Vitamin D and Vitamin B12 Deficiencies Are Common in Patients

Home , Vitamin B12 deficiency, Vitamin D deficiency

ORIGINAL ARTICLE Vitamin D and vitamin B12 deﬁciencies are common in patients with midgut carcinoid (SI-NET)

A Lind1, B Wängberg2 and L Ellegård1

BACKGROUND/OBJECTIVES: Patients with small intestinal neuroendocrine tumours (SI-NET) often have diarrhoea from hormonal overproduction, surgery and medical treatment, leading to malabsorption of bile salts, fats, vitamin B12 and fat-souble vitamins. This could lead to malnutrition. SUBJECTS/METHODS: We assessed nutritional status in 50 consecutive out patients with disseminated SI-NET, 25 patients in each cohort. The first cohort was descriptive and the second cohort supplemented with vitamin D, B12 and calcium. Vitamin D deficiency was defined as o50 nmol/l. All patients were assessed by clinical chemistry and dual-energy X-ray absorptiometry (DXA) and interviewed about weight changes, appetite, gastrointestinal disorders, sunhabits and the use of supplements. RESULTS: In the first cohort, 29% of the patients were severely and 17% moderately vitamin D deficient. In patients without prior substitution, 32% had subnormal vitamin B12 levels. Seventy-six percent had low bone density. In the second cohort with vitamin and mineral supplementation, none had severe vitamin D deficiency, but 28% had moderate deficiency. No patient had subnormal vitamin B12 levels. Sixty percent had low bone density. The serum levels of vitamin D and B12 were higher and parathyroid hormone (PTH) lower in the second cohort compared with the first cohort (P ⩽ 0,022). Vitamin D and PTH were negatively correlated, r = − 30, P = ⩽ 0.036. CONCLUSIONS: Low serum levels of vitamin D and vitamin B12, and low bone density are common in patients with disseminated SI-NET. Supplementation of vitamin D, B12 and calcium resulted in higher serum levels of vitamins, lower PTH levels and diminished severe vitamin D deficiency and is thus recommended as standard care. European Journal of Clinical Nutrition (2016) 70, 990–994; doi:10.1038/ejcn.2016.40; published online 30 March 2016

INTRODUCTION and some are working full time and thus need optimal nutritional Small intestinal neuroendocrine tumours (SI-NETs), formerly status. known as midgut carcinoids, are rare, slow-growing neuroendo- This investigation started 2008 with an en passant finding of crine tumours with fairly good prognosis. The incidence is 2 per severe vitamin D deficiency in a few patients with SI-NET. This 100 000 inhabitants and year.1 The primary tumours are usually drew our attention to the nutritional status of these patients and located in the ileum. Widespread metastatic diesease is common whether we should consider a general preventive supplementa- 2 tion of vitamins and minerals for all patients with SI-NET. To the at diagnosis, but with proper treatment these patients still have a 9 5-year survival close to 70%.3 Disseminated disease often gives best of our knowledge, this has not been previously reported. We fi symptoms of excessive amine and peptide secretion, including rst set out to assess nutritional status, and when we found it watery diarrhoea and rapid intestinal transit,4 as part of the suboptimal we introduced vitamin and mineral supplementation. midgut carcinoid syndrome. Many patients with the midgut carcinoid syndrome1 seem to Aims have a good nutritional status regarding energy intake, weight The aim of the first cohort was to assess nutritional status in stability, body mass index (BMI) and appetite. Still, these patients patients with disseminated SI-NET, and the aim of the second often have several factors negatively affecting nutrient uptake. cohort was to improve nutritional status by supplementation of 5 These include diarrhoea, surgical resections and medical vitamin D, calcium, vitamin B12 and a multivitamin 3 treatment, which can lead to malabsorption of bile salts, fats, containing iron. vitamin B12 and fat-souble vitamins.6 Surgical treatment often involves bowel resections of the terminal ileum.7 Somatostatin analogues (for example, octreotide MATERIALS AND METHODS fl or lanreotide) may reduce intestinal uid secretion and also the Subjects secretion of pancreatic enzymes and bile acids,3 which diminish The study included 50 consecutive patients with disseminated SI-NET, 25 fat absorption. Malabsorption of fat and fat-souble vitamins may fi 6,8 patients in each cohort (11men/14women in the rst cohort, 12 men/13 lead to reduced bone density due to vitamin D deficiency. women in the second cohort). They were all out patients visiting the Patients with SI-NET could thus be suspected to have some degree Department of Surgery, Sahlgrenska University Hospital, Gothenburg, of intestinal failure. Despite this, these patients are often active, Sweden, for regular post-operative examinations, control of symtoms and

1Clinical Nutrition Unit, Department of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden and 2Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. Correspondence: A Lind, Department of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Bruna Stråket 11, Gothenburg 41345, Sweden. E-mail: [email protected] Received 20 August 2015; revised 3 February 2016; accepted 10 February 2016; published online 30 March 2016 Vitamin D and vitamin B12 in patients with midgut carcinoid A Lind et al 991 hormonal hypersecretion. All patients had undergone resections of the Participants were recommended and prescribed a daily supplementation small bowel, except one who declined surgery. The patients in the two with vitamin D (20–40 μg), calcium (1000 mg) and vitamin B12 (1 mg) by cohorts were similar regarding sex, age and weight and were all of the attending surgeon. They were also recommended multivitamins with Caucasian origin. Clinical data on the subjects are given in Table 1. iron, containing 15–18 mg iron. Information regarding medical and surgical treatment, biomarkers for Six to 15 months after the recommendation of supplements, between hormone production, 5-hydroxy indole acetic acid (5-HIAA) and chromo- May 2011 and June 2012, in conjunction with a follow-up at the clinic, granine-A, and co-morbidities were checked from medical records. vitamin status and bone density were assessed by the same procedures Somatostatin analogues were used by 88% in both groups. and protocols as in the first descriptive part of the study. The Inclusion criteria were diarrhoea symptoms and/or resections of the questionnaire-based interview was also repeated (Figure 1). small intestine. Exclusion criteria were expected survival less than 2 years, dementia, liver transplant, long-term treatment with steroids or other immunosuppressive drugs or a fracture during the last 6 months. Nutritional status All of the study subjects gave informed consent, and the study was approved Nutritional status was evaluated by blood tests and measurements of by the Regional Ethical Review Committee of Gothenburg (Dnr: 743-12). weight, height and body composition. Body weight was measured in underwear on an electronic scale to the nearest 0.1 kg. Body height was measured to the nearest half centimetre with a wall-mounted stadiometer. Study design BMI was defined according to World Health Organization (WHO). The first part of the study described the nutritional status by clinical Bone mineral density (BMD) was assessed by DXA using a LUNAR chemistry and by DXA in a cohort of 25 consecutive patients with PRODIGY-scanner (Scanex, Helsingborg, Sweden). BMD of the spine and disseminated SI-NET. The dietician interviewed each patient about weight hip was measured and osteoporosis was defined as a T-score o − 2.5 and history during the last 6 months, appetite, nutritional- and gastrointestinal osteopenia as a T-score between − 1 and − 2.5 according to WHO. Skeletal disorders, a simplified diet history including food choices, meal patterns muscle mass was estimated from DXA and expressed as skeletal muscle and eating habits, vitamin and mineral supplements, anti-diarrhoeal drugs, mass index (SMI/lenght2), where values ♀o6.05 ♂o7.99 indicate supplements with pancreatic enzymes and sun habits. The patients were sarcopenia or low muscle mass.10 included and assessed between April and October 2009 in conjunction with a follow-up at the clinic. The second part of the study included a cohort of another 25 consecutive patients with disseminated SI-NET. These Clinical chemistry patients were treated by oral substitution of vitamins and minerals. Extended clinical chemistry tests included iron status, vitamin D, K and B12, folate, calcium, magnesium, parathyroid hormone (PTH), albumin, creatinine and C-reactive protein (CRP) and were assessed by the SWEDAC- Table 1. Clinical data in 50 patients with disseminated SI-NET accredited Central Laboratory for Clinical Chemistry at the Sahlgrenska University Hospital (accreditation, 1240 ISO 15189). Serum levels of 25-OH Cohort 1 n = 25 Cohort 2 n = 25 vitamin D were analysed with HPLC. Vitamin D o25 nmol/l was defined as severe deficiency, o50 as fi o fi 11,12 Mean ± SD Range Mean ± s.d. Range moderate de ciency and 75 as insuf cient. Vitamin K was expressed as INR, and ratios ⩾ 1.2 was classified as deficient. The presence of Age (years) 69 ± 8.7 50–81 67 ± 855–83 inflammation was defined by CRP 45 mg/l. Hypoalbuminemia was defined BMI (kg/m2) 24.5 ± 4,6 16.5–36.5 24.4 ± 4.2 18.7–33.8 as S-Albo32 g/l and anaemia as Hbo120 g/l (according to WHO). Lower Length of intestinal 72a ± 50 0–190 73b ± 51 15–185 limit for normal values was o2.15 mmol/l for calcium and o140pmol/l for resection (cm) B12 and upper limit for normal value was 468 ng/l for PTH. Time passed since 5.2 ± 4.1 1–15 4.8 ± 5.1 1–16 resection (years) Data analyses 5-HIAA (0-50μmol/l) 132 ± 157 14–590 132 ± 158 15–690 Chromogranin-A 37 ± 70 2.9–322 60 ± 183 4.5–914 All the collected data were made anonymous, using serial numbers. (o6nmol/l) ALP (μkat/l) 2.1 ± 1.8 0.8–8.7 1.8 ± 1.0 0.7–2 Statistical analyses Abbreviations: ALP, alkaline phosphatase; BMI, body mass index; 5-HIAA, Results from biochemical blood tests and DXA are given with descriptive 5-hydroxy indole acetic acid. In cohort 1 without and in cohort 2 with statistics as means and s.d. Differences between the two cohorts were recommended vitamins and minerals. There were no significant differences analysed by a t-test using SPSS software, version (21). A P value o0.05 was between the two cohorts. aMissing data, n = 19. bMissing data, n = 22. considered to be significant. Correlation between variables was assessed by linear regression.

Cohort 1 •Bloodsampling • Bone density Assessment •Questionnaire April-October 2009

Cohort 2a •Vitamin D Inclusion • Calcium •Vitamin B12 Recommmp endation of sup plements • Multivitamin Septembeem r 2010- Novem ber 2011

Cohort 2b •Blooodsampling Assessment> 6 month < 15 month •Bone density May 2011-June 2012 •Questionnaire

Figure 1. Study design. Nutritional status was assessed in 25 consecutive out patients in the ﬁrst cohort, a descriptive study. Another 25 consecutive out patients with recommended supplements underwent the same assessments after 6–15 months, in the second cohort.

© 2016 Macmillan Publishers Limited, part of Springer Nature. European Journal of Clinical Nutrition (2016) 990 – 994 Vitamin D and vitamin B12 in patients with midgut carcinoid A Lind et al 992 RESULTS dose were forgetfulness, difficulty to swallow tablets or changes of Participation and symtoms the prescription dose. One patient deliberately neglected the The study included 50 consecutive patients with disseminated SI- supplementation, in the belief that he was on a proper diet and NET, 25 patients in each cohort. There were no dropouts in the had sufficient sun exposure, and actually had a serum level of first descriptive cohort. In the second cohort, 39 patients started vitamin D of 54 nmol/l. Seventeen of 25 patients took a with the recommended supplements and 36% discontinued the multivitamin in addition to the prescribed supplements with a study because of lack of time, participation in other studies, other content of vitamin D between 5 and 10 μg. diseases or bone fracture. We found no correlations between vitamin D status and age, Most of the patients reported good appetite and had a gender, length of intestinal resection, treatment with somatos- stable weight for the last 6 months, (Table 2). Average BMI was tatin analogues, presence of steatorrhoea or any other clinical almost the same in the two cohorts: 24.5/24.4. Two patients in data shown in Table 1 and Table 2, with the exception of PTH the first cohort and none in the second cohort had a BMIo18.5. (see below). Mean index of skeletal muscle mass was similar in the first However, high sun exposure was correlated to better vitamin D and second cohort: 6.9/6.7 for women and 8.8/8.9 for men. Four status. Most of the patients spent the entire year in Sweden, patients in each cohort had low muscle mass, sarcopenia, where the sun exposure for autosynthesis of vitamin D is sufficient (2men/2women in the first cohort, 1 man/3 women in the second fi — — only in the summer, but four patients in the rst cohort and six cohort), and they also had lower BMI 21.3/20.2 and low bone patients in the second cohort went south on sun holiday in winter. density. Mean serum vitamin D level in these patients was higher, 66 nmol/l The simplified dietary history showed varied food choices with versus 50 in the first cohort and 82 nmol/l versus 70 in the second regular meal times in both cohorts. Nutritional supplements (sip fi feeds) were used by 12% in the first cohort and by 8% in the cohort. A few patients avoided the sun, 2 in the rst cohort and 3 in second cohort. Thirty-six percent in both cohorts avoided foods the second cohort. Mean serum vitamin D levels were lower in with fermentable carbohydrates to avoid flatulence, 20% in the these patients, 13nmol/l versus 50 in the first cohort and 43 nmol/l first cohort avoided fatty foods because of diarrhoea and 24% in versus 70 in the second cohort. the second cohort and 8% in both cohorts avoided indigestible food because of intestinal constriction and 4% in the first cohort fl avoided alcohol because of the provocation of ush as part of the Table 3. Prevalences of vitamin D deficiency in 50 patients with carcinoid syndrome. Gastrointestinal problems were common in disseminated SI-NET patients with disseminated SI-NET. Diarrhoea, steatorrhoea and urgency incontinence were very common in both cohorts and 25-OH vitamin D nmol/l Cohort 1 Cohort 2 could be socially inhibiting. Patient characteristics are shown in n =24a n =25 Table 1 and Table 2. % %

o25 = severe deficiency 29 0 Vitamin D o50 = moderate deficiency 17 28 Almost half of the patients in the first cohort were vitamin D o75 = insufficiency 33 32 deficient (o50 nmol/l). In patients who used daily standard 75–150 = optimum 21 40 vitamin supplements, with a maximum of 5 μg vitamin D per day, fi In cohort 1 without and in cohort 2 with recommended vitamin D 4 out of 6 were de cient. Vitamin D status is presented in Table 3. supplements. aOne patient on vitamin D supplement excluded. In the second cohort, where patients were recommended supplements, mean serum levels were significantly higher than in the first cohort, and no patient was severely vitamin D deficient (Table 4, Figure 2). Reported average intake per day was 22 μg for Table 4. Serum levels of clinical chemical parameters including vitamin D and 800 mg for calcium, which was slightly less than vitamins and minerals in 50 patients with disseminated SI-NET recommended. Forty percent of the patients did not take all of the prescribed vitamin D and calcium. Reasons for not taking the full Unit Cohort 1, n = 25 Cohort 2, n = 25 P by t-test

Mean ± s.d. Mean ± s.d. Table 2. Clinical symptoms, medical treatment and nutrition status in 50 patients with disseminated SI-NET CRP mg/l 6 ± 64± 6 25-OH nmol/l 50 ± 28a 70 ± 29 0.019 Cohort 1 Cohort 2 vitamin D n =25 n =25 Vitamin K INR 1.07 ± 0.16b 1.04 ± 0.09b % % Vitamin B12 pmol/l 402 ± 396 734 ± 333 0.002 Folate nmol/l 23 ± 11c 27 ± 12c Good apppetite 88 92 Haemoglobin g/l 130 ± 15d 130 ± 12 Weight stability 80 80 TIBC μmol/l 70 ± 14d 75 ± 9 Underweight 8 0 Iron μmol/l 14 ± 8d 15 ± 6 Sarcopenia 16 16 Ferritin μg/l 123 ± 80 88 ± 58 Low bone density 76 60 Calcium mmol/l 2.24 ± 0.13 2.36 ± 0.09 Diarrhoea 92 88 Magnesium mmol/l 0.85 ± 0,11 0.84 ± 0.30 Steatorrhoea 48 48 Albumin g/l 39 ± 439± 3 Urgency 80 72 PTH ng/l 94 ± 72 58 ± 21 0.022 Flatulence 84 52 Creatinine μmol/l 86 ± 30 80 ± 13 Abdominal pain 48 24 Cohort 1 without and cohort 2 with recommended supplements of Antidiarrhoeal drugs 56 32 a Pancreatic enzymes 28 40 vitamins and minerals. One patient on vitamin D supplement excluded, n = 24. bFive patients on anti-vitamin K therapy excluded, n = 23/22. Cohort 1 without and cohort 2 with recommended supplements of cMissing data and one patient in cohort 1 on Folate supplement excluded, vitamins and minerals. n = 23/20. dMissing data, n = 24.

Cohort 1 Cohort 2 (Supplement) Cohort 1 Cohort 2 (Supplement) Cohort 1 Cohort 2 (Supplement) Figure 2. Serum levels of vitamin D, PTH and vitamin B12 without supplementation in the ﬁrst cohort and after 6–15 months with recommended supplements in the second cohort. Presented as median, IQR (interquartile range) and range.

Vitamin K DISCUSSION Abnormal INR ratios (⩾1.2) were found in 5 of the patients (22%) in To our knowledge, the present study is the first attempt to the first cohort, two patients on anti-vitamin K therapy excluded evaluate nutritional status, including vitamins and minerals in (n = 23). Three of those five patients had also severe vitamin D patients with disseminated SI-NET. In this study, we compared deficiency. In the second cohort, two patients (9%) had elevated nutritional status in two cohorts. In the first descriptive cohort, we vitamin K values, three patients on anti-vitamin K therapy excluded assessed 25 patients without supplementation and found a high (n = 22), but none of those patients were vitamin D deficient. prevalence of low bone density and of vitamin D and B12 deficiency. In the second cohort, we investigated whether oral Calcium and bone density substitution of vitamins and minerals, for at least 6 months, could Low bone density was common in patients with SI-NET. Seventy- prevent vitamin D and B12 deficiency in 25 other patients. Serum six percent in the first cohort had low bone density; 32% had levels of vitamin D and B12 were significantly higher in the second osteoporosis and 44% had osteopenia. Sixty percent in the second cohort compared with the first cohort, and PTH levels were cohort had low bone density; 24% had osteoporosis and 36% significantly lower. Furthermore, no patients in the second cohort osteopenia. had severe vitamin D or B12 deficiency. Twenty-six percent of the patients with low bone density in the fi rst cohort had total serum levels of calcium below normal value, but Vitamin D and bone density none in the group with normal bone density. In the second cohort A high prevalence of vitamin D deficiency and low bone density with recommended supplements of calcium, mean serum levels was not unexpected as low vitamin D status is common were somewhat higher than in the first cohort, albeit without worldwide due to low dietary intake and low sun exposure.8 statistical significance, and all had normal calcium levels (Table 4). Compared with a healthy Swedish population,13 the average serum vitamin D level was only nominally lower in the first cohort, Parathyroid hormone 47nmol/l versus 60nmol/l, whereas in the second cohort the Twelve patients (48%) had elevated levels of PTH in the first average serum level at 66nmol/l was similar to the healthy cohort, all with low bone density. In the second cohort, PTH levels population group. fi were signi cantly lower and only seven patients (28%) had High prevalence of vitamin D deficiency and osteoporosis has elevated levels, and of these three had low bone density (Table 4, also been reported in patients with intestinal failure (IF).14 Patients Figure 2). Low values of vitamin D were correlated to high PTH with IF and SI-NET have similar problems of malabsorption, caused − values, r = 0.30, P = 0.036. The average serum level of vitamin D by surgical and medical treatment. in patients with elevated levels of PTH was 56 nmol/l in both The presence of severe vitamin D deficiency in the first cohort cohorts. was 29%; this is similar to what has been reported previously in Swedish patients with IF14 where the prevalence was 23%. Vitamin B12 Moderate deficiency was found in 44% compared with 17% in Six of 25 patients (24%) used vitamin B12 supplements in the first our patients. With supplementation in the second cohort, 28% of cohort. In 19 patients without prior substitution, 6 patients (32%) the patients were moderately vitamin D deficient, but none were had subnormal serum levels of vitamin B12 (o140 pmol/l), all of severely vitamin D deficient. them had between 70 and 100 cm of the ileum resected, and 8 Presumably, a higher average daily intake of vitamin D should patients (42%) had serum levels between 140 and 250 pmol/l. result in a better vitamin D status; hence, supplements with a high In the second cohort with recommended supplementation, 24 content of vitamin D and chewable tablets to maximise out of 25 patients took the prescribed dose, and none had compliance are preferred. To evaluate treatment, monitoring of subnormal serum levels of vitamin B12. Only one patient had serum 25-OH vitamin D is recommended. level under 250 pmol/l; this patient had temporarily stopped taking The prevalence of low bone density in SI-NET patients was supplemetation with vitamin B12 (Table 4, Figure 2). similar to Swedish patients with IF,14 88% of IF patients versus 76% in the first cohort and 60% in the second cohort. The IF patients Iron had the same mean age, 68 years. Multivitamins with iron was recommended as iron status was In Sweden, one out of three women aged 70–79 has marginal. Sixteen patients (64%) in the second cohort took a osteoporosis,15 but in patients with disseminated SI-NET the supplement containing in average 12 mg iron per day. Despite the prevalence for women, in that age, was higher. In the first cohort, supplement, iron status was similar in the second cohort. 54% had osteoporosis compared with 38% in the second cohort.

© 2016 Macmillan Publishers Limited, part of Springer Nature. European Journal of Clinical Nutrition (2016) 990 – 994 Vitamin D and vitamin B12 in patients with midgut carcinoid A Lind et al 994 Vitamin B12 and iron CONFLICT OF INTEREST In the first cohort, the prevalence of vitamin B12 deficiency was The authors declare no conflict of interest. higher than expected in these patients who all had undergone – ileum resections of 70 100 cm. It is well known that resections of ACKNOWLEDGEMENTS the distal small intestine decrease the absorption of vitamin B12,7 and thus supplementation with vitamin B12 is generally This study was supported by funds for research and development in Västra Götaland, recommended but obviously not always given. Marginally low Grant No. VGFOUGSB-36541 and VGFOUGSB-148731. serum levels (140–250 pmol/l) were seen in 41% of the patients in the first cohort versus 4% in the second cohort. 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