Scurvy The History and Discovery of Vitamin C

Scurvy is traditionally associated with long sea voyages (Table 1), which typically lasted for several years; the seamen's diets were confined to whatever could be stored at room temperature for long periods. in the absence of refrigeration, their diets typically consisted of dried biscuits and other dry cereal foods (wheat flour and oatmeal), salted meat, dried peas, cheese, butter, and ale, i.e., whatever could be dried and preserved, often for long periods in adverse tropical climates. The signs and symptoms that were commonly described in classical accounts of scurvy, written long before its cause was understood, included lassitude, swollen joints, putrid and bleeding gums, failure of wound healing and the opening of old wounds and sores, intradermal bleeding due to capillary fragility, heart failure, and sudden death (Table 2). Although nowadays we carefully distinguish the symptoms of true scurvy (now known to be produced specifically by vitamin C deficiency) from conditions such as beriberi (thia-mine deficiency, which is associated with oedema of the lower limbs), vitamin A deficiency (associated with night-blindness and corneal lesions), and rickets (caused mainly by a lack of exposure to sunlight in children), in the older literature these conditions were often not recognized as distinct. Signs and symptoms of scurvy occurred on land in times of siege or during prolonged military campaigns where dietary variety and access to fresh foods were severely restricted. While some medical practitioners and leaders became convinced that the cause of scurvy was dietary and that cure and prevention were possible by including fresh plant food such as scurvy grass, decoctions of evergreen needles etc. in the diet (Table 1), many remained convinced, right up to the beginning of the twentieth century, that other factors such as 'foul vapours' or infections were to blame. indeed, before the recognition and discovery of essential micronutrients and experimental animal studies in the early years of the twentieth century, which confirmed that small amounts of certain complex organic molecules are needed in the diet to maintain health, the idea that food needed to supply anything other than energy, protein, certain minerals, and water was not generally accepted.

Although ad hoc treatments for scurvy had been successfully applied in many situations before the eighteenth century, the definitive proof of a dietary cure is attributed to James Lind, whose controlled trial of several different treatments of the disease on board HMS Salisbury, followed by his Treatise of the Scurvy published in 1753, provided the decisive evidence that persuaded the British Admiralty to insist on the inclusion of citrus fruit regularly in the naval diet (Table 1). Lind showed that a 'rob' or decoction of oranges could rapidly cure the disease, and the application of his discovery rapidly brought about dramatic reductions in the incidence of and mortality due to scurvy. However, the labile component in fruit that was responsible for protection against scurvy was not isolated until 1928. its

Table 1 Scurvy and vitamin C; selected historical milestones, 1500-1950

1536 1593 1753

Late eighteenth century

Late nineteenth century Early twentieth century 1928 1933

Mid twentieth century

Jacques Cartier used a leaf extract of evergreen-tree needles to cure scurvy in explorers in Newfoundland

Sir Richard Hawkins successfully used citrus fruit (amongst other cures and precautions) as a cure for scurvy in sailors

James Lind's Treatise of the Scurvy described the first controlled nutrition experiment, in which oranges and lemons, but not other treatments, cured scurvy in sailors Successful public-health practices were introduced to reduce scurvy in the British navy based on citrus-fruit rations (Sir Gilbert Blane); Captain James Cook's long sea voyages used, and benefited from, this new knowledge Outbreaks of 'Barlow's disease' (infantile scurvy) in young children receiving mainly condensed cow's milk

Guinea-pig model of human scurvy developed by Holst and Frohlich in Norway; this enabled antiscorbutic foods and extracts to be studied in the laboratory Isolation of crystalline 'hexuronic acid' by Albert Szent-Gyorgyi in Cambridge, followed by its recognition as 'the antiscorbutic vitamin', alias vitamin C, by Charles King in Pittsburgh Norman Haworth (UK) and Tadeus Reichstein (Switzerland) separately synthesized vitamin C

(L-ascorbic acid) and resolved its structure Human studies showed 10 mg vitamin C per day to be sufficient to prevent or cure scurvy; animal studies showed that vitamin C is essential for normal collagen and hence connective-tissue formation, thereby resolving the biochemical basis for many of the clinical signs of scurvy chemical structure was proved by de novo synthesis from common sugars a few years later (Table 1). Paradoxically, crystalline ascorbic acid (vitamin C) was first isolated, not from a plant source such as fruit or green leaves, but from an animal source, namely adrenal glands, where high concentrations are also found. Indeed, the original motivation for the isolation of the crystalline material by Albert

Szent-Gyorgyi in Hopkins' laboratory in Cambridge arose from his attempt to isolate a new adrenal hormone. The 'hexuronic acid' that he crystallized was not immediately equated with the antiscorbutic vitamin. Fortunately, studies by Charles Glen King in Pittsburgh led to the recognition of this unstable easily oxidized sugar derivative as the long-sought antiscorbutic principle, vitamin C or l-ascorbic acid.

Table 2 The signs and symptoms of scurvy, and evidence of inadequate tissue levels of vitamin C Clinical signs and symptoms of scurvy in adults

Petechiae (small hemorrhagic spots), perifollicular hemorrhages, and larger sheet hemorrhages, especially of the skin of the limbs and trunk

Positive 'Hess test' (pressure or suction test) for increased capillary fragility

Hyperkeratosis of hair follicles; hairs abnormally coiled (ecchymoses)

Swollen and bleeding gums

Swollen painful joints, with effusions and arthralgia

Failure of wound healing and breakdown (reopening) of old wounds

Oedema, dyspnoea, dry eyes and mouth

Lassitude and impaired mental state

Sudden heart failure, often leading to sudden death, in severe cases Clinical signs and symptoms in young infants

Painful joints leading to frog-like lying appearance; bleeding into the joints Swelling ('beading') of rib cage and swelling of long-bone joints

Changes in x-ray appearance of the epiphyses of the long bones: 'ground glass' appearance, differing from that of rickets (with which infantile scurvy was often confused) Intracranial hemorrhages, 'bulging eyes', and anemia in some cases; gums affected only if teeth already erupted

Biochemical evidence of inadequate vitamin C status

Serum or plasma vitamin C concentration <0.2mgdl-1 (<11 imrnolr1)

Buffy-coat vitamin C concentration <15 mg (<85nmol) per 108 white cells

Untreated subjects with clinical scurvy invariably have very low biochemical vitamin C levels, but people may have very low biochemical levels without having clinical evidence of scurvy; very low intakes for periods of months to years, plus additional stresses, increase the likelihood of clinical scurvy

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