Joint Bone Spine 72 (2005) 124–128
http://france.elsevier.com/direct/BONSOI/
Review
Musculoskeletal manifestations of scurvy
Olivier Fain
Internal Medicine Department, Jean Verdier Teaching Hospital, Assistance Publique-Hôpitaux de Paris,
Paris-North University-School of Medicine, UPRES EA 3409, avenue de 14 Juillet, Bondy cedex 93143, France
Received 20 October 2003; accepted 8 January 2004
Available online 09 April 2004
Abstract
Scurvy occurs in individuals who eat inadequate amounts of fresh fruit or vegetables, often because of dietary imbalances related to
advanced age or homelessness. Asthenia, vascular purpura, bleeding, and gum abnormalities are the main symptoms. In 80% of cases, the
manifestations of scurvy include musculoskeletal symptoms consisting of arthralgia, myalgia, hemarthrosis, and muscular hematomas. Vitamin C depletion is responsible for structural collagen alterations, defective osteoid matrix formation, and increased bone resorption. Imaging
studies may show osteolysis, joint space loss, osteonecrosis, osteopenia, and/or periosteal proliferation. Trabecular and cortical osteoporosis
is common. Children experience severe lower limb pain related to subperiosteal bleeding. Laboratory tests show nonspecific abnormalities
including anemia and low levels of cholesterol and albumin. The finding of a serum ascorbic acid level lower than 2.5 mg/l confirms the
diagnosis. Vitamin C supplementation ensures prompt resolution of the symptoms.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Scurvy; Vitamin C; Vitamin deficiency; Hemarthrosis; Osteoporosis; Barlow’s disease
1. Introduction
Scurvy, the constellation of clinical manifestations caused
by vitamin C deficiency, has been increasingly reported over
the last few years [1–12]. Individuals with risk factors for
poor nutrition, such as social isolation, poverty, and homelessness, provide most cases of scurvy, although no subset of
the general population is exempt. Musculoskeletal manifestations may be the presenting symptoms.
2. Historical perspective
Scurvy was known in Ancient Egypt, and a description
ascribed to Hippocrates explains that “sufferers have a foul
breath, boggy gums, and a propensity for nosebleeds; they
may have leg ulcers.” Between the 15th and 18th centuries,
scurvy took the lives of 50–80% of those who embarked on
long sea voyages. In 1753, James Lind, a British Naval Surgeon, reported that eating oranges and lemons was effective
against scurvy. Lemon juice was provided preventively to sea
voyagers in Britain starting in 1795 and in France starting in
1856 [13]. In 1907, Holst and Frolisch induced scurvy in
E-mail address: [email protected] (O. Fain).
© 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.jbspin.2004.01.007
guinea pigs by feeding them a diet low in fresh vegetables.
Five years later, Zylva extracted an antiscorbutic compound
from lemon juice. Finally in 1932, Haworth elucidated the
structure of vitamin C and suggested the name “ascorbic acid”.
Reichstein succeeded in synthesizing ascorbic acid a few
months later.
3. Metabolism
Vitamin C, or ascorbic acid, is a water-soluble compound
vulnerable to heat, ultraviolet radiation, and oxygen. The total
pool in the body is 1500–2500 mg and the daily turnover is
45–60 mg, i.e. about 3% of the total [14]. Vitamin C has a
half-life of 10–20 days. Absorption occurs in the ileum via
an active transport mechanism that becomes saturated when
the oral intake exceeds 180 mg/day. The absorption rate is
about 85%. Concentrations are in the 5–15 mg/l range in the
plasma and erythrocytes but are 80 times higher in the platelets and erythrocytes. Levels in tissues are similar to those in
leukocytes. Vitamin C is not stored in the body, so that some
dietary intake is indispensable, the best sources being fresh
fruit and vegetables. Milk, fish, and meat contain little or no
vitamin C (0–2 mg/100 g). To prevent scurvy, the daily intake
must be no lower than 10 mg/day and the body pool no smaller
than 350 mg [15].
O. Fain / Joint Bone Spine 72 (2005) 124–128
Vitamin C is involved in numerous hydroxylation reactions, including those responsible for procollagen production
via the enzymes proline-oxidase and lysine-oxidase. Vitamin
C deficiency induces collagen abnormalities that explain the
clinical manifestations of scurvy: abnormal dentine production and loss of teeth, vessel wall damage and bleeding, purpura, edema, bone changes (in children) due to the inability
of osteoblasts to produce the osteoid seam, and skin changes
related to keratin abnormalities. The effect of vitamin C on
dioxygenases is essential to the production of carnitine, and
this may explain the fatigue experienced by patients with
scurvy. Vitamin C is a cofactor in the biosynthesis of catecholamines, most notably in the conversion of dopamine to
norepinephrine, which may explain the behavior and mood
disorders associated with vitamin C deficiency. Vitamin C
increases the absorption of nonheme iron [15].
4. Epidemiology
Vitamin C deficiency remains common. Studies done in
the 1970s in the United Kingdom found serum ascorbic acid
levels lower than 2 mg/l in 50% of elderly individuals living
at home [16]. In 1998, Johnston reported vitamin C deficiency (<2 mg/l) in 6% and depletion (<5 mg/l) in 30.4% of
apparently healthy middle-class Americans [17]. In a study
from the Val-de-Marne region near Paris, France, in 1108 nonhospitalized individuals, Hercberg found that serum ascorbic
acid levels were lower than 2 mg/l in 5% of women and 12%
of men overall, and that these proportions increased to 15%
and 20%, respectively, in the subset older than 65 years of
age [18]. We prospectively investigated 184 patients admitted to an internal medicine department in Seine-Saint-Denis,
also near Paris, France; serum ascorbic acid levels were lower
than 5 and 2 mg/l in 47.3% and 16.9% of patients, respectively. In some geographic areas, scurvy remains a scourge:
thus, over 100 000 cases were recorded in the 1990s among
refugees in the horn of Africa [20]. Ascorbic acid levels vary
across seasons, with levels being lowest during the winter
[21].
5. Risk factors for vitamin C deficiency
An inadequate intake of fresh fruit and vegetables is by far
the main cause of vitamin C deficiency. Males who live alone,
older individuals, chronic alcoholics, and individuals who voluntarily eat a restrictive diet or eat only in fast-food restaurants are at high risk for low vitamin C intake. The two risk
factors identified in our study [19] were being retired and
abusing alcohol and cigarettes. Jacob et al. [22] reported that
vitamin C deficiency was more common among males,
whereas Johnston and Thompson [17] found no difference
between males and females. Smoking decreases the intestinal absorption and increases the catabolism of vitamin C.
125
Thus, smoking more than 20 cigarettes per day is associated
with a 40% increase in the daily vitamin C turnover, as compared to nonsmokers [23]. Schectman [24] reported that smokers had a threefold increase in vitamin C deficiency and estimated that they needed a daily intake greater than 200 mg/day.
Kallner et al. [23] showed that alcohol increases vitamin C
requirements.
A study was done in Paris, France, in 87 individuals who
had been homeless for longer than 2 years. Among them, 84%
were chronic alcoholics and 75.5% were smokers. Vitamin C
assays showed depletion in 95% of cases and undetectable
levels in 72% [25]. Other factors associated with vitamin C
deficiency include psychosis and anorexia nervosa; cancer
[26], AIDS, and other wasting diseases; parenteral nutrition
without appropriate vitamin C supplementation; renal replacement therapy by hemodialysis or peritoneal dialysis, which
is associated with increased vitamin C needs; gastrointestinal disorders responsible for decreased vitamin C absorption
such as Crohn’s disease [27], Whipple’s disease [28], and
celiac disease [29]; and increased needs related to growth,
pregnancy, and breast-feeding. Insulin-dependent diabetes
mellitus is also associated with increased needs: even with a
dietary intake within the recommended range, patients with
insulin-dependent diabetes have low vitamin C levels in leukocytes [30] and blood [17]. Finally, renal vitamin C wasting
may occur in patients with iron overload disorders [31].
6. Clinical manifestations
Models of scurvy have provided accurate information on
the time to development of clinical manifestations. Serum
ascorbic acid levels become undetectable 41 days after the
initiation of a diet deficient in vitamin C, cell depletion occurs
after 121 days, and the first skin lesions develop after
132 days. Dental abnormalities occur after 6 months. The constellation of clinical symptoms develops after 1–3 months of
a diet containing no vitamin C at all, when the total body
pool falls below 300 mg and the serum ascorbic acid level
decreases below 2.5 mg/l [17,19]. Hodges reported that the
first clinical manifestations of scurvy occurred when serum
ascorbic acid levels fell to the 1.3–2.4 mg/l range in five
patients with experimental vitamin C deficiency [31]. The earliest manifestations are nonspecific constitutional symptoms
such as asthenia, anorexia, and weight loss.
6.1. Musculoskeletal manifestations
These symptoms develop later and consist of arthralgia in
the knees, ankles, and wrists, as well as myalgia [32]. Musculoskeletal manifestations are present in 80% of patients
with scurvy [33]. Eventually, bleeding occurs within the
joints, mainly the hips, knees, and ankles, the two main
mechanisms being damage to synovial blood vessels and
microfractures [33]. Involvement of the hip may produce
radiographic osteolysis [34,35], sometimes with joint space
126
O. Fain / Joint Bone Spine 72 (2005) 124–128
loss [35]. Other radiographic changes may include osteonecrosis, osteopenia, and cortical thinning with periosteal proliferation [36]. Computed tomography shows bone loss, cortical disruption, and joint effusion [34,35]. Increased uptake
is seen on radionuclide bone scan images. These findings
may suggest malignant osteolysis, septic arthritis, or osteonecrosis. Histologic examination of specimens taking
during hip arthroplasty [34] have shown hemorrhagic bone
infarctions with cartilage destruction. Electron microscopy
examination of the synovial membrane of a patient with
scurvy showed loss of mature collagen fibers in the interstitial and perivascular areas [37].
Osteoporosis affecting both the trabecular and the cortical
bone seems common in patients with scurvy [38]. Vitamin C
depletion results in defective osteoid matrix formation and in
increased bone resorption. Radiographs show nonspecific
changes such as biconcave vertebral deformity with sclerosis
of the edges [39]. Osteoporotic vertebral fractures have been
reported [40,41]. However, in the case described by Barratt
and Summers [42] the causal role for vitamin C deficiency
was questionable, as the patient was a 71-year-old woman
who had experienced the menopause at 43 years of age. In
older individuals, multiple deficiencies are the rule, and concomitant vitamin D deficiency increases the risk of vertebral
fracture. Using the data from the Postmenopausal
Estrogen/Progestin Interventions Trial [43], Hall showed that
supplementation with 100 mg/day of vitamin C was not
associated with an increase in bone mineral density (BMD)
in women with a low dietary calcium intake (<500 mg/day)
but resulted in a significant BMD increase at the femoral
neck in women with adequate calcium intakes. Morton investigated the effects of vitamin C supplementation (mean dosage, 745 mg/day, for longer than 3 years) in postmenopausal
women and found a significant BMD increase as compared to
the controls [44]. In addition, vitamin C supplementation
acted synergistically with estrogens and calcium [44].
Studies of potential links between vitamin C deficiency
and osteoarthritis have produced conflicting results. McAlindon et al. [45] reported slowing of the rate of joint space loss
and decreased pain in patients with knee osteoarthritis who
took large supplements of vitamin C and other antioxidants
(vitamin E and beta-carotene). Wluka, in contrast, found that
antioxidants failed to improve cartilage volume or pain in
patients with knee osteoarthritis [46].
Musculoskeletal manifestations are prominent in pediatric
scurvy or Barlow’s disease [47]. In 1883, Thomas and Barlow described 31 cases of rickets, concluding that “acute
rickets” was actually scurvy, sometimes accompanied with
genuine rickets [48]. Autopsy findings led him to ascribe the
severe lower limb pain to bleeding in the subperiosteal space.
Scurvy affect infants aged 6–18 months who are fed only
formula without vitamin C supplementation. Breast milk
contains enough vitamin C to meet the infant’s needs, provided the mother does not have vitamin C deficiency. The
constitutional symptoms of scurvy in infants include failure
to gain weight, loss of appetite, and irritability. Severe pain in
the thighs and legs is a striking feature of infantile scurvy and
can result in pseudoparalysis. Subperiosteal hematomas may
be palpable as painful swellings over the distal ends of the
femurs and tibias. Radiographs show sheathing of the diaphyseal shafts, broadening of the calcification front at the
anterior end of the ribs and ends of the metaphyses, and
demineralization with metaphyseal fractures.
6.2. Other clinical manifestations
Bleeding, which is a consequence of vessel wall fragility,
manifests primarily as petechiae over the limbs and trunk
centered on the hair follicles, bruising, and hematomas.
Bleeding within nerve sheaths is responsible for “painful
scurvy paralysis”. Intramuscular hematomas may cause
compartment syndrome. Gastrointestinal, gynecological,
and cerebral bleeding has been described. Follicular hyperkeratosis and pigmented ichtyosis may occur, together with
lower limb edema, corkscrew body hair, and alopecia.
Oral cavity abnormalities are characteristic although inconsistent. Hypertrophy and bleeding of the gums occur only
in patients with teeth, being more marked in patients with a
poor dental status. Parodontal lysis is a late feature responsible for loosening of the teeth and, potentially, loss of teeth.
Sicca syndrome with parotid gland hypertrophy has been
reported. Depression is far from uncommon. In patients with
arthralgia, myalgia, sicca, and purpura, Sjögren’s syndrome
[49] or vasculitis [6] may be considered. Bleeding may suggest a blood cell or clotting disorder.
7. Laboratory findings
Laboratory test abnormalities are nonspecific. A common
finding is anemia, which may be hypochromic, normocytic,
or macrocytic. Although bleeding may contribute to induce
anemia, the main factor is concomitant iron and folic acid
deficiency. Folic acid is found in the same foods as vitamin C
and is required for iron absorption. Intravascular hemolysis
may also cause anemia. Leukopenia is not infrequent. Serum
cholesterol levels are often low and vary in lockstep with
serum ascorbic acid levels. Hypoalbuminemia is a marker for
malnutrition found in most patients with scurvy [19]. The
definite diagnosis is achieved by determining the serum
ascorbic acid level, although the result is more heavily dependent on the recent ascorbic acid intake than on the body
pool. The normal range is 5–16 mg/l, and clinical symptoms
occur when values fall below 2.5 mg/l. Serum ascorbic acid
levels should be interpreted in the light of results of tests for
inflammation. Ascorbic acid is transferred from the serum to
the leukocytes during the inflammatory response, so that
ascorbic acid levels decline in the serum and rise in the
leukocytes, although the body pool remains unchanged [50].
Leukocyte ascorbic acid assays provide a more faithful indicator of the body pool but are not available on a routine basis.
O. Fain / Joint Bone Spine 72 (2005) 124–128
Table 1
Recommended daily allowance of ascorbic acid [60]
Population
Infants
Children aged 1–3 years
Children aged 4–6 years
Children aged 7–9 years
Children aged 10–12 years
Adolescents aged 13–19 years
Adults aged 20–60 years
Pregnant women
Breast-feeding mothers
Elderly individuals
Smokers
Patients with diabetes
mg/day
50
60
75
90
100
110
110
120
130
120
140
140
eases, intentional dietary restrictions, and lack of education
about dietary needs. The musculoskeletal and other clinical
manifestations may be misleading, particularly as few physicians in industrialized countries have first-hand knowledge
of scurvy. An early diagnosis is vital, as the specific treatment
is simple, inexpensive, and effective in eliminating the symptoms.
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8. Outcome
[4]
The outcome may be unfavorable if the diagnosis is
missed. Severe bleeding may occur, and deficiencies in cellmediated immunity and phagocytosis produce a risk of severe infection. Seizures and cardiac abnormalities may occur. ST-segment and T-wave changes are not infrequent, and
sudden death has been reported [51]. During the 2003 war in
Afghanistan, the World Health Organization identified
40 cases of fatal scurvy in the Taiwara area alone [52].
Vitamin C depletion (serum levels in the 2–5 mg/l range)
does not consistently result in scurvy but may increase the
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9. Treatment
Supplementation with 1 g/day of oral vitamin C for
2 weeks is the usual treatment. Divided doses distributed
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with intakes greater than 100 mg. Parenteral administration
is required in patients with malabsorption. The bleeding
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