Healing takes energy. Energy requires thiamine. Modern foods, lifestyles, medications and chemical exposures threaten thiamine status in a large percentage of the population. Modern thiamine deficiency does not look like classic thiamine deficiency, and thus, goes largely unrecognized by the medical community. Modern thiamine deficiency does not originate from starvation, but rather, from a state of being well fed and sometimes over-fed. As a result, many of the symptoms are incongruent with current textbook definitions. This presentation discusses the chemistry and symptomology of modern thiamine deficiency.
Thiamine Deficiency Disease, Dysautonomia, and High Calorie MalnutritionHormones Matter
This document discusses thiamine deficiency and its relationship to mitochondrial function. It begins by introducing the authors and their backgrounds in medicine and nutrition research. It then discusses how thiamine is an important cofactor for many mitochondrial enzymes involved in energy production. Thiamine deficiency can thus lead to mitochondrial dysfunction and reduced ATP production. The document argues that thiamine deficiency may be more common than recognized, as subtle metabolic disturbances are often missed, and notes several populations that are at high risk for deficiency. It questions common assumptions about the role of fortification in ensuring adequate nutrient intake.
The document discusses vitamin D, including its synthesis from sun exposure, its role in various bodily processes, and its potential health benefits. Key points include:
- Vitamin D is synthesized in the skin upon exposure to sunlight and can also be obtained through food and supplements. It plays an important role in bone and immune health.
- Vitamin D receptors are found throughout the body and vitamin D has been shown to regulate gene expression, turning genes on and off. This may explain its wide-ranging effects.
- Studies suggest vitamin D may help reduce the risk of various cancers, heart disease, diabetes, respiratory infections, autoimmune diseases, and mental health conditions like depression. Optimal vitamin D levels are important
This document discusses calcium and magnesium metabolism and disorders. It provides an overview of calcium, including its definition, requirements, regulators of metabolism like vitamin D, PTH and calcitonin, functions, and disorders like hypercalcemia and hypocalcemia. It also discusses magnesium, including its distribution in the body, sources, biochemical functions, factors affecting absorption and excretion, and disorders like hypermagnesaemia and hypomagnesaemia. The key causes, signs, symptoms, diagnosis and management of these disorders are summarized.
This document provides information on vitamin A including its history, definition, classification, daily requirements, causes and effects of deficiency, investigations, management, and hypervitaminosis. Key points include:
- Vitamin A is a fat-soluble vitamin required in small amounts for growth, vision, and cellular communication. Deficiency can cause night blindness and dry skin.
- Daily requirements range from 750μg for adults to 300-400μg for infants. Primary causes of deficiency include prolonged dietary deficiency and chronic diarrhea.
- Investigations for deficiency include serum retinol level and ophthalmoscopy. Management includes oral doses of 200,000 IU depending on age. Toxicity from excess intake includes
are nonenergy producing organic compounds essential in minute amount for normal human metabolism and for the help of body.
Vitamins are micronutrients, which are very much essential for growth and for metabolism.
The importance of vitamins as drug in primarily in the prevention and treatment of deficiency diseases.
The document discusses vitamin D, describing it as essential for health and important for numerous functions in the body. It outlines that vitamin D helps absorb calcium for strong bones and teeth, and supports immune function, mental health, and may lower risks of various diseases. It recommends getting vitamin D through moderate sun exposure or dietary supplements, and describes an optimal vitamin D blood level range.
Thiamine (vitamin B1) and biochemical aspects of beriberirohini sane
A comprehensive presentation on Thiamine and biochemical aspects of Beriberi for MBBS, BDS, B Pham and Biotechnology students to facilitate easy leaning.
This document summarizes thyroid and antithyroid drugs. It discusses:
1) How thyroid hormones T3 and T4 are synthesized in the thyroid gland from tyrosine and iodine.
2) How T3 and T4 levels are regulated by TSH from the pituitary gland which is controlled by TRH from the hypothalamus.
3) The biological effects of T3 and T4 which include increased metabolism and growth/maturation.
4) Thyroid drugs like levothyroxine which are used to treat hypothyroidism, while antithyroid drugs like propylthiouracil and radioactive iodine are used to treat hyperthyroidism.
Thiamine Deficiency Disease, Dysautonomia, and High Calorie MalnutritionHormones Matter
This document discusses thiamine deficiency and its relationship to mitochondrial function. It begins by introducing the authors and their backgrounds in medicine and nutrition research. It then discusses how thiamine is an important cofactor for many mitochondrial enzymes involved in energy production. Thiamine deficiency can thus lead to mitochondrial dysfunction and reduced ATP production. The document argues that thiamine deficiency may be more common than recognized, as subtle metabolic disturbances are often missed, and notes several populations that are at high risk for deficiency. It questions common assumptions about the role of fortification in ensuring adequate nutrient intake.
The document discusses vitamin D, including its synthesis from sun exposure, its role in various bodily processes, and its potential health benefits. Key points include:
- Vitamin D is synthesized in the skin upon exposure to sunlight and can also be obtained through food and supplements. It plays an important role in bone and immune health.
- Vitamin D receptors are found throughout the body and vitamin D has been shown to regulate gene expression, turning genes on and off. This may explain its wide-ranging effects.
- Studies suggest vitamin D may help reduce the risk of various cancers, heart disease, diabetes, respiratory infections, autoimmune diseases, and mental health conditions like depression. Optimal vitamin D levels are important
This document discusses calcium and magnesium metabolism and disorders. It provides an overview of calcium, including its definition, requirements, regulators of metabolism like vitamin D, PTH and calcitonin, functions, and disorders like hypercalcemia and hypocalcemia. It also discusses magnesium, including its distribution in the body, sources, biochemical functions, factors affecting absorption and excretion, and disorders like hypermagnesaemia and hypomagnesaemia. The key causes, signs, symptoms, diagnosis and management of these disorders are summarized.
This document provides information on vitamin A including its history, definition, classification, daily requirements, causes and effects of deficiency, investigations, management, and hypervitaminosis. Key points include:
- Vitamin A is a fat-soluble vitamin required in small amounts for growth, vision, and cellular communication. Deficiency can cause night blindness and dry skin.
- Daily requirements range from 750μg for adults to 300-400μg for infants. Primary causes of deficiency include prolonged dietary deficiency and chronic diarrhea.
- Investigations for deficiency include serum retinol level and ophthalmoscopy. Management includes oral doses of 200,000 IU depending on age. Toxicity from excess intake includes
are nonenergy producing organic compounds essential in minute amount for normal human metabolism and for the help of body.
Vitamins are micronutrients, which are very much essential for growth and for metabolism.
The importance of vitamins as drug in primarily in the prevention and treatment of deficiency diseases.
The document discusses vitamin D, describing it as essential for health and important for numerous functions in the body. It outlines that vitamin D helps absorb calcium for strong bones and teeth, and supports immune function, mental health, and may lower risks of various diseases. It recommends getting vitamin D through moderate sun exposure or dietary supplements, and describes an optimal vitamin D blood level range.
Thiamine (vitamin B1) and biochemical aspects of beriberirohini sane
A comprehensive presentation on Thiamine and biochemical aspects of Beriberi for MBBS, BDS, B Pham and Biotechnology students to facilitate easy leaning.
This document summarizes thyroid and antithyroid drugs. It discusses:
1) How thyroid hormones T3 and T4 are synthesized in the thyroid gland from tyrosine and iodine.
2) How T3 and T4 levels are regulated by TSH from the pituitary gland which is controlled by TRH from the hypothalamus.
3) The biological effects of T3 and T4 which include increased metabolism and growth/maturation.
4) Thyroid drugs like levothyroxine which are used to treat hypothyroidism, while antithyroid drugs like propylthiouracil and radioactive iodine are used to treat hyperthyroidism.
Protein Energy Malnutrition (PEM), also known as Protein-Energy Wasting (PEW) or Kidney Disease Wasting (KDW), is a state of decreased body protein and energy stores. PEM is common in patients with kidney disease, affecting up to 40-70% of those with end-stage renal disease. Factors contributing to PEM include poor nutritional intake, increased protein losses, and increased protein catabolism. A thorough nutritional assessment involves evaluating dietary intake, body composition, laboratory values, and scoring systems. Proper nutritional assessment and therapy are important for managing PEM and its negative effects in patients with kidney disease.
This document discusses magnesium disorders and hypomagnesemia. It begins by providing background on magnesium, including where it is stored in the body and its many functions. It then discusses the causes, clinical manifestations, diagnosis, and treatment of hypomagnesemia. Hypomagnesemia can be caused by renal magnesium wasting due to drugs, diseases, or genetic disorders, or by extrarenal losses from poor nutrition, malabsorption, diarrhea, or sweat losses. Symptoms affect the cardiovascular, neuromuscular, skeletal, and central nervous systems. Treatment involves identifying and addressing the underlying cause, as well as oral or parenteral magnesium supplementation.
The document discusses newer aspects of iron supplementation. It summarizes that iron amino acid chelate, or ferrous bis glycinate, has advantages over other forms of iron supplementation, including being non-buffered in the stomach, non-precipitated in the intestine, not antagonized by phytates, and having superior and dependable bioavailability due to its unique chelate design, which potentially allows for smaller doses with fewer side effects. The document examines what is known, unknown, and needs to be known about different forms of iron supplementation and their absorption parameters.
1) Vitamin D is produced in the skin from sunlight exposure and is also obtained in small amounts from dietary sources like fatty fish.
2) In the liver and kidneys, vitamin D is activated to its biological form which acts to regulate calcium and phosphate levels in the body by increasing their absorption in the intestines and mobilization from bones.
3) Vitamin D deficiency can lead to rickets in children and osteomalacia in adults, characterized by soft, weak bones due to poor mineralization.
Visual Aid designs for Pharma Brand ManagersRahul Prasad
Hi Colleagues, presenting you a ppt on Speciality-wise Visual aid pages which I found worth sharing and compiled from Google. This would give more clarity and magnify creative thoughts...This will help the freshers in PMT to understand the layout and text matter.
Hope you find it helpful.
The document discusses disorders of the parathyroid glands. It describes how parathyroid hormone (PTH) regulates calcium and phosphate levels in the blood by stimulating bone resorption and calcium reabsorption in the kidneys. PTH also stimulates vitamin D production, which increases calcium absorption in the intestines. Disorders discussed include hyperparathyroidism, hypoparathyroidism, and hypercalcemia of malignancy. Treatment involves managing calcium levels, identifying and removing tumors, and replacing hormones.
This document discusses calcium homeostasis and disorders, including hypercalcemia and hyperparathyroidism. It provides details on the roles of parathyroid hormone (PTH), vitamin D, and calcitonin in regulating calcium levels. It examines causes of hypercalcemia such as primary hyperparathyroidism, malignancy, and vitamin D toxicity. Guidelines for treatment of asymptomatic primary hyperparathyroidism with surgery or medication are reviewed based on calcium levels, bone mineral density, kidney stones, and age. Non-surgical treatments including vitamin D supplementation and cinacalcet are also discussed.
Artificial Intelligence in Diabetes Care GOPAL KHODVE
Artificial intelligence (AI) is a fast-growing field and its applications to diabetes, a global pandemic, can reform the approach to diagnosis and management of this chronic condition. Principles of machine learning have been used to build algorithms to support predictive models for the risk of developing diabetes or its consequent complications.
This document discusses various drugs used in immunopharmacology, including:
- Imatinib, which inhibits tyrosine kinases like BCR-ABL, c-KIT, and PDGFR and is used to treat CML, GIST, and MDS.
- EGFR inhibitors like erlotinib, gefitinib, cetuximab, and panitumumab which are used to treat various cancers. Trastuzumab targets HER2/neu for breast cancer.
- Anti-VEGF drugs like bevacizumab, sunitinib, sorafenib, ranibizumab, and pegaptanib which are used for cancers and age-
This document discusses peroxisome proliferator-activated receptors (PPARs), including their types (α, β/δ, γ), mechanisms of action, roles, and clinical significance. PPARs regulate lipid and carbohydrate metabolism and are involved in adipocyte differentiation, inflammatory responses, and cancer. PPAR agonists discussed include fibrates (PPARα), thiazolidinediones (PPARγ), and potential dual/pan agonists (PPARα/γ). Conditions treated include dyslipidemia, diabetes, obesity, and metabolic syndrome. Newer selective PPAR modulators aim to reduce side effects of current drugs.
Vitamin D is an essential vitamin that must be metabolized to become biologically active. It plays an important role in calcium homeostasis, bone and muscle health, immune function, and the regulation of cell growth. The best indicator of vitamin D status is the measurement of 25-hydroxyvitamin D in the blood, as it reflects vitamin D from dietary intake and sunlight exposure. Low vitamin D levels have been associated with increased risk of various chronic diseases. Vitamin D deficiency can lead to impaired bone mineralization and increased fracture risk.
Diagnostic Test of Diabetes & HypothyroidismSimmiRockzz
This document discusses diagnostic tests for diabetes and hypothyroidism. It describes the main types of diabetes as Type 1 resulting from a lack of insulin production, Type 2 involving insulin resistance, and gestational occurring in pregnant women. Tests for diagnosing diabetes include fasting plasma glucose, oral glucose tolerance, A1C, and random plasma glucose tests. Hypothyroidism is an underactive thyroid that does not produce enough hormones. It can be diagnosed through blood tests measuring thyroid-stimulating hormone and thyroxine levels.
Was recently asked to discuss whether there is evidence to support the use of B vitamins in managing different aches and pains. Here's my talk delivered last 16 Sept 2016 at the 12th Post Graduate Course of the East Avenue Medical Center Department of Internal Medicine.
Thiamine acts as a coenzyme that facilitates enzyme functions. It plays roles in producing DNA, RNA, triglycerides, and converting carbohydrates to glucose. Without sufficient thiamine, the body cannot effectively use carbohydrates or break down fats and proteins. Thiamine also helps regulate cell membrane functions in nerves and muscles. Deficiencies can cause beriberi diseases of the nervous or cardiovascular systems.
Vitamins and minerals are essential nutrients that the body needs in small amounts. Vitamins are categorized as either fat-soluble or water-soluble, and both have different storage and toxicity characteristics. Common vitamin deficiencies include vitamin D deficiency in 42% of Americans and B12 deficiency in vegetarians/vegans. Minerals are categorized as major or trace, and include calcium, phosphorus, potassium, and others. Different foods provide different vitamins and minerals, such as dark leafy greens containing vitamin K and calcium. While nutritional needs are best met through diet, supplements may be appropriate for some groups including pregnant/older individuals and those with poor diets or nutrient absorption issues.
Excessive vitamin D intake can lead to vitamin D toxicity. The 25-OH metabolite plays a key role in vitamin D intoxication by competing for intracellular receptors, inducing responses normally caused by 1,25-(OH)2-D3. This leads to hypercalcemia through increased calcium absorption and bone resorption, decreasing PTH and kidney function and disrupting calcium homeostasis. Long-term effects include calcinosis, the deposition of calcium and phosphorus in soft tissues like the heart and kidneys. Risk depends on calcium and phosphorus intake in addition to vitamin D exposure.
This document summarizes the key components involved in vitamin D and calcium homeostasis, including the roles of vitamin D, parathyroid hormone (PTH), and calcitonin. It discusses how vitamin D is obtained from sunlight or diet and activated in the body. PTH and calcitonin work in opposition to regulate calcium levels - PTH increases calcium levels by acting on the kidneys and bone, while calcitonin decreases calcium levels by inhibiting bone resorption. PTH and vitamin D also interact, as vitamin D helps absorb calcium from the gut and PTH stimulates its production. Together this maintains appropriate calcium and phosphate levels in the blood and body.
This document presents 4 clinical cases related to parathyroid gland disorders and questions about each case.
Case 1 describes a man with hypercalcemia and elevated PTH who experienced flank pain after running. Increased serum alkaline phosphatase would be predictable. The underlying mechanism is increased bone resorption.
Case 2 involves a woman with hypercalcemia from breast cancer metastases to bone. Compatible lab results would include low PTH and phosphate with high alkaline phosphatase. Hypercalcemia was likely caused by increased PTH-related peptide (PTHrP) production.
Case 3 describes a postmenopausal woman with asymptomatic hypercalcemia and kidney stones. Imaging found a thyroid mass. The diagnosis is likely
This document discusses gut microbiota and its relationship to diabetes. It begins with an overview of gut microbiota functions and compositions. It then describes how gut microbiota can be related to both type 1 and type 2 diabetes pathogenesis through various mechanisms like inflammatory responses and metabolic endotoxemia. The document discusses findings from metagenomic studies that show differences in gut microbiota of diabetes patients compared to healthy individuals. It also presents results from an Indo-Danish collaborative study on gut microbiome signatures associated with pre-diabetes and type 2 diabetes in Indian and Danish populations.
This document discusses vitamins and minerals, including:
- Vitamins are organic compounds that the body needs in small amounts and must be obtained through diet. They are classified as water-soluble or fat-soluble and have various important functions.
- Common dietary sources of vitamins include fruits, vegetables, grains, meat, and fortified foods. Recommended daily allowances are provided.
- Deficiency of certain vitamins can lead to diseases like beriberi, scurvy, and anemia. Too much of some vitamins can also be harmful.
- Minerals are divided into macrominerals and trace elements. Major macrominerals include calcium, phosphorus, magnesium, sodium, and potassium.
The document discusses drug biotransformation and metabolism. It notes that biotransformation converts lipid soluble compounds to lipid insoluble compounds through processes like oxidation, reduction, and hydrolysis. This allows metabolites to be less absorbed and more easily eliminated. The major sites of biotransformation are the liver, gastrointestinal tract, lungs, and kidneys. Cytochrome P450 enzymes and phase 2 conjugation reactions are responsible for the majority of drug metabolism. Genetic and environmental factors can influence interindividual variability in drug metabolism.
The document discusses drug metabolism and biotransformation. It notes that biotransformation converts lipid soluble compounds to lipid insoluble compounds through chemical alterations in the body. This makes compounds less able to penetrate cellular membranes and promotes their elimination. The major sites of biotransformation are the liver, gastrointestinal tract, lungs and kidneys. Biotransformation can produce both active and inactive metabolites through phase I and phase II reactions. Cytochrome P450 enzymes and conjugation reactions play important roles in the metabolic pathways. Factors like genetics and environment can impact individual differences in drug metabolism.
Protein Energy Malnutrition (PEM), also known as Protein-Energy Wasting (PEW) or Kidney Disease Wasting (KDW), is a state of decreased body protein and energy stores. PEM is common in patients with kidney disease, affecting up to 40-70% of those with end-stage renal disease. Factors contributing to PEM include poor nutritional intake, increased protein losses, and increased protein catabolism. A thorough nutritional assessment involves evaluating dietary intake, body composition, laboratory values, and scoring systems. Proper nutritional assessment and therapy are important for managing PEM and its negative effects in patients with kidney disease.
This document discusses magnesium disorders and hypomagnesemia. It begins by providing background on magnesium, including where it is stored in the body and its many functions. It then discusses the causes, clinical manifestations, diagnosis, and treatment of hypomagnesemia. Hypomagnesemia can be caused by renal magnesium wasting due to drugs, diseases, or genetic disorders, or by extrarenal losses from poor nutrition, malabsorption, diarrhea, or sweat losses. Symptoms affect the cardiovascular, neuromuscular, skeletal, and central nervous systems. Treatment involves identifying and addressing the underlying cause, as well as oral or parenteral magnesium supplementation.
The document discusses newer aspects of iron supplementation. It summarizes that iron amino acid chelate, or ferrous bis glycinate, has advantages over other forms of iron supplementation, including being non-buffered in the stomach, non-precipitated in the intestine, not antagonized by phytates, and having superior and dependable bioavailability due to its unique chelate design, which potentially allows for smaller doses with fewer side effects. The document examines what is known, unknown, and needs to be known about different forms of iron supplementation and their absorption parameters.
1) Vitamin D is produced in the skin from sunlight exposure and is also obtained in small amounts from dietary sources like fatty fish.
2) In the liver and kidneys, vitamin D is activated to its biological form which acts to regulate calcium and phosphate levels in the body by increasing their absorption in the intestines and mobilization from bones.
3) Vitamin D deficiency can lead to rickets in children and osteomalacia in adults, characterized by soft, weak bones due to poor mineralization.
Visual Aid designs for Pharma Brand ManagersRahul Prasad
Hi Colleagues, presenting you a ppt on Speciality-wise Visual aid pages which I found worth sharing and compiled from Google. This would give more clarity and magnify creative thoughts...This will help the freshers in PMT to understand the layout and text matter.
Hope you find it helpful.
The document discusses disorders of the parathyroid glands. It describes how parathyroid hormone (PTH) regulates calcium and phosphate levels in the blood by stimulating bone resorption and calcium reabsorption in the kidneys. PTH also stimulates vitamin D production, which increases calcium absorption in the intestines. Disorders discussed include hyperparathyroidism, hypoparathyroidism, and hypercalcemia of malignancy. Treatment involves managing calcium levels, identifying and removing tumors, and replacing hormones.
This document discusses calcium homeostasis and disorders, including hypercalcemia and hyperparathyroidism. It provides details on the roles of parathyroid hormone (PTH), vitamin D, and calcitonin in regulating calcium levels. It examines causes of hypercalcemia such as primary hyperparathyroidism, malignancy, and vitamin D toxicity. Guidelines for treatment of asymptomatic primary hyperparathyroidism with surgery or medication are reviewed based on calcium levels, bone mineral density, kidney stones, and age. Non-surgical treatments including vitamin D supplementation and cinacalcet are also discussed.
Artificial Intelligence in Diabetes Care GOPAL KHODVE
Artificial intelligence (AI) is a fast-growing field and its applications to diabetes, a global pandemic, can reform the approach to diagnosis and management of this chronic condition. Principles of machine learning have been used to build algorithms to support predictive models for the risk of developing diabetes or its consequent complications.
This document discusses various drugs used in immunopharmacology, including:
- Imatinib, which inhibits tyrosine kinases like BCR-ABL, c-KIT, and PDGFR and is used to treat CML, GIST, and MDS.
- EGFR inhibitors like erlotinib, gefitinib, cetuximab, and panitumumab which are used to treat various cancers. Trastuzumab targets HER2/neu for breast cancer.
- Anti-VEGF drugs like bevacizumab, sunitinib, sorafenib, ranibizumab, and pegaptanib which are used for cancers and age-
This document discusses peroxisome proliferator-activated receptors (PPARs), including their types (α, β/δ, γ), mechanisms of action, roles, and clinical significance. PPARs regulate lipid and carbohydrate metabolism and are involved in adipocyte differentiation, inflammatory responses, and cancer. PPAR agonists discussed include fibrates (PPARα), thiazolidinediones (PPARγ), and potential dual/pan agonists (PPARα/γ). Conditions treated include dyslipidemia, diabetes, obesity, and metabolic syndrome. Newer selective PPAR modulators aim to reduce side effects of current drugs.
Vitamin D is an essential vitamin that must be metabolized to become biologically active. It plays an important role in calcium homeostasis, bone and muscle health, immune function, and the regulation of cell growth. The best indicator of vitamin D status is the measurement of 25-hydroxyvitamin D in the blood, as it reflects vitamin D from dietary intake and sunlight exposure. Low vitamin D levels have been associated with increased risk of various chronic diseases. Vitamin D deficiency can lead to impaired bone mineralization and increased fracture risk.
Diagnostic Test of Diabetes & HypothyroidismSimmiRockzz
This document discusses diagnostic tests for diabetes and hypothyroidism. It describes the main types of diabetes as Type 1 resulting from a lack of insulin production, Type 2 involving insulin resistance, and gestational occurring in pregnant women. Tests for diagnosing diabetes include fasting plasma glucose, oral glucose tolerance, A1C, and random plasma glucose tests. Hypothyroidism is an underactive thyroid that does not produce enough hormones. It can be diagnosed through blood tests measuring thyroid-stimulating hormone and thyroxine levels.
Was recently asked to discuss whether there is evidence to support the use of B vitamins in managing different aches and pains. Here's my talk delivered last 16 Sept 2016 at the 12th Post Graduate Course of the East Avenue Medical Center Department of Internal Medicine.
Thiamine acts as a coenzyme that facilitates enzyme functions. It plays roles in producing DNA, RNA, triglycerides, and converting carbohydrates to glucose. Without sufficient thiamine, the body cannot effectively use carbohydrates or break down fats and proteins. Thiamine also helps regulate cell membrane functions in nerves and muscles. Deficiencies can cause beriberi diseases of the nervous or cardiovascular systems.
Vitamins and minerals are essential nutrients that the body needs in small amounts. Vitamins are categorized as either fat-soluble or water-soluble, and both have different storage and toxicity characteristics. Common vitamin deficiencies include vitamin D deficiency in 42% of Americans and B12 deficiency in vegetarians/vegans. Minerals are categorized as major or trace, and include calcium, phosphorus, potassium, and others. Different foods provide different vitamins and minerals, such as dark leafy greens containing vitamin K and calcium. While nutritional needs are best met through diet, supplements may be appropriate for some groups including pregnant/older individuals and those with poor diets or nutrient absorption issues.
Excessive vitamin D intake can lead to vitamin D toxicity. The 25-OH metabolite plays a key role in vitamin D intoxication by competing for intracellular receptors, inducing responses normally caused by 1,25-(OH)2-D3. This leads to hypercalcemia through increased calcium absorption and bone resorption, decreasing PTH and kidney function and disrupting calcium homeostasis. Long-term effects include calcinosis, the deposition of calcium and phosphorus in soft tissues like the heart and kidneys. Risk depends on calcium and phosphorus intake in addition to vitamin D exposure.
This document summarizes the key components involved in vitamin D and calcium homeostasis, including the roles of vitamin D, parathyroid hormone (PTH), and calcitonin. It discusses how vitamin D is obtained from sunlight or diet and activated in the body. PTH and calcitonin work in opposition to regulate calcium levels - PTH increases calcium levels by acting on the kidneys and bone, while calcitonin decreases calcium levels by inhibiting bone resorption. PTH and vitamin D also interact, as vitamin D helps absorb calcium from the gut and PTH stimulates its production. Together this maintains appropriate calcium and phosphate levels in the blood and body.
This document presents 4 clinical cases related to parathyroid gland disorders and questions about each case.
Case 1 describes a man with hypercalcemia and elevated PTH who experienced flank pain after running. Increased serum alkaline phosphatase would be predictable. The underlying mechanism is increased bone resorption.
Case 2 involves a woman with hypercalcemia from breast cancer metastases to bone. Compatible lab results would include low PTH and phosphate with high alkaline phosphatase. Hypercalcemia was likely caused by increased PTH-related peptide (PTHrP) production.
Case 3 describes a postmenopausal woman with asymptomatic hypercalcemia and kidney stones. Imaging found a thyroid mass. The diagnosis is likely
This document discusses gut microbiota and its relationship to diabetes. It begins with an overview of gut microbiota functions and compositions. It then describes how gut microbiota can be related to both type 1 and type 2 diabetes pathogenesis through various mechanisms like inflammatory responses and metabolic endotoxemia. The document discusses findings from metagenomic studies that show differences in gut microbiota of diabetes patients compared to healthy individuals. It also presents results from an Indo-Danish collaborative study on gut microbiome signatures associated with pre-diabetes and type 2 diabetes in Indian and Danish populations.
This document discusses vitamins and minerals, including:
- Vitamins are organic compounds that the body needs in small amounts and must be obtained through diet. They are classified as water-soluble or fat-soluble and have various important functions.
- Common dietary sources of vitamins include fruits, vegetables, grains, meat, and fortified foods. Recommended daily allowances are provided.
- Deficiency of certain vitamins can lead to diseases like beriberi, scurvy, and anemia. Too much of some vitamins can also be harmful.
- Minerals are divided into macrominerals and trace elements. Major macrominerals include calcium, phosphorus, magnesium, sodium, and potassium.
The document discusses drug biotransformation and metabolism. It notes that biotransformation converts lipid soluble compounds to lipid insoluble compounds through processes like oxidation, reduction, and hydrolysis. This allows metabolites to be less absorbed and more easily eliminated. The major sites of biotransformation are the liver, gastrointestinal tract, lungs, and kidneys. Cytochrome P450 enzymes and phase 2 conjugation reactions are responsible for the majority of drug metabolism. Genetic and environmental factors can influence interindividual variability in drug metabolism.
The document discusses drug metabolism and biotransformation. It notes that biotransformation converts lipid soluble compounds to lipid insoluble compounds through chemical alterations in the body. This makes compounds less able to penetrate cellular membranes and promotes their elimination. The major sites of biotransformation are the liver, gastrointestinal tract, lungs and kidneys. Biotransformation can produce both active and inactive metabolites through phase I and phase II reactions. Cytochrome P450 enzymes and conjugation reactions play important roles in the metabolic pathways. Factors like genetics and environment can impact individual differences in drug metabolism.
The document discusses thyroid hormones and their functions. It describes the thyroid gland and its production of the major thyroid hormones T4 and T3. It discusses the regulation and synthesis of thyroid hormones as well as thyroid disorders. The physiological actions, pharmacokinetics, therapeutic uses, and drugs used to treat thyroid disorders are summarized. These include levothyroxine, anti-thyroid drugs like thioamides, radioactive iodine, and iodides. The document provides details on the mechanisms and adverse effects of these drugs.
1. The thyroid gland secretes thyroid hormones that regulate metabolism and growth. Thyroid hormones are synthesized within thyroid follicles by iodination of tyrosine residues on thyroglobulin.
2. Thyroid hormone synthesis and secretion is regulated by a negative feedback loop involving thyroid stimulating hormone (TSH) from the pituitary gland.
3. Disorders of the thyroid gland include hyperthyroidism (overproduction of hormones) and hypothyroidism (underproduction of hormones).
The thyroid gland produces thyroid hormones T3 and T4 which regulate metabolism. T4 is the major hormone produced and is converted to the more active T3 in tissues. Their production involves iodine uptake and coupling of tyrosine residues in thyroglobulin. T3 and T4 act through nuclear receptors to regulate gene expression and increase metabolism. Disorders include hypothyroidism with low hormone levels and hyperthyroidism with excessive levels leading to increased metabolism. Tests are used to evaluate thyroid function and hormone levels.
A power point presentation on thyroid hormones and thyroid inhibitors on subject of pharmacology suitable for reading by undergraduate medical students.
Here are the key points about dopamine:
- Dopamine is a neurotransmitter produced in the substantia nigra and ventral tegmental area of the basal ganglia in the brain.
- Its production involves a two-step process where the amino acid tyrosine first reacts with the enzyme tyrosine hydroxylase to produce L-Dopa.
- L-Dopa then reacts with the enzyme L-Dopa decarboxylase to finally produce dopamine.
- Dopamine provides both excitatory and inhibitory responses by acting on axon networks in the brain.
- It plays an important role in processes like reward, motivation, pleasure, and motor control by signaling between neurons.
This document provides an overview of nutrition science, including definitions of key terms and descriptions of major nutrients. It discusses the study of nutrients and how the body processes them. Major topics covered include macronutrients like carbohydrates, fats, proteins, micronutrients like vitamins and minerals, nutrient deficiencies, and how genetics and genomics relate to nutrition and disease.
Inborn errors of metabolism are rare genetic disorders where the body cannot properly break down food into energy due to defects in enzymes. Phenylketonuria is provided as an example, where a defect in the enzyme phenylalanine hydroxylase prevents the breakdown of phenylalanine, causing it to accumulate to toxic levels and resulting in issues like intellectual disability if left untreated. Treatment involves a low-phenylalanine diet from infancy onwards.
A 50 year old male presented with a lump in the front of the neck that moves with swallowing, breathing difficulties, and a changed voice for the past 4 months. Examination found swelling around the eyes and normal thyroid function tests. The condition is likely a goiter caused by an enlarged thyroid gland.
1) Thyroid disorders involve the thyroid gland, which secretes hormones that regulate growth and metabolism. Common thyroid disorders include hypothyroidism, hyperthyroidism, and thyroid nodules.
2) Hypothyroidism is a syndrome caused by thyroid hormone deficiency and can cause mental retardation if untreated. Hyperthyroidism occurs when there is excessive production of thyroid hormones.
3) Treatment for thyroid disorders involves replacing thyroid hormones for hypothyroidism or suppressing thyroid hormone production and action for hyperthyroidism. Medications like levothyroxine and antithyroid drugs are often used.
The document summarizes a seminar on nutrition and the role of trees. It discusses how knowledge of nutrition is changing and will lead to future advances, the double burden of malnutrition, and maternal nutrition and evolution of epigenetics. It also discusses how plant microRNAs can regulate human gene expression, how royal jelly controls caste differentiation in bees through epigenetic changes, and the sequencing of ant genomes to understand longevity. Finally, it discusses links between nutrition, oxidative stress, antioxidants, calorie restriction, and lifespan in various organisms.
Dr. Sharanya Rajan's document defines obesity and discusses its epidemiology. Key points include:
- Obesity is defined as a BMI ≥ 30 and is caused by an imbalance between energy intake and expenditure.
- Over 1.6 billion adults are overweight globally, with 400 million obese. Obesity is more common in women and increasingly affects poorer populations.
- Hypothalamic and genetic factors contribute to obesity development. Conditions like Prader-Willi syndrome, leptin/leptin receptor deficiencies, and POMC/MC4R mutations can cause monogenic obesity.
- Adipokines like leptin and resistin, as well as gut and pancreatic hormones, help regulate
Hormones regulate the structure and function of target organs and tissues. They circulate in the bloodstream and act in very small amounts on target cells. This document discusses the principles of hormonal regulation including the classification, mechanisms, and regulation of hormone secretion for various hormones like thyroid hormones, sex hormones, and parathyroid hormone. It also covers diseases related to abnormal hormone levels such as hyperparathyroidism, hypoparathyroidism, and Cushing's syndrome.
This document provides information on inborn errors of purine and pyrimidine metabolism. It defines key enzymes involved in purine degradation and salvage pathways such as adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, and adenosine deaminase. It also discusses disorders that result from defects in these enzymes, including the causes and effects of lesions in the purine nucleotide cycle. Additionally, it describes uric acid formation from hypoxanthine and xanthine, and the role of the UMP synthase complex in pyrimidine synthesis. Overall, the document outlines the normal metabolic pathways of
This document defines obesity and discusses the regulation of appetite and factors involved in obesity. It provides epidemiological data on obesity rates globally and in India. Several genetic syndromes and monogenic causes of obesity are described, including deficiencies in leptin, the leptin receptor, POMC, and prohormone convertase 1, which all result in hyperphagia and severe early-onset obesity. Twin and adoption studies support a strong genetic component to obesity.
The document summarizes the key aspects of thyroid hormone synthesis and regulation. It discusses:
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Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
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Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
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2. Introduction
Thiamine Deficiency Disease, Dysautonomia,
and High Calorie Malnutrition
Synopsis: Hiding in Plain Sight: Modern Thiamine
Deficiency
Research analysis and case stories
HormonesMatter.com
Discussion – patient driven
Understanding Mitochondrial Nutrients – FB
Fun - powerlifting
Oldladieslift.com/Oldladieslift - FB
3. Objectives
To provide a framework for understanding and recognizing modern
thiamine deficiency
Well fed but malnourished adults – walking sick
Basic thiamine chemistry
Role in food metabolism
Role in mitochondrial function and OXPHOS
Metabolic patterns associated with insufficient thiamine
Overview of symptoms across time
Treatment options
Resources for more information
5. WHY
THIAMINE?
Thiamine is required for ATP/energy
synthesis
Rate-limiting for effective macronutrient
metabolism and mitochondrial
energetics - OXPHOS
Thiamine is required for
mitochondrial oxidation and cellular
oxygenation
Insufficient thiamine -> hypoxia
No energy, no oxygenation, no life
And lots of ill-health along the way
One of the main drivers of chronic illness
An important component of acute illness
Life requires
energy.
Energy requires
thiamine.
6. What is thiamine?
Vitamin B1 (thiamin, thiamine) found in
Lean pork, poultry and other meats, wheat germ, liver and other organ meats, eggs,
fish, beans, peas, nuts, whole grains, garlic
Processed foods (enrichment/fortification)
Antagonized by
High carbohydrate/sugar diets, coffee, tea, alcohol, tobacco, polyphenol supplements
Many (all) pharmaceutical, environmental, and industrial chemicals
Critical for
Metabolism, mitochondrial energy production, protein expression, and general
function, and array of CNS/PNS functions – life itself
7. Basic kinetics
Humans and animals must consume
Plants and microbes synthesize
Gut microbes synthesize ~2% of total
thiamine – used mainly by colonocytes
Substrate/micronutrient availability
determine microbial balance
Deficiency ↑ pathogenic species (better
with salvage pathways) ↓ more helpful
species
Short half life: 1-12 hours
Limited storage: 2-3 weeks after
complete cessation
Complete cessation is rare in west. Intake
and need wax and wane.
Absorbed mainly in intestine
Passive diffusion at higher
concentrations
Via transporters at low concentrations
At least 7 transporters (see ‘Hiding’
paper) discovered so far.
Transporter activity is susceptible to
Genetic defects that are quite common
Environmental regulation – meds and
other substances block transporters
8. Once absorbed
Free thiamine is phosphorylated into
thiamine pyrophosphate (TPP) also called
thiamine diphosphate (ThDP)
Mg2+ and ATP dependent
TPP = ~90% of circulating thiamine
Phosphates removed or added to form
thiamine monophosphate (TMP), thiamine
triphosphate (TTP)
Microbial thiamine: adenosine thiamine
diphosphate (AThDP) Defects in TPK linked to Huntington’s
disease, possibly other neurodegenerative
disease processes.
9. From food to ATP
MITOCHONDRIA ARE KEY
AND THIAMINE IS RATE-
LIMITING
10. We believe
It doesn’t matter what we eat, so long as there is sufficient intake,
we get ATP.
12. “The presumption is that all calories are created equally
e.g. that calories are calories and no matter the origins of
those calories, the end result will be ATP. Indeed, from the
mitochondrial perspective, each fuel, no matter its origins,
will be broken down to its carbon skeleton and through a
series of reactions, the final output will be ATP. In that sense,
the fuel source makes little difference: the net result will be
ATP.”
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.
13. “However, and this is a big however, what this perspective
fails to recognize, is to get from fats, proteins and
carbohydrates to ATP, there is an entire
factory of enzymatic reactions that absolutely require non-
caloric nutrients - vitamins and minerals – to function
properly.”
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.
14. In reality
Enzymes require nutrient cofactors to perform
metabolic tasks.
When appropriate nutrient co-factors are present in
sufficient concentrations for the enzymes to operate fully,
the food we eat is successfully metabolized into end-
products that are useful for all manner of processes and
cellular energy is produced.
Even in the case of genetic aberrations that limit enzyme
function endogenously, there is evidence that nutrient
manipulation can overcome inadequate enzyme activity.
Pyruvate dehydrogenase deficiencies, Parkinson’s, and
Huntington’s, for example.
Graphic: Elliot Overton, https://www.hormonesmatter.com/beyond-
deficiency-thiamine-metabolic-stimulant/
15. With Co-factor deficiency
When nutrient co-factors are in short-supply, resources are
reallocated.
Metabolism shifts directions, it takes a right turn when it should move left or vice versa.
Different enzymes are activated and metabolism eventually reaches a dead-end but not
before potentially toxic, unused, waste products build up. Dirtier burn.
As toxins build up, other systems become disrupted, inflammatory and immune responses
are activated, demanding ever more energy to resolve.
This is the energy spiral that induces and maintains many of the
illnesses we see today.
16. What the body needs to make energy
Macronutrients
with adequate
micronutrients
to power
enzyme
machinery.
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.
Absent
micronutrients, it
doesn’t matter
how many
calories one
ingests, the
wheel will not
spin (or it will
spin backwards).
17. When it comes to energy
Per glucose molecule
Glycolysis: 2-4 units
TCA/Krebs/Citric acid cycle:
1-2 units
OXPHOS: 30-38 units
Per fat molecule
OXPHOS: >100 units
Protein
Substrates for the synthesis of
other proteins
Glucose via liver gluconeogenesis (-
4)
Glutamine > a-KGDH > 24 units of
ATP
Used primarily in quickly replicating
immune cells and cancer > reverse spin
of TCA
Pyruvate to citric acid cycle or
converted to lactate
90-95% of ATP produced via mitochondrial OXPHOS
El Bacha, T., M. R. M. P. Luz, and A. Da Poian. "Dynamic adaptation of nutrient utilization in
humans." Nat Educ 3, no. 8 (2010).
18. When it comes OXPHOS
Can’t get into the mitochondria
without thiamine.
All roads are blocked
We don’t metabolize foods well
Even glycolysis is challenged
Combs Jr, G.F. and McClung, J.P., 2016. The vitamins: fundamental aspects in nutrition and health. Academic press.
Thiamine is king
19. When we lose thiamine, we lose ATP
Imagine this happening in vivo in different tissues/organs. What
havoc would this initiate? What disease processes might evolve?
20. When OXPHOS is blocked
“OxPhos defects trigger mtDNA
instability and cell-autonomous stress
responses associated with the
hypersecretory phenotype,
recapitulating findings in plasma of
patients with elevated metabokine and
cell-free mitochondrial DNA (cf-mtDNA)
levels. These responses are linked to the
upregulation of multiple energy-
dependent transcriptional programs,
including the integrated stress response
(ISR).” –Jan 2023
Fig. 9: Conceptual model including potential sources of hypermetabolism in cells and patients with mitochondrial diseases.
From: OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
It costs the cell more to do less
Leads to chronic illness
22. Transketolase
Transketolase (TKT)
Located in the cytosol
Connects pentose phosphate pathway (PPP) to
glycolytic and oxidative pathways
Determines energy spent on ribose for
DNA/RNA and NADPH for steroid, myelin and
antioxidants (glutathione, thioredoxin) versus
what is shunted towards glycolysis
TKT↓ TD and long list of other disease processes
TKT activity among the more accurate tests of TD
↑ in tumor cells – an energy siphon
But ↓ in the human
http://thiamine.dnr.cornell.edu/Thiamine_biochemistry.html
Mitochondrion
23. Thiamine dictates fatty metabolism
a-oxidation of fatty acids begins in the
peroxisome
Larger FAs are broken into smaller ones
2-hydroxyacyl-CoA lyase (HACL1) – the enzyme
responsible, is thiamine dependent
Impaired a-oxidation leads to
↓ Acetyl-CoA for mitochondria> ↓OXPHOS >↓ATP
Particularly problematic for the heart
High phytanic acid/sphingolipid foods (beef, lamb,
dairy, eggs) cannot be metabolized fully
May account for some food intolerances; later stage
symptoms - visual field restriction, peripheral
neuropathies, ataxia
Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical
aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207.
24. In the mitochondria
Pyruvate dehydrogenase complex (PDC)
Governs entry into the TCA/Krebs/Citric acid cycle
Pyruvate to Acetyl-CoA
a-ketoglutarate dehydrogenase (a-KGDH)
Metabolic flux through the TCA, direction and
speed of spin
Generates NADH>electrons for ETC
Produces and is susceptible to ROS
Branched chain keto acid dehydrogenase
(BCKAD/BCKADH)
Dictates BCAA catabolism
Influences fatty acid metabolism - > increase in
inflammatory diacylglycerol and ceramides
(hallmarks of metabolic syndrome)
Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical
aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207.
↓ ALZ &
Parkinson’s
Lactate
25. Insufficient thiamine > metabolic
dysfunction
Blocked TKT and PDC > impaired
glucose metabolism
Shifts to polyol/sorbitol, hexosamine,
diacylglycerol/PKC, AGEs
Micro-vascular damage associated with
hyperglycemia
Aging
Increased lactate/poor lactate recycling
capacity
Pyruvate cannot enter the TCA
Fatigue, exercise intolerance and a
laundry list of other symptoms
When severe lactic acidosis
Mechanism of Development of Atherosclerosis and Cardiovascular Disease in
Diabetes Mellitus, September 2017 Journal of Atherosclerosis and Thrombosis
25(1); DOI: 10.5551/jat.RV17014; LicenseCC BY-NC-SA 4.0
26. Even marginally insufficient thiamine
wreaks havoc
Oxalosis and thiamine
Low TKT = low NADPH
↓NADPH > ↓ glutathione
↓ glutathione > poor detox of glyoxal and
methylglyoxal ↑ carcinogenic protein adducts
↓pyridoxal kinase (PK) activity
PK converts inactive B6 (pyridoxine 5-phosphate)
into active (pyridoxal 5-phosphate - P5P)
↓ P5P prevents glyoxylate from being converted
back into glycine, leading to high oxalates
Shangari, N., Depeint, F., Furrer, R., Bruce, W.R. and O’Brien, P.J., 2005. The effects of partial thiamin deficiency
and oxidative stress (ie, glyoxal and methylglyoxal) on the levels of α-oxoaldehyde plasma protein adducts in
Fischer 344 rats. FEBS letters, 579(25), pp.5596-5602.
28. Thiamine Deficiency Induces Hypoxia
TD downregulates PDC and impairs oxidation and oxygenation
Oxidation: ability to utilize O2 in the mitochondria and efficiently
produce ATP
Oxygenation: ability to traffic oxygen (↓arterial O2
saturation/↑venous) – ATP dependent function
Think ‘air hunger’ or the ‘happy hypoxic/hypoxemic’ – at least
initially.
29. ↓ PDC stabilizes HIF1a proteins
HIF1a > signals 100s of genes to
Increase angiogenesis, erythropoiesis, and glycolysis - Warburg
HIFs feedback and degrade PDC further
Upregulates pyruvate dehydrogenase kinases – energy spiral
HIFs are stabilized with any hypoxic condition – universal
response
Unlike obstructive or exertional, there is plenty of O2, but it
cannot be used or trafficked effectively – pseudo-hypoxia
Partly local – cell/mitochondria
Partly neural – brainstem hypoxia > dysautonomic function
Watts, M.E., Pocock, R. and Claudianos, C., 2018. Brain energy and
oxygen metabolism: emerging role in normal function and disease.
Frontiers in molecular neuroscience, 11, p.216.
30. Another reason SAD is bad
Heavy in seed oils
Upregulates pyruvate dehydrogenase kinases (PDKs)
– inactivate PDC
PDKs upregulated in tumor environment
Stabilize HIF1a
Heavy in HFCS
Uses more ATP than it produces
Low in nutrition
Relative to the caloric, toxicant load
31. And yet more hits to the PDC
Magnesium is required to activate/
phosphorylate thiamine
~50% of population is deficient
Riboflavin and alpha-lipoic acid required for
subunits of PDC
Heavy Metals
Arsenic, mercury block ALA, impairs the PDC, induces
HIFs and impairs mitochondrial respiration
Symptoms similar to TD and respond to increased
thiamine
Thiamine chelates heavy metals Graphic: Elliot Overton, from: https://www.hormonesmatter.com/why-
thiamine-supplementation-requires-magnesium/
32. Just how important is the PDC?
In response to severe stress, the PDC translocates to the cell nucleus.
34. When we think of thiamine deficiency
We only think of late stage, frank deficiency in
specific populations with purely neuro symptoms
Beriberi or Wernicke’s encephalopathy in chronic
alcoholics
Ataxia, nystagmus, confusion/memory loss
We miss the earlier symptoms in this and other
populations
And we mostly miss Wernicke’s too
80% of alcohol related Wernicke’s missed 1
58% of pediatric Wernicke’s missed2
Unknown % of hyperemesis gravidarum Wernicke’s missed
Only 16% cases exhibit classic triad1
1. J Neurol Neurosurg Psychiatry. 1986 Apr;49(4):341-5.; 2. Pediatr Neurol. 1999 Apr;20(4):289-94.
35. Lonsdale & Marrs, 2017. Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition
36. We fail to recognize
More subtle, metabolic disturbances
Hyperglycemia and dyslipidemia cascades
Vague, non-specific symptoms that correspond to a long list of disease processes – but at root
reflect poor energy capacity
That develops slowly across time and is non-linear
Food is abundant, obesity reigns
Symptoms wax and wane before reaching critical point – just like thiamine intake and the
stressors that demand increased thiamine
Brain lesions don’t happen overnight
Or that there is even a problem
We solved nutrient deficiency, didn’t we?
37. THIAMINE
DEFICIENCY
WAS SOLVED
Fortification/enrichment eradicated
thiamine deficiency in the west
Intake of processed foods provides
sufficient thiamine (RDA 1.1 – 1.4mg)
Food intake surveys – only 5% of the
population consumes insufficient
thiamine
Average American consumes 4X (NIH)
Right?
38. EVERY
PUBLISHED
STUDY
“A severe depletion is not commonly seen,
except in cases of inadequate nutrition
and/or alcoholism.”
“Cardiac beriberi, or heart failure due to
thiamine deficiency, is considered rare in the
developed world.”
“Thiamine deficiency is rare in developed
countries and is most commonly associated
with chronic alcoholism. The other
predisposing conditions include chronic
dietary deprivation and impaired absorption
or intake of dietary nutrients.”
“Nowadays, in the developed world, it is
relatively rare.”
Suggests TD is
rare and limited
to certain
populations or
conditions
39. IF WE DIG A
LITTLE
DEEPER
Without processed foods
Over 40% of population does not consume
enough thiamine (or other nutrients)
If we look at the research
A large portion of the population is either
frankly or functionally deficient
Frank deficiency – lab confirmed
We rarely measure – so how would we know?
And there problems with the labs – see Hiding
Functional deficiency – problems with thiamine
or OXPHOS machinery; magnesium deficiency;
high consumption/exposure to anti-thiamine
factors e.g. modern foods and medications;
chronic or severe illness that demands much
higher intake of thiamine
It’s not rare at
all
40. Especially with hyperglycemia
‘Healthy’ individuals see a reduction in
thiamine beginning at 55% carb intake
Standard American Diet > 55% carbs
Type 1 and 2 diabetics are frequently
deficient in thiamine
~75% lower thiamine than controls
98% diabetics were deficient
~10% of population is diabetic (NIH)
Hyperglycemia increases demand
“…prevalence of low plasma thiamine
(<70 nmol/L [[23]]) was 98% in the
diabetes group with microalbuminuria
and 100% in the diabetes group without
microalbuminuria and in the control
group.”
41. Just how common is thiamine deficiency?
15-29% of obese patients pre-
bariatric surgery, higher post
surgery (~49%)
No data on those not seeking surgery
20-50% of community dwelling
elderly, 45% of elderly patients in
acute care
30% psychiatric patients
20% ER patients (random sample)
10% ICU patients upon admission (small,
prospective study)
20% after 3 days
70% if septic
Up to 91% congestive heart failure
patients
38% pregnant women
47-63% hyperemesis (likely more, not often
measured until WE is present)
Quite common, it appears.
42. WHY THE
DISCREPANCY?
We assume it is was solved, so we
don’t look for it
We look at intake only and ignore
basic kinetics and dynamics
Absorption/transport
Metabolism (activation)
Utilization
We disregard the myriad of anti-
thiamine factors or that increased
energetic demands require increased
intake – e.g. illness
43. Many roads to thiamine deficiency
Increased dietary demand
Low thiamine relative to sugar intake or toxicant
load
Poor absorption
Dysbiosis, dysmotility disorders, leaky gut
Dietary deactivation/inactivation
Alcohol, tobacco, coffee, tea, other common
foods
Mg2+ deficiency
Genetic factors
SNPs in transporters or enzymes
Medications & environmental
chemicals
Block thiamine transporters,
degrade the molecule,
increase excretion, or just
damage mitochondria
(requiring more)
Two most common: diet and
medications
44. Common medications that deplete
thiamine
Metformin [167]
92 million prescriptions in 2020 (Statista)
Psychiatric medications [168]
13% of adults (CDC)
Metronidazole [169], trimethoprim [170] and other antibiotics
NSAIDs, acetaminophen, and aspirin [172]
Proton pump inhibitors [173]
Diuretics [174]
Chemotherapeutic drugs [175] Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine
Deficiency. Cells, 10(10), p.2595.
45. A key mechanism
“Overall, our comprehensive study was
able to identify 146 inhibitors of ThTR-2,
most of which were not previously
known .”
46. Environmental threats to mitochondrial
function
“However, although many of these chemicals cause effects other than
mitochondrial toxicity, the importance of the mitochondrial effects is in
some cases supported by the fact that there is overlap in the
pathologies observed after exposures and mitochondrial diseases.”
47. What does all of this mean?
Thiamine sufficiency is more than just intake
All sorts of threats to thiamine stability
Deficiency is more common than recognized
Lots of folks are walking around with inadequate thiamine
Impairs metabolism of food into energy
Derails the metabolism of fatty acids, proteins and
carbohydrates (metabolic syndrome)
Diminishes mitochondrial function and oxidative capacity >
forces the switch to glycolysis
Increases hypoxia molecules
Drives inflammation, among other things
It doesn’t look
like we think it
does.
48. “There is often something sinister about familiar concepts. The
more familiar or ‘natural’ they appear, the less we wonder what
they mean; but because they are widespread and well-known, we
tend to act as if we know what we mean when we use them.”
Devisch, I. and Murray, S.J., 2009. ‘We hold these truths to be self‐evident’: deconstructing
‘evidence‐based’medical practice. Journal of evaluation in clinical practice, 15(6), pp.950-954.
50. What does TD look like?
Depends upon severity and chronicity of the deficiency
Classical descriptions depict later stage deficiency
By the time we get to white matter lesions TD has been chronic and/or severe
TD is a long process with ↑morbidity/↓ mortality
Frequently begins in the gut
With caloric sufficiency/excess, one may live with TD for years before presenting classical
symptoms, and may not present with classical symptoms at all
Symptoms may also wax and wane in parallel with periods of thiamine
deficiency/sufficiency
51. A series of studies in the 1930-1940s
Looked at TD across time in a female inpatient population. There were 3 studies in total,
two with four women each and one with 11 women maintained on a diet of .15mg of
thiamine per day for 147 days, .45mg of thiamine for 88 days, and 11 women at ~.15 – .2mg
thiamine per day plus 1mg of thiamine given intermittently for up to 196 days, respectively.
(RDA is 1.2mg)
In the third study, where additional thiamine was provided, when averaged, the total
thiamine consumed was ~.175mg per 1000 calories of food or .35mg for a 2000 calorie per
day diet. Also, in this study, 5 of the 11 women were maintained on the diet for an
undisclosed period before resuming a normal diet, while the remaining 6 were kept on the
diet for as long as 196 days. This is approximately 30% of the recommended daily allowance
needed to stave off deficiency symptoms and syndromes.
https://www.hormonesmatter.com/are-thiamine-deficiency-symptoms-too-narrowly-focused/
52. Case notes on two women
First few weeks: emotional instability, irritability, moodiness, anxiety, agitation, depression, reduced activity, and numerous, often
vague, somatic complaints. Weakness and anorexia begin to present.
30 days: anorexia, weight loss, epigastric distress, increasing weakness, periodic vomiting
50 days: nausea and vomiting after meals, progressive weakness from low energy to bedridden, sometimes constipation
70 days: constant nausea, severe weakness, apathy, confusion, numbness, and tingling in extremities
90 days: inability to read or focus, aberrant to absent sensory recognition, tender calves, inability to stand from squatting position,
hypoactive Achilles tendon reflex, nausea progresses to regular vomiting after meals
110 days: appetite fails, apathy, vagueness and confusion, low blood pressure and heart rate at rest, rapid increase upon ordinary
exertion, aberrant and absent sensory perceptions, aberrant and reduced reflexes, reduced flexion of ankles and knees, ataxia, inability
to stand on toes.
120 days: impaired pain perception on legs, loss of patellar and Achilles reflex, weakness in abduction, adduction, and flexion of thighs,
weakness in the legs with limited ability to extend legs with quadriceps, inability to stand or walk without support, ankle and knee
clonus absent, Babinski response absent.
How many of your patients present with some of these symptoms?
53. Outcome
One of these two subjects developed severe neurological defects at 120 days and so the experiment was
stopped. The researchers noted that appetite had completely failed and remarked that ‘inanition seemed
imminent’.
They also remarked that with 60-80mg of thiamine given orally and parenterally many, but not all, of the
deficits resolved.
Appetite returned and strength was regained within the first week, and within 30 days, the less severely ill
of the two women was mostly recovered.
At 60 days, one of the women was fully recovered.
For the other women, recovery was incomplete, even after 120 days of treatment. Of note, it was the
younger and more active woman who suffered the most serious neurological deficits and who was unable to
fully recover.
54. Insights
.45mg of thiamine for 88 days
“We nevertheless are impressed by the degree of debility induced by the isolated withdrawal of thiamine. Fatigue,
lassitude, and loss of interest in food developed early and increased progressively as the period of deficiency extended,
to the point of intolerance for food. So great was this intolerance that uncontrollable vomiting, even after tube feeding
and parenteral injection of solutions of sodium chloride and dextrose, automatically brought the observations to a
close.”
“The time of development of symptoms and the time of development of severe symptoms differed among the subjects
and seemed to be related to physical activity. The subjects who were more active showed symptoms earlier and were
more seriously affected later than others who from the beginning were less energetic.”
55. WHAT THESE
STUDIES TELL
US
Even with severe dietary restriction of
thiamine
When calories/nutrients maintained, early (and
even late) TD symptoms are non-specific
Food intolerance, dysbiosis and dysmotility are
signs of TD
More active people affected more quickly and
seriously
Hyperglycemia, obesity, sedentary behavior likely
masks TD
Symptoms may wax and wane relative to changes
in thiamine
When women given extra thiamine after periods of
deficiency, recovered, at least temporarily
Recovery takes time
56. On the wax and wane of symptoms
Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine Deficiency. Cells, 10(10), p.2595.
57. Thresholds and tipping points
Time course of cerebral TD relative WE in
rodents (ataxia, loss of righting, rigid
body arching)
2.5 wks: weight loss, progressive anorexia,
hair loss and drowsiness
4.5 wks: rapid progression of symptoms and
decline of health over next 5 days with
incoordination with walking, impairment of
the righting reflex, reluctance to walk,
walking backwards in circles, imbalance, rigid
posturing and eventually a total loss of
righting activity and severe drowsiness
Neuro symptoms became apparent when cerebral
thiamine concentrations reached 20% of normal.
Have to lose 80% of cerebral thiamine before WE
symptoms become noticeable
Recovery began when concentrations climb to 26% of
normal.
58. HOW LONG
DOES IT TAKE
TO LOSE 80%
OF CEREBRAL
THIAMINE AND
INDUCE WE IN
HUMANS?
With severe and consistent dietary restriction –
weeks to months
But with modern diet, thiamine intake varies across time –
it may be years before WE symptoms manifest
Poor intake/poor absorption plus excess elimination
Hyperemesis gravidarum: 2-3 weeks (not often tested
until 6-8 weeks, if then, after serious brain damage has
begun)
Non-pregnant, severe vomiting/diarrhea: 2-3 weeks
depending upon other variables
Poor intake with hyper-metabolism of severe
illness/injury
ICU – a few days
Does the time frame really matter? If thiamine ↑ATP and ATP is needed for
everything, shouldn’t we be providing support well before it reaches this point?
59. What does early TD look like
Mitochondrial in nature – mitochondria fuel everything – wide variety of symptoms
High energy organ systems impacted most dramatically
Nervous system
Cardiovascular system
Gastrointestinal
Musculature
Metabolic changes locally <> systemically
Recall the cell culture study where the heart cells ceased functioning after ~10 days
Everything and nothing
62. General autonomic instability
Inadequate energy supply
to the ANS > inconsistent
regulation.
Too much, too little, too
soon, too late, too long, too
short
Inability to adapt to stress of
any kind
Dysautonomia
Even more oddball
symptoms
63. When to consider thiamine
If the patient has a long list of medically
unexplained symptoms that don’t quite fit
any diagnosis, it’s probably related to poor
mitochondrial function and insufficient
thiamine.
If the history suggest repeat illnesses, poor
healing, diet issues, chronic medication use –
it’s probably related to thiamine.
Metabolic syndrome
Persistent fatigue
If the patient has been vomiting or has severe
diarrhea, or a severely restricted diet due to
food intolerances, they would benefit from
thiamine
Pregnancy and especially hyperemesis
Severe illness or injury demanding increased
energy to heal, they would likely benefit from
thiamine
And any of the conditions listed earlier that
have a high rate of thiamine deficiency
Rules of thumb
In other words, much of the population would
benefit from extra thiamine.
64. “Thiamine deficiency impacts on the most basic survival mechanisms:
oxygenation and oxidation. Both oxygenation of the blood and its delivery to
the tissues for the process of cellular oxidation are dependent on thiamine. Its
deficiency, particularly by its effects on the functions of the limbic system and
brainstem, places the ANS front and center. Both endogenous and exogenous
signals from the brain to body organs become chaotic, leading to a vast array
of symptoms.”
Lonsdale & Marrs, Thiamine Deficiency Disease,
Dysautonomia, and High Calorie Malnutrition.
65. Neurological
Antonio Costantini’s work with
Parkinson’s and dystonia patients
Research link
YouTube video library of patients
before and after
Using thiamine in Alzheimer’s
Dozens of articles
Clinical trial underway
Huntington’s disease
Thiamine/biotin transporter to
SLC19A3
TPK (enzyme that converts free
thiamine to TPP)
Brain thiamine deficiency without apparent nutritional
deficiency
“Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1
dysregulation restores OL maturation and rescues neuronal pathology. Our
insights into HD OL pathology spans multiple brain regions and link OL
maturation deficits to abnormal thiamine metabolism.”
66. How to test
Labs – See Hiding article or book for details
In the office: watch and listen
Too many symptoms, serious, unexplainable decline in health, marked by persistent fatigue
Subtle and not so subtle changes in gait, stability, muscle tone, speech, decrements cognitive
or affective acuity or stability
Asymmetrical pulse pressure, postural hyper- or hypotension, general tachycardia (early stage),
bradycardia (later stage)
Other irregularities in autonomic function
In the hospital or acute setting
History and severity of illness > ↑ energy demand ↑ need for thiamine
If not deficient on admission, likely to become deficient during stay
67. How to treat: option 1
Hard and fast
High dose, IV, IM - theory is to kick start
downregulated enzymes
Warranted in acute care, with WE, severe
neurological symptoms, and where oral intake
and/or absorption is problematic
Dependent upon case and clinical experience
Refeeding responses are real and difficult to
navigate
Need to manage electrolytes and cofactors esp.
those with wet beriberi, affecting the heart
The patient may get worse before getting
better – articles on HM
IV multivitamin/mineral useful
Dosing ranges
Guidelines vary significantly
IV 100-500 mg 1-3X per day for several days to
week followed by oral at a range of doses
Many patients need IV support for months,
followed by high dose oral intake indefinitely
IM – Parkinson’s 100mg 2X per week for
months followed by 1000-3000mg (thiamine
HCL) orally indefinitely – per Costantini’s work.
68. How to treat: option 2
Low and slow
Start at a low dose and gradually increase
over time in stair step fashion
Allows the body to reregulate over time
When IV/IM and regular clinical oversight
are not available
‘Refeeding’ still problematic and can last
for weeks to months
The patient may get worse before getting
better
Difficult with prolonged GI symptoms
Dosing
Dosing varies significantly
Starting dose: from micro-doses, fractions of a
mg to 100s of mgs even grams
How long the patient has to stay at each dose
before increasing varies
What co-factors and electrolyte support is
needed varies
Need a good multi plus good electrolyte
support
What formulation of thiamine the patient can
handle and respond to varies too
69. Oral thiamine supplements
Thiamine mononitrate
In cheap OTC vitamins – not recommended
Thiamine HCL (various brands)
Requires a transporter, lower potency, requires much higher dose
At high doses works well with Parkinson’s, CFS; easier to titrate up than TTFD or benfotiamine
Thiamine tetrahydrofurfuryl disulfide (TTFD) - Thiamax, Allithiamine, Lipothiamine
Chemically modified to cross cell barrier, doesn’t require a transporter, higher potency, requires lower dose
than HCL
Works for a variety conditions, may be too potent for some to begin with, sometimes problematic for those
with sulfur problems, low glutathione and/or high food sensitivities
Benfotiamine
Chemically modified to cross cell barrier, doesn’t require a transporter (different mechanism than TTFD),
higher potency, requires lower dose than HCL
Works well for hyperglycemia, seems to be tolerated better by those with GI issues, by children with
neurodevelopmental disorders (tastes better than TTFD and can be hidden in foods more easily)
Which works best
for the patient is
highly individual.
For info on chemistry of
the different supplements
see: Elliot Overton’s video.
70. Cofactors and electrolytes
As thiamine comes on board, it will unmask other deficiencies – usually
other B vitamins and/or mineral deficiencies
Magnesium needed for thiamine activation
Potassium will be drawn into the cell more readily – increase intake
Calcium reregulation frequently requires additional Ca2+ , will see this with heart
related symptoms, and elevated ‘anxiety’ type symptoms
Cal/Mg - 2/1 supplement typically counters this. See articles on HM.
Low phosphate diets need to be improved or hypophosphatemia
Sodium may need to increased (with POTS, migraine esp.)
Mitochondria cannot process the dietary fuel into cellular fuel without the accompanying micronutrients.
Simply reducing the macronutrients, while it may reduce the ultimate processing
demand on mitochondria, thereby eliciting favorable compensatory
reactions and allowing the enzymes to “catch up,” does nothing to address
what is likely the core problem–that the enzyme machinery within the
mitochondria are starving, and because they are starving, not only are they
incapable of meeting the processing demands to maintain homeostasis, but
also they are initiating a number of compensatory reactions that induce
damage and many of the disease processes we see in modern medicine.
They found that the oxygen saturation of arterial blood (on route to body tissues) in beriberi victims was very low. The venous oxygen saturation was very high (blood returning to the lungs for oxygenation). This means that the pickup of oxygen at the lung was poor and it was transferred to the venous circulation without doing its job in the cells. It is therefore possible that long term, low grade thiamine deficiency could well be the forerunner of cancer.
They found that the oxygen saturation of arterial blood (on route to body tissues) in beriberi victims was very low. The venous oxygen saturation was very high (blood returning to the lungs for oxygenation). This means that the pickup of oxygen at the lung was poor and it was transferred to the venous circulation without doing its job in the cells. It is therefore possible that long term, low grade thiamine deficiency could well be the forerunner of cancer.
Intact and functional PDC can translocate across mitochondrial membranes from the matrix to the outer mitochondrial membrane (Hitosugi et al., 2011). Thus, it would be possible for a chaperone protein to bind PDC from the outer mitochondrial membrane and bring it to the nucleus under conditions that stimulate S phase entry and cell-cycle progression, where histone acetylation is critical.
generating a nuclear pool of acetyl-CoA from pyruvate and increasing the acetylation of core histones important for S phase entry.
Nuclear PDC provides a means for the nucleus to generate acetyl-CoA in an autonomous fashion