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CSB601 > Week 7: Endocrinology - Diabetes, Thyroid Disorders > Flashcards

Week 7: Endocrinology - Diabetes, Thyroid Disorders Flashcards

1
Q

Anatomy of thyroid gland (superficial)

A

Thyroid gland has a pyramidal lobe, right lobe, left lobe and isthmus
Sits just below cricoid cartilage

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2
Q

Anatomy of thyroid gland (cellular)

A

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
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3
Q

How is T3 and T4 produced?

A
  • 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
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4
Q

Physiological stimulation of the thyroid

A

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

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5
Q

Physiological role of thyroid hormones

A
  • 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
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6
Q

Pathology of hypothyroidism

  • Primary hypothyroidism causes
  • Secondary hypothyroidism causes
A

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)
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7
Q

Hypothyroidism - Hashimoto’s disease

A
  • 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
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8
Q

Hypothyroidism - Iodine deficiency

A
  • 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
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9
Q

Symptoms/presentation of hypothyroidism

A
  • 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
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10
Q

Hypothyroidism - Diagnosis

  • Primary hypothyroidism
  • Secondary hypothyroidism
A

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
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11
Q

Hypothyroidism - Treatment

A

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

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12
Q

Hypothyroidism - treatment due to iodine deficiency

A
  • 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
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13
Q

Hypothyroidism - Liothyronine (T3)

- Contraindications and cautions

A

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
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14
Q

Hypothyroidism - Thyroxine (T4)

- Contraindications and cautions

A

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
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15
Q

Hyperthyroidism pathology causes

A

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

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16
Q

Symptoms/presentation of hyperthyroidism

A
  • 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
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17
Q

Hyperthyroidism - Symptoms/presentation

- Grave’s disease distinct set of symptoms

A

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)
18
Q

Hyperthyroidism - Diagnosis

  • Hyperthyroidism
  • Sub-clinical hyperthyroidism
  • Hyperthyroidism secondary to pituitary tumor
A

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
19
Q

Hyperthyroidism - Treatment (3 main options)

A
  1. Pharmacotherapy
    - Carbimazole
    - Propylthiouracil (PTU)
    - Beta blockers to control symptoms
  2. Surgery
  3. Radioactive iodine
20
Q

Hyperthyroidism treatment - Pharmacotherapy (Carbomazole and PTU)

A
  • 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
21
Q

Hyperthyroidism - PTU

- Contraindications and cautions

A

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

22
Q

Hyperthyroidism - Carbimazole

- Contraindications and cautions

A

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

23
Q

Hyperthyroidism - treatment
- Radioactive iodine (RAI)
> Short term effect
> Long term effect

A

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
24
Q

Glucose physiology

- Role of glucose

A

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
25
Q

Production of insulin and glucagon

A

Insulin is produced by the pancreas beta cells

Glucagon is produced by pancreas alpha cells

26
Q

Glucose homeostasis: Insulin secretion

  • Glucose dependent
  • Insulin concentrations
A

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.

27
Q

Glucose homeostasis: Glucagon secretion

A

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

28
Q

Pathophysiology of T1DM

A
  • Condition of insulin deficiency
  • Associated with autoimmune destruction of pancreatic beta cells (no insulin production)
  • Results in hyperglycemia
29
Q

Pathophysiology of T2DM

A
  • Condition of insulin insufficiency
  • Associated with progressive beta cell dysfunction and insulin resistance (amount and effectiveness of insulin decreases over time)
  • Results in hyperglycemia
30
Q

Pharmacotherapy goals of therapy for diabetes

A
  • Manage hyperglycemia
  • Avoid acute complications of hyperglycemia
  • Reduce chronic complications of hyperglycemia
  • Avoid hypoglycemia
31
Q

Pharmacotherapy management of T1DM

  • Characteristics of insulin
  • Formulations of insulin
  • Therapeutic management
  • Adverse effects
  • Practice points
A
  • 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
32
Q

Pharmacotherapy management of T2DM

  • Primary choices
  • Secondary choices
A

Very individualized (see table in AMH/Lecture)

Primary choices

  • Biguanides
  • Sulfonylureas
  • DDP-4 inhibitor
  • SGLT2 inhibitor
  • GLP-1 analogues

Secondary choices

  • Acarbose
  • Pioglitazone
  • Insulin
33
Q

T2DM - Biguanides

  • Example
  • MOA
  • Adverse effects
  • Practice points
A

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
34
Q

T2DM - Sulfonylureas

  • Example
  • MOA
  • Adverse effects
  • Practice points
A

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
35
Q

T2DM - Dipeptidyl peptidase-4 inhibitor

  • Example
  • MOA
  • Adverse effects
  • Practice points
A

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
36
Q

T2DM - Sodium-glucose co-transporter 2 (SGLT2) inhibitors

  • Example
  • MOA
  • Adverse effects
  • Practice points
A

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
37
Q

T2DM - Glucagon-like peptide 1 (GLP-1) analogues

  • Examples
  • MOA
  • Adverse effects
  • Practice points
A

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
38
Q

T2DM - Acarbose

  • Class
  • MOA
  • Practice point
A

Class
- Alpha-glucosidase inhibirot

MOA
- Reduce intestinal carbohydrate absorption (stays in intestine rather than ore to blood)

Practice point
- Very troublesome GI ADR

39
Q

T2DM - Pioglitazone

  • Class
  • MOA
  • Practice point
A

Class
- Thiazolidinedione

MOA
- Increase glucose uptake into peripheral tissue

Practice point
- Increase risk of bladder CA and HF

40
Q

T2DM - Insulin

  • Regime used
  • Practice points
A

Regime
- Initially basal only (not as aggressive as T1DM)

Practice point
- Often reserved until glycaemic targets are not being achieved with oral therapies, hypoglycemia

CSB601 (12 decks)

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