Old Endocrinology Flashcards
What is endocrinology?
The study of hormones, receptors and the intracellular signalling pathways and their associated diseases
Give the differences between water and fat soluble hormones:
Transport
Cell interaction
Half life
Clearance
Transport: Water - unbound Fat - Protein bound
Cell interaction: Water - Bind to surface receptor Fat - diffuse into cell
Half life: Water - short Fat - long
Clearance: Water - Fast Fat - Long
What classes of hormones are water soluble hormones?
Peptide hormones
Monoamines
What classes of hormones are fat soluble hormones?
Thyroid hormones
Steroid Hormones
Where are water soluble hormones stored?
In vesicles
Where are fat soluble hormones stored?
Typically not stored
They are synthesised on demand
Define Endocrine secretion?
Secretions go directly into the bloodstream/lymph to act at distant sites
Define exocrine secretions?
Glandular secretions poured into a duct to the site of action
Typically will act locally
Define paracrine secretions?
Cellular secretions/signals that act on adjacent cells
Define autocrine secretions?
Cellular secretions/signals that feedback on the same cell that secreted the hormone.
What is a negative feedback arch?
- Initial stimulus causes response
- Response feedback to stimulus to reduce
- Response loop shuts off
What is a positive feedback arch?
- Initial stimulus causes response
- Response causes stimulus to increase
- Response continues to increase
- Outside factor required to shut off feedback cycle
Give some basic details about peptide hormones?
- Hydrophilic and water soluble
- Usually stored in secretory granules; released in bursts or as part of a rhythmic cycle
Give an example of a peptide hormone?
Insulin
Explain how insulin exerts its effect at the receptor?
The binding of insulin to it’s receptor causes phosphorylation of the intracellular tyrosine residues associated with the receptor. This offsets the tyrosine kinase signal transduction pathway inside the cell, leading to decreased plasma glucose level.
How does insulin act to reduce blood glucose?
- Translocation of Glut-4 transporter to the plasma membrane and influx of glucose
- Glycogen synthesis (liver)
- Glycolysis
- Fatty acid synthesis (live and adipose tissue)
What are the classes of amine hormones?
Tryptophan derived amines
Tyrosine Derived amines
Give an example of a Tryptophan derived amine hormone?
Melatonin
Give an example of a Tyrosine Derived amine hormone?
Catecholamines - Dopamine, noradrenaline, adrenaline
Thyroid Hormones - T3 and T4
Where are the catecholamines secreted from?
Adrenaline and noradrenaline from the adrenal medulla
Dopamine from the hypothalamus
How does the effect of adrenaline and noradrenaline differ?
Both play a role in the body’s sympathetic nervous system;
- Adrenaline has slightly more of an effect on the heart
- Noradrenaline has slightly more of an effect on blood vessels
Are iodothyronines hydrophobic or Hydrophilic?
Hydrophobic
What are the iodothyronines?
Triiodothyronine (T3)
Thyroxine (T4)
Where are T3 and T4 produced?
T4 produced by the thyroid gland - more abundant
T3 is produced by the conversion of T4 to T3 in the periphery - more active
Explain the synthesis of T3 and T4?
- Thyroglobulin (T4 precursor) is synthesised in cells of thyroid gland and discharged into follicle lumen
- Iodide is actively transported inside the follicular cell
- Iodide is oxidised to iodine.
- Iodine is attached to tyrosine in colloid, forming Diiodotyrosine (DIT) and Monoiodotyrosine (MIT).
- DIT and MIT join together to form T3 and T4;
- MIT + DIT = T3
- DIT + DIT = T4 - T3 and T4 are stored in follicular cell
- lysosomal enzymes cleave T4 and T3 from thyroglobulin and hormones diffuse into bloodstream
What enzyme converts T4 into T3 in the peripheral circulation?
Iodothyronine deiodinase
What are the 2 classes of steroid hormones?
Corticosteroids (Adrenocorticoids)
sex steroids (Gonadal)
Why are the steroid hormones split into 2 classes?
It is based upon the receptor that they bind to!
What class do glucocorticoid and mineralocorticoid fit into?
Corticosteroids
What class do androgens, oestrogens and progestogens fit into?
Sex steroids
What are steroid hormones synthesised from?
Cholesterol
What is the pathway of synthesis of the steroid hormones?
- Cholesterol is converted to Pregnenolone
- Pregnenolone converted to Progesterone
- In adrenal glands, progesterone changed to Cortisol
- In ovaries or testes, progesterone converted to Androstenedione which is converted to Testosterone
- Testosterone converted to Estradiol in the ovaries
Are steroid hormones water or lipid soluble?
Lipid soluble
How are steroid hormones transported around the body?
Vitamin D binding protein
How do steroid hormones bind to receptors and exert their effects?
- 1️⃣ Diffuses through plasma membrane and binds to receptor (lipid soluble)
- 2️⃣ Binds to receptor in cytoplasm producing receptor-hormone complex
- 3️⃣ Receptor-hormone complex moves into nucleus
- 4️⃣ Binding inside the nucleus initiates transcription of gene to mRNA
- 5️⃣ mRNA directs protein synthesis.
How is steroid hormone secretion controlled?
Basal secretion that can be continuous or pulsatile
What are some factors that stimulate the release of steroid hormones?
- Humoral stimulus; released as result of change in environment (e.g. low calcium causes release of PTH)
- Neural stimulus; sympathetic nervous system stimulates adrenal gland to release adrenaline
- Hormone stimulus; hypothalamus releases hormone which stimulates pituitary gland which releases further hormones to stimulate other glands.
How are hormone secretions controlled?
Basal secretion - Continuous or Pulsatile
Superadded Rhythms - Day night cycle
Release inhibiting factors
Release releasing factors
How are hormone actions controlled?
Hormone metabolism
Hormone receptor induction
Hormone receptor down regulation
Synergism
Antagonism
What are the major endocrine organs?
Pituitary gland
Thyroid Gland
Parathyroid Gland
Adrenal Gland
Pancreas
Gonads - Ovary / Testes
What are the different sections of the Adrenal glands and what do they secrete?
Adrenal Cortex:
Zona Glomerulosa - Mineralocorticoids - Aldosterone
Zona Fasciculata - Glucocorticoids - Cortisol/cortisone
Zona Reticularis - Androgens - Oestrogen / Testosterone
Adrenal Medulla:
Catecholamines - Adrenaline, Noradrenaline
Define Appetite?
The desire to eat food
Define Satiety?
The feeling of fullness
Disappearance of appetite after a meal
Define Anorexia?
Lack of Appetite
Define Hunger?
The need to eat
How do you work out BMI?
Weight (kg) / Height (m^2)
What are the categories of BMI?
<18.5 underweight
18.5-24.9 normal
25-29.9 overweight
30-39.9 obese
> 40 morbidly obese
What are the 2 drives of the satiety cascade?
Internal Physiological drive - a feeling that prompts the thought of food and motivates food consumption
External Psychological drive - Explains why we eat in the absence of hunger (eg. at a buffet)
What parts of the brain have key roles in appetite regulation?
The Hypothalamus
Lateral Hypothalamus - Hunger centre
Ventromedial Hypothalamic Nucleus - Satiety centre
Where is the hunger centre in the brain?
Lateral Hypothalamus
Where is the satiety centre in the brain?
Ventromedial Hypothalamic Nucleus
What factors will increase your appetite?
NPY - Neuropeptide Y
MCH - Melanin concentrating Hormone
AgRP - Agouti related peptide
Orexin
Endocannabinoid
What factors will decrease your appetite?
- α-MSH: alpha melanocyte stimulating hormone from POMC
- CART: cocaine and amphetamine regulated transcript
- GLP-1: glucagon like peptide 1
- Serotonin
- Peptide YY (PYY)
- CCK
What appetite factors are released by the brain?
NPY
POMC - α-MSH
What is POMC?
Proopiomelanocortins
Precursor polypeptides that are cleaved into 3 main hormones
ATCH
MSH
Endorphins
What is the role of α-MSH
Induces satiety by binding to the MCR3 and MCR4 receptors in the brain
What is the role of Leptin?
Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetie factors (POMC; CART) and inhibits the release of pro-apeptite factors (NPY; AgRP).
Where is leptin expressed?
In adipose tissue
How can decreased leptin levels lead to obesity?
Through leptin gene deficiency
Through Leptin receptor mutation
What is the role of Leptin?
Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetite factors (POMC; CART) and inhibits the release of pro-appetite factors (NPY; AgRP).
What appetite factors are released by the gut?
Ghrelin
PYY
GLP-1
CCK
What is the role of Ghrelin?
Stimulates GH release
Stimulates appetite (orexigenic)
Where is ghrelin secreted from?
The stomach
What is PYY?
Peptide YY
Structurally similar to NPY - binds to NPY receptors
What is the role of PYY?
Inhibits gastric motility
Reduces appetite
Where is PYY secreted from?
Neuroendocrine cells in the ileum, pancreas, colon in response to food
What is the role of CCK in appetite?
Cholecystokinin
Delays gastric emptying time
gallbladder contraction
Insulin release
Acts on the vagus nerve to stimulate satiety
What appetite factors are released by adipose tissue?
Leptin
What appetite factors are released by the pancreas?
Insulin
How does insulin act in appetite regulation?
In a similar way to Leptin
It inhibits NPY/AgRP release
It stimulates POMC/CART release
Acts to decrease appetite
Give an overview of Appetite control
Leptin and Insulin:
Stimulate POMC/CART neurones - increase CART and alpha-MSH levels
Inhibit NPY/AgRP neurones - Decrease NYP/AgRP
Overall will increase satiety and decrease appetite.
Ghrelin:
Stimulates NPY/AgRP neurone - their levels increase
Increase appetite
PYY:
Binds to an inhibitory receptor on NPY/AgRP neurones - decrease their levels
Decrease appetite
Give a summary for peripheral appetite regulation
Olfactory, visual gustatory stimuli stimulate appetite
Oral receptors monitor food intake and begin to suppress feeding
Food in stomach stimulates Ghrelin initially to increase appetite
Stretch receptors in stomach begin to release satiety factors
Release of CCK, GLP, Insulin and PYY all increase satiety to stop feeding
In the fasting state where does glucose come from?
Liver - breakdown of glycogen
-gluconeogenesis
In the fasting state, what are the levels of insulin?
Low - there is less glucose in the blood so insulin is low because it does not need to stimulate glucose storage
What do muscles use for fuel in the fasting state?
Free fatty acids
In the post prandial state what does the increase of glucose from a meal lead to?
Inhibition of glucagon secretion
Stimulation of insulin
Glucose is taken up by the liver (40%) and peripheral tissues (60%)
What does a high level of insulin and glucose promote?
Inhibition of lipolysis
reduced levels of free fatty acids
What is the site of insulin and glucagon secretion?
Islets of langerhans of the pancrease
Alpha cells - glucagon
Beta cells - Insulin
What is the paracrine function of insulin?
What is the effect of DM on this?
The release of insulin from beta cells acts on the alpha cells of the pancreas to inhibit further glucagon release.
In diabetes the insulin is lost and therefore you lose the alpha cell inhibition mechanism leading to excess glucagon and increased levels of glucose and free fatty acids in the blood.
Explain the process of insulin secretion?
Glucose is taken into the pancreas via GLUT2 transporters
Once in the pancreas glucose is metabolised by glucokinase which forms ATP
ATP then acts on the SUR1 potassium channels to close the K+ channels
This leads to depolarisation of the cell membrane and thus the opening of Ca channels
Calcium influx stimulates exocytosis of insulin secretory granules
Insulin is released
What is the action of insulin on the fat and muscle cells?
Stimulates the metabolism of GLUT4 channels to the cell membrane
Allows for the entry of glucose into the cell
What is the action of insulin?
Suppresses hepatic glucose output - Decrease glycogenolysis, Decrease gluconeogenesis.
Increase glucose uptake into insulin sensitive tissues - fat and muscle.
Suppresses lipolysis and muscle breakdown
What is the action of glucagon?
Increases hepatic glucose output - increase glycogenolysis, increased gluconeogenesis
Reduces peripheral glucose uptake
stimulates peripheral release of gluconeogenic precursors - glycerol and amino acids, lipolysis, muscle glycogenolysis and breakdown.
What is diabetes mellitus (DM)?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
How does DM cause morbidity and mortality?
Acute hyperglycaemia if untreated leads to diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic states (HHS)
Chronic hyperglycaemia leads to tissue complications (macro and microvascular)
Side effects of treatment - hypoglycaemia
What are the major consequences of Diabetes?
Diabetic retinopathy
Diabetic neuropathy
Stroke
Cardiovascular disease
Diabetic Nephropathy
What are the different types of diabetes Mellitus?
Type 1 DM - Insulin dependent
Type 2 DM - Insulin Independent - Maybe be gestational or medication induced)
MODY
Pancreatic diabetes
Endocrine diabetes - Acromegaly, Cushing’s
Malnutrition related diabetes
What is MODY?
Maturity onset diabetes of youth
How is diabetes defined?
Symptoms and random plasma glucose of >11mmol/L
Fasting plasma glucose > 7mmol/L
HbA1c of 48mmol/L (6.5%)
What is the pathogenesis of T1DM?
Autoimmune destruction of pancreatic Beta cells leading to an absolute insulin deficiency.
T4 Hypersensitivity reaction.
What mechanism of autoimmunity is responsible for T1DM?
Beta cells express HLA antigens ( HLA DR3 and HLA DR4) on MHC in response to an environmental event
Activates chronic cell mediated immune response leading to chronic insulitis
What happens to insulin metabolism in T1DM and what is the consequence of this?
Loss of beta cells - Loss of insulin secretion
Leads to:
Continued glycogenolysis in the liver
Unrestricted lipolysis and skeletal muscle breakdown for gluconeogenesis
Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake.
Glucose concentration rises lead to excretion of glucose in urine as renal reuptake routes are saturated (glycosuria)
What happens if T1DM is not treated with insulin?
Increased circulating glucagon - loss of paracrine function of beta cells - leads to increased glucose
Perceived stress increases cortisol and adrenaline secretion
Increases catabolic state and increases ketone production
Explain why fat metabolism is significant in T1DM?
Reduced insulin leads to increase lipolysis and the formation of glycerol and FFAs
FFAs are transported to the liver and oxidised to ketone bodies
Ketogenesis is highly sensitive to insulin
Poor control of diabetes leads to DKA by uncontrolled ketone formation.
What are the consequences of ketoacidosis?
Glucose and ketones are excreted in the urine
Causes osmotic diuresis
Lower blood circulating volume
Ketones cause anorexia and vomiting
Vicious circle of dehydration, hyperglycaemia and increased acidosis leads to circulatory collapse and death
What happens to glucose metabolism in T2DM?
- Insulin resistance and impaired insulin release (though insulin is always detectable)
- This leads to:
- Reduced muscle and fat uptakes after eating
- Failure to suppress lipolysis and high circulating free fatty acids
- Abnormally high glucose output after a meal
- Low levels of insulin enough to prevent muscle catabolism and ketogenesis so muscle breakdown and ketone production rarely excessive
What is the role of basal insulin in T1DM therapy?
Control glucose between meals and at night.
Adjusted to maintain fasting blood glucose between 5-7mmol/L
What is the betst treatment for T1DM?
Intesive basal bolus of insulin
What is the best treatment for T1DM?
Intensive basal bolus of insulin
What is hte role of a bolus of insulin?
Manage glucose according to carbohydrate intake and pre meal glucose
Why should we introduce insulin to those with T2DM?
Progressive damage to pancreatic beta cells and or poor glucose control warrant insulin therapy
What type of insulin is initiated first in T2DM?
Basal insulin
Which insulin analogues are associated with lower risk of symptomatic overall and overnight hypoglycaemia?
Long acting basal insulin analogues
Why are prandial insulins fit for purpose?
Their faster action means they can be adapted to the meal that is eaten
What are the different approaches to insulin therapy in T2DM?
Once daily - basal insulin
Twice daily - Mix insulin
Basal Bolus therapy
What are the advantages of basal insulin in Type 2 diabetes?
- Simple for patient - adjust insulin themselves based on fasting glucose
- Less risk of hypoglycaemia overnight
- Carries on with oral therapy
What are the disadvantages of basal insulin in Type 2 diabetes?
- Doesn’t cover meals
- Best used with long-acting insulin analogues - expensive
What are the advantages of pre-mixed insulin?
- Both basal and prandial components in a single preparation per day
- Can cover insulin requirements for the day
What are the disadvantages of pre mixed insulin?
- Not physiological
- Requires consistent meal and exercise pattern
- Cannot separately titrate individual insulin components
- Higher risk of nocturnal hypoglycaemia
- Higher risk of hyperglycaemia is basal component not high enough
- HbA1c is kept at a higher level
What is hypoglycaemia?
Low plasma glucose causing impaired brain function
What are the clinical definitions of hypoglycaemia?
Mild - self treated episodes
Severe - Requires help from someone to recover
What is the glucose value for neutropenia?
3mm/L
What is the glucose value for hypoglycaemia?
3.9 mmol/L
What are the different classifications of hypoglycaemia?
Level 1
- Alert value
- Plasma glucose of under 3.9 mmol/l (70mg/dl) and no symptoms
Level 2
- Serious biochemical
- Plasma glucose of under 3.0 mmol/l (55mg/dl)
Non-severe symptomatic
- Mild hypoglycaemia
Severe symptomatic
- Level 3
- Severe hypoglycaemia
What are the common symptoms for hypoglycaemia?
- Autonomic
- Trembling
- Palpitations
- Sweating
- Anxiety
- Hunger
- Neuroglycopenic
- Difficulty concentrating
- Confusion
- Weakness
- Drowsiness/Dizziness
- Vision changes
- Difficulty speaking
- Non-specific
- Nausea
- Headache
What is significant about the relationship between HbA1c levels and hypoglycaemic episodes?
The higher the HbA1c levels, the higher the glucose levels can be when the patient experiences a hypoglycaemic episode
What are the risk factors for severe hypoglycaemia for T1DM and T2DM?
- Type 1 DM
- History of severe episodes
- HbA1c > 48 mmol/l (6.5%)
- Long duration of diabetes
- Renal impairment
- Impaired awareness of hypoglycaemia
- Extremes of age
- Type 2 DM
- Advancing age
- Cognitive impairment
- Depression
- Aggressive treatment of glycaemia
- Impaired awareness of hypoglycaemia
- Duration of multi dose insulin therapy
- Renal impairment and other comorbidities
What normally prevents hypoglycaemia?
- Counter-regulatory hormones
- Glucagon
- Adrenaline
How do the normal physiologically mechanisms that prevent hypoglycaemia fail inT1/2DM?
Threshold for secretion of counter-regulatory hormones can be altered, allowing for a lower value of glucose to be maintained and risking hypoglycaemia
What is the impact of non-severe hypoglycaemia?
- Reduced quality of life
- Fear of hypoglycaemia
- Mental illness comorbidity
What are the consequences of hypoglycaemia?
- Accidents
- Fear
- Quality of life
- Prevents desirable HbA1c targets
- Cognitive dysfunction
- Seizures/coma
What forms part of the screening for risk of severe hypoglycaemia?
- Low HbA1c (high pre-treatment HbA1c in Type 2 DM)
- Long duration of diabetes
- History of previous hypoglycaemia
- Impaired awareness of hypoglycaemia
- Recent episodes of severe hypoglycaemia
- Daily insulin dose (>0.85 U/kg/day)
- Physically active
- Impaired renal function
What is a red flag for impaired awareness of hypoglycaemia?
Onset of symptoms below 0.3 mmol/l in blood glucose monitoring
What are the glucose targets for Type 1DM?
- Lowest HbA1c not associated with frequent hypoglycaemia
- May be appropriate to relax targets in patients with advanced disease, complications or limited life expectancy
- In these patients, aim for low enough glucose levels to limit hyperglycaemia symptoms
What are the glucose targets for Type 2 DM?
- Lowest HbA1c not associated with frequent hypoglycaemia
- HbA1c < 7% (53 mmol/l) usually appropriate for recent-onset of disease
- May be appropriate to relax targets
- Severe complications
- Advanced co-morbidities
- Cognitive impairment
- Limited life expectancy
- Unacceptable hypoglycaemia from stringent control
What do patients need to be educated about for hypoglycaemia?
- If on insulin or sulphonylureas
- How to identify and treat symptoms
- Patients should report episodes of hypoglycaemia to doctor/educator
What is the treatment of hypoglycaemia?
- Recognise symptoms
- Confirm the need for treatment with plasma glucose test
- Treat with 15g fast-acting carbohydrate to relieve symptoms
- Retest in 15 minutes to ensure blood glucose > 4 mmol/l and re-treat if needed
- Eat a long-acting carb to prevent recurrence of symptoms
Where does active Ca2+ reabsorption happen in the kidney?
DCT - this is where PTH will act.
Where in the body can Calcium come from to enter the blood?
- Absorbed from the intestine. 2. Resorbed from bone. 3. Reabsorbed at the kidney.
Where in the intestine is calcium actively absorbed?
Duodenum and jejunum.
Where in the intestine is calcium passively absorbed?
Ileum and colon.
Where does the majority of Ca2+ reabsorption happen in the kidney?
At the PCT.
What stimulates the release of PTH?
Low serum Ca2+ detected by receptors in the parathyroid.
Briefly describe the action of PTH.
- It causes bone resorption: increased Ca2+ and phosphate.
- It acts on the kidneys causing increased Ca2+ reabsorption and decreased phosphate reabsorption.
- It stimulates 1-hydroxylase which increases formation of 1,25-(OH)2-vitD and so increases the absorption of Ca2+ and phosphate from the intestine.
What is the action of calcitonin?
It reduces bone resorption and so lowers Ca2. It is the antagonist to PTH.
What do parafollicular C-cells release?
Parafollicular C cells of the Thyroid release Calcitonin.
What triggers the release of calcitonin?
High Ca2+.
Give 3 regulators of phosphate.
- PTH. 2. 1,25-(OH)2-vitD. 3. FGF-23 = major regulator!
What is the action of PTH with regards to phosphate homeostasis?
It increases phosphate absorption at the intestine and decreases phosphate reabsorption at the kidney.
Where does PTH secretion occur?
Chief cells in the parathyroid gland - possess calcium sensing receptors on their cell surface
How does PTH act on bone to increase serum calcium?
Stimulates osteoclasts to release ionic Ca2+ for reabsorption
- How does PTH act on the kidneys to increase serum calcium?
- ↑ passive calcium reabsorption by the PCT - only 1% excreted
- ↓ phosphate reabsorption - 20% excreted
- ↑ 1 alpha hydroxylation of vitamin D to form 1,25-dihydroxyvitamin D - facilitates calcium absorption in the intestines
- How does PTH act on the intestines to increase serum calcium?
↑ calcium absorption via 1,25-dihydroxyvitamin D
- What hormone regulates the decrease in serum calcium?
Calcitonin!
How does Calcitonin decrease serum calcium?
- Reduces bone resorption by inhibiting osteoclast activity
- Reduce renal reabsorption
How else is serum calcium regulated
Negative feedback! Increased serum PTH leads to reduced secretion.
What are the levels of physiological and non-physiological calcium (hypocalcaemia)?
Normal level of serum calcium:
Mild-moderate Hypocalcaemia:
Severe Hypocalcaemia:
Normal level of serum calcium: 2.2 - 2.6mmol/L
Mild-moderate Hypocalcaemia: 1.9 - 2.2 mmol/L
Severe Hypocalcaemia: <1.9 mmol/L
What are the clinical features of hypocalcaemia?
- Parasthesia - abnormal skin sensation (tingling, prickling, numbness)
- Tetany - spasms of the hands, feet, larynx and premature labour
- Seizures
- Basal ganglia calcification - associated with neuropsychiatric and motor symptoms
- Cataracts
- Chvostek and Trousseau signs
What is Chvostek sign?
Tap over the facial nerve - look for spasm of the facial muscles
What is Trousseau sign?
Inflate blood pressure cuff to 20mmHg above systolic for 3-5 minutes - look for carpopedal spasm
What ECG abnormality suggests possible Hypocalcaemia?
Long QT interval - primarily the prolonging of the ST segment; slow ventricular repolarisation as a result of reduced calcium entering the cell through L-type channels.
What are the causes of Hypocalcaemia?
- Hypoparathyroidism
- Acute pancreatitis
- Hyperphosphataemia
- Hypomagnesaemia
- Diuretics (frusemide)
- Pseudohypoparathyroidism
- Congenital disorders
- Critical illness (e.g. sepsis)
Why does Vitamin D deficiency cause Hypocalcaemia?
Inactive Vitamin D is converted to 1,25-dihydroxyvitamin D), which facilitates Ca2+ absorption by the gut
Why does Hypoparathyroidism cause Hypocalcaemia?
Reduced secretion of PTH by Chief cells of the parathyroid. PTH acts in incidences of low serum to increase calcium absorption from bone, kidneys and intestines
What are possible causes of Hypoparathyroidism?
- Surgery - parathyroid removal
- Radiation - parathyroid damage
- Autoimune diseases (e.g. Chronic Mucocutaneous Candidiasis)
- Infiltration - caused by condition, such as Wilson’s disease and Haemochromatosis
- Magnesium deficiency - required for release of PTH
- Syndromes
- Genetic predisposition
Name examples of conditions associated with Hypoparathyroidism.
Acute pancreatitis
Di George Syndrome
Pseudohypoparathyroidism
Why is acute pancreatitis associated with hypoparathyroidism?
Precipitation of calcium stearate (carboxylated calcium) in the abdominal cavity; causes increased calcitonin release.
Why is Di george syndrome associated with hypoparathyroidism?
A developmental abnormality of third and fourth branchial pouches of the pharyngeal arches - this causes;
- Hypoparathyroidism
- Immunodeficiency - linked to thymic hypoplasia
- Cardiac defects
- Cleft palate
Why is pseudohypoparathyroidism associated with hypoparathyroidism?
- Condition associated with the resistance of the body to PTH.
- Causes Type 1 Albright hereditary osteodystrophy which presents with the following signs
- Short stature
- Obesity
- Round facies
- Mild learning difficulties
- Subcutaneous ossification
- Short fourth metacarpals
What are the levels of physiological and non-physiological calcium (hypercalcaemia)?
Normal level of serum calcium:
Mild-moderate Hypercalcaemia:
Severe Hypercalcaemia:
Normal level of serum calcium: 2.2 - 2.6 mmol/L
Mild Hypercalcaemia: 2.7 - 2.9 mmol/L
Moderate Hypercalcaemia: 3.0 - 3.4 mmol/L
Severe Hypercalcaemia: >3.4 mmol/L
What are the clinical features of Hypercalcaemia?
Bones, stones groans and moans!
BONES - osteitis fibrosa cystica, osteoporosis
Renal STONES - kidney stones
Psychic GROANS - neurological symptoms (i.e. confusion, coma)
Abdominal MOANS - constipation, nausea, acute pancreatitis
*Also, thirst as polyuria
What ECG abnormality suggests possible Hypercalcaemia?
Short QT interval - primarily the shortening of the ST segment; faster ventricular repolarisation as a result of increased calcium entering the cell through L-type channels.
What are the causes of Hypercalcaemia?
90% of the time caused;
- Malignancies
- Hyperparathyroidism - primary and teritiary
What are the malignancies associated with hypercalcaemia?
- Myeloma - causes overexpression of RANKL which activates osteoclastic bone resorption
- Bone metastases
- Lymphoma
- PTH-Related Peptide (PTHrP) - produced in excess by a tumour; causes PTH secretion above physiological range
Why does hyperparathyroidism lead to hypercalcaemia?
Increased secretion of PTH by Chief cells of the parathyroid. PTH acts to increase calcium absorption from bone, kidneys and intestines. Excessive PTH causes elevated serum calcium.
What is primary Hyperparathyroidism?
Hyperparathyroidism caused by;
- 80% - sporadic single benign adenoma
- 15-20% - parathyroid hyperplasia
- <0.5% - parathyroid carcinoma
What is Tertiary Hyperparathyroidism?
A result of chronic secondary hyperparathyroidism. High levels of PTH production over a long period of time results in parathyroid hyperplasia; this causes an extent PTH overproduction which increases serum calcium above physiological range.
What is secondary Hyperparathyroidism?
Secondary hyperparathyroidism normally occurs as a a result of long term low serum calcium (e.g. due to kidney failure)
Where are the hypothalamus and pituitary located?
Diencephalon of the brain
What are the two groups of hypothalamic hormones?
- Hormones travelling to the APG (anterior Pituitary Gland)
Travel down the median eminence, a prolongation of the hypothalamus, into the hypophyseal portal system, which carries them to the anterior pituitary where they exert their regulatory functions.
- Hormones travelling to the PPG (Posterior Pituitary Gland)
Hormones synthesised by neurones in the hypothalamus pass down the neuronal axons which travel into the posterior pituitary. Here, they are stored in the distended parts of the axon in the posterior pituitary.
What hormones are released by the hypothalamus?
- Gonadotropin Releasing Hormone (GnRH)
- Growth Hormone Releasing Hormone (GHRH)
- Somatostatin (SST); also known as - Growth Hormone Inhibiting Hormone (GHIH)
- Tryrotropin Releasing Hormone (TRH)
- Dopamine (DA) or Prolactin-Inhibiting Hormone (PIH)
- Corticotrophin Releasing Hormone (CRH)
What is the hypophyseal portal system?
- System of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus to the anterior pituitary.
- Function to rapidly transport hormones between the hypothalamus arcuate nucleus and anterior pituitary gland.
- The capillaries in the portal system are fenestrated.
How do Hypothalamic secretions travel to the APG?
1️⃣ Neurones with cell bodies in the medial hypothalamic nuclei project to the median eminence
2️⃣ Here, the neurones secrete hormones into the pituitary portal veins
3️⃣ Hypothalmic hormones influence secretion of hormones from cells in the anterior lobe of the APG into the venous drainage of the gland.
How do Hypothalamic secretions travel to the PPG?
1️⃣ Neurones with cell bodies in the supra and paraventricular nuclei of the hypothalamus have projections to the posterior pituitary
2️⃣ Neurones release their hormones directly into the venous drainage of the gland.
What hormones are released by the APG?
- ollicle Stimulating Hormone (FSH) → Gonads
- Luteinizing Hormone (LH) → Gonads
- Growth hormone (GH) → Liver (IGF-1) and other tissue (growth)
- Thyroid Stimulating Hormone (TSH) → Thyroid
- Prolactin (PL) → Breasts
- Adrenocorticotropic Hormone (ACTH) → Adrenal Cortex
What hormone are released by the PPG?
- Vasopressin/ ADH - acts to upregulate water retention in the kidneys (aquaporins)
- Oxytocin - induces contractions of the uterus during labour
What is the Pituitary-Thyroid Axis?
1️⃣ TRH from hypothalamus acts on anterior pituitary
2️⃣ Anterior pituitary produces TSH (thyrotroph cells in anterior pituitary has receptors that TRH acts on)
3️⃣ TSH acts on thyroid which produces T4 and T3; these acts as negative feedback on both hypothalamus and pituitary
4️⃣ Deiodinases act to convert T4 to T3 by removal of iodine
What is the Pituitary-Gonadal Axis?
- 1️⃣ Hypothalamus produces GnRH which acts on pituitary
- 2️⃣ Pituitary produces LH and FSH
- 3️⃣ LH travels to the gonads and causes;
- Men
- LH stimulates interstitial cells of the testes to produce testosterone
- FSH stimulates spermatogenesis - Women
FSH and LH act to activate the ovaries to produce oestrogen and inhibin; regulate the menstrual and ovarian cycle - 4️⃣ Negative feedback for hypothalamus and pituitary
- Men
- Testosterone acts on the hypothalamus to inhibit the production of GnRH
- Women
- Oestrogen acts on the hypothalamus directly to inhibit the production of GnRH
- Inhibin acts to inhibit activin, a peripherally produced hormone that positively stimulates GnRH-producing cells
- Men
What is the Hypothalamus-Pituitary-Adrenal Axis?
1️⃣ Hypothalamus produces CRH which acts on the pituitary
2️⃣ Pituitary produces ACTH
3️⃣ ACTH acts on the adrenal glands to produce cortisol
4️⃣ Cortisol acts as negative feedback for pituitary and hypothalamus
What is the Growth Hormone-Insulin Growth Factor-I Axis?
1️⃣ Hypothalamus produces GHRH and Somatostatin which acts on pituitary
2️⃣ Pituitary produces GH which acts on liver
3️⃣ Liver produces Insulin-like Growth Factor 1; this acts as negative feedback for hypothalamic secretions
There are pulsatile secretions of GH and SMS that enable growth during sleep
What is the Hypothalamus-Pituitary-Prolactin Axis?
1️⃣ Hypothalamus produces LHRH which acts on the pituitary
2️⃣ Pituitary produces Prolactin
3️⃣ Hypothalamus also produces dopamine; this acts on the pituitary gland to reduce prolactin secretion
4️⃣ Cortisol acts as negative feedback for pituitary and hypothalamus
What are some diseases of the Pituitary Gland?
- Benign pituitary adenoma
- Craniopharyngioma
- Trauma
- Apoplexy
- Sarcoid/TB
How does a pituitary adenoma cause symptoms?
(VERY KEY POINT)
- Exerts pressure on local structures (e.g. optic nerves)
- Exert pressure on the normal pituitary
- Behaves as a functioning tumour
Name examples of visual field defects associated with a pituitary adenoma?
- Bitemporal hemianopia (Loss of lateral fields of vision in both eye)
Caused by compression of the nasal retinal fibres; responsible for carrying the information along the optic nerve. Specifically, compression of the optic chiasma; the area where optic nerves from the right and left eyes cross near the pituitary gland.
- Compression of Nasal Retinal Fibres
- Inferior nasal fibres cause reduction in upper outfield
- Superior nasal fibres cause reduction in lower outfield
What causes pituitary adenoma-related headaches?
Expansive tumour causes stretching of the dura mater; layer of connective tissue associated with the meninges
What causes pituitary adenoma-related hydrocephalus?
Accumulation of CSF within the brain caused by compression of the brain
What is the primary problem caused by pressure on a normal pituitary?
Hypopituitarism - lack of pituitary function!
Symptoms relate to deficiency of specific hormone secretions
Name clinical features caused by GH deficiency.
- Central obesity
- Decreased muscle mass
- Impaired memory
Name clinical features caused by LH and FSH deficiency.
Associated with low testosterone/ oestrogen and progesterone
- Men → loss of body hair, decreased muscle mass, anaemia, loss of sexual function
- Women → infertility, oligo-/amenorrhea (infrequent/light or absent periods), loss of sexual function
- Children → delayed puberty
Name clinical features caused by ACTH deficiency.
Associated with low cortisol!
- Pallor
- Fatigue
- Weight loss
- Failure to thrive
Name clinical features caused by TSH deficiency.
Associated with hyperthyroidism!
- Tiredness
- Constipation
- Weight gain
- Hair loss
- Low BP and HR.
Name clinical features caused by PRL deficiency.
Inability to breastfeed
Name symptoms caused by ADH deficiency.
Diabetes insipidus!
- Inability to concentrate the urine, leading to polyuria
- Dehydration and, in compensation, extreme thirst (polydipsia)
- Hypernatremia (high serum sodium).
Name symptoms caused by Oxytocin deficiency.
Rare - issues arise during breastfeeding and childbirth
What is a Prolactinoma?
Tumour causing the pituitary to make too much prolactin
What are the clinical features associated with a Prolactinoma?
- Galactorrhoea - abnormal white breast discharge
- Reduced ability to breast feed
- Amenorrhoea/ infertility
- Loss of libido
- Visual field defect - see above
How are Prolactinomas treated?
Dopamine agonist (e.g. Cabergoline or Bromocriptine) - produces prolactin-reducing feedback
Surgery possibly
Acromegaly and Gigantism are caused by the excessive production of which hormone?
Growth hormone
What is the difference between Acromegaly and Gigantism?
Acromegaly occurs in adults - after growth plates are closed
Gigantism occurs in children caused by a pituitary tumour causing increased GH release however the tumour also presses on the pituitary so you get hypopituitarism which means the other hormones do not work and therefore they don’t go through puberty as no testosterone is being produced
What is Cushing’s Syndrome?
Chronic, excessive and inappropriate elevated levels of circulating cortisol.
(not necessarily tumour related)
**Cushing’s syndrome occurring as a result of a pituitary tumour is known specifically as Cushing’s Disease.*
Cushing’s Syndrome is caused by the excessive production of which hormone secreted by the pituitary gland?
ACTH - causes the overproduction of cortisol by the adrenal cortex
What are the clinical features of Cushing’s?
- Carbohydrate metabolism - diabetes, glucose intolerance
- Electrolyte disturbance - hypertension; sodium retention and potassium loss
- Immune suppression
- Central effects - malaise, depression, psychosis
- Suppressed gonadal function - oligo/ amenorrhoea, infertility, loss of libido
What are the most common indication of Cushing’s?
- Obesity
- Muscle wasting (protein catabolism)
- Redistribution of fat around abdomen and top of back
- Hirsutism - excessive growth of coarse hair facial, chest and back hair in women
- Repeated bruising, thin skin, thin hair and stretch marks
- Acne
What is the difference between ACTH-dependent and ACTH-independent Cushing’s?
- ACTH-dependent → caused by a pituitary adenoma (or ectopic, ACTH producing tumour)
- ACTH-independent → caused directly by the adrenal glands
What tests are used to diagnose Cushing’s?
- Urinary free cortisol
- Low dose dexamethasone suppression test - synthetic steroid feedback at pituitary and hypothalamus which leads to reduced CRH and ACTH. Therefore, low levels of cortisol found in blood.
- Late night/midnight serum or salivary cortisol.
What tests are used to diagnose Cushing’s?
- Urinary free cortisol
- Low dose dexamethasone suppression test - synthetic steroid feedback at pituitary and hypothalamus which leads to reduced CRH and ACTH. Therefore, low levels of cortisol found in blood.
- Late night/midnight serum or salivary cortisol.
What is Cushing’s Disease?
Chronic, excessive and inappropriate elevated levels of circulating cortisol that is specifically caused by a pituitary tumour
What is puberty?
Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms
What are the definitive signs of puberty?
- Girls - menarche
- First menstrual bleed
- Boys - first ejaculation
- Often nocturnal
What controls the development of secondary sexual characteristics?
- Girls
- Ovarian oestrogens
- Growth of breasts and female genitalia
- Ovarian and adrenal androgens
- Control pubic and axillary hair
- Ovarian oestrogens
- Boys
- Testicular androgens
- External genitalia and pubic hair growth
- Enlargement of larynx and laryngeal muscles
- Deepening of the voice
- Testicular androgens
What are tanner stages?
Scale of physical development through puberty
What is the volume of testes that signify the commencement of puberty?
> 3ml (>2.5cm in longest diameter)
What is used to measure testicular volume in ml?
Orchidometer
What is thelarche and what initiates it?
- Breast development
- Oestrogen
How long does thelarche take to complete?
3 years
What are the effects of oestrogen on breast tissue?
- Ductal proliferation
- Site specific adipose deposition
- Enlargement of the areola and nipple
What other hormones are involved in breast development?
- Prolactin
- Glucocorticoids
- Insulin
Describe the maturation of the uterus
- Corpus:cervix ratio flips from 1:2 to 2:1
- Changes from tubular shape to pear shape
- Increases in length and volume
- Endometrium thickens
Describe the maturation of the ovaries
- Volume increases
- Change from non-functional to multicystic
What is assessed in a pelvic ultrasound and what care should be taken when reporting findings?
- Are the Mullerian structures present?
- Fallopian tubes
- Uterus
- Uterine cervix
- Superior aspects of the vagina
- Morphology of the uterus
- Morphology of the ovaries
- Requires an experienced examiner so careful when reporting absence of structures
Describe the maturation of the vagina
- Becomes a duller red
- Epithelium thickens
- Cornification of the superficial layer of stratified squamous epithelium
- pH changes from neutral to acidic
- Secretion of clear whitish discharge in the months prior to menarche
- Increase in length
Describe the maturation of the external genitalia and which hormones cause this
- Oestrogens
- Labia majora and minora increase in size and thickness
- Rugation and change in colour of labia majora
- Hymen thickens
- Clitoris enlarges
- Vestibular glands begin secretion
- Adrenal and ovarian androgens
- Growth of pubic hair
What is adrenarche?
- Maturation process of the adrenal gland
- Specialised subset of cells arises forming the androgen producing zona reticularis
When does adrenarche occur?
- Peri-puberty
- Premature or exaggerated adrenarche can occur up to 2 years prior to puberty, especially in obese children
What hormone is associated with adrenarche?
- DHEA
- DHEA-S
- Both precursors of androgens
What happens physiologically during adrenarche?
- Mild advance in bone age
- Axillary hair growth
- Mild acne
- Body odor
What is precocious puberty?
Early puberty
Which population of patients are more likely to have ‘true’ precocious puberty and what is the significance of this?
- Up to 80% female
- If male patients present with precocious puberty, differentials should be ruled out before a diagnosis of idiopathic puberty is given
- Brain tumour may be highly likely or some other significant pathology
What is precocious pseudopuberty?
Resembles puberty, but not from normal hypothalamus activation
What can cause precocious pseudopuberty?
- Adrenal sex hormones excess
- Congenital adrenal hyperplasia
- hCG Secreting Tumours
- Gonads
- Brain
- Liver
- Retroperiteneum
- Mediastinum
What is the differential test for true precocious puberty and precocious pseudopuberty?
- Use of gonadotrophin releasing hormone (or luteinising hormone-releasing hormone) test
- Measure LH and FSH before and 30 and 60 minutes after injection of GnRH (or LHRH)
- If GnRH or LHRH stimulates an increase of LH and FSH, then true puberty
- If there is not a rise of LH:FSH the likely pseudopuberty
- Stimulated LH:FSH ratio > 1 to be true precocious puberty
What is the treatment for precocious puberty?
- Use of GnRH super-agonist suppresses pulsatility of normal physiology
- Stops the process
What are the causes of true precocious puberty?
(GnRH dependent)
Idiopathic precocious puberty
CNS Tumours
CNS Disorders
Secondary central precocious puberty
Psychosocial - adoption from abroad
What are the causes of precocious pseudopuberty?
(GnRH independent)
Increased androgen secretion
Gonadotrophin secreting tumours
McCune Albright syndrome
Ovarian Cyst
Oestrogen secreting neoplasm
Hypothyroidism
Iatrogenic or exogenous sex hormones
What is the main cause of delayed puberty?
- IdiopathicHypogonadotropic Or hypergonadotropic hypogonadism
What causes idiopathic delay in puberty?
Delayed activation of the hypothalamic pulse generator
Which sex is most affected by idiopathic delays in puberty?
Males
How do you diagnose idiopathic (or constitutional) delay of growth and puberty?
Diagnosis of exclusion
What is relevant in the family history for idiopathic delay in growth and puberty?
- Late menarche in mother or sister
- Delayed growth spurt in father
What are the other causes of delayed puberty?
- Hypogonadotropic hypogonadism
- Sexual infantilism related to gonadotrophin deficiency
- Hypergonadotrophic hypogonadism
- Primary gonad problems
What do delays in puberty lead to?
- Delay in acquisition of secondary sex characteristics
- Psychological problems
- Defects in reproduction
- Reduced peak bone mass
What are indications for delayed puberty investigation?
Girls:
Lack of breast development by 13yrs
More than 5yrs between breast development and menarche
Lack of pubic hair by age 14yrs
Absent menarche by 15-16yrs
Boys:
Lack of testicular enlargement by age 14yrs
Lack of pubic hair by age 15yrs
More than 5 years to complete genital enlargement
What does the onset of puberty correlate to?
Bone age
What should you consider when taking a history for delayed puberty?
Totally absent or started and then arrested
Family Hx
Review of Symptoms
Perinatal Hx
Prior Medical Illnesses
Medication
Psychosocial deprivation
Nutrition, exercise and health
Neurological symptoms
Hypoglycaemia
Cancer Hx
Testicular injury
What laboratory investigations should you consider for delayed puberty?
- FBC
- U&Es
- Renal function test
- LFTs
- Coeliac abs
- Testosterone/oestrodiol
- Thyroid function
- Prolactin
- DHEA-S
- ACTH
- Cortisol
- Karyotyping/CGH array
- Where physical examination/biochemistry suggestive of genetic syndrome
- in all girls with short stature
Why can X rays help in identifying delayed puberty?
- Bone age (skeletal maturity)
- Delayed bone age in growth hormone
- Advanced bone age in precocious puberty
What are some functional causes of delayed puberty?
Chronic Renal disease
Chronic GI disease/malnutrition
Sickle cell disease
Chronic lung disease
Anorexia nervosa
Bulimia
Psychosocial stress
Extreme exercise
Drugs
AIDs
Poorly controlled T1DM
Hypothyroidism
Cushing’s Syndrome
Hyperprolactinaemia
What is primary hypogonadism?
- Issue with the gonads
- Also known as hypergonadotropic hypogonadism
- Gonads not responding to stimulus so hypothalamus and pituitary more stimulated
- FHS/LH will both be high
- Sex hormones will be low
What is secondary hypogonadism?
Issue with the pituitary
What is tertiary hypogonadism?
Issue with the hypothalamus
Hypogonadotrophic Hypogonadism is known by what other term?
Secondary and tertiary hypogonadism
What are the causes of hypogonadotropic hypogonadism?
CNS disorders - tumours
Kallmanns’ Syndrome - Gonadotrophin deficiency
Prader willi syndrome
sickle cell
CF
AIDS
What genetic deficits can cause hypogonodatropic hypogonadism?
- Issues with:
- GnRH neurone migration
- GnRH synthesis and release
- GnRH action
- Gonadotropin synthesis
What is the diagnostic dilemma in trying to differentiate between hypogonadotropic hypogonadism and constitutional delay in growth and puberty?
- No gold-standard diagnostic test available
- Inhibin B marker of Sertoli cell number correlates with testicular volume
- In men with central hypogonadotropic hypogonadism and severe GnRH deficiency serum levels of inhibin B are typically very low
- For partial forms of central hypogonadotropic hypogonadism, inhibin B levels overlap with those in patients with constitutional delay in growth and puberty and in healthy controls
Who is mainly affected by Kallmann Syndrome?
Mainly Males
4:1 M:F
What are the symptoms associated with Kallmanns Syndrome?
Anosmia
What causes Kallmann Syndrome?
- Failure of migration of GNRH neurones from hypothalamus to pituitary
- X-linked, autosomal recessive or dominant
What are the main Conditions which fall under the hypergonadotropic hypogonadism?
Klinefelters - Males
Turners Syndrome - Females
What is Turners Syndrome?
45 XO
Loss of an X chromosome
What are signs and symptoms of Turners Syndrome?
- At birth
- Oedema of dorsa of hands and feet
- Loose skinfolds at the nape of the neck
- Webbing of neck
- Low posterior hairline
- Small mandible
- Prominent ears
- Epicanthal folds in high arched pallet
- Broad chest
- Cubitus valgus
- Hyperconvex fingernails
- Cardiovascular malformations
- Renal malformations (horseshoe kidney)
- Recurrent otitis media
- Middle ear infections
- Short stature
- Primary hypogonadism
What is Klinefelters Syndrome?
47 XXY
What are the signs and Symptoms of Klinefleters Syndrome?
- Primary hypogonadism
- Azoospermia
- Gynaecomastia
- Reduced secondary sexual hair
- Osteoporisis
- Tall stature
- Reduced IQ
What risks are associated with Kleinfelter Syndrome?
20-fold increased risk of breast cancer
How can females have Hormone replacement therapy?
Ethinyloestradiole
Oestrogen
- Start low, gradually increase doses to provide time for pubertal growth and gradual breast development
- Over 2 years
- Progesterone added when full replacement dose achieved
How can males have Hormone replacement therapy?
Testosterone Enanthate (most common)
Testosterone Transdermal
- Several incremental steps
- Over 2-4 years
What fertility treatments can be done for patients with Hypogonadotropic Hypogonadism?
- GnRH therapy
- Pituitary must be intact
- Parenteral combination of gonadotropin therapy
- LH/hCG and FSH
What are the general symptoms of hypothyroidism?
- Weight gain
- Tiredness
- Constipation
- Cold intolerance
- Poor concentration
- Poor sleep pattern
- Dry skin
What are the primary causes of Hypothyroidism?
Autoimmune
Hashimotos
Atrophic Thyroiditis
Prior surgery
Radio-ablation
Drugs - Lithium, Amiodarone
Iodine deficiency
Congenital
What are the Transient causes of hypothyroidism?
Post partum Thyroiditis
Subacute thyroiditis
What are the secondary causes of hypothyroidism?
Hypopituitarism
What are the different classes of causes for hypothyroidism?
Primary
Transient
Secondary
What drugs can commonly causes hypothyroidism?
- Iodine, inorganic or organic iodide
- Iodinated contrast agents
- Amiodarone
- Lithium
- Thionamides
- Interferon alpha
What are some common causes of hypothyroidism in neonates.
- Thyroid agenesis - lack of thyroid
- Thyroid ectopia - embryological aberration of thyroid
- Thyroid dyshormonogenesis - genetic defects in the synthesis of thyroid hormones
List some consequences of hypothyroidism during pregnancy.
- Gestational hypertension and pre-eclampsia
- Placental abruption
- Post partum haemorrhage
List some consequences to the baby if hypothyroidism is untreated.
- Low birth weight
- Preterm delivery
- Neonatal goitre
- Neonatal respiratory distress
Which drug is used to treat hypothyroidism?
Synthetic L-thyroxine (T4) - 1.6 mg/kg
How does the monitoring of TSH and T4 differ in primary and secondary/ tertiary hypothyroidism?
-
Primary - monitor TSH
- L-thyroxine (T4) is titrated until TSH is within normal range
-
Secondary/ tertiary - monitor serum T4
- TSH will always be low
How is pre-existing hypothyroidism treated during pregnancy?
- Preconception counselling - ideal preconception TSH <2.5 mIU /L
- Increase thyroxine dose by 30%
- Arrange thyroid function tests in early pregnancy
How are new presentations of overt hypothyroidism treated during pregnancy?
Aim to normalise ASAP!
Start thyroxine 50-100mcg and measure thyroid function every 4-6 weeks
What is Subclinical Hypothyroidism?
Early mild form of hypothyroidism characterised by high TSH levels but free T4 and free T3 are normal.
What groups of people undergo targeted screening for hypothyroidism during pregnancy
- Age > 30
- BMI > 40
- Miscarriage preterm labour
- Personal or family history
- Goitre
- Type 1 Diabetes
- Head and neck irradiation
- Amiodarone, Lithium or contrast use
What is hyperthyroidism?
High serum thyroid hormones caused by;
- Overproduction of thyroid hormone
- Leakage of preformed hormone from thyroid
- Ingestion of excess thyroid hormone
What are the common symptoms of hyperthyroidism?
- Weight loss
- Heat Intolerance
- Sweating
- Diarrhoea
- Tachycardia
- Anxiety
- Tremor
- Menstrual disturbance
How do the clinical signs of primary and secondary hyperthyroidism differ?
- Primary hyperthyroidism
- Increased (free) T4
- Increased (free) T3
- Reduced TSH
- Secondary hyperthyroidism
- Increased (free) T4
- Increased (free) T3
- Excessively high TSH
List some causes of hyperthyroidism.
- 85-90% due to Graves disease
- Less commonly cause by;
- Toxic adenoma or multi nodular goitre
- Gestational thyrotoxicosis,
- Trophoblastic neoplasia
- TSHoma
What is Graves’ Disease?
An autoimmune disease characterised by the development of TSH-receptor activating antibodies. This leads to hyperthyroidism.
Name some clinical manifestations of Graves’ Disease.
- Diffuse goitre - enlargement of the entire thyroid
- Thyroid eye disease (inflitrative)
- Pretibial myxoedema - excess of glycosaminoglycans in the dermis and subcutis of the skin resulting in waxy, orange appearance of skin
- Acropachy - soft tissue swelling of hands and clubbing of the fingers
What drugs can commonly causes hyperthyroidism?
- Iodine, inorganic or organic iodide
- Radiocontrast agents
- Amiodarone
- Lithium
List some consequences of hyperthyroidism during pregnancy if inadequately treated.
- Intrauterine growth resistance (IUGR)
- Low birth weight
- Pre ecclampsia
- Preterm delivery
- Risk of stillbirth
- Risk of miscarriage
What drugs are used to treat hyperthyroidism?
- β-blockers (e.g. propranolol) - symptomatic treatment
- Anti-thyroid medication; Thionamides → Propylthiouracil (PTU) or Carbimazole
- Prevent thyroid peroxidase enzyme coupling and iodinating tyrosine residues on thyroglobulin → reduce T3 and T4
- PTU also inhibits the conversion of T4 to T3
Name some common side effects of Thionamides in the treatment of hyperthyroidism?
- Rash (Most Common)
- Arthralgia
- Neuritis - inflammation of optic nerve
- Thrombocytopenia
- Hepatitis
- Vasculitis - inflammation of small and large blood vessels
- Agranulocytosis (most serious) - bone marrow stops production of WBC resulting in sore throat, fever, mouth ulcers
What groups of people are tested for TSH-R autoantibodies during pregnancy?
Individuals with current Graves’, past Graves’ and mothers who have previously had a child with Graves’
Measured at 22-26 weeks - if raised there is a risk of foetal/neonatal thyrotoxicosis
What is Foetal Thyrotoxicosis?
Transplacental transfer of thyroid stimulating autoantibodies from mother to fetus. These autoantibodies bind to the fetal thyroid stimulating hormone (TSH) receptors and increase the secretion of the thyroid hormones. Begins around 20th week of pregnancy and reaches its maximum by 30th week. Managed using anti-thyroid medication.
What complications is Foetal Thyrotoxicosis associated with?
- IUGR
- Foetal goitre
- Foetal tachycardia
- Foetal hydrops
- Preterm delivery
- Foetal demise
What is Gestational Thyrotoxicosis?
Transient form of thyrotoxicosis caused by excessive stimulation of thyroid gland by hCG. This leads to raise free T4 but low TSH. Usually limited to the first 12-16 weeks of pregnancy
What complications is Gestational Thyrotoxicosis associated with?
- Multiple gestation
- Hydatidaform mole
- Hyperplacentosis
- Choriocarcinoma
What are the differences between Graves Disease and Gestational Thyrotoxicosis?
Graves Disease symptoms predate pregnancy (and are more prominent during pregnancy)
N&V is greater in Gestational Thyrotoxicosis
Graves disease will present with Goitres
Graves disease ill have TSH-R antibodies
What changes in metabolism occur during pregnancy?
- ↑ erythropoetin, cortisol, noradrenaline
- ↑ cardiac output
- ↑ plasma volume
- High cholesterol triglycerides
- Pro-thrombotic and inflammatory state
- Insulin resistance
What medical conditions are associated with pregnancy?
- Pre-eclampsia; hypertension in pregnancy associated with seizures
- Obestetric cholestasis; abnormal liver function
- Gestational hyperthyroidism; excessive stimulation of thyroid gland by hCG
- Postpartum thyroiditis; results in either excessive or deficient secretion of thyroid hormones
- Gestational diabetes
- Transient diabetes insipidus
- Post-natal depression
- Postnatal autoimmune disease
Describe thyroid gland development
- Fetal thyroid follicles and thyroxine synthesis occurs at 10 weeks
- Fetal thyroid axis matures at 15-20 weeks
- For the first trimester (0-12 weeks) the foetus is reliant on maternal T4 to regulates neurogenesis, migration and differentiation then foetal T4
What changes to mother’s thyroid function occur during first trimester?
- ↑ in Thyroid Binding Globulin (TBG)
- ↑ HCG - stimulates TSH receptor
- ↑ free T4 - in response to TSH receptor stimulus by hCG
- ↑ in total T4
- ↓ TSH
- ↑ Iodine clearance
What changes to foetal thyroid function occur throughout pregnancy?
- First trimester: initial increase ↑ in TBG, total T4, TSH, and free T4 which continues throughout development
- Second trimester: ↑ total T3
- Third trimester: ↑ free T3
What type of hormone are TSH, LH, FSH, and hCG?
Glycoprotein hormones! Same α-subunit but a different β-subunit
What is the normal range for TSH during:
First Trimester
Second Trimester
Third Trimester
First Trimester - 0.1-2.5 mlU/L
Second Trimester - 0.2-3.0 mlU/L
Third Trimester - 0.3-3.0 mlU/L
What is Amiodarone?
Potent anti-arrhythmic used in individuals with atrial fibrillation, nodal fibrillation and ventricular tachycardia
Blocks Potassium channels to inhibit repolarisation
Why does Amiodarone commonly cause thyroid dysfunction?
- High in iodine (37% by weight)
- Lipid soluble (stored in adipose tissue)
- Long elimination half life
What two thyroid complications are commonly induced by amiodarone?
- Amiodarone Induced Hypothyroidism (AIH)
- Amiodarone Induced Thyrotoxicosis (AIT)
What is Amiodarone Induced Hypothyroidism?
Amiodarone has an inhibitory effect on thyroid hormone synthesis, leading to downregulation of peripheral receptors and hypothyroidism
What is the difference between Type 1 and 2 Amiodarone Induced Thyrotoxicosis?
Type 1 - Increased synthesis and release of thyroid hormone induced by drug-related iodine excess. Usually associated with pre-existing thyroid disease.
Type 2 - Destruction of the thyroid caused by direct toxicity of amiodarone. Characterised by excessive release of thyroid hormones without excessive production
What do acromegaly vs. gigantism have in common and how do they differ?
Both conditions caused by an excess of growth hormone (GH)
- AcromegalyOccurs in adulthood; following epiphyseal fusion
- GigantismOccurs in childhood; prior to epiphyseal fusionDefined a height >2SD for the patients age and sex
What is the mean age of diagnosis for Acromegaly?
44 years old; mean duration of symptoms is 8 years
Outline the GH axis:
- GHRH
From: arcuate nucleus of hypothalamus → ant. pituitary - GH
From: somatotropic cells of the ant. pituitary
Exhibits pulsatile secretion; levels vary wildly throughout the day - ILG-1
From: liver
Negative feedback: IGF-1 and GH inhibit GHRH secretion BUT promote somatostatin release (GHIH or SRIF).
What is the major cause of acromegaly?
Pituitary adenomas account for >90% of cases
What are rarer causes of Acromegaly?
excess secretion of GH from an ectopic source e.g. lung/adrenal tumours that produce GHRH or GH
Hypothalamic dysfunction e.g. hypothalamic tumours
What are the key clinical features of Acromegaly?
Insidious onset
Often diagnosed late
Headaches and visual changes
Large lips and nose
wide spaced Teeth
Deep skin creases
Large Hands and Feet
Hyperpigmentation
Acanthosis Nigricans
What are the Key Clinical features of Gigantism?
Headache and Visual Changes
Coarse Facial Features
Frontal Bossing
Tall stature
Large Hands and Feet
Obestity
What would you look for on examination for acromegaly /giagantism?
- Wide spaced teeth
- Prognathism: protrusion of lower jaw
- Frontal bossing: prominent, protruding forehead associated with a heavy brow ridge
- Males; deeping of their voice
- Males; carpel tunnel syndrom
What tests might you do you diagnose acromegaly and its complications?
Serum IGF-1 - Raised indicates periods of GH excess
Pituitary MRI
Glucose tolerance test:
patient is given 100g of glucose orally. Serum glucose is measured before and after glucose stimulation.
- In a healthy individual:
GH release is suppressed following the administration of exogenous glucose (i.e. < 0.6 mcg/L).
Now - as assays have improved - we are looking a suppression down to <0.2mcg/L - In a patient with acromegaly:
In patients with acromegaly, GH levels are increased above the testing threshold i.e. GH levels wouldn’t decrease in response to glucose stimulation.
What are the criteria for diagnosing acromegaly?
Acormegaly excluded if:
random GH <0.4ng/ml and normal IGF-1
If either are abnormal, progress to:
75mg glucose tolerance test (GTT)
Acromegaly excluded if:
IGF-1 normal AND GTT lowers GH <1ng/ml
What are some common Acromegaly Co-morbidities?
Hypertension and heart disease
Cerebrovascular events and headache
Arthritis
Insulin resistant Diabetes
Sleep Apnoea
What types of management would you offer your patient with acromegaly?
- Surgery (first-line)
Surgery to remove the pituitary adenoma
Microadenomas tend to have better results than macroadenomas as macroadenomas can be too big and dangerous to remove.
Recurrence is common, ~ >10% - Radiotherapy
Generally reserved for cases in which surgery fails (rarely a primary therapy). The biochemical response to radiotherapy can be slow at > 10 years.
What are the ways of combining medical theraapy with radiotherapy to treat acromegaly?
- Conventional; aka fractionated, therapy delivers a part of the complete radiation dose over several sessions i.e any radiation damage to normal cells can be repaired between treatments.
- Stereotactic; gives radiotherapy from many different angles around the body. The beams meet at the tumour. This means the tumour receives a high dose of radiation and the tissues around it receive a much lower dose.
- Gamma knife; type of stereotactic therapy - focused array of intersecting beams that concentrate at a target
- LINAC; combines two technologies - an MRI scanner and linear accelerator – to precisely locate tumours, tailor the shape of X-ray beams in real time and accurately deliver doses of radiation to moving tumours.
- Proton beam; treatment delivered by accelerated proton beams rather than X-rays
What is the biggest risk of radiotherapy when treating acromegaly?
The development hypopituitarism; therefore, it is generally avoided in those of reproductive age.
What is the main pharmacotherapy that would be used to treat Acromegaly?
What other pharmacological therapies could be used ?
Somatostatin receptor agonists (somatostatin analogues) - Octreotide/Lanreotide - inhibits GH secretion
Dopamine agonists - Cabergoline Bromocriptine
GH antagonists - Pegvisomant - lowers IGF-1 levels
What is the mechanism of action of somatostatin receptor agonists?
Negative regulator of GH
Can achieve control of GH and IGF-1
Prolactinoma is a tumour of what cell type?
Lactotroph
Prolactinomas can lead to a condition called?
Hyperprolactinemia: excess levels of prolactin in the blood
What else can cause hyperprolactinemia?
- Hypothalamic-pituitary stalk damage
- Drug induced e.g. anti-psychotics which block dopamine
- Pregnancy and lactation
- Systemic disorders e.g. CKD or cirrhosis
Outline the key clinical features of a prolactinoma?
Local effects of tumour
(particularly if macroadenoma)
- Headache
- Visual field defect (bitemporal hemianopia)
- CSF leak (rare)
- Systemic effect of prolactin
- Mensuration irregularity/amenorrhoea
- Infertility
- Galactorrhoea
- Low libio
- Low testosterone in males
- Erectile dysfunction in males
- Gynaecomastia in males
- Hypogonadism
How can we diagnose prolactinomas?
- MRI scan
- Prolactin levels in the blood
When is it particularly important to measure prolactin levels in the blood?
- Unexplained milk secretion (galactorrhea)
- Irregular menses or infertility in females
- Males with impaired sexual function and/or milk secretion
How do we manage prolactinomas?
- Medical therapy > Surgery
Recall: endogenous DA secretion from the hypothalamus is normally suppressing the secretion of prolactin from the ant. pituitary
Dopamine agonists (e.g. Cabergoline)
= drastic shrinkage with macroadenomas; reduced pressure on optic chiasm → sight saving
What are the Genes associated with T1DM?
HLA DR3
HLA DR4
What is the cause of T2DM?
Related to Metabolic Syndrome
It has a high environmental factor
Potentially a genetic component - increased risk with first degree relative Dx
What is the criteria to be diagnosed with Metabolic Syndrome?
3 or More of:
Fasting Glucose > 100mg/dl
Triglycerides > 150mg/dl
HDL < 50mg/dl (female) <40mg/dl (male)
Blood pressure >130/85
BMI >35 (female) >40 (male)
What is T1DM?
T4 hypersensitivity Rxn
Auto immune destruction of pancreatic beta cells
Causes absolute insulin deficiency
What is the cause of T1DM?
Triggered by environmental event (eg. virus)
Leads to autoimmune antibodies against beta cells
(HLA DR3 and HLA DR4)
What is the pathogenesis of T1DM?
Autoimmune Beta cell islet destruction - leads to absolute decrease in insulin
Therefore causes Hyperglycaemia
Low cellular glucose - Increased lipolysis and gluconeogenesis
Hyperkalaemia
What are the symptoms of T1DM?
Lean
Young Px
Polydipsia
Polyuria
Polyphagia
Weight loss
Glycosuria
Signs of DKA (ketoacidosis)
Why do patients with T1DM experience polyuria, Polydipsia and Glycosuria?
Increase glucose in blood
Increase glucose filtered in the kidney
Glucose in the kidney draws water into the kidney
Causes increased urination - polyuria
Causes Glycosuria - glucose in urine
Due to increased urination, the blood is hyperosmolar (high glucose)
detected by the hypothalamus and so stimulates thirst centres (causes polydipsia)
Why do patients with T1DM experience Polyphagia and weight loss?
Decreased glucose in the cells (no GLUT4)
Therefore cells need energy from Lipolysis and Gluconeogenesis
Increased Lipolysis and Increase proteolysis leads to weight loss
Leads to increased hunger - causes Polyphagia
How is T1DM diagnosed?
Random Plasma Glucose (RPG) = > 11.1 mmol/L
Fasting Plasma Glucose (FPG) = > 7.0 mmol/L
HbA1C = 48mmol/mol (6.5%)
Is there Pre-diabetes for T1DM and can this be altered with Lifestyle modification?
No - lifestyle modification will not prevent T1DM
What is the Treatment for T1DM?
Basal Bolus Insulin
Basal - longer acting to maintain stable insulin levels through out the day
Bolus - Faster acting - 30mins preprandial
What is the main acute complication in T1DM?
Diabetic Ketoacidosis (DKA)
From poorly managed T1DM
Absolute insulin deficiency - unrestricted lipolysis and gluconeogenesis
Not all glucose is usable so some is converted to ketone bodies
There are acid and their increased concentration leads to ketoacidosis
What are the symptoms of DKA in T1DM?
T1DM Sx +:
Kussmaul Breathing - Deep laboured breaths to blow off CO2 as compensation
Pear drop breath - ketones have a pear drop smell
Reduced tissue turgor - hypotension and tachycardia
What is the Diagnosis of DKA?
Ketones (blood) >3mmol/L
Hyperglycaemia > 11.1mmol/L - RPG
Acidosis (metabolic) - <7.3pH or <15mmol HCO3
+ Ketonuria, Glycosuria and Hyperkalaemia
What is the treatment for DKA?
ABCDE emergency
1st line is ALWAYS FLUID - Px die from dehydration
Then insulin + glucose + K+
What is T2DM?
Peripheral insulin resistance With partial insulin deficiency that tends to present later in life (30+)
What are the risk factors for T2DM?
Genetic link - FHx very strong
Smoking
Obesity
HTN
Sedentary lifestyle
What is T2DM a big risk factor for?
HTN
Silent MI
Nephrotic Syndrome
CKD
What is the pathogenesis of T2DM?
Peripheral insulin resistance (malfunctioned insulin intracellular activation pathway)
Decreased GLUT4 expression due to lower insulin
Some destruction of pancreatic beta cells
Causes hyperglycaemia with an increased insulin demand from a depleted Beta cell population
What are the Symptoms of T2DM?
Obese
Hypertensive
Older Px
Polydipsia
Polyuria
Nocturia
Glycosuria
Acanthosis Nigracans - dark pigmented skin folds
How is T2DM diagnosed?
Same as T1DM:
Random Plasma Glucose (RPG) = > 11.1 mmol/L
Fasting Plasma Glucose (FPG) = > 7.0 mmol/L
HbA1C = 48mmol/mol (6.5%)
What is Pre-diabetes?
Prediabetes is a condition in which your blood sugar or A1C levels are higher than normal but not high enough for a diagnosis of type 2 diabetes.
How is pre-diabetes diagnosed?
OGTT (oral glucose tolerance test) = 7.8-11
FPG = 6-6.9mmol/L
What advice should be given to a Px who is Pre-diabetic?
Lifestyle advice:
Diet
exercise
modify RFs
What is the Treatment for T2DM?
Metformin - Increase peripheral sensitivity to Insulin
If HbA1c >58mmol/mol then add sulfonylurea
If persistently high then consider 3rd drug - DPP4-i/ SGLT2 inhibitor
Then as a last resort give insulin.
What is the main acute complication of T2DM?
Hyperosmolar - Hyperglycaemic State (HHS)
Excessive hepatic gluconeogenesis (when not completely insulin deficient) leads to increased glucose in the blood
therefore become hyperosmolar and hyperglycaemic.
(don’t get ketogenesis so no DKA)
What are the symptoms of HHS in T2DM?
Severe T2DM
Decreased Consciousness - related to plasma osmolarity
How is HHS diagnosed in T2DM?
High Glycosuria
High plasma osmolarity (>300mol/L)
Hyperglycaemia
No ketonuria/hyperketonaemia
What is the treatment for HHS?
First give Insulin
Then give IV fluid
LWMH (Low molecular weight heparin) - anticoagulant as patients have thicker blood due to the glucose.
What are some common chronic T1DM and T2DM complications?
Macrovascular - Cardiovascular, cerebrovascular, peripheral vascular Disease
Microvascular - retinopathy, neuropathy, nephropathy
How does chronic diabetes lead to Macro/microvascular complications?
Hyperglycaemia can lead to glucose conjugating with proteins and lipids to create proinflammatory molecules.
These can lead to inflammation and LDL deposition leading to atherosclerosis
This will lead to Macrovascular complications
What is Hypoglycaemia?
Abnormally low blood glucose levels
What are the different Types of Diabetes?
T1DM
T2DM
MODY (Maturity Onset Diabetes of Youth)
Pancreatic Diabetes
Endocrine Diabetes
Malnutrition related Diabetes
What are the Causes of Hypoglycaemia?
Diabetes drugs:
Sulfonylureas - Stimulate insulin
Insulin
What are the symptoms of Hypoglycaemia?
Reduced consciousness
Dizziness
Sometimes may faint
What is the treatment for Hypoglycaemia?
IV glucose
(if no IV access then IM Glucagon)
Where is the Thyroid located anatomically?
Between C5-T1
2 lobes connected via an isthmus
What is the blood supply to the thyroid?
Inferior thyroid artery - branch of thyrocervical trunk (subclavian)
Superior Thyroid artery - branch of external carotid
How is T3/T4 synthesised?
Iodine is trapped and diffuses into the colloid
It binds to tyrosine residues on Thyroglobulin molecules using Thyroid peroxidase enzyme to produce T1/T2
TSH bind to TSH-R to stimulate the production of T3/T4 from T1/T2.
T3/T4 are released into the circulation.
Who is more likely to get hyperthyroidism?
Women
What is the main causes of hyperthyroidism?
Graves disease (75-80%)
Toxic multinodular Goitre (TMG) - nodules secrete thyroid hormone
Toxic Adenoma
What are the causes for DKA / HHS?
The 6 I
Decreased insulin supply: low insulin
Increased insulin demand (via stress):
Infections
Inflammation
Intoxication
Infarction
Iatrogenic
What is the Main complication found in T1DM and T2DM respectively?
T1DM - DKA
T2DM - HHS (may also get DKA in severe chronic T2DM)
Define Hyperthyroidism and its possible mechanisms?
Excess of thyroid hormones in the blood
Overproduction of thyroid hormone
Leakage of preformed hormone from thyroid
Ingestion of excess thyroid hormone
What is the function of T3 (active thyroid hormone)?
Increase glycogenolysis
Increase glycolysis
Increase lipolysis
What is the characteristic triad of symptoms in Graves disease?
Ophthalmopathy
Pretibial Myxoedema
Acropachy (characteristic rash)
Also diffuse goitre and thyroid eye disease
What is Graves Disease?
Autoimmune disease characterised by the presence of TSH receptor autoantibodies.
These stimulate the TSH-R
Leading to the over production of T3/T4
What are the Signs and Symptoms of Hyperthyroidism?
Symptoms:
Heat intolerance
Diarrhoea
Weight loss + Hyperphagia
Anxiety
Oligomenorrhoea
Signs (everything FAST):
Goitre
Tachycardia
exophthalmos - Protruding eyeball (graves specific)
Pretibial Myxoedema
Muscle wasting
Fine Tremor
What is the Diagnosis of Hyperthyroidism?
TSH-R Abs - In graves disease
Clinical Hx
Thyroid Function Tests (TFTs)
What do the results for Thyroid Function Tests (TFTs) signify
1’ Hyperthyroidism - Decrease TSH, Increase T4
2’ Hyperthyroidism - Increase TSH, Increased T4
Subclinical Hypothyroid - Increased TSH, = T4
Subclinical Hyperthyroid - Decreased TSH, = T4
What drugs can cause Hyperthyroidism?
Amiodarone
Iodine
Lithium
What investigation is done to distinguish between Graves disease and TMG?
Thyroid Ultrasound or RAIU (Radioiodine uptake test)
Presence of multinodular goitres in TMG
What is the treatment for Hyperthyroidism?
1st Line = Carbimazole - inhibits T3 to T4 conversion
(if contraindicated such as in pregnancy = use Propylthiouracil
+ Propranolol alongside - targets symptomatic effects
Can also use radioactive iodine - destroys thyroid tissue
Last resort is surgery
What are the complications of hyperthyroidism?
Thyroid storm - where large amounts of Thyroid hormone is released very quickly (A MEDICAL EMERGENCY)
Rapid deterioration of thyrotoxicosis
leads to systemic compensation causing AF, HTN and coma
What is the treatment for Thyroid storm?
Propylthiouracil + KI
What are some Graves specific signs and symptoms?
Diffuse goitre
Thyroid Eye disease
Pretibial Myxoedema
Acropachy
What are some Graves specific signs and symptoms?
Diffuse goitre
Thyroid Eye disease
Pretibial Myxoedema
Acropachy
What are some consequences of Hyperthyroidism during pregnancy if left untreated?
Low birth Weight
Pre eclampsia
Preterm delivery
Risk of still birth
Risk of Miscarriage
what is a transient hyperthyroidism?
Where the thyroid overproduces thyroid hormone for a short period of time before then it may lead to hypothyroidism.
This usually occurs due to destruction of the thyroid gland and therefore T3/T4 hormones are leaked/released but then greater destruction leads to less T3/T4 being produced causing hypothyroidism
What is a side effect of carbimazole?
Agranulocytosis
Presents as a sore throat
What is hypothyroidism?
Where there is too little thyroid hormone
What are the main causes of hypothyroidism?
Hashimoto’s Thyroiditis - more common in developed world
Iodine Deficiency - more common in developing world
Post partum Thyroiditis
What is Hashimoto’s Thyroiditis?
Hypothyroidism due to aggressive destruction of thyroid cells.
Autoimmune condition where there are Anti-TPO (thyroid peroxidase) Abs that leads to less production of T3 and T4.
What are the symptoms of hypothyroidism?
(everything slow)
Symptoms:
Cold intolerance
Constipation
Weight gain
lethargy
menorrhagia
Signs:
Bradycardia
Slow reflexes
Cold hands
Goitre - in hashimoto’s and I2 deficiency
Pretibial Myxoedema
What are the different potential causes of Hypothyroidism at each level?
Primary:
Hashimoto’s Thyroiditis
Drugs - Lithium, Amiodarone
Iodine Deficiency
Transient:
Post Partum Thyroiditis
Secondary:
Hypopituitarism
Who is more at risk of developing Hypothyroidism?
Women
Elderly
Post partum
What is the Epidemiology of T1DM?
Younger onset (<30yrs)
Usually lean
North European
What is the Epidemiology of T2DM?
Older onset (>30yrs)
Usually overweight
More common in african/asian
What is the Diagnostic test for Hypothyroidism?
TFTs:
1’ Hypothyroidism = High TSH, Low T4
2’ Hypothyroidism = Low TSH, Low T4
Subclinical Hypothyroidism = High TSH, = T4
Anti TPO Antibdoies increased in titres
Typically anaemic
What is the Treatment for Hypothyroidism?
Levothyroxine (T4 analogue) - must be careful with the dose to prevent iatrogenic hyperthyroidism
What is the main complication of Hypothyroidism?
Myxoedema coma - usually infection precipitated
Rapid loss of T4
Hypothermia, loss of consciousness, heart failure
What is the treatment for Myxoedema coma?
Levothyroxine,
Abx
Hydrocortisone until adrenal insufficiency has been ruled out
What are the different types of Thyroid carcinoma?
Papillary - (70%)
Follicular (25%)
Anaplastic - worst prognosis
What are the Symptoms of Thyroid carcinoma?
Presents as Thyroid Nodules - hard and irregular
May have local compression on the recurrent laryngeal nerve - hoarse voice
What is the diagnosis for thyroid carcinoma?
Fine needle aspriation biopsy
TFTs
Thyroid ultrasound
Where are common metastasis sites for thyroid carcinoma?
Lung
Bone
Liver
Brain
What is the treatment for Thyroid carcinoma?
Papillary / Follicular - Thyroidectomy / radioiodine
Anaplastic - palliative care
Describe the feedback loop for water excess?
Ingestion of water
Decrease plasma osmolality
Increase cellular hydration
Decrease thirst - decrease water intake
Decrease ADH secretion - Increase urine excretion of water
Decrease total body water
What does ADH bind to to act?
GPCR:
V1a - in vasculature (similar to adrenoceptors)
V2 - in collecting tubules of nephron - water reabsorption
V1b - In pituitary in the brain
What controlls the release of ADH?
- Osmoreceptors in hypothalamus
- Routine
- Baroreceptors in brain stem and great vessels
- Emergency
Define osmolality?
Concentration of a solute per KG of solution
mOsmol/Kg
What drives osmolality?
The number of molecules (concentration)
What affect does size of particles have on osmolality?
- Size is irrelevant - a molecule of sodium has the same effect as a molecule of albumin
It is the number of particles (concentration) that makes a difference to the osmolality
What molecules are present at a high enough concentration to affect osmolality?
- Sodium
- Potassium
- Chloride
- Bicarbonate
- Urea
- Glucose
What exogenous molecules can affect osmolality?
- Alcohol
- Methanol
- Polyethylene glycol
- Manitol
What is the normal osmolality range?
282-295 mOsmol/kg
How is osmolality calculated?
2x[Na] mmol/L + [Glucose] mmol/L + [urea] mmol/L
Why is sodium doubled in the osmolality calculation?
To account for the anion gap
What is the mechanism of action of vasopressin in the kidney?
- Acts on V2 receptors
- Stimulates an intracellular cascade
- Aquaporin-2 proteins are synthesised and inserted into the apical membrane
- Permeability to water is increased
- Increased reabsorption of water
- Concentration of Urine
What is Diabetes Insipidus now known as?
Arginine Vasopressin Deficiency - Central diabetes insipidus
Arginine Vasopressin Resistance - Nephrogenic diabetes insipidus
What are the signs of AVP deficiency/ AVP resistance?
Polyuria
Polydipsia
No glycosuria
What are the diagnostic parameters for AVP deficiency/ AVP resistance?
- > 3L urine per day
- Check renal function
- Check serum calcium
What are the biochemical signs of AVP deficiency/ AVP resistance?
- Inappropriately dilute urine for plasma osmolality
- Serum osmolality >300 and urine osmolality >200
- Normonatraemia or hypernatraemia
- Water deprivation test
What is AVP Deficiency?
(formerly cranial diabetes insipidus)
Lack of vasopressin (ADH)
What is the cause of AVP deficiency?
Genetic - mutations in ADH gene
Idiopathic
Tumours - Craniopharyngioma, germinoma, metastases
Trauma
Infections - TB, meningitis
Vascular
Inflammatory
What is AVP resistance?
(formerly Nephrogenic Diabetes insipidus)
Resistance to vasopressin (ADH) action - reduced kidney response to ADH
What are the causes of AVP resistance?
Osmotic Diuresis - DM
Renal tubular acidosis
Drugs
Metabolic
ADH-R mutation - V2 receptor defect
What are the symptoms of AVP deficiency/ AVP resistance?
Polyuria
Polydipsia
Hypernatraemia
Lethargy
confusion
Severe dehydration
What is the pathogenesis of AVP deficiency/ AVP resistance?
Decreased ADH secretion/response to ADH
Cannot reabsorb water
Water lost through urine
dilute high volumes of water
dehydration
How is AVP deficiency/ AVP resistance diagnosed?
3+ L of urine daily (24 hrs)
Water deprivation test (no fluid for 8 hrs)
-Normally serum Osm stays normal and urine Osm increases
-AVP Def/Rest - Serum Osm rises and urine Osm does not change
Inject IM desmopressin - differentiates between Deficiency and Resistance
AVP Deficiency - will provide adequate ADH to have an effect and therefore concentrate urine
AVP resistance - Similar mechanism to ADH and therefore will have no effect on the kidney. Urine stays dilute
What is the Treatment for AVP deficiency/ AVP resistance?
Treat underlying condition
AVP Deficiency - Desmopressin
AVP Resistance - Thiazides (hydrochlorothiazide)
How will Thiazides work to treat AVP resistance?
Block Na+/Cl- transporter in DCT
Increases Na+ in filtrate in CD.
encourages Na uptake and H2O follows in CD
will concentrate urine and increase water reabsorption
Loss of K+ ions
What is the definition of Hyponatraemia>
- Mild130-135mmol/l
- Moderate 125-129mmol/L
- Severe <125mmol/l
What is the normal range for sodium?
134-144mmol/l
What are the causes of hyponatraemia?
- Excess water
- SIADH
- Drip arm
- Sodium deficiency
- Renal failure
- Malignancy
- Liver failure
- Addison’s
What can happen to the brain as a result of hyponatraemia?
- Water moves into the brain as a result of reduced osmolality
- Producing brain oedema
- Swelling in the brain leads to expulsion of electrolytes and osmalytes
- Water loss accompanies loss of solutes, reduces brain swelling
- If hypoosmolality is sustained, brain volume normalises and brain becomes adapted to hyponatraemia
What is the difference between acute and chronic hyponatraemia and how does this affect its management?
- Acute - 48 hours
- Rapid correction safer and may be necessary
- Chronic - CNS adapts
- Correction must be slow
- <8mmol/24hr
How can Hyponatraemia be classified?
Biochemically - Mild, Moderate, Severe Na decrease
Syptomatically - Mild, Moderate, Severe
Aetiology - Hypovolaemic, Euvolemic, Hypervolemic
Acuity of Onset - Actue (<48hrs), Chronic (>48hrs)
What are the Signs and Symptoms of Hyponatraemia?
Vomiting
Headache
Decreased GCS
Muscle Weakness
coma
Severe Hyponatraemia
Seizures
Neurological complications
Brainstem herniation
How does hyponatraemia lead to brainstem herniation?
Low Na means increased compensatory H2O
Enters skull and raises ICP
Causes Hyponatraemic encephalopathy
Risk of brainstem herniating through foramen magnum
What is the diagnosis of Hyponatraemia?
Decreased serum Na
Normal Serum K+
High urine Osm as concentrated urine and dilute serum
What is an important differential diagnosis for SIADH?
Na depletion:
Give 0.9 saline
Na depletion - serum Na will normalise
SIADH - Serum fails to normalise
What is SIADH?
Syndrome of Inappropriate ADH:
Too much ADH is released when it should not be
What is an important defining factor when determining if the hyponatraemia is caused by SIADH or fluid overload/dehydration?
SIADH will release more ADH
Will increase water retention but have compensatory Na excretion to maintain euvolemia
Therefore SIADH presents as Euvolemia and Hyponatraemia
Other Hyponatraemia causes can be fluid overload (Liver failure) or dehydration
What causes SIADH
Tumours (SCLC, prostate, pancreatic)
Trauma
Infection - TB, Meningitis
SIADH:
SCLC
Infection/immunosuppressed
Abscesses
Drugs - SSRI
Head trauma
What are the features of SIADH?
Low osmolality
Urine inappropriately concentrated
Normal thyroid and adrenal function
What ar ethe clinical features of SIADH?
Normal circulating volume
No oedema
What is the treatment for Hyponatraemia?
Need to know cause to determine Tx:
If Fluid overload - Restrict fluids
If SIADH - Restrict fluid + hypertonic saline + treat underlying cause
If dehydration - Saline replacement
What is the management of SIADH?
Treat underlying cause
Fluid restrict <1L/24hrs
Sometimes Demeclocycline - decreases responsivity of ADH
Sometimes Vaptan - V2 receptor antagonist
Give some brief detail about the Anterior Lobe of the pituitary gland.
- Glandular tissue
- Accounts for 75% of total weight
- Develops from the roof of the mouth (Rathke’s pouch); loses stalk of rathke’s pouch
Give some brief detail about the Posterior Lobe of the Pituitary Gland?
- Nerve tissue
- Contains axons that originate in hypothalamus.
- Nerves from the floor of the 3rd ventricle
What anatomical structures make up the Parasellar Area.
- Pituitary gland (anterior + posterior)
- Hypothalamus
- Optic chiasm - compression by pituitary tumour can lead to visual defects
- Pituitary stalk
Name some common pituitary mass lesions?
- Non-functioning pituitary adenomas (silent)
- Endocrine active pituitary adenomas
- Malignant pituitary tumours:
- Functional and
- Non-functional pituitary carcinoma
- Metastases in pituitary (breast, lung, stomach, kidney)
- Pituitary cysts: Rathke’s cleft cyst, Mucocoeles.
What is a NFPA?
Non functioning pituitary adenoma
A benign growth in the pituitary gland that does not produce excessive hormones into the blood
What is a craniopharyngioma?
Rare type of brain tumour derived from pituitary gland embryonic tissue.
Where does a Craniopharyngioma arise from?
Squamous epithelial remnants of Rathke’s pouch
What are the two clinical subtypes of Craniopharyngioma?
- Adamantinous (classical)
- Papillary
Are Adamantious Craniopharyngioma more common in adults or children?
Children!
What are the symptoms associated with Craniopharyngioma?
- Headaches and raised intracranial pressure
- Visual defects (20% of children and 80% of adults)
- Hormonal imbalances, leading to;
- Short stature and delayed puberty in children
- Decreased libido
- Amenorrhea
- Diabetes insipidus
Behavioural change; due to frontal or temporal extension
What is a Meningioma?
Tumour forming from the three membranous layers of the meninges
Give some brief detail about Meningiomas?
- Commonest tumour of region after pituitary adenoma
- Slow growing
- 90% benign
- Often a complication of radiotherapy
How do you investigate pituitary dysfunction?
Tumour Mass Effects - Headaches, CSF Rhinorrhoea, Visual field defects, CN palsy
Hormone excess - Hormone tests
Hormone deficiency
How would you measure the Pituitary Thyroid Axis?
> Measure free T4 and TSH in plamsa
- Primary Hypothyroidism
- Raised TSH, low free T4
- Hypopituitary
- Low free T4 with normal/ low TSH
- Graves’ disease
- Suppressed TSH and high free T4
- Thyrotropinoma (TSHoma)
- High free T4 with normal/ high TSH
- Hormone resistance
- High free T4 with normal or high TSH
How would you measure the Gonadal Axis in men?
> Measure Testosterone and FH/ FSH in plasma
- Primary hypogonadism
- Low testosterone, raised LH/FSH
- Hypopituitary
- Low testosterone, low/ normal LH/FSH
- Anabolic steroid use
- Supressed LH, low testosterone
How would you measure the Gonadal Axis in Women?
> Measure Oestradiol and FH/ FSH in plasma
- Before puberty
- Oestradiol very low/ undetectable
- Low LH and FSH; FSH slightly higher than LH
- At puberty
- Pulsatile LH increases
- Oestadiol increases
- During monthly menstrual cycle
- Mid-cycle surge in LH and FSH
- Oestradiol increases throughout the cycle
- Primary ovarian failure (including menopause)
- High LH and FSH; FSH higher than LH
- Low oestradiol
- Hypopituitary
- Low oestradiol
- Normal or low LH and FSH
- Incidence of oligo- or amenorrhoea
How would you measure the Hypothalamus Pituitary adrenal axis?
> Measure Cortisol and ACTH and Short Synacthen Test (SST); response to injection of synthetic ACTH
- Primary Adrenal Insufficiency
- Low cortisol, high ACTH
- Poor response to synacthen
- Hypopituitarism
- Low cortisol, low/ normal ACTH
- Poor response to synacthen
How would you measure the GH/IGF1 axis?
> Measure of Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF1)
- GH is secreted in pulses; greatest pulse at night, low or undetectable levels between pulses
- GH levels fall with age and are low in obesity
- Measure IGF-1 and GH stimulation test
- Insulin stress test
- Glucagon test
- Other
How would you measure the Prolactin levels?
> Measure Prolactin
- Negative feedback control of dopamine
- Measure prolactin or cannulated prolactin; three samples over an hour to exclude stress or venepuncture
- Prolactin maybe raised because
- Stress
- Drugs: antipsychotics
- Stalk pressure
- Prolactinoma
How would you treat pituitary tumours causing hormone deficiencies for each hormone?
GH - Replacement GH
LH/FSH - Testosterone in men, Oestradiol +/- Progesterone in women
TSH - Levothyroxine
ACTH - Hydrocortisone
ADH - DDAVP
What makes up the HPA axis?
- Hypothalamus
- Pituitary
- Adrenals
What are the hormones involved in the HPA axis, where do they get secreted from and where is their action?
- Cortisol
- Released from adrenal glands
- Act on pituitary and hypothalamus
- Corticotrophin releasing hormone
- Released from hypothalamus
- Acts on pituitary
- Adrenocorticotropic hormone
- Released from pituitary
- Acts on adrenal glands
When do you get peaks of cortisol?
- On waking up
- Lunchtime
- Dinnertime
What resets the circadian rhythm clock?
Light
What is the secondary messenger from central to peripheral clocks?
Glucocorticoids
Give a cause of primary adrenal insufficiency
Addison’s disease
What is the cause of Addison’s?
Autoimmune
Give a cause of secondary adrenal insufficiency
Hypopituitarism
Give a cause of tertiary adrenal insufficiency
Suppression of HPA axis from steroids
What can cause the suppression of the HPA axis?
- Steroids
- Oral
- Inhaler
- Creams
What would you look for in the history to diagnose adrenal insufficiency?
- Symptoms
- Fatigue
- Weight loss
- Poor recovery from illness
- Adrenal crisis
- ## HeadachePast history
- TB
- Post partum bleed
- Cancer
- Family history
- Autoimmunity
- Congenital disease
- Drug history
- Any steroid use
- Etomidate
- Ketoconazole
What signs would you look for to suspect adrenal insufficiency?
- Pigmentation and pallor
- Hypotension
What biochemical investigations would you do to diagnose adrenal insufficiency?
- 09:00 Cortisol and ACTH
- If cortisol > 450-500 nmol/l, adrenal insufficiency unlikely
- Cortisol < 100nmol/l high likelihood of adrenal insufficiency
- ACTH > 22pmol/l primary adrenal insufficiency
- ACTH < 5pmol/l secondary adrenal insufficiency
Renin/Aldosterone - Elevated in primary adrenal insufficiency
Synacthen Test
What is the Synacthen Test?
- Stimulation test
- Synacthen is synthetic ACTH
- 250µg IV measure at 0 and 30 mins
- Cortisol >450-550nmol/l, adrenal insufficiency unlikely
How would you treat adrenal crisis?
- Take bloods to test for ACTH and cortisol
- Confirmation of adrenal crisis when patient is stable
- Immediate hydrocortisone (100mg IV, IM)
- Fluid resuscitation (1L N/saline 1 hour)
- Hydrocortisone 50-100mg IV/IM 6 hourly or 200mg/24 hour
- Continue until patient has stabilised
- When stable, wean to normal replacement over 24-72 hours
- If the patient has primary adrenal insufficiency, give fludocortisone (100-200µg)
What should patients with adrenal insufficiency carry with them?
10x 10mg Tablets Hydrocortisone
Why should hydrocortisone be administered without prejudice?
Cannot harm the patient and can be life saving
What’s the recommended glucocorticoid replacement therapy?
Hydrocortisone 15-25mg in 2-3 divided doses
When should glucocorticoid replacement therapy be taken?
- First on waking
- Second midday
- Third 17:00
When should prednisolone be administered in glucocorticoid replacement therapy?
- 3-5mg/d orally once or twice a day
- Patients with reduced compliance to hydrocortisone
When is DHEA given?
Women with low libido and low energy levels
What does DHEA do?
Provides normal body hair in young women with adrenal insufficiency
What is the diagnostic criteria for diabetes generally?
- If symptomatic:
- fasting glucose greater than or equal to 7.0 mmol/l
- random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose tolerance test- OGTT, at 2hrs post ingestion)
- If asymptomatic:the above criteria apply but must be demonstrated on TWO separate occasions
Epidemiology of T1DM:
- Commonest age at diagnosis is 5-15 years but can occur at any age
- Relatively rare: prevalence of 3/1000 among children and adolescents
- ~300,000 patients in the UK
What are the presenting features of T1DM?
- Thirst: osmotic activation of hypothalamus
- Polyuria: osmotic diuresis
- Weight loss: lipid and muscle loss due to unrestrained gluconeogenesis
- Hunger: lack of useable energy resources
- Pruritus vulvae and balanitis (swelling of the foreskin or head of the penis): vaginal candidiasis; chest infections
- Blurred vision: altered acuity due to uptake of glucose/water into lens
Which three main features indicate T1DM?
- Weight loss
- SHORT history of of severe symptoms (weeks)
- Moderate or large urinary ketones
Any 2/3 of these features indicates T1DM and are indication for immediate insulin therapy at ANY age
What are the presenting features of T2DM?
- Usually present > 30 years old
- Onset is gradual
- FH is often positive; familial hypercholesterolemia
- Almost 100% concordance in identical twins
Being able to differentiate between the two is becoming more difficult. Why?
Because of increased levels of obesity, T2DM is being diagnosed in younger patients including children.
Uncontrolled T2DM can present with weight loss and ketonuria
What signs can we use to distinguish T1DM from T2DM
- Early onset in childhood/adolescence
- Lean body habitus; BMI normal or below normal range
- Acute onset of osmotic symptoms; symptoms come on fast
- Prone to ketoacidosis
- High levels of islet autoantibodies
What four associated autoantibodies can you test for in T1DM?
- Anti GAD
- Pancreatic islet cell Ab
- Islet antigen-2 Ab
- ZnT8
What are the aims of treatment in T1DM?
- Relieve symptoms
- Prevent DKA
- Prevent microvascular and macrovascular complications i.e. CVD
What are the microvascular complications of T1DM?
- ~30% in the UK will develop diabetic nephropathy
- Those with nephropathy tend to develop proliferative retinopathy and severe neuropathy (e.g. patients may lose sensation in feet → ulcers → amputations) with major effect on quality of life
How do we treat T1DM?
Insulin treatment: “Basal-bolus” regime - once/twice daily medium acting insulin plus pre-meal quick acting insulin.
Patient need to:
- Have the ability to judge CHO intake
- Be aware of blood glucose lowering effect of exercise
What factors make it difficult for people with diabetes to sustain effective self management?
- Risk of hypoglycaemia
- Too arduous a treatment
- Risk of weight gain
- Interference with lifestyle
- Lack of sufficient training from diabetes teams
Physiologically, what happens to your patient if you miss a T1DM diagnosis?
DKA:
Fat metabolism and the formation of ketones
Reduced insulin → fat breakdown and formation of glycerol (a gluconeogenic precursor) and FFA
FFAs:
- Impair glucose uptake
- Are transported to the liver → provide energy for gluconeogenesis
- Are oxidised to from ketone bodies (β-hydroxy butyrate; acetoacetate; acetone) **which the body can use as a form of energy
How does ketoacidosis manifest and how dose the body respond?
- Absence of insulin and rising counterregulatory hormones = increased hyperglycaemia and rising ketones
- Glucose and ketones escape in the urine but lead to an osmotic diuresis and falling circulating blood volume
- Ketones (which are weak acids) also cause anorexia and vomiting
- = vicious cycle of increasing dehydration; hyperglycaemia and increasing acidosis eventually lead to circulatory collapse and death
What are the symptoms of DKA?
- abdominal pain
- drowsiness/confusion
- polyuria; polydipsia
- dehydration (av fluid loss of 5-6L)
- hypotension and tachycardia
- Kussmaul respiration (deep hyperventilation)
- Acetone-smelling breath (‘pear drops’ smell)
How do we diagnose DKA?
- Blood ketones are ≥3.0 mmol/L OR there is ketonuria (more than 2+ on standard urine sticks)
AND - Blood glucose is >11.1 mmol/L OR known diabetes
AND - Bicarbonate (HCO3) is <15.0 mmol/L AND/OR venous pH is <7.3.
How do we manage DKA?
fluid replacement: most patients with DKA are deplete around 5-8 litres. Isotonic saline is used initially.
- insulin: an intravenous infusion should be started at 0.1 unit/kg/hour. Once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be started
- correction of hypokalaemia (NB: K+ may be high on presentation despite total body K+ deficit - due to acute shift of K+ out of cells with acidosis - levels will subsequently fall with insulin and rehydration therapy, i.e. anticipate this fall!
- long-acting insulin should be continued, short-acting insulin should be stopped
- treat the underlying cause e.g. infection or MI
What are some complications of DKA
- gastric stasis
- thromboembolism: venous and arterial as blood is made thicker by hyperglycaemia
- arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
- iatrogenic due to incorrect fluid therapy:cerebral oedema*, hypokalaemia, hypoglycaemia
- acute respiratory distress syndrome
- acute kidney injury
- aspiration pneumonia in drowsy/comatose patient
What are some symptoms of hypoglycaemia?
- Loss of concentration; confusion and coma
Caused by acute deprivation of glucose within the brain leading to cerebral dysfunction - Sweating; tremor; palpitations (autonomic activation); hunger
Caused by release of glucagon and adrenaline
What is the physiological response to hypoglycaemia?
- Hormonal response
The first response of the body is decreased insulin secretion. This is followed by increased glucagon secretion. Growth hormone and cortisol are also released but later. - Sympathoadrenal response
Increased catecholamine-mediated (adrenergic) and acetylcholine-mediated (cholinergic) neurotransmission in the peripheral autonomic nervous system and in the central nervous system
What does MODY stand for and can you describe it?
Maturity-Onset Diabetes of the Young
It is the commonest type of monogenic diabetes (~1% diabetes) and is usually diagnosed < 25 years old. It is:
- Autosomal dominant
- Non-insulin dependent
- A single gene defect alters beta cell function
- Tends to be non-obese
Because patients are young and not obese, they are often diagnosed as T1DM. But the big difference here is that they are not insulin dependent and therefore wouldn’t need to be taking insulin as opposed to a T1DM patient.
What specific genetic mutations give rise to the different types of MODY?
HNF1A mutation (MODY 3)
HNF4A mutation (MODY 1)
Glucokinase (GCK) gene mutation (MODY 2)
Which presentations may indicate MODY rather than another type of diabetes?
- Parent affected with MODY
- Absence of islet autoantibodies
- Evidence of non-insulin dependence
- Good control on low-dose insulin
- No ketosis
- Measurable C-peptide: in T1DM C-peptide test is negative within 5 years due to compete autoimmune beta cell destruction but in T2DM and MODY, C-peptide persists
When is “Permanent Neonatal Diabetes (PNDB)” diagnosed?
< 6 months (usually de novo; from birth)
Neonates may also present with:
- small size
- epilepsy
- muscle weakness
Which mutations cause PNDM?
Mutations in genes that encode Kir6.2 and SUR1 subunits of the beta cell ATP sensitive K+ channel.
What causes maternally inherited diabetes and deafness (MIDD)?
A mutation in mitochondrial DNA
What are the features of MIDD?
(Maternally Inherited Diabetes and Deafness)
- Loss of beta cell mass
- Overweight
- Sensorineural hearing loss
Overall, a similar presentation as T2DM
What is lipodystrophy?
An abnormal distribution of fat in the body, usually due to a selective loss of adipose tissue.
Associated with severe insulin resistance; dyslipidemia; hepatic stenosis; hyperandrogenism; PCOS
How can diabetes lead to Acute pancreatitis
Due to inflammation; transient hyperglycaemia due to increased glucagon secretion
What commonly causes chronic pancreatitis?
Chronic use of alcohol: it alters secretions; forms proteinaceous plugs that block ducts and act as a foci for calculi formation
Treat by stopping alcohol intake and starting insulin
What is Hereditary Haemochromatosis (HH)?
an accumulation of iron in various organs of the body such as the liver, hear, pituitary and pancreas?
What is the Cause of HH?
Autosomal recessive: a triad of cirrhosis, diabetes and bronzed hyperpigmentation
Treatment: most patients need insulin
What other deposition disease can cause diabetes?
- Amyloidosis
- Cystinosis
How can cystic fibrosis (CF) lead to diabetes?
The CFTR gene regulates Cl- secretion. In patients with defective CFTR, they have thick mucus secretions which can block ducts and lead to pancreatic fibrosis. CF survival rates are better than in the past, but this means people are living longer with the disease and microvascular complications are increasing
25-50% of CF patients will have diabetes. Insulin treatment will be needed.
In which disease do we see an excessive secretion of GH?
Acromegaly
How does Acromegaly lead to diabetes?
Presents similar to T2DM;
Increased GH
insulin resistance rises
impairs insulin action in the liver and peripheral tissue
In which disease do we see a glucocorticoid excess?
Cushing’s syndrome
How can Cushing’s Syndrome lead to Diabetes?
This leads to increased insulin resistance and reduced glucose uptake into peripheral tissues.
Hepatic glucose production is increased through stimulation of gluconeogenesis via increased substrates (proteolysis and lipolysis)
What are phaeochromocytomas?
Rare tumour of adrenal gland tissue → excess epinephrine and norepinephrine
This leads to increased gluconeogenesis and decreased glucose uptake .
Can you name some drugs that can induce diabetes?
- Steroids
- Tacrolimus
- Thiazides
- Protease inhibitors (HIV)
- Antipsychotics
How does diabetes mellitus cause morbidity and mortality?
- Acute hyperglycaemia which can lead to hyperglycaemic hyperosmotic state or diabetic ketoacidosis
- Chronic hyperglycaemia can cause tissue damage and complications (micro and macrovascular)
- Side effects of treatment (namely hypoglycaemia)
What are the macrovascular complications of diabetes mellitus?
- Stroke
- CVD
- Leading cause of mortality
- Peripheral vascular disease
What percentage of diabetes patients experience diabetic neuropathy?
30-50%
What are the symptoms and signs of diabetic neuropathy?
Pain:
Allodynia
Paraesthesia
Burning
Hyperaethesia
Autonomic:
Gastroparesis
Diarrhoea/Constipation
Incontinence
Orthostatic Hypotension - Postural hypotension
Insensitvity:
Foot ulceration
Infection
amputation
Charcot foot
What is Paraethesia?
Abnormal sensation (normally tingling or pins and needles) due to peripheral nerve damage
What is Allodynia?
pain response to normally non-painful stimulus
What is Charcot Foot?
Weakening of the bones of the foot, they are more prone to fractures and the stress of walking leads to deformity of the foot
What is the treatment of diabetic neuropathy?
What is the treatment of diabetic neuropathy?
Describe the progression of diabetic neuropathy
- gloves and stocking sensory loss
- Starts in tips of fingers and toes and works its way up
What are the risk factors for diabetic neuropathy?
- Hypertension
- Smoking
- Poor glycaemic control
- Diabetic duration
- BMI
- Triglycerides
- Total cholesterol
What is the treatment for painful diabetic neuropathy?
- Good glycaemic control
- Tricyclic antidepressants/SSRIs
- Anticonvulsants (carbamazepine, Gabapentin)
- Opioids (tramadol, oxycodone)
- IV lignocaine
- Capsaicin
What screening tests are available for diabetic neuropathy?
- Test sensation
- Vibration perception
- Ankle Reflexes
What percentage of patients with diabetes experience foot ulceration?
15%
What is the risk associated with diabetic foot ulceration?
Amputation
What are the stages in the disease process that lead to amputation in diabetic foot ulceration?
- Neuropathy
- Trauma
- Ulcer
- Failure to heal
- Infection
- Amputation
What are the signs of a ‘high-risk foot’?
- Peripheral neuropathy
- Painless foot
- Lack of sweating in the skin can cause skin to become cracked and dry
- Suggest moisturising
- Peripheral vascular disease
- Deformity
- Increases pressure on the foot that can lead to ulceration
- Hyperextended toes due to extensor muscles of the feet become more dominant
Where is peripheral vascular disease most common?
Distal sites
What are the symptoms and signs associated with peripheral vascular disease?
- Intermittent claudication
- Rest pain
- Diminished or absent pedal pulses
- Coolness of feet and toes
- Poor skin and nails
- Absence of hair on feet and legs
What is the treatment for peripheral vascular disease?
Quit smoking
Walk through the pain
Surgical Intervention
What are the risk factors for diabetic retinopathy?
- Long duration of diabetes
- Poor glycaemic control
- Hypertension
- Insulin treatment
- Pregnancy
Who’s eligible for retinopathy screening?
Patients with diabetes over the age of 11
What is the pathogenesis of diabetic retinopathy?
- Hyperglycaemia induces apoptosis of perictyes (which causes micro-aneurysms) and endothelial cells (which increases permeability of capillaries, proteins leak into retina)
- It does this by increasing blood flow to the retinal capillaries and inducing abnormal metabolism
- Loss of pericytes cause endothelial cells to respond by increasing turnover, which cause thickening of the capillary wall and cause ischaemia
- Vascular growth factors are released in response to ischaemia, which cause the growth of new, fragile blood vessels which are prone to bursting
How does diabetic retinopathy get graded?
- R0 - None detected
- R1 - Background changes; screened once a year
- R2 - Pre-proliferative; early changes screened 6-monthly
- R3 - Proliferative; called into eye clinic to look at interventions to protect vision
- M - Maculopathy; changes that happen close to the fovea
- P - Photocoagulation; laser treatment has been done
- U - Unclassifiable
What’s the treatment for diabetic retinopathy?
- Laser therapy
- Aim is to stabilise the changes
- Target abnormal blood vessels to stop them bleeding
- Does not improve sight
What are the risks of treatment for diabetic retinopathy?
- Difficulty with night vision
- Loss of peripheral vision
- Temporary drop in acuity (if intensive, reversible)
- Vitreous haemorrhage (very rare)
- Benefits far outweigh risks
How successful is the treatment for diabetic retinopathy?
- Very effective
- 90% of severe eye sight loss prevented by early treatment
What is the hallmark of diabetic nephropathy?
Proteinuria
What is nephropathy a major risk for?
CVD
What does diabetic nephropathy lead do?
Progressive decline in renal function
What are the risk factors of Diabetic retinopathy?
Poor blood pressure and blood glucose control
What is the pathophysiology of diabetic nephropathy?
- Glomerulus changes
- Increased injury of glomerulus
- Filtration of proteins
- Diabetic nephropathy
How is diabetic nephropathy classified?
Monitor levels of albumin excreted in urine
What are the levels for Normoalbuminuria
- Spot collection (mg/mmol) (albumin/creatine ratio)
- Male - <2.5
- Female - <3.5
- 24-hour collection (mg/24hr)
- <30
- Timed collection (µg/min)
- <20
What are the levels for Microalbuminuria?
- Spot collection (mg/mmol) (albumin/creatine ratio)
- Male - 2.5-25
- Female 3.5-35
- 24-hour collection (mg/24hr)
- 30-300
- Timed collection (µg/min)
- 20-200
What are the levels for Macroalbuminuria?
- Spot collection (mg/mmol) (albumin/creatine ratio)
- Male - >25
- Female - >35
- 24-hour collection (mg/24hr)
- > 300
- Timed collection (µg/min)
- > 200
If the albumin spot test is normal in a diabetic patient what should you do?
- Repeat the test within 3-6 months
- Preferably first morning midstream void
How is diabetic nephropathy graded?
Chronic kidney disease classification
When does diabetic nephropathy develop in type 1 and type 2 diabetes?
T1DM - Around 10 years after diagnosis
T2DM - Can be present at diagnosis
What is the treatment for diabetic nephropathy?
- Blood pressure control
- Glycaemic control
- ARB/ACEi
- Proteinuria control
- Cholesterol control
What is Cushings Syndrome?
Hypercortisolaemia of any cause - excess cortisol production leading to excess cortisol in the blood
What is Cushings Disease?
Hypercortisolaemia caused by a pituitary adenoma secreting excess ACTH that acts on the adrenals to increase cortisol.
What are the causes of Cushings syndrome?
ACTH dependent - Cushings diseae - Pituitary adenoma (80%) or ectopic ACTH production (5-10%)
ACTH independent - Iatrogenic cause - Steroid use, adrenal carcinoma/adenoma
What is pseudo cushings?
Mimics cushings syndrome
Due to alcohol excess or severe depression.
Resolves in 1-3 weeks
What is the pathogenesis of cushings syndrome?
Constantly high cortisol levels
Therefore CRH and ACTH are inhibited (unless ACTH dependent)
Therefore there is loss of the circadian rhythm release of cortisol
What are the symptoms of Cushings Syndrome?
Moon face
Central obesity
abdominal striae
Osteoporosis
Thin easy bruising
Muscle wasting
Hyperglycaemia - leading to DM, HTN and CVD
plethoric complexion
What is the diagnosis of Cushings syndrome?
Rule out oral steroids - if on steroids then stop these)
Random serum cortisol measured at 12 am
Dexamethasone suppression test:
- Measure Cortisol levels at midnight.
Give dexamethasone
- in Normal person it should supress cortisol production by activating negative feedback loop.
- Measure cortisol 8hrs later
- Non cushings - suppression of cortisol - cortisol levels >50nmol/L
- Cushings - little/no suppression
What is the diagnosis of Cushings syndrome?
Rule out oral steroids - if on steroids then stop these)
Random serum cortisol measured at 12 am
Dexamethasone suppression test
if positive - Measure Plasma ACTH
Low ACTH - adrenal adenomas/carcinomas
High ACTH - Cushings disease
What is the Dexamethasone suppression test?
Measure Cortisol levels
Give low dose dexamethasone
This inhibits CRH and ACTH release
Should decrease cortisol
if cushings is caused by endogenous cortisol then levels would remain unchanged.
What is the treatment of Cushings syndrome/disease?
Cushings disease - Transsphenoidal resection or bilateral adrenalectomy
Cushings syndrome - Drug cause - drug is reduced/withdrawn
adrenal steroid inhibitors.
What are some complications of Cushings syndrome?
Osteoporosis
T2DM
What is adrenal insufficiency?
Where the adrenal glands cannot make enough adrenal hormones such as cortisol.
What is the main cause of Adrenal insufficiency in the Developed and developing world?
Developed - Addisons disease
Developing - TB (+Sarcoidosis)
What is the main cause of 1’ adrenal insufficiency?
Addison’s Disease
What is the main cause of 2’ Adrenal insufficiency?
Iatrogenic - Steroids - suppression of HPA axis
Adrenal mets (lung liver and breast)
Adrenal Haemorrhage (meningococcal septicaemia)
What is Addison’s Disease?
Autoimmune destruction of the adrenal glands.
Auto Abs against 21-alpha-Hydroxylase
reduced cortisol and aldosterone produced.
What is the Pathogenesis of Addison’s Disease?
Destruction of adrenal cortex
Increase ACTH - no feedback
(therefore high ACTH, Low adrenal hormones)
How can you distinguish Addison’s disease from 2’ adrenal insufficiency?
Addison’s disease - High ACTH, Low Adrenal hormones
2’ Cause - HPA suppression - Low ACTH, Low adrenal hormones (no hyperpigmentation)
What is the major symptom of addison’s diseaes?
Hyperpigmentation due to excess ACTH activating melanocytes
What are the symptoms of Adrenal insufficiency?
Lethargy
Weight loss
Postural hypotension (due to reduced aldosterone)
Vitiligo
Hyperpigmentation (in 1’)
Hypoglycaemia
Abdo pain and vomiting
How is adrenal insufficiency diagnosed?
Short Synacthen Test:
- measure basal cortisol at 9am (normally highest here)
- administer Synacthen
- Sample cortisol again after 30 mins.
If plasma cortisol > 580nmol/L after 30 min - not Addisons
Auto 21-alpha-hydroxylase Abs
ACTH (high in 1’) (low in 2’) at 9am.
What is the treatment for adrenal insufficiency?
Hydrocortisone
Fludrocortisone
What is adrenal crisis?
Severe adrenal insufficiency - Hypocortisolaemia
Leads to N + V+, renal failure
Tx is immediate Hydrocortisone, IV saline and dextrose (if hypoglycaemic)
What is Conn’s Syndrome?
Hyperaldosteronism
Excess aldosterone independent of RAAS
What is Conn’s Syndrome the most common cause of?
Secondary HTN
What are the causes of Conn’s Syndrome?
2/3 - Adrenal adenoma
1/3/ Bilateral Hyperplasia
What is the pathogenesis of Conn’s Syndrome?
Increase aldosterone
Increase Na and H2O and decrease K+
Causes Hypertension and Hypokalaemia
What are the symptoms of Conn’s Syndrome?
Resistant HTN (unfixable with ACEi / Bb)
Hypokalaemia
Muscle weakness
Paraesthesia
Polydipsia
Polyuria
How is Conn’s Syndrome diagnosed?
Aldosterone Renin ratio
Serum aldosterone not suppressed with 0.9 IV saline or Fludrocortisone
Hypokalaemic ECG
What is the Treatment for Conn’s Syndrome?
Surgery (Laparoscopic Adrenalectomy)
Spironolactone (aldosterone antagonist)
What is Phaeochromocytoma?
Adrenal medullary tumour that secretes excess catecholamines (NAdr and Adr)
What are the causes of Phaeochromocytoma?
Usually inherited disorder associated with
Men - multiple endocrine neoplasia
Nerurofibromatosis
What are the symptoms of Phaeochromocytoma?
Hypertension
Pallor
Very sweaty
Tachycardic
What is the Diagnosis of Phaeochromocytoma?
Plasma Metanephrines + Normetanephrine
Urinary catecholamines
CT image of tumour
What is the Treatment of Phaeochromocytoma?
Alpha blocker first ( phenoxybenzamine)
Beta blocker second (atenolol)
Surgery if possible.
What is a complication of Phaeochromocytoma?
Hypertension crisis (180/120+ BP)
Tx Phentolamine
What are the causes of Hypercalcaemia?
Hyperparathyroidism
Bone malignancy
drugs - Thiazides
Excess Ca intake
What ECG finding would you see in Hypercalcaemia?
Long QT
What are the Symptoms of Hypercalcaemia?
BONES
STONES
GROANS
MOANS
What would PTH do in hypercalcaemia?
PTH decreases
Except in hyperparathyroidism
What causes Hypocalcaemia?
CKD (decreased Vit D activation)
Severe Vit D deficiency
Hypoparathyroidism
Drugs - Bisphosphates, Calcitonin
Acute Pancreatitis
What ECG finding would you see in Hypocalcaemia?
Short QT
What are the key signs of Hypocalcaemia?
Chvostek sign
Trousseau sign
What would PTH do in hypocalcaemia?
PTH always increases
Except in hypothyroidism
What are the causes of Hyperkalaemia?
AKI
Drugs - NSAIDS, Spironolactone, ACEi
Addison’s Disease
DKA (+DM)
What is the pathogenesis of Hyperkalaemia?
Increase K+
decreases threshold for AP
Easier depolarisation
Arrhythmias
What is the symptoms of hyperkalaemia?
Fast irregular pulse
VF risk
Myalgia
What Ix would you find in hyperkalaemia?
ECG:
Go - Absent P wave
Go long - Prolonged PR interval
Go tall - Tall T waves
Go wide - Wide QRS
Increased K+ on U&Es
What is the treatment of Hyperkalaemia?
If urgent - Calcium Gluconate
If non urgent - Insulin (+dextrose)
What is the cause of Hypokalaemia?
Thiazides = loop diuretics
Conn’s
Renal tubular acidosis
GI losses
Reduced Intake
What are the Symptoms of Hypokalaemia?
Hypotonia
Hyporeflexia
Arrhythmias (AF)
What is the Diagnosis of Hypokalaemia?
ECG:
Small inverted T waves
Prominent U waves
ST Depression
Pr Prolongation
What is the treatment of Hypokalaemia?
K+ replacement
Aldosterone antagonist - Spironolactone
What are the associated autoimmune diseases associated with T1DM?
Hypothyroidism
Addison’s Disease
Coeliac Disease
What requirements Define Diabetic Ketoacidosis?
Hyperglycaemia
Ketones - Urine ketones >2+
Metabolic Acidosis - plasma HCO3 <15mmol/l
What are the sick day rules in adrenal insufficiency?
- What should patients carry with them?
- 10x 10mg tables hydrocortisone
- When ill, what should the patients do to their steroid dose
- If unwell with fever or flu like symptoms, double dose of steroids
- If in doubt, double dose of steroids
- What should the patient do if they’re vomiting and can’t take their medication?
- Emergency injection of hydrocortisone 100mg IM
- If they are unable to inject themselves but are vomiting, what should the patient do?
- 20mg hydrocortisone 6 hourly and repeat if vomited
- Call an ambulance/go to ED
- Why should hydrocortisone be administered without prejudice?
- Cannot harm the patient and can be life saving
A high HbA1c % increases your risk of developing which conditions?
Diabetic retinopathy
Nephropathy
Neuropathy
Microalbuminaemia
What are the 3 main objectives of T2DM treatment?
Reducing blood glucose
Reduce the risk of CDV, CKD, Macro/microvascular complications
Weight reduction, increase physical activity, decrease dietary fat.
What is the first line treatment for T2DM?
Metformin
Then dietary advice
What is the mechanism of action of metformin?
- ↑ insulin sensitivity by enhancing peripheral glucose uptake through inducing phosphorylation of GLUT-4 enhancer factor
- ↓ hepatic gluconeogenesis (via a complex cell signalling pathway!)
What effect does metformin have on weight?
Slight decrease in weight; more likely weight neutral
What are the notable side effects of metformin?
- Gastrointestinal upset
- Lactic acidosis
What is a side effect of sulphonylureas that has reduced their use as a second line treatment for T2DM?
Increased weight gain patients experienced whilst taking them
What is the mechanism of action of sulphonylureas?
Stimulate the release of insulin by pancreatic β-cells.
Initiates cellular depolarisation to cause an influx of Ca2+ into the cell → increased fusion of insulin granulae w/ cell membrane = release of insulin
What are the notable side effects of sulphonylureas?
- Hypoglycaemia
- Weight gain
- Hyponatraemia
Give examples of sulphonylureas?
Gliclazide
Glimepiride
What is replacing sulphonylureas as the 2nd line treatment in T2DM?
SGLT2 inhibitors
What is the mechanism of action of SGLT2 inhibitors?
Inhibit Na/Glu cotransporters (SGLT-2) to inhibit reabsorption of glucose by the kidney (PCT)
What effect do SGLT-2 inhibitors have on weight?
Typically result in weight loss
What are the notable side effects of SGLT2 inhibitors?
- Increased risk of UTI
- Increased risk of candidiasis (thrush)
Give some examples of SGLT2 inhibitors?
- canagliflozin
- dapagliflozin
- empagliflozin
What is the mechanism of action of GLP-1 analogues?
- GLP-1 is excreted by L-cells of the intestine upon ingestion of food.GLP-1 → binds to the GLP-1 receptor → inhibits glucagon release → stimulation of insulin release → decrease of blood sugar
(GLP-1 is has a very short half-life - they are broken down by DPP-4 very quickly - so a GLP-1 analogue can be administered to mimic its action)
- Induces a delay in gastric emptying
What effects do GLP-1 analogues have on weight?
Typically result in weight loss
(a major advantage in T2DM)
What is the route of administration of GLP-1 analogues
Injectable on:
Subcutaneous
What are the notable side effects of GLP-1 analogues?
- Induces nausea and vomiting
- Increased risk of pancreatitis
Give an example of a GLP-1 analogue
Liraglutide
What is the mechanism of action of DPP-4 inhibitors?
- Dipeptidyl-peptidase 4 (DPP-4) is an enzyme present in vascular endothelial lining which inactivates the incretin hormones GIP and GLP-1DPP-4 Inhibitors are competitive antagonists of the DPP-4 enzyme, enhancing the effects of GIP and GLP-1.
- Little effect on gastric emptying
What effect do DPP-4 inhibitors have on weight?
Very little effect, “weight neutral”
Are there any notable side effects to DPP-4 inhibitors?
Generally well tolerated: less likely to cause nausea and vomiting
- Increased risk of pancreatitis
Give examples of DPP-4 inhibitors
- Vildagliptin
- Sitagliptin
Give examples of DPP-4 inhibitors
- Vildagliptin
- Sitagliptin
What is the mechanism of action of Thiazolidinones?
- ↑ adipogenesis and fatty acid uptake by activating PPAR-γ (its endogenous ligand is FFA)
- This leads to altered gene expression = ↑ storage of FFA so there are less FFA in the circulation.
- Other cells become more dependent on glucose for respiration and so increase their uptake of glucose → reduced blood glucose levels
What effect do thiazolidinones have on weight?
Induce weight gain
What are the notable side effects of Thiazolidinones?
- Weight gain
- Fluid retention
- Contraindicated in: CCF; high risk of fractures; macula oedema
- Increased CV risk; lipid abnormalities (apart from Pioglitazone)
Give examples of Thiazolidinones?
Pioglitazone
What surgery could be provided to patients with T2DM?
Bariatric surgery:
Bypass surgery
Sleeve Gastrectomy
