Frederick L Dunn. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.
The complex of clinical disturbances long known as beriberi has been recognized since early in the twentieth century as arising because of a deficiency of thiamine. Like others in the group of B vitamins, thiamine has essential coenzyme functions in intermediary metabolism. The principal role of this water-soluble molecule is that of precursor of thiamine pyrophosphate (thiamine diphosphate), a coenzyme (often referred to as cocarboxylase) in energy generation through oxidative decarboxylation of alpha-ketoacids, such as pyruvic acid and alpha-ketoglutaric acid. Thiamine pyrophosphate serves also as the coenzyme for transketolase, a catalyst in the pentose phosphate pathway of glucose metabolism. Measurement of transketolase activity in erythrocytes and stimulation of activity by added thiamine pyrophosphate is the most convenient and sensitive method for detecting human thiamine deficiency. As the pyrophosphate and/or the triphosphate, thiamine appears also to have a role in facilitating conduction in peripheral nerves.
Like most vitamins, thiamine cannot be synthesized in the body and must be acquired in the diet. It is found in many foods and is most abundant in grains, legumes, nuts, and yeast. All meats and most dairy products contain some thiamine, but the richest sources are pork and eggs. Milk, however, is not a rich source. As a water-soluble vitamin, thiamine is easily lost in cooking water. Fish can supply good amounts, but with fermentation of raw fish, the enzyme thiaminase may alter the thiamine molecule, blocking its biological activity. Dietary thiamine is actively absorbed, mainly in the small intestine. The recommended daily dietary allowance is 1.2 to 1.5 milligrams for adult males and 1.0 to 1.1 milligrams for adult females, depending upon age, with a 50 percent increase in requirements during pregnancy and lactation. Up to about 25 milligrams can be stored by a healthy person, especially in heart muscle, brain, liver, kidney, and skeletal muscle.
With a deficient diet, skeletal muscle soon begins to lose thiamine, followed by the liver, nervous system, and heart. Some intestinal bacteria are known to synthesize thiamine (Altschule 1978: 96), but this action probably contributes little, if at all, to human thiamine stores. Most thiamine excreted in urine is free, but some is also released as the pyrophosphate. Some thiamine may be lost in sweat, but the significance of this loss for workers in hot conditions remains to be clarified. Thiamine is low in toxicity, although very large doses may have some side effects. Large doses, however, are rapidly excreted, and so persistent toxic effects are rare.
The clinical consequences of advanced thiamine deficiency reflect, especially, the involvement of the cardiovascular system and the nervous system, both peripheral and central. The consequences of severe deficiency will certainly be disabling and may be fatal.
In the sections that follow, thiamine deficiency is first considered in the past, then in the present, with due attention to its distribution, to groups and populations at special risk, and to the range of clinical features. Cultural, socioeconomic, and behavioral factors, which influence risk, clinical responses, and outcomes, are noted. The final sections examine the history of research on etiology and of work leading to control and prevention.
Beriberi in the Past
Thiamine deficiency does not appear to leave behind any of the kinds of distinctive pathological evidence that permit paleopathologists to recognize diseases of the past. A comprehensive survey of pathological conditions in human skeletal remains (Ortner and Putschar 1985) includes no conditions assignable to deficiency of any of the B vitamins, and it seems unlikely that future studies of soft tissue remains will reveal any such evidence. Nevertheless, it is likely that thiamine deficiencies occurred in ancient populations, sporadically at least, even long before the beginnings of grain cultivation.
It has been shown that antithiamine factors occur in a variety of foods. Thermolabile thiaminases have been identified in the viscera of fresh fish, in shellfish, and in certain bacteria. Thermostable thiaminases exist in some animal tissues and in plants associated with caffeic and tannic acids (Paige 1988: 558). Some studies have shown an association of these factors with thiamine deficiency, and thus beriberi. S. L. Vimokesant and colleagues (1975), for example, have described thiamine deficiency in Thailand associated with the consumption of fermented raw fish, the chewing of fermented tea leaves, and the use of betel nuts. They suggest that the antithiamine activity of betel nuts and fermented tea may be induced by their high content of tannic acid. Ingestion of raw clams, which contain thiaminase, has also been shown to destroy thiamine in the human gastrointestinal tract. Some of these kinds of dietary preferences and practices have, no doubt, ancient origins in the human diet.
Early grain cultivation provided important new sources of dietary thiamine, and it is unlikely that simple milling procedures, even in rice-growing regions, led to severe thiamine deficiency, although diets based on rice stripped by steam milling and polishing of its thiamine-rich husks were later widely responsible for the disease. Ancient beriberi, as described in China, may more often have been due to thiaminase or other antithiamine activity than to the absence of the vitamin in the diet because of milling practices or dependence on thiamine-poor foods.
August Hirsch (1885: 572-3) records that beriberi, known as kak-ke (“disease of the legs”), can be traced back more than 2,000 years in China:
Inquiries … have succeeded in proving that the word “kak-ke” occurs in a Chinese work dating from about 200 B.C., and that there is an unambiguous description of the disease in another work of some one hundred and thirty years later date. Other references to beriberi in China occur in writings of the third, seventh, and eighth centuries of the present era; and in a medicine book belonging to the end of the tenth century, there is already a distinction drawn between a “dry” or paralytic kak-ke and a “wet” or dropsical [one]. Of the disease in Japan the earliest record is in a medical treatise of the ninth century of our era. … For the East Indies the first notice of it occurs in the medico-topo-graphical treatise of Bontius [De Medicina Indorum by Jacob Bontius (1592-1631), a Dutch physician], who was acquainted with the disease there in the seventeenth century under its colloquial name “beriberi.”
B. C. P. Jansen (1956: 2) provides a slightly earlier Dutch record: “Already in the year 1611 the first Governor-General of the Dutch East India Company wrote that in the Dutch East Indies there was a disease named beriberi which caused paralysis in the hands and feet.”
Beriberi is commonly recorded in dictionaries, encyclopedias, and other modern sources as a term derived from a word in Sinhala (Sinhalese), meaning weakness. Hugh M. Sinclair (1982), however, refers to Bontius’s “excellent account of beriberi, the name meaning ‘sheep,’ since the partial paralysis of the disease caused patients to walk like sheep”—this, indeed, is the correct derivation of the word, as any comprehensive Malay-Indonesian dictionary will show. In Kamus Pelajar Federal (1973), for example, the Malay word biri-biri is assigned two meanings: (1) sheep, and (2) beri-beri (the disease). Hirsch (1885: 569), writing as early as the 1860s, casts doubt on alternative suggestions that the word beriberi derived from “Cingalese” or “Hindustani” words. Hirsch leaned toward a Malay origin, citing Bontius (who offered a mistaken transliteration of biri-biri—”bharyee”—a word said to mean “sheep”). Hirsch also noted another early Dutch author’s suggestion that a Malay language word, “biribi” (obviously biri-biri, pronounced rapidly), meaning an “abrupt and tripping gait,” was the origin of the term beriberi.
Thiamine deficiency remained an endemic problem until the second half of the nineteenth century. Although present in many parts of the world, beriberi usually appeared as a sporadic disease in individuals, groups, or populations at special risk because of “restricted,” thiamine-poor diets. However, with the introduction of the steam-powered rice mill (about 1870), the disease became widespread and at times epidemic in some populations, especially in eastern and southeastern Asia. As a product of industrial and technological expansion, rice—commercially milled and relatively inexpensive—became generally available in a time of maritime competition and increasing establishment, in many societies, of prisons, asylums, military installations, and other institutions that offered only restricted diets.
In the closing decades of the nineteenth century in Japan, for example, beriberi (usually known as kakke) was present throughout the country, but was especially prevalent in military garrisons and on warships and naval training ships (Williams 1961). In Malaya, too, at the turn of the century, beriberi was widely distributed but especially conspicuous in closed institutions, such as jails and asylums for the mentally ill (Byron 1951).
It may be noted, however, that most populations in the Indian subcontinent, and Indian immigrant groups generally, remained almost free of beriberi during this period of technological, military, and institutional expansion—as they still do today. This is understandable because, throughout this region, rice has long been parboiled before milling. The unhusked rice, after preliminary soaking, is boiled in domestic vessels or steamed under pressure in the larger mills. The B vitamins are fixed in the grain so that they are not removed with the bran, and remain behind in the milled rice. The parboiling process has long been preferred because the woody outer husk is split, rendering its removal easier during milling (Davidson and Passmore 1966: 261). Beriberi has been endemic in only one Indian state, along the coast of Andhra Pradesh north from above Madras to Vishakhapatnam, and this, according to Sir Stanley Davidson and R. Passmore (1966: 412), is the only area in India where raw-milled rice is the principal cereal.
The vast literature on beriberi reflects its profound impact on morbidity and mortality during the late nineteenth and early twentieth centuries. But this literature also reveals the confusion that existed about the disease, its identity, its causation, and its clinical effects. Beriberi had acquired many other names—regional, local, and culturally specific—in previous centuries, but cosmopolitan medical practitioners and researchers added a considerable variety of their own terms (for example, endemic multiple neuritis, panneuritis epidemica, polyneuritis endemica, ship beriberi, infantile beriberi). These reflected the notion that beriberi might be several quite different diseases, an idea created by the diverse clinical effects of thiamine deficiency and by the common occurrence of several or multiple nutritional deficiencies in the same thiamine-deficient patient.
Thiamine deficiency disease persists in the modern world, but its epidemiology is very different from that of a century ago. Epidemic classical beriberi is rarely seen today. Although signs and symptoms of famine-related thiamine deficiency occur all too often, they are likely to be accompanied by clinical evidence of multiple deficiencies of vitamins and other nutrients. War, disaster, and drought-induced famines will continue into the future as contributors to deficiencies of thiamine, but beriberi as a distinct clinical entity will probably seldom occur in those circumstances.
As an endemic disease, however, beriberi has not disappeared. Some beriberi still occurs where rice is the staple cereal, polished rice is preferred, parboiling is not practiced, and few other sources of thiamine exist in the diet. In other areas, where rice is not the staple, beriberi may occur occasionally when refined carbohydrate foods are dominant in the diet. Davidson and Passmore (1966: 412), for example, mention the common occurrence of beriberi early in this century in the fishing communities of Newfoundland and Labrador. Often cut off during the long winter from outside provisions, people in these areas depended upon winter stores consisting mainly of flour made from highly milled wheat. Beriberi probably continues to appear today in similar circumstances of prolonged and extreme isolation.
In some countries, beriberi is so intimately associated with culturally maintained dietary preferences and practices that it is likely to persist well into the future. In northern Thailand, as noted, consumption of fermented raw fish has been reported to be an important cause of beriberi. Vimokesant and colleagues (1975) also concluded that antithiamine activity of fermented tea and betel nuts must contribute to persistent thiamine deficiency in that region. However, to what extent these effects may result from destruction of thiamine, or from loose binding and partial blocking of activity, remains unclear. Further evaluation of these findings is warranted because of the wide use of these substances not only in Thailand but elsewhere in Asia. If the extensive use of betel nut in some regions of India interferes with thiamine activity or retention, it appears, nevertheless, that the thiamine-preserving effect of rice parboiling can maintain a sufficient thiamine balance to minimize the appearance of signs and symptoms of deficiency. This too is, however, a topic in need of further study, particularly in relation to the occurrence and significance of subclinical or borderline thiamine deficiency.
In addition to the problem of endemic beriberi, thiamine deficiency occurs sporadically in many countries, especially as a result of chronic alcoholism, but also in association with some chronic illnesses and with long-term parenteral nutrition (Altschule 1978: 98). As Richard S. Rivlin (1988) reports, thiamine absorption is exquisitely sensitive to ingested ethanol, which can significantly interfere with absorption. Alcoholics may fail to absorb most of their dietary thiamine—thiamine which is likely to be limited, in any case, as the diet is increasingly impaired and restricted. Rivlin notes that about 25 percent of alcoholics admitted to general hospitals in the United States have evidence of thiamine deficiency by either clinical or biochemical criteria. He cites evidence as well that alcohol can adversely affect the intermediary metabolism of thiamine, and that chronic liver disease, resulting from alcoholism, may impair the conversion of thiamine to thiamine pyrophosphate.
The clinical distinction between wet and dry forms of beriberi can be traced back at least to the ninth century in Japan (Henschen 1966: 170) and to the tenth century in China (Hirsch 1885). The wet-dry differentiation has continued to appear in clinical classifications of thiamine deficiency disorders to the present day, with infantile beriberi accorded separate status in most breakdowns. Some have chosen to describe the disease in terms of three clinical clusters characterized by edema, nervous system signs and symptoms, and symptoms of disorder in the cardiovascular system (Meade 1993). Sinclair (1982) offers the classification adopted here. He sees severe thiamine deficiency giving rise to the following forms of beriberi:
- Acute beriberi—including acute cardiac beriberi and infantile beriberi, along with Wernicke’s encephalopathy (as the acute or subacute component of the Wernicke-Korsakoff syndrome).
- Chronic beriberi—including dry beriberi, wet beriberi, and chronic beriberi heart (and here Korsakoff’s psychosis may be added as the other, more chronic component of the Wernicke-Korsakoff syndrome).
Acute Cardiac Beriberi
The picture of acute cardiac beriberi is that of congestive failure and cardiac overactivity manifested by dyspnea, orthopnea, precordial pain, palpitations, tachycardia, and edema. In its most fulminant form it has been known in East Asia as Shoshin beriberi. These acute forms of cardiac beriberi, uncommon today, were well known to clinicians in Asia a century ago; many patients died of heart failure. With intravenous thiamine, acute cardiac beriberi can readily be treated, with dramatic results.
Infantile beriberi, a condition in infants who are breast-fed by thiamine-deficient mothers, is, as Sinclair (1982) notes, very similar to acute cardiac beriberi in adults. Once common in eastern Asia, the condition usually occurs very early in life, with sudden onset and rapid progression to death. The anorexic, restless infant shows signs of developing cardiac failure, including tachycardia, dyspnea, edema, and aphonia, responsible for a characteristic grunt (the beriberi cry). Although less often recognized today, infantile beriberi, like cardiac beriberi in the adult, will respond well to intravenous or intramuscular thiamine. Improvement of the nursing mother’s thiamine nutrition is also essential.
First described by Carl Wernicke in 1881, Wernicke’s encephalopathy is an acute or subacute cerebral form of beriberi, only recognized as a consequence of thiamine deficiency during and just after World War II, in prisoner-of-war camps. Today it is a disorder associated principally with chronic alcoholism. The pathological changes are characteristically localized, involving the optic nerve, the gray matter around the third and fourth ventricles, and the aqueduct of Sylvius. Clinical features include nystagmus, diplopia, ophthalmoplegia, anorexia, vomiting, insomnia, mental apathy and disorientation, hallucinations, and variable loss of memory. Ataxia appears occasionally. In many cases, signs of peripheral neuropathy are also evident. The condition responds well to treatment with thiamine injections.
In this once common clinical variety of beriberi, it is primarily the peripheral nervous system that is disordered. Dry beriberi is an ascending symmetrical bilateral peripheral neuritis. Early in the course, the complaints may be vague, beginning with stiffness, leg cramps, and numbness in the feet and ankles. Knee and ankle reflexes are first increased, then diminished, and finally lost as the disease advances. Muscle weakness spreads upward in the lower extremities. Affected muscles become tender, painful, numb, and eventually atrophic, sometimes with hyperextension of the knee joints. Ataxia follows, with a characteristic gait (which led to the coining of the name “beriberi,” meaning sheep). Hands and arms may also be affected, but not usually until signs and symptoms in the legs are pronounced. Thiamine therapy will arrest the progression and relieve the patient of most symptoms, but all of the damage in advanced disease may not be fully reversible.
This chronic form of beriberi is primarily an edematous condition accompanied, in varying degree, by signs and symptoms of cardiac malfunction. Renal function generally remains intact. Early in the course, edema usually begins in the feet and legs, then extends upwards to the abdomen (producing ascites), thorax, pericardium, and face. Muscle wasting, if present, may be masked by edema. With pulmonary congestion, the chambers of the right heart dilate and the heart begins to fail. Anorexia is invariable, vomiting and diarrhea may occur, and thus the body begins to starve. The patient with wet beriberi is always at risk of a sudden increase in edema, circula-tory failure, severe dyspnea, and death.
Chronic Beriberi Heart
Cardiac damage can occur as a result of thiamine deficiency without other signs and symptoms of beriberi. This chronic condition, now referred to as “beriberi heart,” is most often associated with chronic alcoholism and/or a history of marked nutritional deficiency. When these causal factors are present, the diagnosis can be suspected when unexplained tachycardia, palpitations, venous congestion, characteristic electrocardiographic changes, and right heart enlargement are noted. Edema may also appear, but not with the same prominence as in cases of wet beriberi.
As beriberi extended its geographical range, incidence, and prevalence in the second half of the nineteenth century, it attracted increasing attention from medical investigators, who began the long process of causal research that extended into the first decades of the twentieth century. Hirsch, in his great Handbook of Geographical and Historical Pathology, first published between 1860 and 1864, gave many pages to a description of the disease and to a review and analysis of etiologic possibilities. He found it necessary to discard as principal causes climate, soil, lifestyle, and occupation, among other factors. He could only conclude that beriberi must arise as a result of some intoxication, that is, exposure to a poison. Later the idea emerged that beriberi might appear because of infection, and, until late in the century, theorizing was directed principally to these two causal possibilities.
The search for an infectious agent or a chemical poison, probably in food, continued throughout the remainder of the nineteenth century, but no one interested in beriberi and diet in this period considered the possibility of a deficiency of some specific substance (Williams 1961: 16). Two naval officers (the Dutch naval doctor, F. S. van Leent, and the chief of the Japanese naval medical service, K. Takaki) were successful in reducing the incidence of beriberi on shipboard by broadening diets previously limited largely to rice (Jansen 1956; Williams 1961). These achievements, pointing clearly to some dietary factor in beriberi, were not widely known or acknowledged at the time.
The first step toward the recognition of the role of thiamine deficiency in beriberi came in 1890 with the publication of a report by Christiaan Eijkman, a Dutch military surgeon in Java, of his studies of polyneuritis in domestic fowl. His experiments were initiated to uncover a presumed infectious cause of the disease by inoculating laboratory chickens with supposedly infectious material from beriberi patients. These birds, fed on crude rice, remained healthy, but when they were later switched to a diet of boiled and polished white rice, left over from the hospital, they began to show signs of polyneuritis not unlike that in human beriberi.
Still later, the chickens were returned to a crude rice diet, after the hospital chief forbade the use of the polished luxury rice for laboratory animals. The neuritis soon disappeared. Intrigued by this change, Eijkman fed two groups of fowl, one with crude rice, the other with polished rice. The latter group developed the same beriberi-like neuritis. The result of this simple experiment was decisive, not only in the history of beriberi but also as the beginning of the much wider field of research on vitamins and specific nutritional deficiencies. Eijkman expanded his investigations in Java until 1896, when he returned to Holland, eventually to a professorial appointment and to the award in 1929 (one year before his death) of a Nobel Prize in Physiology and Medicine, “for his discovery of the antineuritic vitamin.”
Eijkman’s experimental work with fowl in Java was continued by another Dutch scientist, Gerrit Grijns, who soon became the first to express the theory “that in food there occur in small quantities unknown organic substances essential for health” (Jansen 1956). Grijns called them protective substances. He was able to extract such a substance, soluble in water, from rice bran and to employ it in the treatment of human beriberi. Later Casimir Funk coined the name “vitamine” (later shortened to “vita-min”) for a protective substance, an amine that he had isolated and assumed (wrongly as it turned out) to be the same as that studied by Eijkman and Grijns (Byron 1951; Jansen 1956).
The studies in Java were confirmed and extended in Malaya early in the new century (Byron 1951). W. L. Braddon, who published much evidence to show that the cause of beriberi was connected intimately with the consumption of polished white rice, could only explain his findings as due to a poison in the rice. His work provided a foundation for three scientists, H. Fraser, A.T. Stanton, and W. Fletcher, at the Institute for Medical Research in Kuala Lumpur. During the decade following 1905, in their studies of road workers (and in Fletcher’s study of patients at an asylum), these investigators further demonstrated the significance of rice polishing in the causation of beriberi. Fraser and Stanton also failed in all attempts to isolate a poison from rice, and they concluded, as Grijns had earlier, that the answer to the problem of beriberi must lie in a nutritional defect, that is, in the absence of an essential protective substance. Fraser and Stanton were never able to isolate the substance, but their studies led them to call for, and advocate, practical measures to cure and prevent beriberi—measures that were to prove very successful. After 1911, the use of polished white rice was prohibited in all Malayan government institutions, the danger of polished rice consumption was widely publicized, and government rice mills began to produce undermilled rice for use in hospitals and public institutions, including prisons and asylums. These actions served to lower dramatically the incidence of beriberi in Malaya within just a few years.
After 1910, as the results of the Malayan studies and preventive actions became known, E. B. Vedder and others in the Philippines started similar programs for the prevention and treatment of the disease. Vedder also encouraged Robert Williams, a scientist at the Bureau of Science in Manila, to begin studies that were to lead, in 1933, to the isolation and final chemical characterization of the protective substance. Some years earlier, in Java, Jansen and W. F. Donath had succeeded in isolating crystals of the antiberiberi factor, but their chemical analysis, limited by the apparatus then at hand, was incomplete, missing the presence of sulfur in the molecule (Jansen 1956). After the final synthesis, in 1936, Williams named the chemical “thiamin.” The spelling was later changed to thiamine, but Williams’s original spelling is still often used.
Southeast and East Asian countries pioneered in developing strategies for the prevention of beriberi. As we have seen, prevention of shipboard beriberi through dietary change was initiated by Japanese and Dutch naval medical officers late in the nineteenth century, long before the recognition of thiamine’s role. The section “Causal Research” also took note of the development, early in the twentieth century, of countrywide preventive programs and policies, begun in Malaya and the Philippines many years before thiamine was isolated, characterized, and synthesized. These programs stressed changes in rice milling to preserve bran, together with public education about the risks associated with dependence upon a diet based on polished white rice.
After 1936 the pace quickened as production of inexpensive synthetic thiamine made food enrichment possible. By 1941 the first standards for the enrichment of bread were established in the United States, and enrichment requirements soon followed, during World War II. Enrichment of whole-grain rice presented more problems than flour enrichment for bread, but even these difficulties were overcome so that today thiamine enrichment is available in rice-based diets, as well as in those for which bread is a staple.
For people throughout the world who consume many other kinds of processed foods, including corn and macaroni products, thiamine is also commonly available, as it is in many varieties of vitamin preparations. In the United States today, many individuals are consuming vitamins, often including thiamine, far in excess of the recommended dietary allowances, and it is estimated that one-third of individuals 65 years of age and older in this country are taking some kind of nutritional supplement (Rivlin 1988).
Williams concluded his 1961 book, Toward the Conquest of Beriberi, with a chapter on the prospects for eradication of the disease, as advocated by a joint United Nations committee (World Health Organization 1958). This committee, meeting under the sponsorship of the Food and Agriculture Organization and the World Health Organization, recommended six preventive measures that, taken together, could be expected largely to eliminate, if not actually eradicate, beriberi in countries where rice is a staple food:
- General improvement of the diet to increase its thiamine content.
- Encouragement of the use of undermilled rice.
- Encouragement of the use of parboiled rice.
- Promotion of methods of preparing and cooking rice to preserve its thiamine content to the greatest extent possible.
- Enrichment of rice.
- Increased use of synthetic thiamine in various ways other than rice enrichment.
Each of these measures continues today to have its role in beriberi prevention. It should be noted, however, that the committee was not aware, in the 1950s, of the possible extent of the problem of interference with thiamine activity and availability through the actions of thiaminase and other antithiamine agents. Even now this problem remains largely undefined, although in some countries, certainly in northern Thailand and, probably, in areas of Myanmar (Burma), dietary preferences, especially for fermented raw fish, are considered to be the most important causes of endemic beriberi.
Sporadic and subclinical or marginal thiamine deficiency persists today and will continue to do so. Eradication of this deficiency is not in prospect, but neither is recurrent epidemic beriberi.