Abstract
Context:
Subclinical features of zinc deficiency can be challenging to recognize. The prevalence of zinc deficiency based on blood zinc concentration in an adult outpatient clinic setting has not been well-studied.
Objective:
To estimate the prevalence of low serum zinc concentrations among community-dwelling adults, and to characterize clinical features and risk factors associated with zinc deficiency.
Methods:
This retrospective pilot prevalence study took place from 2014 to 2017 at an outpatient clinic in southeast Ohio. Patients aged 50 years or older with a stable health status were categorized into a case group with zinc deficiency (serum zinc concentration, <0.66 µg/mL) and a control group (serum zinc concentration, ≥0.66 µg/mL). Measurements included serum zinc concentration, nutritional biomarkers (ie, magnesium, calcium, albumin, and total 25-hydroxy vitamin D levels), patient history of fractures and events such as hospitalization, antibiotic use, and self-reported falls that occurred within 1 year prior to the date serum zinc concentration was measured (index date). Patients were excluded if they had a serum zinc measurement within 2 months after a hospitalization, severe renal insufficiency (3 patients with serum creatinine concentration above 2.5 mg/dL), or serum zinc concentration above 1.20 µg/mL.
Results:
This study included 157 patients, consisting of a case group of 41 (26%) patients with zinc deficiency and a control group of 116 (74%) without zinc deficiency. Mean (SD) zinc concentrations of the case and control groups were 0.58 (0.05) µg/mL and 0.803 (0.13) µg/mL, respectively (P<.01). Patients in the case group were more likely to have had a history of hospitalization, antibiotic use, a fall within 1 year before the index date, and a history of fractures and hip fracture (P<.01 in each case). Patients taking gastric acid suppressants had increased odds of lower zinc concentrations (odds ratio, 2.24; 95% CI, 1.08-4.63). Both logistic and multivariate linear regression models revealed that past fractures, hip fractures, and hypoalbuminemia (albumin <3.5 g/dL) were associated with zinc deficiency or lower zinc concentrations.
Conclusion:
This study revealed that 26% of patients in an outpatient adult clinic had zinc deficiency based on serum concentrations. Patients with fracture history and low serum albumin were at higher risk for zinc deficiency.
Micronutrients play an important role in maintaining good health. Lower serum micronutrient concentrations have been shown to predict frailty during a 3-year follow-up among community residents.
1 Micronutrient deficiencies may lead to frailty by disrupting homeostatic mechanisms important for cognition, immunity, and musculoskeletal functioning.
1,2 Zinc is a micronutrient that plays an important role in cellular structure and metabolic function.
3 An estimated 85% of whole-body zinc (roughly 2.0-2.5 g in average adults) is distributed in muscles (55%) and bones (30%), with 11% in the skin and liver.
3 The majority (99.9%) of systemic zinc is located intracellularly, and only a fraction (0.1%) is present in serum.
3 Indication of severe zinc deficiency may appear in many organ systems, including skin, gastrointestinal, central nervous, immunity, and skeletal systems.
4-5 However, mild zinc deficiency can be less blatant and challenging in routine encounters with health care providers due to the lack of a convenient clinical assessment tool.
5-7 Despite this limitation, serum zinc concentration is the main clinical tool to identify zinc deficiency.
6-9
Older adults are particularly vulnerable to zinc deficiency due to low dietary intake
10-12 and increasing demand during acute illness, specifically when hospitalized.
13 Prevalence of low serum zinc concentrations was reported in more than 8% of a US study population older than 10 years of age using the National Health and Nutrition Examination Survey 2011 to 2014 data.
14 Other studies
13,15-17 have shown a prevalence of low serum zinc concentrations among older adults who were hospitalized, ranging from 20% to 38%.
15,17 One study
15 reported that 69% of 51 long-stay geriatric patients (mean age, 85.9 years) had zinc deficiency based on serum zinc concentrations. Globally, it has been estimated that zinc deficiency affects 2 billion people (an estimated 25% of people at risk),
4 with as many as 15% to 20% of the global population having insufficient dietary zinc intake.
18
Because it is challenging for clinicians to identify subtle clinical features of zinc deficiency,
5,19 the objective of this study was to estimate the prevalence of low serum zinc concentrations among patients at an outpatient clinic. We also aimed to characterize clinical features and determine risk factors associated with lower serum zinc concentrations or zinc deficiency.
This study was case-control in design: the case group included patients with zinc deficiency (serum concentration, < 0.66 µg/mL), and the control group included were patients with normal serum zinc concentration. Because the normal reference range for zinc concentration is 0.66 to 1.10 µg/mL (10.09 to 16.82 µmol/L), the cutoff value for zinc deficiency was set at 0.66 µg/mL.
Blood samples were obtained for routine blood tests to screen for disorders as allowed by insurance carriers (eg, Medicare Part B) or Medicaid insurance. Blood samples were obtained when patients were at their usual baseline health. Serum zinc measurement was analyzed by dynamic reaction cell-inductively coupled plasma-mass spectrometry (DRC-ICP-MS) performed by Mayo Clinic Laboratory service (Rochester, MN).
Other nutritional biomarkers, such as vitamin B12, 25-hydroxy vitamin D, and magnesium concentrations, were also collected when available. Red blood cell counts with hemoglobin levels and comprehensive metabolic panels (obtained on or before the index date) were also performed following standard procedures by a hospital-affiliated laboratory service.
Our study collected data on historical events that occurred within 1 year before the date serum zinc concentration was measured (ie, index date). These events included hospitalization, antibiotic use, self-reported fall, diarrhea, and weight change, which was compared with weight 1 year before the index date. During the 1 year preceding the index date, significant weight loss was defined as loss of at least 10 lbs or more than 10% of baseline weight. History of hip and nonhip fracture was confirmed by documented surgical history. Vertebral or pelvic fracture history was confirmed by radiography reports that were ascertained through the hospital-affiliated radiology department and previous health care providers/facilities if patients were from an outside unaffiliated health care system prior to establishing care with this clinic.
Patient medical records were retrieved electronically from 2012 forward, as that was the year the electronic medical record system was implemented at this clinic. Data collection also included demographics, smoking status, medical history, and medication use around the index date. Past medical history (eg, diabetes mellitus, hypothyroidism, and depression) were documented as prior events or diagnoses (recorded as ever vs never). All data was recorded on standardized forms. Medical records under study were reviewed and verified by the investigator for accuracy.
Mean with standard deviation (SD) and percentage were used to report continuous and discrete variables, respectively. χ2 or 2-sample, 2-sided t tests were used to determine whether there was a significant difference between the 2 groups. Univariate logistic regression was used to assess the association between potential risk factors and zinc deficiency.
To identify factors associated with zinc deficiency, potential confounders were included in the multiple logistic regression model, including age, sex, body mass index (BMI), alcohol use, hip fracture, nonhip fracture, low albumin concentration (cutoff value, <3.5 g/dL), and anemia (Hb<12 g/dL for both genders). Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated. Those variables were also included in multiple linear regression models for serum zinc concentrations among our study patients. Results remained similar when serum albumin and blood hemoglobin concentrations were analyzed as continuous variables in the above models. Regression coefficients with 95% CI were estimated.
Regression diagnostics revealed that our multivariable models were reasonable, and there was no collinearity among the models’ independent variables. Statistical significance level (type I error rate) was set at a level of .05. PC SAS version 9.3 software (SAS Institute, Inc.) was used to perform the statistical analyses.
In this study, a total of 157 patients were included, with an age range of 52 to 97 years. We found that 41 adult patients (26%) had zinc deficiency. Both case and control groups were similar regarding BMI, alcohol use, smoking status, and comorbidities, although the mean (SD) age of the case group was older than the mean (SD) age of the control group (82.6 [8.7] vs. 78.2 [8.9] years; P=.007).
The case group had more events than the control group within 1 year prior to the index date, including hospitalizations (18 [44%] vs 18 [16%]), antibiotic use (26 [63%] vs 46 [40%]), and self-reported fall (23 [56%] vs 14 [12%],
Table 1). Self-reported diarrhea within 3 months prior to the index date was also more frequent among cases than controls (6 [15%] vs 5 [4%],
Table 1). Furthermore, cases were more likely to have reported ever event(s) than controls for any fracture (22 [54%] vs 9 [8%]), hip fracture (7 [17%] vs 3 [3%]), nonhip fracture (15 [37%] vs 7 [6%]), and vertebral fracture (7 [17% ] vs 1 [1%]).
Table 1.
Characteristics of Zinc Deficiency and Controls Among Adults at an Adult Clinic in Southeast Ohioa (N=157)
| Variablesb | Zinc deficiency case group (n=41) | Control group (n=116) | P value |
| Demographics | | | |
| Age, mean (SD) | 82.6 (8.7) | 78.2 (8.9) | .007 |
| White | 40 (98) | 100 (86) | .044 |
| Women | 29 (71) | 73 (63) | .368 |
| Weight, lb (SD) | 161.3 (42.1) | 163.4 (38.6) | .769 |
| Body mass index (SD) | 28.6 (6.7) | 27.9 (5.4) | .479 |
| Alcohol use regularly | 8 (20) | 16 (14) | .382 |
| Current smoker | 5 (12) | 11 (10) | .622 |
| Past smoking history | 17 (42) | 51 (44) | .781 |
| Associated comorbidity |
| Diabetes mellitus | 10 (24) | 22 (19) | .459 |
| Hypothyroidism | 9 (22) | 27 (23) | .862 |
| Gastroesophageal reflux disease | 24 (59) | 57 (49) | .301 |
| Depression | 23 (56) | 56 (48) | .389 |
| Events in the past 1 year |
| Hospitalization | 18 (44) | 18 (16) | <.001 |
| Use of antibiotics | 26 (63) | 46 (40) | .009 |
| Fall | 23 (56) | 14 (12) | <.001 |
| Significant weight lossc | 10 (25) | 18 (16) | .178 |
| Diarrhea (reported in past 3 months) | 6 (15) | 5 (4) | .026 |
| History of fractures | | | |
| All fracture | 22 (54) | 9 (8) | <.001 |
| Hip fracture | 7 (17) | 3 (3) | .0034d |
| Nonhip fracture | 15 (37) | 7 (6) | <.001 |
| Vertebral fracture (radiographically confirmed) | 7 (17) | 1 (1) | <.001 |
| Medication use | | | |
| Zinc supplements | 0 (0) | 12 (10) | .037d |
| Iron supplements | 5 (12) | 7 (6) | .202 |
| Magnesium supplements | 16 (39) | 26 (22) | |
| Vitamin D supplements | 31 (76) | 97 (84) | .256 |
| Calcium supplements | 15 (37) | 37 (32) | .584 |
| Proton pump inhibitors | 21 (51) | 37 (32) | .028 |
| H2 receptor antagonists | 3 (7) | 5 (4) | .431d |
| Gastric acid suppressants | 23 (56) | 41 (35) | .020 |
| Diuretics | 15 (37) | 37 (32) | .584 |
| Antihypertensive | 28 (68) | 76 (66) | .747 |
| Antibiotics | 25 (61) | 42 (36) | .006 |
| Narcotic drugs | 15 (37) | 24 (21) | .043 |
Table 1.
Characteristics of Zinc Deficiency and Controls Among Adults at an Adult Clinic in Southeast Ohioa (N=157)
| Variablesb | Zinc deficiency case group (n=41) | Control group (n=116) | P value |
| Demographics | | | |
| Age, mean (SD) | 82.6 (8.7) | 78.2 (8.9) | .007 |
| White | 40 (98) | 100 (86) | .044 |
| Women | 29 (71) | 73 (63) | .368 |
| Weight, lb (SD) | 161.3 (42.1) | 163.4 (38.6) | .769 |
| Body mass index (SD) | 28.6 (6.7) | 27.9 (5.4) | .479 |
| Alcohol use regularly | 8 (20) | 16 (14) | .382 |
| Current smoker | 5 (12) | 11 (10) | .622 |
| Past smoking history | 17 (42) | 51 (44) | .781 |
| Associated comorbidity |
| Diabetes mellitus | 10 (24) | 22 (19) | .459 |
| Hypothyroidism | 9 (22) | 27 (23) | .862 |
| Gastroesophageal reflux disease | 24 (59) | 57 (49) | .301 |
| Depression | 23 (56) | 56 (48) | .389 |
| Events in the past 1 year |
| Hospitalization | 18 (44) | 18 (16) | <.001 |
| Use of antibiotics | 26 (63) | 46 (40) | .009 |
| Fall | 23 (56) | 14 (12) | <.001 |
| Significant weight lossc | 10 (25) | 18 (16) | .178 |
| Diarrhea (reported in past 3 months) | 6 (15) | 5 (4) | .026 |
| History of fractures | | | |
| All fracture | 22 (54) | 9 (8) | <.001 |
| Hip fracture | 7 (17) | 3 (3) | .0034d |
| Nonhip fracture | 15 (37) | 7 (6) | <.001 |
| Vertebral fracture (radiographically confirmed) | 7 (17) | 1 (1) | <.001 |
| Medication use | | | |
| Zinc supplements | 0 (0) | 12 (10) | .037d |
| Iron supplements | 5 (12) | 7 (6) | .202 |
| Magnesium supplements | 16 (39) | 26 (22) | |
| Vitamin D supplements | 31 (76) | 97 (84) | .256 |
| Calcium supplements | 15 (37) | 37 (32) | .584 |
| Proton pump inhibitors | 21 (51) | 37 (32) | .028 |
| H2 receptor antagonists | 3 (7) | 5 (4) | .431d |
| Gastric acid suppressants | 23 (56) | 41 (35) | .020 |
| Diuretics | 15 (37) | 37 (32) | .584 |
| Antihypertensive | 28 (68) | 76 (66) | .747 |
| Antibiotics | 25 (61) | 42 (36) | .006 |
| Narcotic drugs | 15 (37) | 24 (21) | .043 |
×
Among medications, cases were more likely than controls to take gastric acid suppressants (23 [56%] vs 41 [35%]) and narcotics (15 [37%] vs 24 [21%]). Patients taking gastric acid suppressants had increased odds of lower zinc concentrations (odds ratio, 2.24; 95% CI, 1.08-4.63). There was no difference in the percentage of patients taking diuretics (15 [37%] vs 37 [32%]) between case and control groups.
The current study found that 26% of adults in an outpatient clinic had zinc deficiency based on serum concentrations. These patients were also more likely to have lower concentrations of other nutritional biomarkers, such as albumin, calcium, magnesium, and hemoglobin. They had more medical events within 1 year before the index date of zinc measurement, such as hospitalization, receiving antibiotic therapy, and self-reported falls. Our study also demonstrated that a history of hip fractures, nonhip fractures, and lower albumin concentration were independently associated with lower serum zinc concentration and zinc deficiency.
It has been estimated that zinc deficiency might affect 2 billion people globally, with as many as 25% of people at risk.
4 This estimate was very close to our finding of 26% among outpatient clinic adults in southeast Ohio. A lower estimate of zinc deficiency was reported in a previous study
14 in approximately 8% of 4347 US residents older than 10 years (NHANES 2011-2014 dataset).
Our study demonstrated that previous hip and nonhip fractures were significantly associated with zinc deficiency after adjusting for age, sex, BMI, and alcohol use (
Table 3). However, our findings could not establish a causal relationship between zinc status and fractures. The role of zinc in bone health has been reported by a few studies,
20-25 with inconsistent reports
26-28 partially due to small sample sizes among studies. A meta-analysis
29 of 8 studies involving 2188 participants revealed that low serum zinc concentrations were a risk factor for osteoporosis along with other micronutrients (copper and iron). A population-based prospective cohort study
30 of 6576 middle-aged Swedish men (46-68 years old) showed that those in the lowest decile of zinc intake (10 mg daily) had an almost 2-fold increased risk of fracture, as compared with those in the 4
th and 5
th quintiles of zinc intake, with adjustment for confounders, during a mean follow-up period of 2.4 years. Another study
31 randomly assigned 147 premenarcheal girls aged 9 to 11 years to a daily oral zinc tablet (9 mg elemental zinc; n=75) or a placebo (n=72) for 4 weeks, and showed that supplementation significantly increased serum zinc concentrations and also increased serum bone formation markers (procollagen type 1 amino-terminal propeptide) concentrations. Another study
32 demonstrated lower serum zinc concentrations in transfusion-dependent beta-thalassemic adolescent patients with lower bone mineral density; zinc supplementation of 25 mg/day for 18 months improved total-body bone mass in young patients (10-30 years, 32 participants) with thalassemia major in a small clinical trial.
33
Serum zinc concentrations may be affected by the status of zinc-binding proteins such as albumin, which binds 80% to 85% of serum zinc; the rest is bound to alpha 2-macroglobulin (5%-15%) and a small fraction to transferrin (<10%).
5,15 Our study has shown that serum zinc concentration was negatively associated with hypoalbuminemia (
Table 4). A similar coefficient was obtained between serum zinc concentrations and serum albumin when treating both measures as continuous variables. Thus, our study showed that lower albumin concentration or hypoalbuminemia was an independent predictor for lower serum zinc concentration status or zinc deficiency, in agreement with a prior study.
14
Zinc deficiency is often reported in people with inadequate dietary intake, heavy alcohol use,
34 gastrointestinal disorders leading to malabsorption, liver disease and cirrhosis,
35 diabetes mellitus,
36 and use of certain medications leading to zinc depletion.
4 The absorption of zinc can also be affected by high phytate-containing cereal protein intake.
4 On the other hand, zinc supplementation decreases the absorption of copper
37 and iron
38 and may also affect magnesium balance.
39
Although some biomarkers such as metallothionein and zinc transporter of blood leukocytes have been studied for assessing zinc status,
19,40-42 serum zinc concentration is considered reliable (and convenient) for assessing zinc status in adults and the elderly.
9 Our study found that patients with lower serum zinc concentrations also have lower blood concentrations of calcium, magnesium, and albumin, which may serve as clinical indicators to prompt clinicians to test for serum zinc deficiency. Furthermore, patients who have suboptimal nutritional status with recent medical events (hospitalization, falls, fractures) and other conditions well known for the presentation of zinc deficiency—particularly dermatitis (such as acrodermatitis enteropathica), impaired wound healing, and frequent infections (due to low immunity)
4—should be considered for zinc status evaluation.
Our study had limitations. The sample size was relatively small, and data were from 1 study site. Some risk factors, such as age, gender, or ethnicity, may become significant when the sample size is large enough for data analysis. Our study's population was predominately white, and because of the small sample size, our study did not include race or ethnic group as a variable in the logistic regression analysis. Also, “normal” zinc concentrations may not necessarily indicate an adequate total body zinc reserve status since serum zinc concentration reflects only 0.1% of body zinc reserves. Convenient, reliable tools for assessing zinc status are needed for future studies.
Additionally, a NHANES 2011-2014 study
14 revealed that zinc concentrations are related to blood draw time, with afternoon/evening draws negatively associated with serum zinc concentrations. However, the timing of the blood draws was not considered in our data analysis, although most blood draws were performed before noon. Finally, our study did not include repeat measuring blood zinc concentration to exclude the possibility of laboratory errors.
One strength of our study was that zinc concentrations and other nutritional biomarkers were obtained when patients had a stable health status. Documented fracture history before index dates were also confirmed by documented records, not by self-report. This study thus provides perspectives on nutritional deficiencies in some patients who have experienced fractures. Our findings provide rationale for new studies to determine whether repletion of zinc may facilitate their recovery, optimize their health status, or reduce future falls or fracture risks.