Beriberi pathophysiology
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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]
Overview
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.
Pathophysiology
Physiology
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 coA (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). Therefore,
- 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.
Pathogenesis
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.
Genetics
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 WKS.[4]
Associated Conditions
Since beriberi is common in countries with unbalanced food sources in terms of contained nutrients, other vitamin deficiencies may be associated.
Gross Pathology
- 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
- 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, including:
- Mamillary bodies.
- Anterior region of the thalamus
- Medial dorsal thalamus, the basal forebrain
- Median and dorsal raphe nuclei
Microscopic Pathology
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 mamillary bodies.
References
- ↑ Singleton CK, Martin PR (2001). "Molecular mechanisms of thiamine utilization". Curr Mol Med. 1 (2): 197–207. doi:10.2174/1566524013363870. PMID 11899071.
- ↑ Bâ A (2008). "Metabolic and structural role of thiamine in nervous tissues". Cell Mol Neurobiol. 28 (7): 923–31. doi:10.1007/s10571-008-9297-7. PMID 18642074.
- ↑ Bravatà V, Minafra L, Callari G, Gelfi C, Edoardo Grimaldi LM (2014). "Analysis of thiamine transporter genes in sporadic beriberi". Nutrition. 30 (4): 485–8. doi:10.1016/j.nut.2013.10.008. PMID 24607307.
- ↑ Blass JP, Gibson GE (1979). "Genetic factors in Wernicke-Korsakoff syndrome". Alcohol Clin Exp Res. 3 (2): 126–34. doi:10.1111/j.1530-0277.1979.tb05286.x. PMID 391073.
- ↑ https://upload.wikimedia.org/wikipedia/commons/8/88/Late_stage_of_paralysis_with_atrophy_in_dry_beriberi.jpg Attribution: W. Hamilton Jefferys [Public domain
