Thiamine deficiency

Thiamine deficiency commonly presents subacutely and can lead to metabolic coma and death. A lack of thiamine can be caused by malnutrition, a diet high in thiaminase-rich foods (raw freshwater fish, raw shellfish, ferns) and/or foods high in anti-thiamine factors (tea, coffee, betel nuts)^[1] and by grossly impaired nutritional status associated with chronic diseases, such as alcoholism, gastrointestinal diseases, HIV-AIDS, and persistent vomiting.^[2] It is thought that many people with diabetes have a deficiency of thiamine and that this may be linked to some of the complications that can occur.^[3][4]

Well-known syndromes caused by thiamine deficiency include beriberi, Wernicke-Korsakoff syndrome, and optic neuropathy.

Thiamine derivatives and thiamine-dependent enzymes are present in all cells of the body, thus a thiamine deficiency would seem to adversely affect all of the organ systems. However, the nervous system is particularly sensitive to thiamine deficiency, because of its dependence on oxidative metabolism.

Beriberi

Beriberi is a neurological and cardiovascular disease. The three major forms of the disorder are dry beriberi, wet beriberi, and infantile beriberi.^[5] A fourth form, gastrointestinal beriberi, was recognized in 2004.

• Dry beriberi is characterized principally by peripheral neuropathy consisting of symmetric impairment of sensory, motor, and reflex functions affecting distal more than proximal limb segments and causing calf muscle tenderness.^[2]

However, it has been recently recognized that peripheral neuropathy (tingling or numbness in the extremities) due to thiamine deficiency could also present with axonal neuropathy (partial paralysis or sensory loss). Peripheral neuropathy can present with subacute motor axonal neuropathy mimicking Guillain–Barré syndrome; or as a large fibre proprioceptive central-peripheral axonal neuropathy presenting as a subacute sensory ataxia.^[6]

• Wet beriberi is associated with mental confusion, muscular atrophy, edema, tachycardia, cardiomegaly, and congestive heart failure in addition to peripheral neuropathy.^[7]
• Infantile beriberi occurs in infants breast-fed by thiamin-deficient mothers (who may show no sign of thiamine deficiency). Infants may manifest cardiac, aphonic, or pseudomeningitic forms of the disorder. Infants with cardiac beriberi frequently exhibit a loud piercing cry, vomiting, and tachycardia.^[5] Convulsions are not uncommon, and death may ensue if thiamine is not administered promptly.^[2]
• Gastrointestinal beriberi is associated with nausea, vomiting, abdominal pain, and lactic acidosis.^[8][9]

Following thiamine treatment, rapid improvement occurs, in general, within 24 hours.^[5] Improvements of peripheral neuropathy may require several months of thiamine treatment.^[10]

Alcoholic brain disease

Nerve cells and other supporting cells (such as glial cells) of the nervous system require thiamine. Alcoholism can reduce the body’s ability to transport, metabolise and store thiamine. Examples of neurologic disorders that are linked to alcohol abuse include Wernicke's encephalopathy (WE), Korsakoff's syndrome (alcohol amnestic disorder), Wernicke–Korsakoff syndrome as well as varying degrees of cognitive impairment.^[11]

Wernicke's encephalopathy is the most frequently encountered manifestation of thiamine deficiency in Western society,^[12][13] though it may also occur in patients with impaired nutrition from other causes, such as gastrointestinal disease,^[12] those with HIV-AIDS, and with the injudicious administration of parenteral glucose or hyperalimentation without adequate B-vitamin supplementation.^[14] This is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.^[15]

Korsakoff's syndrome is, in general, considered to occur with deterioration of brain function in patients initially diagnosed with WE.^[16] This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative.^[2]

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.^[17]
• 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).^[18]

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. (See delirium tremens.)

Optic neuropathy

Optic neuropathy can also occur in thiamine deficiency and is characterized by bilateral visual loss, cecocentral scotomas and impaired colour perception. The ophthalmological findings usually can show a bilateral oedema of the optic disk in the acute phase, followed by a bilateral optic atrophy.

Genetic diseases

Genetic diseases of thiamine transport are rare but serious. Thiamine responsive megaloblastic anemia (TRMA) with diabetes mellitus and sensorineural deafness^[19] is an autosomal recessive disorder caused by mutations in the gene SLC19A2,^[20] 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.^[21][22] 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.^[23]

Mutations in the SLC19A3 gene have been linked to Biotin-Thiamine Responsive Basal Ganglia Disease^[24] 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,^[25] which may respond to thiamine treatment.^[2]

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).^[26][27][28] 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.^[29] The normal thiamine concentration in EDTA-blood is about 20-100 µg/l.

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.^[30]

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.^[31][32]

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.^[33] 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.^[34] 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.^[35]

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.^[36] 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."^{[36]p. 12006}

In the counties of Blekinge and Skåne (south-most Sweden) mass deaths of especially herring gull but also other species has 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 the last years mammals like Eurasian Elk (Alces alces) has suffered death in unusual high number. Lack of thiamine is the common denominator where analysis is done. The County Administrative Board of Blekinge did in April 2012 find the situation so alarming that they asked the Swedish government to set up a closer investigation.^[37]

References