ABSTRACT
Vitamin C (l‐ascorbic acid) is an essential dietary micronutrient needed for iron absorption, collagen synthesis, antioxidant activity, and immune regulation. This retrospective analysis examines 23 patients seen in a classical hematology clinic in Appalachia between 2020 and 2025 who had severe vitamin C deficiency (< 0.1 mg/dL). Most patients presented with anemia, fatigue, or other dermatologic findings, and over half lived in food‐desert regions. Micronutrient testing often revealed overlapping deficiencies, and 17% of patients experienced a bone marrow biopsy. Principal component analysis of laboratory data identified two main phenotypic clusters: socioeconomic status, which accounted for most of the variability in the data, followed by cell counts and laboratory values. Treatment approaches varied. Normalization of vitamin C levels and cytopenias was seen in patients who attended follow‐up, typically within 2–3 months. This work suggests that vitamin C deficiency remains a contemporary and reversible contributor to cytopenias in hematology practice and highlights the importance of dietary and socioeconomic risk assessment during diagnostic evaluation.
Keywords: anemia, Appalachia, scurvy, vitamin C
1. Background
Vitamin C, also known as l‐ascorbic acid, is found in many foods, most commonly citrus fruits, leafy green vegetables, and berries [1, 2]. It is water‐soluble, and humans cannot produce it endogenously, so it must be obtained through the diet [1, 2]. Vitamin C functions in neurotransmitter synthesis, antioxidant generation, iron regulation, and maintenance of skin and collagen. It acts as a cofactor for the enzyme that converts dopamine to norepinephrine, an essential neurotransmitter [2].
Anemia and iron metabolism are impacted by vitamin C. It enables iron absorption in a few ways: vitamin C reduces ferric iron (Fe3+) to ferrous iron (Fe2+), which is the absorbable form of iron recognized by the divalent metal transporter 1 on the duodenal enterocytes, and it maintains nonheme iron bioavailability by forming iron‐ascorbate complexes in the lumen of the small intestine [2, 3, 4]. Intracellularly, it serves as a cofactor, maintaining iron in its ferrous form in enzymes responsible for collagen synthesis and iron mobilization (ferritin), and indirectly vitamin C helps to maintain the iron redox cycle. Iron metabolism in red blood cell maintenance is well described, and anemia often results from low iron absorption or intake [2, 4].
Its most recognized role is in skin maintenance. Vitamin C is essential for crosslinking collagen, which supports skin, bones, and other connective tissue [2]. Collagen makes up about 75% of the dermis, a key skin layer [5]. Vitamin C also helps regulate the immune system by enhancing neutrophil chemotaxis, supporting caspase‐dependent apoptosis, aiding maturation and proliferation of natural killer cells, and regulating T regulatory cell activity [2]. Loss of vitamin C leads to bruising from fragile skin and blood vessels, poor wound healing, gingival bleeding, and petechiae, symptoms seen in Scurvy—the pathologic presentation of vitamin C deficiency [5].
In Appalachia, the region surrounding the Appalachian mountains, and specifically in West Virginia, food deserts are common [6, 7]. Food deserts are geographic regions with limited access to affordable, nutritious food [6, 7]. In these rural areas, food deserts can mean traveling over 10–20 miles to reach the nearest supermarket [8]. Fifty percent or more of the population in West Virginia is rural compared to about 20% nationally [6]. Lack of access to nutritious food is important because humans need to obtain vitamin C from the diet. This micronutrient is often only found in fresh produce, and without it, deficiency can occur leading to loss of the biochemical regulatory mechanisms previously described [6].
This retrospective cohort analysis aims to explore the relationship between micronutrient deficiency, specifically vitamin C deficiency, and cell count abnormalities, as well as explore the potential association between food deserts and these conditions.
2. Methods
2.1. Study Design and Population
We conducted a retrospective review of adult patients evaluated in a hematology clinic at West Virginia University between January 2020 and October 2025 who were found to have severe vitamin C deficiency. Patients were identified through review of laboratory records and clinical documentation in the electronic health record. Severe vitamin C deficiency was defined as a serum vitamin C concentration below 0.1 mg/dL, measured by mass spectrometry (reference range 0.3–2.7 mg/dL). Initially, 28 patients were identified; five patients with vitamin C levels above this threshold were excluded to ensure analytic consistency, resulting in a final cohort of 23 patients.
This study was reviewed and approved by the West Virginia University Institutional Review Board (protocol 2511256149) and was conducted under a HIPAA waiver permitting review of the minimum necessary protected health information.
2.2. Data Collection
Variables collected included age, sex, smoking status, inpatient versus outpatient evaluation, presenting symptoms, complete blood count parameters, micronutrient testing results. Comorbid conditions included gastrointestinal, psychiatric, neurologic, and end‐stage renal disease. We assessed treatments used for vitamin C deficiency (Table 1). Bone marrow biopsy findings, when performed, were reviewed through pathology reports.
TABLE 1.
Demographics.
| Variable |
Total (95% CI) n = 23 |
Male (95% CI) n = 10 |
Female (95% CI) n = 13 |
|---|---|---|---|
| Age (years) | 51 (43.7–59.3) | 46 (30.1–61.1) | 57 (47.7–64.3) |
| Demographics | |||
| WV (n) | 14 (61%) | 6 (60%) | 8 (62%) |
| PA, MD, OH (n) | 9 (39%) | 4 (40%) | 5 (39%) |
| Low access (n) | 15 (65%) | 7 (70%) | 10 (77%) |
| Low income (n) | 17 (74%) | 7 (70%) | 6 (46%) |
| Low income and low access (n) | 13 (57%) | 8 (80%) | 7 (54%) |
| Social history | |||
| Smoker (n) | 11 (47.8%) | 4 (40.0%) | 8 (61.5%) |
| Pack (years) | 26 (15.2–36.9) | 34 (7.4–60.6) | 22.1 (8–36.1) |
| Drinks alcohol (n) | 4 (17.4%) | 2 (20.0%) | 2 (15.4%) |
| Marijuana use (n) | 5 (21.7%) | 1 (10.0%) | 3 (23.1%) |
| Referral patterns | |||
| Outpatient | 12 (52.2%) | 5 (50.0%) | 8 (61.5%) |
| Inpatient | 10 (43.5%) | 5 (50.0%) | 5 (38.5%) |
| Patients (n) with pressure injury | 4 (17.4%) | 2 (20.0%) | 2 (15.4%) |
| Intensive care (within 3 months) | 8 (34.8%) | 5 (50.0%) | 3 (23.1%) |
| Number of injuries per patient (95% CI) | 1.25 (1.04–1.45) | 1.5 (1.06–1.94) | 1 |
| Bone marrow biopsy (n) | |||
| Bone marrow (n) | 4 (17.4%) | 1 (10.0%) | 3 (23.1%) |
| Treatment types | |||
| Over the counter vitamin C (n) | 8 (34.8%) | 3 (30.0%) | 5 (38.5%) |
| Prescription (n) | 6 (26.1%) | 3 (30.0%) | 3 (23.1%) |
| None (n) | 4 (17.4%) | 3 (30.0%) | 1 (7.7%) |
| Multivitamin (n) | 4 (17.4%) | 1 (10.0%) | 3 (23.1%) |
| Food (n) | 1 (4.3%) | 0 (0.0%) | 1 (7.7%) |
| Extra supplements (n) | 9 (39.1%) | 3 (30%) | 6 (46.2%) |
| Supplements per patient (excluding vitamin C) | 1.9 (1.3–2.5) | 2.3 (0.9–3.8) | 1.7 (0.8–2.5) |
Socioeconomic indicators included income status and food access. Food access designation was determined using the United States Department of Agriculture Food Access Research Atlas, which defines low‐access areas based on distance to the nearest supermarket or large grocery store [8]. Income status was categorized according to USDA‐defined low‐income census tract criteria (Table 1) [8]. Zip code matching was used to ascribe income and access status to each patient.
2.3. Laboratory Evaluation
Vitamin C levels were measured using mass spectrometry. Additional laboratory evaluation was performed at the discretion of the treating hematologist and frequently included iron studies, vitamin B12, folate, copper, and markers of hemolysis. Cytopenias were defined using laboratory reference ranges for leukocyte and platelet counts. Anemia was defined as hemoglobin less than 12 g/dL for females and less than 13 g/dL for males (Table 1).
2.4. Statistical Analysis
Descriptive statistics were used to summarize demographic, clinical, and laboratory characteristics. Continuous variables are reported as means with 95% confidence intervals or medians, as appropriate, and categorical variables as counts and percentages.
Exploratory multivariable analyses were performed using principal component analysis (PCA) to evaluate patterns across laboratory and socioeconomic variables. Variables included in PCA comprised hematologic laboratory parameters as well as selected socioeconomic indicators (low income status and food access designation). Missing data were handled using multivariate imputation by chained equations [9, 10, 11]. PCA was followed by K‐means clustering to explore natural groupings within the cohort. The number of clusters was determined empirically based on variance explained and visual inspection of clustering patterns.
Correlations between variables were assessed using Pearson correlation coefficients for continuous variables and chi‐square tests for categorical variables. Binary variables were coded as yes/no for analysis. Statistical analyses were conducted using R and Python.
Portions of code used for data analysis and visualization were developed with assistance from a large language model (OpenAI) and subsequently reviewed, modified, and validated by the study authors. All analytic decisions, code execution, and interpretation of results were performed by the investigators. The use of a large language model was limited to code generation support and did not involve data interpretation, statistical decision‐making, or manuscript authorship.
3. Results
3.1. Patient Characteristics
Twenty‐three patients with severe vitamin C deficiency were identified between January 2020 and October 2025. All patients were referred for abnormalities in the complete blood count, most commonly anemia (n = 18). At the time of hematology clinic evaluation, anemia was actually present in 14 patients, while others had cytopenias that had partially resolved prior to the appointment (Table 1).
Most were evaluated as outpatients (52.2%, n = 12), while the remainder initially presented as inpatients (43.5%, n = 10) and were discharged with referrals to hematology clinic. Eight patients required intensive care within 3 months of diagnosis (34.8%) (Table 1). Six of these eight patients (75%) carried a neuropsychiatric diagnosis, including four with major depressive disorder. Indications for ICU admission were heterogeneous and included hemodynamic instability, severe anemia requiring close monitoring, and management of comorbid acute illness. About half of the cohort were active smokers (47.8%, n = 11). End‐stage renal disease was present in four patients. Gastrointestinal conditions associated with impaired absorption, such as inflammatory bowel disease or prior small bowel resection, were identified in 17.4% of patients and occurred exclusively among male patients (n = 4). Psychiatric and behavioral medicine related conditions were common (69.6%, n = 16). Among those 16 patients, while there was no standard dietary history noted, when diet was discussed or documented, it was largely described as “processed foods” (n = 14 of 16). Some patients noted specific foods they eat for a majority of meals including: “meat and potatoes” and “pretzels, oatmeal, and ice.” Patients rarely mentioned fresh fruits.
Most patients resided in West Virginia (60.9%, n = 14). The majority lived in areas designated as having low access to nutritious food according to USDA criteria (65.2%, n = 15). Low income status was present in 73.9% of patients (n = 17), and over half of the cohort (56.5%, n = 13) met criteria for both low income and low food access (Table 1).
3.2. Clinical Presentation
Presenting symptoms were included if they were documented from the first note in the hematology clinic. The symptoms included fatigue (30.4%, n = 7), dermatologic manifestations such as purpura, rashes, or poor wound healing (34.8%, n = 8), and anemia, sometimes requiring transfusion support (30.4%, n = 7) (Figure 1 and Table S2). Pressure injuries were documented in 17.4% of patients (n = 4) within 1 year of vitamin C deficiency measurement, with an average of 1.25 injuries per affected individual (95% CI 1.04–1.45).
FIGURE 1.
Skin findings in the left arm (A), left heel (B), and right posterior thigh (C) of three different patients with vitamin C deficiency.
3.3. Laboratory Evaluation and Diagnostic Workup
Micronutrient testing was performed inconsistently. The most frequently assessed micronutrients were vitamin B12 and folate (n = 15 each), as well as copper (n = 12). Several patients exhibited overlapping micronutrient deficiencies, and 50% or more were deficient in vitamin A (n = 6 of 10 measured), vitamin E (n = 1 of 2 measured), and vitamin K (n = 1 of 2 measured) (Tables 1 and S3). Of the micronutrients evaluated in more than 75% of patients (n = 15), 13% were deficient in B12 (n = 2) and folate (n = 2). Evaluation for hemolysis did not reveal evidence of hemolytic anemia.
Bone marrow biopsy was performed in about 17% of patients (n = 4) during evaluation for multi‐lineage cytopenias. Histopathologic findings were variable and largely nonspecific. In one representative case, bone marrow examination demonstrated gelatinous transformation consistent with severe nutritional deficiency (Figure 2) [12].
FIGURE 2.
Bone marrow findings in Vitamin C deficiency. (A) H&E (20× magnification) shows hypocellular bone marrow with abundant extracellular gelatinous material and marked reduction of normal hematopoietic elements. (B) Alcian blue stain (20×) highlights positivity of the extracellular deposits, confirming a mucopolysaccharide‐rich matrix consistent with gelatinous transformation of the bone marrow.
3.4. Statistical Analysis
A principal component analysis was performed using laboratory and socioeconomic variables. The frequency of low income (n = 17) and low access (n = 15) were common among all patients (Figure 3). Psychiatric disorders were also highly represented (n = 16) (Figure 3). The first principal component accounted for 32.1% of the total variance and was driven primarily by socioeconomic variables, including low food access (−0.82) and low income status (−0.78). The second principal component accounted for 18.9% of the variance and was defined by anemia‐related laboratory parameters and markers of illness severity, including hemoglobin (−0.72). Patients demonstrated cluster patterns more closely aligned with socioeconomic risk profiles than laboratory severity alone (Figure 4).
FIGURE 3.
Frequency of risk factors among patients deficient in vitamin C.
FIGURE 4.
Principal component analysis reveals data separation along two axes, principal component one, made of socioeconomic status data, and principal component two, made up of laboratory data. Data clusters based on income (A), access (B) and low income and access together (C) where red denotes patients with the indicator and blue denotes patients without.
3.5. Treatment and Follow‐Up
Treatment strategies included over‐the‐counter vitamin C supplementation (34.8%, n = 8), prescription vitamin C (26.1%, n = 6), multivitamin supplementation (17.4%, n = 4), and food‐based dietary modification (4.3%, n = 1). Four patients (17.4%) did not receive documented vitamin C supplementation (Table 1).
Six patients returned for follow‐up vitamin C testing, all of whom demonstrated normalization of serum vitamin C levels within approximately 2–3 months of treatment initiation. Cytopenias normalized in all six patients with follow‐up laboratory data. Among patients with documented psychiatric follow‐up after vitamin C repletion, four exhibited improvement or stabilization of psychiatric symptoms: documented improvement in depressive symptoms (n = 1, MDD), stable mood without relapse (n = 1, MDD with anxiety), and reported improvement in two additional patients (one with schizoaffective disorder and one with MDD and anxiety). In each of these patients, hematologic parameters either normalized or improved concurrently with psychiatric stabilization. The small number of patients with paired follow‐up and the absence of standardized psychiatric assessment instruments preclude formal correlation analysis.
Time to vitamin C normalization showed a positive but nonsignificant association with improvement in blood counts (r = 0.85, p = 0.15). An inverse association was observed between the number of supplements taken and time to vitamin C normalization (r = −0.839, p < 0.05); this finding should be interpreted cautiously given the small sample size. The average time from referral to hematology evaluation was 67 days (95% CI 31–102). At least five patients were lost to follow‐up.
4. Discussion
In this retrospective case series, we identified 23 patients with severe vitamin C deficiency who were evaluated in a hematology clinic over a 5‐year period. Most patients presented with anemia, fatigue, and dermatologic manifestations, and a subset required transfusion support. Nearly one‐fifth underwent bone marrow biopsy during evaluation for cytopenias. Vitamin C deficiency can mimic primary hematologic disorders and prompt invasive diagnostic testing.
Although commonly seen as a historical condition, biochemical vitamin C deficiency remains in modern populations, with prevalence estimates ranging from approximately 7%–8% depending on diagnostic thresholds [4]. Recent reports continue to describe hematologic manifestations, though no known studies have examined vitamin C deficiency within hematology referral populations. Our findings reveal that severe deficiency may present to hematologists as unexplained cytopenias, specifically anemias.
Socioeconomic risk factors were highly prevalent in this cohort. Exploratory analyses indicated that socioeconomic variables contributed more to cohort variability than laboratory parameters alone. While food insecurity has been linked to iron‐deficiency anemia, its association with other micronutrient deficiencies warrants further study [7, 13]. These data suggest that socioeconomic along with dietary factors may meaningfully influence pretest probability and should be incorporated into clinical reasoning when evaluating cytopenias.
The documentation of restrictive or inadequate dietary intake among almost all patients with a psychiatric comorbidity in our cohort can suggest a clinically meaningful pathway from psychiatric illness to scurvy. Anhedonia, decreased motivation, food selectivity (particularly in autism spectrum disorder), executive dysfunction, and socioeconomic constraints associated with chronic mental illness can each independently reduce intake of fresh fruits and vegetables. Although our small sample and retrospective design do not allow for causal inference, the concurrent improvement in hematologic and psychiatric parameters observed in several patients following ascorbate repletion supports prospective study with structured psychiatric and hematologic endpoints.
The frequency of bone marrow biopsy observed in this cohort is clinically notable. Bone marrow biopsy is invasive and carries bleeding risk, yet it rarely yields diagnostic insight into micronutrient deficiencies [3, 14, 15, 16]. Earlier consideration of vitamin C deficiency in patients with cytopenias and relevant risk factors may reduce the need for unnecessary invasive procedures.
Vitamin C is an essential cofactor for dopamine β‐hydroxylase, and severe ascorbate deficiency may impair catecholamine synthesis with consequent compromise of vascular tone and stress response [2]. The high proportion of ICU admissions in our cohort (34.8%) and the over‐representation of patients with neuropsychiatric comorbidity within this subgroup raise the possibility that profound vitamin C deficiency contributes to hemodynamic vulnerability in acutely ill patients. The retrospective design of this study does not allow us to attribute ICU utilization specifically to ascorbate deficiency rather than to comorbid illness, but the observation supports the consideration of inclusion of vitamin C in the workup of unexplained cytopenias accompanied by hemodynamic instability.
Treatment strategies varied. Among patients with follow‐up, normalization of vitamin C levels and cytopenias occurred within approximately 2–3 months, suggesting that treatment durations of more than 1 month may be required in some cases. In terms of varying supplement options, dosing needs further study. But, given saturable absorption, doses exceeding 200 mg per administration provide minimal additional bioavailability in previous studies [17, 18]. Standard ascorbic acid could be considered a cost‐effective and therapeutic option.
Limitations include this study's retrospective design, limited follow‐up, and small sample size. Vitamin C deficiency is likely under‐recognized due to infrequent testing. Case ascertainment was at the discretion of the treating physicians as they were the ones who ordered the test, and due to clinical variability, not every patient was tested for every micronutrient deficiency. Socioeconomic factors were based on zip code and not on individual patient interviews. Prospective studies are needed to further elucidate screening strategies and treatment dose and duration for vitamin C deficiency.
Overall, vitamin C deficiency remains an underrecognized yet reversible contributor to anemia and cytopenias encountered in hematology practice. Increased awareness of dietary and socioeconomic risk factors may facilitate earlier diagnosis, reduce unnecessary invasive testing, and improve patient care through timely, cost‐effective treatment. A heightened index of suspicion is warranted, particularly in patients living in food‐desert regions. Earlier recognition in primary care and other outpatient clinics of these risk factors may prevent referrals to the hematology clinic, potentially sparing patients the morbidity of bone marrow biopsies and the costs of subspecialty clinics.
Author Contributions
D.D. and S.A.M. conceptualized and designed the study, curated data, conducted formal analysis, and drafted the manuscript, with S.A.M. providing supervision. S.N. contributed to formal analysis, methodology, and validation. H.E. and C.R. provided resources and contributed to investigation, visualization, and drafting. E.P. and W.K. contributed to investigation, validation, and drafting. D.D. led project administration and visualization. All authors participated in investigation, critically reviewed and edited the manuscript, and approved the final version.
Funding
The authors have nothing to report.
Disclosure
The authors declare no conflicts of interest.
Ethics Statement
This study was approved under West Virginia University Institutional Review Board as protocol 2511256149 and utilized HIPAA waiver. The waiver permits review of the minimum necessary information required to complete the research project by 45 CFR 164.512(i).
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Lab variables and treatment time intervals.
Table S2: Presenting symptoms.
Table S3: Concurrent micronutrient deficiencies.
Data Availability Statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Lab variables and treatment time intervals.
Table S2: Presenting symptoms.
Table S3: Concurrent micronutrient deficiencies.
Data Availability Statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.