nature of the study, serum vitamin D levels were not checked periodically in every patient; thus, we used the average values for the analysis. Sixth, we did not take into consideration whether location or season had any effect on serum vitamin D levels in our patient population. Seventh, we did not study the incidence of infectious and noninfectious outcomes. Last, we did not subcategorize the IBD group into ulcerative colitis and Crohn’s disease, which may have important implications due to differences in bowel length. However, we believe that the completion of the current study is an important first step in defining the risk factors and prevalence in this population and have stimulated future questions to drive additional prospective research. In conclusion, only a minority of HPN patients had sufficient vitamin D levels. Patients receiving HPN should be routinely screened for vitamin D deficiency periodically, although the time interval is difficult to specify. However, we suggest that a lower value should prompt clinicians to aggressively supplement and follow up more periodically than once or twice a year. Patients receiving long-term HPN may require more than high doses of oral vitamin D supplementation. Certain characteristics such as absence of a jejunum, no supplementation, and forms of supplementation predict lower vitamin D levels. Prospective studies are needed to assess the right dose, route of vitamin D supplementation, and also an alternative treatment such as UV radiation or a water-micellized form of vitamin D for patients with low levels refractory to supplementation. More studies are needed to assess if lower levels of vitamin D in such patients translate into adverse clinical outcomes.
References 1. DeLuca HF. Vitamin D as a prohormone. Biochem Pharmacol. 1977;26:563-566. 2. Henry HL, Norman AW. Studies on calciferol metabolism, IX: renal 25-hydroxy-vitamin D3-1 hydroxylase. Involvement of cytochrome P-450 and other properties. J Biol Chem. 1974;249:7529-7535. 3. Peterlik M, Cross HS. Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology. Eur J Clin Nutr. 2009;63:1377-1386. 4. Chan TY. Vitamin D deficiency and susceptibility to tuberculosis. Calcif Tissue Int. 2000;66:476-478. 5. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73-S87. 6. Hewison M, Adams JS. Extra-renal 1α-hydroxylase activity and human disease. In: Feldman D, Glorieux F, Pike J, eds. Vitamin D. San Diego, CA: Academic Press; 2005:1379-1400.
685 7. Pilz S, Tomaschitz A, Obermayer-Pietsch B, Dobnig H, Pieber TR. Epidemiology of vitamin D insufficiency and cancer mortality. Anticancer Res. 2009;29:3699-3704. 8. Munger KL, Levin LI, Hollis BW, et al. Elevated serum 25-hydroxyvitamin D predicts a decreased risk of MS. Multiple Sclerosis. 2007;13:280307. 9. Cannell JJ, Vieth R, Umhau JC. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129-1140. 10. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:13401349. 11. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31:48-54. 12. Parker J, Hashmi O, Dutton D. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225236. 13. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D. Washington, DC: National Academies Press; 2011. 14. Raman M, Aghdassi E, Baun M, et al. Metabolic bone disease in patients receiving home parenteral nutrition: a Canadian study and review. JPEN J Parenter Enteral Nutr. 2006;30:492-496. 15. Hamilton C, Seidner DL. Metabolic bone disease in the patient on long term parenteral nutrition. Pract Gastroenterol. 2008;58:20-32. 16. Kumar PR, Raman M. Prevalence of vitamin D deficiency and response to oral vitamin D supplementation in patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2012;36:463-469. 17. Bikle DD. Vitamin D insufficiency/deficiency in gastrointestinal disorders. J Bone Miner Res. 2007;22:S2. 18. Armas LAG, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-(OH) D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007;57:588-593. 19. Mirtallo JM, Holcombe B, Kochevar M, Guenter P. Parenteral nutrition product shortages: the A.S.P.E.N. Strategy. Nutr Clin Pract. 2012;27:385391. 20. Koutkia P, Lu Z, Chen TC, Holick MF. Treatment of vitamin D deficiency due to Crohn’s disease with tanning bed ultraviolet B radiation. Gastroenterology. 2001;121:1485-1488. 21. Coen G. Vitamin D: an old prohormone with an emergent role in chronic kidney disease. J Nephrol. 2008;21:313-323. 22. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281. 23. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73-S87. 24. Staun M, Pironi L, Bozzetti F, et al. ESPEN guidelines on parenteral nutrition: home parenteral nutrition (HPN) in adult patients. Clin Nutr. 2009;28:467-479. 25. Corey B, Ackerman K, Allen P, Sceery N, Rafoth C. Vitamin D status of New England home TPN patients: a snapshot of practice. Nutr Clin Pract. 2009;24:110A. 26. Thomson P, Duerksen DR. Vitamin D deficiency in patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2011;35:499504. 27. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80:1678S-1688S. 28. Levine JA, Sorace M, Spencer J, Siegel DM. The indoor UV tanning industry: a review of skin cancer risk, health benefit claims, and regulation. J Am Acad Dermatol. 2005;53:1038-1044. 29. Pittas AG, Saltzman E. Role of vitamin D in adults requiring nutrition support. JPEN J Parenter Enteral Nutr. 2010;34:70-78. 30. Grossmann RE, Tangpricha V. Evaluation of vehicle substances on vitamin D bioavailability: a systematic review. Mol Nutr Food Res. 2010;54:1055-1061.
research-article2014
NCPXXX10.1177/0884533614539178Nutrition in Clinical Practice X(X)Bharadwaj et al
Clinical Research
Prevalence and Predictors of Vitamin D Deficiency and Response to Oral Supplementation in Patients Receiving Long-Term Home Parenteral Nutrition
Nutrition in Clinical Practice Volume 29 Number 5 October 2014 681–685 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614539178 ncp.sagepub.com hosted at online.sagepub.com
Shishira Bharadwaj, MD1; Tushar D. Gohel, MD1; Omer J. Deen, MD2; Kathleen L. Coughlin, MS, RD, LD, CNSC1; Mandy L. Corrigan, MPH, RD, LD, CNSC1; Jill Fisher, RD, LD, CNSC1; Rocio Lopez, MS1; Abdullah Shatnawei, MD1; and Donald F. Kirby, MD, FACP, FACN, AGAF, CNSC, CPNS1
Abstract Previous studies have suggested a high prevalence of vitamin D deficiency in patients receiving long-term home parenteral nutrition (HPN). The aim of this study was to determine the prevalence and predictors of vitamin D deficiency in long-term HPN patients. Methods: A retrospective, institutional review board–approved study was performed on all adult patients followed by the Cleveland Clinic HPN program receiving HPN therapy >6 months between 1989 and 2013 with a 25-(OH) D3 level reported. Patients were categorized by serum vitamin D status as follows: sufficient, insufficient, and deficient with respective 25-(OH) D3 levels of ≥30 ng/mL, 20–30 ng/mL, and 6 months), assess the response to oral vitamin D therapy, and explore the predictors of vitamin D deficiency.
Materials and Methods Patients The Cleveland Clinic Institutional Review Board approved this historical cohort study. A retrospective chart review of eligible adults (>18 years) enrolled in the Cleveland Clinic HPN database for a minimum of 6 months was conducted. Electronic medical records (HPN database and Epic) were reviewed to extract demographic information and clinical variables.
Patient Groups Eligible patients were categorized by mean serum vitamin D status as follows: (1) vitamin D sufficient, 25-(OH) D3 > 30 ng/ mL; (2) insufficient, 25-(OH) D3 = 20–30 ng/mL; and (3) deficient, 25-(OH) D3 < 20 ng/mL.
Inclusion and Exclusion Criteria Adult patients followed by the Home Nutrition Support Service at the Cleveland Clinic between 1989 and 2013 who required HPN for >6 months were included. Patients were excluded if serum vitamin D levels were not recorded in the HPN database.
Protocol Seventy-nine of 467 patients who received HPN >6 months met eligibility criteria. Demographic and clinical variables,
Nutrition in Clinical Practice 29(5) including age, sex, body mass index (BMI), HPN indication, comorbidities that affect vitamin D homeostasis (inflammatory bowel disease [IBD], celiac disease, liver disease, renal disease, osteoporosis, hypothyroidism), and medications (steroids, bisphosphonates, hydrochlorothiazide, furosemide, heparin, levothyroxine, and oral vitamin D) during the study period, were extracted from electronic medical records. All patients received routine intravenous (IV) multivitamin supplementation, which included 200 IU of vitamin D3 (cholecalciferol). Oral supplementation (50,000 IU) was prescribed for patients identified to have vitamin D level 200 cm Portion of bowel removed Ileum Jejunum Proximal colon Distal colon Entire colon Intestinal transplant
Value 26 (32.9) 23.8 ± 5.2 52.0 ± 12.7 39.2 8 (10.1) 29 (36.7) 9 (11.4) 11 (13.9) 10 (12.7) 9 (11.4) 3 (3.8) 14 (17.7) 2 (2.5) 26 (32.9) 3 (3.8) 9 (11.4) 8 (10.1) 1 (1.3) 8 (10.1) 2 (2.5) 3 (3.8) 4 (5.1) 10 (12.7) 18 (28.6) 6 (9.5) 17 (27.0) 22 (34.9) 22 (27.8) 10 (12.6) 12 (15.1) 6 (7.5) 47 (59.4) 3 (3.7)
Table 2. Vitamin D Deficiency and Prescription in 79 Patients. Characteristic Vitamin D prescription Amount prescribed 50,000 IU once weekly 50,000 IU twice weekly 50,000 IU thrice weekly Vitamin D level, mean ± SD, ng/mL Average vitamin D deficiency degree Sufficient vitamin D Insufficient vitamin D Deficient vitamin D Supplement used any time during the 3 months prior to serum vitamin D level Supplement used any time during the 6 months prior to serum vitamin D level
Value 65 (82.3) 34 (43.0) 44 (55.7) 24 (30.4) 24.5 ± 12.7 20 (25.3) 24 (30.4) 35 (44.3) 10 (12.7) 20 (25.3)
Values are presented as number (%) unless otherwise indicated. IU, International Units.
24 (30.4%) had doses 3 times per week. A total of 79 patients were categorized into deficient (35 [44.3%]), insufficient (24 [30.4%]), and sufficient (20 [25.3%]) groups based on the serum vitamin D levels.
Univariate Comparison of Clinical and Demographic Variables On univariable analysis, younger age, no history of bisphosphonate use, absence of a jejunum, and lack of oral vitamin D supplementation were associated with a higher likelihood of having vitamin D deficiency. For every 5-year increase in the age at the time of measurement, the odds of having deficiency decreased by 10% (P = .043). In addition, patients taking bisphosphonates had a 54% lower likelihood of having deficiency (P = .011). Patients who had their jejunum removed had a 6-fold higher likelihood of vitamin D deficiency. Also, those who had taken supplements any time during the previous 3 and 6 months had a 59% and 45% lower likelihood of having deficiency, respectively (P = .001, P = .032).
Values are presented as number (%) unless otherwise indicated. HPN, home parenteral nutrition; IBD, inflammatory bowel disease.
Multivariate Analysis of Variables Predicting Vitamin D Deficiency in HPN Patients
of small bowel removed if known, and medications (steroids, bisphosphonates, hydrochlorothiazide, furosemide, heparin, levothyroxine, and oral vitamin D supplementation) during the study period. Patients had between 1 and 29 measurements of vitamin D levels done during their HPN therapy, with a median of 4 laboratory measurements per patient (Table 2). Sixty-five (82.3%) patients had at least 1 prescription of oral vitamin D supplementation (50,000 IU) during this time; 34 (43.0%) had once-weekly doses, 44 (55.7%) had twice-weekly doses, and
Table 3 presents the results of the multivariable analysis. Oral vitamin D supplementation, absence of a jejunum, age, and ischemia were kept in the final model. After adjusting for all variables in the model, patients who had taken supplements any time during the previous 3 months had 30% lower odds of having vitamin D deficiency (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.52–0.93; P = .016). In addition, absence of a jejunum was associated with a 5-fold increase in the likelihood of having deficiency after adjusting for all variables in the model (OR, 5.3; 95% CI, 1.9–15.1; P = .002).
684
Nutrition in Clinical Practice 29(5)
Table 3. Multivariable Analysis of Factors Predicting Vitamin D Deficiency in Patients Receiving Long-Term Home Parenteral Nutrition. Characteristic Supplement used any time during the previous 3 months prior to serum vitamin D level History of jejunal resection Age at vitamin D measurement (5-year increase) Ischemia
OR (95% CI)
P Value
0.70 (0.52–0.93)
.016a
5.3 (1.9–15.1) 0.98 (0.96–1.00)
.002a .093
0.57 (0.32–1.01)
.055
CI, confidence interval; OR, odds ratio. a Statistically significant.
Discussion Our study was designed to investigate the risk factors for vitamin D deficiency in patients receiving long-term HPN. In our retrospective study, most patients were vitamin D deficient. Two variables were associated with a higher risk of vitamin D deficiency: absence of a jejunum and lack of vitamin D supplementation. Of particular interest, only a minority of patients reached sufficient levels despite receiving supplementation. Recent research has led to enormous rebirth in interest in vitamin D due to its new role as a prohormone.21 There is controversy as to the optimal vitamin D plasma concentration. Most experts agree that serum vitamin D levels ranging from 20–30 ng/mL are required to prevent rickets and osteomalacia.22 However, recent research has shown that >30 ng/mL may be required to protect against malignancy and infectious, inflammatory, and autoimmune diseases.7,8,23 HPN is a life-sustaining therapy for patients with intestinal failure.24 Patients who require long-term HPN are particularly at risk for deficiency due to risk factors such as lack of exposure to sunlight, suboptimal vitamin D intake, advanced age, and diseases or medication that influence vitamin D metabolism.16 The prevalence of vitamin D deficiency in such patients ranges from 60%–80%.16 In a small study (n = 35) involving New England HPN patients, the prevalence rate of vitamin D deficiency was 77%.25 Another study from Canada found 65% of HPN patients to have vitamin D deficiency.26 Despite supplementation (both with daily injectable and oral), most remained in the insufficient range. Patients requiring HPN therapy may receive a daily multivitamin injection that contains 200 IU (5 µg) of vitamin D. Unfortunately, there has been a nationwide shortage of adult multivitamin injections.19 Also, independent vitamin D parenteral preparations are not available in the United States. Our study further supports the above findings since only a minority of our patients were in the sufficient range. In our present study, absence of a jejunum was associated with a 5-fold increase in the likelihood of vitamin D deficiency, which suggests that such patients may require alternate
methods of vitamin D supplementation. Although our study did not show bowel length to co-relate with serum vitamin D levels, we believe it to be one of the predictors of serum vitamin D levels. However, our study was limited by sample size, and data on bowel length were not available for every patient. Restoration of optimal vitamin D status in such patients with oral vitamin D supplementation or use of alternate routes such as exposure to sunlight or a UV-emitting device may be essential in such patients. A recent study by Kumar and Raman16 found oral supplementation to be ineffective in this population, especially in patients with SBS. However, 1 patient who was an ardent sun tanner had sufficient vitamin D status throughout the study period. Koutkia et al20 found UV radiation to be effective in a patients with Crohn’s disease who had SBS. Although only case reports have been published in the HPN population, exposure to sunlight and UV radiation has been better studied in non-HPN individuals.27 From our study, we believe that in high-risk patients, especially those without a jejunum and patients who are deficient despite receiving oral supplementation, exposure to sunlight or a UV-emitting device could be an effective alternative to be considered. However, the American Academy of Dermatology does not support the use of UV radiation from both the sun and tanning devices since there is no scientifically validated, safe threshold level that allows for maximal vitamin D synthesis without increasing skin cancer risk.28 Although there is no general consensus, Thompson and Duerksen26 recommend to routinely start patients on 1000 IU of vitamin D per day and then increase to 50,000 IU/wk if this fails to normalize vitamin D status. Pittas and Saltzman29 recommend 50,000 IU/wk for 12 weeks in patients below 30 ng/ mL. Vitamin D toxicity has never been reported in HPN patients. Hence, higher oral doses to achieve sufficient levels may be necessary, especially considering many HPN patients have significant malabsorption, including fat malabsorption. Alternatively, future studies must be designed to explore whether a water-micellized form of multivitamins, as used in children with cystic fibrosis, would result in better serum vitamin D levels in patients receiving HPN.30 Our study may have several clinical implications, including identification of high-risk subgroups in the HPN patient population that may require closer monitoring of vitamin D levels, as well as higher oral supplementation or different formulations (either IV or intramuscular) for restoration of optimal vitamin D levels. Also, patients without a jejunum may require a different modality such as a UV-emitting device to maintain optimal vitamin D levels, albeit with an increased risk of skin cancer, which will require dermatologic oversight. There are several limitations to our study. In this retrospective study, we were unable to assess compliance of patients taking oral vitamin D supplements. Second, HPN macronutrient content was not included in this study. However, we assumed that macronutrients, including lipids in HPN, would not affect the metabolism of oral vitamin D supplementation.
Bharadwaj et al Third, considering the retrospective nature of the study, we could not fully preclude bias caused by the selection of patients. Therefore, the findings of the study may be due to chance or type I error. In addition, including only 79 of the 467 patients receiving HPN could have further added to selection bias. The reason for the above is, periodic serum vitamin D level measurements in this patient population have become a recent norm in our institution. Fourth, the study might have incurred referral bias because the Cleveland Clinic is a tertiary care center. Fifth, due to the retrospective nature of the study, serum vitamin D levels were not checked periodically in every patient; thus, we used the average values for the analysis. Sixth, we did not take into consideration whether location or season had any effect on serum vitamin D levels in our patient population. Seventh, we did not study the incidence of infectious and noninfectious outcomes. Last, we did not subcategorize the IBD group into ulcerative colitis and Crohn’s disease, which may have important implications due to differences in bowel length. However, we believe that the completion of the current study is an important first step in defining the risk factors and prevalence in this population and have stimulated future questions to drive additional prospective research. In conclusion, only a minority of HPN patients had sufficient vitamin D levels. Patients receiving HPN should be routinely screened for vitamin D deficiency periodically, although the time interval is difficult to specify. However, we suggest that a lower value should prompt clinicians to aggressively supplement and follow up more periodically than once or twice a year. Patients receiving long-term HPN may require more than high doses of oral vitamin D supplementation. Certain characteristics such as absence of a jejunum, no supplementation, and forms of supplementation predict lower vitamin D levels. Prospective studies are needed to assess the right dose, route of vitamin D supplementation, and also an alternative treatment such as UV radiation or a water-micellized form of vitamin D for patients with low levels refractory to supplementation. More studies are needed to assess if lower levels of vitamin D in such patients translate into adverse clinical outcomes.
References 1. DeLuca HF. Vitamin D as a prohormone. Biochem Pharmacol. 1977;26:563-566. 2. Henry HL, Norman AW. Studies on calciferol metabolism, IX: renal 25-hydroxy-vitamin D3-1 hydroxylase. Involvement of cytochrome P-450 and other properties. J Biol Chem. 1974;249:7529-7535. 3. Peterlik M, Cross HS. Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology. Eur J Clin Nutr. 2009;63:1377-1386. 4. Chan TY. Vitamin D deficiency and susceptibility to tuberculosis. Calcif Tissue Int. 2000;66:476-478. 5. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73-S87. 6. Hewison M, Adams JS. Extra-renal 1α-hydroxylase activity and human disease. In: Feldman D, Glorieux F, Pike J, eds. Vitamin D. San Diego, CA: Academic Press; 2005:1379-1400.
685 7. Pilz S, Tomaschitz A, Obermayer-Pietsch B, Dobnig H, Pieber TR. Epidemiology of vitamin D insufficiency and cancer mortality. Anticancer Res. 2009;29:3699-3704. 8. Munger KL, Levin LI, Hollis BW, et al. Elevated serum 25-hydroxyvitamin D predicts a decreased risk of MS. Multiple Sclerosis. 2007;13:280307. 9. Cannell JJ, Vieth R, Umhau JC. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129-1140. 10. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:13401349. 11. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31:48-54. 12. Parker J, Hashmi O, Dutton D. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225236. 13. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D. Washington, DC: National Academies Press; 2011. 14. Raman M, Aghdassi E, Baun M, et al. Metabolic bone disease in patients receiving home parenteral nutrition: a Canadian study and review. JPEN J Parenter Enteral Nutr. 2006;30:492-496. 15. Hamilton C, Seidner DL. Metabolic bone disease in the patient on long term parenteral nutrition. Pract Gastroenterol. 2008;58:20-32. 16. Kumar PR, Raman M. Prevalence of vitamin D deficiency and response to oral vitamin D supplementation in patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2012;36:463-469. 17. Bikle DD. Vitamin D insufficiency/deficiency in gastrointestinal disorders. J Bone Miner Res. 2007;22:S2. 18. Armas LAG, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-(OH) D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007;57:588-593. 19. Mirtallo JM, Holcombe B, Kochevar M, Guenter P. Parenteral nutrition product shortages: the A.S.P.E.N. Strategy. Nutr Clin Pract. 2012;27:385391. 20. Koutkia P, Lu Z, Chen TC, Holick MF. Treatment of vitamin D deficiency due to Crohn’s disease with tanning bed ultraviolet B radiation. Gastroenterology. 2001;121:1485-1488. 21. Coen G. Vitamin D: an old prohormone with an emergent role in chronic kidney disease. J Nephrol. 2008;21:313-323. 22. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281. 23. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73-S87. 24. Staun M, Pironi L, Bozzetti F, et al. ESPEN guidelines on parenteral nutrition: home parenteral nutrition (HPN) in adult patients. Clin Nutr. 2009;28:467-479. 25. Corey B, Ackerman K, Allen P, Sceery N, Rafoth C. Vitamin D status of New England home TPN patients: a snapshot of practice. Nutr Clin Pract. 2009;24:110A. 26. Thomson P, Duerksen DR. Vitamin D deficiency in patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2011;35:499504. 27. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80:1678S-1688S. 28. Levine JA, Sorace M, Spencer J, Siegel DM. The indoor UV tanning industry: a review of skin cancer risk, health benefit claims, and regulation. J Am Acad Dermatol. 2005;53:1038-1044. 29. Pittas AG, Saltzman E. Role of vitamin D in adults requiring nutrition support. JPEN J Parenter Enteral Nutr. 2010;34:70-78. 30. Grossmann RE, Tangpricha V. Evaluation of vehicle substances on vitamin D bioavailability: a systematic review. Mol Nutr Food Res. 2010;54:1055-1061.
