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Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic ("of, characterized by or having to do with scurvy"). Scurvy often presents itself initially as symptoms of malaise and lethargy, followed by formation of spots on the skin, spongy gums, and bleeding from the mucous membranes. Spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. As scurvy advances, there can be open, suppurating wounds, loss of teeth, jaundice, fever, neuropathy and death. Scurvy was at one time common among sailors, pirates and others aboard ships at sea longer than perishable fruits and vegetables could be stored (subsisting instead only on cured and salted meats and dried grains) and by soldiers similarly deprived of these foods for extended periods. It was described by Hippocrates (c. 460 BC–c. 380 BC), and herbal cures for scurvy have been known in many native cultures since prehistory. Scurvy was one of the limiting factors of marine travel, often killing large numbers of the passengers and crew on long-distance voyages.[1] This became a significant issue in Europe from the beginning of the modern era in the Age of Discovery in the 15th century, continuing to play a significant role through World War I in the 20th century. While today scurvy is known to be caused by a nutritional deficiency, until the isolation of vitamin C and direct evidence of its link to scurvy in 1932, numerous theories and treatments were proposed, often on little or no experimental data. This inconsistency is attributed [according to whom?] to the lack of vitamin C as a distinct concept, an inability to reliably link different foods (notably present in fresh citrus, watercress, and organ meat) to scurvy. An additional concept required to understand scurvy was the degradation of vitamin C by exposure to air and copper and other transition metal salts such as those of iron, thus changing the links of foods to scurvy over time. Treatment by fresh food, particularly citrus fruit, was periodically implemented, as it had been since antiquity. However until the 1930s, treatment was inconsistent, with many ineffective treatments used into the 20th century. It was a Scottish surgeon in the Royal Navy, James Lind, who first proved it could be treated with citrus fruit in experiments he described in his 1753 book A Treatise of the Scurvy,[2] though his advice was not implemented by the Royal Navy for several decades[when?]. In infants, scurvy is sometimes referred to as Barlow's disease, named after Sir Thomas Barlow,[3] a British physician who described it.[4] However, Barlow's disease may also refer to mitral valve prolapse. Other eponyms for scurvy include Moeller's disease and Cheadle's disease. Scurvy does not occur in most animals because they can synthesize their own vitamin C. However, humans and other higher primates (the simians - monkeys and apes - and tarsiers), guinea pigs, most or all bats, and some species of birds and fish lack an enzyme (L-gulonolactone oxidase) necessary for such synthesis and must obtain vitamin C through their diet. Vitamin C is widespread in plant tissues, with particularly high concentrations occurring in cruciferous vegetables, capsicum fruit including chilli and all colours of bell peppers, citrus fruits (oranges, lemons, limes, grapefruits), and almost all fruits including culinary fruits like tomatoes. The fruit with the highest concentration of vitamin C is the Kakadu Plum with nearly 3000 mg per 100g. Cooking significantly reduces the concentration of ascorbic acid. Ascorbic acid has a number of centrally important roles in plants.[5] CauseScurvy or subclinical scurvy is caused by the lack of vitamin C. In modern Western societies, scurvy is rarely present in adults, although infants and elderly people are affected.[6] Vitamin C is destroyed by the process of pasteurization, so babies fed with ordinary bottled milk sometimes suffer from scurvy if they are not provided with adequate vitamin supplements. Virtually all commercially available baby formulas contain added vitamin C for this reason, but heat and storage destroy vitamin C. Human breast milk contains sufficient vitamin C, if the mother has an adequate intake. Scurvy is one of the accompanying diseases of malnutrition (other such micronutrient deficiencies are beriberi or pellagra) and thus is still widespread in areas of the world depending on external food aid.[7] Though rare, there are also documented cases of scurvy due to poor dietary choices by people living in industrialized nations.[8][9][10][11] InuitThe Inuit[12] appear to be very healthy with a diet almost devoid of plants. They appear to get enough Vitamin C from raw fish and organs of marine mammals, and muktuk, the skin of the beluga whale. PathogenesisAscorbic acid is needed for a variety of biosynthetic pathways, by accelerating hydroxylation and amidation reactions. In the synthesis of collagen, ascorbic acid is required as a cofactor for prolyl hydroxylase and lysyl hydroxylase. These two enzymes are responsible for the hydroxylation of the proline and lysine amino acids in collagen. Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking the propeptides in collagen. Defective collagen fibrillogenesis impairs wound healing. Collagen is an important part of bone, so bone formation is affected. Defective connective tissue leads to fragile capillaries, resulting in abnormal bleeding. SymptomsEarly symptoms are malaise and lethargy. After 1–3 months, patients develop shortness of breath and bone pain. Myalgias may occur because of reduced carnitine production. Other symptoms include skin changes with roughness, easy bruising and petechiae, gum disease, loosening of teeth, poor wound healing, and emotional changes. Dry mouth and dry eyes similar to Sjögren's syndrome may occur. In the late stages, jaundice, generalized edema, oliguria, neuropathy, fever, convulsions, and eventual death are frequently seen.[13] PreventionScurvy can be prevented by a diet that includes certain citrus fruits such as oranges or lemons. Other sources rich in vitamin C are fruits such as blackcurrants, guava, kiwifruit, papaya, tomatoes, bell peppers, and strawberries. It can also be found in some vegetables, such as carrots, broccoli, potatoes, cabbage, spinach and paprika. Some fruits and vegetables not high in vitamin C may be pickled in lemon juice, which is high in vitamin C. Though redundant in the presence of a balanced diet,[14] various nutritional supplements are available that provide ascorbic acid well in excess of that required to prevent scurvy, and even some candies contain vitamin C as a preservative.[citation needed] Many animal products, including liver, Muktuk (whale skin), oysters, and parts of the central nervous system, including the brain, spinal cord, and adrenal medulla, contain large amounts of vitamin C, and can even be used to treat scurvy. Fresh meat from animals which make their own vitamin C (which most animals do) contains enough vitamin C to prevent scurvy, and even partly treat it. This caused confusion in the early history of scurvy, since the disease was only seen in people eating long-preserved diets or canned goods, but not in people eating any sort of fresh diet, including arctic diets primarily based upon meat. In some cases (notably in French soldiers eating fresh horse meat), it was discovered that meat alone, even partly cooked meat, could alleviate scurvy. In other cases, a meat-only diet could cause scurvy.[15] Some of these observations that scurvy was associated only with preserved foods prompted explorers to blame scurvy upon some type of tainting or poison which pervaded tinned foods. TreatmentScurvy can be treated by eating food containing vitamin C (such as oranges, papaya, strawberries, lemon), tablets with vitamin C, etc. PrognosisUntreated scurvy is invariably fatal. However, death from scurvy is rare in modern times. Since all that is required for a full recovery is the resumption of normal vitamin C intake, it is easy to treat if identified correctly. Consumption of dietary supplements and/or citrus fruits are means by which to accomplish this. HistoryScurvy was documented as a disease by Hippocrates,[16][17] and Egyptians have recorded its symptoms as early as 1550 BC.[18] The knowledge that consuming foods containing vitamin C is a cure for scurvy has been repeatedly rediscovered and forgotten into the early 20th century.[19] Early modern eraIn the 13th century, the Crusaders frequently suffered from scurvy. In the 1497 expedition of Vasco de Gama, the curative effects of citrus fruit were known.[19] In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree (Eastern White Cedar) to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.[20][21] Such treatments were not available aboard ship, where the disease was most common. Between 1500 and 1800, it has been estimated that scurvy killed at least two million sailors.[22] Jonathan Lamb wrote: "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."[23] In 1593, Admiral Sir Richard Hawkins advocated drinking orange and lemon juice as a means of preventing scurvy.[24] The British civilian medical profession of 1614 believed that it was the acidic principle of citrus fruit which was lacking, although they considered any acid acceptable when ascorbic acid (Vitamin C) was unavailable. In 1614 John Woodall, Surgeon General of the East India Company, published "The Surgion's Mate" as a handbook for apprentice surgeons aboard the company's ships. In it he described scurvy as resulting from a dietary deficiency. His recommendation for its cure was fresh food or, if not available, oranges, lemons, limes and tamarinds, or as a last resort, Oil of Vitriol (sulfuric acid).[25] 18th centuryA 1707 handwritten book by Mrs. Ebot Mitchell discovered in a house in Hasfield, Gloucestershire, contains a "Recp.t for the Scurvy" that consisted of extracts from various plants mixed with a plentiful supply of orange juice, white wine or beer.[26] James Lind, a pioneer in the field of scurvy preventionIn 1734, the Leiden-based physician Johann Bachstrom published a book on scurvy in which he stated that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease" and urged the use of fresh fruit and vegetables as a cure. In 1740, citrus juice (usually lemon or lime juice) was added to the recipe of the traditional daily ration of watered-down rum known as grog to cut down on the water's foulness. Although they did not know the reason at the time, Admiral Edward Vernon's sailors were healthier than the rest of the navy because of the daily doses of vitamin C his sailors received.[27] However, it was not until 1747 that James Lind formally proved that scurvy could be treated and prevented by supplementing the diet with citrus fruit, though not by other acids, in the first ever clinical trial.[2] In 1753, Lind published A Treatise of the Scurvy, in which he explained the details of his clinical trial and how scurvy was successfully eradicated from his test subjects (nuns). He then attempted to sell extracted lime juice as a medicine, but the lime juice had no effect in treating scurvy, due to the oxidization of vitamin C[citation needed]. Therefore, this solution was not adopted by the Royal Navy until the 1790s, and the idea that any acid would suffice continued in Britain into the late 19th century. During the 18th century, scurvy killed more British sailors than enemy action. It was mainly by scurvy that George Anson, in his celebrated voyage of 1740–1742, lost nearly two-thirds of his crew (1300 out of 2000) within the first ten months of the voyage.[28] During the Seven Years' War, the Royal Navy reported that it conscripted 184,899 sailors, of whom 133,708 died of disease or were "missing", and scurvy was the principal disease.[29] James Cook succeeded in circumnavigating the world (1768–1771) in HM Bark Endeavour without losing a single man to scurvy, but his suggested methods, including a diet of sauerkraut and wort of malt,[30] were of limited value. Sauerkraut was the only vegetable food that retained a reasonable amount of ascorbic acid in a pickled state, but it was boiled to reduce it for preservation, and much of the vitamin C content was lost. In Cook's time it was impractical to preserve citrus fruit for long sea voyages. More important was Cook's regime of shipboard cleanliness, enforced by strict discipline, as well as frequent replenishment of fresh food.[31] The most effective rule implemented by Cook was his prohibition against the consumption of fat scrubbed from the ship's copper pans, then a common practice in the Navy. In contact with air the copper formed compounds that catalytically oxidised the vitamin C, destroying its efficacy.[32] The first major long distance expedition that experienced virtually no scurvy was that of Alessandro Malaspina, 1789–1794. Malaspina's medical officer, Pedro González, was convinced that fresh oranges and lemons were essential for preventing scurvy. Only one outbreak occurred, during a 56-day trip across the open sea. Five sailors came down with symptoms, one seriously. After three days at Guam all five were healthy again. Spain's large empire and many ports of call made it easier to acquire fresh fruit.[33] Despite advances, British sailors throughout the American Revolution continued to suffer from scurvy, particularly in the Channel Fleet. Scurvy was finally eradicated from the Royal Navy during the Napoleonic Wars, when Gilbert Blane, the chairman of the Navy's Sick and Hurt Board, implemented the use of fresh lemons. This led to a remarkable health improvement among the sailors and consequently played a critical role in naval battles, notably the Battle of Trafalgar. Other navies soon adopted this successful solution.[25] 19th century Page from the journal of Henry Walsh Mahon showing the effects of scurvy, from his time aboard HM Convict Ship Barrosa. 1841/2The surgeon-in-chief of Napoleon's army at the Siege of Alexandria (1801), Baron Dominique-Jean Larrey, wrote in his memoirs that the consumption of horse meat helped the French to curb an epidemic of scurvy. The meat was cooked but was freshly obtained from young horses bought from Arabs and was nevertheless effective. This helped to start the 19th-century tradition of horse meat consumption in France.[34] Lauchlin Rose patented a method used to preserve citrus juice without alcohol in 1867, creating a concentrated drink known as Rose's lime juice. The Merchant Shipping Act of 1867 required all ships of the Royal Navy and Merchant Navy to provide a daily lime ration to sailors to prevent scurvy. The product became nearly ubiquitous, hence the term "limey", first for British sailors, then for English immigrants within the former British colonies (particularly America, New Zealand and South Africa), and finally, in old American slang, all British people.[35] The plant Cochlearia officinalis, also known as "Common Scurvygrass", acquired its common name from the observation that it cured scurvy, and it was taken on board ships in dried bundles or distilled extracts. Its very bitter taste was usually disguised with herbs and spices; however, this did not prevent scurvygrass drinks and sandwiches becoming a popular fad in the UK until the middle of the nineteenth century, when citrus fruits became more readily available.[36] West Indian limes replaced lemons because they were more easily obtained from Britain's Caribbean colonies[19] and were believed to be more effective because they were more acidic, and it was the acid, not the (then-unknown) Vitamin C that was believed to cure scurvy. In fact, the West Indian limes were significantly lower in Vitamin C than the previous lemons and further were not served fresh but rather as lime juice, which had been exposed to light and air and piped through copper tubing, all of which significantly reduced the Vitamin C. Indeed, a 1918 animal experiment using representative samples of the Navy and Merchant Marine's lime juice showed that it had virtually no antiscorbutic power at all.[19] The belief that scurvy was fundamentally a nutritional deficiency, best treated by consumption of fresh food, particularly fresh citrus or fresh meat, was not universal in Britain in the 19th and early 20th centuries, and thus British sailors and explorers continued to suffer from scurvy into the 20th century. In the Royal Navy's Arctic expeditions in the 19th century it was widely believed that scurvy was prevented by good hygiene on board ship, regular exercise, and maintaining the morale of the crew, rather than by a diet of fresh food. Navy expeditions continued to be plagued by scurvy even while fresh (not jerked or tinned) meat was well known as a practical antiscorbutic among civilian whalers and explorers in the Arctic. Even cooking fresh meat did not entirely destroy its antiscorbutic properties, especially as many cooking methods failed to bring all the meat to high temperature. The confusion is attributed to a number of factors:[19] while fresh citrus (particularly lemons) cured scurvy, lime juice that had been exposed to light, air and copper tubing did not – thus undermining the theory that citrus cured scurvy; fresh meat (especially organ meat and raw meat, consumed in arctic exploration) also cured scurvy, undermining the theory that fresh produce was essential to preventing and curing scurvy; increased marine speed via steam shipping, and improved nutrition on land, reduced the incidence of scurvy – and thus the ineffectiveness of copper-piped lime juice compared to fresh lemons was not immediately revealed. In the resulting confusion, a new hypothesis was proposed, following the new germ theory of disease – that scurvy was caused by ptomaine, a waste product of bacteria, particularly in tainted tinned meat. Infantile scurvy emerged in the late 19th century because children were being fed pasteurized cow's milk, particularly in the urban upper class – the pasteurization killed bacteria but also destroyed vitamin C. This was eventually resolved by supplementing with onion juice or cooked potatoes. 20th centuryAt the time Robert Falcon Scott made his two expeditions (1903 and 1911) to the Antarctic in the early 20th century, the prevailing theory was that scurvy was caused by "tainted" meat, particularly tinned meat.[37] Accordingly, Scott's expeditions suffered from scurvy, though he initially did not record this in his notes on his 1903 expedition, because of stigma associated with the disease.[19] Vilhjalmur Stefansson, an arctic explorer who lived among the Eskimos, proved that the all meat diet they consumed did not lead to vitamin deficiencies. He participated in a study in New York's Bellevue Hospital in 1935, where he and a companion ate only meat for a year while under close medical observation, yet remained in good health.[38] Some Antarctic expeditions, such as Scott's two expeditions and Shackleton's Ross Sea party, suffered from scurvy, mainly during inland sledge journeys when the men had access to a very limited range of food, virtually none of it fresh. Scurvy was rare or absent when they had access to a wider range of stored food or relied on seal meat.[37][39][40] In 1907, the needed biological-assay model to isolate and identify the antiscorbutic factor was discovered. Axel Holst and Theodor Frølich, two Norwegian physicians studying shipboard beriberi contracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons then used in beriberi research. They fed guinea pigs their test diet of grains and flour, which had earlier produced beriberi in their pigeons, and were surprised when classic scurvy resulted instead. This was a serendipitous choice of model. Until that time, scurvy had not been observed in any organism apart from humans and had been considered an exclusively human disease. (Some birds are susceptible to scurvy, but pigeons, as seed-eating birds, were later found to be unaffected by scurvy, as they produce vitamin C.) Holst and Frølich found they could cure scurvy in guinea pigs with the addition of various fresh foods and extracts. This discovery of a "clean" (reliable) animal experimental model for scurvy, which was made even before the essential idea of "vitamins" in foods had been put forward, has been called the single most important piece of vitamin C research.[41] In 1927, Hungarian biochemist Szent-Györgyi isolated a compound he called "hexuronic acid".[42] Szent-Györgyi suspected hexuronic acid, which he had isolated from adrenal glands, to be the antiscorbutic agent, but he could not prove it without an animal-deficiency model. In 1932, the connection between hexuronic acid and scurvy was finally proven by American researcher Charles Glen King of the University of Pittsburgh.[43] King's laboratory was given some hexuronic acid by Szent-Györgyi and soon established that it was the sought-after anti-scorbutic agent. Because of this, hexuronic acid was subsequently renamed ascorbic acid. Experimental human trialsNotable human dietary studies of experimentally induced scurvy have been conducted on conscientious objectors during WWII in Britain and on Iowa state prisoner "volunteers" in the late 1960s. These studies both found that all obvious symptoms of scurvy previously induced by an experimental scorbutic diet with extremely low vitamin C content could be completely reversed by additional vitamin C supplementation of only 10 mg per day. In these experiments, no clinical difference was noted between men given 70 mg vitamin C per day (which produced blood levels of vitamin C of about 0.55 mg/dl, about 1/3 of tissue saturation levels), and those given 10 mg per day (which produced lower blood levels). Men in the prison study developed the first signs of scurvy about 4 weeks after starting the vitamin C-free diet, whereas in the British study, six to eight months were required, possibly because the subjects were pre-loaded with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.[44] Men in both studies on a diet devoid or nearly devoid of vitamin C had blood levels of vitamin C too low to be accurately measured when they developed signs of scurvy, and in the Iowa study, at this time were estimated (by labeled vitamin C dilution) to have a body pool of less than 300 mg, with daily turnover of only 2.5 mg/day.[45] In other animalsAlmost all plant and animal species synthesize vitamin C. Notable mammalian exceptions include most or all of the order Chiroptera (bats), and one of the two major primate suborders, the "Anthropoidea" (Haplorrhini) which include tarsiers, monkeys, and apes, including human beings. The Strepsirrhini (non-tarsier prosimians) can make their own vitamin C, and these include lemurs, lorises, pottos, and galagos. Ascorbic acid is also not synthesized by at least two species of Caviidae, the capybara[46] and the guinea pig. There are known species of birds and fish that do not synthesize their own Vitamin C. All species that do not synthesize ascorbate require it in the diet. Deficiency causes scurvy in humans, and somewhat similar symptoms in other animals.[47][48][49] |
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