Elevated Levels of 1,25-Dihydroxyvitamin D in Plasma as a Missing Risk Factor for Celiac Disease

Figures & data

Table 1 Conditions That Cause Elevated 1,25(OH)₂D in Plasma and Have Indications of Comorbidity with CD

Condition	1,25(OH)2D in Plasma (% Higher Relative to Controls)	CD Comorbidity	OR of CD
Williams syndrome	602a,^Citation28,Citation29	9.4% with Williams syndrome have CD^Citation30	19.36 (8.15–46.02)
Lymphoma	107b,^Citation31,Citation32	RR 2.4 (0.7–8.5) for CD after or with lymphoma^Citation33	2.4 (0.7–8.5)
Turner syndrome	91c,^Citation29,Citation34	6.4% with Turner syndrome have CD^Citation35	12.63 (8.03 −19.89)
Sarcoidosis	88d,^Citation36	OR 3.58 (1.98–6.45) for CD after sarcoidosis^Citation37	3.58 (1.98–6.45)
Hypothyroidism	74^Citation38	OR 2.20 (1.21–4.01) for undiagnosed CD^Citation39	2.20 (1.21–4.01)
Tuberculosis	49^Citation40	OR 2.50 (1.75–3.55) for CD after tuberculosis^Citation41	2.50 (1.75–3.55)
Polycystic ovary syndrome	35e,^Citation42	3x greater IgG seropositivity for gliadin;^Citation43 infertility often comorbid with CD^Citation44	Likely > 1
Klinefelter syndrome	30 f,^Citation45	RR 3.0 (0.8–7.8) for CD^Citation46	3.0 (0.8–7.8)
PHPT	27^Citation47	RR 1.91 (1.44–2.52) for PHPT, 5 years after CD^Citation48	1.91 (1.44–2.52)

Notes: ^ain infancy; ^bamong hypercalcemic cases; ^camong girls provided with estrogen therapy; ^damong hypercalcemic cases; ^eamong those of normal weight; ^famong older boys.

Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; CD, celiac disease; IgG, immunoglobulin G; OR, odds ratio; PHPT, primary hyperparathyroidism; RR, risk ratio.

Table 2 Select Human Trials of High-Dose Vitamin D Supplementation and Its Effects

Study	Population	Vitamin D Exposure	Select Findings	Findings on CD from Literature
Protiva et al^Citation107	Adults at risk of cancer	Supplementation with 1,25(OH)2D at 10 IU per day	“Striking upregulation of genes involved in immune responses, inflammation, extracellular matrix, and cell adhesion” in the rectosigmoid mucosa.	Genes associated with inflammatory response upregulated.^Citation108
Hornsby et al^Citation109	Pregnant women	4400 IU per day vs 400 IU per day	In cord blood from neonates, 4400 IU per day increased expression of TLR2, TLR4, and IL-17A.	Increased TLR2 and TLR4 expression,^Citation110 and IL-17A upregulation.^Citation111
Akhtar et al^Citation112	Pregnant Bangladeshi women	35,000 IU per week vs placebo during third trimester	In cord blood from neonates, 35,000 IU per week increased expression of TNF alpha, INF gamma, CCR4 gene, CXCR4 gene, IL12RB1 gene, and the IL12RB2 gene.	Upregulation of CCR4, CXCR4, IL12RB1, and IL12RB2 gene activity.^Citation99
Goncalves-Mendes et al^Citation113	Vitamin D deficient elderly	100,000 IU per 15 days vs placebo over 3 months with influenza vaccine	Higher levels of TGF beta in plasma.	Higher levels of TGF beta in lamina propia.^Citation114
Bak et al^Citation115	Ten healthy adults	480,000 IU over 15 days	Increased RNA expression of TGF beta and TNF alpha.	Higher levels of TGF beta in lamina propia.^Citation114

Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; CCR4, C-C chemokine receptor type 4; CD, celiac disease; CXCR4, C-X-C chemokine receptor type 4; IL-17A, interleukin 17A; IU, international units; TGF beta, transforming growth factor beta; TLR2, toll-like receptor 2; TLR4, toll-like receptor 4; TNF alpha, tumor necrosis factor alpha; vs, versus.

Table 3 CD Epidemiology and the Vitamin D Hypothesis

Area	CD Epidemiology	Possible Explanation Based on the Vitamin D Hypothesis
Sweden	1984 was the inception of the Swedish CD “epidemic.”^Citation116	March 1983 was the inception of mandatory vitamin D supplementation of milk and margarine in Sweden.^Citation117
Finland	CD prevalence doubled among Finnish adults between 1978 and 2000 based on serology.^Citation6	Oral vitamin D consumption in Finland increased during this time period primarily due to a significant increase in the proportion of the population using vitamin D supplements.^Citation118^–^Citation120
Nordic countries vs Germany	At least five times greater prevalence of CD in Sweden and Finland than in Germany.^Citation6,Citation116,Citation121	Much greater intake of oral vitamin D in Sweden and Finland than in Germany due to greater use of vitamin D supplementation and fortification in Sweden and Finland than in Germany.^Citation76,Citation117,Citation122,Citation123
US	Significant increase in prevalence of CD and CD serology in the US in recent decades.^Citation5,Citation8,Citation124	Increased use of vitamin D supplements, increased doses of vitamin D supplements, and increased levels of vitamin D fortification in the US in recent decades.^Citation125^–^Citation130
Burkina-Faso	No case of CD based on serology among 600 adults in Burkina-Faso, despite wheat consumption by all and some genetic susceptibility.^Citation131	There have historically been no vitamin D supplementation programs or vitamin D fortification programs in Burkina-Faso.^Citation132,Citation133
Karelians	Finnish Karelian children have a CD risk that is 2.3 times greater than Russian Karelian children based on serology and 4.6 times greater based on biopsy.^Citation134	Finland fortifies food with vitamin D and encourages vitamin D supplementation in childhood.^Citation76,Citation135 Russia has not historically fortified food with vitamin D or provided supplemental vitamin D to its population.^Citation136,Citation137
Breastfeeding	Early studies found that breastfeeding decreases risk of CD,^Citation138 while more recent studies do not find such an effect.^Citation139	Vitamin D fortification and supplementation in infancy has increased during the last three decades in much of the developed world.^Citation76,Citation80,Citation135 Infant supplementation in some countries is focused on breastfed infants.^Citation80,Citation140 These effects may outweigh any positive effect of breastfeeding.
Constipation and CD in Finland	Between the late 1970s and 2013 in Finland, there was a 500% increase in constipation as a symptom of CD among newly diagnosed children.^Citation93	During this time, vitamin D intake increased significantly in Finland.^Citation76,Citation118^–^Citation120,Citation135 Vitamin D exposure increases risk of constipation.^Citation92 If vitamin D exposure increases risk of CD, this change in presentation would be expected.
Pregnancy	Greater risk of CD onset during pregnancy and the period immediately following pregnancy.^Citation141,Citation142	Plasma levels of 1,25(OH)2D are elevated during pregnancy and lactation.^Citation143
Helicobacter pylori	Significantly decreased incidence of gastric H. pylori infection observed in children with CD.^Citation144	Plasma levels of 1,25(OH)2D are often elevated in those with CD,^Citation17,Citation22,Citation23 and 1,25(OH)2D activates a lysosomal degradation pathway that is effective in combatting H. pylori infection.^Citation145
African Americans	CD and CD serology is much less common among African Americans than among non-Hispanic White Americans despite some genetic risk.^Citation4,Citation146,Citation147	Vitamin supplementation in general is less common in the African American community than among non-Hispanic White Americans.^Citation148
Smoking	Smoking is associated with decreased risk of CD.^Citation149	Vitamin supplementation in general is less common among smokers,^Citation150 and plasma levels of 1,25(OH)2D are lower among smokers than non-smokers.^Citation151
Socioeconomic	Higher socioeconomic status is associated with increased risk for CD.^Citation152,Citation153	Vitamin supplement use is greater among those of higher socioeconomic status.^Citation154

Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; CD, celiac disease; US, United States; vs, versus.

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