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{{Beriberi}} | {{Beriberi}} | ||
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==Overview== | |||
The lack of thiamine pyrophosphate (TTP) impairs the functions of four enzymes involved in energy production and [[Neurotransmitter|neurotransmitter synthesis]], namely [[pyruvate dehydrogenase]], α-ketoglutarate dehydrogenase, [[transketolase]], and branched-chain α-ketoacid dehydrogenase. Energy deprivation and deficient [[Neurotransmitter|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 (biochemistry)|cofactor]] for four enzymes i.e. these enzymes use TTP to transfer an [[aldehyde]] unit to their substrates in various metabolic pathways.<ref name="pmid11899071">{{cite journal| author=Singleton CK, Martin PR| title=Molecular mechanisms of thiamine utilization. | journal=Curr Mol Med | year= 2001 | volume= 1 | issue= 2 | pages= 197-207 | pmid=11899071 | doi=10.2174/1566524013363870 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11899071 }}</ref> 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 [[Adenosine triphosphate|ATP]] production in the [[Krebs Cycle|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 ([[Glutamic acid|glutamate]]) and the inhibitory neurotransmitter ([[Gamma-aminobutyric acid|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|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|Branched-chain α-ketoacid dehydrogenase (BCKDH)]]: Catalyzes the oxidative decarboxylation of branched amino acids as [[leucine]], [[isoleucine]], and [[valine]].This process generates [[Acetyl-CoA|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|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.<ref name="pmid18642074">{{cite journal| author=Bâ A| title=Metabolic and structural role of thiamine in nervous tissues. | journal=Cell Mol Neurobiol | year= 2008 | volume= 28 | issue= 7 | pages= 923-31 | pmid=18642074 | doi=10.1007/s10571-008-9297-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18642074 }}</ref> 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|thiamine transporter]] genes in individuals with sporadic beriberi.<ref name="pmid24607307">{{cite journal| author=Bravatà V, Minafra L, Callari G, Gelfi C, Edoardo Grimaldi LM| title=Analysis of thiamine transporter genes in sporadic beriberi. | journal=Nutrition | year= 2014 | volume= 30 | issue= 4 | pages= 485-8 | pmid=24607307 | doi=10.1016/j.nut.2013.10.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24607307 }}</ref> Some studies indicated the possibility of genetic predisposition for [[Wernicke-Korsakoff syndrome causes|Wernicke-Korsakoff syndrome]].<ref name="pmid391073">{{cite journal| author=Blass JP, Gibson GE| title=Genetic factors in Wernicke-Korsakoff syndrome. | journal=Alcohol Clin Exp Res | year= 1979 | volume= 3 | issue= 2 | pages= 126-34 | pmid=391073 | doi=10.1111/j.1530-0277.1979.tb05286.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=391073 }}</ref> | |||
== 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). | |||
**[[Paresis|Limb paresis]]/[[paralysis]] | |||
**[[Muscle atrophy|Muscle wasting]] | |||
**Wrist and ankle drop<ref name="pmid30862772">{{cite journal| author=Shible AA, Ramadurai D, Gergen D, Reynolds PM| title=Dry Beriberi Due to Thiamine Deficiency Associated with Peripheral Neuropathy and Wernicke's Encephalopathy Mimicking Guillain-Barré syndrome: A Case Report and Review of the Literature. | journal=Am J Case Rep | year= 2019 | volume= 20 | issue= | pages= 330-334 | pmid=30862772 | doi=10.12659/AJCR.914051 | pmc=6429982 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30862772 }}</ref> | |||
* In advanced stages of wet beriberi, the classic manifestations of [[Congestive heart failure|heart failure]] may be present, including: | |||
** Limb [[edema]] | |||
** Persistent [[wheezing]] and [[cough]] | |||
**[[Jugular vein distention|Prominent jugular veins]] | |||
**[[Hepatomegaly]] +/- [[ascites]] | |||
**[[Cyanosis]] | |||
[[File:Late stage of paralysis with atrophy in dry beriberi.jpg|thumb|center|Late stage paralysis with atrophy in dry beriberi. <ref>https://upload.wikimedia.org/wikipedia/commons/8/88/Late_stage_of_paralysis_with_atrophy_in_dry_beriberi.jpg Attribution: W. Hamilton Jefferys [Public domain</ref>]] | |||
*[[Wernicke-Korsakoff syndrome]]: associated with [[atrophy]] of specific regions of the brain <ref name="pmid30281514">{{cite journal| author=Chandrakumar A, Bhardwaj A, 't Jong GW| title=Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis. | journal=J Basic Clin Physiol Pharmacol | year= 2018 | volume= 30 | issue= 2 | pages= 153-162 | pmid=30281514 | doi=10.1515/jbcpp-2018-0075 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30281514 }}</ref>, including: | |||
**[[Mammillary 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 [[mammillary bodies]]. | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
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{{WikiDoc Sources}} | |||
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[[Category:Needs content]] | [[Category:Needs content]] | ||
[[Category: | [[Category:Endocrinology]] | ||
[[Category:Gastroenterology]] | [[Category:Gastroenterology]] | ||
[[Category:Cardiology]] | [[Category:Cardiology]] | ||
Latest revision as of 15:28, 24 January 2020
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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 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.
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 Wernicke-Korsakoff syndrome.[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[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
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 mammillary 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.
- ↑ Shible AA, Ramadurai D, Gergen D, Reynolds PM (2019). "Dry Beriberi Due to Thiamine Deficiency Associated with Peripheral Neuropathy and Wernicke's Encephalopathy Mimicking Guillain-Barré syndrome: A Case Report and Review of the Literature". Am J Case Rep. 20: 330–334. doi:10.12659/AJCR.914051. PMC 6429982. PMID 30862772.
- ↑ https://upload.wikimedia.org/wikipedia/commons/8/88/Late_stage_of_paralysis_with_atrophy_in_dry_beriberi.jpg Attribution: W. Hamilton Jefferys [Public domain
- ↑ Chandrakumar A, Bhardwaj A, 't Jong GW (2018). "Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis". J Basic Clin Physiol Pharmacol. 30 (2): 153–162. doi:10.1515/jbcpp-2018-0075. PMID 30281514.
