Phase 2 - endocrine Flashcards
What occurs in the fasting state in a non-diabetic human
All glucose from liver (some from kidney)
- breakdown of glycogen
- gluconeogenesis
glucose delivered to insulin independent tissues, brain and RBCs
Insulin levels are low
Muscle uses free fatty acids for fuel (even low levels of insulin will prevent unrestrained breakdown of fat)
alpha cells unrestrained so glucagon secretion
What occurs after feeding (post prandial) in a healthy human
Physiological need to dispose of a nutrient load
- Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
- Ingested glucose helps to replenish glycogen stores both in liver and muscle
- High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall (don’t produce any more ketones)
* Alpha cells kept in state of chronic inhibition (via local insulin release from beta cells)
What % of ingested glucose normally goes to which tissues?
40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
Define diabetes mellitus
A group of chronic disorders characterised by the body’s impaired ability to produce or respond to insulin resulting in abnormal glucose metabolism leading to HYPERGLYCAEMIA
Types of diabetes mellitus
- Type 1
- Type 2
- GESTATIONAL (occurs during pregnancy - usually goes after birth)
- MATURITY ONSET DIABETES OF THE YOUNG (MODY) - autosomal dominant (range of types but usually affects production of insulin)
- NEONATAL diabetes
- WOLFRAM syndrome (rare genetic disorder associated with diabetes mellitus, insipidus, optic atrophy and deafness)
- ALSTROM syndrome (rare genetic syndrome with retinal degradation (first feature noticed in childhood), hearing loss, cardiomyopathy, obesity, type 2 diabetes et more)
- LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA or type 1.5 diabetes - looks similar to type 1 but with some characteristics of type 2)
- Type 3 diabetes (another disease damages pancreas e.g. cancer)
- STEROID INDUCED diabetes (steroids can increase blood glucose levels)
- CYSTIC FIBROSIS diabetes (build up of mucus can lead to inflammation and scarring of pancreas which can damage cells producing insulin) - DUE TO PANCREATITIS
Risk factors for type 1 diabetes
Northern European - esp Finnish
Family history of DM T1
Genetic predisposition- HLA-DR3 or HLA-DR4 / HLA DQ8 (heuman leukocyte antigen genes - name of mhc in humans) in > this occurs in 90% of cases
ENVIRONMENTAL factors- exposure to a specific virus
Family or personal history of autoimmune disease
What is the pathophysiology of diabetes type 1
Glucose is unable to enter the cells of the body as the GLUT transporter (specifically GLUT4) is insulin dependent. This means without insulin, the GLUT4 dont bind to the cell membrane and glucose cannot be transported into cells. All the glucose then stays in the blood which causes hyperglycaemia.
As the cells are unable to access the glucose, the body thinks it is in a fasting state and gluconeogenesis occurs which increases the hyperglycaemia.
What is the typical presentation (Sx) of type 1 diabetes mellitus?
Manifests in CHILDHOOD. Commonly present with DKA.
Get polydipsia (extreme thirst), polyuria, sudden unexplained weight loss
Why is polydipisa a sign/symptom of diabetes mellitus
Excessive water excretion (due to osmotic diuresis from presence of increased glucose) leaves the body thirsty as the thirst centre in the hypothalamus is stimulated.
Explain why polyuria and glycosuria are signs/symptoms of diabetes mellitus?
Glucose draws water into the urine by osmosis this is called osmotic diuresis.
There is high levels of glucose in the blood and not enough glucose can be reabsorbed as kidneys have reached the renal maximum reabsorptive capacity of glucose.
Thus excessive levels of glucose and water are excreted
Why is weight loss a symptom/sign of diabetes mellitus?
Excessive fluid depletion and the accelerated breakdown of fat (lipolysis) and muscle (proteolysis) secondary to insulin deficiency causing weight loss. Sudden weight loss is more common in T1 DM as there is absolute insulin deficiency which means lipolysis and proteolysis occur much more suddenly/quickly compared to T2 DM as T1 has no insulin so no glucose can enter the cells whereas in T2 DM insulin is still produced (relative insulin deficiency) so not as much lipolysis and proteolysis occur until Diabetes is more advanced.
How is diabetes mellitus 1 diagnosed in a symptomatic patient
Symptoms of diabetes mellitus AND
RAISED PLASMA GLUCOSE detected ONCE
- if fasting glucose measured it should be >/= to7mmol/L of glucose
- if random glucose measured: >/= 11.1 mmol/L
What is the normal blood sugar range?
When fasting: 4.0 -5.4 mmol/L (less than 3.9 mmol/L is low and less than 3.0 mmol/L is dangerously low; cause for immediate action)
2 hours after eating: up to 7.8mmol/L
What would a diagnostic blood test for diabetes yield if done on a healthy person?
Random glucose: Below 11.1 mmol/L
Fasting glucose: Below 5.5 mmol/L
2 hour post prandial: Below 7.8mmol/L
How is diabetes diagnosed in an asymptomatic patient
MUST show raised glucose on 2 SEPERATE occasions
- if fasting glucose measured it should be >/= to7mmol/L of glucose
- if random glucose measured: >/= 11.1 mmol/L
- if Oral Glucose tolerence test done:
* Fasting: ≥7mmol/L
* 2 hrs after glucose ≥11.1 mmol/L
What HbA1c level is indicative of DM
≥6.5% (≥48 mmol/mol)– don’t tend to use for T1 as T1 is sudden onset and HbA1c gives average for the last 3 months
42-47 mmol/mol or 6-6.4% is indicative of pre-diabetes
Why is it recommended that patient’s cycle their insulin injection sites
Injecting into the same spot can cause a condition called “lipodystrophy”, where the subcutaneous fat hardens and patients do not absorb insulin properly from further injections into this spot.
A 3-year-old boy with a history of Type 1 diabetes mellitus presents to Accident and Emergency with vomiting and lethargy. On examination, he appears dehydrated. Capillary blood gas and capillary blood ketone tests are performed, which confirm a diagnosis of moderate diabetic ketoacidosis (DKA).
Which of the following treatments should be commenced first?
IV insulin infusion
IV sodium bicarbonate
IV 0.9% sodium chloride
Oral fluids and subcutaneous insulin
Continuous subcutaneous insulin infusion (CSII) pump
Initial management of DKA involves FLUID AND POTASSIUM replacement in order to correct the hypovolaemia, acidosis, ketonemia and total body hypokalaemia associated with this condition. So IV 0.9% sodium chloride is right ans.
It is important to note that fluid replacement, though vital to treatment, should be cautious as there is also an increased risk of cerebral oedema with fluid overload in DKA patients. Therefore, fluid boluses should be avoided if possible and fluid should be replaced at a slightly reduced rate
Define diabetic ketoacidosis
a life threatening, medical emergency. It is defined by its diagnosis
To diagnose DKA you require:
Hyperglycaemia (i.e. blood glucose > 11 mmol/l)
Ketosis (i.e. blood ketones > 3 mmol/l)
Acidosis (i.e. pH < 7.3)
normal pH range of human insides
7.35 - 7.45
Normal blood ketone level
less than 0.6 mmol/L
Causes/risk factors for DKA
*Untreated T1DM or Interruption of insulin therapy
*Undiagnosed DM
*Infection/Illness
*Myocardial Infarction (which is also at increased risk of happening in a low glucose, high ketone/fatty acid environment)
Pathophysiology of DKA
- Ketoacidosis: state of uncontrolled catabolism associated with insulin deficiency
COMPLETE absence of insulin -> unrestrained increased hepatic gluconeogenesis and decreased peripheral glucose uptake -> (hyperglycaemia) -> osmotic diuresis (icreased glucose in urine pulls more water into urine) by kidneys -> DEHYDRATION/loss of electrolytes
Peripheral lipolysis -> increased circulating free fatty acids -> FFAs undergo ketogenesis -> converted to ketone bodies in mitochondira -> acummulate causing METABOLIC ACIDOSIS
POTASSIUM imbalance: insulin normally drives potassium into cells. In DKA serum potassium high or normal (excess lost via urine) but total body potassium low (no potassium stored in cells)
What is a potential danger that can occur once insulin treatment is started after being diabetic ketoacidotic
Severe hypokalaemia can occur quickly as K+ can now be transported into cells via increased sodium-potassium pump activity as insulin is present leaving less K+ in serum. This can lead to fatal arrhytmias and weakness (heart and muscles struggle to contract)
Typical presentation of DKA
Nausea and Vomiting
Dehydration which can cause hypotension
Acetone-smelling breath (‘pear drops’/fruity breath)
Abdominal pain
Drowsy/ Confused can progress to a coma
Reduced consciousness
Hyperventilation (Kussmaul breathing - deep laboured breathing)
Symptoms of DM: polydipsia, polyuria, glycosuria
How is DKA diagnosed? What is normally investigated?
DKA should be recognised from clinical features and confirmed with a blood glucose measurement (hyperglycaemia) and a blood gas sample (metabolic acidosis with respiratory compensation).
Hyperglycaemia (i.e. blood glucose > 11.1 mmol/l)
Ketosis (i.e. blood ketones > 3 mmol/l)
Acidosis (i.e. pH < 7.3 and/or bicarbonate < 15 mmol/L) - ABG
Urea and electrolytes (urea and creatinine raised due to dehydration; Total body potassium low as a result of osmotic diuresis but serum potassium concentration raised because of absence of insulin)
Urine dipstick –glycosuria and ketonuria
Treatment for DKA
Immediate ABC management (Airway, breathing, circulation) if unconscious.
Replace the fluid loss with IV 0.9% saline (recommended to be done slowly over 48 hours to avoid complications)
Replace the deficient insulin: Give insulin + glucose (to prevent hypoglycaemia) which both inhibit gluconeogenesis and thus ketone production
Monitor blood glucose closely- Therapy can lead to a shift of K+ into cells resulting in hypokalaemia so treat this if necessary.
Treat underlying triggers, for example with antibiotics for septic patients.
What is a complication of treatment for DKA
Cerebral oedema
There is initially hypernaetremia in DKA. Decreased osmolarity of blood due to IV fluids being given causes osmotic shift to occur. Water moves into tissues, including brain, which causes brain to swell and potentailly get damaged within confines of skull -> can lead to rapid deterioration, coma, death.
A 47-year-old male presents to his GP with weight loss, polyuria and polydipsia. The GP suspects type 2 diabetes mellitus.
Which one of the following describes the correct cut-off value for diagnosis of type 2 diabetes mellitus?
Fasting plasma glucose >7.9mmol/L
Oral glucose tolerance test ≥11.1 mmol/L
HbA1c ≥ 58mmol/L
Low random C-peptide
Random plasma glucose >6.9mmol/L
Oral glucose tolerance test ≥11.1 mmol/L
Define DMT2
Relative insulin deficiency due to the beta cells of the islets of Langerhans not producing enough insulin and insulin resistance as the body’s cells respond poorly to insulin and which results in hyperglycaemia.
Causes/risk factors for DMT2
Non-Modifiable-
Older age,
Ethnicity (Black, Chinese, South Asian),
Family history
Male
Modifiable-
Obesity,
Sedentary lifestyles,
High carbohydrate diet,
Hypertension
Pathophysiology of DMT2
Repeated exposure to high levels of glucose leads to the repeated release of insulin which makes the cells in the body become resistant to the effects of insulin.
More insulin is made to compensate.
Over time, the pancreas (specifically the beta cells) becomes fatigued and damaged by producing so much insulin and they start to produce less.
A continued onslaught of glucose on the body in light of insulin resistance and pancreatic fatigue leads to chronic hyperglycaemia.
Typical presentation of DMT2
Polydipsia- extreme thirstiness.
Polyuria- excessive urination
Polyphagia-exessive hunger (unexplained weight loss doesn’t become apparent till more serious for T2 DM)
Glycosuria- excessive glucose in urine
Can also get Acanthosis nigricans (darkening of skin creases e.g. like in obesity, cushing’s, hypothyroid)
Why is polyphagia a symptom of DM
Although there’s a lot of glucose in the blood it cannot enter the cell which leaves cells starved for energy. This causes the body to undergo lipolysis and proteolysis which causes weight loss which leaves people hungry.
Which investigations can be done for DMT2? What confirms diagnosis?
1) HbA1c test— Gold standard (tells us average BG for last 3 months)
HbA1c >48mmol/mol = DIABETES DIAGNOSIS
HbA1c >42-47 mmol/mol = PRE-DIABETES DIAGNOSIS
2) Blood tests
Random plasma glucose > 11.1mmol/L = DIABETES DIAGNOSIS
Fasting plasma glucose > 7mmol/L = DIABETES DIAGNOSIS
3) Oral Glucose tolerance test
Fasting > 7mmol/L = DIABETES DIAGNOSIS
2 hrs after glucose > 11.1 mmol/L = DIABETES DIAGNOSIS
(If individual is symptomatic need to have symptoms of hyperglycemia and one abnormal value for one of the above; if asymptomatic requires 2 abnormal values)
Treatment for DMT2
1st line- LIFESTYLE MODIFICATIONS- e.g. weight loss, dietary modifications (low GI food, smoking cessation, exercise, blood pressure control (ACE-i) and hyperlipidaemia control (Statins)
2nd line- METFORMIN (if newly diagnosed patients blood glucose are above 48mmol/L after lifestyle modifications)
3rd line- add either a SULFONYLUREA, PLOGLITAZONE (thiazolidinedione), DPP-4 INHIBITOR (and GLP-1 ANALOGUES), SGLT-2 INHIBITOR. The decision should be based on individual factors and drug tolerance.
4th line- INSULIN
Complications of DM
Macrovascular:
- Atherosclerotic cardiovascular disease (stroke, hypertension, coronary artery disease, peripheral artery disease)
(increased risk of actherosclerosis as hyperglycaemia induces oxidative stress and inflammation which can cause endothelial dysfunction)
Microvascular:
- Nephropathy (diabetic kidney disease)
- Retinopathy
- Peripheral neuropathy (can lead to diabetic foot disease)
- Autonomic neuropathy
Metabolic:
- dylipidaemia
- diabetic ketoacidosis
- hyperosmolar hyperglycaemic state
Hyperglycaemia can also suppress the immune system and provide optimal environment for pathogens
What is the main advantage of metformin as a treatment of DMT2
It rarely causes hypoglycaemia
Action of sulphonylureas. Give examples of these drugs.
- stimulate insulin release by binding to beta cell receptors
- imporove glycaemic control (1-2% in HbA1c)
HOWEVER: does NOT prevent gradual failure of insulin secretion
E.g. gliclazide (most commonly used), glibenclamide
Side effects of sulphonylureas
- significant weight gain
- hypoglycaemia (occasionally prolonged and fatal, particularly in the elderly and when renal function is impaired)
Action of thiazolidinediones. Give the names of specific drugs in this catagory
- Bind to the nuclear receptor PPARy (peroxisome proliferator-activated receptor)
- Activate genes concerned with glucose uptake and utilisation and lipid metabolism
- Improve insulin sensitivity (reduce resistance)
HOWEVER: only has a theraputic effect if the patient has insulin
Glitazones (relatively rarely used but may be used in some sub-groups)
- Pioglitazone (aka ACTOS)
side effects of thiazolidinediones
- weight gain
- increased risk of of heart failure
- increased risk of fractures
(NHS website also said resp infections, eye issues and peripheral pins and needles)
NOTE: doesn’t usually cause hypoglycaemia
What are the qualities of an ideal diabetes type 2 drug
- Reduce appetite and induce weight loss
- Preserve β-cells and insulin secretion
- Increase insulin secretion at meal time
- Inhibit counterregulatory hormones which increase blood glucose such as glucagon
- Not increase the risk of hypoglycaemia during treatment
What are the effects of GLP-1?
- Stimulates insulin release
- Improves insulin sensitivity
- Increases beta cell mass and maintains beta cell function
- Supresses glucagon secretion
Enhances glucose disposal - SLows gastric emptying
- Reduces food intake
Suppresses appetite
Where is GLP-1 secreted
Secreted from L cells in the intestine
What does DPP-4 do
Rapidly degrades GLP-1
Enzymatic cleavage and it has high renal clearance so half-life of native GLP-1 is around 1-2 minutes
Examples of GLP-1 analogues/agonists
Exenatide (BYETTTA) twice daily
Once weekly exenatide (BYDUREON)
Liraglutide (VICTOZA) once daily
Lixisenatide (LYXUMIA) once daily
Dulaglutide (TRULICITY) once weekly
Semaglatide (OZEMPIC - can also be taken orally) once weekly
These are given SUBCUTANEOUSLY and all also reduce weight and CVD independant of glucose lowering so people may take thing slike ozempic purely as weight loss drugs
Oral semaglutide daily given (rybeesus)
DPP-4 inhibitors (oral)
Both these oral options have only modest glucose lowering effect and NO effect on CVD or weight
Action of SGLT2 inhibitors. Give examples of these agents.
Acts in distal section of proximal convoluted tubule to block reabsorption of glucose in the kidney , increase glucose excretion and lower blood glucose levels
Are now licensed in type 1 diabetes
E.g.
Empagliflozin
canagliflozin
dapagliflozin
Side effects of SGLT2 inhibitors
(Cadidiasis) Genital thrush (as you are peeing out sugar), increased risk of euglycaemic ketoacidosis (including in type 2 diabetes)
May have specific benefit in reducing CV mortality, reduces blood volume (less hypertension), and increases weight loss
How is insulin administerd and what are its main side effects
Subcutaneously
HYPOGLYCAEMIA
Weight gain
Lipodystrophy
Action of metformin; main side effects
Increases insulin sensitivity, decreased hepatic gluconeogenesis
Cannot be used in patients with eGFR of <30 ml/min
Side effects:
GI upset, lactic acidosis (as it blocks pyruvate carboxylase which converts pyruvate to oxaloacetate in the first step of gluconeogenesis which leads to a beuild up of lactic acid)
Define Hyperosmolar hypreglycaemic state (HHS)
Life threatening emergancy characterised by marked hyperglycaemia, hyperosmolality (because of increased glucose and potassium levels in serum (osmotic shift?)) and usually no ketosis.
(Typically presents in the elderly with type 2)
Pathophysiology of HHS
Decreased insulin levels are:
- sufficient to inhibit hepatic ketogenesis (i.e. so diabetic ketoacidosis cannot occur as its not absolute insulin deficiency)
BUT
- insufficient to inhibit hepatic glucose production (so cause increased levels of glucose leading to hyperglycaemia)
- Hyperglycaemia results in osmotic diuresis with associated loss of sodium (and some potassium)
Severe volume depletion results in a significant raised serum osmolarity (typically > 320 mOsmol/kg (= 320 mmol/kg) - tho this is actually osmoLality as it is kg not L), resulting in hyper viscosity of blood.
Presentation of HHS
General: fatigue, lethargy, nausea and vomiting
Neurological: altered level of consciousness, headaches, papilloedema (optic disk swelling due to increased intracranial pressure), weakness
Haematological: hyperviscosity (may result in myocardial infarctions, stroke and peripheral arterial thrombosis)
Cardiovascular: dehydration, hypotension, tachycardia
CHARACTERISED BY:
severe hyperglycaemia (>30 mmol/L)
hypotension
hyperosmolarity/osmolality (usually >32 mosmol/kg)
NO significant acidosis (ph > 7.3; bicarb > 15mmol/L) or ketosis
How is HHS diagnosed
CHARACTERISED BY:
severe hyperglycaemia (>30 mmol/L)
hypotension
hyperosmolarity/osmolality (usually >32 mosmol/kg)
NO significant acidosis (ph > 7.3; bicarb > 15mmol/L) or ketosis
Diagnosis is based on these characteristics being present
Treatment of HHS
FLUID REPLACEMENT with 0.9% saline
VTE (venous thrmboembolism) prophylaxis to deminish risk of deep vein thrombosis- these patients are high risk due to dehydration e.g. Low molecular weight heparin (anticoagulant) e.g. Enoxaparin
Give Insulin- Only if high levels of ketones or glucose doesn’t decrease after fluid replacement
Complications of HHS
Stroke, MI (due to thick blood), PE (pulmonary embolism - from deep vein thrombosis)
Insulin related Hypoglycaemia- can occur with excessive high-dose insulin therapy
Treatment related Hypokalaemia- can occur with excessive high-dose insulin therapy
A 56-year-old diabetic female is admitted to hospital in order to have intravenous antibiotics for community acquired pneumonia. On day 4 of admission, she becomes confused and drowsy after which she has a short seizure which spontaneously resolves. Her capillary glucose is noted at 2.6mmol/L and she is unconscious.
What is the most appropriate immediate management of this patient?
Oral glucose tables
IV glucose
IV glucagon
IM insulin
IV glucose (fastest way to get glucose in and reverse hypoglycaemia, also she’s unconscious so can’t give orally anyways)
Definition of hypoglycaemia
Occurs when glucose conc falls below normal fasting range. Usually defined as BLOOD GLUCOSE LEVELS BELOW 4 mmol/L
Normal physiological response to hypoglycaemia
Blood glucose taken up by cells -> blood glucose levels drop.
ALPHA ISLET cells STIMULATED -> produce glucagon, reduce production of insulin
Glucagon acts to increase liver gluconeogenesis and glycogenolysis
ALSO: Decreasing blood glucose -> ↑ Production of adrenaline, growth hormone and cortisol levels which increases blood glucose levels via gluconeogenesis
Pathophysiology of hypoglycaemia depends on its cause and an interruption to one of the above mechanisms
Causes and risk factors of hypoglycaemia
Often related to diabetes and frequently a multifactorial presentation
- excess levels of insulin
- advere effect when start or increasing dose of sulfnlyureas
Nondiabetic causes (acronym ExPLAIN)
- EXogenous medication e.g. insulin, oral hypoglycaemics, alcohol, aspirin overdose, IGF-1 (apparently causes increased peripheral glucose use and inhibits hepatic gluconeogenesis)
- Pituitary insufficiency (loss of function of counter-regulatory hormones)
- Liver failure
- Addision’s disease
- Islet cell tumours e.g. insulinoma
- non-pancreatic neoplasma e.g. fibrosarcoma
Presentation of hypoglycaemia
At blood glucose conc <3.3 mmol/L (autonomic effects): Sweating, shaking, hunger, anxiety, nausea
At blood glucose conc <2.8 mmol/L (neuroglycopenic effects): weakness, vision changes, confusion, dizziness
Severe and uncommon features:
- convulsion
- coma
1st line investigation to help diagnose hypoglycaemia
WIPPLE’S TRIAD
- signs and symptoms of hypoglycaemia
- low blood glucose
- resolution of symptoms with correction og blood sugar
GLOD STANDARD: 48-72 hour fast with serial blood glucose (typically for non-diabetic causes)
Treatment of hypoglycaemia
In community:
- Initially oral glucose 10-20g (liquid, gel, tablet form)
- ‘Hypokit’ may be prescribed which contains a syringe and vial of glucagon for IM/SC (intramuscular/subcutaneous)
In hospital:
- if alert: quick acting carbs
- of unconsious or unable to swallow: sc/im injection of GLUCAGON
- OR IV 20% Glucose solution
A 30-year-old female presents with sudden weight gain (5kg) over the last 2 months. She complains of constipation, hair loss with brittle nails. You notice the loss of hair to the lateral third of the left eyebrows.
Which antibody is most likely to be associated with the condition presented above?
Anti TPO
Anti dsDNA
TSH receptor antibodies
Anti Thyroglobulin antibodies
What is this condition?
Anti TPO (Anti-thyroid autoantibodies)
Hair loss of lateral eyebrows characteristic of Hashimoto’s hypothyroidism
Define hypothyroidism
A clinical syndrome resulting from a deficiency of thyroid hormones, which results in a generalised slowing of metabolic processes
Causes and risk factors of primary hypothyroidism
HASHIMOTO’S THYROIDITIS (Most common cause of primary hypothyroidism - associated with AUTOANTIBODIES ; thyroglobulin and thyroid peroxidase antibodies (TPO) often present at low levels in healthy individuals at risk),
De Quervain’s thyroiditis (painful swelling of the thyroid gland thought to be triggered by a viral infection, such as mumps or flu),
Radiotherapy,
Drug therapy e.g. LITHIUM, AMIODARONE, or anti thyroid drugs such as Carbimazole,
Dietary iodine deficiency (e.g. cause of darbyshire goitre as dietary iodine is usually from seafood which is lacking in the midlands)
Cause of secondary hypothyroidism
From pituitary failure - not enough tsh (rare)
Teritary would be hypothalamic failure (lack of trh)
Which conditions are associated with/increase risk of hypothyroidism (without directly causing hypothyroidism)
Downs syndrome, Turner’s syndrome (only affects females - misssing/partially missing X chromosome), Coeliac disease (immune system attacks own tissues when you eat gluten)
type 1 DM
Pathophysiology
Primary hypothyroidism:
Peripheral thyroid disorder→ T3/T4 not produced (↓ levels) → Compensatory ↑ TSH Levels
Secondary hypothyroidism:
Pituitary disorders→ TSH levels ↓ → T3/T4 levels ↓
Presentation of hypothyroidism
Weight gain, Lethargy, Cold intolerance, Dry, coarse scalp, Loss of lateral aspect of eyebrow, Constipation, Menorrhagia
(may also get general myxoedema (waxy, doughy, swollen but non-pitting, dry))
Incestigations of hypothyroidism
1ST LINE: Thyroid function tests(TFTs)- Primarily look at TSH and T4 levels (Low T4 and High TSH for primary)
Antithyroid peroxidase antibodies- elevated
Other: Fasting blood glucose- Recommended in assessment of patients with non- specific fatigue and weight gain. Primary hypothyroidism is associated with type 1 diabetes mellitus
Treatment of hypothyroidism (all kinds)
Levothyroxine
Define Hashimoto’s Thyroiditis
Autoimmune disease where thyroid gland is attacked by a variety of cell- and antibody-mediated immune processes causing primary hypothyroidism
Pathophysiology of Hashimoto’s
Involves FORMATION OF ANTITHYROID ANTIBODIES that attack the thyroid tissue, causing PROGRESSIVE FIBROSIS.
Associated with type 1 diabetes mellitus, Addison’s or pernicious anaemia (autoimmune condition that affects stomach) and may cause transient thyrotoxicosis in the acute phase (as the thyroid is trying to compensate)
Diagnosis and investigation of Hashimoto’s thyroiditis
1ST LINE = Thyroid function tests (TFTs)- Primarily look at TSH ad T4 levels (Low T4 and High TSH)
GS (gold standard) = Antithyroid peroxidase antibodies- POSITIVE
Define hyperthyroidism
Hyperthyroidism= Increase synthesis of T3 and T4 in the thyroid gland
Thyrotoxicosis= Increase T3 and T4 in circulation (clinical syndrome)
Causes/risk factors of hyperthyroidism
- GRAVE’S DISEASE (most common)
- Toxic multinodular goitre (common)
- Toxic adenoma (apparently common)
- iodine excess
- De Quervain’s thyroiditis
- drug induced (iodine, amiodarone, lithium, radoicontrast agents)
Less common:
- Congenital (neonatal) hyperthyroidism
- Non autoimmune hereditary hyperthyroidism
- Subacute thyroiditis
- Silent thyroiditis
- Postpartum thyroiditis
- Hyperemesis gravidarum
- Molar pregnancy (hCG)
- Thyrotoxicosis factitia
- Metastatic differentiated thyroid - Ca
- Struma ovarii
- Pituitary resistance to thyroid hormone
- Pituitary adenoma (TSHoma)
Pathophysiology of hyperthyroidism
HIGH T3 AND T4, LOW TSH levels
Thyroid hormone plays a major role in metabolism, growth and development
Presentation of hyperthyroidism
Weight loss,
heat intolerance,
palpitations/tachycardia,
increased sweating,
anxiety,
tremor
diarrhoea,
oligomenorrhea,
lid lag + stare
pretibial myxoedema - orange peel appearance on anterior aspect of the lower legs, spreading to the dorsum of the feet, or a non-localised, non-pitting edema of the skin in the same areas - seen esp in Graves’
Diagnosis and investigations for hyperthyroidism
1ST LINE: Thyroid function tests(TFTs)- Primarily look at TSH ad T4 levels (High T4 and low TSH)
Antibodies- TSH-RECEPTOR ANTIBODIES
Treatment for hyperthyroidism
Depends on the cause:
PROPANOLOL - This is often used at the time of diagnosis to control thyrotoxic symptoms such as tremor
CARBIMAZOLE - Blocks thyroid peroxidase -> reduces thyroid levels (AGRANULOCYTOSIS IS A COMMON SE) - CONTRAINDICATED DURING PREGNANCY (increased risk of congenital malformation)
Alternatively: PROPYLTHIOURACIL
- Radioiodine treatment- This emits beta particle which causes ionisation of thyroid cell. May exacerbate thyroid eye disease
- Surgery
Define Graves’ disease
An autoimmune thyroid condition - the most common cause of hyperthyroidism cause by TSH receptor antibodies
Risk factors for Graves’ disease
Alemtuzumab (a drug used to treat MS)
Smoking
Stress
High iodine intake
FEMALE SEX - it mostly affects young or middle aged women - 2% of women will get Graves’ disease pr autoimmune hypothyroidism (5-10 times the frequency in men)
Family history (25% concordance in monozygotic twins)
HLA-DR3 and other immunoregulatory genes contribute
Myasthenia gravis is also associated with Graves’ disease
Pathophysiology of graves disease
TSH receptor antibodies (thyroid stimulating antibodies) stimulate the TSH receptor causing more free t4 to be produced
TSH-R antibodies may cross the placenta can result in neonatal Graves’ disease. (could also result in stillbirth, miscarriage or preterm birth)
Opthalopthy caused by swelling in extraoccular muscles (probs from autoantigen similar to/reacting with thyroid autoantigen)
Types of thyroid autoimmune conditions
Focal thyroiditis and/or positive TPO and thyroglobulin antibodies
Postpartum thyroiditis
Autoimmune hypothyroidism
- Hashimoto’s thyroiditis
- Atrophic thyroiditis
Graves’ disease
- Thyroid associated ophthalmopathy
What is the mechanism of thyroid cell destruction
Cytotoxic (CD8+) T cell-mediated
Thyroglobulin and TPO antibodies may cause secondary damage BUT have no effect ALONE
Uncommonly antibodies against the TSH-receptor may block effects of TSH
Damage to thyroid causes leakage of thyroid hormone (often happens in aftermath of infection)
Presentation of Graves’ disease
Weight loss, heat intolerance, palpitations, increased sweating, pretibial myxoedema, anxiety, tremor
OPTHALMOPATHY/ORBITOPATHY (EXOPHTHALMOS (bulging eyeball) and ophthalmoplegia (weakness of eye muscles))
PRETIBIAL MYXOEDEMA (orange peel shins)
THYROID ACROPACHY (triad of digits clubbing, soft tissues swelling of hands/feet, and periosteal new bone formation)
DIFFUSE GOITRE
Diagnosis and investigations for graves’ disease
Thyroid function tests(TFTs)- Primarily look at TSH ad T4 levels (High T4 and low TSH)
TSH-R-Ab (POSITIVE),
Isotope scan, MRI, CT, Ultrasound
Treatment of Graves’
Anti-Thyroid drugs- block thyroid hormone synthesis, carbimazole (not in pregnancy - propythiouracil used instead), thiamazole (these drugs don’t treat underlying cause BUT have some immune modifying effects like decreased IL-6 and reduced antibody titres)
- for graves’ use a BLOCK AND REPLACE regimen with T4 (6-12) to avoid iatrogenic hypothyroidism (or done long term in patients unwilling to have radioiodine or surgery)
- can also just do a short course to render euthyroid before radioactive iodine or surgery
RADIOACTIVE IODINE THERAPY
Surgery
Patients with active moderate to severe and sight-threatening orbitopathy first-line treatment is intravenous corticosteroid (e.g., methylprednisolone)
