case study of vitamin c deficiency

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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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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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TH made substantial contributions to the conception and interpretation of the study and participated in the writing and editing of the manuscript. WA collected data, reviewed the literature, and assisted in manuscript preparation. KW participated in the conception of the study, literature review, and writing and preparation of the manuscript. All authors read and approved the final manuscript and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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The original version of this article was revised: the authors reported that an out-of-date version of Figure 1 had been incorporated in the published article.

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Additional file 1:.

List of the 62 studies describing 77 cases of children with scurvy English. (DOCX 21 kb)

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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 Case Of Vitamin C Deficiency Manifesting With Easy Bruising: Suggestion For a Supplementation Protocol

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Aisha Zaidi , Padmini Moffett; A Case Of Vitamin C Deficiency Manifesting With Easy Bruising: Suggestion For a Supplementation Protocol. Blood 2013; 122 (21): 4743. doi: https://doi.org/10.1182/blood.V122.21.4743.4743

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Contrary to most animals which are capable of obtaining ascorbic acid (vitamin C) by metabolizing glucose, humans require an exogenous source of vitamin C. It is a water-soluble vitamin found in various foods, including citrus fruits (oranges, lemons, grapefruit), green vegetables (peppers, broccoli, cabbage), tomatoes, and potatoes. It is essential for growth and repair of tissues, particularly blood vessels. Deficiency of vitamin C is relatively rare; the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) found approximately 13% of the US population to be vitamin C deficient. Smoking cigarettes lowers the amount of vitamin C in the body, so smokers are at a higher risk of deficiency. Additionally, alcoholics, the elderly, patients with psychiatric disorders and individuals who experience social isolation are also at risk. Symptoms can manifest after 3 months of deficient intake of vitamin C -containing foods. Since ascorbic acid is required for collagen synthesis, deficiency usually manifests with bleeding gums, ecchymoses, petechiae, coiled hairs and hyperkeratosis. Diagnosis can be established when plasma levels of vitamin C fall below 0.2mg/dl. There are currently no evidence based guidelines for supplementation once low levels are detected. We describe a case of a 33 year old Caucasian female seen in our clinic for easy bruising of 10 years duration. She would wake up in the morning with bruised arms and legs without any inciting trauma. She denied prolonged bleeding after dental extractions, frequent nose bleeds, menorrhagia any genitounrinary or gastrointestinal blood loss. Her exam revealed ecchymoses on her arms and legs with no evidence of perifollicular hemorrhage or gingival hyperplasia. Workup including CBC, Coagulation profile and Von Willibrand factor levels were all within normal limits. She had a vitamin C level of 0.1mg/dl. She was subsequently advised to increase vitamin C intake through fruits and vegetable and was started on vitamin C supplementation with 500mg twice a day for four weeks. Her repeat vitamin C level on her one month follow up was noted to be 1.9mg/dl. She noticed complete resolution of her symptoms. This case illustrates the fact that vitamin C deficiency should be excluded in adults presenting with bruising. It also offers a supplementation regimen that resulted in improvement of clinical symptoms as well as laboratory value normalization.

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• Clinical Case Report
• Published: 03 April 2013

Severe vitamin C deficiency in a critically ill adult: a case report

• S Doll 1 &
• B Ricou 1  

European Journal of Clinical Nutrition volume  67 ,  pages 881–882 ( 2013 ) Cite this article

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Scurvy, a severe form of vitamin C deficiency, killed scores of people until its cause and treatment were firmly established at the end of the eighteenth century. Since then, cases have surged periodically around the world, mostly in developing countries and during times of war and famine. In developed countries, scurvy is still endemic and evidence is growing that vitamin C deficiency might affect up to 30 percent of the population. Low socio-economic status, alcoholism, severe psychiatric illness leading to poor nutrition and critical illness are significant risk factors. We hereby report the case of a patient admitted in a Swiss intensive care unit of a tertiary teaching hospital and presenting with clinical signs and symptoms of severe vitamin C deficiency.

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Doll, S., Ricou, B. Severe vitamin C deficiency in a critically ill adult: a case report. Eur J Clin Nutr 67 , 881–882 (2013). https://doi.org/10.1038/ejcn.2013.42

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• Published: 18 June 2020

The neuropsychiatric effects of vitamin C deficiency: a systematic review

• David Plevin   ORCID: orcid.org/0000-0003-3088-7434 1 , 2 , 3 &
• Cherrie Galletly 2 , 4  

BMC Psychiatry volume  20 , Article number:  315 ( 2020 ) Cite this article

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Vitamin C deficiency may be more common than is generally assumed, and the association between vitamin C deficiency and adverse psychiatric effects has been known for centuries. This paper aims to systematically review the evidence base for the neuropsychiatric effects of vitamin C deficiency.

Relevant studies were identified via systematic literature review.

Nine studies of vitamin C deficiency, including subjects both with and without the associated physical manifestations of scurvy, were included in this review. Vitamin C deficiency, including scurvy, has been linked to depression and cognitive impairment. No effect on affective or non-affective psychosis was identified.

Conclusions

Disparate measurement techniques for vitamin C, and differing definitions of vitamin C deficiency were apparent, complicating comparisons between studies. However, there is evidence suggesting that vitamin C deficiency is related to adverse mood and cognitive effects. The vitamin C blood levels associated with depression and cognitive impairment are higher than those implicated in clinical manifestations of scurvy. While laboratory testing for ascorbic acid can be practically difficult, these findings nonetheless suggest that mental health clinicians should be alerted to the possibility of vitamin C deficiency in patients with depression or cognitive impairment. Vitamin C replacement is inexpensive and easy to deliver, although as of yet there are no outcome studies investigating the neuropsychiatric impact of vitamin C replacement in those who are deficient.

Peer Review reports

Humans, along with guinea pigs, some bats and some other primates, are among the few animals that cannot synthesise vitamin C, which, as summarised in Fig.  1 , has essential biological roles across a number of organ and tissue systems. Vitamin C refers to both ascorbic acid and the oxidised form of this molecule, dehydroascorbic acid, while ascorbate refers to the anion of ascorbic acid [ 1 ]. Vitamin C deficiency can result in scurvy, which manifests as fatigue, impaired bone growth in children, and, as a consequence of the failure of connective tissue to properly form, bleeding, including perifollicular haemorrhages, petechiae, ecchymoses and gingival bleeding [ 2 ].

Sources: [ 1 , 2 , 3 , 4 ]

Vitamin C has a significant role in modulating neurotransmitter synthesis and release in the brain. The functions of vitamin C in the brain include acting as a co-factor for dopamine beta-hydroxylase in the conversion of dopamine to noradrenaline, involvement in the modulation of both dopaminergic and glutamatergic neurotransmission, and regulation of catecholamine and acetylcholine release from synaptic vesicles. Vitamin C also has antioxidant properties in the brain, including limiting the damage caused by ischaemia-reperfusion injury and protecting against glutamate excitotoxicity [ 5 , 6 ].

Physiological intake and storage of vitamin C may be measured by both plasma and leucocyte levels. While plasma ascorbate is reflective of recent intake, it is a less reliable indicator of tissue and body stores than leucocyte ascorbic acid. Nonetheless, in clinical practice, measurement of plasma ascorbate is more common. Compared to measurement of ascorbic acid in leucocytes, measurement of plasma ascorbate requires a smaller volume of plasma, is less technically difficult to undertake, and is not affected by changing numbers of leucocytes [ 1 ].

A number of studies have investigated the point at which vitamin C deficiency manifests clinically. In five healthy prison volunteers, notable signs of clinical scurvy appeared once the whole blood levels of ascorbate had decreased to 17 μmol/L or below [ 7 ]. In a series of seven scurvy cases in Boston, the highest plasma ascorbic acid level among the cases was 10.2 μmol/L [ 8 ]. Finally, in a cohort of seven healthy young male volunteers with vitamin C levels depleted to between 5 and 10 μmol/L, a daily dose of 30 mg vitamin C led to a mean steady state plasma ascorbic acid of 6.9 ± 0.5 to 11.7 ± 0.9 μmol/L. After steady state was reached, a daily dose of 60 mg vitamin C, which was the recommended dietary allowance in the study, resulted in a steady state range of 14.9 ± 1.0 to 58.8 ± 3.1 μmol/L. With respect to clinical symptoms of vitamin C deficiency, six of the seven subjects reported fatigue and/or irritability at the nadir of the vitamin C depletion. In three subjects, these symptoms resolved within 1 week of the 30 mg daily dose, and in the other three subjects, the symptoms resolved within 1 week of the 60 mg daily dose [ 9 ]. It is pertinent to note that the earlier studies are likely to be inaccurate in measurement of vitamin C, as older colorimetric assays were less specific for vitamin C than the high-performance liquid chromatography assay utilised by Levine and colleagues [ 10 ], and indeed the vitamin C levels seen in the latter study are lower than in the earlier studies.

Most reference intervals, however, utilise a higher cut-off to classify vitamin C deficiency. One clinical chemistry text [ 1 ] gives the reference interval for serum vitamin C as 23 to 85 μmol/L, and the definition of deficiency ≤11 μmol/L. The reference interval used by SA Pathology (South Australia) is 26 to 85 μmol/L, and the Royal College of Pathologists of Australasia [ 11 ] notes that, while the reference interval depends on the assay used, the interval is generally between 30 to 80 μmol/L.

There is a sigmoidal relationship between oral vitamin C intake and plasma levels of vitamin C. Relatively small changes in vitamin C intake, therefore, may lead to large changes in plasma vitamin C levels. In one study, oral intakes of 30 mg vitamin C daily resulted in median plasma levels of less than 20 μmol/L, but increasing the intake to 60 mg resulted in median plasma levels of 74 μmol/L [ 12 ]. Another study noted that the steep portion of the sigmoidal dose-concentration curve was at daily doses between 30 and 100 mg [ 9 ].

It is generally assumed that vitamin C deficiency is rare, as vitamin C is plentiful in fresh fruit and vegetables. However, in a population-level study in the United States (n = 7277), the prevalence of vitamin C deficiency in persons aged 6 years or older was 7.1% (95% confidence limits, 5.3 to 9.2%). In this study, vitamin C deficiency was defined as serum concentrations < 11.4 μmol/L; this value was chosen as it was considered to reflect the level at which scurvy may clinically manifest [ 13 ]. In a low-income population in the UK, 25.3% of men and 16.1% of women met the criteria for vitamin C deficiency (levels lower than 11 μmol/L) [ 14 ]. In an Australian mental health setting – a cohort of patients attending a South Australian clozapine clinic – over 50% of patients had vitamin C levels lower than 26 μmol/L [ 15 ]. Vitamin C deficiency is increasingly noticed in other medical specialties. In a New South Wales cohort of patients attending a diabetes clinic, presenting with foot ulcers with delayed healing and/or a low-quality diet, 7 of the 11 patients tested were deficient in vitamin C (defined as ≤40 μmol/L). The median vitamin C level in the deficient group was 15 μmol/L. Furthermore, in the patients with foot ulcers, when vitamin C supplementation was commenced, wound healing began in five of those six patients within two to 3 weeks [ 16 ].

Poor diet is common in people with psychiatric disorders [ 17 ], and so it is possible that vitamin C deficiency might also be more prevalent among psychiatric populations than is generally assumed. The psychiatric effects of vitamin C deficiency have long been appreciated. In 1753, the Scottish physician, James Lind, wrote in his seminal treatise on scurvy that the late stage of this disease was associated with “ affectio hypochondriaca , or the most confirmed melancholy and despondency of mind” [ 18 ]. Even earlier, in 1617, the English military surgeon John Woodall wrote that “a generall lazinesse” was a sign of scurvy [ 19 ].

This paper reviews the available evidence on neuropsychiatric effects of vitamin C deficiency. This is important as vitamin C supplements are inexpensive and readily available, if dietary interventions are not feasible or are unsuccessful.

Literature search

This systematic review was registered through PROSPERO (registration number CRD42018107781). The following databases were searched via PubMed, Elsevier and Ovid platforms, with number of English-language papers found in parentheses:

Medline (1946 to September 2019) (n = 207)

Embase (1974 to September 2019) (n = 75, unique to EMBASE)

Cochrane Library (to September 2019) (nil relevant papers)

PsycInfo (1806 to September 2019) (n = 356)

Only studies published in English were considered for inclusion in this review. The search was not restricted to any particular time frame; the studies included were from the inception of the databases to 4 September 2019. The search strategies for Medline, Embase and PsycInfo are described in Table  1 . In Medline and Embase, the search strategy was to include all terms for vitamin C deficiency, and combine, using the Boolean operator ‘AND’, all terms for neuropsychiatric effects. In PsycInfo, the search strategy only included all terms for vitamin C deficiency; given the relatively small number of hits for these, terms for neuropsychiatric effects were not specifically searched.

The titles and abstracts of all articles were reviewed by a single reviewer (DP) and independently verified by a second reviewer (CG) to identify studies that assessed the effect of vitamin C deficiency on behavior, cognitive functioning and psychiatric diagnoses such as anxiety, depression and schizophrenia.

Data were extracted from papers included in the review using the standardised data extraction tool from the Joanna Briggs Institute (Appendix II in the review protocol published online on the PROSPERO website). The data extracted included specific details about the populations, interventions (e.g. type, intensity and duration), outcomes and study methods.

Data extraction was completed by a single reviewer (DP), with independent verification by a second reviewer (CG) to minimise bias and potential errors in data extraction. Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the online review using standardised critical appraisal instruments from the Joanna Briggs Institute (Appendix I in the online review protocol). Divergent opinions to inclusion were to be resolved by majority opinion with a third independent reviewer, but this was not required. The systematic review was reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.

Three small studies, conducted between 1968 and 2011, with participant numbers ranging from 4 to 7 (mean, 5.7), assessed the neuropsychiatric effects of vitamin C deficiency in individuals with physical manifestations of scurvy. In six generally much larger studies, conducted between 1971 and 2019, vitamin C deficiency was assessed in individuals who did not necessarily present with physical manifestations of scurvy. Participant numbers in these studies ranged from 5 to 921 (mean, 280). The assessment of vitamin C deficiency varied markedly between studies, ranging from moderate-to-severe deficiency defined as a plasma level of 11.91 μmol/L or less, to “inadequate” vitamin C levels being defined as a plasma level of less than 50 μmol/L. Plasma was the blood component typically analysed in studies, but serum and whole blood were also analysed.

Overall, vitamin C deficiency has been associated with depression and cognitive impairment. The systematic review did not indicate any relationship between vitamin C deficiency and schizophrenia or bipolar disorder. Table  2 summarises the studies included in this review. In this table, all blood, serum or plasma levels of vitamin C have been standardised to SI units [ 20 ].

Assessment of bias was conducted on a qualitative basis. Given the paucity of studies available, the majority of identified studies were included in this review. The published case series all had significant methodological deficiencies, including provision of minimal information about the neuropsychiatric outcomes of interest at the time of the report or following vitamin C replacement. The cross-sectional studies were of higher quality, although, notably, two studies did not account for potential confounding factors when investigating the relationship between vitamin C deficiency and neuropsychiatric outcomes. The sole study which was neither a case series nor a cross-sectional study [ 21 ] involved experimental induction of scurvy by provision of a vitamin C-depleted diet in a small group of male prisoners, and did not use a control group, nor were neuropsychiatric outcomes assessed prior to the commencement of the depletion of vitamin C.

Two case series reported the presence of depression or depression-like symptoms in patients with scurvy. A severe depressive state was described in all members of a 1968 cohort of seven dermatology patients with chronic scurvy. The depression resolved within a few days of ascorbic acid replacement therapy [ 22 ]. Four patients in Martinique with scurvy (aged 34 to 77 years; 1 female, 3 male), reported in 2011, all had “intense asthenia”, and one patient had depression. All patients in this cohort had an ascorbic acid level below 3 μmol/L [ 23 ].

In 1971, an experimental cohort of five healthy prisoners, aged 26 to 52 years, with experimentally-induced ascorbic acid deficiency, was divided into groups according to the level of ascorbic acid. It was reported that, for individual patients, vitamin C depletion led to statistically significant higher scores on measures of social inversion and the so-called “neurotic triad” (hypochondriasis, depression and hysteria) on the Minnesota Multiphasic Personality Inventory, and that repletion of vitamin C led to a return to baseline measures [ 21 ]. In a similar fashion to the case series of dermatology patients described earlier, subjects in this study were replenished with varying levels of vitamin C, and the return to baseline measures of personality occurred even in those subjects with the lowest vitamin C daily dose (6.5 mg daily) during the repletion phase.

Two cross-sectional studies quantified mood symptoms in subjects divided into lower and higher vitamin C plasma or serum concentrations. Both of these studies, in which subjects did not necessarily evince the physical manifestations of scurvy, provide further evidence of a link between low vitamin C status and depression. A 2018 study reported on a cohort of male students in Christchurch, New Zealand (n = 139, aged 18 to 35 years) was divided into two groups based on their fasting plasma vitamin C concentration: adequate (≥ 50 μmol/L, n = 99) and inadequate (< 50 μmol/L, n = 40). The level for “inadequate” was considerably higher than the lower limit of the normal range endorsed by the Royal College of Pathologists of Australasia, which is about 30 μmol/L. Using the Profile of Mood States (POMS) questionnaire, participants with inadequate vitamin C status had significantly higher POMS scores (i.e., greater disturbance) for total mood disturbance (p = 0.024), depression (p = 0.012) and confusion (p = 0.022), compared to those with adequate vitamin C status [ 24 ]. In a cohort of 129 women in Italy in 1990, aged 60 to 90 years, depression was assessed using the depression section of the Inventory of Psychic and Somatic Complaints-Elderly. The cohort was divided into two groups, based on their serum ascorbic acid level - the low level group (serum ascorbic acid < 23 μmol/L, n = 27) and high serum ascorbic acid group (≥ 23 μmol/L, n = 102). There was a statistically significantly higher mean depression score in the low serum ascorbic acid group compared to the high serum ascorbic acid group (1.96 ± 0.66 vs. 1.57 ± 0.56, p < 0.005) [ 25 ].

Cognitive impairment

In a case series published in 1971, a degree of confusion was noted in seven elderly women (age range, 70 to 95 years) with ascorbic acid deficiency. One woman also reported lethargy and depression. It is reported that one of these women recovered with a fortnight of ascorbic acid 1 g daily [ 26 ].

Two cross-sectional studies were identified which linked lower vitamin C status to greater cognitive impairment. In a 1996 cohort of elderly people living in Britain (n = 921, ages 65 and over), cognitive function was assessed with the Hodkinson abbreviated mental test, with participants divided into groups based on score (those who scored the maximum of 10 were assessed as having no cognitive impairment; those scoring 9 or less were assessed as having some cognitive impairment). Plasma ascorbic acid status was stratified into three groups: normal (> 27.82 μmol/L, n = 274), mild deficiency (11.92 to 27.82 μmol/L, n = 302), and moderate-to-severe deficiency (≤ 11.91 μmol/L, n = 275). Moderate-to-severe, but not mild, ascorbic acid deficiency was associated with an increased risk of cognitive impairment. For those with mild deficiency, the unadjusted OR was 1.3 (95% CI, 0.9 to 1.8), and for moderate-to-severe deficiency, the unadjusted OR was 1.9 (1.3 to 2.7). Odds ratio was also adjusted for vitamin C daily intake, social class, age (per decade) and stratified diastolic blood pressure. Adjusted OR for mild ascorbic acid deficiency was 1.1 (0.8 to 1.7), and for moderate-to-severe deficiency, 1.6 (1.1 to 2.3) [ 27 ]. In a 2017 cohort of people aged 49 to 51 years in Christchurch, New Zealand (n = 404), higher plasma vitamin C status correlated with lower levels of mild cognitive impairment, as assessed by the Montreal Cognitive Assessment test. The odds ratio (OR) for mild cognitive impairment for those with plasma vitamin C below 23 μmol/L, compared to those with plasma vitamin C above this level, was 2.1 (95% confidence interval [CI] 1.2, 3.7). Notably, in contrast to studies described earlier in this Results section, there was no association between plasma vitamin C status and well-being or depression, as assessed by the Warwick–Edinburgh Mental Wellbeing Scale or the Mini-International Neuropsychiatric Interview [ 28 ]. In a 2019 cohort of healthy adults in Australia (n = 80, ages 24 to 96), cognitive function was assessed by the Modified Mini Mental State Examination (3MS), the Revised Hopkins Verbal Learning Test (HVLT-R), the Symbol Digits Modalities Test (SDMT) and the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB). Plasma vitamin C status was stratified into adequate (≥ 28 μmol/L, n = 67) and deficient (< 28 μmol/L, n = 13). There was no difference between the adequate and deficient groups with respect to assessment of major cognitive impairment with 3MS. However, the adequate vitamin C group had statistically significantly higher scores on measures of recognition and immediate and delayed recall (assessed with HVLT-R) and on SDMT (assessing divided attention, tracking and visual screening) than the deficient group. Finally, using SUCCAB, the ratio of accuracy to reaction time was significantly higher in the adequate vitamin C group for certain tasks (visual perception decision time, immediate and delayed non-verbal recognition memory, and, when adjusting for age, one of two measures of executive functioning and inhibition). There was no difference between the adequate and deficient groups with respect to measures of episodic memory or general alertness and motor speed [ 29 ].

Unfortunately, as noted above, the studies in this review were often of relatively low methodological quality. In addition, those studies that included patients with scurvy were all case series. Furthermore, with the exception of a study that assessed the effects of induced vitamin C deficiency in a small group of healthy male prisoners, the relationship between vitamin C and neuropsychiatric outcomes in other studies was assessed cross-sectionally. Future research may include more robust study designs, such as case-control or cohort studies, to assess the effect of vitamin C deficiency on neuropsychiatric outcomes. Nonetheless, the overall trend from the studies included in this systematic review indicates that vitamin C deficiency is associated with an increase in depression [ 21 , 24 , 25 ] and cognitive impairment [ 27 , 28 , 29 ]. Scurvy – i.e., vitamin C deficiency with physical manifestations – is also associated with depression [ 22 , 23 ] and confusion [ 26 ]. Given the paucity of research in this area to date, one fruitful avenue for future research would be specifically investigating whether vitamin C deficiency is linked to other psychiatric diagnoses, including psychosis and anxiety.

It is noteworthy that so few relevant studies were identified as appropriate for inclusion in this systematic review. It may also be supposed that studies investigating the neuropsychiatric effects of scurvy have been scarce given widespread perceptions about the scurvy’s rarity, incorrect as these assumptions may be. With respect to studies investigating vitamin C deficiency more broadly, there appears to be a sense that studies focusing on individual nutrients are outmoded. The Dietary Guidelines for Americans, for example, address diet in a holistic fashion, noting that “the eating pattern may be more predictive of overall health status and disease risk than individual foods or nutrients” [ 30 ]. It does not negate a the complexity of the interactions between food components and nutrients, or a holistic approach to nutrition, to point out that deficiencies of individual nutrients can, in and of themselves, produce significant clinical problems. In the field of psychiatry, one needs only to consider Wernicke-Korsakoff syndrome or pellagra as pertinent examples. This literature review highlights the importance of considering individual nutrients in psychiatric research, rather than solely focusing on diet in the broader sense. It is also noteworthy that only studies indicating the existence of a link between vitamin C deficiency and neuropsychiatric outcomes were identified in this review; this suggests that there may be systemic biases favouring in the publication of studies with positive results. Nonetheless, there are prima facie strong reasons for associating vitamin C deficiency with neuropsychiatric effects. In humans, neuroendocrine tissue such as the adrenal and pituitary glands have the highest concentration of ascorbic acid [ 31 ], with some studies indicating that the brain also has high ascorbic acid content relative to other organs [ 32 ]. In rats, the ascorbic acid content of cortical neurons is over ten times that of glia, consistent with neurons having a marked increase in oxidative metabolism and an increased susceptibility to oxidative stress [ 33 ]. In both humans and rats, ascorbate content is highest in the amygdala, hippocampus and hypothalamus relative to other brain areas. Rat studies also indicate higher levels of ascorbate in the neocortex and, to a relatively greater degree compared to other brain areas in humans, the nucleus accumbens [ 34 , 35 ]. These areas may be especially vulnerable to oxidative stress. In rats, hypothyroidism-induced oxidative stress, as assessed by lipid peroxidation, has been shown to affect the amygdala and hippocampus, but not the cerebellum, motor cortex or striatum [ 36 ]. There is also a physiological role of reactive oxygen species in vitamin C-rich brain regions, including the hippocampus, hypothalamus, amygdala and cerebral cortex, where they act as second messengers in mechanisms of synaptic plasticity, [ 37 ] which suggests that vitamin C plays a crucial role in maintaining homeostasis of reactive oxygen species. Ascorbic acid also has a role in modulating glutamatergic neurotransmission, [ 38 ] and the distribution of the glutamatergic NMDA receptors is highest in areas of high vitamin C concentration, including areas of the cortex, the amygdala and the hippocampus [ 39 ].

It may be supposed that differential effects of vitamin C deficiency on areas of the limbic and cortical systems involved in cognition and mood regulation may explain the specific phenotype of depressive symptoms and cognitive impairment seen in vitamin C deficiency. Behavioural phenotypes of vitamin C deficiency have been observed in animal models, providing further evidence for the clinical significance of vitamin C status on mood. L-gulono-γ-lactone oxidase, encoded by the GULO gene, is the rate-limiting enzyme in mammalian vitamin C synthesis, and is non-functional in humans. GULO knockout mice fed a vitamin C deficient diet can therefore act as an animal model for scurvy. In one study, GULO knockout mice displayed lower activity levels and indicated a possible mild deficit in motor function [ 40 ]. Another study reported that GULO knockout mice had significantly lower brain levels of dopamine and serotonin metabolites. The gene knockout mice also displayed behavioural changes including lower levels of locomotor activity and altered social behaviour, possibly accounted for by depressive-like behaviour [ 41 ]. The lower activity levels observed in mice may be analogous to some mood symptoms seen in humans, including John Woodall’s 1617 description of “generall lazinesse” [ 19 ].

In this present systematic review, the included studies in this review employed a number of different measurement techniques for vitamin C, including blood levels, leucocyte levels and a vitamin C saturation test. For the included case series of clinical vitamin C deficiency, two older studies published in 1968 and 1971 primarily utilised leucocyte ascorbic acid level [ 22 , 26 ]. Walker [ 22 ] measured vitamin C in milligram per 100 mg of white blood cells, while Mitra [ 26 ] measured vitamin C in milligram per 100 g of white blood cells. (The former study likely reported incorrect measurements; vitamin C in leucocyte layer is typically reported in milligram per 100 g of white blood cells [ 42 ].) As previously noted, leucocyte ascorbic acid, whilst a more difficult assessment to undertake than plasma ascorbate, is a better indicator of vitamin C tissue and body stores. The study by Walker [ 22 ] also included a vitamin C saturation test, whereby subjects were administered 700 mg of vitamin C daily, and 24-h urine specimens were assessed for estimation of total vitamin C content. An excretion of ≥70% of the 700 mg, on the second day of testing, was considered to be normal. It has been suggested that such tests may be beneficial in the clinical diagnosis of scurvy [ 1 ].

In addition, the definition of vitamin C deficiency varied between studies. Three included studies [ 22 , 23 , 26 ] investigated patients with a diagnosis of scurvy. Of the other included studies, only one study included a definition of vitamin C deficiency which was comparable to that which is associated with clinical manifestations of scurvy; in this study, moderate-to-severe deficiency was defined as ≤11.91 μmol/L [ 27 ]. The cut-off definition of vitamin C deficiency in most other studies was comparable to the lower end of the normal laboratory reference range, although one study [ 24 ] defined “inadequate” vitamin C levels as less than 50 μmol/L; it was not clear how this was determined to represent inadequate levels. While there are disparate definitions of vitamin C deficiency in patients without scurvy, the included studies indicate that psychiatric sequelae of vitamin C deficiency may occur at levels higher than those associated with clinical manifestations of scurvy.

From a clinical perspective, the degradation of ascorbic acid with heat and light leads to problems both in dietary intake and in measuring blood or plasma levels. With respect to dietary intake, levels of ascorbic acid do not stay constant in fruits and vegetables, and vary depending on the method of storage. For example, when stored at ambient temperatures, fresh spinach has been shown to lose all of its ascorbic acid content within 4 days, and green peas lost approximately half of the ascorbic acid content within the first 2 days after harvest [ 43 ]. It is therefore possible that many psychiatric patients would have inadequate vitamin C intake even if fruit and vegetables are included in their diets, as the fruit and vegetables may not be fresh.

In addition, testing patients for ascorbic acid levels is difficult, due to the precautions needed with handling blood samples – the samples must be placed on ice immediately, and protected from light. Whilst both difficulties in laboratory testing and the ease and inexpensiveness of vitamin C replacement may suggest that vitamin C supplementation globally in psychiatric patients is warranted, there is still a risk of over-replacement causing morbidity. For example, the relationship between neonatal vitamin D status and schizophrenia is a U-shaped curve – while low vitamin D status in neonates is associated with an increased risk of schizophrenia, so is a high vitamin D status [ 44 ]. Consequently, it may be prudent to judiciously limit vitamin C replacement to those patients with low vitamin C levels or with clinical signs of scurvy, rather than broadly to all mental health patients.

The findings of this systematic review, in addition to the epidemiology of vitamin C deficiency, indicate that vitamin C status should be appropriately assessed in certain psychiatric patient groups, such as patients presenting with symptoms which could be related to vitamin C deficiency (for example, depression, confusion or cognitive impairment) or high-risk patient groups, including those with poor dietary intake. Crucially, mental health clinicians must be alert to the physical signs of scurvy, and the clinical manifestations of this disease on physical examination, such as gingival bleeding, bruising, petechiae and perifollicular haemorrhage [ 2 ]. Furthermore, consultation-liaison psychiatrists, and non-psychiatric medical professionals, must be alert to the psychiatric adverse effects of vitamin C deficiency. As has been noted previously, the occurrence of symptomatic vitamin C deficiency represents “an evidence practice gap of more than 250 years” [ 15 ].

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Abbreviations

Modified Mini Mental State Examination

The Revised Hopkins Verbal Learning Test

The Symbol Digits Modalities Test

The Swinburne University Computerized Cognitive Assessment Battery

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Acknowledgements

The authors wish to acknowledge the assistance of Ms. Maureen Bell in the preparation of the literature search strategy.

The authors declare that this research received no specific funding from any agency in the public or private sectors.

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Plevin, D., Galletly, C. The neuropsychiatric effects of vitamin C deficiency: a systematic review. BMC Psychiatry 20 , 315 (2020). https://doi.org/10.1186/s12888-020-02730-w

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Vitamin C deficiency in a 12-year-old male presenting with knee pain: a case report

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• Volume 24 , pages 544–546, ( 2022 )

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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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Kellie Cloney

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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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Case report article, case report: vitamin c combined with multiple micronutrient deficiencies is associated with pulmonary arterial hypertension in children with autistic spectrum disorder.

• Division of Nutrition, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Children with developmental and behavioral problems including autistic spectrum disorders (ASDs) may have inappropriate feeding behaviors, which leads to an increased risk of multiple nutrient deficiencies. Vitamin C deficiency is one of the common nutrient deficiencies reported in children with inappropriate feeding. This case report illustrates two cases of ASD children with a clinical presentation of pulmonary arterial hypertension, a rare presentation of vitamin C deficiency. Vitamin C supplementation, pulmonary vasodilator, and supportive treatment were provided. Patients could recover from the illness and could be discharged from the hospital in a short time. In addition to vitamin C, the patients also had multiple micronutrient deficiencies. Nutrition counseling was given and micronutrient supplement was continued until follow-up. Regular nutrition assessment and counseling among children with ASD are needed to prevent nutrient deficiencies which may lead to life-threatening complications.

Introduction

Inappropriate feeding behaviors are common in children who have developmental and behavioral issues and they increase the risk of nutrient deficiencies. Vitamin C deficiency was frequently reported in children with highly selective food intake. The common clinical presentations of vitamin C deficiency are joint pain, refuse to walk, and bleeding tendency ( 1 ). In this case report, we summarized the clinical presentations of two vitamin C-deficient autistic spectrum disorder (ASD) children who presented with pulmonary arterial hypertension (PAH), which is a rare presentation of vitamin C deficiency.

Case presentation 1

A 6-year-old boy with a history of ASD, presented with progressive dyspnea for 1 day. He had progressive bilateral knee swelling and refused to walk for 2 months. His symptoms were not improved by analgesics. Dietary history showed that his meals consisted of rice porridge and boiled egg. Some biscuits were provided as a snack. He never drank milk for 2 years and refused red meat, fruits, and vegetables.

At the emergency department, his respiratory rate was 48 breaths per minute, heart rate was 130 beats per minute, blood pressure was 107/78 mmHg, and he had low oxygen saturation at room air (SpO 2 90%) that could be corrected with oxygen via face mask 10 LPM. His weight, length, and BMI were 20 Kg, 112 cm and 15.94 Kg/m 2 , respectively (weight-for-age Z-score; WAZ –0.23, height-for-age Z-score; HAZ –0.86, BMI-for-age Z-score 0.46 according to the WHO growth standard). Physical examination showed that he was pale and had respiratory distress. Neither scorbutic nor rachitic rosary was seen on chest wall. Left leg was swelling and limited movement due to pain. Corkscrew hair was presented over the body. Other physical examinations were unremarkable. Initial laboratory investigations are shown in Table 1 . Echocardiogram showed tricuspid regurgitation (TR) with tricuspid regurgitation pressure gradient (TRPG) of 80 mmHg and D-shape left ventricle (LV). He was diagnosed with severe PAH. No evidence of other causes of PAH such as congenital heart disease, pulmonary embolism, and malignancy was found. He was stabilized in the pediatric intensive care unit. Respiratory support, inotropic drugs, and pulmonary vasodilator were given. Daily 300 mg of vitamin C was given via oral route since the first day of admission. He gradually recovered from respiratory distress and could be discharged in 13 days. Due to improper dietary intake, nutrition counseling was given. The patient was encouraged to take the medical formula as an oral nutritional supplement (ONS) to get optimal micronutrient intake. Micronutrient supplements (multivitamins, vitamin C, vitamin D, iron, and folate) and ONS were continued after discharge. One-month follow-up visit after discharge showed that he was able to mobilize both lower extremities without pain and had no dyspnea while doing the activity. He could have more diet variation but still refused fruits and vegetables. ONS was stopped because of patient refusal and more variation in dietary intake. Micronutrient supplement was continued. Echocardiogram at 2 months after discharge showed no evidence of PAH and the pulmonary vasodilator could be weaned off.

Table 1. Biochemical parameters at diagnosis and follow-up visit.

Case presentation 2

A 5-year-old boy with a history of ASD, allergic rhinitis, and snoring, presented with progressive dyspnea and refuse to walk for 2 weeks. He also had a history of bleeding per gum 3 weeks ago. Dietary history showed that he had only rice porridge without any meat for 1 year, and he just started having some amount of boiled egg for 1 week. He usually drank 12 cartons (6 oz. per carton) of plain UHT milk per day via bottle feeding. He always refused fruits and vegetables and did not receive any vitamin or mineral supplementation.

At the outpatient unit, his respiratory rate was 50 breaths per minute, he had no fever, his heart rate was 136 beats per minute, and his blood pressure was 110/60 mmHg. His weight and height were 30.2 Kg and 115 cm, respectively. (WAZ 3.01, HAZ 0.2, BMI-for-age Z-score 4.14). He had mildly pale conjunctivae, dental caries, and bleeding per gum. No scorbutic rosary and corkscrew hair was seen. There were no signs of joint inflammation or joint deformity, but limited the range of motion due to pain. Other physical examinations were unremarkable. Chest X-ray showed cardiomegaly (cardio-thoracic ratio 0.6), normal pulmonary blood flow, and no pulmonary congestion. He was admitted to the hospital for further investigations. Electrocardiogram showed right axis deviation and low QRS voltage. Echocardiogram showed moderate to severe TR with TRPG 80 mmHg, right atrium and right ventricle enlargement with D-shape LV, impaired RV systolic function, and no evidence of intra-cardiac shunt. PAH was diagnosed. Results of biochemical investigations are shown in Table 1 . Non-invasive respiratory support and pulmonary vasodilator were given. He also received a single dose of 100 mg-thiamine intravenously and daily 300 mg of vitamin C via oral route. His symptoms improved dramatically the next day, he was able to wean himself off of respiratory support, and an echocardiogram revealed that his pulmonary hypertension had improved. He was discharged on the fifth day of admission. Nutrition counseling was given to the caregiver before discharge. Multivitamins, vitamin C, iron, and folate supplement were given and continued after discharge. Follow-up visit at 3 weeks after discharge showed improvement in the quality of dietary intake. The patient could reduce milk intake to four cartons per day but still had bottle feeding. He still refused fruits and vegetables, but took fresh fruit juice daily as a dietary source of vitamin C. No symptoms and signs of vitamin C deficiency were presented. Echocardiogram at 3 months after admission showed no pulmonary hypertension.

Nutrient intake analysis

At diagnosis, dietary history was obtained from 24-h food recall by interviewing the caregiver. Nutrient intakes of both patients were analyzed from the dietary history by INMUCAL software, a computer program for the analysis of nutrients from the Thai food database, developed by the Institute of Nutrition, Mahidol University. 1 The amount of nutrient intakes was compared with dietary reference intakes (DRIs) for Thais 2020 ( 2 ) as shown in Table 2 . Inadequate intake was determined as the amount of nutrient intakes lower than 67% of the amount recommended in DRIs. Both patients had adequate protein intake but no vitamin C-containing food was taken. Many micronutrient intakes in Case 1 were inadequate. Case 2 showed inadequacy of vitamin C, iron, and copper intakes, but the amount of many micronutrients contained in UHT milk was over the DRIs.

Table 2. Nutrient analysis from dietary history at diagnosis compared with dietary reference intakes (DRIs) for Thai 2020.

This is a report of two patients with ASD who were diagnosed with PAH. Both patients had symptoms and signs of vitamin C with subclinical multiple micronutrient deficiencies including iron, zinc, and vitamin D. Growth parameters showed that they were not underweight, wasting, or stunting, which implied that they could obtain adequate calories for growth. Moreover, obesity was presented in case 2 as a result of excess calories from milk intake. However, the analysis of dietary history showed that both patients had inadequate micronutrient intakes ( Table 2 ). ASD children are more likely to have feeding behavior problems such as picky eater or emotional eating even if they grow beyond the toddler period ( 3 , 4 ). Feeding behavior problems lead to inappropriate dietary intake and risk of multiple micronutrient deficiencies. The repetitive dietary pattern was presented in both cases which leads to limit micronutrient intakes despite adequate protein and energy consumption. One of our cases had excess milk intake via bottle feeding. This feeding habit resulted in a decreased intake of other foods and limited diet variation. Our results showed the inadequacy of micronutrient intakes in both patients caused by limited intakes of fruits and vegetables as a dietary source of vitamin C, and meat as a dietary source of trace elements (iron, zinc, and copper). We also found a low 25-OHD level which implied that they had vitamin D deficiency. Vitamin D intake was not analyzed due to the limited database of vitamin D content in Thai foods. We speculated that limited outdoor activity may be the cause of vitamin D deficiency in both cases, because the presentation occurred during the COVID-19 pandemic and the lockdown measures in Thailand.

Typical presentations of vitamin C deficiency are fatigue, weakness, loss of appetite, perifollicular petechial hemorrhage, bruising and ecchymoses, bleeding per gum, and refusing to walk or limping due to bone pain ( 1 ). PAH is an unusual presentation of vitamin C deficiency. Table 3 shows the summary of case reports of vitamin C-associated PAH in children from previous literature. The diseases occurred among children with normal weight, underweight, and obesity. All cases were male subjects and most of them had developmental or behavioral problems.

Table 3. Previous case reports of pulmonary arterial hypertension associated with vitamin C deficiency.

The pathogenesis of PAH caused by vitamin C deficiency was proposed in previous literatures ( 5 , 6 ). First, vitamin C involves in nitric oxide (NO) synthesis which is responsible for pulmonary vascular dilatation. Low NO level in vitamin C-deficient subject causes an increase in pulmonary vascular resistance, which leads to PAH. Second, vitamin C is a cofactor of the prolyl hydroxylases family, which regulates a hypoxia-inducible factor (HIF). Low vitamin C levels cause an increase in HIF, which leads to an increase in the production of vasoconstriction factors ( 7 ). Lastly, some evidence suggest a link between changes in reactive oxygen species (ROS) and the development of PAH ( 8 ). Vitamin C has an antioxidant effect and involves in ROS scavenging. Therefore, vitamin C deficiency causes an imbalance in ROS, which results in PAH.

Although vitamin C involves in many mechanisms related to pulmonary arterial pressure, vitamin C deficiency alone may not a cause of pulmonary arterial hypertension. Most patients with vitamin C deficiency do not present with PAH. Instead, combinations of multiple micronutrient deficiencies, including vitamin D, iron, and flavonoids, are responsible for the pathogenesis of PAH ( 9 ). Our case presentations also exhibited vitamin D and iron deficiency. Previous studies found that the majority of case reports of vitamin C-associated PAH were from ASD children rather than typically developing children, and that they had multiple micronutrient deficiencies ( Table 3 ). As ASD children have more severe eating problems and inappropriate dietary intakes, they may have more severe vitamin C deficiency and other micronutrient deficiencies which lead to the development of PAH.

In addition to vitamin C, children with ASD were reported to have inadequate micronutrient intakes, including vitamin D, calcium, iron, zinc, and fiber, compared to healthy children ( 10 , 11 ). To prevent nutrient deficiencies among ASD children, nutrition counseling should be provided. The nutritional status and dietary intakes of children with ASD should be regularly monitored. Dietary intervention and micronutrient supplements should be appropriately provided. Medical formulas fortified with multiple micronutrients may be used as an optional source of micronutrients. In our cases, both patients could not modify their eating behaviors in a short follow-up time. Therefore, micronutrient supplementation was given until they could increase diet variety and appropriate food intake.

Our case study shows ASD patients with vitamin C deficiency who had a clinical presentation of PAH. We proposed that severe vitamin C deficiency combined with other micronutrient deficiencies may contribute to the pathogenesis of PAH. Feeding behavior problems that are commonly found in ASD children can lead to an increased risk of multiple micronutrient deficiencies. Dietary counseling and regular nutrition assessment among children with ASD are needed to prevent nutrient deficiencies which may lead to life-threatening complications.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by Human Research Ethic Committee, Faculty of Medicine Ramathibodi Hospital, Mahidol University. Written informed consent to participate in this study was provided by the participants or their legal guardian/next of kin.

Author contributions

WS, OD, and SS were pediatric nutritionists who were responsible for nutrition management in both patients in pediatric ward and follow-up visits. WS did the nutrient intake analysis by INMUCAL software and wrote the first draft of the manuscript. OD and SS revised the manuscript. All authors designed case report writing and approved the manuscript before submission.

Acknowledgments

We would like to express our sincere thanks to the patients and their families for giving permission to use their clinical data in this case report. We also thank Marin Satawiriya, MD., a cardiologist who cared for these patients and made suggestions on the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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• ^ https://inmu2.mahidol.ac.th/inmucal/

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Keywords : vitamin C deficiency, autistic spectrum disorder, pulmonary arterial hypertension, micronutrient deficiencies, inappropriate feeding problems

Citation: Sakamornchai W, Dumrongwongsiri O and Siwarom S (2022) Case Report: Vitamin C combined with multiple micronutrient deficiencies is associated with pulmonary arterial hypertension in children with autistic spectrum disorder. Front. Nutr. 9:928026. doi: 10.3389/fnut.2022.928026

Received: 25 April 2022; Accepted: 26 September 2022; Published: 20 October 2022.

Reviewed by:

Copyright © 2022 Sakamornchai, Dumrongwongsiri and Siwarom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Oraporn Dumrongwongsiri, [email protected]

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Case study- scurvy (vitamin c deficiency), case details.

A  4 -year-old boy was brought for consultation for hematuria, edema of lower extremities as well as swollen right leg. He was the 12th born in a poor family, where one previous child died from malnutrition and dehydration in the period of infancy.  The child was fed only with cow’s milk and biscuits.

From the period of five months, the boy manifested irritability, sweating, poor appetite and cried when somebody touched him. At admission the baby was afebrile, pale, and malnourished; his hair was dry and cracked. Clinical evaluation showed no organomegaly, no neurological signs, gingival bleeding was there and only one tooth was present.

Laboratory findings were as follows:

• Red Blood Cell Count 3.5 million/mm 3
• Hemoglobin (Hb) 7 g/dl
• Hematocrit (Hct) 30%
• Serum Iron low
• Liver function tests were in the normal range.
• The ultrasound of the kidney was normal.

Doppler of blood vessels of both legs was normal which excluded thrombophlebitis. The swelling of the right leg indicated radiological investigation. Massive subperiosteal hematoma on the right femur dilatated metaphyses and general osteoporosis had been present on the radiogram.

What is the probable diagnosis for this child?

Case discussion

The child is most probably suffering from Scurvy (Vitamin C deficiency). As history suggests the child had been an ignored child, fed a diet deficient in fruits and vegetables and the signs and symptoms are also typical of scurvy. Bleeding gums, tooth loss, Subperiosteal hematoma, and bony changes are characteristic of scurvy. Iron deficiency anemia is also there which is very common in scurvy due to various reasons.

Thus considering the osteoskeletal manifestations, malnutrition, anemia, irritability and bleeding tendencies as well as the radiological findings, deficiency of vitamin C is concluded.

Scurvy is a state of dietary deficiency of vitamin C (ascorbic acid). The human body lacks the ability to synthesize vitamin C and therefore depends on exogenous dietary sources to meet vitamin C needs. The enzyme, L-gluconolactone oxidase, which would usually catalyze the conversion of L-gluconolactone to L-ascorbic acid, is defective due to a mutation.

Vitamin C – An overview

Vitamin C (ascorbic acid) plays a role in collagen, carnitine, hormone, and amino acid formation. It is essential for wound healing and facilitates recovery from burns. Vitamin C is also an antioxidant, supports immune function, and facilitates the absorption of iron.

Causes of Vitamin C (Ascorbic Acid) Deficiency

Scurvy is caused by a dietary deficiency of vitamin C. The body’s pool of vitamin C can be depleted in 1-3 months.

• Babies who are fed only cow’s milk during the first year of life are at risk.
• Alcoholism and conforming to food fads are risk factors.
• Elderly individuals who eat a tea-and-toast diet are at risk. Retired people who live alone and those who eat primarily fast food face an increased risk of deficiency.
• Economically disadvantaged persons tend to not purchase foods high in vitamin C (eg, green vegetables, citrus fruits), which results in them being at high risk.
• More recently, vitamin C deficiency has been noted in refugees who are dependent on external suppliers for their food and have limited access to fresh fruits and vegetables.
• Cigarette smokers require an increased intake of vitamin C because of lower vitamin C absorption and increased catabolism.
• Pregnant and lactating women and those with thyrotoxicosis require increased intake of vitamin C because of increased utilization.
• People with anorexia nervosa or anorexia from other diseases such as AIDS or cancer are at increased risk of vitamin C deficiency.
• People with type 1 diabetes have increased vitamin C requirements, as do those on hemodialysis and peritoneal dialysis.
• Because vitamin C is absorbed in the small intestine, people with the disease of the small intestine such as Crohn, Whipple, and celiac disease are at risk.
• Iron overload disorders may lead to renal vitamin C wasting.

Pathophysiology

Vitamin C is functionally most relevant for the triple-helix formation of collagen; a vitamin C deficiency results in impaired collagen synthesis.  Proline  and  lysine hydroxylases  are required for the post-synthetic modification of  procollagen  to  collagen.  Vitamin C is necessary as a coenzyme for these hydroxylases. 

Formation of intercellular cement substances in connective tissues, bones, and dentin is defective, resulting in weakened capillaries with subsequent hemorrhage and defects in bone and related structures. Hemorrhaging is a hallmark feature of scurvy and can occur in any organ. Hair follicles are one of the common sites of cutaneous bleeding. 

Bone tissue formation becomes impaired, which, in children, causes bone lesions and poor bone growth. Fibrous tissue forms between the diaphysis and the epiphysis and costochondral junctions enlarge. Densely calcified fragments of cartilage are embedded in the fibrous tissue. Subperiosteal hemorrhages, sometimes due to small fractures, may occur in children or adults.

Clinical Manifestations

• Early symptoms are malaise and lethargy.
• After 1-3 months, patients develop shortness of breath and bone pain.
• Myalgias may occur because of reduced carnitine production.
• Other symptoms include skin changes with roughness, easy bruising and petechiae, gum disease(figure-1), loosening of teeth, poor wound healing, and emotional changes.

Figure-1- showing bleeding gums

• Dry mouth and dry eyes similar to Sjögren syndrome may occur.
• In the late stages, jaundice, generalized edema, oliguria, neuropathy, fever, and convulsions can be seen.
• Vital signs : Hypotension may be observed late in the disease. This may be due to an inability of the resistance vessels to constrict in response to adrenergic stimuli.
• Skin:  Perifollicular hemorrhages (figure-2), purpura, and ecchymoses are seen most commonly on the legs and buttocks where hydrostatic pressure is the greatest. Poor wound healing and breakdown of old scars may be seen.
• Nails : Splinter hemorrhages may occur.

Figure- 2- showing hemorrhages in the nail bed

• Head and neck : Gum swelling, friability, bleeding, and infection with loose teeth; mucosal petechiae; scleral icterus (late, probably secondary to hemolysis); and pale conjunctiva are seen. Conjunctival hemorrhage, flame-shaped hemorrhages, and cotton-wool spots may be seen. Bleeding into the periorbital area, eyelids, and retrobulbar space also can be seen. Alopecia may occur secondary to reduced disulfide bonding.
• Chest and cardiovascular : Scorbutic rosary (ie, sternum sinks inward) may occur in children. High-output heart failure due to anemia can be observed. Bleeding into the myocardium and pericardial space has been reported.

Figure-3- showing scorbutic rosary

• Extremities:  Fractures, dislocations, and tenderness of bones are common in children. Bleeding into muscles and joints may be seen. Edema may occur late in the disease.
• Gastrointestinal:  Loss of weight secondary to anorexia is common. 

Figure-4- showing  perifollicular hemorrhages

Diagnosis is usually made clinically in a patient who has skin or gingival signs and is at risk of a vitamin C deficiency 

Laboratory Investigations

A plasma or leukocyte vitamin C level can confirm the clinical diagnosis.

• Scurvy occurs at levels generally less than 0.1 mg/dL.
• Symptoms occur at levels below 2.5 mg/L, which is considered a deficiency.
• Levels of 2.5-5 mg/L indicate depletion.
• Levels can be low in patients who have tuberculosis, rheumatic fever, or other chronic illnesses; those who smoke cigarettes; and patients on oral contraceptive drugs.
• Capillary fragility  can be checked by inflating a blood pressure cuff and looking for petechiae on the forearm.
• Bleeding time, clotting time and Prothrombin time are normal.
• An iron deficiency anemia is generally observed.

Imaging Studies

Skeletal x-rays  can help diagnose childhood (but not adult) scurvy. Changes are most evident at the ends of long bones, particularly at the knee.

• Early changes resemble atrophy.
• The loss of trabeculae results in a ground-glass appearance .
• The cortex thins.
• A line of calcified, irregular cartilage(white line of Fraenkel) may be visible at the metaphysis.
• The epiphysis may be compressed.
• Healing subperiosteal hemorrhages may elevate and calcify the periosteum.

Differential Diagnosis

In adults, scurvy must be differentiated from arthritis, hemorrhagic disorders, gingivitis, and protein-energy malnutrition.

Patients should take ascorbic acid at 100mg 3-5 times a day until a total of 4 g is reached, and then they should decrease intake to 100 mg daily. Alternately, ascorbic acid may be taken at 1 g/d for the first 3-5 days followed by 300-500 mg/d for a week. Then the recommended daily allowance is resumed.

• Divided doses are given because intestinal absorption is limited to 100 mg at one time.
• Parenteral doses are necessary for those with gastrointestinal malabsorption.

Foods high in vitamin C include the following.

• Citrus fruits, especially grapefruits and lemons
• Vegetables, including broccoli, green peppers, tomatoes, potatoes, and cabbage
• The recommended daily allowance for vitamin C varies. The current recommendation for adults is 120 mg daily, although a dose of 60 mg daily is all that is required to prevent scurvy.
• Diets high in vitamin C have been claimed to lower the incidence of certain cancers, particularly esophageal and gastric cancers.    

Taking>2 g of vitamin C in a single dose may result in abdominal pain, diarrhea, and nausea. Since vitamin C may be metabolized to oxalate, it is feared that chronic, high-dose vitamin C supplementation could result in an increased prevalence of kidney stones. Thus, it is reasonable to advise patients with a past history of kidney stones to not take large doses of vitamin C. There is also an unproven but possible risk that chronic high doses of vitamin C could promote iron overload in patients taking supplemental iron.

• ascorbic acid
• Capillary fragility
• Conjunctival hemorrhage
• flame-shaped hemorrhages
• ground-glass appearance

Reference Books By Dr. Namrata Chhabra

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Lay summary, discordant responses of bone formation and absorption markers in japanese infants with vitamin d deficiency: a comprehensive matched case–control study.

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Keigo Takahashi, Kazushige Ikeda, Kaori Hara-Isono, Akihisa Nitta, Nobuhiko Nagano, Takeshi Arimitsu, Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case–control study, JBMR Plus , 2024;, ziae033, https://doi.org/10.1093/jbmrpl/ziae033

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Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25(OH)D, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 months born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. 116 infants (147 samples) were classified as having vitamin D deficiency (25(OH)D < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25(OH)D ≥ 12.0 ng/mL). In addition to 25(OH)D and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b only measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (p = <0.0001, 0.0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the two groups (p = 0.19, 0.08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.

This retrospective cohort study investigated the effects of vitamin D deficiency on bone health in infants. The study analyzed the levels of various markers related to bone turnover in 456 infants aged less than 12 months. Results showed that infants with vitamin D deficiency had higher levels of a marker associated with bone formation, while markers for bone resorption did not significantly differ between deficient and sufficient groups. These findings provide new insights into how vitamin D deficiency affects the balance between bone formation and resorption in infants.

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8 warning signs of vitamin deficiency (& what to do about it)

Posted: December 30, 2023 | Last updated: December 30, 2023

Common signs you may be vitamin deficient

With all the quick eats out there these days, it’s easy to slip into a diet with few nutrients to nourish your body. Everyone needs a processed snack now and again, but if you don’t have enough vitamin intake, you can start to experience symptoms that will hold you back.

If you recognize the signs, you can make dietary changes that will right the nutrient balance in your body and get you back on track.

1. Brittle nails and hair

While there are many factors involved in brittle hair and nails, one of the big ones is a decreased level of biotin, otherwise known as vitamin B7.

Brittle, thinning and splitting hair and nails can indicate a lack of B7, along with chronic fatigue, muscle pain and cramps, and tingling in the extremities. If you are pregnant, a heavy smoker or drinking or have a digestive disorder, you are at higher risk for this deficiency. If you are using anti-seizure medication or antibiotics over a long period of time,  your risk level is increased  as well.

Be careful about eating  raw egg whites , too, because they contain a protein that binds to biotin, reducing its absorption in the body.

To get your B7 levels up,  eat  egg yolks, fish, meats, dairy, seeds, broccoli, sweet potatoes, whole grains or bananas. There are also supplements available, but  there are few studies  which verify the benefits of such supplements.

2. Hair loss

If your hair is falling out, that can indicate a shortage  of a number of nutrients , including:  iron ,  zinc ,  linoleic acid , and  niacin  (B3), in addition to  biotin  (B7). Iron helps because it is involved in DNA synthesis, particularly that in  hair follicles . Too little of it and hair can  stop growing  or fall out. Zinc works with protein synthesis and cell division, both of which are needed for hair growth.

Meat, fish, eggs, beans and dark leafy vegetables can fortify your zinc and iron levels, and also increase biotin and niacin. Nuts, seeds and whole grains can also replenish these nutrients.

Hair loss is actually quite common; up to 50 percent of people report losing some hair by the time they reach age 50. Watch out for hair loss supplements, though. Some have vitamin A and selenium added, both of which can add to hair loss.

3. Dandruff or patchy scalp

Dandruff and seborrheic dermatitis  typically affect  infants, teens going through puberty and those in mid-adulthood. They present as dry, itchy, flaking skin because they affect the oil-producing areas of the body.

These symptoms  again can indicate low zinc or niacin levels, or possibly low riboflavin (B2) and pyridoxine (B6). To  increase your levels  of these nutrients, try eating whole grains, poultry, meat, fish, eggs, dairy or starchy vegetables.

4. Restless leg syndrome

Restless leg syndrome  affects nearly 10 percent of Americans, and women are twice as likely to experience it as men. Usually, the symptoms spike during times of rest or sleep. It stems from a nerve issue causing uncomfortable sensations in the legs, and an automatic urge to move them.

More study is needed, but initial reviews show that there may be a link between  RLS and low iron levels . The symptoms can often start during pregnancy, when women’s  iron levels  are likely lower than normal.

Supplementing with iron  can help with  iron deficiency , and this generally decreases RLS symptoms, but the effects do vary from person to person. 

To naturally increase your iron levels, try eating meat, poultry, fish, beans, dark green leafy vegetables, nuts, seeds and grains. If you combine these foods with foods high in vitamin C, you’ll be pulling more iron into your system and increasing your absorption of it as well.

5. Mouth lesions

Canker sores and other mouth ulcers also could be linked to  iron deficiency , or low levels of B vitamins. Twenty-eight percent of patients with mouth sores had  B1, B2, or B6 deficiencies  according to one study.

Just like the previous section, you can improve your levels of these vitamins and minerals with meat, poultry, fish, beans, nuts, seeds and whole grains. A diet full of these foods can help assuage many nutrient shortages, so keep that in mind. The  B vitamins  can be increased also with starchy vegetables and eggs.

6. Bleeding gums

Mouth health is extremely important, and there are many factors to keeping your gums healthy, including brushing and flossing regularly, but if your diet has  very little vitamin C  in it, that can  cause your gums to bleed .

Since  we don’t make our own vitamin C , diet is the only way to keep your levels up. Low vitamin C levels are common, with 13-30 percent of people having low levels, and 17 percent of people qualifying as C deficient. Bleeding gums aren’t the only symptom of vitamin C deficiency. People can also experience nosebleeds, slow wound healing and dry skin.

To get enough vitamin C, eat at least two servings of fruit and three portions of vegetables a day.

7. Poor night vision

Vitamin A is necessary for vision, particularly at night or in low light. The vitamin helps produce rhodopsin, a pigment in the retinas that helps people see at night. But it doesn’t stop there. If you have  continued night blindness , it can lead to cornea damage and vision loss at all times. The symptoms, however, can disappear with  vitamin A replenishment .

How can we replenish? Yellow and orange colored vegetables like carrots and sweet potatoes can really help. Also, organ meats, dairy, eggs, fish, and dark leafy vegetables can increase your levels.

Just make sure you don’t overdo it. Too much can cause vitamin A toxicity, with nausea, headaches, and joint pain.

Anemia symptoms  include fatigue, shortness of breath, dizziness, irregular heartbeat, muscle weakness, pale skin, and numbness in extremities. The cause is unhealthy red blood cells that are too large and don’t carry oxygen as efficiently as they should. Red blood cell development requires vitamin B12 and folate, which can be added to your diet through supplements.

The human body is dependent on nutrients we take in from our nutritional choices every day. You’ve probably noticed that most of the deficiencies can be solved through the same types of healthy and varied food groups: protein, produce, dairy and grains. Keep your diet full of fresh ingredients from those food groups and you should experience some relief from these conditions.

This article originally appeared on  Ecowatch.com and was syndicated by MediaFeed.org.

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Vitamin C deficiency (scurvy)--a case report

• PMID: 6605327

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• Oral Hemorrhage / etiology*
• Scurvy / complications*
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• New entity of adult ultra-short coeliac disease: the first international cohort and case–control study
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• http://orcid.org/0000-0001-5528-917X Suneil A Raju 1 , 2 ,
• http://orcid.org/0000-0002-0707-4059 Emily A Greenaway 1 , 2 ,
• http://orcid.org/0000-0002-8493-7698 Annalisa Schiepatti 3 , 4 ,
• Giovanni Arpa 5 , 6 ,
• Nicoletta Vecchione 7 ,
• Chao LA Jian 8 ,
• Charlotte Grobler 9 ,
• Margherita Maregatti 10 ,
• Olivia Green 1 , 2 ,
• Freya J Bowker-Howell 1 , 2 ,
• http://orcid.org/0000-0002-2713-8355 Mohamed G Shiha 1 , 2 ,
• Hugo A Penny 1 , 2 ,
• Simon S Cross 2 ,
• http://orcid.org/0000-0002-7426-1145 Carolina Ciacci 7 ,
• http://orcid.org/0000-0002-2114-2353 Kamran Rostami 11 ,
• Shokoufeh Ahmadipour 12 ,
• Afshin Moradi 13 ,
• Mohammad Rostami-Nejad 14 ,
• Federico Biagi 3 , 4 ,
• Umberto Volta 15 ,
• Michelangelo Fiorentino 15 ,
• Benjamin Lebwohl 16 ,
• Peter HR Green 16 ,
• Suzanne Lewis 16 ,
• Javier Molina-Infante 17 , 18 ,
• Pilar Mata-Romero 18 ,
• http://orcid.org/0000-0003-4416-6216 Valentina Vaira 19 , 20 ,
• http://orcid.org/0000-0002-0873-0759 Luca Elli 10 ,
• Irfan Soykan 21 ,
• Arzu Ensari 22 ,
• David S Sanders 1 , 2
• 1 Academic Unit of Gastroenterology , Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield , UK
• 2 Division of Clinical Medicine, Faculty of Medicine and Population Health , The University of Sheffield Medical School , Sheffield , UK
• 3 Gastroenterology Unit of Pavia Institute , Istituti Clinici Scientifici Maugeri IRCCS , Pavia , Italy
• 4 Department of Internal Medicine and Medical Therapy , University of Pavia , Pavia , Italy
• 5 Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo , University of Pavia , Pavia , Italy
• 6 Anatomical Pathology Unit of Pavia Institute , Istituti Clinici Scientifici Maugeri IRCCS , Pavia , Italy
• 7 Department of Medicine, Surgery, Dentistry , University of Salerno , Fisciano , Italy
• 8 Gastroenterology and Hepatology , MidCentral District Health Board , Palmerston North , New Zealand
• 9 Medlab Central Limited , Palmerston North , New Zealand
• 10 Center for Prevention and Diagnosis of Celiac Disease , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
• 11 Department of Gastroenterology , MidCentral District Health Board , Palmerston North , New Zealand
• 12 Hepatitis ResearcH Center , Lorestan University of Medical Sciences , Khoram-Abad , Iran (the Islamic Republic of)
• 13 School of Medicine, Department of Pathology , Shahid Beheshti University of Medical Sciences , Tehran , Iran (the Islamic Republic of)
• 14 Celiac Disease and Gluten Related Disorders Research Center , Shahid Beheshti University of Medical Sciences , Tehran , Iran (the Islamic Republic of)
• 15 Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
• 16 Celiac Disease Center , Columbia University Medical Center , New York , New York , USA
• 17 Department of Gastroenterology , Centro de Investigación Biomédica en Red , Madrid , Spain
• 18 Department of Gastroenterology , Hospital Universitario de Caceres , Caceres , Spain
• 19 Department of Pathophysiology and Transplantation , University of Milan , Milano , Italy
• 20 Division of Pathology , Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico , Milano , Italy
• 21 Department of Gastroenterology , Ankara University Faculty of Medicine , Ankara , Turkey
• 22 Department of Pathology , Ankara University Faculty of Medicine , Ankara , Turkey
• Correspondence to Dr Suneil A Raju, Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK; suneilraju{at}gmail.com

Background Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD.

Methods Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease.

Findings Patients with USCD (n=137, median age 27 years, IQR 21–43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1–5.9) vs 12.6×ULN (IQR 3.3–18.3), p<0.001).

Patients with USCD had the same number of symptoms overall (median 3 (IQR 2–4) vs 3 (IQR 1–4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).

Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.

At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440–2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2–1.4) vs 0.7 ULN (IQR 0.2–2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms.

Interpretation Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

• coeliac disease
• gluten free diet
• gluten sensitive enteropathy
• celiac disease

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/gutjnl-2023-330913

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WHAT IS ALREADY KNOWN ON THIS TOPIC

The first study of ultra-short coeliac disease in adults in 2016 identified patients with villous atrophy confined to the duodenal bulb with positive coeliac serology.

Systematic review and meta-analyses suggest that taking a duodenal bulb biopsy can increase the diagnostic yield of adult coeliac disease by 8%.

There are limited further studies and no data on how these patients respond to treatment.

WHAT THIS STUDY ADDS

Our study provides the first international data of patients with ultra-short coeliac disease.

At presentation, adult patients with ultra-short coeliac disease are significantly younger, have a similar symptomatic burden but lower serological titres.

Adult patients with ultra-short coeliac disease improve both clinically and serologically when on a gluten-free diet.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Our data support adherence to undertaking a bulb biopsy.

Once identified these patients can be treated effectively with a gluten-free diet.

Introduction

Coeliac disease is a common autoimmune disorder that affects individuals worldwide, with a global prevalence between 0.7% and 1.4%. 1 Despite being an increasingly significant global health problem, a significant proportion of individuals with coeliac disease remain undiagnosed (5%–76%). 2 3 There is a global delay in diagnosing coeliac disease which is reported to be between 9.7 and 13.3 years. 4–6 Furthermore, 5%–12.4% of patients have had a previous gastroscopy (where no biopsies were taken) prior to their diagnosis representing a missed opportunity to diagnose coeliac disease. 7 8 A gluten-free diet (GFD) remains the only treatment, and adherence improves quality of life for the individual and potentially reduces the burden to the healthcare system. 9 10

The conventional form of coeliac disease is characterised by villous atrophy (VA) and crypt hyperplasia in the second part of the duodenal mucosa (D2) with concurrent positive coeliac serology ( figure 1 ). 11 Historical early reports of the value of acquiring biopsies from the duodenal bulb (D1) were disregarded in favour of biopsies from the distal duodenum as it was suggested that histological interpretation was potentially impaired by the presence of Brunner’s glands, gastric heterotropia and duodenitis. 12 Ultra-short coeliac disease (USCD) is defined as patients with VA only present in the duodenal bulb (D1) and concurrent positive coeliac serology ( figure 1 ). This term was coined in 2016 and systematic review and meta-analyses suggest that taking a duodenal bulb biopsy can increase the diagnostic yield of adult coeliac disease by 8%. For paediatric populations, this was shown to be 4% (95% CI 1% to 9%; p<0.001). 12

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Subtypes of coeliac disease divided by extent of villous atrophy.

Subsequently, the American College of Gastroenterology and British Society of Gastroenterology (BSG) now recommend bulb biopsy as standard practice when an upper endoscopy is undertaken to assess for ‘suspected coeliac disease/malabsorption’. However, adherence to biopsy protocols is low (37.0%–39.5%). 11 13–15 One reason for this may be a perceived increase in cost or alternatively a perception that a patient with histological changes confined to the bulb may not benefit from a GFD. 7 The value of taking D1 biopsies remains controversial and there is only a single centre study of 26 adult patients from the UK describing the clinical presentation of VA confined to D1. 11 14–17

Understanding the phenotype and therapeutic outcomes of patients with USCD is crucial for optimising diagnostic approaches and treatment strategies, as well as improving overall patient care and long-term health outcomes. There is a paucity of data regarding the phenotype of patients with USCD by comparison to conventional coeliac disease. Furthermore, there are limited data on the benefit of a GFD in patients with USCD. To address this, we present the first, multicentre, international study of patients with USCD.

The study was proposed after the 19th International Society for the Study of Celiac Disease Conference, Sorrento, October 2022, as an international, multicentre, observational cohort study enrolling all patients with USCD between 2009 and 2022. Patient data were collected from hospital databases that prospectively record information about patients with coeliac disease. One centre collected information retrospectively from hospital records based on positive histological findings. Ten tertiary coeliac disease centres participated in the study: Sheffield, UK; Caceres, Spain; New York City, USA; Palmerston North, New Zealand; Ankara, Turkey; Bologna, Pavia, Milan and Salerno, Italy; Tehran, Iran.

Group 1: For this cohort study, adult (≥16 years) patients were identified from 10 tertiary hospitals between January 2009 and December 2022. Patients were defined as having USCD if they had a combination of positive serological markers (immunoglobulin A-tissue transglutaminase (IgA-tTG) or immunoglobulin A-endomysial antibody (IgA-EMA)) and histologically confirmed VA confined to D1 while on a gluten containing diet. D2 biopsies were architecturally non-diagnostic of coeliac disease (Marsh grades 0–2) and diagnoses were made locally by gastroenterologists with expertise in coeliac disease.

Group 2: For the age-matched and sex-matched case-control study, controls were identified from databases of adult patients with coeliac disease diagnosed in each centre. Each age-matched and sex-matched control was from the same centre as the patient with USCD. Age-matched and sex-matched adult coeliac disease controls were then randomly selected using IBM SPSS V.27.0 (IBM) case control matching function.

Both USCD and age-matched and sex-matched controls had D1 and D2 biopsies.

Data were collected following assessment by a clinician with a special interest in coeliac disease at each centre. Data were reviewed in case notes, endoscopy records and the referral. Data were collected on presenting symptoms, serology at time of presentation (including haemoglobin, vitamin B 12 , folate, iron, vitamin D, IgA-tTG and IgA-EMA), human leucocyte antigen (HLA) typing and histology of duodenal biopsies. Patients with USCD and the case–control patients were then followed up to determine the effects of a GFD on their serological markers and symptoms. All patients were assessed for commonly occurring symptoms in coeliac disease both at presentation and follow-up.

In order to assess for any potential differences between USCD and conventional coeliac disease when specifically considering age and sex at presentation, a further analysis was undertaken comparing all patients with USCD (n=137) to those with conventional coeliac disease from the Sheffield, UK coeliac database (n=434).

IgA-tTG antibody levels were measured by different ELISA kits (Aeskulisa Diagnostics (Wendelsheim, Germany), ELiA Celikey (Thermo Fisher, Freiburg, Germany), ARUP Laboratories (Utah, USA), QuantaLite (Inova Diagnostics, San Diego, California), Eu-tTG (Eurospital, Italy) and Euroimmune (Luebeck, Germany)). Therefore, levels were standardised using the upper limit of normal (ULN) based on the manufacturer’s supplied reference ranges. IgA-EMA was detected by immunofluorescence on primate oesophagus sections (Binding Site, Birmingham, UK). The normal ranges of blood tests differed by centre, and therefore, to allow for direct comparison, the lower limit of normal (LLN) was used for ferritin, vitamin B 12 , folic acid and vitamin D based on the manufacturer’s supplied reference ranges of each test. All blood tests were complete prior to endoscopy as part of the referral process.

HLA typing was performed for HLA-DQ2 and DQ8 at six centres and full genomic HLA typing at three. One centre did not perform HLA typing ( table 1 ).

• View inline

Number of cases of ultra-short coeliac disease from each centre

Biopsies and histology

Multiple biopsies were taken in D1 and quadrantic biopsies in D2 and the most severe histological findings used for diagnosis and analysis. The biopsy specimens were first preserved in formalin and then embedded in paraffin wax. Afterwards, they were thinly sliced into sections measuring 3 µm in thickness. These sections were subsequently stained using H&E. Duodenal biopsies were assessed by experienced histopathologists with an interest in gastroenterology. The biopsies were all orientated by experienced biomedical scientists in the histopathology laboratory and three levels were cut from each specimen. This ensured that in at least some of the levels there were full length villi present and the interpreting histopathologists looked for the longest villi that were present in all three levels. Grading was completed using the modified Marsh criteria: Marsh 1 lesions demonstrated increased intraepithelial lymphocytes (IEL), Marsh 2 lesions demonstrated crypt hyperplasia and Marsh 3 lesions demonstrated VA. 18

CD3 antibody was measured using streptavidin biotin peroxidase method by automated Ventana Benchmark XT system (Roche, Ventana Medical Systems, Tucson), Clone:LN10: Leica Concentrate and immunohistochemistry anti-human Cd3 Dako or GenScript. CD8 antibody was measured with clone: C8/44B; Dako RTU Link and CD4 with clone:4B12; Dako RTU Link. An average of two biopsies was tested for both D1 and D2.

Follow-up data were collected in each centre based on clinical improvement (Likert scale) divided into four categories: ‘symptoms worse’, ‘symptoms the same’, ‘symptoms improved’ and ‘symptoms completely resolved’ after clinical assessment as part of routine care. Serological follow-up was completed using the blood tests as described above. The length of follow-up varied based on the time the patient was known to the centre.

Statistical analysis

Data handling was completed using Microsoft Excel (2016); statistical analysis was conducted in IBM SPSS V.27.0 (IBM).

The prevalence of each presenting symptom was compared between cohorts using χ 2 test of two proportions where there was adequate sample size and if not, Fisher’s exact test was used. 19 Shapiro-Wilk test was used to assess for Gaussian distribution of continuous data such as age and IgA-tTG titre. Where normally distributed and no outliers, a t-test was used, otherwise the Mann-Whitney U test used. A p<0.05 was considered statistically significant.

Role of the funding source

No funding was acquired to complete this study.

When comparing age and sex between individuals diagnosed with conventional coeliac disease (n=434), and USCD, it was observed that those with USCD presented at a younger age (27 years (IQR 21–43 years) vs 38 years (IQR 26–53 years), p<0.001) but no difference in sex ratio (66.6% vs 73.7% females, respectively, p=0.12).

For other comparisons, group 1 patients with USCD (n=137) were compared with group two patients with conventional coeliac disease (n=137) ( table 1 ). Group 1 patients were referred from primary care, were self-referring, referred from other departments within the same hospital (with symptoms or positive coeliac disease serology) or referred from other hospitals (68%, 19%, 10%, 3%, respectively).

Patients with USCD (group 1) when compared with age-matched and sex-matched conventional coeliac disease (group 2) had the same number of symptoms overall (median 3 (IQR 2–4) vs 3 (IQR 1–4), p=0.875).

The most common presenting symptoms for patients with USCD were abdominal pain, diarrhoea and bloating ( table 2 ). When compared with age-matched and sex-matched patients with conventional coeliac disease, patients with USCD had more flatulence (13.1% vs 5.1%, p=0.021). Patients with conventional coeliac disease also demonstrated more iron deficiency (41.8% vs 22.4%, p=0.006). Patients with USCD had higher index ferritin levels than age-matched and sex-matched patients with conventional coeliac disease (2.5×LLN (IQR 1.0 x-5.8xLLN) vs 1.2xLLN (IQR 0.6×−2.7xLLN), p<0.001) though there was no difference in iron deficiency anaemia (p=0.181).

Presentation of patients with ultra-short coeliac disease (USCD) and age-matched and sex-matched patients with conventional coeliac disease

In total, 65.3% of patients had HLA typing complete. More patients with USCD were HLA-DQ2 homozygous than patients with conventional coeliac disease (40.4% vs 25.8%, p=0.038) ( table 2 ). Patients with USCD also had lower IgA-tTG titres compared with patients with conventional coeliac disease (1.8×ULN (IQR 1.1–5.9) vs 12.6×ULN (IQR 3.3–18.3), p<0.001). Similarly, a lower proportion of patients with USCD tested positive for IgA-EMA (76.5% vs 89.2%, p=0.043) ( figure 2 ).

Comparison of serological markers in coeliac disease at baseline and follow-up. Serological comparisons made between patients with ultra-short coeliac disease and age-matched and sex-matched controls at baseline and follow-up for: (A) immunoglobulin A—tissue transglutaminase titre, (B) ferritin, (C) folate, (D) vitamin B 12 , (E) vitamin D, (F) immunoglobulin A—endomysial antibody. LLN, lower limit of normal; ULN, upper limit of normal.

Biopsy findings

Patients with USCD had a similar number of biopsies taken compared with patients with conventional coeliac disease from D2 (4 (IQR 4–4) vs 4 (IQR 4–4), p=0.870) and D1 (2 (IQR 1–2) vs 2 (IQR 1–2), p=0.164). In total, 16.8% of patients with USCD had a previous gastroscopy of which only 45.5% had a previous D1 biopsy taken. In patients diagnosed with USCD, biopsies from D2 were histologically normal in 41.6% of cases, Marsh grade 1 in 41.6% of cases and Marsh grade 2 in 16.8% of cases. In the age-matched and sex-matched controls, 94.6% had VA in D1.

The immunophenotype of the intraepithelial lymphocytes was the same in both D1 and D2 with all the intraepithelial lymphocytes staining with CD3 and CD8, but not with CD4 ( figure 3 ).

Biopsies of D2 and D1 from a patient with ultra-short coeliac disease. In the H&E-stained sections of D2 (A) there is a normal villous height, no significant crypt hyperplasia but there is an increased number of intraepithelial lymphocytes. In the H&E-stained sections of D1 (E) there is complete villous atrophy, gross crypt hyperplasia and an increased number of intraepithelial lymphocytes. The immunophenotype of the intraepithelial lymphocytes is the same in both sites with all the intraepithelial lymphocytes staining with CD3 (B, F) and CD8 (D, H) but none of them stain with CD4 (C, G).

Serological and clinical assessment occurred after a median of 1181 days (IQR 440–2160 days). Following recommendation of a GFD patients with both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2–1.4) vs 0.7 ULN (IQR 0.2–2.6), p=0.312) and similar levels of IgA-EMA positivity (26.9% vs 23.1%, p=0.598) ( figure 2 ). Levels of vitamin B 12 , iron, folate and vitamin D all improved after undertaking a GFD ( figure 2 ). Symptomatic improvement occurred in both patients with USCD and in the age-matched and sex-matched controls (95.7% vs 89.1%, p=0.115). In total, 16.1% of patients with USCD had complete resolution of their symptoms, 79.6% reported a partial improvement, 3.2% reported no change in their symptoms and 1.1% reported symptoms to be worse after following a GFD.

This is the first multicentre international study of USCD. We have demonstrated that patients with USCD are younger than those with conventional coeliac disease and have lower IgA-tTG titres. Despite only having VA in the duodenal bulb patients with USCD are both symptomatic and derive benefit from a GFD. This study endorses the recommendation of taking samples from D1 as a mandatory component of coeliac disease diagnostic workup.

A single-centre study (n=26) from our centre previously identified patients with USCD as younger and having lower IgA-tTG titres. Furthermore, this work demonstrated that an additional D1 biopsy can increase the diagnostic yield by 9.7%. 16 Despite endorsement from the American College of Gastroenterology and BSG, the adherence to biopsy protocols in general remains low (37.0%–39.5%). 11 13–15 As a result, there remains a global delay in diagnosing coeliac disease between 9.7 and 13.3 years. 4–6 Of the patients with USCD, 41.6% and 16.8% had Marsh 1 and Marsh 2 lesions in D2, respectively, therefore, if only D2 biopsies were taken, these patients may have been incorrectly diagnosed as having potential coeliac disease. 11 The implications for both the patient and the clinical recommendation to follow a GFD are different in ‘real-world’ practice when faced with a patient with potential coeliac disease by comparison to VA (Marsh 3) confirmed coeliac disease. The BSG guidelines have made no recommendation for the role of a GFD in patients with ‘potential coeliac disease’.

Conversely in a prospective randomised controlled study of 23 patients with potential coeliac disease (Marsh grades 1–2, raised IEL only or raised IEL and crypt hyperplasia but no VA) individuals who were randomised to commence a GFD showed both symptomatic benefit and a reduction in their tTG titres. 20 In this historical study from 2003 to 2008, none of the patients had a duodenal bulb biopsy. It could be suggested that these patients may have had USCD.

It is perceived that a bulb biopsy strategy may increase healthcare utilisation costs. This may be due to the use of a second histopathology pot (for the bulb biopsy), processing costs and increased pathology reporting time. This may explain some of the reluctance to take biopsies, however, adequate duodenal biopsy strategies potentially avoid diagnostic delays for patients with undiagnosed adult coeliac disease and are a cost-effective approach in improving the quality-adjusted life-years of patients with coeliac disease. 21 22

It may be possible to place D1 and D2 biopsy samples in the same histopathology pot. A historical paediatric study (n=198) found that ‘intraepithelial lymphocytosis was easily recognised in bulb biopsies, and that although the normal villous-to-crypt ratio is lower in the bulb than in the more distal duodenum, significant VA was usually apparent’. When samples were reviewed by experienced histopathologists, the changes of coeliac disease were still identifiable and the risk of interobserver variability was low. 23

We found that patients with conventional coeliac disease were more likely to have iron deficiency than those with USCD, which may correlate with more extensive mucosal inflammation and impaired absorptive capacity of the duodenum in the former. Interestingly, there was no difference in iron deficiency anaemia.

When considering the paediatric population, in a study of 834 paediatric patients diagnosed with coeliac disease, 11% were diagnosed with USCD, these USCD paediatric patients were also found to have lower tissue transglutaminase antibody titres and less iron deficiency than patients with conventional coeliac disease. 24 This suggests that the paediatric and adult USCD cases are similar. This is corroborated by capsule endoscopy studies that demonstrate an association between iron deficiency anaemia, increased age and extent of disease in conventional coeliac disease. 25

Our study demonstrates that HLA DQ2 homozygosity is more common in conventional CD by comparison to USCD (40.4% vs 25.8% p=0.038). This could suggest that the HLA genotype may have a quantitative relationship between the DQ heterodimer and phenotype. Supporting this, a study of seven patients with USCD that found the HLA-DQ2 haplotype to be less common in patients with USCD and no difference in HLA-DQ8 haplotype. 26 However, all these findings are based on small sample sizes and further investigation is required to determine the significance of a possible different HLA haplotype in USCD.

A limitation of this study is that histology samples could be affected by interindividual variability between histopathologists, however, as all histopathologists have a specialist interest in coeliac disease the risk of this is reduced. It is uncertain how this would translate to ‘real-world’ clinical practice beyond centres with an interest in coeliac disease.

Another limitation is the lack of a central reference lab so there was no standardisation between IgA-tTG assays; to address this, the results were evaluated in relation to the ULN as stated by the manufacturer for each assay. Centres involved have a special interest in coeliac disease, and therefore, there may be a referral bias.

In conclusion, this is the first multicentre international study to evaluate the new entity of USCD. Patients with USCD are younger than those with conventional coeliac disease and have lower serological markers of coeliac disease. Despite only having VA in the duodenal bulb, patients with USCD are both symptomatic and derive benefit from a GFD. This study endorses the recommendation of taking samples from D1 as a mandatory component of coeliac disease diagnostic workup.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

All clinical data were anonymised prior to analysis. Patients underwent clinical tests and assessments as part of their routine care. The Sheffield UK Coeliac Research Database was approved by the Yorkshire and the Humber Sheffield Research Ethics Committee, under registration number 14/YH/1216 renewed 19/YH/0095. The database is used to identify efficiently and comprehensively patients eligible for a specific healthcare intervention in order to help recruitment into trials, and for using routine clinical data to study the course of disease and effectiveness of healthcare used in daily coeliac clinical practice. Where necessary, all data collection was approved locally by research and development/audit departments within the country of collection. The study protocol was approved by the ethical committee of the Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Science Tehran (protocol IR.SBMU.RIGLD.REC.1395.87), the local research committee at Palmerston North Hospital, the Columbia University Irving Medical Center Institutional Review Board (protocol IRB-AAAB0960), the local Institution Review Board of Caceres or the Ethics Committee of IRCCS Pavia, ICS Maugeri, Pavia, Italy (protocol number CE2381).

Acknowledgments

We would like to thank Dr Nuria Fernandez-Gonzalez for preparing the histological samples.

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Twitter @DrSunnyR, @Mo_Shiha

Contributors SAR, EAG and DSS conceptualised and designed the study with comments from AS, GA, NV, CLAJ, CG, MM, OG, FJB-H, MGH, HAP, SSC, CC, KR, SA, AM, MR-N, FB, UV, MF, BL, PHRG, SL, JM-I, PMR, VV, LE, IS and AE. Data were collected by all authors and collated by SAR. Data analysis was completed by SAR and interpreted by all authors. Writing of the manuscript was completed by SAR and edited initially by DSS and then all authors. DSS is the guarantor. The final version was approved by all authors.

Funding DSS has previously received an educational grant from Dr Schaer (a gluten‐free food manufacturer). Dr Schaer has no involvement in this study. HAP funded by a Clinical Lecturers grant (CL-2021-04-002) from the NIHR.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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Case Report

Severe vitamin b 12 deficiency in a 15-year-old boy: presentation with haemolysis and pancytopenia, ebru yılmaz keskin.

1 Department of Pediatric Hematology and Oncology, Samsun Education and Research Hospital, Samsun, Turkey

Mahmut Keskin

2 Department of Pediatric Cardiology, Samsun Education and Research Hospital, Samsun, Turkey

A 15-year-old boy on a vegetarian diet presented with severe macrocytic anaemia (haemoglobin, 5.1 g/dL; mean corpuscular volume, 116 fL) in addition to leucopenia and thrombocytopaenia (pancytopenia), icterus secondary to haemolysis and splenomegaly. Laboratory investigations revealed severe vitamin B 12 (cobalamin) deficiency. Following cobalamin replacement therapy, the patient reported increased well-being, including appetite and weight gain, and his icterus resolved. In the follow-up laboratory examinations, leucocyte and platelet counts in addition to serum bilirubin and lactate dehydrogenase levels normalised. At the end of 2 months, laboratory findings, including haemoglobin level, were all within the normal range. We present this case as a reminder that severe vitamin B 12 deficiency may present with findings mimicking acute leukaemia (pancytopenia and splenomegaly) and findings suggestive of pseudothrombotic microangiopathy.

Inadequate consumption of animal foods and pernicious anaemia (loss of intrinsic factor due to autoimmune atrophic gastritis) are the most common causes of severe vitamin B 12 deficiency worldwide in children and adults, respectively. 1 2

Vitamin B 12 deficiency may cause reversible megaloblastic anaemia and/or demyelinating central nervous system disease. For unclear reasons, the severity of megaloblastic anaemia in vitamin B 12 -deficient individuals is inversely correlated with the degree of neurological dysfunction. 1

Although most of the vitamin B 12 -deficient cases have only mild haematological findings, in approximately 10% of patients, life-threatening conditions such as symptomatic pancytopenia, severe anaemia (defined as a haemoglobin level <6 g/dL) and haemolytic anaemia have been reported. 3 We report an adolescent boy with severe cobalamin deficiency who consumed inadequate food of animal origin. He presented with severe anaemia, findings of haemolysis and pancytopenia. Haematological findings resolved completely following appropriate replacement therapy.

Case presentation

A 15-year-old vegetarian boy born to non-consanguineous parents presented with easy fatigue, breathlessness and pain in the legs on walking, noted during the past few weeks. Paleness and icterus in the sclerae had been noted by the parents for about 2 years, although these findings became more obvious within the last few weeks. The vegetarian patient had not consumed any food of animal origin for many years. Besides, the family only rarely ate fresh fruits or vegetables.

The patient had a history of an upper respiratory tract infection that began about 15 days earlier and resolved 1 week later. No fever was noted. In the physical examination, the patient looked pale and weak, and his sclerae were icteric. His heart rate was 96 bpm, and a 2/6 mesocardiac systolic murmur was heard.

Investigations

Laboratory investigations revealed severe macrocytic anaemia (haemoglobin 5.1 g/dL; mean corpuscular volume (MCV), 116 fL), leucopenia (white cell count 2540/µL; neutrophil count 1230/µL) and thrombocytopaenia (107 000/mm 3 ). Reticulocyte percentage was 0.8%. Serum indirect bilirubin, lactate dehydrogenase (LDH), aspartate and alanine aminotransferases and uric acid levels were 4 mg/dL (0–0.8), 5565 U/L (135–225), 150 U/L (8–40), 51 U/L (8–41) and 8.5 mg/dL (2.4–8), respectively. C reactive protein, direct Coombs and testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency (screening test) were all negative. Serum vitamin B 12 , folic acid, iron, iron-binding capacity and ferritin levels were 58 pg/mL (211–911), 5.84 ng/mL (3–17), 281 µg/dL (33–193), 6 µg/dL (125–392) and 464 ng/mL (15–200), respectively. Plasma homocysteine level was markedly elevated (>50 µmol/L; normal 5–12 µmol/L). Epstein-Barr virus and cytomegalovirus serologies were both indicative of a past infection (no recent infection). These findings were thought to be consistent with severe vitamin B 12 deficiency. Antiendomysial and anti-tissue transglutaminase IgA antibodies for screening celiac sprue, and anti-intrinsic factor (anti-IF) and antiparietal cell antibodies for pernicious anaemia were all negative.

A peripheral blood smear showed anisocytosis and poikilocytosis with macrocytes and small, fragmented red cells (schistocytes) mimicking microangiopathic haemolytic anaemia, in addition to hypersegmented neutrophils. No blastic cells were seen. Abdominal ultrasonography revealed splenomegaly, the vertical margin of the spleen being 130 mm in length (normal <120 mm). ECG and echocardiographic examinations were normal. Bone marrow aspiration study demonstrated macromegaloblastic erythropoiesis, and ruled out leukaemia.

Differential diagnosis

In the differential diagnosis, haemolytic anaemia of any cause (ie, G6PD deficiency, autoimmune haemolytic anaemia, haemolytic uraemic syndrome, hereditary spherocytosis), haematological malignancy, infectious causes, aplastic anaemia, storage disorders and haemophagocytic lymphohistiocytosis (due to pancytopenia and splenomegaly), vitamin B 12 or folic acid deficiency (due to macrocytic anaemia) and autoimmune lymphoproliferative syndrome (due to the combined finding of haemolysis, pancytopenia and splenomegaly) were considered. Bone marrow aspiration study ruled out leukaemia, and the laboratory results consistent with severe vitamin B 12 deficiency were thought to explain all the abnormal findings at presentation (severe macrocytic anaemia, pancytopenia, findings of haemolysis and low reticulocyte count).

As the patient's anaemia was caused by nutritional deficiency, and there was no sign of heart failure, he was not transfused. Intramuscular cyanocobalamin was started (0.5 µg/kg/day for 2 days followed by 100 µg/day for 2 days and 1000 µg/day for 1 week; thereafter, he received 1000 µg cyanocobalamin weekly for 1 month, and would receive it once every month for 6 months). In the second week of therapy, oral iron (ferrous glycine sulfate; 4 mg/kg/day of elemental iron) and folic acid (5 mg/day) were initiated due to the expected increase in iron utilisation and borderline serum folic acid level (tested as 2.8 ng/mL 5 days after treatment initiation), respectively.

Outcome and follow-up

The patient reported an increased level of well-being, including a good appetite, only a few days following therapy. Five days after treatment initiation, his haemoglobin, white cell count and neutrophil counts rose to 6.5 g/dL, 5160/µL and 1660/µL, respectively, whereas his platelet count dropped to 91 000/mm 3 . His serum indirect bilirubin and LDH levels declined to 2.7 mg/dL and 5225 U/L, and plasma homocysteine dropped to 6.3 µmol/L (normal 5.0–12.0 µmol/L). Reticulocytosis was not assessed due to the unavailability of testing at the time. At the end of 2 weeks, thrombocytopaenia and indirect hyperbilirubinaemia were found to be resolved. In the follow-up examination at the end of 2 months, the patient was found to have gained weight markedly (due to increased appetite). Laboratory findings performed at that time were all normal (haemoglobin 15.7 g/dL; MCV 86.6 fL; leucocyte count 6710/µL; platelets 255 000/mm 3 ; serum indirect bilirubin 0.3 mg/dL; LDH 179 U/L; aspartate aminotransferase 20 U/L; alanine aminotransferase 11 U/L; uric acid 7.8 mg/dL; iron 69 µg/dL; iron binding capacity 230 µg/dL; ferritin 168 ng/mL; vitamin B 12 318 ng/mL; folic acid 10.1 ng/mL and plasma homocysteine 7.8 µmol/L).

In humans, vitamin B 12 is needed as a cofactor for two reactions: methylcobalamin is the cofactor for the cytoplasmic enzyme, methionine synthase, while adenosylcobalamin is the cofactor for the mitochondrial enzyme, methylmalonyl coenzyme A mutase. Hence, vitamin B 12 deficiency results in the accumulation of homocysteine and methylmalonic acid. Cobalamin is essential for DNA synthesis, haematopoiesis and myelination. 1 2 4

Since humans cannot synthesise vitamin B 12 , it needs to be ingested in the diet from foods of animal origin. The most common cause of cobalamin deficiency in infants and children is inadequate consumption due to dietary restriction or lack of access to animal-sourced food. 2 Cobalamin stores last for several years after restriction of intake or malabsorption. 1 Our 15-year-old boy had consumed no meat, poultry, fish, eggs, milk or other dairy products for years, which well explains his severe vitamin B 12 deficiency status.

In a study including 201 adults with well-documented cobalamin deficiency, approximately 10% of the patients were found to have life-threatening haematological manifestations. 3 Among these were pancytopenia (5%), severe anaemia (defined as a haemoglobin level <6.0 g/dL; 2.5%) and haemolytic anaemia (1.5%). Our patient had severe macrocytic anaemia, pancytopenia and findings of haemolysis (fragmented, misshapen cells in the peripheral smear mimicking microangiopathic haemolytic anaemia, indirect hyperbilirubinaemia and marked increase in LDH). Notably, reticulocyte count at admission was low. Concurrent haemolysis in patients with vitamin B 12 deficiency is a well-recognised phenomenon and has been attributed mainly to intramedullary destruction of erythrocytes (ineffective erythropoiesis). 5 In their study comparing patients with pseudothrombotic microangiopathy (pseudo-TMA) due to vitamin B 12 deprivation patients with thrombotic thrombocytopaenic purpura (TTP), Noël et al always found the reticulocyte count to be low in pseudo-TMA cases in contrast to patients with TTP, and concluded that in a patient with mechanical haemolysis accompanied by thrombocytopaenia, very high LDH levels and a low reticulocyte count, strongly suggest pseudo-TMA and cobalamin deficiency as possible underlying cause. The combination of a low reticulocyte count and markedly elevated LDH levels is suggestive of intramedullary haemolysis.

The parents of our patient had noted overall paleness and icterus in their son's sclerae for about 2 years, which became more obvious during the last few weeks. A viral infection may have aggravated the haemolytic process. However, the low reticulocyte count at admission points to intramedullary haemolysis (due to cobalamin deficiency) rather than haemolysis due to an infection.

In addition to intramedullary haemolysis due to ineffective erythropoiesis, homocysteine accumulation due to vitamin B 12 or folate deficiency was found to increase haemolysis in vitro. 6 7 Plasma homocysteine concentration was found markedly elevated (>50 µmol/L) in our patient, and declined to normal within 1 week of cobalamin replacement.

Cobalamin is essential for DNA synthesis and haematopoiesis, and its severe deficiency not only causes megaloblastic anaemia, but may also result in thrombocytopaenia and leucopenia (neutropenia), as in our patient. 8–10 Splenomegaly and/or hepatomegaly have also been reported in cases with severe cobalamin deficiency. 8 Hepatosplenomegaly in these patients may be attributed to increased extramedullary haematopoiesis compensatory to haemolytic anaemia complicating nutritional cobalamin deficiency.

Owing to the remarkable dietary history of our patient, we thought inadequate dietary intake to be the cause of cobalamin deficiency. However, the patient is 15 years of age, and pernicious anaemia has been reported as the most common cause of severe cobalamin deficiency in adults. 1 3 5 Additionally, pseudo-TMA associated with cobalamin deficiency has been reported most frequently in adults with pernicious anaemia rather than in those with malabsorption or dietary insufficiency. 3 5 In cobalamin-deficient individuals, the identification of the underlying cause is important, as the management is distinct in different conditions (in dietary deficiency, a change in diet habits can improve serum vitamin B 12 levels and eliminate the need for intramuscular cobalamin injections, whereas in pernicious anaemia, lifelong treatment is indicated). Testing for anti-IF and antiparietal cell antibodies were negative in our case, the sensitivities of which are 50% and 80% for pernicious anaemia, respectively. 1 Chronic atrophic gastritis may also cause cobalamin deficiency, and it can be diagnosed on the basis of an elevated fasting serum gastrin level and a low level of serum pepsinogen I. 1 Some authors recommend endoscopic examination to confirm gastritis and rule out gastric tumours, since patients with pernicious anaemia are at increased risk for such cancers. As our patient had been on a vegetarian diet for years, and anti-IF and antiparietal cell antibodies were found negative, no endoscopic examination was performed.

We have described a patient with nutritional cobalamin deficiency who presented with severe anaemia, haemolysis and findings mimicking acute leukaemia (pancytopenia and splenomegaly). Care givers should be aware of these possible presentations secondary to vitamin B 12 deficiency, particularly in high-risk populations. Besides, appropriate treatment provides rapid resolution of the associated signs and symptoms.

Learning points

• Inadequate intake of vitamin B 12 is the most common cause of vitamin B 12 deficiency in children.
• Vitamin B 12 deficiency may present with findings mimicking acute leukaemia (ie, pancytopenia and organomegaly).
• Severe vitamin B 12 deficiency may cause haemolytic anaemia, which may be mainly explained by ineffective erythropoiesis and elevated homocysteine levels.
• In the presence of mechanical haemolysis and thrombocytopaenia, the combination of markedly elevated lactate dehydrogenase levels and a low reticulocyte count, are strongly suggestive of pseudothrombotic microangiopathy and cobalamin deficiency as the possible underlying cause.
• Appropriate treatment results in rapid resolution of associated symptoms and of abnormal laboratory findings.

Competing interests: None declared.

Patient consent: Obtained.

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