Scurvy's Systemic Clinical Picture: A Multiorgan Presentation of a Conspicuous Disease

Ascorbic acid is an important cofactor for enzymatic reactions (1). Humans are one of the few mammals who cannot synthesize it and, since it cannot be stored in the body, it is necessarily obtained through diet (2). In the past, scurvy was a common and serious disease among sailors (1) and, to date, its prevalence has decreased strikingly by greater access to vitamin C sources. However, there are groups considered to be at risk, including those who are elderly, housing insecure, experiencing alcohol addiction, and malnourished (2, 3).

A 56-year-old man with a history of hiatal hernia presented to the emergency department with fatigue, jaundice, unintended weight loss of 12 kg, facial asymmetry, and pruriginous skin lesions. Hereditary, medical, trauma, and surgical history were unremarkable. He did not report alcohol consumption or recreational drug use. Further investigation revealed a poor social background, low access to health services, lack of family support, and a diet based on chicken, fish, and whole grain bread for the last 14 years.

His vital signs were abnormal due to hypotension and tachycardia. Findings of the physical examination revealed a punched-out ulcer on the upper gingiva (Figure 1, A), pale skin with conjunctival jaundice, left peripheral facial paralysis, jugular engorgement, and bilateral lower-limb edema. On the skin, purpuric patches and plaques with scaling were observed on the lower extremities, and the lumbar region featured a large and pigmented lichenified plaque (Figure 1, B–D). With dermoscopy, perifollicular purpura was identified (Figure 1, E).

Laboratory results revealed severe ferropenic hypoproliferative normocytic hypochromic anemia, moderate thrombocytopenia, hyperbilirubinemia, hypoalbuminemia, altered coagulation tests, Kidney Disease: Improving Global Outcomes (KDIGO)II acute kidney injury, hyperlactatemia, and an elevated B-type natriuretic peptide. A peripheral blood smear showed dysplastic neutrophils (irregularly lobulated nuclei). Infectious, autoimmune, and neoplastic causes were ruled out: hemolysis profile, VDRL, acute/chronic viral hepatitis profile, cryoglobulins, C-reactive protein, erythrocyte sedimentation rate, antinuclear antibodies, antineutrophil cytoplasmic antibodies, serum/urine protein electrophoresis, immunofixation, and free light chains were normal. Electrocardiogram showed no abnormalities. A triphasic computed tomography (CT) scan of the chest and abdomen showed fluid overload, alveolar edema, bilateral pleural effusion, periportal edema, ascites, enlarged inferior vena cava (Figure 2, A), and hypodense soft-tissue images suggestive of hematomas.

An echocardiogram revealed dilatation of the right chambers, with a diastolic diameter of the right ventricle of 36 mm, systemic venous congestion with a dilated inferior vena cava of 3 cm without inspiratory collapse, and right atrium pressure of 15 mm Hg with pulmonary hypertension (pulmonary artery systolic pressure 42 mm Hg) (Figure 2, B–C) without left ventricular dysfunction. During hospitalization, reticulocyte index, platelet count, bilirubin, and the cutaneous lesions evolved from purpuric to hyperpigmented as the patient received a nutrient-rich diet.

Flourine-18 fluorodeoxyglucose positron emission tomography (PET)/CT demonstrated heterogeneously increased metabolism (maximum standardized uptake value [SUVmax] 6.6) in the cutaneous lesions, as well as osteopenia and bone marrow hypermetabolism of the axial skeleton (Figure 3, A).  Bone marrow aspiration and bone biopsy were performed, which revealed mild hypocellularity with adequate maturation of the 3 lines without myelofibrosis (Figure 3, B). A skin biopsy of the lumbar region with hypermetabolism in PET was performed as the result of suspected proliferative pathology, with a report of lymphocytic folliculitis with perifollicular fibrosis and extravasation of erythrocytes with infundibular dilation, compatible with scurvy and deep dermal fibrosis (Figure 3, C–E). Vitamin C levels obtained at admission were undetectable (<0.2 mg/dL, normal range 0.4–1.5 mg/dL). Thiamin levels were normal. After supplementation with 1 g of ascorbic acid per day for 2 weeks, his symptoms improved, the bleeding disappeared, and his laboratory values normalized (Figure 4). He was discharged, and 3 months later, his symptoms had disappeared.

The main clinical concerns were unexplained weight loss, a disseminated purpuric dermatosis with patches and plaques, an uncommon dilation of the inferior vena cava and right heart chambers, severe hypoproliferative ferropenic anemia, hyperbilirubinemia, and left facial palsy. The initial differential diagnoses were systemic vasculitis, lymphoproliferative infiltrating neoplasm, or nutritional deficiencies.

Vitamin C is essential for the hydroxylation of procollagen precursors into collagen (4). In scurvy, the final collagen product is aberrant, and there is an increased disulfide crosslinking of hair keratins, which explains the cutaneous findings in this case: the follicular hyperkeratosis and the coiled hairs into “corkscrew” configurations and “swan-neck” deformities. In contrast, the perifollicular hemorrhage predominantly involving the lower extremities was a consequence of capillary fragility due to a decrease in perivascular collagen, which leads to the inability to withstand the elevated hydrostatic pressure as the result of gravity (2).

Right ventricular dysfunction and dilation of the inferior vena cava were other relevant findings. Recently, these have been associated with the development of pulmonary hypertension through different mechanisms (5, 6). The first is vasodilatation through an increase of nitric oxide (6). In addition, ascorbate participates in the degradation of the hypoxia-inducible factor through its hydroxylation. The absence of vitamin C decreases the degradation of hypoxia-inducible factor, which leads to pulmonary hypertension due to its role on hypoxic pulmonary vasoconstriction (6, 7).

Anemia, present in 80% of patients with scurvy, is multifactorial (1). Tissue fragility, due to aberrant collagen, favors spontaneous bleeding, perpetuating a small-but-constant blood loss that, on reabsorption, produces hyperbilirubinemia. In addition, ascorbic acid enhances nonheme iron absorption in the gut, but recent evidence suggests its role in other areas of iron metabolism, such as the stimulation of ferritin synthesis, inhibition of the lysosomal ferritin degradation, and decreased cellular iron efflux (4). Another mechanisms involved in the anemia is hemolysis and decreased hematopoiesis in the bone marrow caused by the inability to incorporate iron into the hemoglobin, which also might explain the elevated bilirubin levels seen in the patient at presentation.

As the result of inappropriate diet habits, concomitant deficit of other vitamins was feasible. We demonstrated low levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (11.4 ng/mL and 11.7 pg/mL, respectively), but thiamin (B1) was within normal ranges (3.9 mcg/dL); this is important in the differential diagnosis of dilated reversible heart failure, discarding wet beriberi. In vitamin K deficiency, we would expect a prolonged prothrombin time and activated partial thromboplastin time, given the participation of intrinsic and extrinsic pathway factors (II, VII, IX, and X), but our patient only had prolongation of prothrombin time. Thromboelastography found INTEM and EXTEM normal clotting time, which translates into the absence of coagulation factor deficiency in both pathways, ruling out vitamin K deficiency.

An unusual finding was peripheral facial palsy. Vitamin C is important to the nervous system during myelination and Schwann cell differentiation, and reported neurologic symptoms in scurvy include neuralgia, focal weakness, fatigue, decreased concentration, anxiety, imbalance, and headaches (8). However, the association with Bell's palsy has been described recently (9). Theories include the role of vitamin C as an antioxidant and free radical scavenger, as well as its protective effect against viral infections by enhanced immunity (9).

Finally, the flourine-18 fluorodeoxyglucose PET/CT images with soft-tissue hypermetabolic lesions required ruling out a lymphoproliferative disorder. It served as a guide to perform the skin biopsy by choosing the lesion with the greatest SUVmax to improve the diagnostic yield. This method has high sensitivity (91%-98%) in differentiating soft-tissue sarcomas against benign fluid collections such as hematomas or abscesses. (10).

In conclusion, vitamin C's role in many physiologic processes explains the varied, systemic, and reversible manifestations that can be present in scurvy. The broad clinical picture coupled with scurvy's rarity make it a diagnostic challenge. Awareness of its clinical picture will allow an early recognition and timely treatment.