Beriberi (Thiamine Deficiency)

When healthy individuals are deprived of thiamine, thiamine stores are depleted within 1 month. However, within a week after thiamine intake stops, healthy people develop a resting tachycardia, weakness, and decreased deep tendon reflexes; some people develop a peripheral neuropathy.

Dry beriberi

Thiamine deficiency with nervous system involvement is termed dry beriberi.[17] This presentation usually occurs when poor caloric intake and relative physical inactivity are present. The neurologic findings can be peripheral neuropathy characterized by symmetrical impairment of sensory, motor, and reflex functions of the extremities, especially in the distal lower limbs. Histologic analysis has shown that the lesions arise from a degeneration of the myelin in the muscular sheaths without inflammation.

Another presentation of neurologic involvement is Wernicke encephalopathy,[18] in which an orderly sequence of symptoms occurs, including vomiting, horizontal nystagmus, palsies of the eye movements, fever, ataxia, and progressive mental impairment leading to Korsakoff syndrome.[19, 12, 20, 21] Improvement can be achieved at any stage by the addition of thiamine, unless the patient is in frank Korsakoff syndrome. Only half of the patients treated at this stage recover significantly.

Wet beriberi

Wet beriberi is the term used for thiamine deficiency with cardiovascular involvement. The chronic form of wet beriberi consists of 3 stages. In the first stage, peripheral vasodilation occurs, leading to a high cardiac output state. This leads to salt and water retention mediated through the renin-angiotensin-aldosterone system in the kidneys. As the vasodilation progresses, the kidneys detect a relative loss of volume and respond by conserving salt. With the salt retention, fluid is also absorbed into the circulatory system. The resulting fluid overload leads to edema of the dependent extremities.

By the time significant edema occurs, the heart has been exposed to a severely high workload in order to pump the required cardiac output needed to satisfy end organ requirements. Parts of the heart muscle undergo overuse injury, which results in the physical symptoms of tachycardia, edema, and high arterial and venous pressures. These changes can lead to myocardial injury, expressed as chest pain.

A more rapid form of wet beriberi is termed acute fulminant cardiovascular beriberi, or Shoshin beriberi. The predominant injury is to the heart, and rapid deterioration follows the inability of the heart muscle to satisfy the body's demands because of its own injury. In this case, edema may not be present. Instead, cyanosis of the hands and feet, tachycardia, distended neck veins, restlessness, and anxiety occur. Treatment with thiamine causes low-output cardiac failure, because systemic vasoconstriction is reinstated before the heart muscle recovers. Support of heart function is an added requirement at this stage, and recovery is usually fairly quick and complete if treatment is initiated promptly. However, if no treatment is available, death occurs just as rapidly (within hours or days).

Lack of thiamine intake

Lack of thiamine intake can occur via diets consisting mainly of the following:

• Food containing a high level of thiaminases, including milled rice, raw freshwater fish, raw shellfish, and ferns

• Food high in anti-thiamine factor, such as tea, coffee, and betel nuts

• Processed food with a content high in sulfite, which destroys thiamine

The following diet-related factors can also cause reduced thiamine intake:

• Alcoholic state

• Starvation state

• Gastric bypass surgery - Due to limited caloric intake during postsurgical repair (approximately 600-900 kcal/day)[22, 23, 24]

• Parental nutrition without adequate thiamine supplementation[25]

Increased consumption states

Increased metabolic consumption of thiamine can result from the following:

• Diets high in carbohydrate or saturated fat intake

• Pregnancy

• Hyperthyroidism[26]

• Lactation

• Fever - Severe infection/sepsis[27]

• Increased physical exercise

• Refeeding syndrome (carbohydrate metabolism is increased)[27]

Increased depletion

Increased thiamine depletion can result from the following[28] :

• Diarrhea

• Diuretic therapies

• Peritoneal dialysis

• Hemodialysis/continuous renal replacement therapy[29]

• Hyperemesis gravidarum[19]

Loss of thiamine through renal excretion can occur with most, if not all, diuretics. It has been seen with the use of such diuretics as mannitol, acetazolamide, chlorothiazide, amiloride, and loop diuretics.[30] Thiamine loss is associated with the increase in urine flow rate, but it is not related to sodium excretion. This suggests that patients with polyuria, even if the condition is unrelated to diuretics, may benefit from thiamine supplementation.

One cross-sectional observational study showed that up to 33% of patients admitted with a diagnosis of congestive heart failure (CHF) had a thiamine deficiency due to chronic loop diuretic use, usually for more than 1 month.[31] (However, thiamine deficiency found in patients with heart failure has been present in up to 98% of patients in other studies.[2] )

Risk factors for the development of thiamine deficiency in the study's patients consisted of the following:

• Normal renal function

• Lack of thiamine supplementation (as little as 1.5 mg thiamine/day has been effective in the prevention thiamine deficiency)

• Preadmission spironolactone therapy (indicating more advanced disease)

Repletion of thiamine in patients with CHF has been shown to improve left ventricular function.

Decreased absorption

The following factors can result in decreased thiamine absorption:

• Chronic intestinal disease

• Alcoholism

• Malnutrition

• Gastric bypass surgery

• Malabsorption syndrome - Celiac and tropical sprue

• Folate deficiency - For example, in patients undergoing chemotherapy with high-dose methotrexate

Bariatric weight-loss surgery

In a study of 59 superobese patients who underwent bariatric weight-loss surgery, Aasheim et al concluded that the risk of thiamine deficiency in the first months following a duodenal switch procedure may be higher than it is after a gastric bypass, while the risk of vitamin A and D deficiencies following duodenal switch surgery may be greater in the first year than it is after gastric bypass.

The investigators compared the vitamin status of individuals who underwent laparoscopic Roux-en-Y gastric bypass to that of patients in whom laparoscopic biliopancreatic diversion with duodenal switch was performed.[32] The investigators found that following surgery, a steeper drop in thiamine levels occurred in the duodenal switch patients than in the patients who underwent gastric bypass. In addition, mean concentrations of vitamin A and 25-hydroxyvitamin D were lower in the duodenal switch group. Follow-up examinations were conducted at 6 weeks, 6 months, and 1 year after surgery.

The term bariatric beriberi is coined from this etiology.[27]

Folate deficiency

Thiamine serves as a coenzyme (in the form of thiamine pyrophosphate) in a variety of metabolic processes. In these processes, thiamine pyrophosphate is regenerated via the donation of a proton from the reduced form of nicotinamide adenine dinucleotide (NADH).

Folic acid is essential to having enough dihydrofolate reductase to regenerate NADH from its oxidative form. This regeneration allows NADH to continue to be present to regenerate thiamine pyrophosphate without being consumed in the process.

If folic acid is deficient in cells, it causes an indirect thiamine deficiency, because thiamine is present but cannot be activated.

Infantile beriberi

Infantile beriberi occurs in infants aged 2-4 months who are fed only breast milk and whose mothers are thiamine deficient.[15, 33]

Other

A retrospective study by Nath et al indicated that obesity is a risk factor for clinical thiamine deficiency, with such deficiency found in 66 out of 400 patients with a body mass index of 35 kg/m2 or above (16.5%).[34]

Occurrence in the United States

Beriberi is observed in developed nations in persons with alcoholism, people on fad diets, persons on long-term peritoneal dialysis without thiamine replacement, persons undergoing long-term starvation, or persons receiving intravenous fluids with high glucose concentration. No accurate statistics are available on the incidence of this condition.

International occurrence

Developing countries are known to have more vitamin deficiency problems in general, but there has been a lack of accurate statistics for thiamine deficiency. Beriberi has been reported among refugees who are relying on emergency food aid.[35] This is due to the lack of available micronutrition supplementation.

A study by Whitfield et al found a high incidence of thiamine deficiency in Cambodia among mothers and their young children. Using a nationally representative population sample of women of childbearing age and their young offspring, as well as an erythrocyte thiamine diphosphate concentration cutoff of under 120 nmol/L as a designation of thiamine deficiency, the investigators found such deficiency in 27% of mothers and 15% of children. Using a cutoff of under 180 nmol/L, thiamine deficiency rates reached 78% in mothers and 58% in their children. A particularly high prevalence of thiamine deficiency (38%) was found in infants aged 6-12 months (38%), as measured using the cutoff of less than 120 nmol/L.[36]

Beriberi can be quickly fatal or can slowly rob an individual of almost all energy for even the simplest of daily activities. However, it is one of the most easily treatable conditions, with a remarkable recovery being possible even in severe cases. Thus, the patient prognosis for beriberi is usually good, unless patients have established Korsakoff syndrome. When patients have progressed to this stage, the degree of damage is only minimally reversible.

In cases of wet beriberi, clinical improvement can be observed within 12 hours of treatment, with normalization of heart function and size occurring in 1 or 2 days. The recovery is so dramatic that treatment with thiamine is a diagnostic test, which can be used in cases of acute heart failure and insidious peripheral neuropathy.

A retrospective study by Harel et al indicated that thiamine deficiency in infancy can lead to long-term motor function problems. The study looked at children aged 5-6 years who, during the first 2 years of life, had been fed a faulty milk substitute that was deficient in thiamine, comparing them with age-matched controls. The Movement Assessment Battery for Children and the Zuk Assessment indicated that motor function difficulties existed in 56% and 59%, respectively, of the thiamine-deficient formula group, compared with 10% and 3%, respectively, of the control group. The results suggested that infantile thiamine deficiency affects gross and fine motor function, as well as balance skills.[37]

Most patients have no symptoms and signs of thiamine deficiency; therefore, it must be suspected in the appropriate clinical setting. Early symptoms and signs are often nonspecific and vague, such as fatigue. However, high-output cardiac failure should prompt investigation of thiamine deficiency as a cause. The same applies to neuropathic symptoms, particularly in the distal extremities.

Neurologic signs and symptoms of thiamine deficiency are as follows[11] :

• Poor memory, irritability, sleep disturbance

• Wernicke encephalopathy,[12] Korsakoff syndrome

• Bilateral, symmetrical lower extremity paresthesias, burning pain

• Muscle cramps

• Decreased vibratory position sensation

• Absent knee and ankle jerk

• Muscle atrophy

• Foot drop (late stage)

• Nystagmus (early sign)[39]

A study from Singapore, by Saini et al, reported that while Guillain-Barré syndrome (GBS) is an important cause of acute flaccid paralysis, thiamine deficiency should be considered an important differential diagnosis, particularly in patients with a history of dietary deprivation and incarceration.[38]

Cardiovascular signs and symptoms are as follows:

• Tachycardia

• Chest pain

• Wide pulse pressure

• Heart failure[13] (orthopnea with or without edema, warm skin due to vasodilation)

• Hypotension, shock

Gastroenterologic signs and symptoms are as follows:

• Anorexia

• Abdominal discomfort

• Constipation

• Dysphagia[14]

Infantile beriberi signs and symptoms are as follows[15] :

• CHF

• Aphonia

• Absent deep tendon reflex

The aforementioned study by Saini et al indicated that although the acute presentation of thiamine deficiency is similar to the presentation of GBS, thiamine deficiency is the more likely disorder when patients exhibit the following[38] :

• Subacute symptom evolution, with symptom evolution over weeks or more
• Presence of nystagmus and cerebellar dysfunction
• Encephalopathy (particularly if specific features of Wernicke disease/Korsakoff psychosis exist)
• Disproportionate vocal cord dysfunction, with paucity of other cranial nerve involvement
• Optic neuropathy
• Signs of volume overload
• Unexplained serum lactate elevation
• Normal cerebrospinal fluid protein
• Absence of sural sparing pattern on nerve conduction studies

A study by Mifsud et al described the characteristics of 56 cases of thiamine deficiency that were seen at a French tertiary hospital. A history of alcohol abuse was found in 45 patients (80%), and while neurologic symptoms were the basis for diagnosis in the majority of individuals, there were frequent instances of nonspecific and digestive symptoms. Moreover, the criteria for malnutrition were fulfilled in 34% of patients. Of the 54% of patients in whom brain magnetic resonance imaging (MRI) scans were performed, abnormal scans were found in 63% of cases.[39]

A study by Isenberg-Grzeda et al indicated that thiamine deficiency may be a frequent occurrence among inpatients with cancer, even in those who are of normal weight or overweight, lack other vitamin deficiencies, and are receiving multivitamin supplements. The single-center study found thiamine deficiency in 55.3% of 217 patients, with risk factors for the deficiency including active cancer treatment and fluorouracil-based chemotherapy.[40]

A literature review by Jain et al comparing the incidence of thiamine deficiency in patients with heart failure to that in controls reported an odds ratio of 2.53, with possible reasons for the deficiency in heart failure including diuretic use, dietary changes, and alterations in the absorption and metabolism of thiamine. The literature also indicated that thiamine supplementation may improve symptoms and ejection fraction in patients with heart failure.[41]

Alcoholism

Persons with chronic alcoholism have low thiamine intake, impaired thiamine uptake and storage, accelerated destruction of thiamine diphosphate, and varying degrees of energy expenditure. Alcohol is a direct neurotoxin. The effects on the body's supply of thiamine and on brain tissue are detrimental. Persons with known alcoholism should be administered parenteral thiamine as a routine action when they present to a medical facility.

Dieting

A patient’s dieting history also may hold a clue regarding thiamine deficiency. Fad diets often do not contain the necessary amounts of thiamine.

Dialysis and high energy consumption

Dialysis also robs thiamine from the circulation. In addition, states of high energy consumption, such as hyperthyroidism, pregnancy, or severe illness, require more thiamine and other nutrients.

Bariatric weight-loss surgery

Persons with a history of gastric bypass may also have beriberi.[24, 42, 43] For bariatric surgery patients, it is believed that a deficiency occurs primarily during the first 6 months after surgery, when individuals undergo the most rapid weight loss.

For practical reasons, replacing thiamine as an initial test may be most feasible. If the patient responds to treatment, it is safe to assume that a measure of thiamine deficiency was responsible for the condition. Thiamine is not toxic in high levels, which means that this route carries little risk. In addition, time is saved in treating the patient and money is saved in testing. (However, although observation of a patient's clinical response to thiamine administration remains the easiest, least expensive form of testing, clinicians usually miss the subclinical forms of beriberi.)

If laboratory confirmation is needed,[44] measure blood thiamine, pyruvate, alpha-ketoglutarate, lactate, and glyoxylate levels. Also, measure urinary excretion of thiamine and its metabolites. A scarcity of any of these chemicals strongly suggests thiamine deficiency.[16]

In conjunction with whole blood or erythrocyte transketolase activity preloading and postloading, a thiamine loading test is the best indicator of thiamine deficiency. An increase of more than 15% in enzyme activity is a definitive marker of deficiency. However, this test is expensive and time consuming; it is performed only for criterion-standard proof of deficiency.

Measure urinary methylglyoxal; also measure serum thyroid-stimulating hormone (TSH), to rule out thyrotoxicosis-induced high-output heart failure, if applicable.

An increase in troponin I has been found in heart failure due to thiamine deficiency.[45] Thiamine is an important enzymatic cofactor in several energy pathways. Its deficiency disrupts cellular processes and leads to myocardial death. Thiamine is also an important factor in the cellular production of glutathione, an antioxidant that myocardial cells need to counteract free radicals. In the absence of glutathione, these cells would die prematurely.

Metabolic acidosis can be seen in thiamine deficiency. This is due to increased lactic acid production from thiamine deficiency. Thiamine pyrophosphate (thiamine derivative) is the coenzyme for the conversion of pyruvate to acetyl coenzyme A. Without it, pyruvate is under used and converts to lactate. It is important to consider thiamine deficiency in the presence of unexplained metabolic acidosis, specifically, lactic acidosis.[46, 27]

Gastrointestinal beriberi is a condition in which patients report abdominal pain due to lactic acidosis.[47]

A retrospective study by Wani et al indicated that cranial ultrasonography can be used in the diagnosis of infantile encephalitic beriberi, with a finding of hyperechogenicity of the basal ganglia having a sensitivity and specificity of 71% and 92%, respectively, for the disease.[48]

In suspected cases of thiamine deficiency, prompt administration of parenteral thiamine is indicated. The recommended dose is 50 mg given intravenously or intramuscularly for several days. The duration of therapy depends on the symptoms, and therapy is indicated until all symptoms have disappeared. Maintenance is recommended at 2.5-5 mg per day orally unless a malabsorption syndrome is suspected.

Thiamine, even at high concentrations, is not toxic in a person with normal renal function. No cases of thiamine toxicity have been reported from the use of thiamine at the dosages indicated, even in patients in critical condition.

An optimal method for delivering the needed thiamine in a bioavailable form must be determined for the long-term treatment of each patient. Depending on the cause of the vitamin deficiency, a referral to an alcohol dependency clinic may be needed.

Most outpatient care is targeted at delivering thiamine in a bioavailable form to rehabilitated patients. Clinical follow-up with measurement of thiamine diphosphate activity may be warranted if relapse or noncompliance is suspected.

Support for cardiac function is necessary in cases of wet beriberi, because lack of cardiac support leads to low-output cardiac failure when the thiamine deficiency is corrected.

Follow-up care until delivery of current pregnancy, intensive care for advanced cardiomyopathy, definitive care for hyperthyroidism, or further workup of intestinal derangement may be warranted in patients with thiamine deficiency.

The level of activity and the presence of a high energy consumption state (eg, hyperthyroidism, pregnancy, lactation, severe disease) increase the daily requirements of thiamine.

The goals of pharmacotherapy are to correct the vitamin deficiency, reduce morbidity, and prevent complications. Suspected cases of thiamine deficiency are treated with prompt administration of parenteral thiamine; therapy continues until all symptoms of the deficiency have disappeared. Even at high concentrations, thiamine is not toxic in a person with normal renal function. Most outpatient care is targeted at delivering thiamine in a bioavailable form to rehabilitated patients.

Class Summary

Vitamins are essential for normal deoxyribonucleic acid (DNA) synthesis. Thiamine pyrophosphate, the biologically active form of thiamine (vitamin B-1), acts as a coenzyme in carbohydrate metabolism through the decarboxylation of alpha ketoacids. It also takes part in the formation of glucose by acting as a coenzyme for the transketolase in the pentose monophosphate pathway.

Thiamine

Thiamine is used to replenish the body's stores of the coenzyme thiamine pyrophosphate. The duration of parenteral thiamine therapy depends on the symptoms of thiamine deficiency; treatment is administered until all symptoms are gone.