Curr Rheumatol Rep (2015) 17: 26 DOI 10.1007/s11926-015-0503-6
ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Rheumatic Manifestations of Scurvy Claudia Ferrari & Niccolò Possemato & Nicolò Pipitone & Bernhard Manger & Carlo Salvarani
Published online: 9 April 2015 # Springer Science+Business Media New York 2015
Abstract This paper reviews the rheumatological manifestations of scurvy, based on articles published in English from 1965 until October 2014, with a particular focus on rheumatological manifestations. Scurvy is a rare, uncommon disease in developed countries. Due to its clinical heterogeneity, the disease can easily mimic rheumatologic conditions leading to a delay in diagnosis and treatment. Keywords Scurvy . Arthritis . Pseudovasculitis . Rheumatic manifestations . Musculoskeletal manifestations
Methods A literature search using PubMed platform was performed for articles published in English from 1965 until October 2014. MeSH keywords used for this search were Bscurvy^ or/and Bascorbic acid deficiency^ matched with Brheumatic disease,^ Barthritis,^ Bhemarthrosis,^ Bpurpura,^ Bvasculitis,^ and Bmusculoskeletal disease.^ We included only articles about rheumatological manifestations of vitamin C deficiency in adults (age >18). Relevant articles were reviewed and additional articles were obtained through the analysis of references of articles from the original literature search.
Introduction Scurvy is a nutritional disorder caused by a deficiency in Vitamin C. Nowadays, its incidence in developed countries is limited to individuals with risk factors for poor nutrition such as poverty, social isolation, or psychiatric disorders. The rarity of the condition and the wide range of clinical manifestations related to the disease, like deep vein thrombosis, pseudovasculitis, musculoskeletal manifestations, and systemic bleeding disorders, can lead to a delay in the diagnosis. In case of rheumatologic manifestations of difficult interpretation, it is important for rheumatologists to consider scurvy as a possible cause. This article is part of the Topical Collection on Orphan Diseases C. Ferrari : N. Possemato : N. Pipitone : C. Salvarani (*) Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Viale Risorgimento 80, 42123 Reggio Emilia, Italy e-mail: [email protected] B. Manger Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany e-mail: [email protected]
Literature Review Vitamin C is an essential dietary nutrient required as a cofactor for many enzymes, and humans are among the few animals that lack the ability to synthesize the compound from glucose. The reduced form of the vitamin, ascorbic acid, is an especially effective antioxidant owing to its high electron-donating power and ready conversion back to the active reduced form [1]. Ascorbic acid is an enzymatic cofactor necessary for the synthesis of mature collagen formed by three polypeptide molecules combined into a triple helix. Collagen abnormalities may affect blood vessels’ integrity due to impaired synthesis of the constituents of the vessel wall and the surrounding connective tissue. Moreover, ascorbic acid is a cofactor in the metabolism of tyrosine and synthesis of carnitine, norepinephrine, and peptide hormones. It increases iron absorption and is also an important antioxidant agent [2]. Vitamin C is present in fruits and vegetables. Estimates of vitamin C amounts in foods depend on season, transport of the food, shelf time prior to purchase, storage, and cooking practices [3]. The recommended daily intake by the US Food and Nutrition Board of the Institute of Medicine for men 18 years
26 Page 2 of 5
of age or older is 90 mg of vitamin C daily; for women 18 years of age or older, it is 75 mg daily; for pregnant women 18 years of age or older, it is 85 mg daily; and for breastfeeding women 18 years of age or older, it is 120 mg daily. An inadequate intake of fresh fruit and vegetables is the main cause of vitamin C deficiency, in particular in older people, chronic alcoholics, and anorexic and homeless subjects. Moreover, smoking decreases the intestinal absorption and increases the catabolism of vitamin C. For instance, smoking more than 20 cigarettes per day is associated with a 40 % increase in the daily vitamin C turnover compared to non-smokers [4]. Other interesting studies have shown that some pathological conditions, such as gastrointestinal disorders like Crohn’s disease [5] and Whipple’s disease [6], can be responsible for a decreased absorption of vitamin C. Insulindependent diabetes is also associated with an increased need of vitamin C [7].
Clinical Features Constitutional Symptoms Nonspecific constitutional manifestations are present in scurvy, like weariness especially in the lower limbs, weakness, and malaise. In the literature are also described depression, nervousness, and lethargy. The origin of these mental changes is not clear, but ascorbic acid may be involved because it is a factor in some neurotransmitter functions in the brain [2]. Laboratory Findings The abnormalities of laboratory tests are not specific. Frequently, anemia is present in scurvy and its degree correlates with the severity and duration of scurvy. Causes of anemia can be multiple. Bleeding is common in vitamin C deficiency, and this may result in normocytic anemia with an increased reticulocytes count. Other concomitant contributing factors may be folic acid and iron deficiency. Folic acid is present in the same vegetables and fruits that contain vitamin C a n d i s f u n d am e n t a l f o r i n t e s t i n al ir o n i n t a k e . Intravascular hemolysis may also cause anemia. Sometimes, leukopenia and hypoalbuminemia are present [8, 9]. The elevations of acute phase reactants is frequent, in particular elevated values of ESR are described in many cases of scurvy [2, 10, 11]. The cause is probably related to a hepatic overexpression of inflammatory chemokines, stimulated by ascorbic acid deficiency [12]. However, the relationship between blood levels of ascorbic acid and increase in inflammatory markers is unclear. Autoimmunity is generally negative in patients with scurvy although some authors have
Curr Rheumatol Rep (2015) 17: 26
described in some patients the presence of low-titer speckled antinuclear antibodies [10]. Cutaneus Findings Dermatological manifestations are common in scurvy. Vitamin C deficiency frequently leads to skin dryness and roughness due to the development of hyperkeratosis. Biopsy samples demonstrate follicles filled with soft keratin [2]. Skin hemorrhages are the most common findings in scurvy. The capillary fragility has been linked to the loss of the blood vessel walls’ int e g r i t y. P e t e c h i a e o r p u r p u r a m a y b e p r e s e n t . Occasionally, the purpura became palpable and the ecchymoses widespread, thus mimicking vasculits. Histological findings are perifollicular hemorrhages, fibrosis, keratin plugging, and hyperkeratosis, in the absence of an underlying inflammatory process [13]. Nails can present abnormalities (like splinter hemorrhages) resembling rheumatic diseases such as scleroderma, systemic lupus erythematosus (SLE), rheumatoid arthritis, and antiphospholipid syndrome. Some patients present alopecia or develop hair fragility because ascorbic acid is fundamental in the disulfide bonding that occurs with hair formation. A particular hair growth called Bcorkscrew^ or Bswan neck^ is observed [2]. Skin biopsy of the scalp often demonstrates a coiled hair in its follicle [14]. Musculoskeletal Manifestations The musculoskeletal manifestations are frequent, and the rheumatologist is often part of the diagnostic work-up. Myalgias and Arthralgias Fain and coworkers described myalgias and arthralgias as frequent manifestations in scurvy (about 80 % of patients). Lower extremities are commonly affected, especially the ankles and knees. However, virtually any joint can be involved. Joint Synovitis of affected joints is rare, while spontaneous hemarthrosis is a common event. Histologically, the synovial membrane shows interstitial hemorrhage and large fibroblasts but little collagen and some disarray of vascular basement membrane [15]. Synovial fluid specimens characteristically lack inflammatory components whereas are rich in hematic cells. The role of vitamin C deficiency in the development of osteoarthritis is not proved, some authors described a protective role of high doses of vitamin C supplementation and a recent study found that vitamin C and vitamin D levels were inversely associated with the presence of knee osteoarthritis [16]. Bone Recent animal studies have provided insights into the involvement of vitamin C in osteoclastogenesis and
Curr Rheumatol Rep (2015) 17: 26
osteoblastogenesis, and into its role as a mediator of bone matrix deposition, affecting both the quantity and quality of bone collagen [17]. Bone pain is a common finding in scurvy. Skeletal X-rays are typically normal, but sometimes bone sclerosis, ischemic necrosis, bone infarction, cortical thinning, osteopenia, osteolysis, and fractures have been described [10]. Magnetic resonance findings include bone marrow edema and joint swelling [18]. The involvement of the spine and pelvis can mimic an axial spondyloarthritis [19]. Computed tomography usually show bone loss, cortical fractures, and joint effusion. Osteolytic findings and increased uptake on radionuclide bone scan images can suggest a neoplasm or a septic arthritis. Scurvy may also lead to osteoporosis via different mechanisms: ascorbic acid is involved in collagen synthesis and normal bone turnover, essential for a healthy bone. Moreover, the nutritional deficiency typically linked to scurvy disease is often associated with severe hypovitaminosis D and poor dietary intake of calcium. Bone histology performed during total hip arthroplasty shows hemorrhagic bone infarctions with cartilage destruction [20]. Muscle Myositis is rare but myalgia, weakness, and widespread muscular pain are frequently reported. Magnetic resonance sometimes shows muscle edema that resolves with vitamin C supplementation [21]. Muscle tears have also been described as scurvy presentation [22]. Miscellaneus Eye and Mouth Hood and colleagues described the development of sicca syndrome in a group of five men with scurvy. Two of them showed a keratoconjunctivitis sicca with enlargement of the salivary glands mimicking Sjögren’s syndrome [23]. Lung Lung nodules due to capillary leakage and pulmonary hypertension were described, resembling systemic vasculitis [24]. Recently, Kupary and collegues described a case of a scurvy-associated pulmonary arterial hypertension and suggested a possible link with impaired availability of endothelial nitric oxide and inappropriate activation of the hypoxiainducible family (HIF) of transcription factors. HIF coordinates the body’s responses to hypoxia and requires vitamin C and iron as cofactors. Deficiency of these elements could lead to uncontrolled HIF activity and reversible pulmonary vasoconstriction [25].
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deformities, and swollen, purplish gums, can lead to a correct diagnosis, especially if associated with a history of poor vitamin C intake. However, due to the extreme variety of clinical presentations, the diagnosis can be difficult. Normal plasma concentration of Vitamin C ranges between 0.2 and 2.0 mg/dL (11– 114 μmol/L). There are different tests available to measure blood levels of ascorbic acid even if, usually, the rapid clinical response to vitamin C supplementation allows to establish the diagnosis without laboratory studies (See Figs. 1, 2, and 3a–b).
Treatment Brubacher et al. published a meta-analysis of Vitamin C concentrations in plasma as a function of the dietary intake. The study demonstrated that in the general population, the assumed optimal plasma concentration of 50 mumol/L, as proposed by a consensus conference, can be achieved by the intake of 100 mg per day [26]. Supplementation of 500– 1000 mg/day of oral vitamin C for 2–4 weeks is considered an efficacious treatment for scurvy [9, 10]. Divided doses distributed throughout the day should be used, to improve the absorption [9].
Conclusions Scurvy is a rare, uncommon disease in developed countries. When the symptoms are not typical, the diagnosis can be challenging. Different clinical features of scurvy can mimic rheumatological disease, in particular when arthritis, arthralgias, manifestations mimicking cutaneous vasculitis, or high levels of ESR occur. The variety of the disease presentations and its relative rarity can often lead to a delay in the diagnosis and treatment with possible inappropriate and potentially harmful treatments.
Diagnosis Typical clinical features, such as follicular hyperkeratosis and perifollicular hemorrhage associated with ecchymosis, hair
Fig. 1 Ecchymosis of the right lower leg after minor knee trauma in a patient with scurvy (serum vitamin C concentration
ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Rheumatic Manifestations of Scurvy Claudia Ferrari & Niccolò Possemato & Nicolò Pipitone & Bernhard Manger & Carlo Salvarani
Published online: 9 April 2015 # Springer Science+Business Media New York 2015
Abstract This paper reviews the rheumatological manifestations of scurvy, based on articles published in English from 1965 until October 2014, with a particular focus on rheumatological manifestations. Scurvy is a rare, uncommon disease in developed countries. Due to its clinical heterogeneity, the disease can easily mimic rheumatologic conditions leading to a delay in diagnosis and treatment. Keywords Scurvy . Arthritis . Pseudovasculitis . Rheumatic manifestations . Musculoskeletal manifestations
Methods A literature search using PubMed platform was performed for articles published in English from 1965 until October 2014. MeSH keywords used for this search were Bscurvy^ or/and Bascorbic acid deficiency^ matched with Brheumatic disease,^ Barthritis,^ Bhemarthrosis,^ Bpurpura,^ Bvasculitis,^ and Bmusculoskeletal disease.^ We included only articles about rheumatological manifestations of vitamin C deficiency in adults (age >18). Relevant articles were reviewed and additional articles were obtained through the analysis of references of articles from the original literature search.
Introduction Scurvy is a nutritional disorder caused by a deficiency in Vitamin C. Nowadays, its incidence in developed countries is limited to individuals with risk factors for poor nutrition such as poverty, social isolation, or psychiatric disorders. The rarity of the condition and the wide range of clinical manifestations related to the disease, like deep vein thrombosis, pseudovasculitis, musculoskeletal manifestations, and systemic bleeding disorders, can lead to a delay in the diagnosis. In case of rheumatologic manifestations of difficult interpretation, it is important for rheumatologists to consider scurvy as a possible cause. This article is part of the Topical Collection on Orphan Diseases C. Ferrari : N. Possemato : N. Pipitone : C. Salvarani (*) Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Viale Risorgimento 80, 42123 Reggio Emilia, Italy e-mail: [email protected] B. Manger Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany e-mail: [email protected]
Literature Review Vitamin C is an essential dietary nutrient required as a cofactor for many enzymes, and humans are among the few animals that lack the ability to synthesize the compound from glucose. The reduced form of the vitamin, ascorbic acid, is an especially effective antioxidant owing to its high electron-donating power and ready conversion back to the active reduced form [1]. Ascorbic acid is an enzymatic cofactor necessary for the synthesis of mature collagen formed by three polypeptide molecules combined into a triple helix. Collagen abnormalities may affect blood vessels’ integrity due to impaired synthesis of the constituents of the vessel wall and the surrounding connective tissue. Moreover, ascorbic acid is a cofactor in the metabolism of tyrosine and synthesis of carnitine, norepinephrine, and peptide hormones. It increases iron absorption and is also an important antioxidant agent [2]. Vitamin C is present in fruits and vegetables. Estimates of vitamin C amounts in foods depend on season, transport of the food, shelf time prior to purchase, storage, and cooking practices [3]. The recommended daily intake by the US Food and Nutrition Board of the Institute of Medicine for men 18 years
26 Page 2 of 5
of age or older is 90 mg of vitamin C daily; for women 18 years of age or older, it is 75 mg daily; for pregnant women 18 years of age or older, it is 85 mg daily; and for breastfeeding women 18 years of age or older, it is 120 mg daily. An inadequate intake of fresh fruit and vegetables is the main cause of vitamin C deficiency, in particular in older people, chronic alcoholics, and anorexic and homeless subjects. Moreover, smoking decreases the intestinal absorption and increases the catabolism of vitamin C. For instance, smoking more than 20 cigarettes per day is associated with a 40 % increase in the daily vitamin C turnover compared to non-smokers [4]. Other interesting studies have shown that some pathological conditions, such as gastrointestinal disorders like Crohn’s disease [5] and Whipple’s disease [6], can be responsible for a decreased absorption of vitamin C. Insulindependent diabetes is also associated with an increased need of vitamin C [7].
Clinical Features Constitutional Symptoms Nonspecific constitutional manifestations are present in scurvy, like weariness especially in the lower limbs, weakness, and malaise. In the literature are also described depression, nervousness, and lethargy. The origin of these mental changes is not clear, but ascorbic acid may be involved because it is a factor in some neurotransmitter functions in the brain [2]. Laboratory Findings The abnormalities of laboratory tests are not specific. Frequently, anemia is present in scurvy and its degree correlates with the severity and duration of scurvy. Causes of anemia can be multiple. Bleeding is common in vitamin C deficiency, and this may result in normocytic anemia with an increased reticulocytes count. Other concomitant contributing factors may be folic acid and iron deficiency. Folic acid is present in the same vegetables and fruits that contain vitamin C a n d i s f u n d am e n t a l f o r i n t e s t i n al ir o n i n t a k e . Intravascular hemolysis may also cause anemia. Sometimes, leukopenia and hypoalbuminemia are present [8, 9]. The elevations of acute phase reactants is frequent, in particular elevated values of ESR are described in many cases of scurvy [2, 10, 11]. The cause is probably related to a hepatic overexpression of inflammatory chemokines, stimulated by ascorbic acid deficiency [12]. However, the relationship between blood levels of ascorbic acid and increase in inflammatory markers is unclear. Autoimmunity is generally negative in patients with scurvy although some authors have
Curr Rheumatol Rep (2015) 17: 26
described in some patients the presence of low-titer speckled antinuclear antibodies [10]. Cutaneus Findings Dermatological manifestations are common in scurvy. Vitamin C deficiency frequently leads to skin dryness and roughness due to the development of hyperkeratosis. Biopsy samples demonstrate follicles filled with soft keratin [2]. Skin hemorrhages are the most common findings in scurvy. The capillary fragility has been linked to the loss of the blood vessel walls’ int e g r i t y. P e t e c h i a e o r p u r p u r a m a y b e p r e s e n t . Occasionally, the purpura became palpable and the ecchymoses widespread, thus mimicking vasculits. Histological findings are perifollicular hemorrhages, fibrosis, keratin plugging, and hyperkeratosis, in the absence of an underlying inflammatory process [13]. Nails can present abnormalities (like splinter hemorrhages) resembling rheumatic diseases such as scleroderma, systemic lupus erythematosus (SLE), rheumatoid arthritis, and antiphospholipid syndrome. Some patients present alopecia or develop hair fragility because ascorbic acid is fundamental in the disulfide bonding that occurs with hair formation. A particular hair growth called Bcorkscrew^ or Bswan neck^ is observed [2]. Skin biopsy of the scalp often demonstrates a coiled hair in its follicle [14]. Musculoskeletal Manifestations The musculoskeletal manifestations are frequent, and the rheumatologist is often part of the diagnostic work-up. Myalgias and Arthralgias Fain and coworkers described myalgias and arthralgias as frequent manifestations in scurvy (about 80 % of patients). Lower extremities are commonly affected, especially the ankles and knees. However, virtually any joint can be involved. Joint Synovitis of affected joints is rare, while spontaneous hemarthrosis is a common event. Histologically, the synovial membrane shows interstitial hemorrhage and large fibroblasts but little collagen and some disarray of vascular basement membrane [15]. Synovial fluid specimens characteristically lack inflammatory components whereas are rich in hematic cells. The role of vitamin C deficiency in the development of osteoarthritis is not proved, some authors described a protective role of high doses of vitamin C supplementation and a recent study found that vitamin C and vitamin D levels were inversely associated with the presence of knee osteoarthritis [16]. Bone Recent animal studies have provided insights into the involvement of vitamin C in osteoclastogenesis and
Curr Rheumatol Rep (2015) 17: 26
osteoblastogenesis, and into its role as a mediator of bone matrix deposition, affecting both the quantity and quality of bone collagen [17]. Bone pain is a common finding in scurvy. Skeletal X-rays are typically normal, but sometimes bone sclerosis, ischemic necrosis, bone infarction, cortical thinning, osteopenia, osteolysis, and fractures have been described [10]. Magnetic resonance findings include bone marrow edema and joint swelling [18]. The involvement of the spine and pelvis can mimic an axial spondyloarthritis [19]. Computed tomography usually show bone loss, cortical fractures, and joint effusion. Osteolytic findings and increased uptake on radionuclide bone scan images can suggest a neoplasm or a septic arthritis. Scurvy may also lead to osteoporosis via different mechanisms: ascorbic acid is involved in collagen synthesis and normal bone turnover, essential for a healthy bone. Moreover, the nutritional deficiency typically linked to scurvy disease is often associated with severe hypovitaminosis D and poor dietary intake of calcium. Bone histology performed during total hip arthroplasty shows hemorrhagic bone infarctions with cartilage destruction [20]. Muscle Myositis is rare but myalgia, weakness, and widespread muscular pain are frequently reported. Magnetic resonance sometimes shows muscle edema that resolves with vitamin C supplementation [21]. Muscle tears have also been described as scurvy presentation [22]. Miscellaneus Eye and Mouth Hood and colleagues described the development of sicca syndrome in a group of five men with scurvy. Two of them showed a keratoconjunctivitis sicca with enlargement of the salivary glands mimicking Sjögren’s syndrome [23]. Lung Lung nodules due to capillary leakage and pulmonary hypertension were described, resembling systemic vasculitis [24]. Recently, Kupary and collegues described a case of a scurvy-associated pulmonary arterial hypertension and suggested a possible link with impaired availability of endothelial nitric oxide and inappropriate activation of the hypoxiainducible family (HIF) of transcription factors. HIF coordinates the body’s responses to hypoxia and requires vitamin C and iron as cofactors. Deficiency of these elements could lead to uncontrolled HIF activity and reversible pulmonary vasoconstriction [25].
Page 3 of 5 26
deformities, and swollen, purplish gums, can lead to a correct diagnosis, especially if associated with a history of poor vitamin C intake. However, due to the extreme variety of clinical presentations, the diagnosis can be difficult. Normal plasma concentration of Vitamin C ranges between 0.2 and 2.0 mg/dL (11– 114 μmol/L). There are different tests available to measure blood levels of ascorbic acid even if, usually, the rapid clinical response to vitamin C supplementation allows to establish the diagnosis without laboratory studies (See Figs. 1, 2, and 3a–b).
Treatment Brubacher et al. published a meta-analysis of Vitamin C concentrations in plasma as a function of the dietary intake. The study demonstrated that in the general population, the assumed optimal plasma concentration of 50 mumol/L, as proposed by a consensus conference, can be achieved by the intake of 100 mg per day [26]. Supplementation of 500– 1000 mg/day of oral vitamin C for 2–4 weeks is considered an efficacious treatment for scurvy [9, 10]. Divided doses distributed throughout the day should be used, to improve the absorption [9].
Conclusions Scurvy is a rare, uncommon disease in developed countries. When the symptoms are not typical, the diagnosis can be challenging. Different clinical features of scurvy can mimic rheumatological disease, in particular when arthritis, arthralgias, manifestations mimicking cutaneous vasculitis, or high levels of ESR occur. The variety of the disease presentations and its relative rarity can often lead to a delay in the diagnosis and treatment with possible inappropriate and potentially harmful treatments.
Diagnosis Typical clinical features, such as follicular hyperkeratosis and perifollicular hemorrhage associated with ecchymosis, hair
Fig. 1 Ecchymosis of the right lower leg after minor knee trauma in a patient with scurvy (serum vitamin C concentration
