TPP0010.1177/2045125320978106Therapeutic Advances in PsychopharmacologyM Ott and U Werneke research-article20209781062020

Therapeutic Advances in Psychopharmacology Review

Ther Adv Psychopharmacol Wernicke’s encephalopathy — from 2020, Vol. 10: 1–24

DOI:https://doi.org/10.1177/2045125320978106 10.1177/ basic science to clinical practice. Part 1: 2045125320978106https://doi.org/10.1177/2045125320978106 © The Author(s), 2020. Article reuse guidelines: Understanding the role of thiamine sagepub.com/journals- permissions Michael Ott and Ursula Werneke

Abstract: Wernicke’s encephalopathy (WE) is an acute neuropsychiatric state. Untreated, WE can lead to coma or death, or progress to Korsakoff syndrome (KS) – a dementia characterized by irreversible loss of anterograde memory. Thiamine (vitamin B1) deficiency lies at the heart of this condition. Yet, our understanding of thiamine regarding prophylaxis and treatment of WE remains limited. This may contribute to the current undertreatment of WE in clinical practice. The overall aim of this review is to identify the best strategies for prophylaxis and treatment of WE in regard to (a) dose of thiamine, (b) mode of administration, (c) timing of switch from one mode of administration to another, (d) duration of administration, and (e) use of magnesium along thiamine as an essential cofactor. Evidence from randomized controlled trials and other intervention studies is virtually absent. Therefore, we have to resort to basic science for proof of principle instead. Here, we present the first part of our clinical review, in which we explore the physiology of thiamine and the pathophysiology of thiamine deficiency. We first explore both of these in their historical context. We then review the pharmacodynamics and pharmacokinetics of thiamine, exploring the roles of the six currently known thiamine compounds, their transporters, and target enzymes. We also explore the significance of magnesium as a cofactor in thiamine-facilitated enzymatic reactions and thiamine transport. In the second (forthcoming) part of this review, we will use the findings of the current review to make evidence-based inferences about strategies for prophylaxis and treatment of WE.

Keywords: beriberi, Korsakoff syndrome, magnesium, thiamine, thiamine deficiency, vitamin B1, Wernicke encephalopathy

Received: 10 August 2020; revised manuscript accepted: 10 November 2020.

Introduction administration, (c) timing of switch from one Correspondence to: Ursula Werneke Wernicke’s encephalopathy (WE) is an acute mode of administration to another, (d) duration of Department of Clinical neuropsychiatric state. Untreated, WE can lead administration, and (e) use of magnesium along Sciences, Division of Psychiatry, Sunderby to coma or death, or progress to Korsakoff syn- thiamine as an essential cofactor. Evidence from Research Unit, Umeå drome (KS). KS is a dementia characterized by randomized controlled trials and other interven- University, Umeå, 1,2 Sweden irreversible loss of anterograde memory. tion studies is virtually absent. Therefore, we have [email protected] Thiamine (vitamin B1) deficiency lies at the heart to resort to basic science for proof of principle Michael Ott of this condition. Hence, understanding thiamine instead. In the first part of our clinical review, we Department of Public Health and Clinical is essential for understanding the etiology of WE, explore the physiology of thiamine and the patho- Medicine, Division of its prophylaxis and treatment. physiology of thiamine deficiency in their histori- Medicine, Umeå University, cal context. In the second (forthcoming) part of Umeå, Sweden The overall aim of this review is to identify the this review, we will use the findings of the current best strategies for prophylaxis and treatment of review to make evidence-based inferences about WE in regard to (a) dose of thiamine, (b) mode of strategies for prophylaxis and treatment of WE.

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Historical perspective on thiamine thiamine intake is 1.4 mg for adult males and First descriptions of states compatible with thia- 1.0 mg for adult females. In pregnancy, daily thia- mine deficiency in form of beriberi appeared in mine requirements rise to 1.6–1.8 mg daily. In the Japan in the 9th century. The concept of WE United Kingdom (UK), the average daily intake emerged 1000 years later. Between 1876 and from food sources is about 1.5 mg.51 If the daily 1878, the neurologist Carl Wernicke at the Charité thiamine intake falls below 0.2 mg/1000 kcal, uri- Hospital in Berlin identified three cases of a hem- nary excretion becomes low. Clinical symptoms orrhagic encephalitis, which now bears his name.3 of thiamine deficiency may then emerge within The etiology remained unknown at the time; the 8 weeks.52 Thiamine can be found in many food- concept of vitamins emerged only 25 years later. It stuffs including meat, wholegrain products, forti- then took another 30 years to identify the link fied grain products, pulses, and some fruits. Yeast between thiamine deficiency and WE (Table 1). extracts contain most thiamine, and sugar is Whether “thiamin” or “thiamine” is the correct devoid of thiamine. As a general rule, unless forti- spelling has been debated ever since the name was fied, processed foods contain less thiamine than proposed.4 Today, both spellings are used. comparable non-processed food stuffs (Table 3). Of all meats, pork has the highest thiamine con- tent. Food preparation involving heat can lead to Manifestations of thiamine deficiency a 20% thiamine loss. Thiamine deficiency can arise from (a) reduced intake, (b) impaired absorption, (c) inability to convert thiamine to its biologically active form, or Thiamine compounds (d) excessive elimination. Alcohol use disorder There are six known thiamine compounds, free accounts for about 50% cases of WE. Bariatric thiamine, thiamine monophosphate (TMP), thia- surgery, consuming illnesses, malabsorption syn- mine diphosphate (TDP), adenosine thiamine dromes, and hyperemesis are other examples of diphosphate (ATDP), thiamine triphosphate possible causes.40,41 We will discuss such causes (TTP), and adenosine thiamine triphosphate in more detail in the second, forthcoming, part of (ATTP)5,55 (Figure 1). this review. TDP is also referred to as thiamine pyrophos- Thiamine deficiency is often divided in two dif- phate (TPP). In humans, free thiamine, and ferent disease entities, Wernicke-Korsakoff- TMP account for 5–15% of the total thiamine. syndrome and beriberi. Beriberi has been TDP is the principal biologically active form, and categorized further according to organ involve- accounts for 80–90% of total thiamine. TDP pre- ment into dry, wet, and gastrointestinal beriberi. sents in high concentrations in skeletal muscle, As WE and beriberi overlap, it may be more accu- liver, heart, kidneys, and brain. The remaining rate to use thiamine deficiency as an umbrella three components, TTP, ATTP, and ATDP, term, to then be specified further to reflect the account for only 1% of total thiamine in humans.55 respective clinical problem (Table 2).42 In this Whole blood thiamine levels can vary significantly way, six different thiamine deficiency states can between populations (Table 4). be described, WE, KS, dry and wet beriberi, Shoshin beriberi, and thiamine-deficiency-associ- Approximately 75% of whole blood thiamine is ated lactic acidosis. Gastrointestinal beriberi is stored in the erythrocytes, 15% in leukocytes, and probably a manifestation of thiamine-deficiency- 10% in plasma.61 The compounds can be phos- mediated lactic acidosis. Thiamine deficiency phorylated or dephosphorylated as required. The occurs not only in adults; both beriberi and WE enzymes necessary are under genetic control have been described in children.43,44 (Table 5).

Free thiamine and TMP are the thiamine trans- Dietary thiamine port compounds that deliver thiamine to and The recommended daily thiamine intake depends from the cells. TDP and TTP are the compounds on age, sex, and calorie and carbohydrate intake. that unfold the biological action. The different As a rule of thumb, thiamine intake should be at forms are constantly converted into each other to least 0.4 mg/1000 kcal. The recommended dietary maintain thiamine availability.

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Table 1. A brief history of thiamine.5–10

Year Milestone

As early as 640 In China and Japan, the term “kakkè” 脚気/かっけ is used to describe what later turns out to be beriberi.11

1873–1874 The Dutch naval surgeon Fredrik Johannes van Leent ascribes high mortality from beriberi among Indian crews to their diet, and reduces the incidence of beriberi from 60% to 7% by adding vegetables, meat, bacon, and butter.12

1875 The French surgeon and ophthalmologist Charles Jules Alphonse Gayet describes a case of diffuse encephalitis, later thought to have been due to thiamine deficiency.13

1876–1878 The German physician Carl Wernicke describes three cases of the hemorrhagic encephalopathy without being able to clarify the etiology.3

1884 The Japanese naval medical officer Takaki Kanehiro prevents beriberi effectively by enriching the white rice diet with meat and vegetables, assuming protein deficiency as cause.6

1887 The Russian physician Sergei Korsakoff describes cases of a dementia with anterograde amnesia without being able to clarify the etiology.14

1886 The Dutch government sends professor Cornelis Pekelharing and neurologist Cornelis Winkler to Jakarta (at that time Batavia, part of the Dutch East Indies) to investigate beriberi. They tentatively conclude that beriberi is of bacterial origin.15 They return home and leave their assistant Christiaan Eijkman to isolate the causative organism.

1890–1897 Eijkman conducts experiments in chicken and demonstrates that a diet of polished rice, not bacteria, is associated with a beriberi-like illness.16 He confirms the causative association of polished rice and beriberi in an observational study with Adolphe Vorderman in 279,623 prison inmates.17 He postulates the presence of an antidote for the disease in the silver skin of rice.

1901 Gerrit Grijns, successor to Eijkman in the Indonesian laboratory, concludes that there is rather a protective substance in rice, but even meat and vegetables, essential to maintain the function of the nervous system. “Partial starvation”, for example, absence of that micronutrient, which is destroyed by cooking, leads to beriberi.18

1906 Eijkman establishes that the protective substance is water-soluble.19

1910–1912 The Polish scientist Casimir Funk identifies an “antineuritic substance”, which he called beriberi “vitamine” (vita: life; amine: nitrogen containing compound).20

1920 The British biochemist Jack Drummond suggests the term vitamin (without “-e” and the distinction of vitamins by name of the alphabet.21

1926 The Dutch chemist Barend Jansen together with his colleague Willem Donath isolates pure vitamin B1.22

1929 Eijkman, jointly with Sir Frederick Hopkins, receives the Nobel Prize for Physiology or Medicine for the discovery of vitamins.23

1936 The American chemist Robert Williams synthesises thiamine and later licenses the production process to Merck.24

1937 Several European countries accept the name “aneurine” for vitamin B1. Williams suggests the name “thiamin”, derived from the Greek “theion” = sulfur and amine.25

1941 A. C. P. Campbell and Ritchie Russell at the Scottish Mental Hospital’s Laboratory in Edinburgh suggest vitamin B1 deficiency as a cause of Wernicke’s encephalopathy.10

1963 The Bread and Flour Regulations 1963 require the addition of vitamin B1 to non-wholegrain bread in Britain.26

1974 In collaboration with the local baker, general practitioner Max Kamien fortified the bread with thiamine, niacin and iron in a small town in the Australian outback, eliminating vitamin B deficiency signs in Aboriginal people.27 Thiamine fortification of flour becomes mandatory in Australia 1991.28

1999 Thiamine transporter 1 (SLC19A2) is cloned by several groups.29–32 Organic cation transporter (OCT) 3 is shown to have thiamine as substrate.30

2000 Thiamine transporter 2 (SLC19A3) is identified and characterized.33

2001 The reduced folate carrier (SLC19A1) is shown to transport phosphorylated thiamine compounds.34

2011 Prion proteins are shown to bind thiamine.35

2014 The human colonic thiamine pyrophosphate transporter (SLC44A4) is identified.36 OCT 1 is recognised as thiamine transporter in the liver.37 The role of multidrug and toxin extrusion proteins (MATE) and OCT 2 in renal excretion of thiamine is discovered.38 A putative thiamine transporter (SLC35F3) is characterized.39

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Table 2. Thiamine deficiency states.42,45–50

WE Korsakoff´s Dry beriberi Wet beriberi Shoshin Thiamine syndrome beriberi deficiency mediated lactic acidosis/ gastrointestinal beriberi

Organ system Central nervous system Peripheral nervous Cardiovascular system Ubiquitous predominantly system affected

Onset Acute Chronic Chronic Subacute Acute Acute

Symptoms Nystagmus, Memory loss, Symmetrical Hyperdynamic heart failure, Anorexia, nausea, classically ophthalmoplegia, anterograde peripheral oedema, ↓ peripheral vomiting and described ataxia, confusion and neuropathy with vascular resistance, abdominal retrograde, both sensory hypotonia, metabolic pain, Kussmaul amnesia, and motor acidosis breathing apathy impairments, ↑ lactate mostly of the distal extremities Etiology ↓ thiamine intake As WE or as ↓ thiamine intake ↓ thiamine ↓ thiamine ↓ thiamine intake ↓ thiamine or sequel of intake + intake + ↓ thiamine absorption WE without ↓ folate? ↓ folate? absorption ↑ thiamine current ↑ thiamine elimination thiamine elimination deficiency

WE, Wernicke’s encephalopathy.

Thiamine metabolism dehydrogenase (PDHG), α-ketoglutarate dehydro- Mechanism of thiamine uptake and transport genase (α-KGDH), branched chain α-keto acid through the body has crucial implications for the dehydrogenase E1 (BCAKDH E1), and 2-hydroxy- understanding of the etiology of WE and treat- acyl CoA lyase 1 (HOACoL).5,70–76 These enzymes ment rationale. Humans cannot synthesize thia- hold key roles in mitochondrial energy (ATP) gen- mine but depend on two exogenous sources: eration in body and nerve cells, nucleic acid synthe- dietary and bacterial thiamine.69 Transport of sis, carbohydrate, fatty acid metabolism, and amino thiamine and conversion of various thiamine acid metabolism. If these enzymes do not function compounds into each other are under genetic properly, energy metabolism becomes impaired and control. These mechanisms require further clari- oxidative stress increases. At the same time, unde- fication (Table 4). sirable compounds may accumulate if chemical reactions are re-routed. For instance, if α-KGDH is impaired, glutamate is produced instead of succinyl Thiamine actions and implications for CoA. If PDHG is impaired, lactate is produced deficiency states instead of acetyl CoA70 (Table 6, Figure 2). Thiamine plays a central role in energy metabo- lism. Thiamine is also implicated in the physiol- Thiamine deficiency therefore disrupts energy ogy of neurotransmission. metabolism and ATP production. α-KGDH and TK are two key enzymes in the pathophysi- ology. Decreased α-KGDH activity can develop Energy metabolism within 4 days of thiamine deficiency.1 Decreased TDP acts as an important cofactor in glucose, fatty α-KGDH activity results in increased oxidative acid, and protein metabolism, as well as adenosine stress, lactate acidosis, excitotoxicity, for triphosphate (ATP) generation. Thus, TDP is a instance through glutamate accumulation, critical cofactor for transketolase (TK), pyruvate inflammation and disturbed blood brain barrier

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Table 3. Comparable foods of higher and lower thiamine content.53,54

Item Thiamine (mg/100 g) Item Thiamine (mg/100 g)

Higher thiamine contenta Lower thiamine contenta

Ham 0.80 Turkey slices 0.05

Pork chop, grilled, lean 0.78 Chicken breast, coated, baked 0.10

Bacon, streaky, fried 0.75 Pork sausages, grilled traces

Cornflakes fortified 0.60 Cornflakes unfortified traces

Peas, frozen 0.26 Peas, canned in water, reheated, 0.09 drained

Bread, whole meal, average 0.25 Cakes from “healthy eating” ranges 0.06

Bread, white, average 0.24 Sponge cake, home made 0.08

Chapati, made without fat 0.23 Rice cakes 0.02

Peanuts, dry, roasted 0.18 Potatoes crisps, fried in sunflower oil 0.09

Potatoes, old, boiled 0.18 Potato chips, from fast food outlet 0.07

Spaghetti, dried, whole wheat, cooked 0.11 Spaghetti, dried, white, cooked 0.08

Rice, brown, wholegrain, cooked 0.11 Rice, long grain, boiled traces

Lentils, red, boiled 0.11 Chickpeas, canned in water, reheated, 0.05 drained

Oranges 0.11 Apples 0.04

For comparison Yeast extract 4.10 Sugar 0.00

aEstimates based on several food samples in each category.

(BBB) permeability, cerebral edema, and, ulti- This can be deducted from the observation that the mately, neuronal death.71,79 Decreased TK can metabolic thiamine antagonist oxythiamine can develop within 1 week of thiamine deficiency.1 increase acetylcholine release.74,80 The role of TDP in the modulation of glutamate neurotransmission arises from its impact on α-KGDH. Thiamine may Signal transmission also regulate the activity on the astrocyte glutamate Thiamine phosphates have even non-enzymatic aspartate transporters.81 These transporters are actions on neurotransmitters and hormones through under genetic control. Defects may result in insuf- second messengers. Whereas other B-vitamins acti- ficient clearance of glutamate and hence to an vate the adenyl cyclase system, thiamine activates increase of interstitial glutamate. This could lead to the guanyl cyclase system. cGMP is an important hyperexcitability, neurotoxicity and cell death as second messenger for peptide hormones and nitric possible consequences.81–83 oxide (NO), facilitating smooth muscle relaxation, mediating penile erection, regulating vascular and Finally, thiamine may also modulate other neu- airway tone, peristalsis, and insulin secretion.5,75 rotransmitters such as serotonin.1 Ultimately, TDP also acts as a cofactor for PDGH and facili- much of what we know is based on in vitro and tates acetylcholine synthesis. Thiamine even modu- animal experiments. Our understanding of thia- lates choline neurotransmission non-enzymatically. mine function in the brain remains limited.55,74

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Figure 1. Thiamine compounds. *In red blood cells. #Thiamine phosphate esters are hydrolyzed by various phosphatases and nucleotide diphosphatases.

The journey of thiamine through the body cells may involve prion proteins (PrP).84 PrP are membrane-anchored proteins, particularly abun- Thiamine transport in and out of cells: general dant in neuronal cells in vertebrates. It has been principles shown that thiamine binds to PrP.35 The thiamine For the human organism, thiamine is an extremely transporters are quickly saturated when extracel- valuable substance due to its central role in many lular thiamine concentrations exceed the physio- metabolic processes (Table 6). As thiamine cannot logical range. Thiamine transporter functions be synthesised by humans, it is crucial to secure a partly overlap. For instance, the reduced folate steady supply to the cell. This involves maximizing carrier (RFC/SLC19A1) can take over transport uptake and minimizing loss. In most cells, different from Thiamine transporter 1 (ThTR-1). General systems of transporters are available to facilitate cation-transporters, which are not specific to thia- uptake into the cell and into the mitochondria mine, can also transport thiamine at higher con- (Table 7). The kidneys are fine-tuned to either centrations. Such include transporters belonging reabsorb or excrete thiamine depending on the to the organic cation-transporter (OCT) and mul- actual thiamine plasma concentration. A further tidrug and toxin extrusion proteins (MATE) fam- mechanism of facilitating thiamine uptake into the ily (Table 7). This partial overlap of thiamine

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Table 4. Whole blood thiamine concentrations in four populations.56–60

n Sex Age range Free TMP TDP (nmol/l) TTP Total Ratio phosphorylated (year) (nmol/l) (nmol/l) (nmol/l) (nmol/l) thiamine (TMP + TDP + TMP)/ free thiamine

Japana

509 M 21–80 7 (2–18) 17 (5–47) 124 (70–229) 0 (0–4) 150 (89–262) 22 (9–58)

460 F 18–70 6 (2–17) 16 (4–60) 114 (63–200) 0 (0–3) 139 (80–235) 22 (8–58)

Norway 1991b

15 M 32–54 33.4 (10.4) 10.9 (5.1) 165.0 (40.4) <2

15 F 23–60 29.6 (10.0) 9.7 (2.3) 121 (29.6) <2

The Netherlandsb

65 4.3 (1.9) 4.1 (1.6) 120 (17.5) <4

Belgiumb

7 4 (3) 10 (4) 138 (33) 13 (4)

The Netherlandsc 98 115 (70–185)

aMean (95% confidence interval). bMean (standard deviation). cMean (range) F, female; M male, TDP, thiamine diphosphate; TMP, thiamine monophosphate; TTP, thiamine triphosphate.

transporters may be the reason why not all thia- an electrochemical gradient via protein channels.110 mine transporter deficiencies are associated with This suggests that, within limits, passive thiamine pathologies. transport is a non-saturable process.109,111 Active and passive thiamine transport may operate ­simultaneously.112 The active transport follows a From food to enterocyte Michaelis–Menten kinetic and seems to be satu- Dietary thiamine exists mainly in phosphorylated rated at a concentration of 2-2.5 µmol/l.113–115 As forms. Exogenously acquired thiamine is thought to shown in lines of heterogenous human epithelial be first de-phosphorylated to free thiamine by gas- colorectal adenocarcinoma cells (Caco-2 cells), trointestinal phosphatases.107 Free thiamine is then active transport has evolved to maximize thiamine absorbed in the small intestine, preferentially in the uptake in scenarios of low availability.116 Animal jejunum. There are two transport mechanisms, experiments have shown that thiamine uptake in the active and passive (Figure 3). The active transport small intestine can be increased dramatically during system involves ThTR-1 and ThTR-2.108 The pas- thiamine deficiency. However, during chronic alco- sive transport is proportional to the thiamine con- hol use, thiamine uptake is reduced. In the presence centration in the intestinal lumen.109 Where of alcohol, expression of both ThTR-1 and ThTR-2 epithelial and endothelial linings are made up by diminished significantly.117 tight junctions, only small molecules can pass through by simple passive diffusion. As thiamine is An alternative source of thiamine is bacterial. a relatively large molecule, its passive transport most Bacteria flora in the large intestine may synthesize likely occurs in the form of facilitated diffusion, along both free thiamine and TDP.36,103,104 Previously,

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Table 5. Enzymes required for the conversion of thiamine compounds.1,55,62–66

HGNC Cytogenic Transporter/enzyme Reaction Magnesium Pathologies associated approved gene location expressed requirement with genetic change symbol

TPK1 protein 7q35 Thiamine Free thiamine Divalent cations, Thiamine metabolism network diphosphokinase/ → TDP best activation with dysfunction syndrome Thiamine Mg2+ 5: onset of acute diphosphotransferase encephalopathic EC 2.7.6.2 episodes in early childhood67

Thiamine-diphosphate TDP → TTP Mg2+ required by kinase several animal EC 2.7.4.15 organisms, but not shown for humans

AK1 9q34.11 Erythrocyte adenolate TDP → TTP in Mg2+ required Defect associated with kinase red blood cells hemolytic anaemia68 EC 2.7.4.3

THTPA protein 14q11.2 Thiamine- TTP → TDP Mg2+ required network triphosphatase/TTP Hydrolase EC 3.6.1.28

ALPI 2q27.1 Alkaline phosphatase TDP → TMP Intestine. Mg2+ used 1p36.12 EC 3.1.3.1 TMP → free as a cofactor thiamine

Multiple Multiple Acid phosphatase TTP → TDP Mg2+ used as a EC 3.1.3.2 TDP → TMP cofactor

Not available Not available Nucleoside- TDP → TMP Mg2+ not required triphosphate phosphatase/ unspecific diphosphate phosphohydrolase EC 3.6.1.15

Not available Not available Thiamine phosphate TMP → free Mg 2+ enhanced (mono) phosphatase thiamine membrane-bound EC 3.1.3.100 activity 1.7-fold, soluble enzyme independent of Mg 2+ (based on animal experiments)

ALPI, alkaline phosphatase, intestinal; EC, Enzyme Commission; HGNC, HUGO Gene Nomenclature Committee; Mg2+, bivalent magnesium cation; TDP, thiamine diphosphate; THTPA, thiamine triphosphatase; TMP, thiamine monophosphate; TPK1, thiamine pyrophosphokinase; TTP, thiamine triphosphate.

it has been assumed that this colonic thiamine From enterocyte to blood cannot be used. Now, based on animal cell cul- In the enterocyte, as in any other cell, free thiamine ture experiments, it has been suggested that can be phosphorylated directly to TDP. The microbiota generated TDP is taken up into the enterocyte uses a part of this TDP for its own meta- colonocytes by a human TDP transporter. At bolic needs. The rest is broken down to TMP and present it remains unclear how much colonic thi- free thiamine. Free thiamine and TMP are then amine contributes to physiological functions of transported out of the cell into the plasma.64,112 TDP across the body (Figure 3).36,69,104 The release of thiamine into plasma has been

8 journals.sagepub.com/home/tpp M Ott and U Werneke et al. ↓ energy supply ↓ nucleotide synthesis ↓ fatty acid synthesis → facilitating demyelination ↑ oxidative stress Amino acid imbalance Clinical implication in deficiency states implication Clinical Unclear Peroxisome biogenesis defects → impeding the breakdown of certain nutrients including amino acids degeneration and β -oxidation of fatty acids ↑ phytanic acid → Refsum disease ↓ fatty acid synthesis → demyelination ↑ Valine, leucine and isoleucine corresponding α -ketoacids → maple syrup urine disease ↓ fatty acid synthesis → demyelination ↓ Energy (ATP) production Leigh phenotype ↑ nitric oxide and peroxidase activity → oxidative stress ↓ energy production Lactate acidosis and ↑ focal extracellular glutamate → oedema → excitotoxicity → BBB permeability → neuronal death 78 2 May structurally alter TPP to change TPP affinity for TK Substrates in the glycolytic pathways Generation of d-ribose-5-P → Nucleotide synthesis → RNA/DNA synthesis NADPH as a reducing agent for fatty acid and acetylcholine synthesis, maintenance of myelin sheaths Aromatic amino acid synthesis Functions of metabolic products products of metabolic Functions other pathways and resulting intermediates Formate → CO Isobuturyl CoA, α -methylbuturyl isovaleryl CoA → acetyl CoA, acetoacetate, succinyl CoA → Fatty acid, ketone bodies and acetylcholine synthesis, maintenance of myelin sheaths Fatty acid, ketone bodies and acetylcholine synthesis, maintenance of myelin sheaths Generation of Acetyl CoA Generation of citrate, the first component in the TCA cycle Energy production (ATP) Generation of succinyl CoA Yes Yes Magnesium as a further cofactor Yes Yes Yes Yes 5,62,65,70–75,77 As TK Pentose phosphate pathway Pathway/function Oxidation of 3-methyl branched fatty acids such as phytanic acid and 2-hydroxy fatty acids ( α -oxidation) Degradation of branched chain amino acids, valine, leucine and isoleucine, facilitating the oxidative decarboxylation step Glycolysis (rate- limiting co-factor) TCA (citric acid) cycle a a Cytosol, nucleus Cytosol, extracellular exosome, nucleus, peroxisome, vesicles Subcellular location Subcellular Mitochondrion, nucleus, PDHG complex (GO:0045254) Cytosol, peroxisomes Mitochondrion, nucleus, OGDC (GO: 0045252) Mitochondrion Xq28 3p21.1 Cytogenic Cytogenic location Xp22.12 3p25.1 7p13 19q13.2 TKTL 1 TKT HGNC approved gene symbol PDHA1 HACL1 OGDH BCKDHA Key metabolic enzymes that use thiamine pyrophosphate as a cofactor. enzymes that use thiamine pyrophosphate metabolic Key Note that this term represents a location and not a function. a location represents that this term Note TK protein 1 EC 2.2.1.1 TK EC 2.2.1.1 Enzyme a -keto acid dehydrogenase; Co A, coenzyme A; EC, Enzyme Commission numbers; GO, gene ontology; HGNC, HUGO Gene Nomenclature Committee; NADPH, Committee; HGNC, HUGO Gene Nomenclature GO, gene ontology; numbers; A; EC, Enzyme Commission Co A, coenzyme acid dehydrogenase; chain α -keto BCKDH, branched adenosine triphosphate; ATP, TK, acid cycle; tricarboxylic cycle, TCA dehydrogenase; PDHG, pyruvate P, phosphate; complex; dehydrogenase ODGC, oxoglutarate form); i.e. reduced (hydrogenated, phosphate adenine dinucleotide nicotinamide TPP, thiamine pyrophosphate. transketolase; PDHG EC 1.2.4.1 2-hydroxyacyl CoA lyase 1 (HACL1) EC 4.1.-.- α -ketoglutarate dehydrogenase α -KGDH/OGDC EC 1.2.4.2 BCKDH E1 subunit α EC 1.2.4.4 Table 6. Table

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Figure 2. Thiamine- and magnesium-dependent metabolic pathways. Red arrows, thiamine- and magnesium-dependent reactions; black arrows, reactions not dependent on thiamine. α-KGDH, α-ketoglutarate dehydrogenase; BCAKDH, branched chain α-keto acid dehydrogenase; F6P, d-fructose 6-phosphate; G3P, d-glyceraldehyde 3-phosphate; G6P, d-glucose 6- phosphate; HOACol, 2-hydroxyacyl CoA lyase 1; PDHG, pyruvate dehydrogenase complex; TKL, transketolase.

ascribed to ThTR-1,108 but other transporters may From blood to tissue be involved. As an organic cation, thiamine can be Once in the plasma, free thiamine and TMP are dis- transported by organic cation/antiport systems into tributed throughout the body. Phosphorylated thia- the enterocyte.107 From there, organic cation trans- mine is bound partly to plasma proteins.119 Both free porter proteins (OCT) 1 and 3 can transport thia- thiamine and TMP can enter the cell. Free thiamine mine into the blood.92,112 OCT 1 and 3 can take up in the cationic form crosses the cell membrane with thiamine in concentration ranges from 10 to help of ThTR-1.108 The mechanism by which TMP 500 µmol/l (Figure 4).112 This may be the mecha- crosses the cell membrane is not well described. RFC nism behind the passive thiamine transport at high (SLC19A1) has been implicated (Table 4).86,120 concentrations. However, it remains currently Once free thiamine enters the cell, it is phosphoryl- unclear how far this extracellular “flooding” of cells ated to TDP directly without generation of TMP as with free thiamine leads to higher intracellular lev- an intermediary. The responsible enzyme is thiamine els of pharmacologically active phosphorylated thi- diphosphokinase, which catalyzes the following reac- amine forms. Alcohol can impair the active intestinal tion: free thiamine + ATP → TDP + AMP. A transport mechanism.69,117 However, alcohol does small part can be phosphorylated further to TTP. not seem to affect passive uptake of thiamine at high TTP can be dephosphorylated to TDP, TDP to doses.114,118 TMP, and TMP to free thiamine (Figure 4).55,64

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Figure 3. From food to blood. OCT, organic cation transporter; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TMP, thiamine monophosphate; TTP, thiamine triphosphate.

In a study of thiamine kinetics in six healthy was phosphorylated to TDP. At the same time, ­volunteers,121 large increases in thiamine blood thiamine was eliminated seven times faster from concentration after intravenous (i.v.) injection the plasma than blood cells. These findings hint reflected increases in extracellular plasma con- at thiamine phosphorylation rather than thiamine centrations. Only a little free thiamine was stored transport being the rate-limiting factor for TDP in the blood cells. Further, only a small amount availability.

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38 101 Three 87 97 94 and various 97 and microvessels of 95,96 94 38 Renal tubular secretion of Intestinal uptake of 105 but a lower affinity than 91 98 Association of the 30 88 39 Autosomal dominant deafness has been but even in microvessels of the blood- 106 103,104 OCT3 in human liver cells showed a higher Association with seizures and brain atrophy 92,93 89,90 Renal tubular secretion/reabsorption of thiamine. 97 Expressed on basolateral side of renal tubular cells. 67 Renal tubular secretion of thiamine. 99,100 97 Expressed on luminal side of renal tubular cells. 86 Expressed in microvessels of the blood-brain barrier. 92,93 38 Can act as transporter for TDP (Zhao 2001) and/or TMP in some tissues when ThTR-1 fails. Expressed on luminal side of renal tubular cells. Association with arterial hypertension. Predominantly expressed in kidney, but even neurons Intestinal uptake of thiamine. Specifically expressed in the kidney Acts also as a TDP transporter (human transporter) in the colon and facilitate uptake of microbiota-generated thiamine. Thiamine created by colon microbiota exists in form to TDP. Primary hepatic uptake transporter of thiamine. Comment/possible defect Comment/possible High-affinity transporter for thiamine intake. the blood-brain barrier. High-affinity transporter for thiamine intake. SLC19A3 associated disorders present as neurological that bear some features similar to WE. ThTR. Expressed in microvessels of the blood-brain barrier megaloblastic anaemia and with diabetes mellitus hearing loss. thiamine? brain regions. genetic variants found in 25 patients with alcohol-associate WE, only one of these variants found in healthy controls. attributed to defects in the choline transporter function. Mediates thiamine uptake into mitochondria. Believed to be important for brain development and interfere with α -KGDH activity. brain barrier. Expressed on basolateral side of renal tubular cells. thiamine. affinity but lower capacity compared with OCT1 in early infancy. 102 Leigh syndrome, Thiamine metabolism dysfunction syndrome 3 (microcephaly Amish type), Thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration and progressive polyneuropathy type). Autosomal dominant deafness Pathologies associated with genetic associated Pathologies change Thiamine metabolism dysfunction syndrome 1 (Thiamine-responsive megaloblastic anaemia syndrome/Rogers syndrome) Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine- responsive encephalopathy type), Leigh syndrome, Infantile lethal encephalopathy 1,55,63–65,67,85 Folate transporter (FOLT)/ reduced folate carrier (RFC) MATE1 Putative thiamine transporter Organic cation transporter 2 (OCT 2) Organic cation transporter 3 (OCT 3) Mitochondrial TDP carrier. Choline transporter like protein MATE2-K Transporter/enzyme expressed Transporter/enzyme Thiamine transporter 1 (ThTR-1) Organic cation transporter 1 (OCT 1) Thiamine transporter 2 (ThTR-2) 21q22.3 17p11.2 1q42.2 6q25.3 6q25.3 17q25.1 6p21.33 17p11.2 Cytogenic Cytogenic location 1q24.2 6q25.3 2q36.3 Thiamine transporters. SLC19A1 SLC47A1 SLC35F3 SLC22A2 SLC22A3 SLC25A19 SLC44A4 SLC47A2 [number] family carrier solute SLC, protein; extrusion multidrug and toxin kidney-specific MATE2-K, protein; extrusion multidrug and toxin MATE1, Committee; HGNC, HUGO Gene Nomenclature TTP, thiamine triphosphate. TMP, thiamine monophosphate; number] TKT; TDP, thiamine diphosphate; [letter, family HGNC approved HGNC approved gene symbol SLC19A2 SLC19A3 SLC22A1 Table 7. Table

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Figure 4. From blood to cell. α-KGDH, α-ketoglutarate dehydrogenase; BCAKDH, branched chain α-keto acid dehydrogenase; HOACol, 2-hydroxyacyl CoA lyase 1; OCT, organic cation transporter; PDHG, pyruvate dehydrogenase; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TK, thiamine kinase; TMP, thiamine monophosphate; TPC, mitochondrial thiamine pyrophosphate carrier; TTP, thiamine triphosphate.

From blood to brain (BCSFB).120 The BBB is the barrier between Data from small post-mortem studies indicate cerebral blood vessels and brain tissues. The brain thiamine concentrations between 25.1 and BCSFB is the barrier between the blood and the 32.5–36.2 pmol/mg protein.58,122 These are lower CSF on the one hand and the CSF and brain tis- concentrations than reported in rodents or other sues on the other. The choroid plexus forms the primates. TDP is by far the most prominent interface between the blood/CSF component. compound. The above concentrations translate The arachnoid membrane forms the interface to 283 nmol thiamine/100 g fresh brain tissue.55 between the CSF/brain tissue component.110,125 Standard textbooks report “thiamine” concen- Within the brain, there is no barrier between the trations in the brain between 0.14 mg and extracellular space and the CSF.110,126 Substance 0.44 mg/100 g fresh brain tissue.123,124 However, transport over the BCSFB is not thought to con- these data are not referenced. For an average tribute relevantly to the metabolic needs of the brain of 1300 g, this would amount to 1.82–5.72 g brain.127 or 5.6–17.5 µmol. About 2% of all available thia- mine is transported into the brain.117 As any The anatomical structure of the BBB with tight other solute, thiamine cannot freely enter the cellular junctions limits the possibility of thia- brain. Instead, all solutes need to cross either the mine passing into the brain by simple passive BBB or the blood-cerebrospinal fluid barrier diffusion. Indeed, has it been suggested that,

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Figure 5. From blood to urine or urine to blood.

“normally,” less than 10% of B vitamins is concentrations.111,130,131 Thiamine may also be transferred into the brain by simple passive dif- taken up passively via facilitated diffusion.120,132 fusion.128 How exactly thiamine enters the brain remains unclear. The BBB consists of vascular TMP may possibly enter the brain via active endothelium, pericytes, and astrocyte end-feet. transport involving the reduced folate carrier.120 The space between endothelial cells is rendered This transport system is half-saturated at normal impermeable by tight junctions. Therefore, con- plasma concentration of 25 µmol/l. Overall, there trary to permeable endothelial cells in other are about 10 µmol thiamine in the brain. The rate parts of the body, substances cannot by-pass the of thiamine turnover in the brain is about 60– endothelial cells in the brain. Instead, they have 100% per day. This suggests that thiamine home- to pass through the endothelial cells. Like neu- ostasis in the brain is managed tightly to render a rons and glial cells, BBB-forming cells have spe- steady state between thiamine entering and leav- cific solute carriers.129 Free thiamine seems to ing the brain.120 Thus, administration of large enter the brain via active transport, most likely amounts of thiamine for medicinal purposes may involving ThTR-2. The transport system is half- not necessarily lead to increased thiamine con- saturated at normal plasma concentration of centrations in the brain.56,110 An animal experi- 0.1–0.3 µmol/l. Lack of the other major thia- ment reported in 1968 supports this assumption. mine transporter, ThTR-1, leads to thiamine- Rats fed a thiamine-deficient diet developed overt responsive megaloblastic anaemia syndrome but encephalopathy, in which thiamine brain concen- not to WE. Therefore, ThTR-1 may not be tration fell to less that 20% of normal. Increasing essential for thiamine uptake into the brain.120 thiamine to only 26% of normal concentration Parallel to the active carrier-mediated process, a reversed symptoms to an essentially normal neu- non-saturable process also exists at higher rologic state.133 In humans, reversibility of

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Figure 6. Renal regulation of thiamine. hMATE, human multidrug and toxin extrusion protein; OCT, organic cation transporter; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TMP, thiamine monophosphate.

symptoms is variable. Prompt treatment can thiamine depletion may occur within approxi- reverse symptoms as long permanent damage and mately 2-3 weeks of thiamine deficiency. cell death has not occurred.2,71

Deactivation and metabolism Body stores Thiamine can be broken down by two thiami- The body can store about 30 mg of thiamine.70,74 nases: type I and II. These cleave thiamine into its Again, most of this can be expected to be intracel- pyrimidine and thiazole moieties.137 In humans, lular in the form of TDP. The concentrations are thiaminase activity is negligible under normal con- highest in heart, skin, kidneys, adipose tissue, ditions. However, thiamine deficiency can occur lung, and colon.134 It remains unclear how long when thiaminase-containing foods are ingested these stores last in circumstances of thiamine excessively or not processed properly. Thiaminase I deficiency. One study investigated the urinary is found in fish, shellfish, ferns, and some bacteria. excretion of thiamine in eight young men. These Thiaminase II is found in some bacteria.138 consumed a 2800 kcal diet that provided 400 g of Thiaminases are usually heat-labile; they can be carbohydrates and 0.11–0.18 mg thiamine a day. destroyed through cooking.70 Thiaminase I in nar- This corresponded to 10% of the recommended doo (Marsilea drummondii), an Australian fern nutritional intake (RNI) of thiamine. Urine thia- can, however, withstand high temperatures. One mine decreased to <50 µg a day within 6 days and historical account of beriberi due to thiaminase became undetectable on the 18th day of thiamine poisoning stems from the Burks and Wills expedi- depletion.135 Another study of three volunteers tion to cross Australia from coast to coast from found a half-time excretion for thiamine of 9.5, 1860 to 1861. Of the four participating European 13, and 18.5 days.136 These studies suggest that men, only one survived. During their journey, the

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men began eating nardoo-based flour, preparing it mediate thiamine uptake from urine into the tubu- the European way instead of the Aborigine way. It lar cells. ThTR-1 as well as OCT2 and 3 in the is speculated that they did not soak the fern suffi- basolateral membrane mediate thiamine uptake ciently long in water to diminish the activity of from tubular cells into the blood. ThTR transport- nardoo thiaminase 1.139 ers have a much higher affinity than OCT. They are also saturated at lower concentrations. Principally, Polyhydroxyphenols, caffeic acid, phenols, flavo- all transporters are bidirectional.38,85,146–148 noids, and tannins, can also serve as anti-thiamine factors. Such polyhydroxyphenols are found, for In thiamine deficient states, thiamine transporters instance, in coffee, tea, betel nuts, blueberries, are upregulated.149 Ziporin et al. showed that uri- blackcurrants, Brussels sprouts, and red cabbage. nary thiamine excretion could decrease to unde- They destroy thiamine by an oxidative process tectable levels.135 transforming thiamine to non-absorbable thia- mine disulfide.140 Polyhydroxyphenols are heat- In states of thiamine excess, for example, achieved stable components and cannot be destroyed through pharmacological dosing, thiamine is elimi- through cooking.70 Therefore, excessive ingestion nated completely by the kidneys.145 Elimination is can lead to thiamine deficiency.141 increased by switching from reabsorption to active secretion. In that case, thiamine that has not been filtrated in the glomerulus is excreted via the renal Recycling and elimination in the kidney tubular cells. Thiamine directly inhibits ThTR-1 In humans, a multitude of metabolites have been mediated uptake.30 In such circumstances, the identified by radioactive labelling of the pyrimi- ThTR mediated pathway may be reversed from dine or thiazole moiety of thiamine.136 Studies in thiamine uptake to secretion.147 Additionally, the rats demonstrated up to 22 different thiamine kidneys can eliminate thiamine through two types metabolites identifiable in the urine.142–144 The of cation transporters: OCTs and multidrug and kidneys can largely adapt their handling of free toxin extrusion proteins (MATEs). Thiamine thiamine to the current plasma concentration enters the renal tubular cells from the blood through (Figure 5). Therefore, free thiamine is eliminated OCT 1 and 2 located in the basolateral mem- or reabsorbed renally, depending on thiamine sta- brane.148 From there, thiamine is excreted across tus. However, thiamine metabolites cannot be the brush border membrane into the urine through reabsorbed in the kidney. Paradoxically, the MATE1 and MATE2-k.38,150–152 This mechanism amount of metabolites excreted is not decreased can lead to complete plasma thiamine elimination in a state of thiamine deficiency.135 from all the blood passing through the kidneys (renal blood flow). The elimination amounts to five In the glomerulus, thiamine is filtrated freely, like times the glomerular filtration rate (Figure 6).145 any other small solute. Glomerularly filtrated thia- mine is then processed in the proximal tubule. Thiamine stored in blood cells or bound to protein Magnesium as cofactor for thiamine cannot be filtrated. Data on plasma protein bind- Magnesium is an alkaline earth metal with an ing is again conflicting. Thom et al. found that, atomic weight of 24.31. In the body, magnesium under physiological conditions, up to 30% of occurs mostly ionized as the bivalent cation Mg2+. plasma thiamine may be bound to albumin (10% Mg2+ is the fourth most abundant cation in the TMP, 20% TDP).119 These thiamine compounds body after sodium, potassium, and calcium, and may bind to albumin via the phosphate moiety of the second most abundant intracellular cation after the molecule. At thiamine concentrations over potassium.153–155 Mg2+ is a cofactor to more than 119.5 µmol/l, albumin binding decreases to 2%. 600 enzymatic reactions.156 Mg2+ is implicated in Weber et al., however, suggested that plasma thia- the energy metabolism of macronutrients, oxidative mine was not bound to protein.145 phosphorylation, protein and nucleic acid synthe- sis, neuro-muscular signal conduction, and regula- Under physiological conditions, up to a concentra- tion of cell membrane permeability.154,155 Despite its tion of 200 nmol/l, thiamine is reabsorbed to mini- crucial contribution to physiology, magnesium is mize excretion. Phosphorylated thiamine, mostly in relatively under-researched compared with other the form of TMP, is dephosphorylated to free thia- nutrients, such iron or calcium. Therefore, clini- mine in the tubule.145 ThTR-1, ThTR-2, and cians may be much less vigilant to possible states of OCT1, expressed in the brush border membrane magnesium deficiency.156 Part of the problem is

16 journals.sagepub.com/home/tpp M Ott and U Werneke et al. that magnesium deficiency is difficult to assess by a organs. An average adult stores about 24 g Mg2+ in simple blood test; more than 99% magnesium is the body. Only 0.8% of magnesium is found in the intracellular.154,157 blood, 0.3% in serum, and 0.5% in erythrocytes. There is a constant exchange between Mg2+ stored and Mg2+ in the blood. The kidney can filtrate Significance of magnesium for thiamine about 10% of bodily Mg2+, corresponding to a function renal filtration rate of 2.4 g/day. Between 5% and A significance of magnesium for alcohol-associ- 70% can, however, be reabsorbed and re-entered ated WE was first suggested in 1964.158 Along into the redistribution cycle.153,156,157 with thiamine, magnesium has since turned out to be an essential cofactor to several key metabolic enzymes (Table 5) that govern glucose, fatty acid, Magnesium deficiency and protein metabolism as well as ATP genera- Magnesium deficiency may manifest itself in neu- tion. Magnesium is also required as cofactor for rological symptoms, such as neuromuscular thiamine transport and conversion of the various hyperexcitability and weakness. Magnesium defi- thiamine compounds into each other (Table 6). ciency is also associated with electrocardiographic Without magnesium, thiamine cannot function (ECG) changes and arrhythmias, hypoparathy- properly. This implies that magnesium deficiency roidism, and vitamin D deficiency. There are also can impair thiamine activity. But we do not know biochemical changes, including hypocalcaemia, how substantial magnesium deficiency has to hypokalaemia, and metabolic alkalosis.159,160 become to trigger clinical symptoms of thiamine However, unless severe, symptoms of magnesium deficiency (cf. magnesium deficiency below). deficiency can be difficult to spot. Normal magne- sium serum concentration lies in a range from 0.7 to 1.0 mmol/l. Magnesium deficiency may occur Dietary magnesium when the serum magnesium concentration falls Recommendations for daily intake depend on age below 0.66 mmol/l. Yet, clinical symptoms may and sex. They vary somewhat internationally. In become observable only at levels below the UK, the recommended daily magnesium 0.5 mmol/l.161 As magnesium is over 99% intracel- intake is 300 mg for adult males and 270 mg for lular, a normal magnesium serum concentration adult females.51 In the United States (US), the rec- does not exclude deficiency. Such normo-magne- ommended daily intake is slightly higher, 420 mg semic magnesium deficiency may occur in patients for men and 320 mg for women aged between 31 with chronic harmful use of alcohol.162 and 50 years. No extra magnesium is required dur- ing pregnancy. However, an additional 50 mg per Magnesium deficiency can occur in three con- day is required for women who breastfeed to com- texts: (a) decreased uptake or absorption, (b) pensate for magnesium losses in breast milk.53 increased gastrointestinal or renal elimination, or Magnesium is found in nearly all foods. As a cen- (c) shift from the extracellular to the intracellular tral component of chlorophyll, magnesium is par- space.163,164 Reduced magnesium uptake can ticularly common in leafy vegetables. Whole grain occur in the context of total nutritional defi- cereals, nuts, and yeast extracts are also rich ciency. It can also occur with one-sided nutrition sources of magnesium.51,53,157 with low magnesium content. Inflammatory bowel diseases and treatment with proton pump inhibitors such as omeprazole are associated with Magnesium metabolism reduced magnesium absorption. Increased gas- Mg2+ absorption and excretion depend on nutri- trointestinal magnesium elimination occurs for tional uptake, intestinal absorption, and renal instance in the context of excessive vomiting or capacity for reabsorption. Magnesium can be laxative abuse. Renal magnesium wasting can taken up anywhere across the intestine. It has been also occur in the context of treatment with loop suggested that the duodenum takes up 11% of all or thiazide diuretics, cisplatin, amphotericin, the magnesium absorbed, the jejunum 22%, the aminoglycosides, ­foscarnet, cyclosporine, and ilium 56%, and the colon 11%.157 Of all absorbed tacrolimus.155,164 Increased renal elimination Mg2+, between 20% and 70% are excreted again occurs when tubular reabsorption becomes in the feces.156 The remainder is distributed impaired, for instance in the context of osmotic throughout the body. About 50–60% are stored in diuresis or some renal diseases. Such include the bone, 20–30% in muscles and 20–25% in other interstitial nephritis, Gitelman, Bartter, and

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Fanconi syndromes. Shifts from extracellular to Janssen, Novartis, Otsuka/Lundbeck, Servier, intracellular space occur in settings of refeeding, Shire and Sunovion. treatment of diabetic ketoacidosis or other meta- bolic acidosis, hungry bone syndrome or pancrea- ORCID iDs titis. Alcohol dependency is associated with Michael Ott https://orcid.org/0000-0003- several risk factors for magnesium deficiency, 2393-9750 including poor nutrition, gastrointestinal prob- Ursula Werneke https://orcid.org/0000-0002- lems associated with proton pump inhibitor use 5023-3254 and reduced absorption, increased diuresis, excessive urinary excretion, and vomiting.160,165

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