Week 7: Endocrinology - Diabetes, Thyroid Disorders Flashcards
Anatomy of thyroid gland (superficial)
Thyroid gland has a pyramidal lobe, right lobe, left lobe and isthmus
Sits just below cricoid cartilage
Anatomy of thyroid gland (cellular)
Made up of thyroid cells
- Follicular cells are filled with stored thyroglobulin which is a precursor of thyroid hormones T3 and T4
- Parafollicular cells or C cells produce calcitonin
How is T3 and T4 produced?
- Both are made from amino acid Tyrosine combined with iodine inside the thyroid follicular cells
- T3 (triiodothyronine) contains 3 atoms of iodine and is more potent than T4; thus has a much higher binding affinity on target receptors; secreted in smaller quantities (Most T3 is made by cleavage of T4)
- T4 (tetraiodothyronine) contains 4 atoms of iodine and is less potent than T3 as well as being secreted in larger quantities
Physiological stimulation of the thyroid
Hypothalamus released thyroid releasing hormone (TRH) which stimulates anterior pituitary to release thyroid stimulating hormone (TSH) which acts on the thyroid to produce hormones (T3 and T4)
T3 has a negative feedback loop with the anterior pituitary
T4 has a negative feedback loop with the hypothalamus
Negative feedback loops control the release of TRH and TSH in response to circulating levels of T3 and T4
Physiological role of thyroid hormones
- Most T4 is converted to T3 by enzymes close to target cell
- Both T3 and T4 increase basal metabolic rate resulting in
> Increase temp
> Increase HR
> Breakdown of muscle and liver energy stores causing increased attention/faster reflexes
> In children it promotes growth and maturation of the brain
Pathology of hypothyroidism
- Primary hypothyroidism causes
- Secondary hypothyroidism causes
Primary hypothyroidism
- Autoimmune thyroiditis (Hashimoto’s disease) - most common cause in adults
- Latrogenic - exposure to excessive radiation or surgical removal of part/all thyroid gland
- Iodine deficiency
- Enzymatic defects in thyroid (genetic)
- Cretinism
- Postpartum thyroiditis
Secondary hypothyroidism
- Pituitary disease (lack of TSH)
- Hypothalamic hypothyroidism (lack of TRH)
Hypothyroidism - Hashimoto’s disease
- Develop antibodies against thyroid gland
- Leads to destruction and low levels of T3 and T4
- Caused by genetic factors, secondary to radiation
- Risk increased if another autoimmune disease is present
Hypothyroidism - Iodine deficiency
- If diet lacks iodine for too long, the thyroid cannot make adequate thyroid hormones
- Levels of T3 are low leading to no negative feedback to anterior pituitary
- Anterior pituitary continues to release TSH stimulating the growth of thyroid tissue
- Leads to development of abnormal growth of thyroid = Goiter
Symptoms/presentation of hypothyroidism
- Slow metabolism
- Dry, course hair
- Loss of eyebrow hair
- Puffy face
- Goiter
- Slow heartbeat
- Weight gain
- Arthritis
- Cold intolerance
- Depression
- Dry skin
- Fatigue
- Forgetfulness
- Heavy menstrual period
- Infertility
- Muscle aches
Hypothyroidism - Diagnosis
- Primary hypothyroidism
- Secondary hypothyroidism
Primary hypothyroidism
- Free TSH is elevated
- Low free and/or total T3/T4
- If it is autoimmune - antibodies present
Secondary hypothyroidism
- Free TSH is low
- Low free and/or total T3/T4
Hypothyroidism - Treatment
Pharmacological treatment based on replacing the thyroid hormones to restore normal concentrations
- Synthetic T4 is preferred to synthetic T3 as T3 is less shelf stable and replacing T4 creates a pool of T4 in body that can be converted to T3 by body when required
> e.g. L-thyroxine or levothyroxine
Hypothyroidism - treatment due to iodine deficiency
- Supplement iodine in diet
- Restore T4/T3 levels with levothyroixine
- Long standing goiters are unlikely to shrink with treatment therefore must be removed with surgery
Hypothyroidism - Liothyronine (T3)
- Contraindications and cautions
Elderly
- Require slower dosage adjustment and higher risk of CV ADR
Children
- Not preferred as developing brain prefers T4
Pregnancy
- Safe but rarely needed
- Thyroxine preferred
Caution
- Diabetes may need to reduce diabetic medication when starting
- CVD may worsen arrhythmia or ischemia
Hypothyroidism - Thyroxine (T4)
- Contraindications and cautions
Elderly
- Require slower dosage adjustment
- Higher risk of CV ADR
Children
- Preferred over T3
Pregnancy and breastfeeding
- Safe and dose usually increased
Caution
- Diabetes may need to reduce diabetic medications
- CVD may worsen arrhythmia or ischemia
Hyperthyroidism pathology causes
Grave’s disease
- Most common cause
- Genetic
TSH-secreting pituitary tumour
- Stimulates thyroid to keep producing T3/4 regardless of circulation levels
Multinoduar goiter (Plummer disease) - Hyperplasia of thyroid tissue which leads to excess production of thyroid hormones
Thyroiditis
- Secondary to viral syndrome - genetic predisposition
- Can be painful subacute/painless sporadic or painless postpartum
Drug induced - Amiodarone > Type 1 causes excessive iodine > Type 2 causes destructive thyroiditis - Exogenous thyroid hormone (Over replacement)
Toxic adenoma
- Genetic mutation of TSH receptor gene or GPCR which activates the receptor, turning it on
Ectopic thyroid tissue (only women)
- Struma ovarii - growth of ovary that contains follicular cells which produce excess thyroid hormones
Symptoms/presentation of hyperthyroidism
- Hair loss
- Bulging eyes
- Goiter
- Sweating (heat intolerance)
- Rapid heartbeat
- Weight loss
- Frequent bowel movements
- Difficulty sleeping
- Infertility
- Irritability
- Muscle weakness
- Nervousness
- Scant menstrual period
Hyperthyroidism - Symptoms/presentation
- Grave’s disease distinct set of symptoms
In addition to normal hyperthyroidism symptoms they have the ‘classic triad’ of diagnostic symptoms
- Marked exophthalmos (eyelids retract, periorbital edema)
- Thyroid dermopathy (seen on shins, swelling and lumpiness under skin due to accumulation of mucopolysaccarhides and hyaluronic acid)
- Thyroid acropachy (clubbing of fingers/toes due to periostitis of metacarpals)
Hyperthyroidism - Diagnosis
- Hyperthyroidism
- Sub-clinical hyperthyroidism
- Hyperthyroidism secondary to pituitary tumor
Hyperthyroidism
- Low free TSH
- High T4 levels
Sub-clinical hyperthyroidism
- Low free TSH
- Normal T4 levels
Hyperthyroidism secondary to pituitary tumor
- High free TSH
- High T4 levels
Hyperthyroidism - Treatment (3 main options)
- Pharmacotherapy
- Carbimazole
- Propylthiouracil (PTU)
- Beta blockers to control symptoms - Surgery
- Radioactive iodine
Hyperthyroidism treatment - Pharmacotherapy (Carbomazole and PTU)
- Both are Thioureas
- Both inhibit biosynthesis of thyroid hormones
> Divert iodine away from iodination sites on thyroglobulin
> Inhibit MIT and DIT from coupling and forming T3/T4 - Carbimazole is a prodrug and converted to active MMI
Hyperthyroidism - PTU
- Contraindications and cautions
Children
- Avoid due to higher risk of hepatoxicity
Pregnancy
- Preferred in 1st trimester
- Use lowest effective dose and monitor
- 2nd and 3rd trimester prefer Carbimazole
Hepatic
- Caution; hepatoxicity higher risk with PTU; monitor liver function
Watch for fever, mouth ulcers, sore throat, rash, abdominal pain, jaundice - agranulocytosis
Hyperthyroidism - Carbimazole
- Contraindications and cautions
Children
- Not recommended; avoid due to increased risk of hepatoxicity
Pregnancy
- Preferred in 2nd and 3rd trimester
- Monitor every 6 weeks
- 1st trimester prefers use of PTU
Hepatic
- Monitor liver function regularly
Watch for fever, mouth ulcers, sore throat, abdominal pain and jaundice
Hyperthyroidism - treatment
- Radioactive iodine (RAI)
> Short term effect
> Long term effect
Short term effect
- Incorporated into thyroid hormones and thyroglobulin
- Radioactive isotopes means they are biologically inactive
Long term effect
- Follicles with RAI and surrounding start to suffer necrosis
- Damaged tissue can no longer produce/secrete thyroid hormones
Glucose physiology
- Role of glucose
Glucose
- Source of fuel for cellular energy
- Consumed in diet as polysaccharides (dense carbohydrates) and digested to monosaccharides (glucose)
- Glucose from diet is stored via insulin and glucose release from storage occurs via glucagon
- Glucose is excreted via renal mechanisms
Production of insulin and glucagon
Insulin is produced by the pancreas beta cells
Glucagon is produced by pancreas alpha cells
Glucose homeostasis: Insulin secretion
- Glucose dependent
- Insulin concentrations
Blood glucose levels become too high (hyperglycaemia) due to
- Food consumption
- Glycogen breakdown
Causes pancreatic beta cells to release insulin causing glycogenesis thus glucose is removed from the blood and stored as glycogen in skeletal muscle, liver and adipose tissue
- The release of insulin is glucose dependent with increase food consumption causing rise in plasma glucose as well as release of incretins (GLP-1 and GIP) which both act to stimulate the release of insulin
- Incretins are naturally inhibited/broken down by enzyme in body called dipeptidyl peptidase-4
Insulin concentration (microunits/mL) is directly related to food intake (Prandial insulin secretion), however as basal insulin secretion is maintained between meals.
Glucose homeostasis: Glucagon secretion
Blood glucose levels become too low (hypoglycaemia) due to
- Nil food consumption
- Glycogen production
Causes pancreatic alpha cells to release glucagon enabling glycogenolysis and glucose release into blood
Pathophysiology of T1DM
- Condition of insulin deficiency
- Associated with autoimmune destruction of pancreatic beta cells (no insulin production)
- Results in hyperglycemia
Pathophysiology of T2DM
- Condition of insulin insufficiency
- Associated with progressive beta cell dysfunction and insulin resistance (amount and effectiveness of insulin decreases over time)
- Results in hyperglycemia
Pharmacotherapy goals of therapy for diabetes
- Manage hyperglycemia
- Avoid acute complications of hyperglycemia
- Reduce chronic complications of hyperglycemia
- Avoid hypoglycemia
Pharmacotherapy management of T1DM
- Characteristics of insulin
- Formulations of insulin
- Therapeutic management
- Adverse effects
- Practice points
- Insulin is a huge protein
- Exogenous insulin mimics the effects of endogenous insulin
- Not orally bio available (must be injected)
Insulin comes in a variety of different formulations
- Ultra short acting insulin (e.g. insulin aspart - bolus regime)
- Long acting insulin (e.g. insulin glargine - basal regime)
Therapeutic management aims to replace insulin
- Most common approach is basal-bolus regime which combines ultra short acting and long acting insulin to meet individual daily insulin requirements
Adverse effects
- Hypoglycemia
Practice points
- Temp sensitive storage
- Delivery options subcut or insulin pump
- Monitor levels of blood glucose, HbA1c and ketones
Pharmacotherapy management of T2DM
- Primary choices
- Secondary choices
Very individualized (see table in AMH/Lecture)
Primary choices
- Biguanides
- Sulfonylureas
- DDP-4 inhibitor
- SGLT2 inhibitor
- GLP-1 analogues
Secondary choices
- Acarbose
- Pioglitazone
- Insulin
T2DM - Biguanides
- Example
- MOA
- Adverse effects
- Practice points
Example (only one in this class)
- Metformin
MOA
- Reduce intestinal absorption of carbohydrates
- Increase insulin sensitivity
- Increase uptake of glucose into peripheral tissue
- Reduce hepatic glucose production (glycogenolysis)
Adverse effects
- N/V/D
Practice points
- First line agent for T2DM management
- Cannot cause hypoglycemia on its own
- Can come in immediate release or extended release forms
- Lactic acidosis
T2DM - Sulfonylureas
- Example
- MOA
- Adverse effects
- Practice points
Examples
- Gliclazide
- Glipizide
- Glibenclamide
MOA
- Increase pancreatic insulin secretion (independent of food)
Adverse effects
- Hypoglycemia
- Weight gain
Practice points
- Will cause hypoglycemia on their own
- Food MUST be taken at same time
T2DM - Dipeptidyl peptidase-4 inhibitor
- Example
- MOA
- Adverse effects
- Practice points
Example
- Linagliptin
- Sitagliptin
- Saxagliptin
MOA
- Inhibit DDP4 to increase concentration of incretins which increases glucose dependent insulin secretion
Adverse effects
- Well tolerated (maybe musculoskeletal pain)
Practice points
- Very unlikely to cause hypoglycemia on own
- Relatively new drug
T2DM - Sodium-glucose co-transporter 2 (SGLT2) inhibitors
- Example
- MOA
- Adverse effects
- Practice points
Example
- Empagliflozin
- Dapagliflozin
- Ertugliflozin
MOA
- Inhibit renal SGLT2 which reduces glucose resportion which increases glucose excretion via urine
Adverse effects
- Polyuria
- Genital infection (UTI)
- Euglycemic ketoacidosis
Practice points
- Very unlikely to cause hypoglycemia on own
- With glucose follows sodium - mild blood pressure reduction
- With sodium follows water - mindful of dehydration
- Do not administer in renal impairment
- Brand new drug
T2DM - Glucagon-like peptide 1 (GLP-1) analogues
- Examples
- MOA
- Adverse effects
- Practice points
Examples
- Dulaglutide
- Liraglutide
- Exenatide
MOA
- Mimics effects of GLP-1 to increase glucose dependent insulin secretion
Adverse effects
- Gastrointestinal ADR
- Injection site reaction
Practice points
- Very unlikely to cause hypoglycemia on own
- Only available through s/c injection
T2DM - Acarbose
- Class
- MOA
- Practice point
Class
- Alpha-glucosidase inhibirot
MOA
- Reduce intestinal carbohydrate absorption (stays in intestine rather than ore to blood)
Practice point
- Very troublesome GI ADR
T2DM - Pioglitazone
- Class
- MOA
- Practice point
Class
- Thiazolidinedione
MOA
- Increase glucose uptake into peripheral tissue
Practice point
- Increase risk of bladder CA and HF
T2DM - Insulin
- Regime used
- Practice points
Regime
- Initially basal only (not as aggressive as T1DM)
Practice point
- Often reserved until glycaemic targets are not being achieved with oral therapies, hypoglycemia
