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Non-classical presentation of vitamin D deficiency: a case report

• Mohanad Kamaleldin Mahmoud Ibrahim 1 &
• Mustafa Khidir Mustafa Elnimeiri 2  

Journal of Medical Case Reports volume  14 , Article number:  126 ( 2020 ) Cite this article

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Vitamin D is a fat-soluble vitamin; vitamin D is essential to sustain health and it protects against osteoporosis. It is crucial to the human body’s physiology in terms of muscular movement and neurological signal transmission, and to the immune system in defense against invading pathogens.

Case presentation

This was a case of a 26-year-old Sudanese woman who presented with a 2-year history of anosmia, recurrent nasal polyps, back pain, and chronic fatigue. She was diagnosed as having a case of vitamin D deficiency and responded well to treatment.

There is an association between vitamin D deficiency and recurrent allergic nasal conditions.

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Vitamin D is a fat-soluble vitamin; it is naturally present in some foods and as dietary supplements. It is also produced endogenously through exposure to ultraviolet rays from sunlight. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and produces 25-hydroxyvitamin D (25(OH)D), also known as calcidiol. The second occurs in the kidney and forms the physiologically active 1,25-dihydroxy vitamin D (1,25(OH) 2 D), also known as calcitriol [ 1 ].

Vitamin D is found in cells throughout the body; vitamin D is essential to sustain health and it protects against osteoporosis. It is crucial to the human body’s physiology in terms of muscular movement and neurological signal transmission, and to the immune system in defense against invading pathogens [ 2 ].

Although there are different methods and criteria for defining vitamin D levels, the criteria Holick proposed have been widely accepted. In this proposal, vitamin D deficiency is defined as blood level of less than 20 ng/ml; insufficiency of vitamin D is defined as blood levels ranging between 20 and 29.9 ng/ml and sufficiency if greater than or equal to 30 ng/ml [ 3 ]. About one billion people globally have vitamin D deficiency and 50% of the population has vitamin D insufficiency. The majority of affected people with vitamin D deficiency are the elderly, obese patients, nursing home residents, and hospitalized patients. Vitamin D deficiency arises from multiple causes including inadequate dietary intake and inadequate exposure to sunlight. Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, some medications and cystic fibrosis may also lead to vitamin D deficiency [ 4 ].

Vitamin D deficiency is now more prevalent than ever and should be screened in high-risk populations. Many conflicting studies now show an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and neuropsychiatric disorders [ 5 , 6 ].

This was a case of a 26-year-old Sudanese woman, married, who has a 3-year-old boy. This woman presented to our ear, nose, and throat (ENT) department complaining of anosmia for the past 2 years. She had a history of two functional endoscopic sinus surgeries (FESSs) for nasal polyps: the first one was 6 years ago and the second one was 3 years prior to presentation. She complained of being highly sensitive to different irritants including dust, weather change, perfumes, and pets.She also stated that she attended more than three different physicians due to generalized fatigue and getting tired easily after simple daily activity in addition to sleeping for more than 10 hours a day.She attended an orthopedic clinic for unspecified lower back pain that was not related to any type of trauma or physical activity; a lumbosacral magnetic resonance imaging (MRI) was done and revealed no abnormal findings.She mentioned that she is known to be anxious most of the time and aggressive toward simple reactions from her family members. She had no psychiatric history and was not using any medications.

She was not known to be diabetic or hypertensive or to have any chronic illnesses; she was not on any regular medication. She is a housewife of high socioeconomic status; she is well educated, graduated from dental school with a bachelor’s degree, but currently not employed. She has never consumed tobacco or alcohol; she practiced regular cardio exercises.On examination, she looked healthy, well, not pale or jaundiced. Her pulse rate was 74/minute and her blood pressure was 118/70. Her body mass index (BMI) was 26.8. All systems examinations were normal except for bilateral nasal polyps. Complete blood count (CBC), renal function test (REF), electrolyte, liver function test (LFT), thyroid function test (TFT), urine analysis (general urine test), antinuclear antibody (ANA), and rheumatoid factor (RF) were all normal. An imaging profile included lumbo-sacral MRI, a computed tomography (CT) scan of her sinuses, and electrocardiogram (ECG), which were normal except for bilateral nasal polyps and severe sinusitis that looked allergic to fungi in nature.She underwent FESS surgery to remove the polyps and clean out her sinuses; up to 6 weeks after surgery she used nasal steroids (mometasone furoate 0.005%) two times a day, but her symptoms regarding anosmia were not improved. MRI of her brain and a CT scan of her sinuses were done and both revealed normal features. A vitamin D deficiency was suggested and the laboratory results revealed a low vitamin D level of 7 ng/ml. Treatment with vitamin D supplement was prescribed at 50,000 international units (IU) weekly for 8 weeks and then 1000 IU maintenance dose daily, she was advised to take food rich in vitamin D and get exposed to sunlight for 20 minutes three times a week after the loading dose of supplement. She was at regular follow-up for 6 months; at rates of weekly for the first month, every 2 weeks for the second month, and monthly for the rest of the follow-up period. At each visit, she was assessed with clinical history and examination. It was noticed that the symptoms of tiredness, sleeping, anosmia, and back pain were dramatically improving during that period. At the 6 months follow-up, her blood level of vitamin D was normal, she described her condition as free from all symptoms, and she returned back to normal physical activity.

Discussion and conclusions

This was a non-classical case of vitamin D deficiency of a 26-year-old woman who presented with chronic anosmia and recurrent nasal polyps. She was diagnosed as having a case of vitamin D deficiency and responded well to vitamin D replacement therapy. This case correlated an association between decreased levels of vitamin D and recurrent nasal polyps that led in time to chronic anosmia as a result of chronic high sensitivity reactions triggered by our patient’s autoimmune system. The literature links chronic rhinosinusitis with nasal polyps (CRSwNP) with asthma and allergic rhinitis, but the cellular and molecular mechanisms that contribute to the clinical symptoms are not fully understood. Sinonasal epithelial cell barrier defects, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis [ 7 ].

Despite all the previous surgical and medical interventions over the past 6 years, our patient’s condition did not improve and she still complained of anosmia. A study revealed that this patient was experiencing excessive allergic reactions that led to recurrent nasal polyps. It is well known that classical clinical effects of vitamin D deficiency are bones and musculoskeletal-related disorders, several lines of evidence demonstrate the effects of vitamin D on pro-inflammatory cytokines, regulatory T cells, and immune responses, with a conflicting interpretation of the effects of vitamin D on allergic diseases [ 8 ].

The working diagnosis was suggested in relation to some musculoskeletal symptoms and chronic fatigue especially when the imaging profile for her lower back and all routine investigations were normal. It has been suggested that clinicians should routinely test for hypovitaminosis D in patients with musculoskeletal symptoms, such as bone pain, myalgias, and generalized weakness which might be misdiagnosed as fibromyalgia and chronic fatigue [ 9 ]. The most common causes of anosmia were assessed as well and they were negative, these included sinonasal diseases, post infectious disorder, and post-traumatic disorder, and congenital defects and disorders caused by neurodegenerative disease [ 10 ].

Thus blood level for vitamin D was requested and the results were of low D level.

In the past history of the previous nasal polyps surgeries, our patient noted that there was no anosmia and her main complaints were classic complaints of sinusitis, including sneezing, nasal blockage and headache. Soon after surgery her symptoms improved except for the allergy-related symptoms, despite usage of inhaled steroids spray. She stated that, at the last time, the presentation was different since it was only anosmia, indicating that there was significant inflammation that affected the smell receptors around the olfactory epithelium. After the last nasal polyps and sinuses drainage surgery, the symptoms related to allergic reactions, including chronic sneezing, did not improve for up to 6 weeks and she was still suffering from hyposmia, although that was a fair postoperative period for recovery.

The symptoms of anosmia and sneezing, and other systematic symptoms, gradually started to improve after vitamin D supplements, indicating that the main reason behind her symptoms was vitamin D deficiency. She was followed up for up to 6 months after establishment of vitamin D supplements and at the last follow-up she had a normal sense of smell, and she was free from back pain, fatigue, and allergy-related symptoms.

This was a non-classical presentation as our patient was young and she did not have alkaline phosphatase, calcium, and phosphorus abnormalities [ 11 ] that are expected in cases of vitamin D deficiency.

This case revealed an association between decreased levels of vitamin D and recurrent nasal polyps that led to anosmia as a result of hypersensitive reactions produced by the body’s systems.

Although vitamin D deficiency is prevalent, measurement of serum 25(OH)D level is expensive, and universal screening is not supported. However, vitamin D testing may benefit those at risk for severe deficiency.

It is highly recommended to consider vitamin D deficiency among all patients with unspecified symptoms or in cases of non-diagnosed disorder regardless of the presenting complaint.

In conclusion, there is an association between vitamin D deficiency and recurrent allergic nasal conditions.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Chronic rhinosinusitis with nasal polyps

Computed tomography

Electrocardiogram

Ear, nose, and throat

Functional endoscopic sinus surgery

Body mass index

Complete blood count

Renal function test

Liver function test

Thyroid function test

Antinuclear antibody

Rheumatoid factor

International unit

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Community Medicine and Epidemiology, Faculty of Medicine, Ibn Sina University, Khartoum, Sudan

Mohanad Kamaleldin Mahmoud Ibrahim

Preventive Medicine and Epidemiology, Alneelain University, Khartoum, Sudan

Mustafa Khidir Mustafa Elnimeiri

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MI analyzed and interpreted the findings of the case report and was the major contributor in writing the manuscript. ME reviewed the report and added valuable comments. All authors read and approved the final manuscript.

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Correspondence to Mohanad Kamaleldin Mahmoud Ibrahim .

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Ibrahim, M.K.M., Elnimeiri, M.K.M. Non-classical presentation of vitamin D deficiency: a case report. J Med Case Reports 14 , 126 (2020). https://doi.org/10.1186/s13256-020-02454-1

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Is vitamin C enough? A case report of scurvy in a five-year-old girl and review of the literature

• Timothy Hahn 1 ,
• Whitney Adams 1 &
• Keith Williams   ORCID: orcid.org/0000-0002-6762-4585 1  

BMC Pediatrics volume  19 , Article number:  74 ( 2019 ) Cite this article

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A Correction to this article was published on 16 May 2019

This article has been updated

Numerous cases of scurvy secondary to diet limitations have been reported in the literature with most being boys with special needs. To date, the focus of the literature describing vitamin C deficiency has been the medical sequelae of the deficiency. There has been little attention given underlying diet limitations causing the vitamin C deficiency.

Case presentation

A five-year-old female with typical development initially presented with rash, then later for pain in both lower extremities. After evaluation revealed vitamin C deficiency, she was admitted into an intensive day treatment feeding program. A feeding assessment found she had life-long problems with eating and had a diet that never exceeded ten foods. Across the course of treatment, she learned to eat 29 new foods. At six-month follow-up her body mass index had increased from the 1st to the 61st percentile. At one-year follow-up her body mass index was at the 85th percentile. All sequalae of her deficiency resolved.

Conclusions

This case is unusual as most reported studies describe males with special needs. The severity of her eating issues suggest providers may consider referral to allied health professionals to address diet limitations for both children identified with nutrient deficiencies as well as children whose selective eating places them at risk for nutritional deficiencies or problems with growth. The child we described was anemic, like 42% of children described in the case literature on scurvy and like 32% of the children in this literature, our patient was underweight. In the literature, comorbid nutrient deficiencies were reported in 22% of the scurvy case studies. We suggest vitamin C supplementation is a necessary component for addressing vitamin C deficiency, but insufficient for addressing the diet limitations causing the nutrient deficiency.

Peer Review reports

While scurvy has been described as very uncommon [ 1 ] or rare [ 2 ] in the pediatric population, a recent study examining the scurvy in a large pediatric health care facility identified 32 children with vitamin C deficiency over a five-year span [ 3 ]. Of these 32 cases, four children developed scurvy as the result of a lack of diet diversity, with three having the comorbid diagnosis of autism and one with intellectual disability [ 3 ]. In this sample, there were no children with typical development who developed scurvy from a primary dietary deficiency. Reviews of the literature have also found few children with typical development develop scurvy as the result of a limited diet. One review examining 18 cases of scurvy and reported only case of a boy with typical development whose limited diet resulted in scurvy [ 2 ] while second review examined 23 cases of scurvy associated with selective eating and found four boys and one girl with typical development [ 4 ]. A case series conducted at a metropolitan hospital found seven children with scurvy secondary to dietary insufficiency over a period of 18 years, all of whom had special needs, mostly autism spectrum disorder [ 5 ]. In the following case study, we describe scurvy in a five-year-old girl without special needs. After description of the case, we discuss the treatment of vitamin C deficiency in the context of both the current case and the existing literature on vitamin C deficiency. The child in this case study is unusual due to her gender and absence of special needs. This study is the first to examine the dietary aspects of vitamin C deficiency.

A five-year-old typically developing female was referred by her primary care provider for evaluation of a rash reported to be sensitive to sunlight and had been reoccurring for the last 4 years. Cutaneous exam revealed fine scale on her trunk and extremities as well as small pink flat papules on lower left leg. She was diagnosed with ichthyosis vulgaris and provided with a treatment plan. She was subsequently referred to gastroenterology for decreased appetite. Two weeks later the child presented to the Emergency Department for right knee pain. Her mother reported her daughter had experienced bilateral lower extremity pain and had been limping. During the evaluation she was able to walk for the physician without reporting pain and no tenderness was reported with palpation. The mother reported her daughter was bitten by a tick about 1 year ago and that no workup or treatment was conducted. Radiographic scans of the right knee and leg showed no abnormalities. Laboratory testing for Lyme disease was conducted and found to be negative. She was discharged with the diagnosis of tenosynovitis. The child presented again to the Emergency Department the following week for left knee and ankle pain. She reported pain in her left calcaneus when asked to bear weight. Migratory arthralgia was noted and further laboratory testing, including a vitamin C level, was ordered. Her vitamin C level was found to be < 5 umol/L (reference range: 23 to 114 umol/L). Her prealbumin level was also low, 14 mg/dl (reference range: 17–36 mg/dl) as was both her ferritin 3.9 ng/ml (reference range: 6.2–137.0 ng/ml) and her iron saturation 15% (reference range: 20–55%). Both vitamin A and vitamin D were found to be within the normal reference range. With the diagnosis of the vitamin C deficiency, the child was started on ascorbic acid and referred to the feeding program.

The participant was the youngest of six children and raised by her biological parents in a middle-class household in a small town. She was born full term by caesarian section with a birth weight of 3.88 kg. There were no prenatal or postnatal complications. No delays in development were noted by the primary care provider or parents. She scooted at 6 months and walked before 1 year. No problems were noted with her gait until several weeks prior to the initial visit to the Emergency Department for knee pain.

At 1 year of age, she transitioned from infant formula to milk and cereal snacks. She never accepted baby food. For 4 years after transitioning off infant formula her diet consisted of cereal snacks, one type of cracker, and, inconsistently, chocolate pudding, vanilla ice cream, chocolate, and banana. Except for the occasional banana, she never ate fruit, vegetables, or meats. She drank skim milk, water, and, rarely, soda. She refused to taste new foods or drinks. Additionally, at the time of her diagnosis with vitamin C deficiency, her body mass index was at the 1st percentile. Based upon her inadequate growth and extremely limited diet, she was admitted to an intensive day treatment feeding program. During the course of intensive treatment she learned to eat 29 foods from all food groups through the use of an intervention involving gradual repeated exposure to novel foods [ 6 ]. In 6 months after intensive treatment, her weight had increased by four kilograms, her height increased by three centimeters, and her body mass index reached the 61st percentile. At 1 year after completion of intensive treatment, her height had increased by 7.6 cm and her weight had increased by seven kilograms Her body mass index reached the 85th percentile (see Fig.  1 ). Across the span of the 1 year after intensive treatment she continued to be monitored as an outpatient by a feeding therapist who continued to address the child’s diet variety and helped the family maintain the gains made during intensive treatment. At all outpatient appointments, a meal was conducted allowing the therapist to verify the child’s consumption of a variety of foods.

BMI percentile changes across treatment

How unusual was this case?

To determine how this case compared to the existing literature, articles describing cases of scurvy secondary to diet limitations published from 2000 to 2018 were reviewed. PubMed and Google Scholar were searched using the search terms, “scurvy” and “ascorbic acid deficiency”. The reference section and citation listing of each article identified from these searches were then examined to identify additional articles. Sixty-one articles describing either a case study or a case series reported on 77 children diagnosed with scurvy as a result of diet insufficiencies (see Additional file  1 for an alphabetical listing of all studies). Selected demographics from these studies are shown in Table  1 . While the child in the current study was only slightly younger than median age as the children in the existing literature, she differed from most of these children who were predominantly males with special needs, most often, autism spectrum disorder. Of the 77 reported cases, only six were females without special needs.

While all 77 children reported in these studies had limited diets, it is not clear that all could be described as selective eaters or to what degree their diets were the result of refusal to eat a variety of foods. Six of the children exhibited oral motor dysfunction which limited the range of foods they could eat [ 7 , 8 ]. While some, or possibly all, of these six children might have obtained sufficient nutrition by consuming lower texture foods, oral supplement, or multi-vitamins, it is probable their parents did not know how to modify their diets to match their oral motor limitations. There were also three children dependent upon tube feeds who either received an insufficient amount of enteral formula [ 9 ] or received homemade tube feeds deficient in vitamin C [ 10 ]. There were other children whose diets were not adjusted to meet their specific health needs, for example, one child receiving a ketogenic diet was not receiving any vitamin supplementation [ 11 ] and another child received only a limited diet due to multiple food allergies [ 12 ]. For various reasons, the parents of 18 children, (five children with typical development, 14 children with special needs other than autism) limited their diets to the point these children developed vitamin C deficiency. Of the nine children with typical development with parent-limited diets, all but two were less than 2 years of age.

Fifty-nine of the children described in the existing literature could be described as selective eaters whose scurvy resulted from their limited intake. Of these children, 41% had autism spectrum disorder, 31% had intellectual disabilities, and 86% were male. Four of these 59 children were females with typical development like the girl in the current study. The child in the current case study had a diet similar to the diets of these 59 children identified as selective eaters in the existing literature on vitamin C deficiency. None of these children reportedly consumed vegetables or fruits, most consumed only starches and dairy products, with a few eating a limited number of proteins. The child in our case study was anemic, as were 42% of the children in the existing literature, an expected finding given the role of vitamin C in iron absorption. While the child in our case study did not exhibit signs or symptoms indicative of additional nutrient deficiencies, other deficiencies were considered likely so she was placed on a multivitamin within a day of the initial diagnosis of vitamin C deficiency. Her pediatrician conducted further testing and found her vitamin A and vitamin D levels were within the normal range. Of the 59 children described in the existing literature, 22% were identified with an additional nutrient deficiency beyond anemia (e.g. vitamin A, vitamin D). Given the diets reported for these 59 children, it is possible, if not probable, that more of these children had other nutrient deficiencies, but further deficiencies were either not reported or not identified.

The girl described in our case study had a body mass index at the 1st percentile prior to her feeding treatment. Underweight was also a common problem among the 59 children in the existing literature, with 32% being described as underweight. It is not surprising so many of these children were underweight. Many of children had anemia, which decreases appetite and eating was no doubt uncomfortable or even painful for many of these children, 71% of whom exhibited gingival symptoms.

Discussion and conclusions

Every study in the existing literature on scurvy resulting from dietary insufficiency described the use of ascorbic acid to address the Vitamin C deficiency. In many instances, the case studies describe the rapid and almost complete resolution of all symptoms secondary to the vitamin deficiency. While we would not argue vitamin C supplementation does not resolve vitamin C deficiency, we do suggest vitamin C supplementation alone is insufficient for many children. For the 22% of the children with additional nutrient deficiencies, vitamin C alone would be inadequate for meeting their nutritional needs. While vitamin supplementation can, and does, correct nutrient deficiencies, supplementation does not correct the selective eating patterns of these children, which is the underlying reason the child in the current case study, and 59 children in the existing literature, developed scurvy. As demonstrated by the child in this case study, it is possible to address the underlying eating problems which led to vitamin deficiency. It is not known if the failure to address the eating problems underlying the nutritional deficiencies described in these 59 children puts them at risk for future nutritional deficiencies or problems with growth.

Research on children who exhibit more extreme patterns of selective eating have been shown to exhibit these patterns over prolonged periods of time [ 13 ]. There is no evidence that children who self-limit their intake to the extent they develop nutritional deficiencies will change their patterns of eating without intervention. Even though the presentation of a child with a vitamin C deficiency secondary to either selective eating or parents limiting the child’s diet may not be a common occurrence, it may also not be considered rare, with 61 published studies in the last 18 years. In our own healthcare organization, the current case was the fifth case of vitamin C deficiency in less than 5 years. Three other children presented to pediatric hematology for hematological complications and were subsequently diagnosed with scurvy secondary to diet limitations [ 14 ] and one child receiving homemade tube feedings presented with scurvy [ 10 ]. While the current study described a child presenting with a vitamin C deficiency and discussed the literature describing cases of scurvy in the pediatric population, nutrient deficiencies are not limited to vitamin C, other clinical presentations involving other vitamin deficiencies, including vitamin A [ 15 ], vitamin B 1 [ 16 ], and vitamin D [ 17 ] have all been reported in children with limited diets. Even though the presentation of children with nutrient deficiencies may not be commonplace for most providers, children at-risk for nutrient deficiencies will be seen far more often. In a sample of 422 children referred to our feeding program, 95 ate ten or fewer foods [ 18 ].

While the case studies and case series in the existing literature all report resolution of the vitamin deficiency, the long-term outcomes of these children are unclear. Follow-up information from 6 months or longer after initial treatment of the vitamin C deficiency was reported for only nine children from the existing literature. Based upon our experience with selective eaters more generally, these children remain at risk for additional nutrient deficiencies or problems with weight, either underweight or possibly overweight.

The child in the current case study had a limited diet since being weaned, despite receiving regular pediatric care. In the existing literature, reports of contact with pediatric providers prior to diagnosis of the vitamin C deficiency were noted in numerous studies. There are no indications that children diagnosed with vitamin deficiencies are not receiving regular healthcare. Based upon our experience with the current case and the children referred to our organization’s feeding program, we suggest the extent of some children’s diet limitations are not always clear to healthcare providers. One large population-based study found 46% of parents identified their children as picky eaters at some point during childhood and picky remitted in two-thirds of cases within 3 years [ 19 ]. Picky eating does persist in some children, with one study showing picky eating as a stable trait through age 11 [ 20 ]. As providers hear about picky eating often and it usually resolves, it may be difficult to differentiate the transient picky eating commonly seen from the selective eating that could result in nutrient deficiencies.

While the role of dietary limitations on the development of nutritional deficiencies, namely vitamin C, was the focus of this case study and literature review, it is worth mentioning the child in this case study demonstrated a significant increase in her body mass index, increasing from the 1st to 85th percentile in 1 year. Certainly, some of this growth can be attributed to the increased number of calorie-dense foods she learned to eat, we also hypothesize the increased total variety of foods, including fruits and vegetables, also helped with weight gain. It is known that eating a food or limited foods over time results in monotony, or a decreased desire to eat this food or foods [ 21 ]. Increasing diet diversity can decrease the effects of monotony and lead to increased weight gain, especially if the diet contains some foods high in energy density [ 22 ]. Thus, increasing a child’s diet variety can not only prevent nutritional deficiencies, it can support adequate intake.

While the child in our case study was a young girl with typical development, our review of the clinical cases of vitamin C deficiency revealed children with special needs, especially children with autism spectrum disorders, were over-represented. This is consistent with the broader literature on childhood feeding problems which shows feeding problems occur at a higher prevalence in children with special needs [ 23 ]. As children with special needs are more at risk for long-term problems with feeding or eating, healthcare providers may provide additional attention to these children to determine the need for referral to providers to address feeding or eating problems.

Change history

16 may 2019.

Following publication of the original article [1], the authors reported that an out-of-date version of Figure 1 had been incorporated in the published article.

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Hahn, T., Adams, W. & Williams, K. Is vitamin C enough? A case report of scurvy in a five-year-old girl and review of the literature. BMC Pediatr 19 , 74 (2019). https://doi.org/10.1186/s12887-019-1437-3

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A brief review on vitamin b 12 deficiency looking at some case study reports in adults.

1. Introduction

2. vitamin b 12 and anemia, 3. vitamin b 12 and neurological disorders, 4. vitamin b 12 deficiency and hyperhomocysteinemia, 5. conclusions, author contributions, conflicts of interest, abbreviations.

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Azzini, E.; Raguzzini, A.; Polito, A. A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults. Int. J. Mol. Sci. 2021 , 22 , 9694. https://doi.org/10.3390/ijms22189694

Azzini E, Raguzzini A, Polito A. A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults. International Journal of Molecular Sciences . 2021; 22(18):9694. https://doi.org/10.3390/ijms22189694

Azzini, Elena, Anna Raguzzini, and Angela Polito. 2021. "A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults" International Journal of Molecular Sciences 22, no. 18: 9694. https://doi.org/10.3390/ijms22189694

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• Case Study: Vitamin B12 Deficiency

Volume 35 Number 4 | August 2021

Minh kosfeld, phd, mlt(ascp) cm, patient physical examination on admission.

Our patient is a previously healthy 56-year-old white man who presents with progressive neuropathy and declining mental status over several months. The patient initially developed numbness of his fingertips and the balls of his feet and began to lose motor control of his hands, which manifested as dropping objects or flinging them as he tried to pick them up. As symptoms progressed, he had visual tracking problems that were severe enough to interfere with driving a car, and he developed short-term memory loss and slowing of cognitive function.

Laboratory Results

Diagnosis and Treatment

Based on the clinical presentation and laboratory findings, a diagnosis of psychomotor regression due to B12 deficiency was made. The patient was then treated with a series of B12 intramuscular injections, which resulted in rapid remission of associated neurological symptoms. In follow-up laboratory examinations, his B12 level was normalized in two months (606 pg/mL), and MMA in eight months (197 nmol/L).

B12 is the largest and most complex of the water-soluble B vitamins. Since it contains cobalt, compounds with B12 activity are collectively called “cobalamins.” For humans, the only natural dietary sources of B12 are animal products (meat, dairy), in which it is bound to protein. The B12 absorption mechanism is complex, requiring several transporter proteins. First, it must be freed from the food matrix by gastric HCl and pepsin. Once liberated, it is transported to the duodenum by haptocorrin (transcobalamin I), a cobalamin-binding protein produced in the saliva. In the duodenum, pancreatic digestive enzymes free B12 from haptocorrin, allowing it to bind intrinsic factor (IF), a transporter protein synthesized by the parietal cells of the gastric mucosa. This B12-IF complex travels to the terminal ileum where it is absorbed and the B12 is separated from IF. B12 then is delivered to peripheral tissues and the liver by transcobalamin II and haptocorrin, respectively. 1,2

B12 is essential for DNA synthesis, hematopoiesis, and myelination. In different metabolically active forms, it functions as a cofactor for two different enzymes. As methylcobalamin, B12 activates cytoplasmic methionine synthase to convert homocysteine to the essential amino acid methionine. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, proteins, and lipids. As adenosylcobalamin, B12 activates the mitochondrial L-methylmalonyl-CoA mutase to convert L-methylmalonyl-CoA to succinyl-CoA in the metabolism of propionate, a short-chain fatty acid. 3,4 In B12 deficiency, these cofactors are unavailable, causing homocysteine and MMA to accumulate.

Despite our understanding of the metabolic disturbances resulting from B12 deficiency, its pathogenesis is not as well understood. Deficiency of B12 can lead to two major clinical syndromes, megaloblastic anemia and neuropathy. 1,3,4 It is thought that severe B12 deficiency interferes with the synthesis of DNA needed for hematopoiesis, leading to megaloblastic anemia, the appearance of hypersegmented neutrophils, and possible pancytopenia. 5 Regarding neuropathy, it is thought that long-term B12 deficiency may lead to impaired synthesis of ethanolamine, phospholipids, and sphingomyelin, resulting in altered myelin integrity. 6 An enigmatic feature of B12 deficiency is that its clinical presentations vary and may entail only hematologic or neurological abnormalities, or both. 1

Common diagnostic lab tests for B12 deficiency typically begin with serum B12 measurement and a complete blood count (CBC). Low B12 levels and evidence of megaloblastic anemia (decreased RBC, Hgb, Hct, WBC, platelet count, increased MCV, large oval RBCs and hypersegmented neutrophils) indicate B12 deficiency. For ambiguous results, MMA and homocysteine levels should also be measured to confirm. 2,4 Serum MMA is the most sensitive marker of B12 status where its increase indicates decreased tissue B12. However, it also rises with renal insufficiency and tends to be higher in older adults. Plasma homocysteine is a sensitive indicator for early B12 deficiency where it rises quickly as B12 status declines. However, it also rises in folate or B6 deficiency and especially with renal insufficiency, reducing its specificity. 3,4 Additional tests include serum or RBC folate to differentiate causes of macrocytic anemia, and Anti-IF or Anti-parietal cell antibodies to confirm pernicious anemia. 1,2

Caregivers should be aware of the different clinical presentations of B12 deficiency and screen for it in high-risk populations. Risk factors include insufficient dietary B12 intake (vegetarians), lack of intrinsic factor (autoimmune pernicious anemia), food-bound malabsorption (atrophic gastritis of aging or chronic H. pylori infection), gastrointestinal surgery (post gastrectomy or ileal resection), pancreatic or intestinal disorders (chronic pancreatitis, Crohn’s, or Celiac disease), genetic disorders (Transcobalamin II deficiency), and use of certain drugs (long-term use of metformin, H2 receptor antagonists or Proton-pump inhibitors). 1,2,3

Diagnosis of B12 deficiency can be complicated since symptoms may be vague and lab test results can be equivocal. Despite the low B12, high MMA, and significant neurologic symptoms, this patient’s homocysteine level was normal, and he was not anemic. With no known risk factor for B12 deficiency, assays were done for anti-IF antibodies to evaluate for pernicious anemia and AChR binding antibodies for Myasthenia Gravis. However, this patient’s positive symptomatic and serologic responses to B12 supplementation suggest that simple vitamin B12 deficiency was the etiology. Fortunately, B12 therapy reversed his most severe neurological symptoms, although that may not always be the case. Since the reason for the deficiency is unknown, he will continue to receive B12 supplementation indefinitely.

• Michael J Shipton and Jecko Thachil, Vitamin B12 deficiency–A 21st century perspective. Clin Med (Lond). 2015 Apr; 15(2): 145–150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4953733/
• https://labtestsonline.org/conditions/vitamin-b12-and-folate-deficiencies
• Vitamin B12. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/
• Bishnu Prasad Devkota. Methylmalonic Acid. https://emedicine.medscape.com/article/2108967-overview#showall
• Mark J Koury, Prem Ponka. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-31. https://pubmed.ncbi.nlm.nih.gov/15189115/
• Brahim El Hasbaoui, Nadia Mebrouk, Salahiddine Saghir, Abdelhkim El Yajouri, Rachid Abilkassem, and Aomar Agadr. Vitamin B12 deficiency: case report and review of literature. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140678/

Minh Kosfeld is Director/Assistant Professor, Investigative and Medical Sciences Program, in the Department of Clinical Health Sciences at Saint Louis University in Missouri.

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Multivitamin Use and Mortality Risk in 3 Prospective US Cohorts

Affiliations.

• 1 Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
• 2 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
• 3 Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
• PMID: 38922615
• PMCID: PMC11208972
• DOI: 10.1001/jamanetworkopen.2024.18729

Importance: One in 3 US adults uses multivitamins (MV), with a primary motivation being disease prevention. In 2022, the US Preventive Services Task Force reviewed data on MV supplementation and mortality from randomized clinical trials and found insufficient evidence for determining benefits or harms owing, in part, to limited follow-up time and external validity.

Objective: To estimate the association of MV use with mortality risk, accounting for confounding by healthy lifestyle and reverse causation whereby individuals in poor health initiate MV use.

Design, setting, and participants: This cohort study used data from 3 prospective cohort studies in the US, each with baseline MV use (assessed from 1993 to 2001), and follow-up MV use (assessed from 1998 to 2004), extended duration of follow-up up to 27 years, and extensive characterization of potential confounders. Participants were adults, without a history of cancer or other chronic diseases, who participated in National Institutes of Health-AARP Diet and Health Study (327 732 participants); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (42 732 participants); or Agricultural Health Study (19 660 participants). Data were analyzed from June 2022 to April 2024.

Exposure: Self-reported MV use.

Main outcomes and measures: The main outcome was mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.

Results: Among 390 124 participants (median [IQR] age, 61.5 [56.7-66.0] years; 216 202 [55.4%] male), 164 762 deaths occurred during follow-up; 159 692 participants (40.9%) were never smokers, and 157 319 participants (40.3%) were college educated. Among daily MV users, 49.3% and 42.0% were female and college educated, compared with 39.3% and 37.9% among nonusers, respectively. In contrast, 11.0% of daily users, compared with 13.0% of nonusers, were current smokers. MV use was not associated with lower all-cause mortality risk in the first (multivariable-adjusted HR, 1.04; 95% CI, 1.02-1.07) or second (multivariable-adjusted HR, 1.04; 95% CI, 0.99-1.08) halves of follow-up. HRs were similar for major causes of death and time-varying analyses.

Conclusions and relevance: In this cohort study of US adults, MV use was not associated with a mortality benefit. Still, many US adults report using MV to maintain or improve health.

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Vitamin D: An Evidence-Based Review

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Vitamin D is a fat-soluble vitamin that plays an important role in bone metabolism and seems to have some anti-inflammatory and immune-modulating properties. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states. Low vitamin D levels are associated with increased overall and cardiovascular mortality, cancer incidence and mortality, and autoimmune diseases such as multiple sclerosis. Although it is well known that the combination of vitamin D and calcium is necessary to maintain bone density as people age, vitamin D may also be an independent risk factor for falls among the elderly. New recommendations from the American Academy of Pediatrics address the need for supplementation in breastfed newborns and many questions are raised regarding the role of maternal supplementation during lactation. Unfortunately, little evidence guides clinicians on when to screen for vitamin D deficiency or effective treatment options.

• Background and Physiology

Vitamin D is a hormone precursor that is present in 2 forms. Ergocalciferol, or vitamin D 2 , is present in plants and some fish. Cholecalciferol, or vitamin D 3 , is synthesized in the skin by sunlight. Humans can fulfill their vitamin D requirements by either ingesting vitamin D or being exposed to the sun for enough time to produce adequate amounts. Vitamin D controls calcium absorption in the small intestine and works with parathyroid hormone to mediate skeletal mineralization and maintain calcium homeostasis in the blood stream. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states, probably caused by its anti-inflammatory and immune-modulating properties and possible affects on cytokine levels.

Vitamin D 3 can be manufactured in the skin by way of ultraviolet (UV) B rays. UVB rays are present only during midday at higher latitudes and do not penetrate clouds. The time needed to produce adequate vitamin D from the skin depends on the strength of the UVB rays (ie, place of residence), the length of time spent in the sun, and the amount of pigment in the skin. Tanning beds provide variable levels of UVA and UVB rays and are therefore not a reliable source of vitamin D.

Vitamin D 3 is synthesized from 7-dehydrocholesterol in the skin. The vitamin D binding protein transports the vitamin D 3 to the liver where it undergoes hydroxylation to 25(OH)D (the inactive form of vitamin D) and then to the kidneys where it is hydroxylated by the enzyme 1 αhydroxylase to 1,25(OH)D, its active form. 1 This enzyme is also present in a variety of extrarenal sites, including osteoclasts, skin, colon, brain, and macrophages, which may be the cause of it's broad-ranging effects. 1 The half-life of vitamin D in the liver is approximately 3 weeks, which underscores the need for frequent replenishment of the body's supply.

Vitamin D and Mortality

Vitamin D may be a determinant of mortality because of its anti-inflammatory and immune-modulating effects. It has been used to treat secondary hyperparathyroidism in people on dialysis. Retrospective trials show that vitamin D supplementation is associated with decreased mortality in people on dialysis. 2 Low serum vitamin D levels are also related to increased mortality in most patients with chronic kidney disease before dialysis. 3 However, there have been no randomized prospective trials examining this relationship. 4

In patients not on dialysis, low vitamin D levels are associated with increased levels of inflammation and oxidative load. A prospective study of more than 3000 male and female patients scheduled for coronary angiography found a positive association between low vitamin D levels and cardiovascular as well as all-cause mortality. 5 Data analysis from the National Health and Nutrition Examination Survey III (more than 13,000 adults) showed that people with vitamin D levels in the lowest quartile had a mortality rate ratio of 1.26 (95% CI, 1.08–1.46). 6 A recent meta-analysis demonstrated that intake of a vitamin D supplement at normal doses also was associated with decreased all-cause mortality rates. 7 These data suggest that vitamin D may play a part in multiple causes of death, although causality has not been determined.

Vitamin D and Cardiovascular Disease

Vitamin D receptors are present in vascular smooth muscle, endothelium, and cardiomyocytes and may have an impact on cardiovascular disease. Observational studies have shown a relationship between low vitamin D levels and blood pressure, coronary artery calcification, and existing cardiovascular disease. A large cohort study that included more than 1700 participants from the Framingham offspring study looked at vitamin D levels and incident cardiovascular events. 8 During a period of 5 years, participants who had 25-OH D levels of <15 were more likely to experience cardiovascular events (hazard ratio, 1.62; 95% CI, 1.11–2.36). The relationship remained significant among people with hypertension but not among those without hypertension. 8

Vitamin D and Diabetes

Recent studies in animal models and humans have suggested that vitamin D may also play a role in the homeostasis of glucose metabolism and the development of type 1 and type 2 diabetes mellitus (DM). Epidemiologic data has long suggested a link between exposure to vitamin D early in life and the development of type 1 DM. 9 ,10 Vitamin D 3 receptors have strong immune-modulating effects. In some populations the development of type 1 DM is associated with polymorphisms in the vitamin D receptor gene. 11 ,12 There is also some evidence that increased vitamin D intake by infants may reduce the risk of the development of type 1 DM. 13

Vitamin D has recently been associated with several of the contributing factors known to be linked to the development of type 2 DM, including defects in pancreatic βcell function, insulin sensitivity, and systemic inflammation. Several physiologic mechanisms have been proposed, including the effect of vitamin D on insulin secretion, the direct effect of calcium and vitamin D on insulin action, and the role of this hormone in cytokine regulation. 9 ,12 ,13 Although most studies indicating this relationship are observational, one meta-analysis showed a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalence of type 2 DM or metabolic syndrome. The study concluded that the highest type 2 DM prevalence, 0.36 (95% CI, 0.16–0.80), among participants who were not black was associated with the lowest blood levels of 25-hydroxyvitamin D. In addition, metabolic syndrome prevalence of 0.71 (95% CI, 0.57–0.89) was highest among those with the lowest dairy intake. There was also an inverse relationship between type 2 DM and metabolic syndrome incidences and vitamin D and calcium intake. 14

Vitamin D and Osteoporosis

Osteoporosis is the most common metabolic bone disease in the world. A low vitamin D level is an established risk factor for osteoporosis. Inadequate serum vitamin D levels will decrease the active transcellular absorption of calcium.

Although combination calcium and vitamin D supplementation is associated with higher bone mineral density and decreased incidence of hip fractures, 15 the evidence for vitamin D supplementation alone is less clear. A recent evidence summary found that vitamin D supplementation at doses of more than 700 IU daily (plus calcium) prevented bone loss compared with placebo. 16 However, vitamin D supplementation (300 to 400 IU daily) without calcium did not affect fractures. 16 A Cochrane review found unclear evidence that vitamin D alone affected hip, vertebral, or other fracture rates but supported the use of vitamin D with calcium in frail, elderly nursing home residents. 17 A subsequent meta-analysis of trials looking at vitamin D and fracture rates concurred that calcium was also necessary to affect a significant difference. 18

The most recent meta-analysis of 12 randomized, controlled trials that included more than 42,000 people found that vitamin D supplementation of more than 400 IU daily slightly reduced incidence of nonvertebral fractures (rate ratio, 0.86; 95% CI, 0.77–0.96). 19 The effect was dose dependent and was not significant if doses were ≤400 IU daily.

Vitamin D and Falls among the Elderly

Vitamin D status is increasingly recognized as an important factor in fall status among elderly patients. Several trials have demonstrated that vitamin D supplementation decreases the risk of falling. One proposed mechanism is that higher vitamin D levels are associated with improved muscle function.

A randomized, controlled trial from Australia evaluated women with at least one fall in the preceding 12 months and with a plasma 25-hyroxyvitamin D level <24.0 ng/mL. 20 All women were given calcium 1000 mg per day and were randomized to receive either ergocalciferol 1000 IU per day or placebo. Women in the study group had fewer falls after 12 months, but this was not a significant difference (53% versus 62.9%; odds ratio, 0.66; 95% CI, 0.41–1.06). After correction for height difference in the 2 groups, the ergocalciferol group had a significantly lower risk of falling (odds ratio, 0.61; 95% CI, 0.37–0.99).

A dose of 800 IU daily significantly reduced the risk of falling compared with a placebo in a dose-stratified analysis of the effect of 5 months of vitamin D supplementation on fall risk (72% lower incidence rate ratio; rate ratio, 0.28; 95% CI, 0.10–0.75). Lower doses of vitamin D, however, did not significantly change the rate of fall incidence compared with placebo. 21

A review of 12 randomized, controlled trials studying the effect of vitamin D supplementation on fall risk among both nursing home residents and community dwellers found a small benefit of supplementation on fall risk (odds ratio, 0.89; 95% CI, 0.80–0.99), 9 an effect that was also shown in a review of randomized, controlled trials with strict inclusion criteria, which included 1237 men and women with a mean age of 70 years and supplementation for 2 months to 3 years. The pooled results showed a significant 22% decrease in fall risk among those treated with vitamin D versus placebo or calcium only. The number needed to treat from the pooled results was 15 to prevent 1 person from falling 22 Assessing vitamin D levels in a population at high risk for falling and supplementing with 800 to 1000 IU daily of vitamin D should be a part of any fall prevention program.

Vitamin D and Cancer

Both observational studies in humans and animal models support that vitamin D has a beneficial role in cancer prevention and survival. The mechanism of action is probably related to its role in the regulation of cell growth and differentiation. 23 In the Health Professionals Follow-Up study (a cohort study of 1095 men), each increment in 25(OH)D level of 25mmol/L was associated with a 17% reduction of total cancer cases. 24 However, the National Health and Nutrition Examination Survey of 16,818 men and women did not find a relationship between total cancer mortality and vitamin D level. There was an inverse relationship between vitamin D level and colorectal cancer, however. In this study, serum 25(OH)D levels of ≥80 nmol/L conferred a 72% reduction in risk of colorectal cancer compared with a level lower than 50 nmol/L. 25

A recent meta-analysis of 63 observational studies looked at the relationship between vitamin D levels and cancer incidence and mortality. 26 Twenty of the 30 studies looking at vitamin D and colon cancer showed that people with higher vitamin D levels had either a lower incidence of colon cancer or decreased mortality. Similarly, 9 of the 13 studies about breast cancer and 13 of the 26 studies about prostate cancer showed beneficial effects of vitamin D levels on cancer incidence or mortality (some of the studies included more than one type of cancer). 26

A population-based randomized, control trial found that postmenopausal women who were supplemented with calcium and vitamin D had a reduced risk of cancer after the first year of treatment (rate ratio, 0.232; 95% CI, 0.09–0.60). 27 There was not a group that was supplemented with vitamin D alone.

Vitamin D and Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative, T lymphocyte-mediated, autoimmune disease of uncertain etiology. Although genetic susceptibility may be involved, epidemiologic studies suggest environmental influence because the development of MS correlates most strongly with rising latitude in both the northern and southern hemispheres. 28 Migration studies show that risk can be modified at an early age from both low to high and high to low prevalence rates. 28 Exposure to sun in early childhood is associated with reduced risk of developing MS 29 and population-based studies about MS in Canada have also shown that birth timing is a risk factor for MS because there are statistically significantly fewer patients with MS born in November and more born in May compared with controls. 30 A birth-timing association suggests that seasonality and sunlight exposure may also have an effect on the developing fetus in utero. 30 ,31

Several studies have shown that vitamin D affects the growth and differentiation of immune-modulator cells such as macrophages, dendritic cells, T cells, and B cells. 32–34 This immune-modulatory effect has implications for a variety of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosous, type I DM, inflammatory bowel disease, and MS. 33

Despite the wealth of epidemiologic studies supporting a relationship between vitamin D and MS in humans, data showing a link between serum vitamin D levels and MS are only beginning to emerge. One prospective, nested, case-control study examined the serum samples of 7 million military veterans and compared serum samples of 257 MS patients before diagnosis with those of matched controls. 35 An inverse relationship between vitamin D levels and MS risk was found, particularly for vitamin D levels measured in patients younger than 20. Another case-control study compared the serum vitamin D levels of 103 MS patients with 110 controls and found that for every 10-nmol/L increase of serum 25(OH)D level the odds of MS was reduced by 19% in women, suggesting a “protective” effect of higher vitamin D levels. 36 In addition, a negative correlation was found between Expanded Disability Status Scale scores among female MS patients and 25(OH)D levels. Several other studies have supported the finding that lower levels of vitamin D in MS patients are associated with more severe disability. 37 Lower levels during relapses have also been reported in patients with relapse-remitting MS. 38–40

The potential effects of oral vitamin D intake have been observed in several different ways. A Norwegian case-control study found that fish and cod liver oil have a protective effect against the development of MS. 29 A large observational study in the United States that followed 2 large cohorts of women—the Nurses’ Health Study (92,253 women followed from 1980 to 2000) and the Nurses’ Health Study II (95,310 women followed from 1991 to 2001)—found that vitamin D supplementation in the form of a multivitamin seemed to lower their MS risk by 40%. 41 However, several methodological weaknesses in study design made the results inconclusive. 42

Despite the overwhelming amount of data describing the association between vitamin D and MS, there is a paucity of research describing the benefit of vitamin D supplementation to these patients. One small safety study of 12 patients taking 1000 μg per day (40,000 IU) of vitamin D for 28 weeks showed a decline in the number of gadolinium-enhancing lesions on magnetic resonance imaging per patient; this led to a 25(OH)D serum concentration of 386 nmol/L (158 ng/mL) without causing hypercalcemia, hypercalciuria, or other complication. 43

Vitamin D and Cognition

Observational studies have shown that people with Alzheimer dementia have lower vitamin D levels than do matched controls without dementia. 44 The biological plausibility of this relationship includes vitamin D's antioxidative effects and the presence of vitamin D receptors in the hippocampus, which has been seen in rats and humans. 44 A cross-sectional study of 225 outpatients diagnosed with Alzheimer disease found a correlation between vitamin D levels (but not other vitamin levels) and their score on a Mini Mental Status Examination. 45

Vitamin D and Chronic Pain

Because of the important role vitamin D plays in bone homeostasis, some have questioned whether vitamin D deficiency may also correlate with chronic pain syndromes, including chronic low back pain. Several case series and observational studies have suggested that vitamin D inadequacy may represent a source of nociception and impaired neuromuscular functioning among patients with chronic pain.

The data to support this conclusion are mixed. A recent review of 22 relevant studies found no convincing link between prevalence and latitude and no association between serum levels of 25-OH vitamin D in chronic pain patients and controls. Interestingly, though, there was a contrast in treatment effects between randomized, double-blind trials that minimized bias and those with studies known to be subject to bias. In those that blinded the vitamin D therapy, only 10% of patients were in trials showing a benefit of vitamin D treatment, whereas among those who did not blind the treatment 93% were in trials showing a benefit of vitamin D supplementation. 46

A second review examined the role of vitamin deficiency in patients from outpatient and inpatient rehab units. Fifty-one articles were reviewed and a direct correlation was noted between vitamin D deficiency and musculoskeletal pain. Treatment of vitamin D deficiency produced an increase in muscle strength and a marked decrease in back and lower-limb pain within 6 months. 47 Although these data were suggestive of a link between vitamin D and pain, the available evidence does not imply causality. The verdict on this topic will remain undecided until this is evaluated by double-blind, randomized, controlled trials stratified by baseline vitamin D level with defined treatments and comparison placebo groups.

• Vitamin D Supplementation for Infants and Breastfeeding Mothers

Breast milk is an ideal form of nourishment for a newborn. Because of most nursing mother's own vitamin D deficiency, however, and despite the mother taking a prenatal vitamin, breast milk alone is not sufficient to maintain newborn vitamin D levels within a normal range. 48 Many nursing mothers or their infants require vitamin D supplementation for optimal health. 49

In 2003, the American Academy of Pediatrics recommended that 200 IU of vitamin D be used as supplementation for all infants beginning during the first 2 months after birth. 50 More recently, in 2008 the recommendation has been increased to a minimum of 400 IU daily during the first days of life to prevent vitamin D deficiency that may lead to rickets. 48

A 2004 systematic review looked at 166 cases of nutritional rickets diagnosed between 1986 and 2004 in 17 states from the mid-Atlantic region to Texas and Georgia. A disproportionate number of rickets cases were found in African-American, breastfed infants. 51 In addition to rickets and the risk of developing type I DM, other pediatric and adult health conditions may be impacted by insufficient vitamin D levels in infants and their mothers. 52 Both bone mineral accrual in early childhood 53 and the risk of recurrent wheezing episodes in children at age 3 54 were linked to insufficient vitamin D intake by women during pregnancy. If a fetus or breastfeeding infant receives an inadequate amount of vitamin D from its mother it can have a direct impact on the baby's health as an adult. Because of these findings, in 2007 the Canadian Pediatric Society recommended 2000 IU of vitamin D 3 for pregnant and lactating mothers with periodic blood tests to check levels of 25 (OH)D and calcium. 52 The American Academy of Pediatrics recommendations focus on supplementing the infant and make no specific recommendations about universally supplementing breastfeeding mothers. 48

Supplementing the Newborn: 2008 Recommendations from the American Academy of Pediatrics

The American Academy of Pediatrics recommends supplementing all children who are exclusively breastfed with 400 IU of vitamin D from the first few days of life. Children who are fed by breast and formula or who are exclusively formula fed should also be supplemented until they are consistently ingesting 1 L of formula a day (approximately 1 quart). The supplementation should continue until 1 year of age, when children begin ingesting vitamin D-fortified milk. 48 All formulas sold in the United States contain at least 400 IU/L of vitamin D 3 ; therefore, 1 L per day would meet the vitamin D recommendations set by the American Academy of Pediatrics. 55

Preparations for Supplementation

There are many available preparations for newborns ( Table 1 ). Some companies make a single-drop preparation that contains 400 IU, but caution should be used when prescribing this product because of the ease of dispensing too much vitamin D to a newborn with just a few drops. 48

• View inline

Vitamin D Preparations for Newborns

Checking Serum Levels in Infants

Clinicians should obtain a serum vitamin D level (25-OH-D not 1,25-OH 2 -D) among infants with malabsorption disorders or who take anticonvulsants because they may need additional supplementation above 400 IU daily. Actual values of 25-OH-D that determine vitamin D insufficiency in children have not been defined. The ≥20 ng/mL of 25-OH-D that determines a sufficient vitamin D level for adults has been used for children. 48

Supplementing Breastfeeding Mothers

Mothers who were supplemented with 400 IU of vitamin D daily produced milk with vitamin D levels that ranged from <25 to 78 IU per liter. 48 Supplementing the mother alone with 400 IU—equivalent to a prenatal vitamin—produced inadequate vitamin D levels in the breastfed infants. 55 A randomized, controlled trial evaluated 19 breastfeeding mothers who were supplemented with 6000 IU of vitamin D 3 and a prenatal vitamin with 400 IU of vitamin D. The vitamin D levels found in their breast milk and in the exclusively breastfed infants themselves were found to be equivalent to the infants who received oral supplementation (300 IU per day). This level of maternal supplementation showed no toxic effects and provided adequate vitamin D to nursing infants without needing to supplement the infant. 56 Safety and efficacy of this dosing during pregnancy and lactation has not been confirmed. In the meantime, screening high-risk women is appropriate and supplementing breastfeeding women who are vitamin D 3 deficient is warranted. 57

• Testing for Vitamin D Deficiency

There are many causes of vitamin D deficiency, as listed in ( Table 2 ), 59 and despite growing attention to this deficiency, there are no established guidelines to help clinicians decide which patients warrant screening laboratory testing. The US Preventive Services Task Force does not comment for or against routine screening for vitamin D deficiency. One approach is to consider serum testing in patients at high risk for vitamin D deficiency but treating without testing those at lower risk.

Causes of Vitamin D Deficiency 58

An Australian working group issued a position statement itemizing groups of people at risk for vitamin D deficiency. The risk groups include: (1) older people in low- and high-level residential care; (2) older people admitted to hospital; (3) patients with hip fracture; (4) dark-skinned women (particularly if veiled); and (5) mothers of infants with rickets (particularly if dark-skinned or veiled). 58

If electing to test vitamin D status, serum 25-hydroxyvitamin D is the accepted biomarker. 60 Although 1,25-OH-D is the active circulating form of vitamin D, measuring this level is not helpful because it is quickly and tightly regulated by the kidney. True deficiency would be evident only by measuring 25-OH-D. Of note, questions have been raised regarding the need for standardization of assays. 61 A large laboratory (Quest Diagnostics) recently reported the possibility of thousands of incorrect vitamin D level results. 62 Sunlight exposure questionnaires are imprecise and are not currently recommended. 63

Controversy exists regarding the optimum level of serum 25-hydroxyvitamin D in a healthy population. Most experts agree that serum vitamin D levels <20 ng/mL represent deficiency. However, some experts recommend aiming for a higher minimum target level of 30 ng/mL of 25-hydroxyvitamin D 49 in a healthy population. Vitamin D intoxication can occur when serum levels are greater than 150 ng/mL. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and weakness probably caused by the resultant hypercalcemia. Of note, sun exposure alone cannot lead to vitamin D intoxication as excess vitamin D 3 is destroyed by sunlight.

Given concern about skin cancer, many patients and clinicians are cautious regarding sun exposure recommendations. However, exposure of arms and legs for 5 to 30 minutes between the hours of 10 am and 3 pm twice a week can be adequate to prevent vitamin D deficiency. 59

Natural dietary sources of vitamin D include salmon, sardines, mackerel, tuna, cod liver oil, shiitake mushrooms, and egg yolk. 58 Fortified foods include milk, orange juice, infant formulas, yogurts, butter, margarine, cheeses, and breakfast cereals. 59

Over-the-counter multivitamin supplements frequently contain 400 IU of vitamins D 1 , D 2 , or D 3 . Alternatively, over-the-counter vitamin D 3 supplements can be found in 400, 800, 1000, and 2000 IU strengths. Prescription-strength supplementation choices include vitamin D 2 (ergocalciferol), which provides 50,000 IU per capsule, and vitamin D 2 liquid (drisdol) at 8000 IU/mL. 59

To prevent vitamin D deficiency in healthy patients, the 1997 Institute of Medicine recommendations suggested a daily vitamin D intake of 200 IU for children and adults up to 50 years of age; 400 IU for adults 51 to 70 years of age; and 600 IU for adults 71 years or older. 64 The upper limit recommended was 2000 IU daily. However, some experts consider this to be too low and recommend that children and adults without adequate sun exposure consume 800 to 1000 IU daily to achieve adequate serum vitamin D levels. 59

Treatment recommendations vary depending on the cause of the deficiency. For example, patients with chronic kidney disease are recommended to have 1000 IU of vitamin D 3 daily. 59 The expected blood level response to a given vitamin D dose varies, probably because of differences in the cause of the deficit as well as the starting point for correction. A recent editorial reported that supplemental intakes of 400 IU per day of vitamin D increase 25(OH)D concentrations by only 2.8 to 4.8 ng/mL (7–12 nmol/L) and that daily intakes of approximately 1700 IU are needed to raise these concentrations from 20 to 32 ng/mL (50–80 nmol/L). 65 Responses to vitamin D supplementation or sun exposure may vary by patient, so clinicians may need to continue to monitor abnormal levels.

This article was externally peer reviewed.

Funding: none.

Conflict of interest: none declared.

• Received for publication February 27, 2009.
• Revision received July 10, 2009.
• Accepted for publication July 13, 2009.
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Vitamin C deficiency in a 12-year-old male presenting with knee pain: a case report

• Clinical Correspondence
• Published: 09 May 2022
• Volume 24 , pages 544–546, ( 2022 )

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• Kellie Cloney 1 ,
• Suzanne Ramsey 2 &
• Emma Burns   ORCID: orcid.org/0000-0001-8042-7124 3  

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Introduction

Vitamin C deficiency is a relatively rare pediatric disease, the literature in children being largely made up of case reports. However, the incidence of vitamin C deficiency in children may be on the rise [ 1 ]. Increased risk for nutritional deficiencies is especially true given the COVID-19 pandemic. It is estimated that since March 2020, food insecurity has tripled in households with young children [ 2 ] making it more important than ever to understand this diagnosis.

Vitamin C deficiency can result in symptoms of scurvy after only 3 months of restricted intake. Vitamin C is crucial for making pro-collagen, therefore deficiency results in collagen abnormalities throughout the body: abnormal dentition, changes in vasculature, and abnormal osteoid matrix [ 3 ]. Consistent with abnormal collagen production symptoms of 3 ]. Musculoskeletal (MSK) changes are also commonly present, including joint pain, myalgias, weakness, and decreased weight-bearing [ 4 ]. Here we outline the case of a pediatric patient presenting with leg pain who was ultimately diagnosed with vitamin C deficiency.

Clinical presentation

A 12-year-old male with high functioning autism spectrum disorder (ASD) was brought to the emergency department (ED) after falling down two stairs, landing on his right knee. Weeks prior to the fall, he was having non-specific leg pain, located at the mid-quadriceps level bilaterally. After the fall, he complained of painful gait, right knee and ongoing quadricep pain. His right knee was tender, with mild bruising over the patella, but no joint effusion, joint line tenderness or instability. He had no hip pain and had a normal hip exam. He was found to have a petechial rash on his shins (Fig.  1 A) that was reportedly present intermittently over the last few months. He was systemically well. X-rays were done of his knee and hip with no evidence of fracture, slipped capital femoral epiphysis, or joint effusions (Fig.  1 B, C ). He was discharged home with a diagnosis of soft tissue injury.

A Patient’s lower legs showing petechial rash consistent with perifollicular hemorrhagic rash. B Plain film, AP view, of right knee, showing healthy and open growth plates of the femur, fibula, and tibia (arrows) and no evidence of fractures, osteopenia, or soft tissue inflammation. Increased lucency on the diaphysis side, in keeping with Frankel’s lines (black arrowhead). C Plain film, frog leg view of the hips, showing healthy and open growth plates of the femur (arrows), with no displacement of the femoral head. No fractures

The patient returned to the ED 2 days later with increasing leg pain and inability to weight bear. He remained systemically well with an unchanged exam, making a septic joint unlikely. Due to progression of symptoms, bloodwork was sent. His CBC, INR and PTT were normal. His inflammatory markers were elevated (CRP of 26.4 mg/L, ESR of 50 mm/h). A consultant in the ED recognized the perifollicular hemorrhagic rash as consistent with vitamin C deficiency. Upon review of the patient’s dietary history, he was found to have an extremely limited diet with no consumption of fruits, vegetables, or vitamin supplements. His diet had worsened during the pandemic lockdown. Vitamin C levels were drawn, and vitamin C 500 mg po BID was started in the ED based on the high index of suspicion and risk of bleeding.

In the ED, the differential for difficulty weight-bearing is lengthy and includes, trauma, infection, hemarthrosis, neoplasm, and inflammatory causes. However, in children with a restricted diet, nutrient deficiencies must be considered. Eighty percent of patients with scurvy present with musculoskeletal pathology [ 4 ]. Symptoms include, arthralgias in the knees or ankles, and myalgias. Children often first present with limp or refusal to walk [ 4 ]. Unlike physical exam findings with inflammatory joint changes range of motion of affected joints can be normal. This results in a seemingly well child whose sole complaint is decreased weight-bearing. To confirm the diagnosis, serum vitamin C levels must be assessed; however, radiographic investigations can yield diagnostic clues. X-ray findings include diffuse osteopenia, as well as Frankel’s lines — lucent areas at the zone of calcification that represent disorganized osteoid matrix, as seen on the images of our patient’s femur (Fig.  1 B). MRI changes are also common in scurvy. The typical findings are areas of decreased signal on T1-weighted imaging and increased signal on T2-weighted images within the bone marrow [ 6 ]. These changes were seen in the pelvis, hip, and femur of our patient.

Symptoms of scurvy are varied, and early signs and symptoms can be vague, such as fatigue and malaise, resulting in a difficult diagnosis to make in the ED. Dermatological findings can be an important sign of vitamin C deficiency [ 3 ]. Oral mucosa will often have gingival disease, highlighted by bleeding from the gums and loose teeth. Skin changes include a spectrum from petechia through significant ecchymoses and hemorrhage. Corkscrew hairs and hyperkeratosis can also occur. Lower limb petechia are commonly found at the base of the hair follicles (Fig.  1 A) [ 3 ]. The presence of a perifollicular hemorrhagic rash should raise suspicion of vitamin C deficiency.

The most abundant sources of vitamin C are fruits and vegetables [ 5 ]. Patients with ASD often have challenges with sensory input, and eating can be a source of difficulty resulting in nutrient deficiencies. In a time where food security is of increasing concern, a quick dietary screen in the emergency department can be essential [ 1 ]. Our patient’s serum vitamin C level confirmed the diagnosis with a level of < 5umol/L (normal > 28umol/L). Vitamin C deficiency is easy to treat, and often results in timely symptom reversal while awaiting lab confirmation.

Take-home points

Musculoskeletal symptoms, such as knee and ankle pain, resulting in antalgic gait and decreased weight-bearing, are a common feature of vitamin C deficiency. Symptoms can mimic inflammatory arthropathy, including elevated inflammatory markers. However, patients have normal joint exams and no evidence of inflammatory changes on plain film joint images. It is important that vitamin C deficiency be included in the differential diagnosis for children with MSK complaints in the Emergency Department.

Perifollicular hemorrhagic rash can be a dermatologic representation of vitamin C deficiency. Coagulation profiles are normal.

Children with ASD and/or food insecurity often have restricted diets, which can result in nutritional deficiencies. Although vitamin C deficiency is rare in pediatrics, certain comorbid conditions and exacerbating circumstances put children at higher risk.

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Pediatric Resident, Dalhousie University, IWK Health, 5850 University Ave, Halifax, NS, B3J 3G9, Canada

Kellie Cloney

Division of Pediatric Rheumatology, Dalhousie University, IWK Health, Halifax, NS, Canada

Suzanne Ramsey

Division of Pediatric Emergency Medicine, Dalhousie University, IWK Health, Halifax, NS, Canada

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Cloney, K., Ramsey, S. & Burns, E. Vitamin C deficiency in a 12-year-old male presenting with knee pain: a case report. Can J Emerg Med 24 , 544–546 (2022). https://doi.org/10.1007/s43678-022-00317-w

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OTC Case Studies: Vitamins

Four case studies focus on vitamins and supplements.

Case 1: Vitamin D for Cardiovascular Health and Cancer Prevention

Q: HT, a 45-year-old man, is seeking a recommendation for a vitamin D supplement. His brother was recently given a diagnosis of prostate cancer, and HT recalls hearing about the beneficial effects of vitamin D supplementation in preventing cancer, which he is interested in for himself. HT reports that he follows up routinely with his primary care provider and has undergone all appropriate age-related screenings. He is healthy and reports no allergies or use of chronic maintenance medications. What can you suggest regarding vitamin D supplementation?

A: In 2018, a landmark large-scale, placebo-controlled, randomized study seemed to shed additional light on the potential extraskeletal effects of vitamin D. In the VITAL trial, almost 26,000 middle-aged and older adults without a history of cardiovascular disease (CVD), cancer, or other serious conditions were randomized to receive vitamin D3 at a dose of 2000 IU per day and omega-3 fatty acids at a dose of 1000 IU per day for the prevention of cancer and CVD. After a median follow-up of 5 years, investigators found that the use of these supplements did not reduce the occurrence of major cardiovascular events or invasive cancers. 1 For HT, this is an opportunity to emphasize and reiterate the importance of adhering to a healthy lifestyle, which includes eating healthy food, not drinking too much alcohol, and not smoking. Encourage him to continue following up with his provider and to undergo indicated health screenings to reduce his risk of cancer and other diseases. If HT is insistent on a recommendation for a supplement, encourage him to follow national dietary guidelines for his age and gender, including evaluating vitamin D intake from food sources, to ensure that he is receiving 600 IU per day. 2

Case 2: Health Benefits of Omega-3 Fatty Acid Supplementation

Q: FS, a 69-year-old woman, has a question about fish oil supplements. She has been taking an omega-3 fish oil supplement for several years, not at the advice of her physician but because she read that it may be beneficial for brain and heart health and could reduce cancer risk. FS has a significant family history for all these conditions, so she wants to make sure that she is doing everything possible to keep herself healthy. She recently came across a report that suggested there might be no benefit to supplementing with the product. FS denies allergies to medications and reports no other significant medical history. What counseling can you provide regarding the benefits of omega-3 fatty acid supplementation, in light of the findings of this recent study?

A: In the VITAL study, mentioned in the previous case, investigators evaluated the effects of omega-3 fatty acid supplements in preventing CVD. 1 In the nearly 26,000 patients with an average age of 67 without known CVD enrolled in this study, randomized to receive either 1 g of fish oil (eicosapentaenoic acid plus docosahexaenoic acid) or a placebo daily, a similar number of major cardiovascular events, such as cardiovascular-related death, nonfatal myocardial infarction (MI), and stroke, occurred in patients receiving the supplement compared with the placebo at the mean follow-up of 5.3 years. 1 There was a significantly lower incidence of MI in the group receiving the fish oil supplement, but the absolute difference between the groups was small (1.1% vs 1.5%) during the treatment period. Results of an additional trial in patients with diabetes but without CVD randomized to receive 1 g of fish oil capsules or a placebo showed similar outcomes.3 Given these emerging data, FS should be told that the evidence does not support the use of omega-3 fatty acid supplements for preventing cardiovascular events in patients without a history of CVD. Remind her about the importance of routine medical care, and encourage her to follow up with her primary care provider if she thinks that she is experiencing any changes in her health or has any medical complaints.

Case 3: Lung Cancer Risk with B Vitamin Supplementation

Q: KW, a 62-year-old man, is seeking advice regarding the dietary supplements he takes. For years, at the advice of his wife, he has taken a B vitamin combination each day. KW recalls recently reading that there may be a relationship between B vitamins and the development of lung cancer in men, and he wants to know whether this is a warning he should consider or just media hype. He suffers from other chronic medical conditions and takes several medications and supplements each day, and he would be happy to discontinue this supplement if it is potentially harmful. What suggestions for use of this supplement can you provide?

A : An analysis of the data of more than 77,000 individuals aged 50 to 76 years participating in the previously mentioned VITAL cohort, a study conducted in Washington from 2000 to 2002, was conducted to evaluate the 10-year average daily doses from individual and multivitamin supplements to evaluate the correlation, if any, with development of primary, invasive lung cancer. 4 Investigators concluded that although use of supplemental vitamins B6, B12, and folic acid was not associated with lung cancer risk among women, supplementing with vitamins B6 and B12 from individual supplements, not multivitamins, was associated with a 30% to 40% increase in lung cancer risk in men, with men who consume the highest amounts of daily intake of these nutrients having a nearly 2-fold increase in risk and higher risks observed in male smokers. 4 Inquire about KW’s smoking history, and encourage him to discuss these findings and the use of the supplements findings with his physician if he has additional questions.

Case 4: Vitamin Supplements for CVD Prevention and Treatment

Q: FM, a 64-year-old woman, wants to speak to a pharmacist about the use of vitamin supplements to reduce her risk of a heart attack. She has been managing dyslipidemia and hypertension for years but was recently admitted to a local hospital for evaluation of chest pain. After undergoing a cardiac catheterization, FM was instructed to remain compliant with her medications and encouraged to pursue lifestyle modification. However, she wants to know whether, in addition to losing weight and modifying her diet as instructed by her physician, a vitamin supplement can promote heart health. What information can you provide for the use of vitamin supplements to prevent and treat CVD?

A: A recent systematic review and meta-analysis of systematic reviews, meta-analyses, and randomized controlled trials concluded that of the 4 most commonly used supplements (multivitamins, vitamin D, calcium, and vitamin C), supplementation with none of these had a significant effect on cardiovascular outcomes of all-cause mortality. 5 Reiterate FM’s physician’s recommendations for dietary modification and weight loss to lower her blood pressure and cholesterol levels, and remind her that dietary sources are best for ensuring optimal daily intake of nutrients and vitamins. For more information about the evidence for the use of supplements for reducing the risk of cardiovascular events, encourage her to speak with her cardiologist or primary care provider.

Mary Barna Bridgeman, PharmD, BCPS, BCGP , is a clinical associate professor at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, New Jersey, and an internal medicine clinical pharmacist at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. Rupal Patel Mansukhani, PharmD, CTTS, FAPhA , is a clinical associate professor at the Ernest Mario School of Pharmacy at Rutgers University and a transitions-of-care clinical pharmacist at Morristown Medical Center in New Jersey.

• Manson JE, Cook NR, Lee IM, et al; VITAL Research Group. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med . 2019;380(1):33-44. doi: 10.1056/NEJMoa1809944.
• Institute of Medicine, Food and Nutrition Board, Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, DC: National Academies Press; 2010.
• ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects on n-3 fatty acid supplements in diabetes mellitus. N Engl J Med . 2018;379(16):1540-1550. doi: 10.1056/NEJMoa1804989.
• Brasky TM, White E, Chen CL. Long-term, supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort. J Clin Oncol . 2017;35(30):3440-3448. doi: 10.1200/JCO.2017.72.7735.
• Jenkins DJA, Spence JD, Giovannucci EL, et al. Supplemental vitamins and minerals for CVD prevention and treatment. J Am Coll Cardiol . 2018;71(22):2570-2584. doi:10.1016/j.jacc.2018.04.020.

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Clare Collins is affiliated with the Priority Research Centre for Physical Activity and Nutrition, the University of Newcastle, NSW. She is an NHMRC Senior Research and Gladys M Brawn Research Fellow. She has received research grants from NHMRC, ARC, Hunter Medical Research Institute, Meat and Livestock Australia, Diabetes Australia, Heart Foundation, Bill and Melinda Gates Foundation, nib foundation. She has consulted to SHINE Australia, Novo Nordisk, Quality Bakers, the Sax Institute and the ABC. She was a team member conducting systematic reviews to inform the Australian Dietary Guidelines update and 2017 evidence review on dietary patterns for the Heart Foundation.

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In Australia’s most recent nutrition survey, 29% of people reported having taken at least one dietary supplement . This proportion was even higher in the United States at 52% .

A new study out today aimed to examine the benefits of vitamin and mineral supplements for prevention of heart disease, stroke and premature death (termed “ all-cause mortality ”). This found the most commonly studied ones had no effect, while some less common ones did have an effect. The review also found some supplements can be harmful.

Read more: Health Check: can vitamins supplement a poor diet?

What did the study find?

The study was a systematic review , meaning the team of researchers examined all relevant research papers (179 in total) and combined the results. The supplements examined included vitamins A, B1 (thiamin), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B9 (folic acid), C, D, E, beta-carotene, and the minerals calcium, iron, zinc, magnesium and selenium. Multivitamins were defined as including most of these vitamins and minerals.

In studies testing the four common supplements of multivitamins, vitamin D, calcium and vitamin C, there was no reduction in incidence of heart disease, stroke or premature death. This means there was no benefit from taking them, but also no harm.

They also evaluated less common supplements that did have positive impacts on early death, heart disease and stroke. Here they found folic acid supplements showed a reduction in heart disease and stroke.

It was calculated that in order to prevent one case of heart disease or stroke, 111 people needed to be taking folic acid supplements (this is termed the “ numbers needed to treat ”). For stroke, 167 people would need to take folic acid to prevent one case, and 250 people would have to take B-complex vitamins (which contain folic acid, which is vitamin B9) to prevent one case.

Before you rush out to buy folic acid supplements, there are a few cautions. First, there are some concerns that high levels of folic acid in the blood may increase the risk of prostate cancer, although the results are mixed .

Read more: Health Check: four myths about vitamin supplements

Second, of the studies testing folic acid supplements, stroke was reduced in only two of the seven gold-standard studies (called randomised controlled trials). One of these was a very large study of 20,000 people in China. China does not have a folic acid food fortification program, whereas in Australia and the US, it’s commonly added to breads and breakfast cereals.

While a small benefit for taking folic acid was found, researchers also found some adverse effects from supplementation. Among those taking statin medication to lower blood cholesterol, slow or extended release vitamin B3 (niacin) increased the risk of early death by 10%, with a “ number needed to harm ” of 200. This means 200 people would have to take statins and niacin before we would see one case of early death.

For studies testing “antioxidant” supplements, there was marginally significant increased risk of early death, with a “number needed to harm” of 250 people.

The most studied supplement was vitamin D. Researchers found no benefits for heart disease or stroke prevention, but also no harm. This was a surprise, given vitamin D is commonly taken for other conditions, such as diabetes. But there was no benefit seen for early death, although the study’s authors acknowledged longer follow-up may be needed.

What does it all mean?

The authors concluded there is low-to-moderate quality evidence for taking folic acid for the prevention of heart disease and stroke, and also for taking B-complex vitamins that include folic acid for stroke.

Most people in Western countries don’t have an optimal diet. This review shows taking supplements as an “insurance policy” against poor dietary habits does not work. If it did, there would have been a reduction in early death.

Read more: Kids' vitamin gummies: unhealthy, poorly regulated and exploitative

Taking supplements is very different from eating whole foods. Complications or health problems due to nutrient intakes are virtually always due to taking supplements, not eating foods. When you concentrate on one vitamin, mineral or nutrient in a supplement, you miss out on the other phytonutrients found in plant foods that contribute to overall health.

The increase in early death for taking some categories of supplements should be a wake-up call that stronger regulations are needed around supplements, and people need a lot more support to eat better.

The bottom line is we need to eat more nutrient-rich whole foods, including foods high in folate such as green leafy vegetables, legumes, seeds, poultry, eggs, cereals and citrus fruits. Many breads and breakfast cereals in Australia are fortified with folate. Good food sources of niacin (vitamin B3) are lean meats, milk, eggs, wholegrain breads and cereals, nuts, leafy green vegetables and protein-containing foods.

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• Published: 14 March 2018

Vitamin K deficiency: a case report and review of current guidelines

• Maria Rosaria Marchili 1 ,
• Elisa Santoro 2 ,
• Alessandra Marchesi 1 ,
• Simona Bianchi 1 ,
• Lelia Rotondi Aufiero 1 &
• Alberto Villani 1  

Italian Journal of Pediatrics volume  44 , Article number:  36 ( 2018 ) Cite this article

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Vitamin K, a fat soluble vitamin, is a necessary cofactor for the activation of coagulation factors II, VII, IX, X, and protein C and S. In neonatal period, vitamin K deficiency may lead to Vitamin K Deficiency Bleeding (VKDB).

Case presentation

We present the case of a 2 months and 20 days Caucasian male, presented for bleeding from the injections sites of vaccines. At birth oral vitamin K prophylaxis was administered. Neonatal period was normal. He was exclusively breastfed and received a daily oral supplementation with 25 μg of vitamin K. A late onset vitamin K deficiency bleeding was suspected. Intravenous Vitamin K was administered with complete recovery.

Conclusions

Nevertheless the oral prophylaxis, our case developed a VKDB: it is necessary to revise the current guidelines in order to standardize timing and dosage in different clinical conditions.

Vitamin K, a fat soluble vitamin, is a necessary cofactor for the activation of coagulation factors II, VII, IX, X, and protein C and S. Vitamin K deficiency may lead to Vitamin K Deficiency Bleeding (VKDB). The VKDB is a disorder of hemostasis in which coagulation parameters are quickly corrected by vitamin K supplementation. The term VKDB replaced the wording of hemorrhagic disease of the newborn since vitamin K deficiency bleeding may also occur in the postnatal period.

The diagnosis is suggested by an International Normalized Ratio (INR) ≥ 4 or a Prothrombin Time (PT) greater than 4 times the normal values, in the presence of a normal platelet count and normal fibrinogen level. Diagnosis confirmation requires vitamin K-dependent factors dosage, which levels are quickly corrected by parenteral administration of 1 mg of vitamin K [ 1 ].

There are different forms of VKDB: early, classic and late.

Early form occurs within the first 24 h of life in infants born from mothers treated during pregnancy with anticonvulsants (carbamazepine, phenytoin and barbiturates), antituberculosis drugs (isoniazid, rifampicin), some antibiotics (cephalosporins) or vitamin K antagonists (warfarin) and who did not received vitamin K prophylaxis before the delivery [ 1 ]. It incidence in at-risk neonates without vitamin K supplementation varies from 6% to 12%. The classic form occurs between 24 h to 7 days of life and is more often idiopathic; in term born not receiving vitamin K prophylaxis it presents an incidence of 0,25–1,5% in older reviews [ 2 ] and 0,01–0,44% in more recent reviews [ 3 ]. The classic form is related to the low placental transfer of vitamin K, low concentration in breast milk, lack of gastrointestinal flora in the newborn gut, and poor oral intake that commonly occurs in the newborn period as breastfeeding is initiated. The late form occurs between the 2nd week and the 6th month of life, with a peak between 3 and 8 weeks after birth; it has an incidence of 1/15.000–1/20.000 births and it is typical of exclusive breastfed infants or newborns with malabsorption or cholestasis because vitamin K absorption is closely dependent on the intestinal availability of bile. The hemorrhagic manifestations mainly involve gastrointestinal tract and skin, but also the central nervous system in late forms [ 4 , 5 ]. Late VKDB carries a significant morbidity and mortality rate, with a mortality as high as 20–50% and a morbidity characterized by neurologic defects including hydrocephalus, cerebral atrophy, encephalopathy, epilepsy, and developmental delay [ 6 ].

Breastfeeding has been implicated as risk factor for the development of VKDB because human milk vitamin K concentration (median 2.5 mg/L [0.85–9.2 mg/L]) is significantly lower than currently available formula milk (4–25 mg/100 kcal approximately corresponding to 24–175 mg/L) [ 7 , 8 ]. On average daily vitamin K intake of breastfed infants is < 1 mg within the first 6 months of life, whereas the intake of formula-fed infants is on average up to 100 times higher [ 9 ].

Vitamin K deficiency leads to the synthesis of under-carboxylated proteins called PIVKA (protein induced by vitamin K absence), that are unable to bind calcium and therefore inactive. PIVKAs are released from the liver into the blood and their level increases with the severity of the deficiency. PIVKAs are, however, much more commonly reported in breastfed infants [ 10 ].

We reported the case of a 2 months and 20 days white Caucasian male, presented for bleeding from the injections sites of the first dose of hexavalent and pneumococcal vaccine.

He was born from unrelated parents at 41 weeks of gestational age by urgent cesarean section, with a birth weight of 3200 kg and a 5-min Apgar score of 10. His mother reported no use of drug during pregnancy and a previous miscarriage. At birth oral vitamin K prophylaxis was administered. Neonatal period was normal. He was exclusively breastfed and he received a daily supplementation of 25 μg of vitamin K and 400 IU of vitamin D.

At admission he was in fairly good general conditions, he was awake and responsive, with a valid crying and age-appropriate neurological findings. On the anterior region of both thighs, the injection sites of vaccines were recognizable, with a slight bleeding from the injection site on the left leg, without signs of edema. He had a normal cardiorespiratory activity and normal vital signs (blood pressure 70/46 mmHg, heart rate 126 bpm, respiratory rate 30 acts/min, body temperature 36 °C).

Blood tests showed a progressive anemia with a minimum value of hemoglobin of 7.8 g/dl (laboratory findings are shown in Table  1 ). The dosage of coagulation factors showed low values of the vitamin-K dependent factors (factor II 2%, factor VII 4%, factor IX 2%, factor X 5%) and normal values of factor V (128%). Abdominal and brain ultrasound excluded an ongoing bleeding. Fecal elastase on three samples and serology for HIV, HCV, HBV, CMV, EBV, HHV-6, Parvovirus B19 were negative (except for positive IgG for CMV).

Based on the clinical history and laboratory findings, a vitamin K deficiency bleeding “late onset” was suspected. Intravenous Vitamin K (Konakion 10 mg) was administered together with a continuous infusion of 1 g of tranexamic acid. Considering the low hemoglobin values, he was transfused without any adverse reaction.

After vitamin K administration a normalization of the coagulation parameters with persistence of anemia (Hb 8.8 g/dl) was observed. Treatment was therefore continued with oral vitamin K, and iron and folic acid supplementation.

During hospitalization, he did not presented further bleeding or other symptom. At discharge coagulation parameters were normal (PT 12.4 s, INR 0.94, aPTTs 28.5 s, aPTT-r 0.98, PLT 328,000/μl, fibrinogen 414 mg/dl) and hemoglobin values were increased (Hb 9.8 g/dl). The child was discharged with the indication to continue oral vitamin K supplementation with Konakion 10 mg twice weekly until weaning.

Since 1961 the American Academy of Pediatrics has recommended that all neonates receive a single intramuscular dose of 0.5-1 mg of vitamin K for the prevention of VKDB [ 11 ].

NICE guidelines of 2015 reiterated the recommendation to administer vitamin K at birth; in particular, they recommended to administer 1 mg of vitamin K intramuscularly to all newborns in order to prevent VKDB. If intramuscular administration is rejected by parents, the administration of multiple oral doses is recommended. These recommendations are based on the evidence that intramuscular administration of vitamin K is clinically more effective than oral administration, and that multiple oral doses of Vitamin K are necessary to obtain adequate protection against the late VKDB onset in breastfed children [ 12 , 13 ].

A Joint Position Statement from the Canadian Paediatric Society and the College of Family Physicians of Canada, published in 1997 and re-affirmed in 2014, recommended that a single intramuscular dose of vitamin K (0.5 mg for birthweight ≤1500 g or 1.0 mg for birthweight ≥1500 g) should be administered to all newborns within the first 6 h after birth. If intramuscular vitamin K is refused by parents, an oral dose of 2 mg vitamin K was recommended at the time of first feeding, followed by a second dose at 2 to 4 weeks, and a third dose at 6 to 8 weeks [ 14 ]. Similar recommendations are provided by two practice guidelines, one from Perinatal Services British Columbia [ 15 ] and one from the Winnipeg Regional Health Authority [ 16 ].

In 1992 Golding et al. reported an increased risk of developing childhood cancer after intramuscular vitamin K prophylaxis [ 17 ]. Subsequent studies, however, showed no significant correlation between parenteral vitamin K prophylaxis at birth and development of tumors in childhood [ 18 , 19 ]. But since the report of Golding et al. an increasing trend towards oral vitamin K administration had become.

A single vitamin K oral dose at birth is efficacy in prevention of classic VKDB, but it does not protect against late VKDB because of the shorter duration of oral vitamin K activity compared to intramuscular administration. In fact studies suggest that after a single oral dose vitamin K levels fall to unsupplemented levels within 2 weeks. Several mechanism can explain the major efficacy of intramuscular vitamin K administration, including poor absorption after oral administration and depot effect at the site of intramuscular injection [ 20 ].

Although it is clear that more than a single oral dose is needed, especially in exclusively breastfed infants, there is no consensus in the literature regarding the best oral vitamin K regimen to prevent late VKDB. In the absence of evidence there is a heterogeneity in prophylactic strategies, concerning the route of administration and the dosage of vitamin K used, with differences not only between countries, but also within the same country, as in the case of Italy. So a variety of continuous oral regimens have been studied (Table  2 ), but clinical trials comparing their efficacy and safety are lacking.

Primarily epidemiological data from several European countries showed that the most effective dosing strategy seems to be a continuous oral prophylaxis with weekly doses of 1 mg (Danish scheme) or daily doses of 25 μg (Dutch scheme) for 3 months. In particular, Danish scheme is based on an important study of Hansen et al., published in 2003, which has established that 1 mg of oral vitamin K given weekly during the first 3 months of life, following an initial oral dose of 2 mg of vitamin K directly after birth, is as effective as 1 mg of vitamin K given intramuscularly at birth [ 21 ]. Afterwards a surveillance study of 2005, published in 2008, in Netherland evidenced that daily dose of 25 μg was not effective in preventing idiopathic late VKDB. For this reason the authors suggested to double the daily dose of vitamin K to 50 μg for all breastfed babies from 1 to 13 weeks to prevent bleeding in also infants with underlying cholestatic liver disease [ 22 ].

Recently Witt et al. evaluated whether a prophylactic regimen of 1 mg vitamin K orally at birth followed by 150 μg daily during weeks 2 to 13 sufficiently prevented VKDB in breastfed infants. Their data in high-risk group, for example undiagnosed children with biliary atresia, showed that this regimen does not successfully prevent VKDB in these children, in contrast to a regimen consisting of a single intramuscular injection of 2 mg vitamin K at birth. They concluded that a prophylactic regimen for breastfed infants consisting of 1 mg vitamin K orally at birth, followed by either 25 μg or 150 μg daily during weeks 2 to 13, does not sufficiently prevent VKDB in breastfed infants with still undiagnosed biliary atresia. They assumed that this insufficient prevention is also present in infants with yet undiagnosed others forms of neonatal cholestasis. In their study efficient prevention was obtained by regimen consisting of single intramuscular injection of 2 mg vitamin K at birth [ 23 ].

However, cases of VKDB in exclusively breastfed healthy newborns, despite intramuscular prophylaxis at birth, have been described, suggesting that prophylaxis with a single dose of intramuscular vitamin K may be inadequate to prevent all cases of late VKDB [ 24 , 25 , 26 ].

In consideration of these reports, since 2004, the Italian Society of Neonatology recommends an oral administration of vitamin K in all exclusively breastfed newborns in the period from the 2nd to 14th weeks of age [ 27 ].

In our clinical case the child had been subjected at birth to oral administration of vitamin K and, subsequently, to a daily oral supplementation with 25 μg. Nevertheless, he developed a late-onset VKDB, although he had not cholestatic disease or malabsorption, but exclusively breastfeeding as only risk factor.

The reporting of late-onset VKDB in breastfed children invite us to reflect on the problem of prophylaxis in breastfed infants and the need of reviewing the guidelines and, in particular, the dose of oral supplementation with vitamin K in children taking only breast milk, considering, in addition, that hat oral supplementation is dependent on the compliance of the parents administering the vitamin in form of drops (with the real risk that the assumed dose is less than the desired dose).

Finally, despite evidence of major efficacy of intramuscular administration in preventing late forms of VKDB, mostly in children with risk factors (breastfeeding, unknown conditions of cholestasis or malabsorption), in the absence of shared guidelines there are still some birth Centers where oral prophylaxis is routinely performed at birth.

NICE guidelines of 2015 recommend to administer 1 mg of vitamin K intramuscularly to all newborns in order to prevent VKDB. If intramuscular administration is rejected by parents, the administration of multiple oral doses is recommended as a second option. These recommendations are based on the evidence that intramuscular administration is clinically more effective than oral administration, and that multiple oral doses of vitamin K are necessary to obtain adequate protection against late onset VKDB in breastfed children [ 12 , 13 ].

Nevertheless the exact dosage and timing of oral administration after the starting dose at birth, are not yet well defined [ 28 ]. On the other hand, late-onset VKDB cases have also been reported in children undergoing intramuscular administration of vitamin K at birth (not followed by subsequent oral supplementation) [ 24 , 25 , 26 ].

No data are available regarding the incidence of late onset VKDB after intramuscular prophylaxis at birth followed by oral supplementation [ 29 ].

Studies should be performed to evaluate the incidence of late onset VKDB in children who receive prophylaxis with vitamin K intramuscularly at birth, compared to those who receive it orally, with the same successive regimen of oral supplementation.

On the basis of such results we think that it will be necessary a review of guidelines about VKDB prophylaxis in order to standardize timing and dosage in different clinical conditions.

Abbreviations

Central nervous system

International normal ratio

National Institute for Health and Care Excellence

Protein induced by vitamin K absence

Prothrombin Time

Vitamin K deficiency bleeding

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Pediatric and Infectious Disease Unit, Bambino Gesu’ Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, Rome, Italy

Maria Rosaria Marchili, Alessandra Marchesi, Simona Bianchi, Lelia Rotondi Aufiero & Alberto Villani

Pediatric Department, University of Tor Vergata, Rome, Italy

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MRM: She wrote the manuscript. SB: She collected the clinical and laboratory data. MVG: She reviewed the current guidelines, in order to write the discussion. ES: She collected the bibliography. AV: He reviewed the manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. MRM, who wrote the manuscript, received no grant nor other form of payment to produce the manuscript. All authors read and approved the final manuscript.

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Marchili, M.R., Santoro, E., Marchesi, A. et al. Vitamin K deficiency: a case report and review of current guidelines. Ital J Pediatr 44 , 36 (2018). https://doi.org/10.1186/s13052-018-0474-0

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A large analysis of data from nearly 400,000 healthy U.S. adults followed for more than 20 years has found no association between regular multivitamin use and lower risk of death. The study, led by researchers at the National Institutes of Health’s National Cancer Institute, was published June 26, 2024, in JAMA Network Open .

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The learning network | when something’s missing: diagnosing vitamin deficiencies.

When Something’s Missing: Diagnosing Vitamin Deficiencies

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Overview | What happens when essential vitamins and minerals are missing from our diets? In this lesson, students consider what they already know and believe about vitamins and supplements, research nutrient deficiencies and then create, analyze and discuss patient case studies.

Materials | Computers with Internet access; materials about nutrition, vitamins and minerals; packaging and nutrition labels from food packages and vitamin and mineral supplement packages; poster board (if desired).

Warm-Up | Before class, collect packaging and nutrition labels from various multivitamin supplements and a variety of foods, like fortified cereals, dairy products and packaged fruits, vegetables and beans. Alternatively, ask students to bring in packaging from their households.

At the start of class, initiate a discussion about vitamins and minerals. Ask: What vitamins and minerals can you list? How do people get the nutrients they need? Why do some people take vitamin and mineral supplements? Can you name any examples of common vitamins and minerals? Do you associate certain health benefits with any specific vitamins or minerals?

Hold a brief discussion, and write ideas on the board. Next, circulate the vitamin and mineral supplement packages. Let students examine the labels.

Ask: What vitamins, minerals and nutrients are contained in these supplements? Does the packaging give any clues as to their purpose? Add any additional answers to the list on the board. Shift the discussion to food by asking: Aside from supplements, how else do people get the nutrients they need?

Next, circulate the food packages and labels. Ask: What vitamins and minerals are contained in these foods? When food packaging mentions vitamins, does that mean that the food is good for you? Can you tell whether the vitamins and minerals occur naturally in the food or have been added? Compare the nutrition information with the ingredients list. What is fortified food? Why do manufacturers fortify foods?

At this point, you might take raw student ideas and create a chart, listing vitamins and minerals in the first column with facts about each one’s role or importance in the second column and the foods it is associated with in the third.

Next, explain that you will read an article about vitamin D deficiency.

Related | In the Well blog post “Reasons That Vitamin D May Matter,” Jane Brody explains recent research about the importance of vitamin D:

At least once a week, someone, usually a woman over 50, asks me about vitamin D. Perhaps a routine checkup has revealed a deficiency, prompting the doctor to recommend an over-the-counter supplement or, in severe cases, large prescription doses to correct the problem. Often, though, the concern is bone health. Without vitamin D, the body cannot properly absorb calcium, and bones become fragile. At the annual meeting of the American Academy of Orthopaedic Surgeons last month, researchers reported that among 889 adult patients treated for a fracture at a Missouri trauma center, blood levels of vitamin D were “insufficient” in 78 percent and “frankly deficient” in 39 percent. The study group excluded those with known risk factors for vitamin D deficiency. A second report, by doctors in Seoul, South Korea, found that vitamin D levels were “significantly lower” among 104 postmenopausal women who had broken a wrist than among 107 age-matched controls without a fracture.

Read the entire article with your class, using the questions below

Questions | For reading comprehension and discussion:

• What is a vitamin deficiency?
• What health problems are linked to vitamin D deficiencies?
• Which groups of people are at risk of vitamin D deficiency? Why?
• What are the scientific uncertainties surrounding links between vitamin D deficiencies and health problems?

RELATED RESOURCES

From the learning network.

• Good for You?
• All About Food
• Adolescent Health | Nutrition, Healthy Weight and Eating Disorders

From NYTimes.com

• Childhood: Vitamin D Means Fewer Fractures for Girls
• It Could Be Old Age, or It Could Be Low B12
• Well: More Evidence Against Vitamin Use

Around the Web

• Mayo Clinic: Drugs and Supplements
• Harvard School of Public Health: The Nutrition Source
• UNICEF: Child Nutrition

Activity | Explain to students that they will work in groups, first to research vitamins and minerals and then create to a fictional case study of a patient experiencing a vitamin deficiency. Then, they will exchange case studies, diagnose each other’s patients and present their findings to the class.

Divide the class into six small groups and assign each group a vitamin or mineral to research. Tell groups not to share which vitamin or mineral they are researching because groups will diagnose each other’s patients in the next part of the activity.

Suggested vitamins and minerals include vitamin D , calcium , folate and folic acid , iron , vitamin B6 and vitamin B12 .

Using available resources, each group should create a chart for the vitamin that shows why it’s important, who is at risk for deficiency and symptoms of deficiency.

Then, on a separate sheet of paper or on poster board, each group creates a narrative describing a fictional patient who is either experiencing a vitamin or mineral deficiency or is likely to have a deficiency. Patient profiles should include fictional details like name, age, gender, risk factors and symptoms. They should not include the name of the vitamin at issue because another group will attempt to diagnose the patient.

A model for these narratives is the Well blog’s “Think Like a Doctor” series , as well as the related “Diagnosis” column in The Times Magazine. Students might read some of these before creating their patient profiles.

When profiles are complete, post them around the room and have students circulate and jot down notes. They then return to their groups and work together to diagnose the patients’ vitamin deficiencies, using materials about vitamins and minerals . Groups should also recommend a course of action, like eating more of a certain type of food or taking a supplement, and provide justification for the suggestions.

When groups have finished, invite groups to weigh in on each “case” and lead a short discussion. Ask: Were the diagnoses correct, according to the creators of the profiles? Were the recommendations for patients appropriate? Is it difficult to diagnose vitamin deficiencies? Why or why not? Were any of the diagnoses incorrect? Do some deficiencies have similar risk factors and symptoms? What additional information would you need to make definitive diagnoses?

Return to the supplement packaging and food labels. Ask: Why do people take supplements? What risks are associated with them? Can we get proper nutrition from eating food alone?

Going Further | Students keep food diaries for one week, documenting everything they eat. They then use resources like the vitamin and mineral charts at TeensHealth to determine which vitamins and minerals are contained in the foods they have consumed. They might consider consulting a pediatrician or nutritionist to guide their examination of their vitamin and mineral intake.

Alternatively, students interview the director of their school meal program to discuss the vitamin and mineral content in this week’s school lunches. Are there any United States Department of Agriculture school lunch requirements regarding vitamins and minerals ? How does the school staff meet the requirements? What criticisms have been made of national school meal requirements?

Standards | This lesson is correlated to McREL’s national standards (it can also be aligned to the new Common Core State Standards ):

Health 1. Knows the availability and effective use of health services, products and information. 6. Understands essential concepts about nutrition and diet. 7. Knows how to maintain and promote personal health. 8. Knows essential concepts about the prevention and control of disease.

Science 11. Understands the nature of scientific knowledge. 12. Understands the nature of scientific inquiry. 13. Understands the scientific enterprise.

Language Arts 4. Gathers and uses information for research purposes. 5. Uses the general skills and strategies of the reading process. 7. Uses skills and strategies to read a variety of informational texts. 8. Uses listening and speaking strategies for different purposes.

Thinking and Reasoning 1. Understands and applies the basic principles of presenting an argument. 2. Understands and applies basic principles of logic and reasoning. 6. Applies decision-making techniques.

Working With Others 1. Contributes to the overall effort of a group. 4. Displays effective interpersonal communication skills.

Comments are no longer being accepted.

This exercise is a misguided attempt at teaching nutrition because it potentially reinforces the notion that supplements are a valid source of vitamins, minerals, anti-oxidants, and other nutrients.

By focusing on supplement pills and packaged foods, you are suggesting that they are a valid first source of such essential nutrients, when in fact, natural unprocessed food such as fruits and vegetables should be the primary source.

Vitamin deficiencies should also only be treated once identified with blood tests because otherwise there is a risk of overdose and toxicity with certain vitamins. For example, a blood measurement of Vitamin D above the 125 ng/ml can be toxic.

Hello Steven – Thank you for writing in. The warm-up activity is meant to prompt students to reflect and think critically about their associations with, and claims about, vitamins. In the main activity, students do research into good sources of vitamins and minerals as well as the symptoms associated with deficiencies. The lesson also suggests an activity in which students keep a food diary and then analyze it, perhaps with the guidance of a nutritionist or physician, for their natural vitamin and nutrient intake. It certainly does not suggest that anyone take a course of action with respect to their health – it is merely meant to help students become more educated about vitamins overall. – Holly

I have got a problem of white sore scratches that comes out at sides of my mouth and they are irritating me, what I want to know what can I do about them. I went to 2 different pharmacies and they told me its lack of vitamin in my body. I want to know which vitamin is that and what do I have to eat.

Look up “Angular Chelitis” or chelosis on wikipedia and see if that is what you are talking about. There is a possibility of a deficiency with this chelosis. Read about the food sources of riboflavin, iron and zinc and see if you are eating enough of those foods.

Choosing a healthy diet plan is imperative to reduce the risk of chronic diseases, overweight and obesity through improved nutrition and physical exercise.

Check out how students from Lehigh University are conducting research to develop handheld sensors and disposable chips that will detect Vitamin A deficiency. (It is in the second-to-last section in the article). //bit.ly/ZUNgym

What's Next

For healthy adults, taking multivitamins daily is not associated with a lower risk of death

• Posted: June 26, 2024

240-760-6600

A new study questions the benefits of regular multivitamin use.

A large analysis of data from nearly 400,000 healthy U.S. adults followed for more than 20 years has found no association between regular multivitamin use and lower risk of death. The study, led by researchers at the National Institutes of Health’s National Cancer Institute, was published June 26, 2024, in JAMA Network Open .

Many adults in the United States take multivitamins with the hope of improving their health. However, the benefits and harms of regular multivitamin use remain unclear. Previous studies of multivitamin use and mortality have yielded mixed results and been limited by short follow-up times.

To more deeply explore the relationship between long-term regular multivitamin use and overall mortality and death from cardiovascular disease and cancer, the researchers analyzed data from three large, geographically diverse prospective studies involving a total of 390,124 U.S. adults who were followed for more than 20 years. The participants included in this analysis were generally healthy, with no history of cancer or other chronic diseases.

Because the study population was so large and included lengthy follow-up and extensive information on demographics and lifestyle factors, the researchers were able to mitigate the effects of possible biases that may have influenced the findings of other studies. For example, people who use multivitamins may have healthier lifestyles in general, and sicker patients may be more likely to increase their use of multivitamins.

The analysis showed that people who took daily multivitamins did not have a lower risk of death from any cause than people who took no multivitamins. There were also no differences in mortality from cancer, heart disease, or cerebrovascular diseases. The results were adjusted for factors such as race and ethnicity, education, and diet quality. 

The researchers noted that it is important to evaluate multivitamin use and risk of death among different kinds of populations, such as those with documented nutritional deficiencies, as well as the potential impact of regular multivitamin use on other health conditions associated with aging.

Erikka Loftfield, Ph.D., M.P.H., Division of Cancer Epidemiology and Genetics, National Cancer Institute

“Multivitamin Use and Mortality Risk in 3 Prospective US Cohorts” appears June 26, 2024, in JAMA Network Open .

About the National Cancer Institute (NCI):  NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCI’s intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Center—the world’s largest research hospital. Learn more about the intramural research done in NCI’s Division of Cancer Epidemiology and Genetics . For more information about cancer, please visit the NCI website at  cancer.gov  or call NCI’s contact center at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  nih.gov .

Watch CBS News

Taking a daily multivitamin does not help you live longer, study finds

By Sara Moniuszko

Edited By Sarah Lynch Baldwin

June 27, 2024 / 11:20 AM EDT / CBS News

Many adults take daily multivitamins in hopes of bettering their health. But a new study is calling their usefulness into question.

In the study, published in JAMA Network Open Wednesday, researchers analyzed data from nearly 400,000 healthy U.S. adults followed for more than 20 years and found no association between regular multivitamin use and lower risk of death.

The study was led by researchers from National Institutes of Health's National Cancer Institute, who noted the participants studied were generally healthy, meaning more research is needed for populations with nutritional deficiencies.

"What we're seeing is whether it's death from cancer, from heart disease, from stroke, we're not seeing a benefit from taking multivitamins," Dr. Céline Gounder, CBS News medical contributor and editor-at-large for public health at KFF Health News, said of the study on "CBS Mornings" Thursday .

In general, it's better to get vitamins from whole foods like fruits and vegetables, she added. But the potential benefits of taking a multivitamin also depend on the person.

"There are some people who are at risk for vitamin deficiencies, so people with chronic kidney disease, people who might not absorb vitamins because they've had bariatric surgery or because they have GI issues," she said.

People who are pregnant, for example, should be taking a multivitamin with folate to prevent defects, Gounder said.

"There are certain populations where it makes sense, but not everybody," she said.

In a statement to CBS News, the Council for Responsible Nutrition, a trade organization for vitamins, said the study fails to recognize the range of health benefits of multivitamin use.

Gounder noted the study looked only at risk of death, not other potential benefits.

"There is data, for example, that taking a multivitamin can reduce your cognitive decline as you get older, so your memory and so on. There's also evidence, for example, macular degeneration, that you can head off with certain vitamins," she explained. "So it depends on what you're looking at. Are you looking at mortality, risk of death? Are you looking at certain other specific disease outcomes? I think that's where, again, for certain populations, it may make sense to be taking a vitamin."

• Supplements

Sara Moniuszko is a health and lifestyle reporter at CBSNews.com. Previously, she wrote for USA Today, where she was selected to help launch the newspaper's wellness vertical. She now covers breaking and trending news for CBS News' HealthWatch.

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Daily multivitamin supplements don't help you live longer, study shows

The study analyzed data from nearly 400,000 healthy adults over 20 years.

Multivitamin supplements have become a routine addition to many Americans' diets, with as many as 1 in 3 U.S. adults consuming them regularly, but are these daily doses improving overall health and longevity?

A study from the National Institutes of Health (NIH) published Wednesday found that multivitamins won't help extend your life, with researchers reporting, "multivitamin use to improve longevity is not supported."

MORE: 22 sets of twins tried both vegan and meat diets. Here's how their health fared

The study analyzed data from nearly 400,000 adults over 20 years. Participants had a median age of 61.5 years old and were generally healthy, with no history of chronic diseases, according to the study published in JAMA Network Open.

The study found no evidence that daily multivitamin consumption reduced the risk of death from conditions such as heart disease or cancer.

Rather than living longer, otherwise healthy people who took daily multivitamins were slightly more likely (4%) than non-users to die in the study period, according to researchers.

Researchers reported nearly 165,000 deaths occurring during the follow-up period of the study, out of the initial group of 390,000 participants.

MORE: Vitamins, minerals and fad diets? ‘Don’t waste your money': Study author

The study, however, did not analyze data from people with pre-existing vitamin deficiencies.

"What this study shows is that, generally, multivitamins aren't going to help you live longer," Dr. Jade A Cobern, MD, MPH, board-certified physician in pediatrics and general preventive medicine, told ABC News.

"Even though the cost of many multivitamins isn't high, this is still an expense that many people can be spared from," Cobern said.

Cobern explained that, when possible, it's best to get vitamins and minerals from your diet, focusing on increasing vegetable intake and limiting red meat consumption, rather than relying solely on a supplement.

"We can all likely benefit from adding more vegetables and whole grains or legumes into our diets, reducing red meat intake, decreasing our sedentary time and reducing alcohol intake," Cobern suggested.

MORE: What to know about the Mediterranean diet

While taking a multivitamin supplement does not increase longevity, Cobern said it's important for people to ask their doctor to know if a multivitamin or specific vitamin supplement would be helpful in their case, based on their health history and diet.

"If a doctor prescribes a vitamin for someone, it's important to take that medication," Cobern said, adding, "I recommend everyone get routine health checkups and to talk to doctors about your dietary history and disclose any supplements you're taking in those appointments."

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Daily Multivitamin Use In Healthy Adults Doesn’t Decrease Risk Of Death, Study Suggests: What To Know About Pros And Cons Of Multivitamins

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Researchers suggest Americans get their nutrients from food rather than supplements after a new study found daily multivitamin use doesn’t decrease the risk of death, which is the newest research in the long debated topic about the benefits of multivitamins.

a handful of vitamins.

The researchers used the health records of over 390,000 participants with a median age of 61.5 years who were generally healthy, had no history of chronic disease and were followed for over 20 years, according to the study published Wednesday in JAMA Network Open.

People with healthier lifestyles and those who are sick may have an increased chance of taking multivitamins, so the researchers mitigated these effects so they didn’t have an impact on the study’s results.

The group of participants who took daily multivitamins had lower BMIs and better sleep quality than the participants who didn’t use daily multivitamins, and were slightly more likely to be college educated.

However, the study found those who took daily multivitamins had 4% higher mortality risk for all causes, though there were no differences in mortality risks from cancer, heart disease or cerebrovascular diseases like stroke, aneurysms.

Since the study’s population consisted of generally healthy adults, the researchers noted further research must be done to include other groups like people with nutrient deficiencies, and to evaluate the potential impact of regular multivitamin use on other health conditions associated with aging.

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Crucial Quote

“Refocusing nutrition interventions on food, rather than supplements, may provide the mortality benefits that multivitamins cannot deliver,” researchers with the National Cancer Institute wrote as part of a commentary on the JAMA study. “Vegetables, fruits, legumes and cereal grains are staples in areas of remarkable longevity.”

Is There Any Evidence Multivitamins Work?

Though the benefits of multivitamins have been a long debated topic, over 31% of Americans 19 years and older take multivitamins . Men who take daily multivitamins may have an 8% lower cancer risk and a lower risk of developing cataracts, according to a previous JAMA study . Several studies have found multivitamins can improve memory in older adults. Multivitamins may also offer benefits for those with mood disorders. Older male participants who took multivitamins over an eight-week period had significant reductions in depression and anxiety compared to the placebo group, according to research published in Human Psychopharmacology: Clinical & Experimental.

What Vitamins May Actually Work?

Taking standalone vitamins may provide some benefits. Doctors recommend patients with vitamin deficiencies like vitamin D take supplements, especially those with lactose intolerance, milk allergies, fat absorption issues and people with darker skin tones and more melanin, according to Yale Medicine. Vitamins are also useful during pregnancy: Pregnant women can benefit from taking prenatal vitamins containing vitamin D and calcium to help the baby’s teeth and bones grow, according to the Mayo Clinic.

Are Multivitamins Regulated By The Fda?

Multivitamins, herbs, minerals and other dietary supplements are not approved by the Food and Drug Administration, though the FDA regulates them. However, most of the regulation happens after they hit the shelves, and many companies manufacture and sell multivitamins without notifying the FDA.

$177.5 billion. That’s how much the global dietary supplement industry was worth in 2023, according to market research firm Grand View Research. This number is expected to grow by 9% between 2024 and 2030.

Key Background

The U.S. Preventive Services Task Force concluded in 2022 there was “little to no benefit” in taking vitamins and mineral supplements, and recommended against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. Multivitamin use did not reduce the risk of cancer or heart disease in participants in a 2021 study by the USPSTF. Researchers also found taking iron supplements—which is added to many multivitamins—can lead to iron overload and increase the risk of diabetes, dementia and heart disease.

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Deaths Linked to Japanese Supplement Suddenly Rise to 80

The case, involving a supplement intended to reduce cholesterol, has put attention on how companies are allowed to self-report claims about their products.

By River Akira Davis and Hisako Ueno

Reporting from Tokyo

A Japanese pharmaceutical company is investigating 80 deaths possibly linked to a yeast-containing supplement it sells in Japan, the country’s health ministry said Friday, in a shocking increase from an earlier revelation that is focusing attention on how supplements are regulated.

The company, Kobayashi Pharmaceutical, in March had reported five deaths potentially linked to its CholesteHelp rice and red-yeast pills. Japanese government health officials said the supplement, which claimed to help reduce cholesterol, contained puberulic acid, a highly toxic compound that is a product of mold.

In response to the sudden surge in reported deaths, Health Minister Keizo Takemi said it was “extremely regrettable” that Kobayashi Pharmaceutical had not updated the ministry sooner. The company, which is based in Osaka, had not provided new information on deaths potentially linked to CholesteHelp since March.

Since then, Kobayashi Pharmaceutical has received reports that 1,656 people sought medical advice for CholesteHelp-related health concerns, and 289 people have been hospitalized, the company reported. CholesteHelp has been recalled in Japan and China, the only countries the supplement was sold in, according to a spokeswoman for Kobayashi Pharmaceutical.

Mr. Takemi said the government would step in to take a more active role in investigating, after allowing the company to self-report its findings. “We cannot leave Kobayashi Pharmaceutical alone to handle it anymore,” he said.

Kobayashi Pharmaceutical was founded in 1919. While it is not one of Japan’s top pharmaceutical companies, it produces a variety of supplements and health products such as hand warmers and air fresheners, some of which are sold in the United States and elsewhere in Asia.

Quality-control guidelines related to supplements and other products making health claims were established in Japan in 2015. Those regulations are perceived to be less stringent than Japan’s rules governing prescription medications. Companies are typically responsible for self-reporting compliance rather than undergoing state screenings.

In the United States, where the dietary supplement market is booming , organizations like the American Medical Association have urged the Food and Drug Administration to introduce stricter rules to ensure supplement safety. Dietary supplements marketed for weight loss and muscle building have been linked with a number of deaths in the United States.

At a news conference in March when the potentially CholesteHelp-related deaths were first disclosed, the president of Kobayashi Pharmaceutical, Akihiro Kobayashi, apologized for not providing information sooner and said he had “no words.”

River Akira Davis covers Japan, including its economy and businesses, and is based in Tokyo. More about River Akira Davis

Hisako Ueno is a reporter and researcher based in Tokyo, writing on Japanese politics, business, labor, gender and culture. More about Hisako Ueno

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Case Report

Severe vitamin c deficiency in a child newly diagnosed with t-cell all due to nutrient gap.

A 10-year-old boy developed a perifollicular rash during interim maintenance of T-Cell acute lymphoblastic leukaemia. Differential diagnoses included drug reaction and inflammatory process. Before diagnosis, the patient had a limited diet—low in vegetables and fruits—due to selective eating, with later anorexia and taste aversions due to chemotherapy treatment. Despite nutritional counselling and starting a multivitamin, the patient incurred severe weight loss (18.5% of his usual body weight). Serum levels of ascorbic acid were non-detectable, at <5 μmol/L, indicative of vitamin C deficiency. The patient began vitamin C supplementation containing 125 mg ascorbic acid three times a day for 7 days, then 125 mg once daily for 3 months to normalise serum vitamin C. After ascorbic acid treatment was completed, the patient started a complete multivitamin and made efforts to eat fruits and vegetables rich in vitamin C. His serum ascorbic acid concentrations normalised to 52 μmol/L 3 months after receiving supplementation.

Inadequate energy intake is an undesirable yet frequently observed complication in children with leukaemia receiving chemotherapy treatment. Chronic malnutrition in this population may result in depletion of serum concentrations of several nutrients, affecting immune status, growth and wound healing.

Vitamin C (ascorbic acid) is a necessary nutrient for immune function, cell regeneration and growth. Dietary sources of vitamin C include fruits and vegetables, with orange juice, guava, red and yellow peppers, and papaya serving as rich sources.

Clinical manifestations of vitamin C deficiency or scurvy include gingival inflammation and bleeding, perifollicular petechiae and bone pain. 1

The objective of this article is to describe the association between chronically low vitamin C dietary intake and dermatological manifestations of vitamin C deficiency in a paediatric patient with leukaemia.

Case presentation

We report a case of a 10-year-old boy with T-Cell acute lymphoblastic leukaemia (ALL) in the interim maintenance phase of therapy. He originally presented the ALL with small raised lesions on his scalp, which were biopsied and found to be T-cell ALL. Bone marrow confirmed the diagnosis. He was started on chemotherapy and tolerated induction relatively well. When he was in the interim maintenance phase of therapy, he presented to hospital with bilateral perifollicular petechiae to the arms, knees and legs, which progressed into hyperpigmentation suspected to be related to a drug reaction or inflammatory process ( figure 1 ). He was otherwise well, with no other significant symptoms.

Leg showing perifollicular petechial rash.

Since diagnosis, the patient had consistently poor energy intake, specifically limited in vegetable and fruit consumption, and, as a result, incurred a severe weight loss of 18.5% of his usual body weight. Despite dietary education and recommendations to increase overall energy intake, and specifically dietary consumption of vegetables and fruits, the patient was unable to improve his energy intake.

Investigations

Dermatology service personnel were consulted and, post clinical assessment, requested a serum level of vitamin C for the patient, as they felt the rash was pathognomonic for vitamin C deficiency. The resultant blood work showed low vitamin C levels with serum concentrations of <5 μmol/L, indicative of vitamin C deficiency. All other investigations were normal.

Differential diagnosis

• Drug reaction
• Inflammatory process
• Folliculitis.

The patient was placed on treatment doses of oral supplemental ascorbic acid: 125 mg three times a day for 7 days, then once daily for a period of 3 months to normalise serum levels of vitamin C.

Outcome and follow-up

Serum vitamin C levels were checked in follow-up and both values resulted as sufficient:

• Three months postsupplement administration: 52 μmol/L
• Six months postsupplement administration: 84 μmol/L

A serum level ≥25 μmol/L is considered a sufficient serum level of vitamin C.

The vitamin C deficiency treatment was completed and the symptoms resolved. The patient then made a concerted effort to include food sources rich in vitamin C into his diet.

Vitamin C deficiency is rare. Although uncommon, some case studies have documented reports of children with scurvy who have poor socioeconomic status, restrictive religious practices, developmental delays such as autism or cerebral palsy, or in whom overall nutritional intake of vegetables and fruits is limited. 1–3

Altered nutritional status is common in children at diagnosis and during treatment for cancer. Protein energy malnutrition is frequently seen with significant weight loss, as can occur at diagnosis of cancer, and is associated with deficiencies in essential nutrients and vitamins. A recent review of paediatric patients at diagnosis of cancer found that the vitamin C level was significantly decreased compared with controls, and this decrease continued at 6 months following diagnosis. 4

Overall, patients at diagnosis are at risk of nutrient deficiencies, including of vitamin C, and this must be considered in their care.

Learning points

• Dietary screening/monitoring plays a crucial role in detecting gaps in nutrient intake. Nutrition education can impart an important role in preventing nutrient deficiencies, deficits that can compromise the health status of the patient.
• Patients diagnosed or being treated for cancer can have significant nutrient deficiencies and these should be screened for if there is a gap in nutrient intake, as they are at risk for deficiency of essential vitamins.
• Although rare, vitamin C deficiency exists in paediatric populations within Canada.

Competing interests: None declared.

Patient consent: Obtained.

Provenance and peer review: Not commissioned; externally peer reviewed.