Abstract
Objective:
Vitamin D deficiency is prevalent worldwide and is usually treated with oral supplementation. Bioavailability of vitamin D may differ among individuals due to variable absorption and metabolism in the body.
Methods:
A 66-year-old woman presented for evaluation of low 25-hydroxyvitamin D (25[OH]D) level. She had no known prior history of gastric or intestinal surgeries or malabsorptive conditions. She had previously been treated with oral vitamin D3 at 2,000 IU daily with poor response. She was then treated with oral vitamin D2 at 50,000 IU weekly, with persistently low 25(OH)D level at 14 ng/mL after 8 weeks of treatment.
Results:
Celiac screen was negative and duodenal biopsy was normal. Due to demonstration of poor oral absorption, she was prescribed vitamin D2 at 50,000 IU sublingually for 8 weeks and then changed to over-the-counter vitamin D3 drops sublingually (1,000 IU/drop) at 4,000 IU twice daily due to suboptimal response with vitamin D2. 25(OH)D level improved gradually to 28 ng/mL after 12 weeks on this regimen and was at 37 ng/mL at 1 year.
Conclusion:
Sublingual vitamin D3 may be an effective alternative mode of vitamin D supplementation in patients who demonstrate poor oral vitamin D absorption despite adequate supplementation for various reasons.
INTRODUCTION
Vitamin D plays a major role in regulating calcium and phosphorous levels in the body, with its deficiency leading to osteomalacia and rickets (1). Bioavailability of vitamin D differs among individuals due to variable absorption or altered metabolism in the body (2). For example, it is influenced by several different factors after ingestion including gastric pH, gastric enzymes including pepsin and trypsin, and duodenal enzymes (proteases, amylase, and lipase). These influence the release of vitamin D from the food matrix and its bioavailability. Additionally, other factors may play a role in the absorption of fat-soluble vitamins in the small intestine (1,3,4).
Medications that are administered via the sublingual (SL) route are rapidly absorbed through the SL blood vessels, bypassing the first-pass hepatic metabolism. We report a patient with severe vitamin D deficiency who was resistant to oral vitamin D supplementation in the absence of known impaired vitamin D absorption. The patient responded nicely to SL administration of vitamin D3 drops using a widely available, over-the-counter preparation with improvement in 25-hydroxyvitamin D (25[OH]D) levels. This may be an effective approach to replace vitamin D in these patients.
CASE REPORT
A 66-year old woman with history of osteoporosis presented for initial evaluation of low vitamin D levels with a 25(OH)D level of 14 ng/mL. Past medical history was significant for osteoporosis, multinodular thyroid goiter, diverticulosis, lactose intolerance, occasional diarrhea, and gastroesophageal reflux disease. She did not have a known history of malabsorption, gastric or intestinal surgery, or obesity. She had a body mass index of 28 kg/m2. Her diet included 24 ounces of buttermilk, 24 ounces of almond milk, and 1 cup of kefir daily. In terms of medications she was on bisoprolol, aspirin, valsartan, and atorvastatin. She was not taking any proton pump inhibitors at the time.
She had previously taken alendronate for 5 years for osteoporosis (drug holiday for 4 years), and had a history of non-traumatic ankle fracture. Physical exam was significant for multinodular goiter, but unremarkable otherwise. Initial laboratory work showed normal calcium at 9.2 mg/dL (reference range is 8.6 to 10.4 mg/dL), creatinine of 0.8 mg/dL, and albumin of 4.6 g/dL (reference range is 3.6 to 5.1 g/dL). Phosphorus, magnesium, and parathyroid hormone (60 pg/mL with a reference range of 14 to 64 pg/mL) were normal and celiac screen was negative. A complete blood count showed hemoglobin of 13.6 g/dL, and thyroid-stimulating hormone was normal at 2.78 μg/mL. Her urinary ratio of calcium to creatinine was 41 mg/g creatinine (reference range is 10 to 320 mg/g creatinine), bone-specific alkaline phosphatase was 18.6 μg/L (reference range is 5.6 to 29.0 μg/L), and urinary cross-linked N-telopeptide was 30 nmol bone collagen equivalents/mmol creatinine (reference range is 4 to 64 nmol bone collagen equivalents/mmol creatinine).
Prior to the referral, she had received vitamin D3 at 2,000 IU orally daily for a couple of months after initial vitamin D level was noted to be 16 ng/mL, with no improvement in the level. Subsequently, she received vitamin D2 at 50,000 IU orally weekly for 8 weeks with persistently low serum 25(OH)D level at 14 ng/mL (reference range is 30 to 100 ng/mL). The patient reassured us that she was taking the vitamin D supplement properly.
After her initial evaluation, the patient was asked to take SL vitamin D2 at 50,000 IU by puncturing gel caps on a biweekly basis for 2 weeks followed by weekly SL administration for an additional 6 weeks. Eight weeks later, her 25(OH)D levels had improved to 23 ng/mL. As 25(OH) D level was still relatively low even after this high-dose replacement, the treatment was changed to over-the-counter vitamin D3 drops (1,000 IU/drop) taken SL at 4,000 IU daily. The authors had previously noted success with this mode of replacement in patients resistant to oral vitamin D replacement. Repeat 25(OH)D level was 24 ng/mL 8 weeks later, and she was asked to increase the vitamin D3 drops to SL 4,000 IU twice daily with further improvement in 25(OH)D level.
The patient’s 25(OH)D level was checked mainly using immunoassays, as that was the assay used at the lab preferred by her insurance. However, we were able to get the 25(OH)D level checked once using liquid chromatography-tandem mass spectrometry, at which time her total 25(OH)D was 31 ng/mL (normal range is 30 to 100 ng/mL) with 25(OH)D2 of 5 ng/mL and 25(OH)D3 of 26 ng/mL. A subsequent 25(OH)D level was 28 ng/mL. The patient was maintained on this regimen and her 25(OH)D level a year later was 36 ng/mL (Table 1 and Fig. 1).
Table 1.
Vitamin D Doses, Forms, and Routes of Administration Over Time
| 25-hydroxyvitamin D level (ng/mL) | Dosage and route of administration | |
|---|---|---|
| At diagnosis | 14* | Vitamin D3 2,000 IU daily, oral |
| Week 8 | 16* | Vitamin D2 50,000 IU weekly for 8 weeks, oral |
| Week 16 | 14* | Vitamin D2 50,000 IU twice a week for 2 weeks then weekly, SL |
| Week 24 | 23* | Vitamin D3 drops 4,000 IU daily, SL |
| Week 32 | 24* | Vitamin D3 drops 4,000 IU twice daily, SL |
| Week 36 | 31** (D3- 26 ng/mL, D2- 5 ng/mL) | Vitamin3 D drops 4,000 IU twice daily, SL |
| Week 40 | 28* | Vitamin D3 drops 4,000 IU twice daily, SL |
| 1 year | 36* | Vitamin D3 drops 4,000 IU twice daily, SL |
*Immunoassay;
**Liquid chromatography-tandem mass spectrometry.
Fig. 1.
Change in 25-hydroxyvitamin D level over time.
During follow up the patient was noted to have low fasting urinary ratio of calcium to creatinine at 50 mg calcium/gram creatinine, despite adequate calcium intake and improvement in her 25(OH)D level. There was concern that the patient may have underlying malabsorption as she had not responded well to the oral vitamin D supplementation also. She was referred to a gastrointestinal specialist, who evaluated her for celiac disease. Laboratory work-up was negative for celiac antibodies. Upper and lower endoscopies were unremarkable and duodenal biopsy for celiac disease was also negative. She did have a history of lactose intolerance and loose bowel movements for which she took loperamide off and on. Based on this, the possibility of some form of underlying malabsorption cannot be excluded, which may explain her resistance to oral supplements.
DISCUSSION
Vitamin D sufficiency is evaluated by measuring 25(OH)D, the active metabolite of vitamin D (5). The Endocrine Society defines vitamin D deficiency as 25(OH) D levels <20 ng/mL, insufficiency between 21 to 29 ng/mL, and optimal as >30 ng/mL. Levels <12 ng/mL are considered severe deficiency (6). As our patient was post-menopausal with a history of osteoporosis, we used these cutoffs for her rather than the ones recommended by the Institute of Medicine for the general population (7). The Endocrine Society recommends treating vitamin D deficiency with either vitamin D2 at 50,000 IU once weekly for 8 weeks, or its equivalent oral vitamin D2 or D3 at 6,000 IU daily, to achieve optimal levels. Once optimal levels are reached, maintenance therapy consists of 1,500 to 2,000 IU vitamin D2 or D3 daily (6).
Vitamin D is lipid soluble, and when taken orally it is absorbed through the aqueous lining of the intestine after undergoing emulsification in the intestinal lumen with bile salts (1). Increasing age, obesity, malabsorptive conditions, as well as genetic variation in protein-mediated transport, lipase, and vitamin D-binding protein levels can all impair absorption of vitamin D. The bioavailability of vitamin D in the gastrointestinal tract can also be affected by differences in the food matrix and the physiochemical state of vitamin D. Changes in the pH and concentration of bile salts also influence the absorption of vitamin D (4).
SL absorption bypasses the first-pass metabolism and can increase serum levels up to 3 to 10 times more than via the oral route. Absorption occurs through numerous capillaries underneath the tongue and reaches the reticulated veins and the systemic circulation. Multiple factors can affect SL absorption, the most important one being lipid solubility which assists with passive diffusion (8).
Patients with malabsorptive diseases such as Crohn disease and celiac disease are more prone to lower intestinal absorption of vitamin D (9) and should be evaluated for these conditions. Our patient had negative serological testing for celiac disease and had normal duodenal biopsy and colonoscopy. In patients with malabsorptive conditions, the only effective treatment to increase 25(OH)D is exposure to ultraviolet B rays (9) as injectable vitamin D is not approved by the U.S. Food and Drug Administration.
Alternative routes of vitamin D supplementation have been reported including buccal and gingival routes (1). McCullough and Heaney (4) reported a case of severe vitamin D deficiency in a patient with history of Crohn disease and ileostomy. The initial 25(OH)D level was 6.1 ng/mL. The patient was initially treated with oral vitamin D3 at 5,000 IU twice daily followed by SL vitamin D2 at 50,000 IU administered by puncturing the gel cap and squirting the contents under the tongue. Her levels improved to 28 ng/mL at day 30 (9). A crossover study compared oral versus buccal vitamin D3 spray at a dose of 1,000 IU/day in healthy patients, with half the patients on oral formulation and the rest on buccal spray (1). Oral supplementation increased the 25(OH)D level by 22.5%, while the buccal spray increased it by 42%.
Our patient initially received oral vitamin D2 at 50,000 IU, followed by SL vitamin D2 with minimal improvement. Finally, she was treated with SL vitamin D3 at 4,000 IU twice daily with significant increase in 25(OH)D levels over time. Conversion of vitamin D2 to D3 is not 1:1, and some have suggested that vitamin D2 at 50,000 IU weekly is equivalent 5,000 to 15,000 IU/day of vitamin D3 (3). 25(OH)D immunoassays tend to underestimate vitamin D2 levels which can be measured more accurately using liquid chromatography-tandem mass spectrometry as it detects both 25(OH)D2 and 25(OH)D3 levels (10). We also checked 25(OH)D levels using liquid chromatography-tandem mass spectrometry assay in our patient shortly after she was switched to SL vitamin D3. The results showed a higher level of 25(OH)D3 compared to 25(OH) D2. This case report shows that SL vitamin D3 can also result in improvement in 25(OH)D levels, which has not been previously reported in the literature. SL vitamin D2 has previously been shown to increase serum 25(OH)D levels (9).
There are a few reported cases of vitamin D deficiency correction with SL administration of vitamin D2. Our case is unique in that it reports improvement in 25(OH)D levels after SL administration of over-the-counter vitamin D3 drops, showing this to be an effective and widely available means to improve 25(OH)D levels. Larger prospective studies need to investigate SL vitamin D3 drops, specifically in patients with malabsorption and vitamin D deficiency.
CONCLUSION
SL vitamin D3 supplementation is an effective method of vitamin D supplementation in patients with persistently low vitamin D levels despite oral supplementation. Prospective studies will be helpful in understanding the pharmacokinetics of SL vitamin D3 absorption as well as to establish a recommended standard dose. This may prove to be an alternative mode of vitamin D supplementation in patients with malabsorption.
Abbreviations
- 25(OH)D
25-hydroxyvitamin D
- SL
sublingual
Footnotes
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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