Thiamine Transporters 1/2 and pharmaconutrition

​Mechanisms and consequences

The thiamine transporters Thiamine Transporter 1 (THTR1) and Thiamine Transporter 2 (THTR2) transfer thiamine and pyridoxine, and are associated with two transfer systems, being –

• THTR1 – the nutrient concentration is low and therefore uptake requires energy,
• THTR2 – the nutrient concentration is high (thiamine > 2 mmol/L), and therefore uptake involves passive nutrient diffusion.

Thiamine transporters sites

THTR1 and THTR2 are highly expressed in the cells of various organs including skeletal muscle, heart, liver, kidney and its proximal tubules, pancreas, brain, placenta, adipose tissue, bone marrow, and retina.

THTR1 transporter is located on the basolateral membranes of the intestines, and is also highly expressed in skeletal muscle and brown adipose tissue.

THTR2 is found on the apical surface of the intestines, and also in adipose tissue, breast and placenta.

Deficiencies

THTR1 and THTR2 are up-regulated in thiamine deficiency. THTR1/2 deficiencies can be long term or short term, and are likely due to –

• Inherited metabolic disorders – examples include –
• THTR1 deficiency which manifests as Thiamine-responsive megaloblastic anaemia (TRMA) and includes megaloblastic anaemia, sensorineural deafness, and non-type 1 diabetes), other signs such as congenital heart diseases, optic atrophy, retinal dysfunction, and cerebrovascular accidents;
• THTR2 deficiency which manifests as Biotin-thiamine responsive encephalopathy, and Leigh Syndrome, and includes episodic encephalopathy, gait ataxia, seizures, and bulbar dysfunction (difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, drooling, dysphagia, and dysphonia);
• Polymorphisms (variants) – examples include –
• two single-nucleotide THTR2 polymorphisms are associated with absent/minimal diabetic retinopathy and nephropathy despite long-term type 1 diabetes;
• potential variation in the 7 amino acid residues that are responsible for pyridoxine transport;
• Environmental – likely to manifest at any age and is dependent upon the environmental insult; thiamine and pyridoxine supplementation are likely to confer benefit in these disorders. Identified causes include –
• ethanol impairs intestinal absorption of thiamine by inhibiting the gene expression of thiamine transporter THTR1 but not thiamine transporter THTR2 in the small intestine, and inhibits the gene expression of both THTR1 and THTR2 in the large intestine, therefore even if thiamine is present in the intestinal tract, it is not absorbed in the presence of ethanol, consequently only intravenous thiamine will be an effective intervention;
• Chronic Kidney Disease is associated with a significant downregulation of THTR1 and THTR2 in the small intestine, heart, liver and brain;
• pro-inflammatory cytokines such as IL-1β significantly inhibit THTR1 expression and the degree of inhibition is a function of duration of exposure; the inhibition is reversible upon removal of IL-1β;
• neuroinflammation interferes with transcriptional mechanisms that result in dysfunctional thiamine transporters;
• the triggers that cause thiamine to inhibit pyridoxine uptake and that cause pyridoxine to inhibit thiamine uptake are currently unclear;
• prescription medicines that inhibit include –

• THTR1 includes – Trimethoprim, Amprolium,
• THTR2 includes (those predicted to be clinically relevant) – Amitriptyline, Amoxapine, Didanosine, Fedratinib, Hydroxychloroquine, Metformin, Penicillamine, Posaconazole, Quinidine, Quinapril, Sertraline, Telmisartan, Trimethoprim, Verapami

What are the consequences of THTR1/2 deficiencies?

• Thiamine is really important in the metabolism of energy, and if there is insufficient thiamine then the energy that is not metabolized is stored as fat;
• Pyridoxine –

• enhances magnesium concentrations which is essential for thiamine activation,
• is important in the activation of niacin and the production of NAD+; inadequate NAD+ changes energy metabolism from oxidative phosphorylation to aerobic glycolysis.

There is speculation that genetic disorders linked to THTRs may also involve defects in the pyridoxine transport function in addition to, or rather than, defects in thiamine transport, with the outcome being pyridoxine deficiency. Therefore, it may be worthwhile considering pyridoxine intervention if thiamine deficiency is considered to be due to transporter-related metabolic disorders or transporter polymorphisms.

Clinical Questions

What actions will you initiate when you see someone whose prescribed medications include THTR inhibitors, will you –

• clarify adequacy of dietary intake of thiamine and pyridoxine, request blood tests for thiamine and pyridoxine status, and then compare findings?
• If there is disagreement between oral intake and blood test results, will you question inhibition of the transporters?
• trial an intervention program in those with a known negative environmental impact and monitor for benefit?
• recommend nutrient interventions be administered at different times from the prescribed medicines?
• document the expressed signs and symptoms that support your request, the intervention(s) trialled, and submit as a Case Study at relevant conferences?

Conclusions

THTR downregulation has profound consequences for those with metabolic disorders and polymorphisms, and for which direct nutrient interventions may or may not confer benefit, however, in those with environmentally-induced downregulation of their THTRs, those profound consequences are reversible with either removal of the environmental insult and/or direct nutrient intervention.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Summary data

Medical History with Nutritional Aspect

Biochemistry with Nutritional Aspect

Medications That May Adversely Affect Nutritional Status

Transporter-mediated interactions and nutrients

Biochemistry 

Biochemistry indicates

   – low potassium – is likely to be exacerbated by esomeprazole prescription; advisable to recheck status and if still low then intervention recommended;

   – elevated MCV + low B12 – is likely to be exacerbated by esomeprazole prescription; advisable to recheck status and if still low then intervention recommended;

   – low vit D – ostelin (2/day) is likely to be exacerbated by atorvastatin and prednisolone prescriptions; advisable to recheck status and if still low then intervention recommended.

Glycaemia 

Currently prescribed 6 medications that may alter glycaemia.

Pharmaconutrition

The side effects of Mrs AGW’s prescribed medicines include –

– 9 medications that include nausea and diarrhoea.

– 8 medications that include vomiting and constipation.

– 5 medications that include hypokalaemia, altered taste, altered appetite, altered weights, and sweating.

– 4 medications that include hyponatraemia and dry mouth.

– 3 medications that may alter zinc status.

– 2 medications that include anaemia, hypomagnesaemia, altered calcaemia, thirst, salivation, dysphagia, and tremor.

Regular monitoring sodium levels recommended whilst citalopram prescribed.

Esomeprazole decreases B12, vitamin C, magnesium, zinc and iron levels, may decrease calcium absorption, and decreases thiamine availability.

Ferro-f decreases zinc absorption.

Indapamide impairs zinc status.

Dietary levels of caffeine intake in conjunction with paracetamol inhibit antinocieception.

Concurrent ingestion of paracetamol and iron resulted increased rate of iron absorption and decreased extent of drug absorption. The authors advise drug and iron to be administered at different times from each other.

There is an inverse correlation between vitamin D status and the anti-inflammatory effects of glucocorticoids such as prednisolone.

The evidence is increasing that proton pump inhibitors such as esomeprazole significantly impair magnesium absorption. Magnesium is important in muscle function, especially cardiac muscle, amongst other functions. Magnesium deficiency manifests as confusion, disorientation, personality changes, loss of appetite, depression, muscle cramps, tingling, numbness, hypertension, cardiac dysrhythmia, seizures. Magnesium is an intracellular ion therefore serum levels are unlikely to detect early depletion of status. Cellular magnesium status is unknown whilst magnesium levels within acceptable range however if magnesium levels are low then typically indicates significant cellular depletion and intervention recommended. Advisable to clarify magnesium status.

Statins interfere early in the cholesterol metabolic pathway and consequently decrease –

   – conversion of sun exposure to vitamin D – vitamin D intervention recommended,

   – production of CoQ10 – important in cellular energy production; CoQ10 intervention recommended,

   – DHEA production – low DHEA associated with increased risk of metabolic syndrome; intervention recommended.

Cholesterol is important in brain structure and cognitive function therefore advisable to clarify lipid levels and if either within acceptable range or below 3.0 nmol/L then review necessity for atorvastatin’s continued prescription.

Bowel management

   Regular aperient prescribed.

   No PRN interventions prescribed.

   No Nurse Initiated interventions administered.

Staff comments

Staff advise ordinary appetite and not large amounts of food in room.

Observations

Mrs AGW is a small, pale, well-rounded Turkish lady who was sitting in the Day Room watching TV when I went to speak to her – she told me she is not eating as much as previously.

Mrs AGW has been steadily losing weight for the last 3 months.

Pharmaconutrition assessment

Mrs AGW has been prescribed prednisolone since admission and likely before. Prednisolone may decrease iodine uptake and protein-bound iodine concentrations which in turn may alter thyroid function. Advisable to check thyroid function and clarify current thyroid status.

Since evidence indicates iron deficiency anaemia is unlikely to resolve whilst a proton pump inhibitor is prescribed, advisable to consider administering a non-oral iron intervention.

PPI 

Mrs AGW has been prescribed a proton pump inhibitor since admission ie 18 months ago, and likely before. The evidence is increasing that long-term proton pump inhibitor prescription is associated with –

   – increased risk of food sensitivities at a level of peanut allergy;

   – increased risk of coeliac disease;

– altered gut microbiome;

   – increased risk of scurvy;

   – generalised malnutrition due to impaired absorption of a range of nutrients such as B12, vitamin C, magnesium, zinc, iron, etc;

   – altered gastric pH which reduces absorption dynamics of a range of drugs and nutrients. Altered drug availability is relatively easily identified however reduced nutrient absorption is rarely identified due to the non-specific nature of their signs and symptoms.

Consequently, advisable to review necessity for ongoing proton pump inhibitor prescription.

Since evidence indicates iron deficiency anaemia is unlikely to resolve whilst a proton pump inhibitor is prescribed, advisable to consider administering a non-oral iron intervention.

Chronic pain

Mrs AGW’s diagnoses include chronic pain. Nutritional factors that may be useful to consider in pain management include –

   – vitamin D – current intervention may not be adequate to attain adequate range. Evidence indicates increasingly brittle pain control with decreasing vitamin D levels. Currently prescribed atorvastatin and prednisolone which decrease vitamin D status. Advisable to check vitamin D levels and if still low then review current vitamin D management strategy;

   – vitamin C – pain increases the reactive substances (formerly Reactive Oxygen Species) within cells. Vitamin C is important in quenching reactive substances and if there is insufficient vitamin C then cell status becomes compromised and the cells typically die which also causes pain. Advisable to consider a vitamin C intervention even although vitamin C is not considered part of the pain management armament as it won’t cause harm and evidence suggests it may confer benefit. Currently prescribed esomeprazole which decreases conversion of vitamin C to its active form;

   – evidence indicates substantial relief of neuropathic pain by thiamine, pyridoxine and cobalamin separately, and in combination there was a synergistic benefit. Currently prescribed esomeprazole and Ferro-F which interfere with thiamine and cobalamin absorption, and ferro-f which decreases magnesium absorption (important for thiamine activation);

   – low B12 – exacerbates elevated TNF- α which is an inflammatory response marker; elevation of the inflammatory response can include a pain response and currently prescribed esomeprazole therefore advisable to clarify B12 status as neuro-imaging research shows a direct causal link between B12 status and damage to the brain, and recommend B12 interventions once levels are less than 300 pmol/L;

   – magnesium – proposed mechanism magnesium blocks the NMDA receptor channels in the spinal cord and thus limits the influx of calcium ie reduces the risk of excitotoxicity and consequent exacerbation of pain. Currently prescribed esomeprazole which decreases magnesium absorption therefore advisable to clarify and monitor magnesium status.

Falls

Nutritional factors that may be contributing to falls include –

   – low potassium – prescribed esomeprazole and currently low potassium status. Advisable to recheck status and if still low then intervention recommended – and not administered at the same time as esomeprazole;

   – low calcium – more likely to be low if potassium and/or magnesium low;

   – low vitamin D – currently prescribed atorvastatin and prednisolone therefore advisable to clarify and monitor status on a regular basis, and intervene once levels are at low end of acceptable range;

   – low B12 – is important in the righting reflex when a person stumbles and currently prescribed esomeprazole therefore advisable to check status;

   – low Hb – advisable to regularly monitor status as currently prescribed esomeprazole which is likely to compromise iron status;

   – low zinc – more likely to be low if loss of weight or prescribed a proton pump inhibitor – currently both losing weight and prescribed esomeprazole therefore advisable to clarify status and consider an intervention if low. Note – zinc interventions are unlikely to be effective whilst a proton pump inhibitor prescribed;

   – low magnesium – magnesium is important in muscle function, especially cardiac muscle, amongst other functions. Also currently prescribed esomeprazole which significantly decreases magnesium absorption. Magnesium is an intracellular ion therefore serum levels are unlikely to detect early depletion of status therefore advisable to clarify magnesium status, monitor on a regular basis, and initiate an intervention if low.

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The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.

Yvonne Coleman

Yvonne Coleman has 30+ years of experience in aged care as a dietitian. Her mission is to make information about interactions between medicines and nutrition easy to access for those working in the healthcare sector. She has created a comprehensive resource identifying drug-nutrient and drug-food interactions from a nutrition perspective.

Her areas of competency include food science & nutrition, dietetics and health education. You can find out more about her work on LinkedIn, AusMed, the Enlightened Pharmacist podcast, and The FX Medicine Podcast.