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]