NROSCI-BIOSC 1070Human PhysiologyNovember 30, 2015

Gastrointestinal 3(Metabolism)

MetabolismDefinition: all the chemical reactions in all the cells of the bodyQuantification: heat production by the body★ Defined as the quantity of heat required to raise 1

gram of water by 1°C, and abbreviated by “c” (lower case)

★ Since this value is so small, the Kilocalorie (1000 calories) is used as a base. The Kilocalorie is defined by “C” (upper case)

★ 2000 Calories (typical daily intake)=enough heat to raise 2,000 Kg (2,000 L) of water by 1°C

Measurement: direct calorimetry (direct measurement of heat production)

Subject in insulated, air-filled chamberHeat from subject’s body warms airAir pumped through pipes in cool water bathRate of heat gain by water = rate of heat liberation of body (~ metabolic rate)

Indirect CalorimetryDefined by rate of oxygen utilization> 95% of energy expended in body is derived from reactions involving oxygen

Good approximation of metabolic rateAmount of energy released when 1 L of O2 reacts with… - Glucose = 5.01 Calories of energy- Starches = 5.06 Calories of energy- Fat = 4.70 Calories of energy- Protein = 4.60 Calories

- Average = 4.825 Calories/L O2

Average man who lays in bed all day uses ~1650 Calories of energyIf the man lies in bed but eats, he utilizes ~1850 Calories of energyUp to 3000 Calories per day can be utilized if an individual is involved in strenuous activity

Caloric Utilization

Basal Metabolic RateMinimal energy required to exist – processes to “just keep you alive”Highly variable depending on sex, age, body size, etc. Skeletal muscle accounts for ~20-30% of BMR (might help explain above)Most of BMR: accounted for by CNS, heart, kidney, and other organ functions

BMRDecline of BMR with age: decreased muscle mass, increased adipose tissue (lower rate of metabolism)Lower BMR in females: generally lower muscle massThyroid and growth hormones also affect BMR

93% of secreted thyroid hormone is thyroxine (T4)

T4

T3

TSH from anterior pituitary

T4

T3Deiodination of T4 in tissues

Over several days: almost all T4 is converted to T3

Thyroid Hormone(s)Are both hormones the same in their actions? – yes, but they act with different efficacyDiffer in rapidity and intensity of actionT3 is ~4 times as potent as T4T3 – lower plasma concentration, shorter half life

Anatomy of theThyroid Gland

Cuboidal epithelial cells secrete colloid into the middle of a division of the thyroid gland, which is called a follicle. The major constituent of colloid is the thyroid hormones, which can be stored for a considerable period of time. When needed, the hormones are absorbed from the center of the follicle by the cuboidal epithelial cells, and then secreted into the blood.

Normal thyroid gland

Histological section

Anatomy of the Thyroid Gland

Synthesis of Thyroid Hormone T3 and T4 are unusual

molecules, as they contain iodine. About 1 mg of iodine must be consumed per week in order for adequate quantities of T3 and T4 to be produced. To insure that iodine deficiencies are not common, table salt is typically iodized with one part sodium iodide to every 100,000 parts sodium chloride.

Question for Discussion

Why were iodine tablets

given to Japanese citizens after the

recent nuclear power plant disaster?

Transport of Thyroid Hormone

T3 and T4 must bind to a carrier protein in the blood to be transported. The carrier is made in the liver, and is typically thyroxine-binding globulin. As noted above, T4 is typically deiodinated to form T3 as it circulates.Once T3 is released from the carrier, it passes into target cells by simple diffusion and binds to specific intracellular receptors that are bound to chromatin. By binding to these receptors, T3 affects the expression of specific genes.

Half-Life of Thyroid Hormone

This is best demonstrated in the case of an individual whose thyroid gland has been removed, and is injected with a single dose of thyroxine.Essentially no effects can be discerned for 2-3 days, and maximal effects do not occur until about 10 days after injection.

After secretion of T3 and T4 it can take a long time for the effects of the hormones to

become apparent.

Effects of Thyroid HormonesGrowth and Development

✴ Thyroid hormone plays an important role in stimulating growth.

✴ Essential for proper nervous system developmentCarbohydrate Metabolism✴ Thyroid hormone stimulates almost all aspects of

carbohydrate metabolism, including rapid uptake of glucose by cells, enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption of sugar from the GI tract, and even greater insulin secretion.

✴ These effects are due to a generalized increase in the production of cellular metabolic enzymes.

Effects of Thyroid HormonesFat Metabolism

✴ Almost all aspects of fat metabolism are also enhanced by thyroid hormone, including mobilization of lipids from fat tissue and acceleration of oxidation of free fatty acids by cells.

✴ Thus, fat stores of the body are rapidly depleted when thyroid hormone secretion is high.

Vitamin Requirements✴ Because thyroid hormone increases the levels of

many enzymes in the body and thus enhances enzymatic reactions, the demands for cofactors for those reactions is increased.

✴ Thus, an otherwise normal consumption of vitamins may be insufficient in a hyperthyroid patient.

Effects of Thyroid Hormone

Because thyroid hormone increases metabolism in almost every cell of the body,excessive quantities of the hormone vastly increase BMR. In fact, BMR can double with extremely high levels of thyroid hormone.

Effects of Thyroid HormoneBody Weight✴Typically, high levels of metabolism associated with high levels of thyroid hormone result in a drop in body weight.

✴This does not always occur, however, as appetite and food intake also increase when thyroid hormone levels are raised.

Effects of Thyroid HormoneCardiovascular System Physiology

✴ Increased metabolic rate in almost every body tissue results in an increased oxygen usage and the formation of high levels of metabolic wastes.

✴ These agents serve as paracrine factors that increase blood flow to a region. Blood flow to the skin becomes especially high with high levels of thyroid hormone, as body heat increases and must be dissipated.

✴ The lowered peripheral resistance in almost every tissue demands that cardiac output must increase tremendously.

✴ Thyroid hormone affects the rate of enzymatic reactions in the myocardial muscle itself. These effects coupled with excessive work can lead to cardiac failure in the chronic hyperthyroid patient.

Effects of Thyroid HormoneRespiratory System Physiology

✴ Because of the enhanced levels of aerobic metabolism in hyperthyroid patients, oxygen demands of the body rise. This triggers an increase in both the rate and depth of respiration.

Gastrointestinal Physiology✴ Increased levels of thyroid hormone are typically

associated with increased food consumption, which obviously affects the gastrointestinal system.

✴ Furthermore, thyroid hormone directly stimulates increased gastrointestinal secretion and motility. As a result, a common complaint of hyperthyroid patients is diarrhea.

Effects of Thyroid HormoneNervous System Physiology✴ In general, neuronal excitability is increased as levels

of thyroid hormones rise.✴ This can result in a wide range of neurological and

psychiatric problems, including tremor, psychoneurotic tendencies, anxiety, and even paranoia.

✴ In addition, hyperthyroid patients have great trouble in sleeping, despite the fact that their high level of metabolic activity leaves them feeling very tired.

Effects of Thyroid Hormone

Muscle Physiology✴ Slight increases in the level of thyroid hormone

results in a small increase in muscle strength and reactivity because of the generalized acceleration of metabolism.

✴ However, very high levels of thyroid hormone can result in protein catabolism and muscle weakness.

Control of Thyroid Hormone Secretion: TSH

Effects of TSH:Increased release of T3 and T4 via proteolysis of thyroglobulinIncreased rate of iodide trappingIncreased iodination of tyrosineThyroid gland hyperplasia, increased secretion, and overall hypertrophyTSH does this by binding to receptors on basal membrane of follicular cells – cAMP second messenger

What Controls TSH Secretion?

TRH (thryotropin-releasing hormone) from the hypothalamus. Temperature plays a primary role in controlling the secretion of TRH into the portal blood system.Feedback on anterior pituitary and hypothalamus by T3 and T4

Hypothalamus

Anterior Pituitary

ThyroidGland

TRH

TSH

T3 and T4

Nuclear Receptors

T3 and T4

-

+

+

+

Temperature(low body temp)

+

-

Diseases Affecting Thyroid Hormone Secretion

Autoimmune diseases affecting the thyroid gland

Can cause both hypo- and hyperthyroidism

Cancer in thyroid gland or anterior pituitaryIodide deficiency

HyperthyroidismThyroid gland increased to two to three times normal size – hyperplasia; also greatly increased secretion of thyroid hormonePlasma TSH less than normal in nearly all patientsImmunoglobulin antibodies that bind to TSH receptors on membranes of cuboidal thyroid follicular cells; TSH agonistsCause: excess of thyroid antigens released – formation of antibodies against thyroid gland

Continual activation of cAMP system of cells

Anterior Pituitary

ThyroidGland

T3 and T4

Nuclear Receptors

T3 and T4

-

+B cells producing antibodiesThat bind to TSH receptors

+

Hyperthyroidism

Hypothalamus

-

Hyperthyroidism – note apparent hyperplasia and infolding of thyroid epithelium

Note enlarged right lobe

HyperthyroidismSymptoms easily predicted by considering what excess thyroid hormone would doAlso – exophthalamos (protrusion of the eyeballs) in the most common form of the disease (Grave’s disease)Protrusion caused by antibodies attacking extraocular musclesTreatment: surgical resection of gland or delivery of radioactive iodide

HypothyroidismCommonly, again, autoimmunity develops against the thyroid glandNow, autoimmunity destroys glandular tissueDeterioration/fibrosis of gland

Decreased secretion of thyroid hormone

Hypothalamus

Anterior Pituitary

ThyroidGland

TRH

TSH

Nuclear Receptors

T3 and T4

+

+

Temperature(low body temp)

+

B cells producing antibodiesThat destroy Thyroid

-

Hypothyroidism

Note lymphoid tissue, small follicles

Hypothyroidism

Goiter: a hallmark of some types of hypothyroidism

2 Types of Goiters in Hypothyroidism

Endemic goiter – due to lack of iodide in the diet – low production of thyroid hormone – increased TSH secretion – increased stimulation of thyroid glandIdiopathic nontoxic colloid goiter – same situation as above, but cause of low thyroid hormone production is unknown“Hypo” thus refers to gland secretions and not size

Clinical Implications (Hypothyroidism)

Symptoms easily predicted from consideration of a low level of thyroid hormoneTreatment often involves oral ingestion of thyroid hormoneIf pathology occurs early in development – cretinsim – marked by failure of body growth and mental retardation

Growth HormonePeptide released from anterior pituitaryBound in plasma by GH binding proteinStimulates protein synthesis, fat breakdown, hepatic glucose output, and bone/cartilage growth

GlucocorticoidsSteroid hormones secreted by the adrenal cortexMost predominant hormone is cortisolEffects:

Raise blood glucose levelsStimulate gluconeogenesis in liver, breakdown of skeletal muscle proteins, fat breakdownPlays an important role in protecting the body against hypoglycemia

Adrenal Cortex

glomerulosa

fasciculata

reticularis

Fasciculata: glucocorticoids

Hypothalamus

Anterior Pituitary

AdrenalCortex

CRH

ACTH Cortisol

Nuclear Receptors

Cortisol

-

+

+

+

Low plasmaglucose

+

-

Note similarities to T3-T4 secretion;Same general

pattern,Also “independent”

Stimulus for release

Other Actions of GlucocorticoidsBesides essentially combating

hypoglycemia, these steroids are involved in response to stressful situationsCortisol also has an anti-inflammatory effect (inhibits T-cell proliferation)May contribute to “flash bulb memories”

ApplicationsBefore development of nonsteroidal anti-inflammatory drugs, cortisol metabolites (i.e. cortisone) prescribed for swellingTopical creams (i.e. Cortaid) and injectable glucocorticoids (i.e. dexamethasone) are availablePrednisone is a commonly-prescribed cortisol analog

Side Effects of Glucocorticoid Therapy

Difficulty sleepingIncreased appetiteIncreased sweatingIndigestionMood changesNervousness

Addison’s DiseaseAutoimmune disease attacking the adrenal glandLoss of cortisol secretion – impossible to maintain normal blood glucose levels between mealsReduced mobilization of proteins and fats from tissues – decrease in several metabolic functionsHigh ACTH levels – darkening of skin (stimulation of melanocytes and deposition of melanin)

Question for Discussion

Which Presidential candidate benefited from Addison’s disease?

Cushing’s SyndromeProduced by an ACTH secreting tumorResults in elevated blood glucose as well as muscle weakness

Question for Discussion

Why does prolonged glucocorticoid therapy lead to water retention?