Hektoen International

A Journal of Medical Humanities

Liver, lime, and vitamins

The history of vitamins traces back to the ancient Egyptians, Greeks, and Romans, who observed that certain foods were important in maintaining health. These observations were later supplemented by clinical studies.

Among these studies were those of the Russian physician Nikolai Lunin. As a student in Basel in 1881, he fed groups of mice with either whole milk or with artificial mixtures of proteins, fats, carbohydrates, and salts. He found that mice receiving whole milk developed normally whereas the others died. He concluded that “a natural food such as milk must therefore contain…small quantities of unknown substances essential to life.”

In 1905 Cornelis Adrianus Pekelharing reported in a Dutch medical journal the results from similar studies. Sir Frederick Gowland Hopkins, while lecturer in biochemistry at Guy’s Hospital Medical School, also found that animals maintained on a diet composed solely of purified proteins, carbohydrates, fats, or minerals failed to thrive, highlighting the need for certain indispensable dietary components. From his studies he concluded that certain “accessory food factors” were required in trace amounts to sustain normal growth, leading to the concept of vitamins.

The term “vitamin” was coined in 1912 by the Warsaw-born Polish biochemist Casimir Funk after he isolated substances he believed were vital for life. He referred to these substances as “vital amines,” combining the Latin word “vita” meaning life with “amine,” an organic compound derived from ammonia. When it became evident that not all vitamins contained amines, the term was changed to “vitamin.” Funk has gone down in history as the “father of vitamins.”

Beriberi (thiamin or vitamin B1 deficiency)

In 1887 the twenty-nine-year-old Dutch physician Christiaan Eijkman carried out research in Java on beriberi, a prevalent neurologic disease characterized by paralysis, sensory loss, and mental changes. Thinking that the disease was caused by an infection, he thought he would study it in chickens but found that all fell ill despite isolating them in separate cages. He then noted that the chickens served polished rice developed beriberi whereas those fed rough, unpolished rice remained healthy. Later he demonstrated that beriberi in prisoners that could also be prevented by a change in diet. He called the presumed curative element present in the rough rice the “anti-beriberi factor.”

In 1913 two investigators, Lafayette Mendel and Thomas Osborne, almost simultaneously isolated this anti-beriberi factor, as did Funk in 1914. Called thiamine or vitamin B1 and found essential for the metabolism of carbohydrates, it was isolated and crystallized in 1926 from rice bran by two Dutch chemists, B.C.P. Jansen and W.F. Donath. In 1934 its structure was determined by the American Robert Runnels Williams.

Scurvy (ascorbic acid or vitamin C)

Known since ancient times, though often confused with other diseases, scurvy most commonly affected sailors during long sea voyages. The efforts of the Edinburgh-born James Lind are remembered as some of the earliest attempts to prevent it. He had attended surgical lectures in Edinburgh and in 1738 joined the Royal Navy as a surgeon’s mate on a ship that was fighting the Spanish Navy. Like many others, he attributed scurvy at that time to a poor diet, foul air, and lack of exercise. But in 1747, while his ship was blockading the British Channel, he allocated two men each to six different dietary regimens for a period of fourteen days and found that only the group given lime fruit did not develop scurvy whereas the control groups did. Lind retired from the Navy in 1748 and published in 1753 a 400-page “Treatise on Scurvy” in which he described the results of his trial, followed later by two further books. His recommendation of using lemons and limes to avoid scurvy was adopted by the British Royal Navy, leading to the nickname “limey” for British sailors.

Also important in preventing scurvy in sailors was the Glasgow physician Gilbert Blaine. He sailed to the West Indies in 1779 as private physician to Admiral Rodney and was in charge of the fleet from 1779 to 1783. He instituted many reforms, and on his return was appointed physician to St. Thomas’s Hospital and later to three successive Princes of Wales. In 1795 he persuaded the Admiralty to order that every sailor in the Navy should receive three quarters of an ounce of lemon juice daily, causing the disease to virtually disappear from Royal Navy ships.

In 1928 the Hungarian biochemist Albert Szent-Györgyi isolated a compound from citrus fruits that he named “hexuronic acid.” Working with a fellow researcher Joseph Svirbely, he gave a sample to the American biochemist Charles Glen King, who proved it effectively countered scurvy in his long-established guinea pig assay. Later identified as ascorbic acid, it was named Vitamin C. In 1937, Szent-Györgyi was awarded the Nobel Prize.

Pellagra (niacin or vitamin B3)

Pellagra, often mistaken for leprosy, was first identified among Spanish peasants by Don Gaspar Casal in 1735 and called “mal de la rosa.” Referred to as the disease of the four Ds—dermatitis, diarrhea, dementia, and death—it was particularly common as the “corn disease” in the south of the United States, afflicting in the early twentieth century over 100,000 people per year, causing severe skin rashes, diarrhea, and dementia, and being fatal in 40% of cases. As late as 1913, pellagra was believed to be caused by an unidentified microbe. Then Joseph Goldberger, appointed to investigate the cause of the disease, was impressed that well-to-do people seemed never to develop the condition and postulated that the disease was due to a dietary deficiency.

He carried out studies at two large institutions and showed that the disease could be prevented by a sizeable increase of animal and leguminous protein foods such as milk, buttermilk, eggs, beans, and peas. Initially Goldberger faced immense skepticism, as the theory of vitamin deficiencies causing diseases was not yet widely accepted. However, his persistence and scientific rigor eventually convinced the medical community. In 1937, the “pellagra preventive factor” was isolated from yeast by Conrad Elvehjem and identified as niacin, also known as vitamin B3.

Pernicious anemia (cobalamin or vitamin B12)

This formerly universally fatal disease was described early on by James Combe of Edinburgh (1824) but in more detail by Thomas Addison of Guy’s Hospital. It was called Addisonian anemia by the French physician Trousseau and studied in detail by Michael Biermer of Bamberg, Germany. In 1925 George Whipple was able to correct severe anemia in dogs by feeding them raw liver, inspiring George Minot and William Murphy to achieve the same result in humans. George Whipple subsequently showed that the absorption of a curative “extrinsic factor” depended on an “intrinsic factor” made by the stomach, drawing attention eventually to the role of an atrophic gastritis caused by an autoimmune process. In 1948 two independent teams established that the deficient stimulating agent, cyanocobalamin or vitamin B12, was a cobalt-containing complex. It exhibited remarkable hematopoietic properties and revolutionized the treatment of this once universally fatal disease. Then in the 1950s, Dorothy Hodgkin, a pioneering crystallographer, used X-ray crystallography to determine the complex structure of B12. This remarkable feat, which earned her a Nobel Prize, not only unraveled the vitamin’s intricate architecture but also paved the way for future research on its function.

Night blindness (provitamin A carotenoids)

The eye disease called nyctalopia or night blindness was known to ancient Egyptian and Chinese physicians, who treated their patients with the liver of oxen or asses. Working in rural Russia, the German physician C.A. von Bergen described epidemics of night blindness in 1754. Laboratory studies on animals maintained on deficiency diets followed. In 1817, Jean Magendie observed corneal ulcers in dogs fed for several weeks a diet limited to sugar and water. The Austrian naval physician Eduard Schwarz found during an around-the-world scientific expedition (1857–1859) that he could prevent or cure corneal lesions by prescribing boiled ox or pig liver, or, more appetizingly, cod liver oil.

In 1919, during World War I, Carl E. Bloch fed institutionalized malnourished Danish children suffering from night blindness and keratomalacia with either animal fat (whole milk and butter) or vegetable fat (margarine). The animal fat group remained healthy, whereas 50% of the vegetable fat group developed corneal xerosis but were rapidly cured with cod-liver oil. He concluded that whole milk, butter, and cod-liver oil contained a fat-soluble substance that protected against these corneal lesions and blindness. Further studies resulted in the discovery of vitamin A, its chemical structure, its synthesis, and the confirmation that this fat-soluble vitamin is essential for vision.

Rickets (vitamin D)

The story of vitamin D, the second fat-soluble vitamin considered here, unfolds over centuries, intertwined with the fight against a crippling childhood disease—rickets. The early 1600s saw the first descriptions of rickets, characterized by bowed legs and bone deformities in children. Later it was noticed that children confined indoors and lacking exposure to sunlight were particularly susceptible to the disease.

In the late nineteenth century, scientists such as Sir Edward Mellanby in the UK suspected that rickets was caused by a dietary deficiency. By carrying out experiments with dogs, Mellanby demonstrated that cod liver oil could prevent rickets. Later in the US, Elmer McCollum, Marguerite Davis, and Harry Steenbock co-discovered a fat-soluble factor in butter and cod liver oil, later termed vitamin A, that promoted growth in animals, and in the 1920s Adolf Windaus in Germany isolated an anti-rachitic substance from irradiated ergosterol, a plant sterol. This was vitamin D2, the first form of vitamin D identified. Further research revealed that sunlight exposure triggered the production of vitamin D3 in the skin.

 By the 1930s, the chemical structures of vitamin D2 and D3 were elucidated, solidifying their role in bone health. Soon rickets became largely preventable through sunlight exposure, cod liver oil supplementation, and later, by fortifying foods with vitamin D.

Blood clotting (vitamin K)

In the early twentieth century, the Danish biochemist Henrik Dam investigated the role of a cholesterol-deficient diet in chickens and to his surprise, observed that chickens on such diets suffered from uncontrolled bleeding. Further experimentation revealed that the addition of certain fats could alleviate this bleeding tendency. Dam initially referred to this fat-soluble compound as “coagulation vitamin.”

Dam’s work caught the attention of the American biochemist Edward Adelbert Doisy, whose team identified a substance in alfalfa that facilitated blood clotting and named it “vitamin K” (the “K” taken from “Koagulation” in German). In 1939, Doisy and Dam were jointly awarded the Nobel Prize in Physiology or Medicine for their discovery of vitamin K. Its deficiency is rare but occurs in malabsorption disorders. Some newborns are born with limited vitamin K stores, and all are recommended to receive a vitamin K injection shortly after birth to prevent bleeding. It has also suggested that vitamin K may improve bone health and prevent cardiovascular disease.

Other vitamins

Vitamin E is the fourth fat-soluble vitamin discovered in the past century. The other water-soluble vitamins, not discussed here, are riboflavin (vitamin B2), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin H), and folic acid (vitamin B9).

GEORGE DUNEA, MD, Editor-in-Chief

Spring 2024



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