Beriberi pathophysiology: Difference between revisions
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==Pathophysiology== | ==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: | 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 coA (the precursor for the neurotransmitter [[acetylcholine]]) | *[[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 [[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]]). Therefore, | * 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]]). 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 ([[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 | *[[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 (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. | *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.<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 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 WKS.<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 == | |||
There are no gross pathological features that are specific to beriberi. | |||
== Microscopic Pathology == | |||
There is no specific microscopic picture in tissues affected with beriberi. | |||
==References== | ==References== | ||
Revision as of 18:42, 7 November 2019
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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]
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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
There are no gross pathological features that are specific to beriberi.
Microscopic Pathology
There is no specific microscopic picture in tissues affected with beriberi.
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.