Week 6 Flashcards
Function of thyroid hormones
Control of metabolism: energy generation and use
Regulation of growth
Multiple roles in development
Control of TH secretion
Hypothalamus secretes TRH to pituitary which stimulates release of TSH which then stimulates the thyroid to release T4 (mainly) and T3 to target tissue
Negative feedback mechanism
Thyroid hormone synthesis
Produced by follicular thyroid cells
Synthesised from the thyroglobulin precursors
Iodine is absorbed from bloodstream and concentrated in follicles
Thyroperoxidase binds iodine to tyrosine residues in thyroglobulin molecules to form MIT and DIT
MIT & DIT =T3
DIT & DIT= T4
What is T3
Triiodothyronine
What is T4
Thyroxine
Prohormone, inactive form
Thyroid hormone synthesis 2
TSH binds to TSHR on the basolateral membrane of one of the follicular cells
I- uptake by Na/I symporter NIS
Iodination of thyroglobulin tyrosyl residues by thyroperoxidase TPO
Coupling of iodotyrosyl residues by TPO
Export of mature thyroglobulin to colloid where its stored
Thyroid gland anatomy
Located in neck
Brownish-red
25-30g
Thin fibrous capsule of connective tissue
Right and left lobes united by a narrow isthmus
T3
biologically active hormone
Produced by mono-deiodination of T4 which is most abundant
Deiodinase (D1, D2, D3) enzymes present in peripheral tissues
Tests of thyroid function
Serum TSH
Serum free T4
Serum free T3
Hyperthyroidism
Produce more thyroid hormones
Negative feedback
Decreased serum TSH
Increased serum free T4 and T3
Hypothyroidism
Doesn’t produce enough thyroid hormones
Increased serum TSH
Decreased serum free T4 and T3
What is a goitre
Enlargement/ swelling of the thyroid gland
Aetiology of hyperthyroidism
Graves’ hyperthyroidism
Toxic nodular goitre (single or multinodular)
Thyroiditis (silent, subacute) inflammation
Exogenous iodine
Factitious (taking excess thyroid hormone)
TSH secreting pituitary adenoma
Neonatal hyperthyroidism
Symptoms and signs of hyperthyroidism
Cardiovascular: tachycardia, atrial fibrillation, shortness of breath, ankle swelling
Neurological: tremor, myopathy (muscle weakness), anxiety
Gastrointestinal: weight loss, diarrhoea, increased appetite
Eyes/skin: sore gritty eyes, double vision, staring eyes, pruritus (itching) skin
Graves’ disease
60-80% cases of hyperthyroidism
Pathogenic antibodies to TSH receptor on thyroid follicular cells (long acting thyroid stimulators)
Interplay between genetic and environmental factors (gender, stress, infection, pregnancy and drugs)
Long acting antibodies (auto-antibody to receptor), stimulate hormone synthesis, unregulated overproduction of the thyroid hormones
Extrathyroidal manifestations
Eyes: lid lag/retraction, conjunctival oedema (swelling), periorbital puffiness, proptosis (bulging), ophthalmoplegia (weakness of eye muscle)
Skin: pretibial myxoedema, acropachy (swelling of hands and clubbing of fingers)
Neonatal hyperthyroidism
TSH-R antibodies cross the placenta
Control hyperthyroidism in mother during pregnancy to help condition in child
Speeding up metabolism
Treatment of hyperthyroidism
Anti thyroid drugs to block hormone synthesis
Surgical removal of thyroid- not done as frequently
Radioiodine 131I therapy
Aetiology of hypothyroidism
Autoimmune- hashimoto thyroiditis (fibrosis and shrinkage) (TPO and Tg antibodies- genetic predisposition)
After treatment of hyperthyroidism
Subacute/silent thyroiditis
Iodine deficiency
Congenital (thyroid agenesis (absence of thyroid tissue)/enzyme defects)
Symptoms and signs of hypothyroidism
Cardiovascular: bradycardia (slow heart rate), heart failure, pericardial effusion (build up of fluid in pericardium- double layered structure around heart)
Gastrointestinal: weight gain, constipation
Skin: myxoedema, rash on legs, vitiligo
Neurological: depression, psychosis, carpal tunnel syndrome (pressure on nerve in wrist causes pain and numbness in hand)
Significance of thyroid nodules
May cause thyroid dysfunction
May cause compression
Need to exclude thyroid cancer
Features suggestive of malignancy
Age <20 or >60
Firmness of nodule on palpation
Rapid growth
Fixation to adjacent structures
Vocal cord paralysis
Regional lymphadenopathy (swelling of lymph nodes)
History of neck irradiation
Family history of thyroid cancer
Four types of thyroid cancer
Papillary carcinoma
Follicular carcinoma
Anaplastic carcinoma
Medullary carcinoma
What are the two major cell types of islets of Langerhans
Alpha cells
Beta cells
Alpha cells
Secrete glucagon as a response to low blood glucose
29-amino-acid polypeptide
Potent hyperglycaemic agent
Major target= liver
Promotes: glycogenolysis, gluconeogenesis, release of glucose to blood from liver cells
What is glycogenolysis
The breakdown of glycogen to glucose-1-phosphate and glucose
What is gluconeogenesis
Synthesis of glucose from lactic acid and non-carbohydrates inside the liver and kidneys
Stimulated by glucagon
Beta cells
Secrete insulin
51-amino-acid protein
2 amino acid chains linked by disulphide bonds
Synthesised as part of pro-insulin
Cleaved to make functional insulin
Potent hypoglycaemic agent
Enhances transport of glucose into cells
Counters metabolic activity that would enhance blood glucose levels
Insulin binding
Insulin receptor- tyrosine kinase enzyme
After glucose enters a cell, insulin binding triggers enzymatic activity that:
Catalyses oxidation of glucose for ATP production
Polymerises glucose to from glycogen
Converts glucose to fat especially in adipose tissue
When is glucagon released
Low blood sugar
When is insulin released
High blood sugar
Hypoglycaemic agents
Pancreatic B cells secrete insulin -regulated by plasma glucose levels
Lowers blood glucose
Glucose enters B cells by glucose transport molecule (GLUT 1,3), increasing production of ATP through a series of processes, this decreases activity of ATP-sensitive K+ channel , decreasing efflux of K+ leading to depolarisation (reduced Hyperpolarisation), this opens Ca2+ channels so Influx of Ca2+, leading to exocytosis of insulin
What happens to glucose transporters in people with diabetes
They become unresponsive to glucose or down regulate so can’t detect presence of glucose
Glucose must be present for insulin to be secreted
Insulin release is biphasic
1st phase- very rapid insulin secretion, after eating a meal
2nd phase- lower, reaches small intestine and is absorbed
Type 2 diabetes only have the second peak
Type 1 diabetes have no insulin peaks, excess glucose
Insulin receptor
In liver, muscle and fat
Multi-subunit proteins: a (x2)- extracellular (binding site), b(x2)- transmembrane (tyrosine kinase)
Phosphorylation of insulin receptor substrate IRS proteins
Enzyme activation + gene transcription
Increases glucose uptake (expression of GLUT-4 transporter)
Increases glycogen synthesis
Link between activity of insulin receptor and ability of glucose to enter cells
Type 1 diabetes management
Tailored to each patient
Carbohydrate counting- training
Dietary advice: balanced diet
Managing insulin doses to minimise glucose fluctuations when changing diet
Exercise: reduced cardiovascular risk, effects on insulin dosage and carb intake, regulated HbA1c measurement
Self monitoring of plasma glucose: finger prick regular times a day, continuous monitoring devices
What is the HbA1c measurement for
HbA1c- glycated haemoglobin form of haemoglobin that’s chemically linked to sugar-glucose
Measures amount of glucose attached to haemoglobin
Reflects previous 10 weeks of ambient circulating glucose
Gives a long term view on how good a persons glucose control has been
>48mmol/mol =diabetes
Types of insulin
Short acting- e.g. just before a meal, onset 30 mins, peak 2-4hrs, soluble insulin
Long acting-simulate what you would see normally (2nd peak on graph), onset 1-2hrs, peak 4-12 hrs, insulin complexes. Different time regimes per patient
Diabetes mellitus type 2
Still secrete insulin, no major loss of B cells
Increased basal insulin levels in blood
Loss of phase 1 of insulin secretion
Insulin resistance: dysfunction of IR signalling cascade proteins, associated with inflammation in adipose tissue
Type 2 management
Complex: genetics, socioeconomic factors, demographic factors
Primary management: diet, exercise, lifestyle modification, intermittent fasting, very low calorie diets (VLCD)- not many compliant
If doesn’t work: drugs ( ACE inhibitors, statins etc), 1/3 will eventually need insulin,
Affect of oral agents: biguanides e.g. metformin
Decreases gluconeogensis, increases fatty acid oxidation, via activation of AMP-activated protein kinase, decreases carbohydrate absorption in intestine, increases glucose uptake by skeletal muscle
Side effects: no hypoglycaemia, no increased appetite, lactic acidosis, gastrointestinal disturbances (has effect on flora in large intestine), slow release better
It’s first choice drug
Sulfonylureas
Beta cells- bind part of Katp channel
Binding causes channel to close
Depolarisation of beta cell
Ca2+ entry and increased insulin secretion
Increased tissue sensitivity to insulin
Side effects: hypoglycaemia, diuretic actions
What is a thyroid storm
Rare, an undiagnosed or poorly controlled overactive thyroid can lead to life-threatening condition- thyroid storm
Sudden flare up of symptoms such as very high body temperature, rapid heartbeat, shortness of breath
Triggered by an infection, pregnancy, not taking medicine correctly
What is the transporter responsible for the transport of iodine into thyrocytes
Na+/I- symporter
What is Hashimoto’s thyroiditis
Caused by the immune system attacking the thyroid gland which damages it and makes it swell
Can cause thyroid to not make enough thyroid hormone as thyroid is destroyed over time
Symptoms may include: goiter, tiredness, weight gain, muscle weakness, dry skin. Symptoms of hypothyroidism
Medication for hypothyroidism
Levothyroxine taken to replace the missing thyroxine
Medication used for hyperthyroidism
Thionamides commonly used, they stop thyroid producing excess hormones
Main types used are carbimazole and propylthiouracil
What is the most relevant blood test in assessing the dose of thyroxine replacement in primary hypothyroidism
Serum thyroid stimulating hormone (TSH)
Anti thyroid drugs
Carbimazole
Propylthiouracil
Treatment of hypothyroidism
Levothyroxine
