Thiamine deficiency (beriberi)

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Thiamine deficiency
Other names	Beriberi, vitamin B1 deficiency, thiamine-deficiency syndrome
A person with beriberi during the early twentieth century in South-East Asia
Specialty	Neurology, cardiology, pediatrics
Symptoms	Wet: Fast heart rate, shortness of breath, leg swelling Dry: Numbness, confusion, trouble moving the legs, pain
Types	Wet, dry, gastrointestinal
Causes	Not enough thiamine
Risk factors	Diet of mostly white rice; alcoholism, dialysis, chronic diarrhea, diuretics
Prevention	Food fortification
Treatment	Thiamine supplementation
Frequency	Rare (US)

Thiamine deficiency is a medical condition of low levels of thiamine (vitamin B1). A severe and chronic form is known as beriberi. There are two main types in adults: wet beriberi, and dry beriberi. Wet beriberi affects the cardiovascular system resulting in a fast heart rate, shortness of breath, and leg swelling. Dry beriberi affects the nervous system resulting in numbness of the hands and feet, confusion, trouble moving the legs, and pain. A form with loss of appetite and constipation may also occur. Another type, acute beriberi, is found mostly in babies and presents with loss of appetite, vomiting, lactic acidosis, changes in heart rate, and enlargement of the heart.

Risk factors include a diet of mostly white rice, as well as alcoholism, dialysis, chronic diarrhea, and taking high doses of diuretics. Rarely it may be due to a genetic condition which results in difficulties absorbing thiamine found in food. Wernicke encephalopathy and Korsakoff syndrome are forms of dry beriberi. Diagnosis is based on symptoms, low levels of thiamine in the urine, high blood lactate, and improvement with treatment.

Treatment is by thiamine supplementation, either by mouth or by injection. With treatment symptoms generally resolve in a couple of weeks. The disease may be prevented at the population level through the fortification of food.

Thiamine deficiency is rare in the United States. It remains relatively common in sub-Saharan Africa. Outbreaks have been seen in refugee camps. 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.

Signs and symptoms

Beriberi

Symptoms of beriberi include weight loss, emotional disturbances, impaired sensory perception, weakness and pain in the limbs, and periods of irregular heart rate. Edema (swelling of bodily tissues) is common. It may increase the amount of lactic acid and pyruvic acid within the blood. In advanced cases, the disease may cause high-output cardiac failure and death. 

Symptoms may occur concurrently with those of Wernicke's encephalopathy, a primarily neurological thiamine-deficiency related condition.

Beriberi is divided into four categories as follows. The first three are historical and the fourth, gastrointestinal beriberi, was recognized in 2004:

• Dry beriberi specially affects the peripheral nervous system.
• Wet beriberi specially affects the cardiovascular system and other bodily systems.
• Infantile beriberi affects the babies of malnourished mothers.
• Gastrointestinal beriberi affects the digestive system and other bodily systems.

Dry beriberi

Dry beriberi causes wasting and partial paralysis resulting from damaged peripheral nerves. It is also referred to as endemic neuritis. It is characterized by:

• Difficulty in walking
• Tingling or loss of sensation (numbness) in hands and feet
• Loss of tendon reflexes
• Loss of muscle function or paralysis of the lower legs
• Mental confusion/speech difficulties
• Pain
• Involuntary eye movements (nystagmus)
• Vomiting

A selective impairment of the large proprioceptive sensory fibers without motor impairment can occur and present as a prominent sensory ataxia, which is a loss of balance and coordination due to loss of the proprioceptive inputs from the periphery and loss of position sense.

Brain disease

Wernicke's encephalopathy (WE), Korsakoff's syndrome (alcohol amnestic disorder), Wernicke–Korsakoff syndrome are forms of dry beriberi.

Wernicke's encephalopathy is the most frequently encountered manifestation of thiamine deficiency in Western society, though it may also occur in patients with impaired nutrition from other causes, such as gastrointestinal disease, those with HIV/AIDS, and with the injudicious administration of parenteral glucose or hyperalimentation without adequate B-vitamin supplementation. This is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.

Korsakoff's syndrome is, in general, considered to occur with deterioration of brain function in patients initially diagnosed with WE. This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative.

Alcoholics may have thiamine deficiency because of the following:

• 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.
• 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 utilization of any thiamine that does reach the cells will further exacerbate the thiamine deficiency.
• Ethanol per se inhibits thiamine transport in the gastrointestinal system and blocks phosphorylation of thiamine to its cofactor form (ThDP).

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.

Wet beriberi

Wet beriberi affects the heart and circulatory system. It is sometimes fatal, as it causes a combination of heart failure and weakening of the capillary 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
• Elevated jugular venous pressure
• Dyspnea (shortness of breath) on exertion
• Paroxysmal nocturnal dyspnea
• Peripheral edema (swelling of lower legs)
• Dilated cardiomyopathy

Gastrointestinal beriberi

Gastrointestinal beriberi causes abdominal pain. Gastrointestinal beriberi is characterized by:

• Abdominal pain
• Nausea
• Vomiting
• Lactic acidosis

Infants

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.

In the acute form, the baby develops dyspnea and cyanosis 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 caused by nerve paralysis
• Weight loss, becoming thinner and then marasmic as the disease progresses
• Vomiting
• Diarrhea
• Pale skin
• Edema
• Ill temper
• Alterations of the cardiovascular system, especially tachycardia (rapid heart rate)
• Convulsions occasionally observed in the terminal stages

Cause

Beriberi may also be caused by shortcomings other than inadequate intake: diseases or operations on the digestive tract, alcoholism, dialysis, genetic deficiencies, etc. All these causes mainly affect the central nervous system, and provoke the development of what is known as Wernicke's disease or Wernicke's encephalopathy. 

Wernicke's disease is one of the most prevalent neurological or neuropsychiatric diseases. In autopsy series, features of Wernicke lesions are observed in approximately 2% of general cases. Medical record research shows that about 85% had not been diagnosed, although only 19% would be asymptomatic. In children, only 58% were diagnosed. In alcohol 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. 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.

Genetics

Genetic diseases of thiamine transport are rare but serious. Thiamine responsive megaloblastic anemia (TRMA) with diabetes mellitus and sensorineural deafness is an autosomal recessive disorder caused by mutations in the gene SLC19A2, a high affinity thiamine 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. 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 the pyruvate dehydrogenase complex.

Mutations in the SLC19A3 gene have been linked to biotin-thiamine responsive basal ganglia disease which is treated with pharmacological doses of thiamine and biotin, another B vitamin. 

Other disorders in which a putative role for thiamine has been implicated include subacute necrotising encephalomyelopathy, opsoclonic cerebellopathy (a paraneoplastic syndrome), and Nigerian seasonal ataxia. In addition, several inherited disorders of ThDP-dependent enzymes have been reported, which may respond to thiamine treatment.

Pathophysiology

Thiamine in the human body has a half-life of 18 days and is quickly exhausted, particularly when metabolic demands exceed intake. A derivative of thiamine, thiamine pyrophosphate (TPP), is a cofactor involved in the citric acid cycle, as well as connecting the breakdown 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 neurotransmitters glutamic acid and GABA. Additionally thiamine may also be directly involved in neuromodulation.

Diagnosis

Oxidation of thiamine derivatives to fluorescent thiochromes by potassium ferricyanide under alkaline conditions

 

A positive diagnosis test for thiamine deficiency can be ascertained by measuring the activity of the enzyme transketolase in erythrocytes (Erythrocyte Transketolase Activation Assay). Thiamine, as well as its phosphate derivatives, can also be detected directly in whole blood, tissues, foods, animal feed, and pharmaceutical preparations following the conversion of thiamine to fluorescent thiochrome derivatives (Thiochrome Assay) and separation by high-performance liquid chromatography (HPLC). In recent reports, a number of Capillary Electrophoresis (CE) techniques and in-capillary enzyme reaction methods have emerged as potential alternative techniques for the determination and monitoring of thiamine in samples. The normal thiamine concentration in EDTA-blood is about 20-100 µg/l.

Treatment

Many people with beriberi can be treated with thiamine alone. Given thiamine intravenously (and later orally), rapid and dramatic recovery can occur within hours. In situations where concentrated thiamine supplements are unavailable, feeding the person with a thiamine-rich diet (e.g. whole grain brown bread) will lead to recovery, though at a much slower rate.

Following thiamine treatment, rapid improvement occurs, in general, within 24 hours. Improvements of peripheral neuropathy may require several months of thiamine treatment.

Epidemiology

Historically, beriberi was associated with a diet including much polished rice (white rice); when the relationship between polishing rice and the disease was discovered, it became possible to prevent and treat the deficiency condition, for example with inexpensive rice bran. Beriberi caused by inadequate nutritional intake is rare today in developed countries because of quality of food and the fact that many foods are fortified with vitamins. No reliable statistics are given for beriberi in developed countries in the 19th century or earlier; neither are statistics available before the last century in countries in extreme poverty.

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. High rates of illness and death in overcrowded Haitian jails were traced in 2007 to the traditional practice of washing rice before cooking. In the Ivory 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%.

Populations under extreme stress may be at higher risk for beriberi. Displaced populations, such as refugees from war, are susceptible to micronutritional deficiency, including beriberi. The severe nutritional deprivation caused by famine also can cause beriberis, although symptoms may be overlooked in clinical assessment or masked by other famine-related problems. An extreme weight-loss diet can, rarely, induce a famine-like state and the accompanying beriberi.

History

Earliest written descriptions of thiamine deficiency are from Ancient China in the context of chinese medicine. One of the earliest is by Ge Hong in his book Zhou hou bei ji fang (Emergency Formulas to Keep up Your Sleeve) written sometime during 3rd century. Hong called the illness by the name jiao qi, which can be intepreted as "foot qi". 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 like fermented soybeans in wine. Better known examples of early descriptions of "foot qi" are by Chao Yuanfang (who lived during 550–630) in his book Zhu bing yuan hou lun (Sources and Symptoms of All Diseases) and by Sun Simiao (581–682) in his book Bei ji qian jin yao fang (Essential Emergency Formulas Worth a Thousand in Gold).

In the late 19th century, beriberi was studied by Takaki Kanehiro, a British-trained Japanese medical doctor of the Imperial Japanese Navy. 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. In 1883, 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. 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. This convinced Takaki and the Japanese Navy that diet was the cause. In 1884, Takaki observed that beriberi was common among low-ranking crew who were often provided free rice and thus ate little else, but not among crews of Western navies, nor among Japanese officers who consumed a more varied diet. 

In 1897, Christiaan Eijkman, a Dutch physician and pathologist, demonstrated that beriberi is caused by poor diet, and discovered that feeding unpolished rice (instead of the polished variety) to chickens helped to prevent beriberi. The following year, Sir Frederick 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. In 1901, Gerrit Grijns, a Dutch physician and assistant to Christiaan Eijkman in the Netherlands, correctly interpreted beriberi as a deficiency syndrome, and between 1910 and 1913, Edward Bright Vedder established that an extract of rice bran is a treatment for beriberi. In 1929, Eijkman and Hopkins were awarded the Nobel Prize for Physiology or Medicine for their discoveries.

Etymology

Although according to the Oxford English Dictionary, the term "beriberi" comes from a Sinhalese phrase meaning "weak, weak" or "I cannot, I cannot", the word being duplicated for emphasis, the origin of the phrase is questionable. It has also been suggested to come from Hindi, Arabic and few other languages, with many meanings like "weakness", "sailor" and even "sheep". Such suggested origins were listed by Heinrich Botho Scheube among others. Edward Vedder wrote in his book Beriberi (1913) that "it is impossible to definitely trace the origin of the word beriberi". Word berbere was used in writing at least as early as 1568 by Diogo do Couto, when he described the deficiency in India.

"Kakke", which is a Japanese synonym for thiamine deficiency, comes from the way "jiao qi" is pronounced in Japanese. "Jiao qi" is an old word used in Chinese medicine to describe thiamine deficiency. "Kakke" is supposed to have entered in the Japanese language sometime between the 6th and 8th centuries.

Other animals

Poultry

As most feedstuffs used in poultry diets contain enough quantities of vitamins to meet the requirements in this species, deficiencies in this vitamin do not occur with commercial diets. This was, at least, the opinion in the 1960s.

Mature chickens show signs 3 weeks after being fed a deficient diet. In young chicks, it can appear before 2 weeks of age.

Onset is sudden in young chicks. There is anorexia and an unsteady gait. Later on, there are locomotor signs, beginning with an apparent paralysis of the flexor of the toes. The characteristic position is called "stargazing", meaning a chick "sitting on its hocks and the head in opisthotonos".

Response to administration of the vitamin is rather quick, occurring a few hours later.

Differential diagnosis include riboflavin deficiency and avian encephalomyelitis. In riboflavin deficiency, the "curled toes" is a characteristic symptom. Muscle tremor is typical of avian encephalomyelitis. A therapeutic diagnosis can be tried by supplementing thiamine only in the affected bird. If the animals do not respond in a few hours, thiamine deficiency can be excluded.

Ruminants

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, star gazing or opisthotonus (head drawn back over neck), and muscle tremors. The most common cause is high-carbohydrate feeds, leading to the overgrowth of thiaminase-producing bacteria, but dietary ingestion of thiaminase (e.g., in bracken fern), or inhibition of thiamine absorption by high sulfur intake are also possible. Another cause of PEM is Clostridium sporogenes or Bacillus aneurinolyticus infection. These bacteria produce thiaminases that will cause an acute thiamine deficiency in the affected animal.

Snakes

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.

Wild birds and fish

Thiamine deficiency has been identified as the cause of a paralytic disease affecting wild birds in the Baltic Sea area dating back to 1982. 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 the herring gull (Larus argentatus), common starling (Sturnus vulgaris) and common eider (Somateria mollissima). Researches 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 suffer from thiamine deficiency as well."

In the counties of Blekinge and Skåne (south-most Sweden), 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 of salmon (Salmo salar) in the river Mörrumsån is reported, and mammals such as the Eurasian 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.