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Bone mineral density and fat-soluble vitamin status in adults with cystic fibrosis undergoing lung transplantation: a pilot study.

INTRODUCTION

Maintenance of bone health in patients with cystic fibrosis (CF) is an ongoing challenge, especially as the disease becomes more severe and the need for lung transplantation (LTX) becomes more eminent [1]. Pre-LTX and post-LTX, individuals with CF are at high risk for low bone mineral density (BMD) related to chronic use of corticosteroid and other immunosuppressive therapy (such as tacrolimus), antibiotic use and chronic undernutrition secondary to poor intake, increased energy expenditure, and pancreatic insufficiency [2-4]. Suboptimal fat-soluble vitamin intake due to inadequate or poor diet quality and/or noncompliance to prescribed vitamin supplementation can also contribute to low BMD. Several studies have shown that fat-soluble vitamins can be low preLTX [5-7], whereas post-LTX, hypervitaminnosis A can contribute to low BMD [8].

The University of Alberta Lung Transplant Program provides LTX for patients with end-stage lung disease from Alberta, including individuals with CF who have a reported 60%-75% 5-year survival rate [9]. With increased survival, poor bone health is a significant concern, especially as it relates to increased morbidity and mortality and overall quality of life [4, 10]. Limited exposure to sunlight in northern climates also increases the risk for vitamin D (vitD) deficiency and subsequent poor bone health. For these reasons, patients are routinely supplemented with commercially available fatsoluble vitamins (A, D, E, and K) pre- and post-LTX. Although suboptimal vitamin K (vitK) status has been shown to be a contributor to low bone health in many clinical populations [11], it is currently unknown what the current prevalence of suboptimal vitK status is in adult patients post-LTX. This is particularly relevant in the CF population, as on-going fat malabsorption due to pancreatic insufficiency is not corrected or improved by lung transplantation. This pilot study describes BMD and fat-soluble vitamin status in adult CF subjects, pre- and post-LTX.

METHODS

Ethics approval (Pro 00001737) was obtained from the Human Research Ethics Board at the University of Alberta prior to study initiation. Adult CF patients (age >18 years) who were referred to the University of Alberta Lung Transplant program between 2005 and 2012 were recruited and enrolled over a 12-month period. Study inclusion criteria included those on anti-resorptive therapy, as this is part of routine clinical care. Exclusion criteria included terminal illness, intensive care unit stay >72 hours, and subjects who were unable to provide informed consent. A total of 25 patients with CF undergoing lung transplant assessment were screened for eligibility; 13 were excluded due to coinciding illness requiring hospitalization, early lung TX, and/or refusal to participate. No significant differences in demographic or anthropometric variables were noted between those who agreed to participate in the study and those who did not. Informed consent was obtained from all participants. Height and weight were measured using validated techniques.

Blood was collected for measurement of vitamins A, D, E, and K (protein indicated in vitamin K absence (PIVKA-II)) and parathyroid hormone (PTH) at LTX assessment and at 3, 6, and 12 months post-LTX. The samples were analyzed according to standardized methodologies in the Core Laboratory at Alberta Health Services [12]. Serum 25-hydroxy vitamin D (25(OH)D) concentrations were assessed according to the Canadian Endocrine Practice Guidelines (<75 nmol/L, insufficient/suboptimal; >75 nmol/L, optimal) [13]. BMD was measured using hologic dual-energy X-ray absorptiometry 450 at LTX assessment and at 9 and 18 months postLTX (whole body, hip, femoral-neck (FN), femoral-trochlea, lumbar-spine).

Analyses were performed using Statistical Analysis Software (SAS; version 9.4 SAS Institute, Cary, NC, USA). Data were analyzed by treating individual patient data as single measures, rather than repeated measures due to the small sample size at each individual time point. Continuous variables were expressed as mean [+ or -] SD. Normality was assessed using the Shapiro-Wilk test. Non-parametric variables were log transformed. Continuous variables were analyzed using dependent t test to assess differences pre- and post-LTX with adjustments for potential confounding variables (season, age, sex). Statistical significance was determined at P < 0.05.

RESULTS

Demographic, anthropometric, and laboratory data

Anthropometric and demographic data for the 12 patients pre- and post-LTX are shown in Table 1. No significant age difference at time of LTX assessment was observed between sexes (males, 29 [+ or -] 10 years vs. females, 31 [+ or -] 6 years; P = 0.70). A total of 42% (n = 5) and 17% (n = 2) of participants had a mean BMI reflective of suboptimal nutritional status (BMI < 18.5) pre- and post-LTX, respectively. Laboratory data are shown in Table 2. Although there was no significant difference in estimated glomerular filtration rate (GFR), values in 58% of patients were indicative of renal insufficiency (GFR <60; stage 3 chronic kidney disease) post-LTX. In addition, significant differences in urea, creatinine, and PTH pre- and post-LTX were noted, indicating worsening renal function and secondary hyperparathyroidism in 83% of patients post-LTX. The majority of patients (67% pre-LTX and 58% postLTX) had optimal 25(OH) vitD levels (>75 nmol/L), likely secondary to vitD supplementation (400-8700 IU/d) [13]. A total of 58% and 55% of patients had suboptimal vitK status (PIVKA-II values >3 ng/mL) pre- and post-LTX, respectively, despite routine recommendation for vitK supplementation (>1 mg/d). Significant differences in serum retinol levels and vitamin E levels were also observed pre- and post- LTX (P < 0.05) with daily vitamin A (26 501 [+ or -] 14 040 IU/d) and vitamin E (260 [+ or -] 179 IU/d) supplementation. Routine vitamin supplementation was typically in the form of single vitD (>1000 IU) and/or multivitamin preparations.

Bone mineral density

BMD data are shown in Table 1 and Figure 1. No significant differences pre- and post-LTX were observed at the different site measures (lumbar-spine, FN, hip and femoral-trochlea) (P > 0.05). With the exception of spinal-BMD (absolute; females, 0.91 [+ or -] 0.08 vs males, 0.82 [+ or -] 0.09 gm/[cm.sup.2]; P = 0.002) and T scores (females, -1.27 [+ or -] 0.79 vs males, -2.25 [+ or -] 1.26; P = 0.015), no significant differences in absolute or T scores were observed between sexes at the different sites measured (P> 0.05). BMD T scores (<-2) indicative of osteoporosis were present in lumbar-spine, hip, FN, and femoral-trochlea in 33%, 17%, 17%, and 25% individuals pre-LTX, respectively. In contrast, BMD T scores (<-2) were present in lumbar--spine, hip, FN and femoral-trochlea in 58%, 33%, 58%, and 33% individuals post-LTX, respectively.

[FIGURE 1 OMITTED]

DISCUSSION

This is a descriptive, pilot study that describes fat-soluble vitamin status and BMD in adults with CF pre- and post-LTX in a northern Canadian LTX program. A significant finding is that the majority of patients had reduced BMD and suboptimal vitK status, despite healthcare practitioner recommendation for fat-soluble vitamin supplementation. Several factors may have influenced these findings such as low patient adherence to prescriber recommendation, ongoing pancreatic insufficiency and malabsorption refractive to pancreatic enzyme replacement therapy, poor diet quality, reduced weight-bearing activities, and use of immunosuppressive medications such as corticosteroids, tacrolimus, and antibiotics (e.g., tobramycin) [14, 15]. Many patients in this cohort were underweight at the time of LTX and hence had suboptimal nutritional status. Although, weight status improved post-LTX, deficits in nutritional intake and weight-bearing activity, ongoing pancreatic insufficiency and the use of corticosteroid therapy (typically 10-15 mg/d, but tapered down to alternative day therapy and/or discontinuation by 6-12 months), and/or other medications such as tacrolimus may have contributed to reduced BMD [9, 15-17].

Suboptimal vitD status is highly prevalent in northern climates like Alberta [18, 19]. Although patients in general had serum 25(OH)D levels above 75 nmol/L and normal PTH levels, higher vitD levels in conjunction with weight-bearing activities may be needed to optimize bone health pre- and post-LTX. Findings regarding poor bone health are similar to other LTX centres where ongoing nutritional challenges in adult LTX recipients place them at high risk for poor bone health [20]. A major limitation in this study includes the small sample size, which limits the overall generalizability of the findings. However, a post-hoc power test indicated sufficient power ([beta] > 0.8) to discriminate reduced BMD at the different sites pre- and post-LTX.

Unique findings include the high prevalence of suboptimal vitK status post-LTX. These findings underscore the importance of routine follow-up by healthcare practitioners in patients with CF undergoing LTX. Future studies should focus on assessing adherence to vitamin therapy, and the impact of vitK supplementation on bone health parameters.

RELEVANCE TO PRACTICE

Patients with CF are at high risk for poor bone health and micronutrient insufficiency. This underscores the need for highly specialized medical teams to address ongoing micronutrient deficiencies in this population. Registered Dietitians are uniquely positioned to help optimize bone health and micronutrient status by developing effective nutrition care plans and exploring the barriers and facilitators to achieving nutritional goals in complex care populations.

Acknowledgements

The authors gratefully acknowledge the participants in this study.

Funding: Canadian Lung Transplantation Study Group. Personal funding for ASA by the King Abdullah Program for Scholarship- Saudi Cultural Bureau is also gratefully acknowledged.

Conflicts of interest: None to report.

References

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GRACE HUBERT, RD BSc (a); THERESA TAM CHUNG, RD BSc (a); CONNIE PROSSER, PhD FCACB (b); DALE LIEN, MD (c); JUSTIN WEINKAUF, MD (c); NEIL BROWN, MD (c); MARIANNE GOODVIN, RN BNSc (d); KATHY JACKSON, RN BNS (c d); JOAN TABAK, RN (e); JOSETTE SALGADO, RN BNSc (e); ABEER SALMAN ALZABEN, MSc (f); DIANA R. MAGER, PhD MSc RD (f g)

(a) Nutrition Services, Alberta Health Services, Edmonton, AB; (b) Department of Laboratory Medicine, University of Alberta, Edmonton, AB; (c) Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB; (d) Lung Transplant Program, Alberta Health Services, Edmonton, AB; (e) Adult Cystic Fibrosis Clinic, Alberta Health Services, Edmonton, AB; (f) Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB; (g) Department of Pediatrics, University of Alberta, Edmonton, AB
Table 1. Anthropometric and bone health variables pre- and
post-LTX in adult patients with cystic fibrosis.

                       Pre-LTX              Post-LTX
Anthropometrics   (n=12; 7M, 5F) (a)   (n=12; 7M, 5F) (a)     P

Age (y)             29 [+ or -] 8        30 [+ or -] 8      0.371
                       (19-49)              (19-52)

Weight (kg) (b)   54.8 [+ or -] 9.0    60.3 [+ or -] 5.6    0.098
                     (39.1-71.0)          (51.4-67.8)

Height (m)        1.68 [+ or -] 0.08   1.68 [+ or -] 0.08   >0.05
                     (1.55-1.81)          (1.55-1.81)

BMI (kg/          19.3 [+ or -] 3.2    21.4 [+ or -] 2.4    0.103
[m.sup.2]) (b)       (15.1-25.7)          (17.5-25.0)

Spine BMD         0.86 [+ or -] 0.11   0.86 [+ or -] 0.10   0.992
(gm/[c.sup.2])       (0.69-1.03)          (0.69-1.07)
(c)

Hip BMD           0.82 [+ or -] 0.14   0.77 [+ or -] 0.12   0.262
(gm/[cm.sup.2])      (0.57-1.08)          (0.54-1.04)
(c)

Femoral-neck      0.71 [+ or -] 0.10   0.67 [+ or -] 0.11   0.324
BMD (gm/             (0.56-0.90)          (0.54-0.91)
[cm.sup.2])(c)

Femoral--         0.60 [+ or -] 0.11   0.55 [+ or -] 0.10   0.166
trochlea BMD         (0.43-0.82)          (0.40-0.77)
(gm/[cm.sup.2])
(c)

(a) Data are presented as mean [+ or -] standard division (range).

(b) The number of measurements post-LTX was 11.

(c) The number of repeated measurements post-LTX was 22.

Note: LTX, lung transplantation; M, male; F, female; BMI, body
mass index; BMD, bone mineral density.

Table 2. Laboratory variables pre- and post-LTX in adult patients
with cystic fibrosis

Biochemical             Pre-LTX (n=12) (a)      Post-LTX (n=12) (a)

Vitamin A                1.4 [+ or -] 0.3        2.7 [+ or -] 0.8
([micro]mol/L) (b)           (0.8-2.0)               (1.3-4.0)

PIVKA II (ng/mL) (c)    80.0 [+ or -] 171.9      6.4 [+ or -] 14.2
                            (0.1-427.8)             (0.1-64.2)

Vitamin E               26 [+ or -] 9 (10-      40 [+ or -] 18 (13-
([micro]mol/L) (b)              43)                     86)

Calcium (mmol/L) (d)    2.25 [+ or -] 0.10      2.26 [+ or -] 0.13
                            (2.08-2.38)             (2.10-2.80)

PTH (pmol/L) (b)         4.4 [+ or -] 3.9        9.8 [+ or -] 11.9
                            (1.4-16.0)              (2.1-61.0)

25(OH)D (nmol/L) (b)    83 [+ or -] 40 (10-     85 [+ or -] 23 (43-
                               154)                    141)

Urea (mmol/L) (e)        4.3 [+ or -] 1.5        7.1 [+ or -] 2.8
                             (1.2-6.8)              (1.9-10.7)

Creatinine              64 [+ or -] 18 (35-    108 [+ or -] 35 (48-
([micro]mol/L) (f)              99)                    166)

GFR (ml/min/1.73       60 [+ or -] 0 (60-60)   53 [+ or -] 9 (30-60)
[m.sup.2]) (g)

Hemoglobin A1C (%)      6.34 [+ or -] 0.57      6.11 [+ or -] 0.47
(h)                          (5.5-7.4)               (5.4-7.1)

Biochemical             Normal reference       P
                             ranges

Vitamin A                    1.5-3.5         <0.001
([micro]mol/L) (b)

PIVKA II (ng/mL) (c)   [less than or equal   0.206
                              to]3

Vitamin E                     12-45          0.010
([micro]mol/L) (b)

Calcium (mmol/L) (d)        2.10-2.60        0.773

PTH (pmol/L) (b)             1.2-6.8         0.025

25(OH)D (nmol/L) (b)           <75           0.798

Urea (mmol/L) (e)            2.5-8.0         0.006

Creatinine             M: 50-115 F: 50-105   <0.001
([micro]mol/L) (f)

GFR (ml/min/1.73               >60           0.090
[m.sup.2]) (g)

Hemoglobin A1C (%)            <6.1           >0.05
(h)

(a) Data are presented as mean [+ or -] standard division (range).

(b) The number of measurements pre-LTX was 12; the number of
repeated measurements post-LTX was 33.

(c) The number of measurements pre-LTX was 11; the number of
repeated measurements post-LTX was 20.

(d) The number of measurements pre-LTX was 12; the number of
repeated measurements post-LTX was 34.

(e) The number of measurements pre-LTX was 12; the number of
repeated measurements post-LTX was 13.

(f) The number of measurements pre-LTX was 12; the number of
repeated measurements post-LTX was 24.

(g) The number of measurements pre-LTX was 6; the number of
repeated measurements post-LTX was 17.

(h) None of the participants pre-LTX were on exogenous insulin
vs 83% post-LTX who were on exogenous insulin.

Note: LTX, lung transplantation; PIVKA II, proteins induced by
vitamin K absence II; PTH, parathyroid hormone; 25(OH)D, 25-hydroxy
vitamin D; GFR, glomerular filtration rate.
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Title Annotation:Report / Rapport
Author:Hubert, Grace; Chung, Theresa Tam; Prosser, Connie; Lien, Dale; Weinkauf, Justin; Brown, Neil; Goodv
Publication:Canadian Journal of Dietetic Practice and Research
Geographic Code:1CANA
Date:Dec 1, 2016
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