Beriberi

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

Beriberi is a dietary-deficiency disease caused by a lack of thiamine in the diet. Thiamine, initially named “the anti-beriberi factor” in 1926 was the first B vitamin to be identified and is therefore referred to as vitamin B1. Thiamine is soluble in water and partly soluble in alcohol. It consists of a pyrimidine and a thiazole moiety, both of which are essential for its activity. Thiamine functions in the decarboxylation of α-ketoacids, such as pyruvate α-ketoglutarate, and branched-chain amino acids and thus is a source of energy generation. In addition, thiamine pyrophosphate acts as a coenzyme for a transketolase reaction that mediates the conversion of hexose and pentose phosphates.

The word “Beriberi” is derived from the Sinhalese language, meaning “I cannot, I cannot”. It used to be quite common, especially in East Asia in the 19th century. Two scientists (Dr Christiaan eijkman and Sir Frederick Hopkins) attributed beriberi to thiamine deficiency and were awarded the Nobel prize in 1929.

Beriberi is usually classified into two types based on the main system affected (Wet and dry). The two forms may appear in the same patient, but one form dominates the disease phenotype. Other forms as infantile beriberi or Wernicke-Korsakoff syndrome occur in special populations.

The lack of thiamine pyrophosphate (TTP) impairs the functions of four enzymes involved in energy production and neurotransmitter synthesis, namely pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase, and branched-chain α-ketoacid dehydrogenase. Energy deprivation and deficient neurotransmitter synthesis probably explain the neural and cardiac dysfunctions, observed with beriberi.

Thiamine deficiency can generally result from inadequate intake (as with anorexia or alcoholism), increased losses (as with excessive vomiting), and inadequate absorption (as after bariatric surgeries)

Beriberi should be differentiated from other causes of cardiac dysfunction (wet beriberi), peripheral neuropathy (dry beriberi), delirium (WKS), and other disorders caused by excessive alcohol drinking. However, the differential diagnosis is broad due to the non-specific symptoms of cardiac and neural involvement associated with the condition.

No clear data are available on the incidence and prevalence of beriberi; however, it is generally more common in countries with excess white rice consumption and unbalanced food supply.

The most common risk factors is consumption of diet deficient in thiamine as white rice, as well as alcoholism and being born to thiamine-deficient mothers. Other less common risk factors include inherited genetic mutations and undergoing bariatric surgery.

There is insufficient evidence to recommend routine screening for beriberi.

In infants born to thiamine-deficient mothers, the symptoms may start as early as one month of age. The hepatic stores of thiamine last for only 18 days. Lack or deficient consumption leads to gradual appearance of manifestations.

Complications for beriberi include cachexia, heart failure, limb paralysis, delirium, and psychosis.

Beriberi is an easily treatable condition with rapid improvements on thiamine administration. However, Wernicke-Korsakoff syndrome is largely irreversible and has a poor prognosis. If untreated, children with infantile Beriberi may die shortly or develop long-term motor function abnormalities.

Monitoring the patient’s response after thiamine administration is the most cost-effective diagnostic study. A positive response is recorded if the patients clinical condition or cardiac function improved following thiamine administration.

The symptoms of beriberi are usually vague and therefore, the diagnosis must be considered in the clinical and geographical contexts. Common symptoms for wet beriberi include tachycardia, respiratory distress, and edema, while common symptoms for dry beriberi include parasthesia, muscle pain, weakness.

There are no specific signs for Beriberi. Therefore, it should be suspected in light of the patient’s symptoms and clinical setting. However, in advanced stages, the signs of cardiac dysfunction (wet beriberi) or peripheral neuropathy (dry beriberi) may be present.

The diagnosis of beriberi is assisted by a dietary history suggestive of a low thiamine intake and clinical manifestations. The most sensitive lab tests to detect thiamine deficiency are measurements of erythrocyte transketolase activity (ETKA) and the thiamine pyrophosphate effect (TPPE). Other tests include measurements of urinary concentrations of thiamine and its metabolites, as well as methylglyoxal.

There are no x-ray findings associated with beriberi.However, in advanced wet beriberi, the X-ray picture of heart failure may appear, including chamber enlargement, pleural effusion, and increased vascular markings. There are no CT scan findings associated with Beriberi. Even in Wernicke-Korsakoff syndrome, the CT scan is usually normal.In Wernicke-Korsakoff Syndrome patients, MRI may show some changes, including atrophy of mamillary bodies and hyperintense signals in the mesial dorsal thalami and periaqueductal grey matter.

There are no other diagnostic studies associated with Beriberi.

Beriberi is an easily treatable condition, using thiamine hydrochloride via oral or parentral routes. A rapid and dramatic recovery within hours can be made when this is administered to patients with beriberi.

Surgical intervention is not recommended for the management of Beriberi.

The most important preventive measure against Beriberi is increasing thiamine intake in diet. Other measures include reducing alcohol consumption and proper prenatal care of women in susceptible geographical areas.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

The word “Beriberi” is derived from the Sinhalese language, meaning “I cannot, I cannot”. It used to be quite common, especially in East Asia in the 19th century. Two scientists (Dr Christiaan eijkman and Sir Frederick Hopkins) attributed beriberi to thiamine deficiency and were awarded the Nobel prize in 1929.

• The origin of the word is from a Sinhalese phrase meaning “I cannot, I cannot”, the word being doubled for emphasis.
• It is a disease that has killed probably close to a million people worldwide.
• References to this disease can be found in Chinese medical texts dating as far back as 2697 BC.
• In the 19th century it was the “national disease” of Japan.
• It first attracted the attention of Western scientists in the 1880s, when Dutch military personnel experienced an epidemic of the disease while operating in Sumatra.
• Its association with the consumption of highly polished rice was noted in the first decade of the twentieth century.
• It took some 50 years and lifetimes of dedication by dozens of scientists from many different fields and of various nationalities before the mysteries of beriberi were unraveled.
• Christiaan Eijkman, a Dutch physician and pathologist first demonstrated that beriberi is caused by poor diet led to the discovery of vitamins. Together with Sir Frederick Hopkins, he was awarded the 1929 Nobel Prize for Physiology or Medicine for the discovery, but the ability to produce a synthetic vitamin on a commercial scale has been by no means the end of the story.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Abdelrahman Ibrahim Abushouk, MD[2]

Beriberi is usually classified into two types based on the main system affected (Wet and dry). The two forms may appear in the same patient, but one form dominates the disease phenotype. Other forms as infantile beriberi or Wernicke-Korsakoff syndrome occur in special populations.

• Beriberi is usually classified into two types based on the main system affected (Wet and dry).
• The two forms may appear in the same patient, but one form dominates the disease phenotype.
• Other forms as infantile beriberi or Wernicke-Korsakoff syndrome occur in special populations.^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

The lack of thiamine pyrophosphate (TTP) impairs the functions of four enzymes involved in energy production and neurotransmitter synthesis, namely pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase, and branched-chain α-ketoacid dehydrogenase. Energy deprivation and deficient neurotransmitter synthesis probably explain the neural and cardiac dysfunctions, observed with beriberi.

The active form of thiamine, “thiamine pyrophosphate or TTP” is an essential cofactor for four enzymes i.e. these enzymes use TTP to transfer an aldehyde unit to their substrates in various metabolic pathways.^[1] These enzymes are:

• Pyruvate dehydrogenase: Involved in glycolysis (energy production) and synthesis of acetyl coenzyme A (the precursor for the neurotransmitter acetylcholine).
• α-ketoglutarate dehydrogenase: Regulates oxidative phosphorylation and ATP production in the Krebs cycle. The Kreb’s cycle is the main source of ATP production and is important for the synthesis of some neurotransmitters as the excitatory neurotransmitter (glutamate) and the inhibitory neurotransmitter (GABA).
• Transketolase: Involved in the hexose monophosphate shunt, which links glycolysis and pentose phosphate pathway. It is essential for the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), which is involved in intra-mitochondrial electron transport, as well as the synthesis of fatty acids ans steroids in the liver and adrenal gland.
• Branched-chain α-ketoacid dehydrogenase (BCKDH): Catalyzes the oxidative decarboxylation of branched amino acids as leucine, isoleucine, and valine.This process generates acetyl coA and assists in the production of cholesterol and other neurotransmitters as glutamate and GABA.

Deficiency of TTP leads to impaired activity of the four aforementioned enzymes, causing energy deprivation and deficient synthesis of acetylcholine, glutamate and GABA neurotransmitters. Thiamine deficiency mainly affects the tissues that require high amounts of energy (ATP) as the heart and the brain. It is believed that energy deprivation and deficient neurotransmitter synthesis are responsible for the neural defects in dry beriberi. Other studies revealed non-coenzyme functions for thiamine in the brain as maintaining cell membrane stability and possibly acting as a trophic factor.^[2] Although energy deprivation is also believed to be the main mechanism of wet beriberi, the full pathophysiological picture of this subtype is not yet fully elucidated.

• In most cases, beriberi is a sporadic condition with no family history. However, a rare condition known as genetic beriberi may prevent the body from absorbing thiamine.
• A study by Bravata et al. could not identify specific mutations in thiamine transporter genes in individuals with sporadic beriberi.^[3] Some studies indicated the possibility of genetic predisposition for Wernicke-Korsakoff syndrome.^[4]

Since beriberi is common in countries with unbalanced food sources in terms of contained nutrients, other vitamin deficiencies may be associated.

• In advanced stages of dry beriberi, paralysis and atrophy of limb muscles occur (See image below).
  • Limb paresis/paralysis
  • Muscle wasting
  • Wrist and ankle drop^[5]

• In advanced stages of wet beriberi, the classic manifestations of heart failure may be present, including:
  • Limb edema
  • Persistent wheezing and cough
  • Prominent jugular veins
  • Hepatomegaly +/- ascites
  • Cyanosis

• Wernicke-Korsakoff syndrome: associated with atrophy of specific regions of the brain ^[7], including:
  • Mammillary bodies
  • Anterior region of the thalamus
  • Medial dorsal thalamus, the basal forebrain
  • Median and dorsal raphe nuclei

There are no specific microscopic features in tissues affected with beriberi. However, in advanced stages, the tissues might show the microscopic features of:

• Peripheral neuropathy and muscle atrophy (dry beriberi): Neuronal loss, deficient myelination, and distal axonopathy.
• Wernicke-Korsakoff syndrome: Neuronal loss, gliosis, hemorrhage, and degeneration in the mammillary bodies.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

Thiamine deficiency can generally result from inadequate intake (as with anorexia or alcoholism), increased losses (as with excessive vomiting), and inadequate absorption (as after bariatric surgeries).

Thiamine deficiency can be a result of:^[1][2][3]

• Inadequate intake:
  • Alcoholism
  • Anorexia
  • Intentional dieting
  • Starvation
  • Bulimia
  • Protein energy malnutrition in developing countries
  • Total parenteral nutrition
  • Infants breast fed by thiamine deficient mother
• Increased losses:
  • Protracted vomiting in chemotherapy patients
  • Hyperemesis gravidarum in pregnant women
• Inadequate absorption:
  • Post gastric bypass surgery patients
  • Genetic loss of ability to absorb thiamine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

Beriberi should be differentiated from other causes of cardiac dysfunction (wet beriberi), peripheral neuropathy (dry beriberi), delirium (Wernicke-Korsakoff syndrome) andexcessive alcohol drinking. However, the differential diagnosis is broad due to the non-specific symptoms of cardiac and neural involvement associated with the condition.

Beriberi should be differentiated from other causes of cardiac dysfunction (wet beriberi), peripheral neuropathy (dry beriberi), delirium (WKS), and other disorders caused by excessive alcohol drinking. However, the differential diagnosis is broad due to the non-specific symptoms of cardiac and neural involvement associated with beriberi.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Abdelrahman Ibrahim Abushouk, MD[2]

No clear data are available on the incidence and prevalence of beriberi; however, it is generally more common in countries with excess white rice consumption and unbalanced food supply.

• No clear data are available on the incidence rate of beriberi.

• Due to the absence of clear data on beriberi prevalence in children, the World Health Organization suggested that infant mortality curves can reflect thiamine deficiency in infants.^[1]
• The main reason an exact prevalence rate cannot be identified is that different studies used different blood thiamine concentration cutoffs.^[2]

• The infantile form of beriberi occurs in infants under one year of age: Cardiac form (1 to 3 months), aphonic (4 to 6 months), and pseudomeningitic (7 to 9 months).

• There is no racial predilection to beriberi.

• Beriberi affects men and women equally. However, pregnant women may be at risk.

• The majority of beriberi cases are reported in geographical regions with inadequate dietary intake (developing countries). In developed countries, it may occur in individuals with chronic illness or alcoholism.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

There is insufficient evidence to recommend routine screening for beriberi.

There is insufficient evidence to recommend routine screening for beriberi.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdelrahman Ibrahim Abushouk, MD[2]

Untreated beriberi may lead to significant complications as heart failure, limb paresis, and delirium. However, it is an easily treatable condition with rapid improvements on thiamine administration. However, Wernicke-Korsakoff syndrome is largely irreversible and has a poor prognosis. If untreated, children with infantile Beriberi may die shortly or develop long-term motor function abnormalities.

• In infants born to thiamine-deficient mothers, the symptoms may start as early as one month of age.
• The hepatic stores of thiamine last for only 18 days. Lack or deficient consumption leads to gradual appearance of manifestations.
• If left untreated, patients with beriberi may progress to develop heart failure, limb paresis, and delirium. However, thiamine treatment is highly effective and leads to rapid improvements.

• Common complications of Beriberi include:
  • Heart failure
  • Limb paralysis
  • Delirium
  • Psychosis
  • Cachexia

• Except for Wernicke-Korsakoff Syndrome (which is largely irreversible), other forms of beriberi are reversible and have good prognosis with rapid recovery within hours of thiamine administration.
• Wet Beriberi is usually more acute than dry beriberi. However, treatment results in normalization of cardiac function and size in few days. Sushin Beriberi may have very poor prognosis if left untreated.^[1]
• If untreated, Wernicke-Korsakoff syndrome has a high mortality rate (around 20%) and long-term neurological complications are common.
• If untreated, children with infantile Beriberi may die shortly or develop long-term motor function abnormalities.^[2]

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