A 35-year-old male with Crohn’s disease (CD) presents with diarrhea, frequent abdominal cramps, and fatigue. He is on a tumor necrosis factor-alpha (TNF-α) inhibitor, infliximab 5 mg/kg infusion every eight weeks. Arthralgia of the hands and knees limits his activity. On exam, he has mild abdominal tenderness. Labs reveal CRP 2.1 mg/L, fecal calprotectin 250 mcg/g, therapeutic trough level of infliximab, and 25-hydroxy vitamin D (25(OH)D) 30 nmol/L. Infectious stool studies, including Clostridium difficile, were negative. Colonoscopy demonstrated mild, patchy inflammation throughout the colon. Biopsies obtained during the colonoscopy demonstrated chronic active inflammation. On immunohistochemical stains, cytomegalovirus was negative. He was then started on a short course of steroids followed by a long-term oral vitamin D3 supplement (cholecalciferol) 2,000 IU/day. A year later, his 25(OH) D level improved to 80 nmol/L along with clinical improvement and endoscopic healing.
Vitamin D is traditionally known for its role in regulating calcium and maintaining bone homeostasis.1 More recently, it has been implicated in a variety of autoimmune, infectious, cardiovascular, and malignant diseases.2-5 This expanded understanding has led to increased emphasis on assessing and replenishing vitamin D levels.6 In the immune system, vitamin D exerts immunomodulatory effects through its receptors, which are expressed on key components of the innate and adaptive immune system, including B and T cells, dendritic cells, and macrophages.2 Vitamin D deficiency has been observed at a higher prevalence among individuals with autoimmune disorders such as inflammatory bowel disease (IBD).7,8 As of 2020, an estimated 2.39 million individuals in the U.S. were affected by IBD, with associated healthcare costs of around $3 billion annually.8,9 Growing evidence suggests that IBD patients with vitamin D deficiency experience greater symptom severity and higher disease burden compared to those who are vitamin D-replete.
Overview of the Data
Low vitamin D levels and IBD
Low vitamin D levels have been associated with relapse of symptoms in IBD patients, which leads to higher utilization of healthcare resources such as hospitalizations and surgeries related to IBD.7 A low vitamin D level affects the inflammatory pathway, gastrointestinal bacterial flora, and the epithelial integrity of intestinal cells.7,8 Oral cholecalciferol may reduce inflammation by suppressing activated B cells and decreasing cytokine activity.7 The pathogenesis of IBD is complex and involves the dysregulation of intestinal mucosa and T-helper lymphocytes and the production of pro-inflammatory cytokines (interferon-gamma and TNF-alpha). The mechanism by which vitamin D modulates the immune response is not well understood. However, cholecalciferol has been shown to downregulate pro-inflammatory cytokines, such as interleukin-6, interferon-gamma, and TNF-alpha, and to activate anti-inflammatory T-helper cells. C-reactive protein, a marker of inflammation, has been inversely linked with serum 25(OH)D levels, suggesting vitamin D may lower inflammation.10 The vitamin D receptor also regulates tight junction proteins, which are integral to the maintenance of the mucosal barrier function.11,12
Different professional organizations define vitamin D deficiency and insufficiency variably. 25(OH)D reflects stored vitamin D, while vitamin D 1,25-dihydroxy, aka calcitriol or 1,25(OH)2D, is the biologically active version. The Endocrine Society classifies deficiency as a 25(OH)D level under 50 nmol/L (20 ng/mL) and insufficiency as a 25(OH)D level between 50 and 75 nmol/L (20 to 30 ng/mL).7 The National Academy of Medicine’s cutoff for vitamin D deficiency is under 30 nmol/L (12 ng/mL) and for vitamin D insufficiency is 30 to 50 nmol/L (12 to 20 ng/mL).7
Vitamin D can also be found in dietary supplements. Attaining a serum 25(OH)D level of 75 to 125 nmol/L helps to decrease inflammation, thereby leading to decreased IBD activity.7 One double-blind, placebo-controlled study showed that a 2,000 IU daily dose of oral vitamin D can increase serum 25(OH)D concentration and reduce disease activity in ulcerative colitis (UC) patients, improving their quality of life. The study recommended assessing vitamin D levels in all UC patients because they may benefit from vitamin D therapy.13
The target dose of vitamin D supplementation remains unclear, but studies have investigated giving fixed doses versus variable doses of oral vitamin D or weekly intramuscular vitamin D supplementation. Serum 25(OH) D level can be monitored every three to four months. A subtherapeutic level may be due to patient non-adherence to supplementation and/or malabsorption of the supplement. Determining the reason for a low vitamin D level can help the clinician determine how to adjust supplementation dosing. When considering dosing, per the U.S. Preventive Services Task Force, a high dose of vitamin D (500,000 IU annually) leads to increased risk of falls and fractures.14 Sources of vitamin D include sunlight exposure and diet, such as oily fish (e.g., herring, mackerel, salmon, and sardines), liver, red meat, egg yolks, and fortified foods (e.g., fat spreads and breakfast cereals).
The efficacy of a commonly used IBD medication class, tumor necrosis factor (TNF) inhibitors, can be bolstered when vitamin D levels are optimized to at least 75 nmol/L.7 Attaining a normal vitamin D level prior to TNF inhibitor treatment can reduce relapses and, therefore, lead to sustained remission in three months.7 A retrospective study showed that higher vitamin D levels before starting an immune checkpoint inhibitor predicted significant endoscopic improvement in UC patients. Improving vitamin D levels also lowered C-reactive protein levels significantly in CD patients and can play a role in improved clinical and endoscopic outcomes in patients with IBD.15
Additional Effects of Low and High Vitamin D Levels
In addition to IBD, vitamin D deficiency is frequently observed in celiac disease. A retrospective analysis of 91 patients with celiac disease revealed that 41% exhibited serum 25(OH)D levels below 50 nmol/L. This deficiency is primarily attributed to chronic intestinal inflammation and resultant villous atrophy, which impairs vitamin D absorption. If left untreated, persistent malabsorption may lead to significant metabolic complications, such as osteoporosis.16 Additionally, emerging evidence suggests that vitamin D supplementation, in conjunction with a gluten-free diet, may facilitate mucosal healing and mitigate disease severity in celiac disease. This effect is likely mediated through its immunomodulatory properties, including the attenuation of inflammation, reinforcement of intestinal tight junction integrity, and modulation of the gut microbiome composition, thereby contributing to improved intestinal barrier function and overall gastrointestinal health.17
Vitamin D deficiency has widespread multisystem effects, impacting skeletal, immune, metabolic, and neurological health. Impaired calcium absorption leads to bone demineralization, osteoporosis, and increased fracture risk due to disrupted bone remodeling.
In the immune system, vitamin D modulates immune responses via vitamin D receptors on immune cells, and its deficiency is associated with heightened susceptibility to autoimmune diseases and chronic inflammation. Metabolically, low vitamin D levels contribute to insulin resistance, potentially increasing the risk of type 2 diabetes mellitus. It also plays a crucial role in neuroprotection, with deficiency linked to cognitive decline, mood disorders, and neurodegenerative diseases, likely through its effects on neuronal integrity, neuroinflammation, and neurotransmitter regulation.18
Hypervitaminosis D, or vitamin D toxicity, is a rare condition that arises from excessive vitamin D intake, typically due to chronic supplementation exceeding 10,000 IU per day over an extended period. The pathophysiology of this disorder is driven by the resultant hypercalcemia, which manifests in a spectrum of clinical symptoms. Neurological manifestations may include confusion and lethargy, while gastrointestinal disturbances can present as nausea, vomiting, abdominal pain, and constipation. Additionally, hypercalcemia-induced renal dysfunction may lead to polyuria, polydipsia, and nephrocalcinosis. Laboratory findings indicative of vitamin D toxicity include elevated serum calcium, suppressed parathyroid hormone levels, and markedly increased 25-hydroxyvitamin D concentrations (over 375 nmol/L). Management primarily involves cessation of vitamin D supplementation, aggressive hydration to promote calcium excretion, and, in severe cases, administration of bisphosphonates to mitigate hypercalcemia.19
Application of the Data to the Original Case
This 35-year-old man had mild to moderate persistent symptoms of his Crohn’s disease and had a vitamin D deficiency. He had non-sustained improvement with a TNF-alpha inhibitor. Supplementation with vitamin D likely contributed to a reduction of his inflammatory cytokines while also taking a TNF-alpha inhibitor. As a result, he had an overall improvement in disease status, symptoms, and management.
Bottom Line
Vitamin D plays a key, though only partially understood, role in reducing inflammation in IBD. Optimizing vitamin D levels in IBD patients is associated with lower disease severity index scores, fewer hospitalizations and surgeries, and better quality of life.8
Quiz
1. Which of the following best describes the relationship between low vitamin D levels and inflammatory bowel disease (IBD)?
a. Low vitamin D levels are only a consequence of reduced sun exposure in IBD patients
b. Vitamin D deficiency is associated with increased intestinal inflammation and disease severity in IBD
c. Vitamin D supplementation has no impact on inflammatory markers or disease activity in IBD
d. Vitamin D deficiency is unrelated to immune dysregulation in IBD and affects only bone health
Correct Answer: B. Evidence suggests that low vitamin D levels correlate with greater disease severity, increased inflammation, and a higher risk of relapse in IBD patients. Vitamin D plays a role in modulating the immune system, and its deficiency has been linked to increased pro-inflammatory responses in IBD patients. Some studies also suggest that vitamin D supplementation may help reduce inflammation and improve disease outcomes.
2. What is the most appropriate initial screening test to evaluate vitamin D deficiency?
a. 24, 25(OH)2D vitamin D
b. 25-hydroxy vitamin D
c. Vitamin D-1, 25(OH2D)
d. 7-dehydrocholesterol
Correct Answer: B. 25-hydroxy vitamin D, aka 25(OH)D, is produced in the liver and measures both vitamin D2 and vitamin D3 as an estimate of vitamin D storage. Vitamin D-1, 25(OH2D), the active form, can be normal or elevated in vitamin D deficiency. It can be useful in evaluating patients with renal disease, vitamin D-dependent rickets (in which there is a hereditary deficiency of alpha-hydroxylase or resistance to 1,25-dihydroxyvitamin D), sarcoidosis, or other granulomatous diseases. 24, 25(OH)2D vitamin D is the inactive metabolite after reaching the kidneys that is associated with renal function. 7-dehydrochlesterol is the precursor to 25-hydroxyvitamin D.
Dr. Antonucci
Dr. McIntyre
Dr. Firestein
Dr. Avalos
Dr. Vuong
Dr. Ally
Dr. Antonucci is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego School of Medicine in San Diego. Dr. McIntyre is an associate clinical professor in the division of hospital medicine at the University of California, San Diego School of Medicine in San Diego. Dr. Firestein is an associate clinical professor in the division of hospital medicine at the University of California, San Diego School of Medicine in San Diego. Dr. Avalos is an associate clinical professor of medicine at the University of California, San Diego Health in San Diego. Dr. Vuong is an assistant clinical professor of medicine in the division of hospital medicine at the University of California, San Diego School of Medicine in San Diego. Dr. Ally is a clinical professor in the division of hospital medicine at the University of California, San Diego School of Medicine in San Diego.
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