Scurvy

Scurvy
Classification and external resources
Scorbutic gums, a symptom of scurvy. Note gingival redness in the triangle shaped interdental papillae between teeth
ICD-10	E54
ICD-9	267
OMIM	240400
DiseasesDB	13930
MedlinePlus	000355
eMedicine	med/2086 derm/521 ped/2073 radio/628
MeSH	D012614

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 separated from 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. 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.

Today scurvy is known to be caused by a nutritional deficiency, but until the isolation of vitamin C and its direct link to scurvy in 1932, numerous theories and treatments were proposed, often on little or no experimental data. This inconsistency is attributed to the lack of vitamin C as a distinct concept, the varying vitamin C content of different foods (notably present in fresh citrus, watercress, and organ meat), and how vitamin C can be destroyed by exposure to air and copper.

Treatment by fresh food, particularly citrus fruit, was periodically implemented, as it had been since antiquity, but the ultimate cause of scurvy was not known until 1932, and treatment was inconsistent, with many ineffective treatments used into the 20th century. It was a Scottish surgeon in the British 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,^[1] though his advice was not implemented by the Royal Navy for several decades.

In infants, scurvy is sometimes referred to as Barlow's disease, named after Sir Thomas Barlow,^[2] a British physician who described it.^[3] (N.B. Barlow's disease may also refer to mitral valve prolapse.) Other eponyms 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 and tarsiers), guinea pigs, most or all bats, and some species of birds and fish lack an enzyme 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 citrus fruits (oranges, lemons, limes, grapefruits), tomatoes, potatoes, cabbages, and green peppers.

Cause

Scurvy 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.^[4] 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.^[5] Though rare, there are also documented cases of scurvy due to poor dietary choices by people living in industrialized nations.^[6][7][8][9]

Pathogenesis

Ascorbic 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 also an important part of bone, so bone formation is also affected. Defective connective tissue also leads to fragile capillaries, resulting in abnormal bleeding.

Symptoms

Early 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, and convulsions, and eventual death are frequently seen.^[10]

Prevention

Scurvy 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,^[11] various nutritional supplements are available that provide ascorbic acid well in excess of that required to prevent scurvy, and even some candies and most soft drinks contain vitamin C as a preservative.

Many animal products, including liver, Muktuk (whale skin), oysters, and parts of the centrail nervous sytem, including the brain, spinal cord, and adrenal medula, 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 aleviate scurvy. Some of these observations that scurvy was only associated with preserved foods, prompted explorers to blame scurvy upon some type of tainting or poison which pervaded tinned foods.

Treatment

Scurvy is treated with vitamin C.

Prognosis

Untreated 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.

History

Herbal cures for scurvy have been known in many native cultures since prehistory.^{[citation needed]} Scurvy was documented as a disease by Hippocrates,^[12][13] and Egyptians have recorded its symptoms as early as 1550 BC.^[14] The knowledge that consuming foods containing vitamin C is a cure for scurvy has been repeatedly rediscovered and reforgotten into the early 20th century.^[15]

Early modern era

In 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.^[15] 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.^[16][17] 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.^[18] According to Jonathan Lamb, "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."^[19]

In 1593 Admiral Sir Richard Hawkins advocated drinking orange and lemon juice as a means of preventing scurvy.^[20]

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).^[21]

18th century

A 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.^[22]

In 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, due to the daily doses of vitamin C the sailors received.^[23] 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 such as limes or lemons, though not by other acids, in the first ever clinical trial.^[1] 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. 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 1740–2, lost within the first ten months nearly two-thirds of his crew (1300 out of 2000).^[24] 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.^[25]

James Cook succeeded in circumnavigating the world (1768–71) in HM Bark Endeavour without losing a single man to scurvy, but his suggested methods, including a diet of sauerkraut and wort of malt, 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 replenishing of fresh food.^[26] The most effective regime 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 the hot copper, this fat acquired substances which possibly irritated the gut and prevented proper absorption of vitamins.^[27]

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.^[28]

Despite advances, British sailors throughout the American Revolutionary period continued to suffer from scurvy, particularly in the Channel Fleet. The eradication of scurvy from the Royal Navy in the 1790s was finally due to the chairman of the Navy's Sick and Hurt Board, Gilbert Blane, who finally put Bachstrom and Lind's long-ignored prescription of fresh lemons to use during the Napoleonic Wars. It 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.^[21]

19th century

The 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.^[29]

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 that same year 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 an English immigrant in the former British colonies (particularly America, New Zealand and South Africa), and finally, in old American slang, all British people.^[30]

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 didn't 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.^[31]

West Indian limes replaced lemons because they were more easily obtained from Britain's Caribbean colonies,^[15] 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. This was mistaken – the West Indian limes were significantly lower in Vitamin C than the previous lemons (having only ¼ the Vitamin C content), and further were not served fresh, but rather as lime juice, which had been exposed to air and piped through copper tubing, both of which significantly reduced the Vitamin C. Indeed, an 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.^[15]

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, so that 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:^[15]

• while fresh citrus (particularly lemons) cured scurvy, lime juice that had been exposed to 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 floated, 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 due to children 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 century

At 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.^[32] Accordingly, Scott's expeditions suffered from scurvy, though he initially did not record this in his notes on his 1903 expedition, due to stigma associated with scurvy.^[15]

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 nothing but meat for a year while under close medical observation, yet remained in good health.^[33] 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 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.^[32][34][35]

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 unsusceptible to 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.^[36]

In 1927, Hungarian biochemist Szent-Györgyi (who won the 1937 Nobel Prize for Medicine) for his studies in the biological functions of the compound "hexuronic acid" while working with antioxidant compounds in the adrenal cortex.^[37] Szent-Györgyi suspected hexuronic acid, which he had isolated from adrenal glands, to be the antiscorbutic agent, but could not prove it without an animal-deficiency model.

It was not until 1932 that the connection between hexuronic acid and scurvy was finally proven by American researcher Charles Glen King of the University of Pittsburgh.^[38] King's laboratory was given some hexuronic acid by Szent-Györgyi and soon established that it was "vitamin C". In honor of its antiscorbutic properties, hexuronic acid was named "ascorbic acid" by Szent-Györgyi.

Experimental human trials

Notable human dietary studies of experimentally-induced scurvy have been conducted on conscientious objectors during WW II 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 a day. In these experiments, there was no clinical difference 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 due to the pre-loading of this group with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.^[39] 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.^[40]

In other animals

Most plant and animal species synthesize vitamin C. Notable mammalian group exceptions include most or all of the order chiroptera (bats), and one of the two major primate suborders, the "Anthropoidea" (Haplorrhini) (tarsiers, monkeys and apes, including human beings). The Strepsirrhini (non-tarsier prosimians) can make their own vitamin C (these include lemurs, the Aye-aye, lorises, pottos, and galagos). Ascorbic acid is also not synthesized by at least two species of Caviidae, the capybara^[41] 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.^[42][43][44]

References

1. ^ ^{a b} Lind, James (1753). A Treatise on the Scurvy. London: A. Millar. 
2. ^ Evans PR (December 1983). "Infantile scurvy: the centenary of Barlow's disease". Br Med J (Clin Res Ed) 287 (6408): 1862–3. doi:10.1136/bmj.287.6408.1862. PMC 1550031. PMID 6423046. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1550031. 
3. ^ Carpenter, Kenneth J. (1988). The History of Scurvy and Vitamin C. Cambridge University Press. p. 172. ISBN 0521347734. 
4. ^ Hampl JS, Taylor CA, Johnston CS (2004). "Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994". Am J Public Health 94 (5): 870–5. doi:10.2105/AJPH.94.5.870. PMC 1448351. PMID 15117714. http://www.ajph.org/cgi/content/full/94/5/870. 
5. ^ WHO (June 4, 2001) (PDF). Area of work: nutrition. Progress report 2000. http://www.who.int//mipfiles/2299/MIP_01_APR_SDE_3.en.pdf. 
6. ^ Davies IJ, Temperley JM (1967). "A case of scurvy in a student". Postgraduate Medical Journal 43 (502): 549–50. doi:10.1136/pgmj.43.502.539. PMC 2466190. PMID 6074157. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2466190. 
7. ^ Sthoeger ZM, Sthoeger D (1991). "[Scurvy from self-imposed diet]" (in Hebrew). Harefuah 120 (6): 332–3. PMID 1879769. 
8. ^ Ellis CN, Vanderveen EE, Rasmussen JE (1984). "Scurvy. A case caused by peculiar dietary habits". Arch Dermatol 120 (9): 1212–4. doi:10.1001/archderm.120.9.1212. PMID 6476860. 
9. ^ McKenna KE, Dawson JF (1993). "Scurvy occurring in a teenager". Clin. Exp. Dermatol. 18 (1): 75–7. doi:10.1111/j.1365-2230.1993.tb00976.x. PMID 8440062. 
10. ^ Lynne Goebel, MD. "Scurvy Clinical Presentation". Medscape Reference. http://emedicine.medscape.com/article/125350-clinical. 
11. ^ Rivers JM (1987). "Safety of high-level vitamin C ingestion". Ann. N. Y. Acad. Sci. 498 (1 Third Confere): 445–54. doi:10.1111/j.1749-6632.1987.tb23780.x. PMID 3304071. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1749-6632.1987.tb23780.x. 
12. ^ Hippocrates described symptoms of scurvy in book 2 of his Prorrheticorum and in his Liber de internis affectionibus. (Cited by James Lind, A Treatise on the Scurvy, 3rd ed. (London, England: G. Pearch and W. Woodfall, 1772), page 285.) Symptoms of scurvy were also described by: (i) Pliny, Naturalis historiae, book 3, chapter 49 ; and (ii) Strabo, Geographicorum, book 16. (Cited by John Ashhurst, ed., The International Encyclopedia of Surgery, vol. 1 (New York, New York: William Wood and Co., 1881), page 278.)
13. ^ Stone I (1966). "On the genetic etiology of scurvy". Acta Genet Med Gemellol (Roma) 15 (4): 345–50. PMID 5971711. http://www.seanet.com/~alexs/ascorbate/196x/stone-i-acta_genet_med_et_gemell-1966-v15-p345.htm. 
14. ^ Bradley S Buckler MD, Anjali Parish MD. "Scurvy". EMedicine. http://emedicine.medscape.com/article/985573-overview. 
15. ^ ^{a b c d e f} (Cegłowski 2010)
16. ^ Jacques Cartier's Second Voyage, 1535 Winter & Scurvy.
17. ^ Martini E (2002). "Jacques Cartier witnesses a treatment for scurvy". Vesalius 8 (1): 2–6. PMID 12422875. 
18. ^ Drymon, M. M. (2008). Disguised As the Devil: How Lyme Disease Created Witches and Changed History. Wythe Avenue Press. p. 114. ISBN 0615200613. http://books.google.com/books?id=w-x8LwQ2ZeYC&pg=PA114&dq#v=onepage&q=&f=false. 
19. ^ Lamb, Jonathan (2001). Preserving the self in the south seas, 1680-1840. University of Chicago Press. p. 117. ISBN 0226468496. http://books.google.com/books?id=hSoj1DR4ZSMC&pg=PA117&dq#v=onepage&q=&f=false. 
20. ^ Kerr, Gordon (2009). Timeline of Britain, Canary press.
21. ^ ^{a b} Bown, Stephen R. "SCURVY: How a Surgeon, a Mariner and a Gentleman Solved the Greatest Medical Mystery of the Age of Sail", Viking 2003.
22. ^ Telegraph newspaper, 5 March 2009, http://www.telegraph.co.uk/news/newstopics/howaboutthat/4943570/Cure-for-scurvy-discovered-by-a-woman.html
23. ^ "The Blood of Nelson" by Glenn Barnett — Military History — Oct 2006.
24. ^ "Captain Cook and the Scourge of Scurvy". BBC – History.
25. ^ A. S. Turberville (2006). "Johnson's England: An Account of the Life & Manners of His Age". ISBN READ BOOKS. p.53. ISBN 1406727261
26. ^ Fernandez-Armesto, Felipe (2006). Pathfinders: A Global History of Exploration. W.W. Norton & Company. pp. 297. ISBN 0-393-06259-7. 
27. ^ BBC  — History — Captain Cook and the Scourge of Scurvy.
28. ^ Fernandez-Armesto, Felipe (2006). Pathfinders: A Global History of Exploration. W.W. Norton & Company. pp. 297–298. ISBN 0-393-06259-7. 
29. ^ Larrey is quoted in French by Dr. Béraud, Études Hygiéniques de la chair de cheval comme aliment, Musée des Familles (1841-42).
30. ^ Simpson, J and Weiner, E: "The Oxford English Dictionary", Oxford University Press, 1989.
31. ^ Mabey, Richard (1972). Food for free. Collins. pp. 93, 94. ISBN 9780007247684. 
32. ^ ^{a b} Scott, Robert F."The Voyage of the Discovery", John Murray, London, 1929.
33. ^ http://www.biblelife.org/stefansson3.htm
34. ^ Shackleton Ernest"South: The Endurance Expedition", Penguin Books, 2008.
35. ^ [1]
36. ^ Norum KR, Grav HJ (June 2002). "[Axel Holst and Theodor Frolich--pioneers in the combat of scurvy]". Tidsskr. Nor. Laegeforen. 122 (17): 1686–7. PMID 12555613. 
37. ^ Carpenter, Kenneth J. (2004-06-22). "The Nobel Prize and the Discovery of Vitamins". http://www.nobelprize.org. Nobel Foundation. http://nobelprize.org/nobel_prizes/medicine/articles/carpenter/index.html. Retrieved 2008-01-25. 
38. ^ "The Albert Szent-Gyorgyi Papers Szeged, 1931-1947: Vitamin C, Muscles, and WWII". http://profiles.nlm.nih.gov. U.S. National Library of Medicine. http://profiles.nlm.nih.gov/WG/Views/Exhibit/narrative/szeged.html. Retrieved 2008-01-25. 
39. ^ J Pemberton. Medical experiments carried out in Sheffield on conscientious objectors to military service during the 1939–45 war. International Journal of Epidemiology 2006 35(3):556-558; doi:10.1093/ije/dyl020 full text.
40. ^ Hodges, R. E.; Baker, E. M.; Hood, J.; Sauberlich, H. E.; March, S. C. (1969). "Experimental Scurvy in Man". American Journal of Clinical Nutrition 22 (5): 535–548. PMID 4977512. http://www.ajcn.org/cgi/reprint/22/5/535. 
41. ^ Cueto GR, Allekotte R, Kravetz FO (2000). "[Scurvy in capybaras bred in captivity in Argentine."]. J Wildl Dis. 36 (1): 97–101. PMID 10682750. http://www.jwildlifedis.org/cgi/reprint/36/1/97. 
42. ^ "Vitamin C". Food Standards Agency (UK). http://www.eatwell.gov.uk/healthydiet/nutritionessentials/vitaminsandminerals/vitaminc/. Retrieved 2007-02-19. 
43. ^ "Vitamin C". University of Maryland Medical Center. January 2007. http://www.umm.edu/ency/article//002404.htm. Retrieved 2008-03-31. 
44. ^ Higdon, Jane, Ph.D. (2006-01-31). "Vitamin C". Oregon State University, Micronutrient Information Center. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/. Retrieved 2007-03-07. 

Further reading

1. SCURVY: How a Surgeon, a Mariner, and a Gentleman Discovered the Greatest Medical Mystery of the Age of Sail by Stephen R. Bown. Published by Thomas Dunne Books 2004.
2. The history of scurvy & vitamin C. by Kenneth J. Carpenter. Published by Cambridge University Press 1986.
3. Cegłowski, Maciej (March 7, 2010). "Scott and Scurvy". http://idlewords.com/2010/03/scott_and_scurvy.htm