Nonalimental Scurvy With Relapse Symptoms After Stopping Oral Vitamin C Supplementation
Abstract
Historically linked to sea voyagers in the 18th century, scurvy has become extremely rare during the last century in developed countries. However, it is still present in some at-risk populations and often overlooked in pediatric patients with restricted diets due to behavioral, neurodevelopmental, or psychiatric problems. So far, the only known etiology of developing scurvy is nutritional deficiency of vitamin C. In this report, we describe the case of a 3-year-old previously healthy Swiss girl without any history of previous poor dietary intake, who presented a picture of systemic inflammation including persisting fever, palpable purpura located on the extensor sides of the extremities, refusal to bear weight, and gingival bleeding. Blood tests revealed a significant increase of inflammatory markers and hypoalbuminemia. Full-body MRI revealed symmetrical bone marrow edema consistent with findings in previously reported cases of children with scurvy. After starting a high-dose oral vitamin C supplementation, the patient showed rapid clinical, laboratory, and radiologic improvement, but after stopping the treatment 4 months later, the patient developed relapse symptoms with pronounced fatigue, refusing to walk, and hair loss. These symptoms led us to restart the oral supplementation, which resulted in secondary normalization of her condition. The cause of her symptoms still remains unclear and presents the first case to our knowledge describing scurvy symptoms that are not directly linked to deficient dietary intake.
- IgA —
- immunoglobulin A
- IgG —
- immunoglobulin G
- IgM —
- immunoglobulin M
- SVCT1 —
- sodium-dependent vitamin C transporter 1
- SVCT2 —
- sodium-dependent vitamin C transporter 2
As one of the most ancient diseases, scurvy was first described around 1500 BC1 but only in 1747 was Sir James Lind able to perform a controlled prospective study with scorbutic sailors2 revealing a link to citrus fruit as its prevention and cure.
Unlike other mammalian species, which produce ascorbic acid from glucose via converting enzymes, humans are not able to do so3 and are thus dependent on dietary intake of vitamin C.4
A plasma concentration of vitamin C <11 μmol/L is usually considered a deficiency.5 However, measurements of plasma concentration do not reflect the actual tissue levels because of false high values after recent vitamin C intake.6 Levels of ascorbic acid in leukocytes reflect the body storage better6 but testing is, as it was in our case, rarely available.
Pediatric patients prone to develop scurvy are either without access to balanced nutrition7 or suffer from behavioral problems, neurodevelopmental, or autism spectrum disorders with consecutive restricted eating patterns.8
Scurvy is characterized by generalized weakness, fever, poor wound healing, and gingival swelling and bleeding.9 Dermatological findings include petechiae, ecchymoses, perifollicular papules with surrounding hemorrhage, and coiled hair.10 Musculoskeletal pain in the lower limbs leading to refusal to bear weight are typically seen in childhood scurvy.11 Anemia and increased inflammation parameters are common laboratory findings,12,13 but diagnosis is made after clinical presentation.9 Disruption of vascular integrity in the collagen-containing tissues is due to the impaired building of collagen, where ascorbic acid is needed as a cofactor for the hydroxylation of prolinresidues.14 The easy accessibility of fresh fruit and vegetables and the omnipresence of vitamin C in processed food as a preservative made scurvy become rare in developed countries.
Here, we present the case of a 3-year-old girl with clinical and radiologic signs of scurvy without previous history of poor dietary intake. Vitamin C supplementation resulted in rapid clinical improvement, normalization of inflammation markers, and MRI findings. Lack of neurodevelopmental abnormalities, adequate objectified eating protocols, and relapse with new onset of symptoms after pausing the treatment are not consistent with a sole dietary deficiency. Therefore, this represents the first case to our knowledge with scurvy of unknown etiology other than nutritional and suggests the possibility of other causes of low vitamin C levels in body tissues.
Case Report
In February 2016, a 3.5–year-old previously healthy Swiss girl presented to our emergency department with a 1-week history of fever, reduced general condition, loss of appetite, and papules located on the elbows and extensorsides of the lower extremities (day 0 = day of the first symptom). On day 2, she complained about abdominal pain and pain in both legs with refusal to bear weight and showed gingival bleeding, rectorrhagia, and livid discoloration of the right lateral midfoot. On day 3, she was presented to her pediatrician, who suspected Henoch-Schönlein purpura and instructed the parents to perform daily urinary dipstick testing to detect proteinuria or hematuria. On day 6, the girl was brought to our emergency department with hematuria and proteinuria by test strip.
Physical examination revealed eutrophic weight and length and stable vital signs. She presented swollen gums and dried blood on the gingiva and the nostrils.
Skin examination revealed perifollicular papules on both elbows and petechiae and papules on the extensor sides of the lower limbs and gluteal region. The right dorsolateral midfoot revealed a hematoma and an edematous swelling to the upper ankle joint (Fig 1). Cardiorespiratory, abdominal, and neurologic examinations were normal.
Figure 1. Clinical picture on day 6 .
There was no history of recent travel or animal contact. She took no medication and had an adequate vaccination status. Drinking and eating patterns were reported to be normal before the onset of her symptoms.
Laboratory tests revealed elevated inflammation parameters, and albumin was decreased (Tables 1–4). Urinary testing revealed a mild proteinuria (0.2 g/L) without hematuria.
Evolution in Time of Blood Analysis Values
Infectiological Findings
Immunological Findings and Inflammatory Parameters
Vitamin Values
Abdominal ultrasound revealed a transient ileoileal intussusception. Chest radiograph was normal. Blood cultures were taken, but antibiotic treatment was withheld because she did not have any signs of bacterial infection.
During this first hospital admission from day 6 to 11, she was treated symptomatically, because blood cultures were sterile, and there was a good response to antipyretics. The skin findings were regressing. Because of a persisting heart rate around 130 beats per minute, an electrocardiogram was performed and revealed a sinus tachycardia. The edema on the right foot persisted. Urinary testing became normal.
After discharge, continuous pain in both legs with inability to walk, reduced general condition, fever, inappetence, and new gingival bleeding led to a second admission on day 26.
Physical examination revealed mucosal lesions in the mouth and an anal marisca. The knees and the right ankle joint were swollen without redness or hyperthermia. Laboratory tests revealed continuous increased inflammatory parameters with anemia. Quantitative immunoglobulin testing for immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) as well as antinuclear antibodies and vasculitis marker were within normal limits (Tables 1–4).
During the second admission, the patient underwent a bone marrow biopsy that excluded leukemia and other malignant processes. The echocardiography was unremarkable.
Fecal calprotectin was highly elevated. Chronic inflammatory bowel disease or dysplasia were excluded by endoscopy.
By histopathology, the marisca revealed a chronic inflammation without evidence of vasculitis. Pharyngolaryngeal and nose endoscopy revealed friable mucosa and gingival hypertrophy.
Flow cytometric immunophenotyping of lymphocytes using cluster of differentiation markers revealed a physiologic cellular immune system. Serological testing of frequent infectious diseases produced negative results (Tables 1–4). On day 34, full-body MRI was performed and revealed multifocal bone edema on the lower extremities accentuated on metaphyses with strictly symmetric bilateral hyperintense signal abnormalities in the bone marrow and periosteal as well as in adjacent soft tissue (Fig 2). Although a history of previous malnutrition was absent, the patient’s symptoms and MRI findings suggested the diagnosis of scurvy.
T2-weighted MRI pictures before (left) and after (right) 4 months of vitamin C supplementation.
The analysis of the vitamin C level was performed at the Swiss Vitamin Institute in Épalinges, Switzerland (http://www.swissvitamin.ch) by using reversed phase high-performance liquid chromatography with electrochemical detection. The coefficient of variation was <5% and the detection limit was <1 µmol/L and revealed a low serum vitamin C level within normal limits. However, the test was performed after 6 days of tube feeding containing vitamin C and therefore did not represent the actual body tissue level.
To detect other causes beside an alimentary deficit, heavy metal analysis was performed and was normal for lead, mercury, cadmium, and nickel.
On day 35, high-dose oral vitamin C supplementation (36 mg/kg per day equal to 500 mg per day) was started, causing significant improvement of her symptoms (Fig 3). The patient was discharged on day 41. Over the course of 6 weeks of daily supplementation of vitamin C, the patient was completely asymptomatic and inflammation markers returned to the normal range.
Time evolution of the body temperature (left axis) and CRP (right axis). The dotted lines indicate the starting days of TF (left) and vitamin C supplementation (right). CRP, C-reactive protein; GB, gingival bleeding; RW, refusal to walk; TF, tube feeding.
A follow-up full-body MRI after 4 months of continuous treatment revealed a marked resolution of the bone marrow edema. The supplementation was then stopped.
Although our nutritionists confirmed sufficient dietary vitamin C intake afterward, a relapse of symptoms with alopecia, fatigue, and refusal to walk occurred 2 weeks later, which prompted us to resume the supplementation, improving in turn the patient’s symptoms again. Since then, no further interruption of the supplementation has been attempted.
Discussion
This case reveals a clinical picture of scurvy in a previously healthy child with rapid response to high-dose oral vitamin C supplementation. The MRI findings were consistent with previous MRI findings in vitamin C deficiency,15,16 but in contrast to all cases reported before and known to us, our patient did not present signs of malnutrition or neurodevelopment abnormalities explaining a pathologic nutritional pattern. Even more importantly, she showed recurrent objectified symptoms including alopecia that was observed at the time of relapse after stopping the vitamin C supplementation. Alopecia is a condition described in early pediatric scurvy.17 The case suggests the existence of an underlying individual mechanism on a genetic level leading to low vitamin C levels in the body.
Vitamin C uptake, renal reabsorption, and tissue distribution are controlled by sodium-dependent vitamin C transporter 1 (SVCT1) and sodium-dependent vitamin C transporter 2 (SVCT2), both members of the SLC23 family.18 Genetic variations of these transporters were found to be linked to increased risk of spontaneous preterm delivery, gastric cancer, and lymphoma.18–20 Timpson et al21 identified a genetic variant in SVCT1 that is reliably associated with reduced circulating levels of vitamin C in the general population. No mutation in SLC23 has yet been reported to be directly linked to scurvy. We therefore performed molecular testing of the SLC23 gene in this patient. Exome sequencing for SLC23A1 and SLC23A2, coding genes for SCVT1 and SCVT2, revealed neither mutations nor variants.
However, it is known that vitamin C is also actively released by the human adrenal gland in response to corticotropin, but efflux mechanisms are still unknown.9 One possible mechanism of nonalimental vitamin C deficiency could thus be due to mutations involved in efflux mechanisms in the adrenal gland with consecutive poor secretion of vitamin C in stress situations like acute illness.
Further genetic testing of polymorphism and mutations hold potential implications for new risk-prediction markers to tailor the dosage of vitamin C to the individual’s requirements. Our case suggests that there are other possible causes besides nutritional intake, holding potential for the treatment of patients with unclear systemic inflammation disorders. This case reveals that pediatricians should include a detailed nutritional assessment especially in unclear inflammatory clinical pictures and consider scurvy as a differential diagnosis if the clinical picture matches. Treating ex juvantibus with vitamin C in scorbutic patients without evidence of previous nutritional deficiency is the second implication of this report, so that genetically or immunologically susceptible patients can benefit from this safe and cost-efficient treatment.
Footnotes
- Accepted April 27, 2018.
- Address correspondence to Nina Vaezipour, MD, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. E-mail: nina.vaezipour{at}insel.ch
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
References
- Copyright © 2018 by the American Academy of Pediatrics
