World J Surg (2011) 35:1540–1545 DOI 10.1007/s00268-011-1096-5
ORIGINAL SCIENTIFIC REPORTS
Selenium Deficiency a Factor in Endemic Goiter Persistence in Sub-Saharan Africa P. A. Kishosha • M. Galukande • A. M. Gakwaya
Published online: 27 April 2011 Ó Socie´te´ Internationale de Chirurgie 2011
Abstract Background Goiter is still common in Uganda, despite the present iodized salt coverage of at least 95%. Where there is endemic goiter after adequate iodine supplementation, selenium deficiency could be a factor for the continued occurrence of goiter. The objectives of the present study, therefore, were to determine the serum selenium levels among goitrous patients and nongoitrous controls and to determine the association between goiter and selenium levels among these patients. Methods The investigation was designed as a case control study in which 92 subjects were enrolled, 46 cases and 46 controls of similar age and sex distribution. Subjects were interviewed and examined. Blood samples were taken and selenium concentrations were determined by electrothermal atomic absorption spectrometry. Results The overall mean serum selenium levels were 77.25 lg/l (SD 16.78) for the goiter patients and 95.50 lg/l (24.47) for the nongoiter controls. The difference between goitrous and nongoitrous populations was statistically significant (p = 0.0001). Selenium levels above 102.8 lg/l had a statistically significant protective effect against goiter with adjusted odds ratio 0.3 (0.13–0.69); p = 0.005. Other
P. A. Kishosha Mwanza Zonal Military Hospital, P.O. Box 589, Mwanza, Tanzania P. A. Kishosha (&) M. Galukande Department of Surgery, Makerere University College of Health Sciences, Makerere University, P.O. Box 7072, Kampala, Uganda e-mail:
[email protected] A. M. Gakwaya Department of Surgery, Mulago Hospital, Kampala, Uganda
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factors, such as age, main food constituent, and use of iodized salt, had no association with goiter. Conclusions There were significant differences between selenium levels among goitrous patients and nongoitrous controls. High selenium levels seem to have a protective effect against goiter. Selenium supplementation as a preventive strategy is worth further exploration
Introduction Goiter in Uganda was shown initially to be decreasing with iodization efforts through USI (Universal Salt Iodization Strategy) by the World Health Organization (WHO): from 74% in 1991 to 60.2% in 1999 [1–3]. Since 1999, however, the incidence of goiter has remained nearly the same. The USI ensures that only adequately iodized salt enters Uganda. With the efforts of the government through USI strategy and WHO on the iodination of salt, Uganda has attained a USI coverage of 95% [4, 5]. At present there are no comprehensive data on goiter prevalence; however, the available evidence suggests that the incidence and prevalence of goiter have remained high [6, 7]. In addition to iodine status, selenium status is a key factor in the maintenance of normal thyroid morphology and protection of the gland [8]. Selenium was discovered in 1817 by Berzelius, and it was considered for a long time to be a toxic element for humans and animals. It is only in the last decade that its essential role in animals was proven. It is thought to prevent cancer and heart diseases, to delay ageing and enhance humoral, cell-mediated, and nonspecific immunity [9]. The pivotal role of interactions between selenium status and thyroid metabolism has been proved by studies showing that selenocysteine residue is present at the active center of all three iodothyronine deiodinases (D1, D2, D3), the
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substances that govern the conversion of thyroid hormones [10–12]. Moreover, the best characterised and ubiquitous selenoenzymes—the glutathione peroxidases (GPXs)— protect thyrocytes against peroxidative damage by decreasing hydrogen peroxide concentrations [13]. The biological interactions between iodine and selenium depend in large part on the status of these two trace elements [14]. When iodine status is normal and satisfactory, selenium deficiency and other environmental factors should be evaluated: selenium deficiency affects thyroid function and decreases the thyroid response to iodine supplementation, as reported by Zimmermann et al. in a longitudinal intervention trial carried out in two rural villages in the western Coˆte d’Ivoire in 2000 [15]. This study undertook to evaluate selenium status and whether it is a factor in endemic goiter persistence.
goiter were interviewed for the demographic data, duration of the clinical symptoms, utilization of iodinated salts, and type of staple diet. With the information provided a standardized pretested questionnaire was completed for each patient. For serum selenium analysis, 5 ml blood samples from each patient were collected in a Vacutainer. Samples were stored in a refrigerated box and transferred to an accredited Lancet laboratory in Kampala. Selenium concentrations were determined after sample dilution by electrothermal atomic absorption spectrometry in a Perkin-Elmer 4100 ZL model fitted with longitudinal Zeeman background correction and an electrodeless discharge lamp (EDL). Data were analyzed with the STATA 10 Statistical Package. Data were collected from March to May 2010. A total of 92 patients from the Endocrine Clinic in Mulago Hospital were interviewed.
Materials and methods
Ethical considerations
Study subjects
The study was approved by Research and Ethics Committee on behalf of the National Council for Sciences and Technology. Written informed consent was obtained from all participants.
A case control study Cases were defined as patients diagnosed with goiter according to the 1974 standard of Perez, published in Querido et al., who defined goiter as ‘‘an enlargement of the thyroid whereby the lateral lobes have a volume greater than the terminal phalanges of the thumb of the person being examined’’ [16]. The controls were patients without goiter, having minor injuries or injuries requiring 24 h of observation who had been well before the accident that caused their injury. The definition of no goiter was established by physical examination; this included inspection of the patient in profile while standing upright or seated and while swallowing a sip of water. If a goiter is present, it will move up as the water is swallowed. If this test suggests a goiter, palpation is performed from behind the patient, whose neck is relaxed and or hyperextended. For the patients in this series, each lobe was palpated for size, consistency, nodules, and tenderness. The size of each lobe was measured in two dimensions with a tape measure. The sample size was estimated separately for each study objective; the formula for comparing two proportions, adapted from Designing Clinical Research by Hulley et al. [17], gave the biggest sample size that was considered for this study. A total of 92 subjects were recruited from the surgical units.
Data analysis The mean or median serum selenium levels among goitrous and nongoitrous patients were computed and means were compared with Student’s t-test; p B 0.05 was considered significant. The lower and upper limits on the normal serum selenium levels within a 95% confidence interval were considered to be the known normal ranges for the study population with no goiter. Serum selenium below the normal range was considered low selenium, while that above the upper limit was considered high. The associations at bivariate analysis between serum selenium levels, other predictors, and goiter among surgical patients were determined by odds ratios, with selenium levels below 88.23 lg/l considered low and compared to the presence of absence of a goiter. Odds ratios with p B 0.05 were considered significant. At multivariate analysis, predictors with a p B 0.1 were included in the logistic regression models to determine the predictors’ adjusted odds ratios.
Results
Data collection
Demographic characteristics
Patients, who were identified as cases and controls after a physical examination for presence of goiter or absence of
All cases and controls were Ugandan residents; 90 subjects were females and 2 were males; i.e., of all the cases, 45
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were females and 1 was male, the controls had a matching sex ratio. Age ranged from 18 to 75 years. Cases and controls had a similar age distribution pattern. The mean age was 37 years, and most of the patients were in the age group 18–40 years (55%), followed by the age group 41–63 years (33%). Most of the study subjects were from Kampala, which is the main city of Uganda, and whose altitude is between 1,000 and 2,000 m above sea level; most of the subjects were peasants (41.3%) and housewives (19.6%). Serum selenium distribution in the study population We found that for the goiter patients the overall mean serum selenium levels of 77.25 lg/l (SD 16.78) and the median of 77.48 lg/l (IQR 18.19) were almost equal, while the mean serum selenium levels of 95.50 lg/l (24.47) and the median of 102.85 lg/l (IQR 46.84) for the nongoiter controls were slightly different. Because the data for the two groups were almost normally distributed, we compared the means in the two populations with Student’s t-test. We also computed the 5% trimmed mean of the selenium levels among the goiter patients and nongoiter patients; the 5% trimmed mean is the mean that would be obtained if the lower and upper 2.5% of values of the variable were deleted; it is the mean of the values that lie in the 95% confidence interval (Table 1). The difference between goitrous and nongoitrous populations was statistically significant, with a p value of 0.0001 (Student’s t-test was 4.17). Using the normal ranges of selenium levels of (88.23–102.76) lg/l, we considered results below 88.23 lg/l to be low selenium levels and those above 102.76 lg/l to be high (Fig. 1, Table 1). For the purposes of the present study, we had enrolled 90 females and two males, so the association between selenium levels and goiter was found in a population that was mainly female. Table 1 shows that selenium levels above 102.8 lg/l were found to be significantly protective of goiter, with an adjusted odds ratio of 0.3 (0.13–0.69); p = 0.005. Other factors, such as main food constituent (cassava, maize, or matooke) and use of iodized salt had no association with goiter. Subjects aged 41–63 years were more likely to develop a goiter, but after adjusting for confounders and interaction, this relationship was not significant; the adjusted odds ratio was 0.73 (0.10–5.32); p = 0.758.
Discussion The primary aim of the present study was to assess the role of selenium and its contribution to the existence of endemic goiter. A case control study was chosen because it is both
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economical and addresses the issues of association between selenium levels and goiter. We found that selenium explains goiter formation, although there could still be other factors. Hashimoto’s disease could be another factor but no data exist, and extrapolation suggests that a small percentage of the population would be affected: 0.5%. Iodine deficiency too could contribute; however, in Uganda, the iodized salt coverage is over 95% to date possibly diminishing the impact of iodine deficiency. A study done in the western Ivory Coast showed an association between selenium deficiency and goiter [14]; however, literature from the rest of sub-Saharan Africa is scanty. The etiology of thyroid disease is complex and multifactorial. Host factors—namely age, sex, genetic features, and immunological characteristics—interact with environmental agents such as iodine and selenium intake to determine or condition the incidence and clinical presentation of thyroid disorders [5]. This study suggests a protective role of selenium against goiter, especially when iodine supplementation is adequate [4, 5, 8, 14, 15]. Selenium levels in the study population This study shows a difference between selenium levels in goitrous patients and nongoitrous controls (p = 0.0001). The mean serum selenium level for adults in the control group observed in this study was 95.50 lg/l (SD 24.47), which was similar to another study reported from Denmark [18]. In the Nutritional Prevention of Cancer (NPC) Trial, a selenium level of 80 lg/l is considered the minimum level of plasma selenium necessary in the bloodstream for maximum production of selenoproteins (glutathione peroxidases, thioredoxin reductase, etc.) [19, 20]. None of our study subjects had selenium levels below 26 lg/l, which is also a rare (1.1%) finding [8, 21]. Various studies have demonstrated that selenium levels have local/regional variation with no accepted international ranges, with levels below 30 lg/l being seen in China and levels between 80 and 180 lg/l in Canada [19, 22]. However Ne`ve classified these areas into areas of low or poor selenium when the inhabitants have mean selenium levels lower than 50–60 lg/l and high selenium or selenium ‘‘rich’’ areas when values are higher than 100–120 lg/l [19]. Values between the two extremes are classified as intermediate, and this describes Uganda [19] (Table 1). Selenium levels near 330 lg/l are regarded as toxic [19]. Selenium is required in thyroid metabolism, converting inactive thyroid hormone into active thyroid hormone [23], maintenance of normal thyroid morphology, and protection of the gland [8].
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Table 1 Serum selenium levels and their association to goiter among patients enrolled in the study Exposure
Goiters (n = 46)
Nongoiter controls Totals Unadjusted odds ratio p value Adjusted odds ratio p value (n = 46) (95% CI) (95% CI)
Selenium levels, lg/l Mean (SD)
77.25 (16.78)
95.50 (24.47)
95% CI
(72.26–82.23)
(88.23–102.76)
5% trimmed mean
77.34
95.55
Median (IQR)
77.48 (18.19)
102.85 (46.84)
Low selenium (\88.23 lg/l)
34
18
52
1.05 (0.24–4.14)
0.94
High selenium ([102.8 lg/l) Normal (88.23–102.76 lg/l)
3 9
23 5
26 14
0.072 (0.01–0.46) 1
0.0005
64–75 years
03
1
4
4.5 (0.41–48.85)
0.18
41–63 years
21
12
33
2.63 (1.05–6.60)
0.033
18–40 years
22
33
55
1
Yes
33
30
63
0.83 (0.25–2.68)
0.75
Not sure
5
10
15
0.38 (0.077–1.82)
0.21
No
8
6
14
1
Male
1
1
2
1 (0.012–80.2)
1.000
Female
45
45
90
Yes
18
17
35
1.1 (0.43–2.78)
0.83
No Maize
28
29
57
Yes
25
22
47
1.3 (0.53–3.19)
0.53
No
21
24
45
Yes
40
42
82
0.63 (0.122–2.92)
0.50
No
6
4
10
0.3 (0.13–0.69)
0.005a
0.73 (0.10–5.32)
0.758
Age category
Use of iodized salt
Sex
Cassava
Matooke
a
Statistically significant
Association of selenium with goiter It has demonstrated that serum selenium levels above 102 lg/l are significantly protective against goiter, with an adjusted odds ratio of 0.3 (95% CI 0.13–0.69); p = 0.005 (Table 1). The association between low selenium level and goiter was found in a population that was mainly females. Most of goiter patients in this study had multinodular goiter followed by thyrotoxic goiter, and most of these patients had stage 2 goiter according to a modified Perez classification; all of these findings have been associated with selenium deficiency [8, 24, 25], although in this study there was no significant association with low selenium levels. These findings replicate previous studies that have showed that deficient selenium levels are associated with goiter [24–28]. These findings
are similar to a French adult study which showed an inverse association between selenium status and thyroid volume (p = 0.003) in a population mainly of women and a protective effect of selenium against goiter (odds ratio 0.2, 95% CI 0.06–0.7) [8]. Limitations There is the likelihood of a recall bias in reporting foods previously consumed by Ugandan patients, like cassava, matooke, sweet potatoes, and cabbages. This recall bias could have affected the degree of association between the foods consumed and the development of goiter. This explains the difference from some other studies that have demonstrated that consumption of cassava, because it has goitrogens, may increase the risk of goiter [5].
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Conclusions High selenium levels seem to have a protective effect against goiter in the Ugandan context. Selenium supplementation may be a preventive strategy worth further exploration Acknowledgments The authors are grateful to the Department of Surgery of Makerere University, Lancet laboratories, and the patients who volunteered to participate in this study. They also acknowledge and thank the Tanzania Ministry of Defence and National Service for sponsoring this study.
References Fig. 1 The box and whisker plots for selenium levels among goiter and nongoiter patients. The words ‘‘Yes’’ and ‘‘No’’ refer to the presence or absence of goiter which is the outcome variable of interest
Other confounders to this study include vitamin A deficiency [29], which was sought through its symptomatic presentation of night blindness; none of our patients had this symptom and also confounders were accounted for by logistic regression that was done in the analysis. Implications of diet The typical Ugandan diet consists mainly of cassava, maize, matooke (bananas), sweet potato, cabbage, and green vegetables. Cassava and cabbages are known goitrogens [5] while grains and vegetables are known to contain significant amounts of selenium [30–33], which is protective against goiter. Natural selenium, an essential mineral in human nutrition, is present in the diet of humans in the form of organic selenoproteins, such as selenomethionine and selenocysteine [34]. Deficiencies of selenium contribute to the prevalence and severity of iodine deficiency disorders, which are the most important and well-known global nutritional problems, primarily in less developed countries [35]. Plant foods, such as vegetables, are the most common dietary sources of selenium. The amount of selenium present in the vegetables consumed depends on how much of the mineral was in the soil where the plants grew. Fish, shellfish, red meat, grains, eggs, chicken, liver, and garlic are all good sources of selenium. Meats produced from animals that eat grains or plants found in selenium-rich soil have higher levels of selenium. Brewers’ yeast, wheat germ, and enriched breads are also good sources of selenium [30– 33]. Although there are large variations in selenium concentration and availability in soil and food all over the world, its bioavailability in foods of plant origin is higher than in animal products [36]. Therefore family income should not be a significant factor in primary prevention.
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1. Bimenya GS, Okui O, Kaviri D et al (2002) Monitoring the severity of iodine deficiency disorders in Uganda. Afr Health Sci 2:63–68 2. Kajubi S (1977) Thyroid disorders seen at the Mulago Radioisotope Laboratories 1969–1974. East Afr Med J 54:65–72 3. Kakitahi J, Okui O (1991) Iodine deficiency disorders in Kisoro, Bundibugyo, Hoima and Kapchorwa districts. Preliminary report to MOH, Uganda December 1991 4. World Health Organization (2006) UNICEF, The Micronutrient Initiative, The Global Alliance for Improved Nutrition. Vitamin and Mineral Deficiency in Sub-Saharan Africa 5. Fauci AS, Kasper DL, Longo DL et al (2008) Disorders of the thyroid gland. In: Fauci AS, Braunwald E, Kasper DL (eds) Harrison’s principles of internal medicine, 17th edn., chap 335. http://www.franklin.com/estore/dictionary/bbal0071641149dlda/ Accessed 1 April 2011 6. Nyonyintono JA (2007) Comparison of aspiration and non aspiration fine needle techniques in providing standard amount of follicullar cells for cytodiagnosis of thyroid nodules at Mulago Hospital. A dissertation for Masters of Medicine in Surgery, Makerere University 7. Mulago Hospital in patient and outpatient Register, 2005–2009 8. Derumeaux H, Valeix P, Castetbon K et al (2003) Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults. Eur J Endocrinol 148:309–315 9. Neve J (1991) Physiological and nutritional importance of selenium. Experientia 47:187–193 10. Behne D, Kyriakopoulos A, Meinhold H et al (1990) Identification of type I iodothyronine 50-deiodinase as a selenoenzyme. Biochem Biophy Res Commun 173:1143–1149 11. Salvatore D, Low SC, Berry M et al (1995) Type 3 iodothyronine deiodinase: cloning, in vitro expression and functional analysis of the placental selenoprotein. J Clin Invest 96:2421–2430 12. Salvatore D, Bartha T, Harney JW et al (1996) Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 137:3308–3315 13. Beckett GJ, Arthur JR (2005) Selenium and endocrine systems. J Endocrinol 184:455–465 14. Arnaud J, Malvy D, Richard MJ et al (2001) Selenium status in an iodine deficient population of the west Ivory Coast. J Physiol Anthropol 20:81–84 15. Zimmermann MB, Adou P, Torresani T et al (2000) Effect of oral iodized oil on thyroid size and thyroid hormone metabolism in children with concurrent selenium and iodine deficiency. Eur J Clin Nutr 54:209–213 16. Querido AF, Delange F, Dunn JT et al (1974) Definition of endemic goiter and cretinism, classification of goiter size and
World J Surg (2011) 35:1540–1545
17.
18.
19. 20.
21.
22. 23.
24. 25.
severity of endemias and survey techniques, vol 292. Pan American Health Organization Scientific Publications, Washington, DC, pp 267–272 Hulley SB, Cummings SR, Browner WS et al (2001) Estimating sample size and power. Designing a clinical research: an epidemiological approach, 2nd edn., chap 6, p 85–90 Rasmussen BL, Hollenbach B, Laurberg P et al (2009) Serum selenium and selenoprotein P status in adult Danes—8-year follow-up. J Trace Elem Med Biol 23:265–271 Ne`ve J (1991) Methods in determination of selenium status. J Trace Elem Electrolytes Health Dis 5:1–17 Duffield-Lillico AJ, Reid ME, Turnbull BW et al (2002) Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 11:630–639 Ne`ve J (1995) Human selenium supplementation as assessed by changes in blood selenium concentration and glutathione peroxidase activity. J Trace Elem Med Biol 9:65–73 Thomson CD (2004) Selenium and iodine intakes and status in New Zealand and Australia. Br J Nutr 91:661–672 Napolitano G, Bonomini M, Bomba G et al (1996) Thyroid function and plasma selenium in chronic uremic patients on hemodialysis treatment. Biol Trace Elem Res 55:221–230 Samir M, el-Awady MY (1998) Serum selenium levels in multinodular goitre. Clin Otolaryngol Allied Sci 23:512–514 Wertenbruch T, Willenberg HS, Sagert C et al (2007) Serum selenium levels in patients with remission and relapse of Graves’ disease. Med Chem 3:281–284
1545 26. Dabbaghmanesh MH, Sadegholvaad A, Ejtehadi F et al (2007) Low serum selenium concentration as a possible factor for persistent goiter in Iranian school children. BioFactors 29:77–82 27. Contempre B, Dumont JE, Denef JF et al (1995) Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism. Eur J Endocrinol 133:99–109 28. Goyens P, Golstein J, Nsombola B et al (1987) Selenium deficiency as a possible factor in the pathogenesis of myxoedematous endemic cretinism. Acta Endocrinol 114:497–502 29. Zimmermann MB (2009) Iodine deficiency. Endocr Rev 30: 376–408 30. Institute of Medicine, Food, Nutrition Board (2000) Dietary reference intakes: vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington, DC 31. Rakel D (2007) Integrative medicine, 2nd edn. Saunders-Elsevier, Philadelphia 32. Hamrick I, Counts S (2008) Vitamin and mineral supplements. Wellness Prev 35:729–747 33. Goldman L, Ausiello D (eds) (2007) Cecil medicine, 23rd edn. Saunders-Elsevier, Philadelphia 34. Schrauzer GN, Katz RN (1978) Reductive dechlorination and degradation of mirex and kepone with vitamin B12. Bioinorg Chem 9:123–143 35. Vanderpas JB, Contempre B, Duale NL et al (1990) Iodine and selenium deficiency associated with cretinism in northern Zaire. Am J Clin Nutr 52:1087–1093 36. Fairweather-Tait SJ (1997) Bioavailability of selenium. Eur J Clin Nutr 51:520–523
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