Thiamine deficiency is a medical condition of low levels ofthiamine (vitamin B1).[1] A severe and chronic form is known asberiberi.[1][7] The name beriberi was possibly borrowed in the 18th century from theSinhalese phraseබැරි බැරි (bæri bæri, “I cannot, I cannot”), owing to the weakness caused by the condition. The two main types in adults are wet beriberi and dry beriberi.[1] Wet beriberi affects thecardiovascular system, resulting in afast heart rate,shortness of breath, andleg swelling.[1] Dry beriberi affects thenervous system, resulting innumbness of the hands and feet, confusion, trouble moving the legs, and pain.[1] A form with loss of appetite andconstipation may also occur.[3] Another type, acute beriberi, found mostly in babies, presents with loss of appetite, vomiting,lactic acidosis, changes in heart rate, and enlargement of the heart.[8]
Treatment is by thiamine supplementation, either by mouth or by injection.[1] With treatment, symptoms generally resolve in a few weeks.[9] The disease may be prevented at the population level through thefortification of food.[1]
Thiamine deficiency is rare in the United States.[10] It remains relatively common insub-Saharan Africa.[2] Outbreaks have been seen inrefugee camps.[6] Thiamine deficiency has been described for thousands of years in Asia, and became more common in the late 1800s with the increased processing of rice.[11]
Dry beriberi causes wasting and partialparalysis resulting from damaged peripheralnerves. It is also referred to as endemic neuritis. It is characterized by:
Difficulty with walking
Tingling or loss of sensation (numbness) in hands and feet
A selective impairment of the large proprioceptive sensory fibers without motor impairment can occur and present as a prominent sensoryataxia, which is a loss of balance and coordination due to loss of the proprioceptive inputs from the periphery and loss of position sense.[13]
Wernicke's encephalopathy is the most frequently encountered manifestation of thiamine deficiency in Western society,[14][15] though it may also occur in patients with impaired nutrition from other causes, such as gastrointestinal disease,[14] those withHIV/AIDS, and with the injudicious administration ofparenteral glucose orhyperalimentation without adequate B-vitamin supplementation.[16] This is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.[17]
Korsakoff syndrome, in general, is considered to occur with deterioration of brain function in patients initially diagnosed with WE.[18] This is an amnestic-confabulatory syndrome characterized byretrograde andanterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative.[19]
Alcoholics may have thiamine deficiency because of:
Inadequate nutritional intake: Alcoholics tend to intake less than the recommended amount of thiamine.
Decreased uptake of thiamine from the GI tract: Active transport of thiamine into enterocytes is disturbed during acute alcohol exposure.
Liver thiamine stores are reduced due to hepatic steatosis or fibrosis.[20]
Impaired thiamine utilization: Magnesium, which is required for the binding of thiamine to thiamine-using enzymes within the cell, is also deficient due to chronic alcohol consumption. The inefficient use of any thiamine that does reach the cells will further exacerbate the thiamine deficiency.
Ethanolper se inhibits thiamine transport in the gastrointestinal system and blocks phosphorylation of thiamine to its cofactor form (ThDP).[21]
Following improved nutrition and the removal of alcohol consumption, some impairments linked with thiamine deficiency are reversed, in particular poor brain functionality, although in more severe cases, Wernicke–Korsakoff syndrome leaves permanent damage. (Seedelirium tremens.)
Wet beriberi affects theheart and circulatory system. It is sometimes fatal, as it causes a combination ofheart failure and weakening of thecapillary walls, which causes the peripheral tissues to become edematous. Wet beriberi is characterized by:
Increased heart rate
Vasodilation leading to decreased systemic vascular resistance, and high-output heart failure[22]
Infantile beriberi usually occurs between two and six months of age in children whose mothers have inadequate thiamine intake. It may present as either wet or dry beriberi.[2]
In the acute form, the baby developsdyspnea andcyanosis and soon dies of heart failure. These symptoms may be described in infantile beriberi:
Hoarseness, where the child makes moves to moan, but emits no sound or just faint moans[30] caused by nerve paralysis[12]
Weight loss, becoming thinner and thenmarasmic as the disease progresses[30]
It may also be caused by shortcomings other than inadequate intake –diseases or operations on the digestive tract,alcoholism,[23]dialysis orgenetic deficiencies. All those causes mainly affect the central nervous system, and provoke the development of Wernicke's encephalopathy.
Wernicke's disease is one of the most prevalent neurological or neuropsychiatric diseases.[31] Inautopsy series, features of Wernicke lesions are observed in approximately 2% of general cases.[32] Medical record research shows that about 85% had not been diagnosed, although only 19% would be asymptomatic. In children, only 58% were diagnosed. Inalcohol abusers, autopsy series showed neurological damages at rates of 12.5% or more. Mortality caused by Wernicke's disease reaches 17% of diseases, which means 3.4/1000 or about 25 million contemporaries.[33][34] The number of people with Wernicke's disease may be even higher, considering that early stages may have dysfunctions prior to the production of observable lesions at necropsy. In addition, uncounted numbers of people can experience fetal damage and subsequent diseases.
Genetic diseases of thiamine transport are rare but serious.Thiamine responsive megaloblastic anemia syndrome (TRMA) withdiabetes mellitus andsensorineural deafness[35] is an autosomal recessive disorder caused by mutations in the geneSLC19A2,[36] a high affinitythiamine transporter. TRMA patients do not show signs of systemic thiamine deficiency, suggesting redundancy in the thiamine transport system. This has led to the discovery of a second high-affinity thiamine transporter,SLC19A3.[37][38]Leigh disease (subacute necrotising encephalomyelopathy) is an inherited disorder that affects mostly infants in the first years of life and is invariably fatal. Pathological similarities between Leigh disease and WE led to the hypothesis that the cause was a defect in thiamine metabolism. One of the most consistent findings has been an abnormality of the activation of thepyruvate dehydrogenase complex.[39]
Thiamine in the human body has a half-life of 17 days and is quickly exhausted, particularly when metabolic demands exceed intake. A derivative of thiamine,thiamine pyrophosphate (TPP), is a cofactor involved in thecitric acid cycle, as well as connecting thebreakdown of sugars with the citric acid cycle. The citric acid cycle is a central metabolic pathway involved in the regulation of carbohydrate, lipid, and amino acid metabolism, and its disruption due to thiamine deficiency inhibits the production of many molecules including the neurotransmittersglutamic acid andGABA.[42] Additionally, thiamine may also be directly involved inneuromodulation.[43]
Oxidation of thiamine derivatives to fluorescent thiochromes by potassium ferricyanide under alkaline conditions
A positive diagnosis test for thiamine deficiency involves measuring the activity of the enzymetransketolase inerythrocytes (Erythrocyte transketolase activation assay). Alternatively, thiamine and its phosphorylated derivatives can directly be detected in whole blood, tissues, foods, animal feed, and pharmaceutical preparations following the conversion of thiamine tofluorescent thiochrome derivatives (thiochrome assay) and separation byhigh-performance liquid chromatography (HPLC).[44][45][46] Capillary electrophoresis (CE) techniques and in-capillary enzyme reaction methods have emerged as alternative techniques in quantifying and monitoring thiamine levels in samples.[47]The normal thiamine concentration in EDTA-blood is about 20–100 μg/L.
Many people with beriberi can be treated with thiamine alone.[48] Given thiamine intravenously (and later orally), rapid and dramatic[23] recovery occurs, generally within 24 hours.[49]
Improvements of peripheral neuropathy may require several months of thiamine treatment.[50]
Beriberi is a recurrent nutritional disease in detention houses, even in this century. In 1999, an outbreak of beriberi occurred in a detention center in Taiwan.[51] High rates of illness and death from beriberi in overcrowded Haitian jails in 2007 were traced to the traditional practice of washing rice before cooking; this removed a nutritious coating which had been applied to the rice after processing (enrichedwhite rice).[52] In theIvory Coast, among a group of prisoners with heavy punishment, 64% were affected by beriberi. Before beginning treatment, prisoners exhibited symptoms of dry or wet beriberi with neurological signs (tingling: 41%), cardiovascular signs (dyspnoea: 42%, thoracic pain: 35%), and edemas of the lower limbs (51%). With treatment, the rate of healing was about 97%.[53]
Populations under extreme stress may be at higher risk for beriberi.Displaced populations, such asrefugees from war, are susceptible to micronutritional deficiency, including beriberi.[54] The severe nutritional deprivation caused byfamine also can cause beriberis, although symptoms may be overlooked in clinical assessment or masked by other famine-related problems.[55] An extreme weight-lossdiet can, rarely, induce a famine-like state and the accompanying beriberi.[23]
Workers on Chinese squid ships are at elevated risk of beriberi due to the cheap refined grain and raw fish diet they are fed and the long period of time between shoring. Between 2013 and 2021, 15 workers on 14 ships have died with symptoms of beriberi.[56]
Earliest written descriptions of thiamine deficiency are from ancient China in the context ofChinese medicine. One of the earliest is byGe Hong in his bookZhou hou bei ji fang (Emergency Formulas to Keep up Your Sleeve) written sometime during the third century. Hong called the illness by the namejiao qi, which can be interpreted as "footqi". He described the symptoms to include swelling, weakness, and numbness of the feet. He also acknowledged that the illness could be deadly, and claimed that it could be cured by eating certain foods, such as fermented soybeans in wine. Better known examples of early descriptions of "foot qi" are byChao Yuanfang (who lived during 550–630) in his bookZhu bing yuan hou lun (Sources and Symptoms of All Diseases)[57][58] and bySun Simiao (581–682) in his bookBei ji qian jin yao fang (Essential Emergency Formulas Worth a Thousand in Gold).[59][58][60][61]
In the mid-19th century, interest in beriberi steadily rose as the disease became more noticeable with changes in diet in East and Southeast Asia. There was a steady uptick in medical publications, reaching one hundred and eighty-one publications from 1880 and 1889, and hundreds more in the following decades. The link to white rice was clear to Western doctors, but a confounding factor was that some other foods like meat failed to prevent beriberi, so it could not be easily explained as a lack of known chemicals like carbon or nitrogen. With no knowledge ofvitamins, theetiology of beriberi was among the most hotly debated subjects in Victorian medicine.[62]
The first successful preventative measure against beriberi was discovered byTakaki Kanehiro, a British-trained Japanese medical doctor of theImperial Japanese Navy, in the mid-1880s.[63] Beriberi was a serious problem in the Japanese navy; sailors fell ill an average of four times a year in the period 1878 to 1881, and 35% were cases of beriberi.[63] In 1882, Takaki learned of a very high incidence of beriberi among cadets on a training mission from Japan to Hawaii, via New Zealand and South America. The voyage lasted more than nine months and resulted in 169 cases of sickness and 25 deaths on a ship of 376 men. Takaki observed that beriberi was common among low-ranking crew who were often provided free rice, thus ate little else, but not among crews of Western navies, nor among Japanese officers who consumed a more varied diet. With the support of the Japanese Navy, he conducted an experiment in which another ship was deployed on the same route, except that its crew was fed a diet of meat, fish, barley, rice, and beans. At the end of the voyage, this crew had only 14 cases of beriberi and no deaths.[63] This emphasis on varied diet contradicted observations by other doctors, and Takaki's carbon-based etiology was just as incorrect as similar theories before him, but the results of his experiment impressed the Japanese Navy, which adopted his proposed solution. By 1887 beriberi had been completely eliminated on Navy ships.[62]
In the same year, Takaki's experiment was described favorably inThe Lancet,[64] but his incorrect etiology was not taken seriously.[65] In 1897,Christiaan Eijkman, aDutchphysician andpathologist, published his mid-1880s experiments showing that feeding unpolished rice (instead of the polished variety) to chickens helped to prevent beriberi.[66] This was the first experiment to show that not a major chemical but some minor nutrient was the true cause of beriberi. The following year, SirFrederick Hopkins postulated that some foods contained "accessory factors"—in addition to proteins, carbohydrates, fats, and salt—that were necessary for the functions of the human body.[67][68] In 1901,Gerrit Grijns, a Dutch physician and assistant toChristiaan Eijkman in the Netherlands, correctly interpreted beriberi as a deficiency syndrome,[69] and between 1910 and 1913,Edward Bright Vedder established that an extract ofrice bran is a treatment for beriberi.[citation needed] In 1929, Eijkman and Hopkins were awarded theNobel Prize for Physiology or Medicine for their discoveries. In 1935,Robert R. Williams isolated and cheaply synthesized thiamine from rice bran, based on discoveries he had made as a researcher in Manila's Bureau of Science in 1910. Williams assigned the patents to a fund that worked to promote thiamine-enriched rice in Asia, and inBataan in particular.[70]
Although the identification of beriberi as a deficiency syndrome was proven beyond a doubt by 1913, a Japanese group headed byMori Ōgai and backed byTokyo Imperial University continued to deny this conclusion until 1926. In 1886, Mori, then working in the Japanese Army Medical Bureau, asserted that white rice was sufficient as a diet for soldiers. Simultaneously, Navy surgeon general Takaki Kanehiro published the groundbreaking results described above. Mori, who had been educated under German doctors, responded that Takaki was a "fake doctor" due to his lack of prestigious medical background, while Mori himself and his fellow graduates of Tokyo Imperial University constituted the only "real doctors" in Japan and that they alone were capable of "experimental induction", although Mori himself had not conducted any beriberi experiments.[71]
The Japanese Navy sided with Takaki and adopted his suggestions. In order to prevent himself and the Army from losingface, Mori assembled a team of doctors and professors from Tokyo Imperial University and the Japanese Army who proposed that beriberi was caused by an unknown pathogen, which they described asetowasu (from the GermanEtwas, meaning "something"). They employed various social tactics to denounce vitamin deficiency experiments and prevent them from being published, while beriberi ravaged the Japanese Army. During theFirst Sino-Japanese War andRusso-Japanese War, Army soldiers continued to die in mass numbers from beriberi, while Navy sailors survived. In response to this severe loss of life, in 1907, the Army ordered the formation of a Beriberi Emergency Research Council, headed by Mori. Its members pledged to find the cause of beriberi.[72] By 1919, with most Western doctors acknowledging that beriberi was a deficiency syndrome, the Emergency Research Council began conducting experiments using various vitamins, but stressed that "more research was necessary". During this period, more than 300,000 Japanese soldiers contracted beriberi and over 27,000 died.[73]
Mori died in 1922. The Beriberi Research Council disbanded in 1925, and by the time Eijkman and Hopkins were awarded the Nobel Prize, all of its members had acknowledged that beriberi was a deficiency syndrome.
Although according to theOxford English Dictionary, the term "beriberi" comes from aSinhalese phrase meaning "weak, weak" or "I cannot, I cannot", the word beingduplicated for emphasis,[74] the origin of the phrase is questionable. It has also been suggested to come from Hindi, Arabic, and a few other languages, with many meanings like "weakness", "sailor", and even "sheep". Such suggested origins were listed byHeinrich Botho Scheube, among others.Edward Vedder wrote in his bookBeriberi (1913) that "it is impossible to definitely trace the origin of the word beriberi". The wordberbere was used in writing at least as early as 1568 byDiogo do Couto, when he described the deficiency in India.[75]
Kakke (脚気), which is a Japanese synonym for thiamine deficiency, comes from the way "jiao qi" is pronounced in Japanese.[76] "Jiao qi" is an old word used in Chinese medicine to describe beriberi.[57] "Kakke" is supposed to have entered into the Japanese language sometime between the sixth and eighth centuries.[76]
Mature chickens show signs three weeks after being fed a deficient diet. In young chicks, it can appear before two weeks of age. Onset is sudden in young chicks, with anorexia and an unsteady gait. Later on, locomotor signs begin, with an apparent paralysis of the flexor of the toes. The characteristic position is called "stargazing", with the affected animal sitting on its hocks with its head thrown back in a posture calledopisthotonos. Response to administration of the vitamin is rather quick, occurring a few hours later.[77][78]
Polioencephalomalacia (PEM) is the most common thiamine deficiency disorder in young ruminant and nonruminant animals. Symptoms of PEM include a profuse, but transient, diarrhea, listlessness, circling movements, stargazing or opisthotonus (head drawn back over neck), and muscle tremors.[79] The most common cause is high-carbohydrate feeds, leading to the overgrowth of thiaminase-producing bacteria, but dietary ingestion of thiaminase (e.g., inbracken fern), or inhibition of thiamine absorption by high sulfur intake are also possible.[80] Another cause of PEM isClostridium sporogenes orBacillus aneurinolyticus infection. These bacteria producethiaminases that can cause an acute thiamine deficiency in the affected animal.[81]
Snakes that consume a diet largely composed of goldfish and feeder minnows are susceptible to developing thiamine deficiency. This is often a problem observed in captivity when keeping garter and ribbon snakes that are fed a goldfish-exclusive diet, as these fish contain thiaminase, an enzyme that breaks down thiamine.[82]
Thiamine deficiency has been identified as the cause of a paralytic disease affecting wild birds in the Baltic Sea area dating back to 1982.[83] In this condition, there is difficulty in keeping the wings folded along the side of the body when resting, loss of the ability to fly and voice, with eventual paralysis of the wings and legs and death. It affects primarily 0.5–1 kg-sized birds such as theEuropean herring gull (Larus argentatus),common starling (Sturnus vulgaris), andcommon eider (Somateria mollissima). Researchers noted, "Because the investigated species occupy a wide range of ecological niches and positions in the food web, we are open to the possibility that other animal classes may develop thiamine deficiency, as well."[83]p. 12006
In the counties ofBlekinge andSkåne, mass deaths of several bird species, especially the European herring gull, have been observed since the early 2000s. More recently, species of other classes seems to be affected. High mortality ofsalmon (Salmo salar) in the riverMörrumsån is reported, and mammals such as theEurasian elk (Alces alces) have died in unusually high numbers. Lack of thiamine is the common denominator where analysis is done. In April 2012, the County Administrative Board of Blekinge found the situation so alarming that they asked the Swedish government to set up a closer investigation.[84]
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