Phase 2 - Endo 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 RBCsInsulin levels are lowMuscle 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 FinnishFamily history of DM T1Genetic predisposition- HLA-DR3 or HLA-DR4 / HLA DQ8 (heuman leukocyte antigen genes - name of mhc in humans) in > this occurs in 90% of casesENVIRONMENTAL factors- exposure to a specific virusFamily 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 ANDRAISED 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 for diabetics?
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/LFasting glucose: Below 5.5 mmol/L2 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 months42-47 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 infusionIV sodium bicarbonateIV 0.9% sodium chloride Oral fluids and subcutaneous insulinContinuous 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 diagnosisTo 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 therapyUndiagnosed 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 deficiencyCOMPLETE 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 electrolytesPeripheral lipolysis -> increased circulating free fatty acids -> FFAs undergo ketogenesis -> converted to ketone bodies in mitochondira -> acummulate causing METABOLIC ACIDOSISPOTASSIUM 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 VomitingDehydration which can cause hypotensionAcetone-smelling breath (‘pear drops’/fruity breath)Abdominal painDrowsy/ Confused can progress to a comaReduced consciousnessHyperventilation (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) - ABGUrea 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 oedemaThere 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/LOral glucose tolerance test ≥11.1 mmol/LHbA1c ≥ 58mmol/LLow random C-peptideRandom 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 historyMaleModifiable- 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 urinationPolyphagia-exessive hunger (unexplained weight loss doesn’t become apparent till more serious for T2 DM)Glycosuria- excessive glucose in urineCan 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 DIAGNOSISHbA1c >42-47 mmol/mol = PRE-DIABETES DIAGNOSIS2) Blood testsRandom plasma glucose > 11.1mmol/L = DIABETES DIAGNOSIS Fasting plasma glucose > 7mmol/L = DIABETES DIAGNOSIS 3) Oral Glucose tolerance testFasting > 7mmol/L = DIABETES DIAGNOSIS2 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 neuropathyMetabolic:- dylipidaemia- diabetic ketoacidosis- hyperosmolar hyperglycaemic stateHyperglycaemia 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 secretionE.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 insulinGlitazones (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 secretionEnhances glucose disposal- SLows gastric emptying- Reduces food intakeSuppresses appetite
Where is GLP-1 secreted
Secreted from L cells in the intestine
What does DPP-4 do
Rapidly degrades GLP-1Enzymatic 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 dailyOnce weekly exenatide (BYDUREON)Liraglutide (VICTOZA) once dailyLixisenatide (LYXUMIA) once dailyDulaglutide (TRULICITY) once weeklySemaglatide (OZEMPIC - can also be taken orally) once weeklyThese 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 drugsOral 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 levelsAre now licensed in type 1 diabetesE.g.Empagliflozincanagliflozindapagliflozin
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
SubcutaneouslyHYPOGLYCAEMIAWeight gainLipodystrophy
Action of metformin; main side effects
Increases insulin sensitivity, decreased hepatic gluconeogenesisCannot be used in patients with eGFR of <30 ml/minSide 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 vomitingNeurological: altered level of consciousness, headaches, papilloedema (optic disk swelling due to increased intracranial pressure), weaknessHaematological: hyperviscosity (may result in myocardial infarctions, stroke and peripheral arterial thrombosis)Cardiovascular: dehydration, hypotension, tachycardiaCHARACTERISED BY:severe hyperglycaemia (>30 mmol/L)hypotensionhyperosmolarity/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)hypotensionhyperosmolarity/osmolality (usually >32 mosmol/kg)NO significant acidosis (ph > 7.3; bicarb > 15mmol/L) or ketosisDiagnosis is based on these characteristics being present
Treatment of HHS
FLUID REPLACEMENT with 0.9% salineVTE (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 therapyTreatment 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 tablesIV glucoseIV 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 insulinGlucagon acts to increase liver gluconeogenesis and glycogenolysisALSO: Decreasing blood glucose -> ↑ Production of adrenaline, growth hormone and cortisol levels which increases blood glucose levels via gluconeogenesisPathophysiology 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 sulfnlyureasNondiabetic 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, nauseaAt blood glucose conc <2.8 mmol/L (neuroglycopenic effects): weakness, vision changes, confusion, dizzinessSevere 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 sugarGLOD 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 TPOAnti dsDNATSH receptor antibodiesAnti Thyroglobulin antibodiesWhat 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 levelsThyroid hormone plays a major role in metabolism, growth and development
Presentation of hyperthyroidism
Weight loss, heat intolerance, palpitations/tachycardia, increased sweating, anxiety, tremordiarrhoea, oligomenorrhea, lid lag + starepretibial 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)SmokingStressHigh iodine intakeFEMALE 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 contributeMyasthenia 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 producedTSH-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 antibodiesPostpartum thyroiditisAutoimmune hypothyroidism - Hashimoto’s thyroiditis - Atrophic thyroiditisGraves’ disease - Thyroid associated ophthalmopathy
What is the mechanism of thyroid cell destruction
Cytotoxic (CD8+) T cell-mediatedThyroglobulin and TPO antibodies may cause secondary damage BUT have no effect ALONEUncommonly antibodies against the TSH-receptor may block effects of TSHDamage 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, tremorOPTHALMOPATHY/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 surgeryRADIOACTIVE IODINE THERAPYSurgery Patients with active moderate to severe and sight-threatening orbitopathy first-line treatment is intravenous corticosteroid (e.g., methylprednisolone)
30-year-old man presents to the acute medical unit with agitation, restlessness and palpitations. He has steadily been getting worse over the last four weeks, feeling increasingly tired and run down. He is previously well with no significant past medical or family history. On examination he is noted to have a swollen and painful neck anteriorly. He is tachycardic at 130 reg bpm. He is apyrexial.Thyroid blood tests reveal:Thyroid stimulating hormone (TSH) 1.1 (0.5-5.5mu/L)Free Thyroxine (T4) 30 (9-18pmol/L)Which of the following is the most likely diagnosis?Acute thyroiditis De Quervain’s (Subacute) Thyroiditis Autoimmune thyroiditis Thyroid cancer
De Quervain’s (Subacute) Thyroiditis – important is the fever like symptoms as this is preceded by a viral infectionapyrexial means no fever
Define De Quervain’s thyroiditis
Subacute granulomatous thyroiditis is a self-limited inflammation of the thyroid gland. It results in the rapid swelling of the thyroid gland resulting in pain and discomfort(often thought occur after viral infection)
Pathophysiology of De Quervain’s thyroiditis
There are typically 4 phases:Phase 1- lasts 3-6 weeks: hyperthyroidism (initial presentation), painful goitre, Raised ESRPhase 2- Lasts 1-3 weeks: Euthyroid (normal function)Phase 3- weeks to months: HypothyroidismPhase 4- Thyroid structure and function goes back to normal
Presentation of De quervain’s
Neck Pain (may move to jaw and ears), difficulty eating, tender, firm, enlarged thyroid, fever, palpitations (Occur in >70% of patients who have symptoms of thyrotoxicosis)
Diagnosis and investigation of De quervain’s
1ST LINE: Total T4, T3 resin uptake, free thyroxine index- ALL ELEVATED, CRP (c-reactive protein - produced by live; high levels indicate inflammation) = elevated
Treatment for De quervain’s
Hyperthyroid phase- NSAIDs and corticosteroids may be used for pain. Hypothyroid phase- Normally no treatment given but if severe hypothyroidism occurs give small dose of levothyroxine
Though it usually resolves itself what complications can occur
Thyroid storm, Long term hypothyroidism
What is the differential diagnosis for de quervain’s thyroiditis
Graves’ disease, Hashimoto’s, Thyroid cancer, Toxic multinodular goitre
Define goitre
Palpable & visible thyroid enlargementVariety of causesCommonly sporadic or autoimmuneEndemic in iodine deficient areas
What is the commonest endocrine disorder
Sporadic non-toxic goitreNon-toxic means it is euthyroid (doesn’t affect thyroid function)A goitre can also be toxicIt can be diffuse (spread even;y acrose thyroid gland), multinodular (multiple nodules of thyroid affected but not evenly), solitary nodule (only one nodule affected), or dominant noduleNeed to make sure to differentiate benign from malignant
A 55-year-old women with a thyroid carcinoma undergoes a total thyroidectomy. The post operative histology report shows a final diagnosis of medullary type thyroid cancer. Which of the tests below is most likely to be of clinical use in screening for disease recurrence?Serum CA 19-9 levels Serum thyroglobulinSerum TSH Serum Calcitonin
Serum calcitonin - Medullary thyroid cancers often secrete calcitonin and monitoring the serum levels of this hormone is useful in detecting sub clinical recurrence
What are the 4 main thyroid malignancies and what % of thyroid malignancies do they account for collectively
Papillary (70%) - local followed by pulmonary and skeletal - younger peak of incidence than follicular -overall good prognosis Follicular (10-20%) - pulmonary and skeletal - 3x more common in women - good prognosis if caught early but still poorer than papillaryAnaplastic (1-5%) - local, liver, lung, skeletal spread - 25% familial associated with MEN type 2 - prognosis is highly dependant on age and stageMedullary (<3%) - Local, skin, brain spread (maybe co-existing differentiated thyroid cancer) - mean age of onset 65, highly aggressive - poor prognosis, median survival 3-6 monthsCollectively 98%
Risk factors for thyroid cancer
Head and neck irradationFemale sex
Presentation of thyroid cancer
Palpable thyroid nodule
Diagnostic investigations for thyroid cancer
1st line: Ultrasound neck, fine needle biopsylaryngoscopy
Treatment of thyroid cancer
Thyroidectomy followed by radioactive iodine ablation and suppression of TSH
Complications of thyroidectomy
increased risk of recurrent laryngeal nerve damageHypoparathyroidism If whole thyroid removed -> hypothyroidism
Define thyroid storm
(also known as thyroid or thyrotoxic crisis) represents the severe end of the spectrum of thyrotoxicosis and is characterized by compromised organ function (Rare)
Causes/risk factors for thyroid storm
Graves disease, Post thyroidectomy, Infection, Trauma, MI, DKA, Pregnancy etc, Exogenous iodine, Abrupt cessation/Lack of adherence with Antithyroid drugs
Presentation of thyroid storm
Fever, cardiovascular dysfunction, profuse sweating, tachyarrhythmias, nausea and vomiting
DIagnostic investigation for thyroid storm
Free thyroxine and TSH- in thyroid storm TSH is completely suppressed with high thyroxine
Treatment for thyroid storm
1ST LINE: Antithyroid treatment- Carbimazole (or Propylthiouracil (PTU)) Hydrocortisone administration is also recommended. It treats possible relative adrenal insufficiency while also decreasing T4 to T3 conversion (t3 is active form so less free t3 means less hyperthyroidism symptoms)Gold Standard: Thyroidectomy
Name conditions caused by pituitary adenoma
prolactinoma (the name of the type of tumour)AcromegalyCushing’s syndrome (chronic abnormal elevation of cortisol)
What are the 2 types of Cushing’s syndrome
ACTH independant - ACTH levels normal but cortisol levels highACTH dependant - ACTH levels high anf cortisol levels high
Causes of ACTH independent Cushing’s syndrome
Iatrogenic- caused by oral steroids such as glucocorticoid e.g. PREDNISOLONE – MOST COMMON CAUSEAdrenal adenoma- benign tumour of the adrenal gland that secretes increased levels cortisol.
causes of ACTH dependant Cushings
An anterior pituitary adenoma which secretes increased ACTH leading to increased levels of cortisol– MOST COMMON ACTH DEPENDENT CAUSE* Ectopic ACTH production - Essentially neoplasm somewhere in the body secreting excessive levels of ACTH - Especially small cell lung cancer and carcinoid tumours (type of neuroendocrine tumour that grows from neuroendocrine cells)ACTH depedant causes are rare
Presentation of Cushing’s syndrome
Round moon faceCentral ObesityAbdominal striaeBuffalo Hump (fat pad on upper back)Proximal limb muscle wasting— due to proteolysisMood change (depression, lethargy, irritability, psychosis)Irregular periods of ammenorheaAcneHirsutism (male-like pattern of excessive hair growth)
Diagnostic investigations for Cushing’s
1st-line test - raised plasma cortisol (Don’t rely on random plasma cortisol as they may mislead, as illness, time of day, and stress (eg venepuncture) influence results)Gold standard- Dexamethasone suppression test (dexamethasone suppresses cortisol secretion):- Low dose 1mg: * If low cortisol then cortisol secretion normal * if high/normal cortisol -> cushing’s- High dose test (8mg): * low cortisol -> cushing’s disease (i.e pituitary adenoma) * high/normal cortisol ** ACTH low -> adrenal cushing’s *** ACTH high -> ectopic ACTHOther tests:24-hour urinary free cortisol can be used as an alternative to the dexamethasone suppression test but does not indicate the underlying cause.MRI brain for pituitary adenomaChest CT for small cell lung cancerAbdominal CT for adrenal tumours
Treatment of Cushing’s
If the cause was iatrogenic - STOP taking steroids!If adrenal adenoma - adrenalectomyIf pituitary adenoma - trans-sphenoidal surgery to removeIf ectopic ACTH production - surgery to remove neoplasm if it can be located and hasn’t metastesisedIf surgical removal of cause if not possible - alternative: remove both adrenal glands and give patient replacement steroid hormones for life
Complications of Cushing’s
DMT2HypertensionCardiovascular disease (including stroke)Osteoporosis(DVT and potentially pulmonary embolism)
Explain how a low dose dexamethasone supression test works
A normal response is for the dexamethasone to suppress the release of cortisol by effecting NEGATIVE FEEDBACK on the HYPOTHALAMUS and PITUITARY. The hypothalamus responds by REDUCING THE CRH OUTPUT. The pituitary responds by REDUCING ACTH OUTPUT. The lower CRH and ACTH levels result in a LOW CORTISOL LEVEL. When the cortisol level is not suppressed, this is the abnormal result seen in Cushing’s Syndrome
Explain how a high dose dexamethasone test works and allows us to differentiate between different type’s of cushing’s
The high dose dexamethasone suppression test is performed after an abnormal result on the low dose test.In Cushing’s Disease (pituitary adenoma) the pituitary still shows some response to negative feedback and 8mg of dexamethasone is enough to suppress cortisol.Where there is an adrenal adenoma, cortisol production is independent from the pituitary. Therefore, cortisol is not suppressed however ACTH is suppressed due to negative feedback on the hypothalamus and pituitary gland.Where there is ectopic ACTH (e.g. from a small cell lung cancer), neither cortisol or ACTH will be suppressed because the ACTH production is independent of the hypothalamus or pituitary gland
Define acromegaly
Endocrine disorder resulting from secretion of too much growth hormone
What is the difference between acromegaly and gigantism
Gigantism- Excessive GH production in children BEFORE fusion of the epiphyses of the long bones (the excess growth hormone delays puberty so their bones don’t fuse and they continue to grow more for longer thus resulting in gigantism)Acromegaly- Excess GH in adults
Causes of acromegaly
Anterior Pituitary adenoma (remember adenoma is a benign tumour) this leads to unregulated GH secretion(or as part of MEN 1)In rare cases acromegaly can be secondary to a cancer, such as lung or pancreatic cancer which secretes GHRH or GH
What are MEN 1 and MEN 2
Multiple endocrine neoplasia type 1 and 2. They are genetic, hereditary conditions.Type 1 typically causes tumors to grow in pituitary, parathyroid and/or pancreasType 2 typically causes tumours in medullary thyroid, parathyroid and/or adrenal/pheochromocytoma (also lips, mouth, eyes and digestive tract)The tumors may be benign or malignant
Pathophysiology of acromegaly
GHRH is released from the hypothalamus and stimulates the release of GH from the anterior pituitary.The excess growth hormone (GH) from the anterior pituitary results in excessive production of insulin like growth factor (IGF-1 - made in liver) which is responsible for inappropriate growth. This stimulates bone and soft tissue growth
Presentation of acromegaly
- Bi-temporal hemianopia (cos of tumor)* facial differences: - Large ears, large nose, large tongue, frontal bossing, large protruding jaw (‘prognathism’)* Large spade like hands and feet* Acroparaesthesia - tingling and numbness of arms/legs* Arthralgia (joint pain - growing pains) * Back ache * Oily skin* Excessive sweating * Headache (cos of tumor)* Amenorrhoea (absence of period)* Mood disturbances(can also cause insulin resistance so potentially diabetic symptoms after a while?)
Why is bitemporal hemianopia a typical presentation of acromegaly
Acromegaly is caused by an anterior pituitary adenoma. The optic chiasm, where the optic nerves from eyes cross over to diff sides of the head, sits just above the pituitary gland. A large enough pituitary tumor will press on the optic chiasm which leads to the optic nerve fibres that cross over (nasal fibres) being compressed and no longer working properly. This causes loss of vision in the temporal visual fields (outer visual field/outer halfs) of both eyes described as a bitemporal hemianopia.
What inhibits the release of GH?
Somatostatin!High levels of glucosedopamine to a smaller degree
Diagnostic investigations for acromegaly
1st line- Insulin-like Growth Factor 1 (IGF-1) (elevated levels)(GH levels fluctuate too much, IGF1 more stable so better to measure this)GS- Oral glucose tolerance test- Give patient glucose. Normally serum GH would decrease. In individuals with Acromegaly GH release isn’t supressed. (will chack both blood glucose and gh levels before giving glucose, 30 mins after glucose, 60 mins after, 90 mins after, 120 mins after)MRI brain for the pituitary tumour- to assess the size and extent of the tumour.
Treatment of acromegaly
Trans-sphenoidal surgery of the pituitary tumour is gold standard tx for acromegaly secondary to pituitary adenomas.Surgical removal of cancer is tx for acromegaly secondary to cancer.If the above don’t work there are medication that can be used to block GH. 2nd line-Somatostatin analogues (oral) to block GH release (e.g. octreotide)3rd line- Pegvisomant (GH antagonist given subcutaneously and daily) ORDopamine agonists (oral) to block GH release (e.g. bromocriptine)SURGERY first, MEDS IF SURGERY FAILS
Complications of acromegaly
Type 2 diabetes - due to constant high glucose levels (insulin resistance)Heart disease- due to possible hypertrophy of the heart due to increased GH HypertensionArthritis - due to overgrowth of cartilageCarpal tunnel - as muscle growth compresses nervesVisual fields defect- Bitemporal Hemianopia
Why are plasma GH levels not used as a diagnostic factor for acromegaly
Secretion is pulsatile and increases at certain times such as when stressed, during sleep, puberty, pregnancy. If high GH levels then proceed to Oral glucose tolerance test.
A 40 year old man attends his GP because of headaches that have been going on for 3 months. It is also uncovered that he has been experiencing erectile dysfunction and he is low in mood because of this.Following referral to the Neurologists, he has an MRI scan to investigate his headache. This reveals a pituitary adenoma.What is the most likely cause for his problems?ACTH producing tumourGrowth hormone producing tumourTSHomaProlactinomaNon-secreting tumour
Prolactinoma (benign lactotroph adenoma expressing and secreting prolactin in anterior pituitary)Increase in Prolactin inhibits release of GnRH from hypothalamus -> Decrease in LH, FSH from anterior pituitary > This decreases release of oestrogen and progesterone in females and in males decreases the release of Testosterone
What is Prolactin
A a hormone made by lactotrophs (huggy, grabby cells) in the anterior pituitary gland.It causes the breasts to grow and make milk during pregnancy and after birth (let down reflex). Prolactin levels are normally high for pregnant women and new mothers. Levels are normally low for non-pregnant women and for men
Risk factors for prolactinoma
Biologically female, Peak incidence during childbearing years (20-40 years)
Pathophysiology of prolactinoma
Hypersecretion of prolactin causes secondary hypogonadism due to its inhibitory effects on gonadotrophin-releasing hormone.(Hypogonadism is when sex glands called gonads produce little, if any, sex hormones.)
Presentation of prolactinoma
in females:Amennorrhoea/oligomenorrhoeaInfertility - prolactin inhibits GnRH which is required for ovulationLow libido (due to hypogonadism)Glactorrhoea In males:Low testosteroneLow libidoErectile dysfunctionReduced facial hairAlso potentially galactorrhoeaBitemporal hemianopia only happens if the adenoma is big enough
Diagnostic investigations for prolactinoma
1st line) Serum prolactin levels: if elevated -> prolactinoma2nd line) Pituitary MRI- to detect adenoma
Treatment of prolactinoma
1st line:DOPAMINE AGONISTS e.g. ORAL CABERGOLINE/BROMOCRIPTINE- dopamine inhibits prolactin and enough dopamine can shrink tumour significantly till it is no longer an issue2nd line- Hormone replacement therapy e.g. oestrogen, where fertility and galactorrhoea are not an issue (additional oestrogen could make infertility worse?)
Complications of prolactinoma
Infertility, sight loss, raised intracranial pressure due to adenoma growth in the brain.
What is aldosterone and what is its function
It is a mineralocorticoid (made by zona glomerulosa (because aldosterone works in glomerulus!!) - outermost region of adrenal cortex)
How does the RAAS system normally function
In the afferent arteriole in the kidney there are juxtaglomerular cells which sense the blood pressure in these vessels. When JUXTAGLOMERULAR cells in AFFERENT arteriole in kidneys sense LOW BP in the arteriole they SECRETE RENIN. The LIVER SECRETES ANGIOTENSINOGEN (protein). Renin converts angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II in the lungs by angiotensin converting enzyme (ACE). Angiotensin II stimulates the release of aldosterone from the adrenal glandsAldosterone acts on PRINCIPAL CELLS of collecting ducts. Increases expression of apical epithelial Na+ channels to reabsorb sodium (which causes water to move in by osmosis). Increased Na+/K+ ATPas activity so Potassium lost in urine as sodium reabsorbed.
Define Conn’s
A type of primary hyperaldosteronism caused by an adrenal adenoma.Primary hyperaldosteronism is when the adrenal glands are directly responsible for producing too much aldosterone. Serum renin will be low as it is suppressed by high BP.
Causes of primary hyperaldosteronism
Bilateral adrenal hyperplasia (most common ~70%) An adrenal adenoma secreting aldosterone (known as Conn’s Syndrome)
What is secondary hyperaldosteronism + causes
where excessive renin stimulates the adrenal glands to produce more aldosterone. Serum renin will be high.Causes (anything that causes lower BP in kidneys):- Renal artery stenosis- Heart Failure- Liver cirrhosis + ASCITES
Presentation of Conn’s syndrome
Often ASYMPTOMATICAlso:- Hypertension (primary hyperaldosteronism is usually indistinguishable from hypertension unless Renin and aldosterone are measured)- Headaches (from hypervolemia?)- symptoms of hypokalaemia (due to excretion of K+) * Wakness/cramps * paraesthesia (tingling/numbness) * polyuria, nocturia and polydipsia
Diagnostic investigations for Conn’s
1st line) FBC/U&E/LFT (liver function tests)* Plasma potassium: Low= Primary* Aldosterone/renin ratio: High ratio (high aldosterone and low renin )= taken alongside a low plasma potassium this means Primary hyperaldosteronismBlood gas analysis:- Aldosterone causes ALKALOSIS as it increases activity of Na-H+ exchange protein -> LOSS OF H+ in urine- CT/MRI to locate adrenal lesions- Renal artery imagingSelective adrenal venous sampling (Gold Standard - determines cortisol and aldosterone levels in each of the adrenals)
Treatment of Conn’s
ALDOSTERONE ANTAGONISTS:- EPLERENONE- SPIRONOLACTONETreat underlying cause- Surgical removal of adenoms (Adrenalectomy)
Treatment of secondary hyperaldosteronism
Percutaneous renal artery angioplasty (via femoral artery) to treat renal artery stenosis (a cause of secondary hyperaldosteronism)
Define adrenal insufficiency
Where adrenal glands don’t produce enough steroid hormones, esp cortisol and aldosteroneSteroids are essential for life so condition is lifethreatenin unless hormones are replaced
Define Addison’s disease
a specific condition where the adrenal glands have been damaged, resulting in reduced cortisol and aldosterone.i.e. another name for primary adrenal insufficiency
Causes of adrenal insufficiency
Addison’s/primary adrenal insufficiency:- AUTOIMMUNE ADRENALITIS (most common in developed countries)- TB (most common worldwide)Secondary:- loss of/damage to pituitary gland (inadequate ACTH simulating adrenals)- tumours- surgery- radiotherapy- trauma(- Sheehan’s syndrome - postpartum haemorrhage -> avascular necrosis of pit gland)Tertiary:- suppression of hypothalamus via LONG TERM (> 3 weeks) ORAL STEROIDS - doesn’t wake up quickly enough when steroids stopped suddenly -> adrenal crisis
Presentation of adrenal insufficiency/Addison’s
Key symptom of Addison’s: HYPERPIGMENTATION esp in PALMAR CREASESNon-specific symptoms:* fatigue* weight loss* nausea* vomiting* abdominal pain* hypotension - esp postural apparently (low aldosterone - less water)
Diagnostic investigations for adrenal insufficiency
Glod standard - SHORT SYNACTHEN test:- ideally performed in morning when adrenals are most ‘fresh’* give SYNACTHEN (synthetic ACTH)* Blood cortisol measured at: - baseline - 30 mins - 60 minsIn healthy patientsthis should stimulate adrenals to make cortisol and cortisol should at least double.- if CORTISOL DOESN’T RISE -> ADDISON’SAlso bloods to check:- Sodium will be LOW as low aldosterone- Potassium will be HIGH (low aldosterone)- Cortisol will be LOW- ACTH will be: * HIGH in PRIMARY/ADDISON’S (due to feedback loop) * LOW/LOW NORMAL in SECONDARY- Renin will be HIGH in ADDISON’S- Aldosterone will be LOW in ADDISON’S
Treatment for adrenal insufficiency
HYDROCORTISONE (glucocorticoid drug) to replace cortisolFLUDROCORTISONE (mineralocorticoid drug) to replace aldosterone - will correct hypotension byy increasing Na+ and decreasing K+
Complications of Addison’s
Addisonian/Adrenal crisis - life threatening* reduced consiousness* hypotension* hypoglycaemia, hyponaetermia, hyperkaelemia* generally very unwell (potentially)can be the FIRST PRESENTATION of Addison’s or TRIGGERED by INFECTION, TRAUMA or other ACUTE ILLNESS(can also present if someone on LONGTERM STEROIDS suddenly withdrew - secondary adrenal insufficiency)requires IMMEDIATE TREATMENT
Management of Addisonian Crisis
Intensive monitoring if unwellParenteral steroids (i.e. IV hydrocortisone 100mg stat then 100mg every 6 hours)IV fluid resuscitationCorrect hypoglycaemiaCareful monitoring of electrolytes and fluid balance
What is SIADH
Syndrome of inappropriate secretion of ADH.A condition where there is inappropriately high amounts of ADH secretion
Causes of SIADH
- Idiopathic- Post-operative from major surgery- Infection, particularly atypical pneumonia and lung abscesses- Medications (thiazide diuretics, carbamazepine, antipsychotics, SSRIs, NSAIDSs,) (iatrogenic)- Malignancy, particularly small cell lung cancer- Meningitis- Head injury (physical damage to secretory structures/sensory organs?)
Pathophysiology of SIADH
ADH is produced in the hypothalamus and secreted by the posterior pituitary gland. It stimulates water reabsorption from the collecting ducts in the kidneys. Excessive ADH results in excessive water reabsorption in the collecting ducts. This water dilutes the sodium in the blood so you end up with a low sodium concentration (hyponatraemia). The water reabsorption is not usually significant enough to cause a fluid overload, therefore you end up with a EUVOLEMIC HYPONATRAEMIA. The urine becomes more concentrated as less water is excreted by the kidneys therefore patients with SIADH have a HIGH URINE OSMOLALITY and HIGH URINE SODIUM.
Presentation of SIADH
Symptoms largely due to the Hyponatremia:- Headache- Fatigue, confusion- Muscle aches and crampsSevere hyponatraemia can cause seizures and reduced consciousness
How is SIADH diagnosed
Usually via exclusion- Clinical signs will show EUVOLEMIA- U+Es will sho HYPONATRAEMIA- Serum osmolality/osmolarity will be LOW- Urine sodium and osmolality will be HIGHDo imaging/investigations to establish cause
How do you treat SIADH
First establish the underlying cause- most commonly caused by medications so stop causative medicine if possibleFLUID RESTRICTION: - reduce fluid intake to 500mls - 1L- may be enough to correct hyponatraemia without needing medications(Na+ depletion normally treated with IV saline but in SIADH IV saline will not normalise serum levels)VASOPRESSIN RECEPTOR ANTAGONIST for chronic SIADH- TOLVAPTAN
Complcations of SIADH treatment
CENTRAL PONTINE MYELINOLYSIS- rapid rise in sodium conc results in movement of water for brain cells- important to correct sodium slowly to avoid this
A 45-year-old male is seen in the endocrinology clinic for suspected diabetes insipidus. Based on the patient’s history, the endocrinologist suspects a central cause of the diabetes insipidus.Which of the following is a cause of nephrogenic diabetes insipidus?CraniopharyngiomaLithiumHead TraumaCNS InfectionsPituitary Surgery
LithiumThe others are all causes of cranial diabetes insipidus
What is diabetes insipidus
A disease characterised by either the decreased secretion of ADH from the posterior pituitary (Cranial DI) or an insensitivity to ADH (Nephrogenic DI)Cranial/central DI is most common
Causes of Cranial/central DI
Can be idiopathicBrain tumoursHead injuryBrain infections (meningitis, enchepalitis and TB)Brain surgery or radiotherapy
Causes of nephrogenoc DI
commonly inherited - mutation in ADH receptorDrugs - LITHIUM (used for bipolar affective disorder)Systemic disease e.g. chronic kidney diseaseElectrolyte disturbance - hypokalaemia (impairs urinary concentrating ability so urine ends up more dilute - also ADH just doesn’t work as well) and hypercalcaemia (causes targeted autophagic degredation of aquaporin-2?)
Pathophysiology of DI
ADH deficiency results in impaired water retention thus leading to large volumes of dilute urine being produced - polyuria
Presentation of DI
POLYURIA (excessive urine production)POLYDIPSIA (excessive thirst)DehydrationPostural hypotensionHYPERNATRAEMIA
Diagnostic investigations for DI
Urine osmolality - LOWSerum osmolality - HIGHSerum Na+ - HIGHSerum glucose - checked to exclude diabetes mellitus (assuming the patient doesn’t have glycosuria as that is very indicative of DM and NOT DI)GOLD STANDARD - Water deprivation test
What is the water deprivation
Step 1: confirm DI- Patients are deprived of fluids for 8 hours - Urine osmolality is measured hourly: * If urine still dilute this indicates DI as a normal response would have responded to dehydration (via feedback loop) -> proceed to step 2Step 2: defferentiate between cranial and nephrogenic DI- Desmopressin (synthetic ADH) is administered intramuscularly.- 8 hours later - urine osmolality measured * If cranial: Increase in urine osmolality (to >750 mmol/kg) and reduction in urine output as their collecting ducts respond to the desmopressin * If nephrogenic: no increase in urine osmolality - their collecting ducts are insensitive to ADH and thus desmopressin
Treatment for DI
Identify underlying cause and treat it if possibleCranial DI: give DESMOPRESSIN (synthetic ADH - substitute)Nephrogenic DI: Thiazide diuretics e.g. ORAL BENDROFLUMETHIAZIDE
Complication of Diabetes Insipidus
Severe hypernatraemia
Why are Thiazide diuretics given for nephrogenic DI
These work in the DISTAL CONVOLUTED TUBULE to excrete water which will produce a mild hypovolaemia. This will encourage the kidneys to take up more Na+ and water in the PROXIMAL TUBULE, thereby reducing urine output.
Causes of Hyperparathyroidism
Primary (most common):- 80% of cases due to solitary adenoma- 20% due to hyperplasia of glands (leads to additional secretive tissue -> increased PTH)- less than 0.5% due to parathyroid cancerSecondary:- insufficient VITAMIN D- CHRONIC RENAL FAILUREboth lead to: low absorption of calcium from intestines, kidneys and bone -> HYPOCALCAEMIA * causes parathyroid to release more PTH and becomes hyperplastic further increasing excess PTH secretionTertiary:- usually occurs after prolonged secondary hyperparathyroidism- glands become AUTONOMOUS producing excess PTH even after hypocalcaemia is corrected (they don’t respond to negative feedback)- LONG-STANDING KIDNEY DISEASE is most common cause
Risk factors for hyperparathyroidism
Elderly women who have gone through menopause are at riskIf the individual has had PROLONGED, SEVERE CALCIUM or VIT D deficiency
How do you distinguish between different types of hyperparathyroidism by looking at serum levels
Primary: high PTH, High Calcium, Low PhosphateSecondary: High PTH, Low/Normal Calcium (PTH is high in response to loe calcium)Tertiary: High PTH, High Calcium, High Phosphate (cause more bone is being resorbed due to high PTH so more calcium and phosphate released - even with increased phosphate excretion in kidneys it isn’t enough to get rid of all the phosphate - esp as most common cause of tertiary is kidney disease)
Presentation of hyperparathyroidism
BONES, STONES, GROANS ans MOANS (like a graveyard on Halloween)painful bonesrenal stonesAbdominal groans i.e. constipation, nausea and vomitingPsychiatric moans i.e. fatigue, depression and psychosis
Diagnostic investigations for Hyperparathyroidism
PTH, CALCIUM and PHOSPHATE:- Primary: high PTH, High Calcium, Low Phosphate- Secondary: High PTH, Low/Normal Calcium - Tertiary: High PTH, High Calcium, High PhosphateCheck BONES - DEXA bone scan for osteoporosisCheck STONES - Ultrasound kidneys/renal system!Check GROANS - ABDOMINAL X-RAY (checks for renal clculi or nephrocalcinosis)Check for ADENOMAS with RADIOISOTOPE SCANNING
Treatment for Hyperparathyroidism
Primary- surgical removal of tumourSecondary- Treat Vitamin D deficiency or Kidney transplant in individuals with CKDTertiary- Total or subtotal parathyroidectomyUse a Calcimimetic e.g.Cinacalet -increases the sensitivity of parathyroid cells to Ca2+ thereby causing less PTH secretion
What levels of calcium indicate Hypocalcaemia
<8.5 mg/dL/ <2.20 mmol/L
Normal range of serum calcium
2.2 - 2.7 mmol/L
Causes of Hypocalcaemia
Hypoparathyroidism (typically post thyroid/parathyroid surgery)pseudohypoparathyroidism (PTH normal but inadequate response to it - hereditary condition)vit D deficiencyhyperventilationdrugsmalignancytoxic shock
Presentation of Hypocalcaemia
SPASMODICSpasmPerioral paraesthesiaAnxious, irritableSeizuresMuscle tone increase (smooth muscle)Orientation impared impaired and confusionDermatitisImpetigo herpetiformis (rare but serious)Chvosteck’s sign (hyperexcitability of facial nerve - facial mmuscles will contract if you tap the masseter at angle of mandible) / Cardiomyopathy (long QT interval)OR CATS go numbConvulsionsArrhythmiasTetany (twitching from hyperstimulated peripheral nerves)Spasms and stridorNumbness in fingers
Diagnostic investigations for hypocalcaemia
Lab test: - PTH level- Vit D- Albumin- Phosphorus- MagnesiumCheck serum Ca2+ - it will be less than 8.5 mg/dL or 2.2 mmol/LECG - prolonged QT interval (Arrythmias)
Treatment of hypocalcaemia
IV CALCIUM GLUCONATE - 10ml of 10% solution over 10 minsIV calcium chloride (more likely to cause local irritation)Vit D supplementation for persistant hypocalcaemia (50000 IU orally once a week for 8 weeks)
Complcations of hypocalcaemia
Seizure or cardiac arrest (hypocalcaemia decreases heart rate and contractility) - Emergency!Long QT syndrome
A 62-year-old man with metastatic prostate cancer presents to the emergency department with constipation, vomiting, abdominal pain and excessive urination. His wife says that he has become increasingly confused and has complained of increased thirst.Blood tests reveal the following:Calcium: 3.2 (2.1-2.6 mmol/L)Phosphate: 1.8 (0.8-1.4 mmol/L)Albumin: 25 (35-50 g/L)Alkaline phosphatase: 204 (30-130 umol/L)What is the most appropriate initial management option?Vitamin D and calcium supplementation IV zoledronic acid Calcitonin IV 0.9% sodium chloride
IV 0.9% sodium chloride – rehydrate
Causes of hypercalcaemia
HYPERPARATHYROIDISMMALIGNANCYSarcoidosis (granulomas often in lungs and lymphnodes)ThyrotoxicosisDrugs (including alcohol)excessive vit D, vit A or calcium suplemmentation
Presentation of hypercalcaemia
BONES, STONES, GRONES and MOANSECG abnormality - Short QT
Diagnostic investigations of hypercalcaemia
Take fasting serum calcium and phosphate samples (to confirm mild hypercalcaemia)Serum PTH and Ca2+ levels - ELEVATED if hyperparathyroidism* Do ULTRASOUND if investigations point to primary hyperparathyroidism24hr URINARY CALCIUM - measured in young adults to exclude FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA in which PTH levels are also raised
Define hypercalcaemia
Increased calcium, decreased PTH (in the appropriate response)
Treatment of hypercalcaemia
Initially: REHYDRATE with normal salineBISPHOSPHONATES (following rehydration)Loop diuretics (e.g. FUROSEMIDE) are sometimes used
A 60-year-old female has a routine health check where she has her observations, ECG and routine blood tests done. The ECG shows a prolonged corrected QT interval.What abnormality found on her blood test may account for the ECG findings?Hypokalaemia Hypernatraemia Hyperkalaemia Hyponatraemia
Hypokalaemia = long QT syndrome
Define Hypokalaemia
Serum potassium level <3.5 mmol/L
Causes of hypokalaemia
General:- Decreased potassium intake- increased potassium entry into cells-increased excretion (sweat, urine, GI tract)- magnesium depletion- hyperaldosteronismHypokalaemia with alkalosis:- VOMITING- THIAZIDE and LOOP diuretics- Cushing’s syndrome- Conn’s syndromeHypokalaemia with acidosis:- Diarrhoea- Renal tubular acidosis- Acetazolamide (drug for glaucoma, epilepsy etc.)- Partially treated DKA
Presentation of hypokalaemia
Muscle weaknesshypotonia (decreased muscle tone)HyporeflexiaCrampsTetany (intermittent muscle spasm)PalpitationsArrythmiasLight headednessConstipationsOn ECG:- Small/inverted T wave- Prominent U wave- Long PR interval- Depressed (goes below baseline) ST segments- Can cause long QT segment
Diagnostic investigation for hypokalaemia
Metabolic panelECGUrine and electrolytes- useful in differentiating renal from non-renal causes of hypokalaemia
Treatment for hypokalaemia
For mild - usually asymptomatic (3.0-3.4 mmol/L):- Oral replacement - consider IVFor severe (<2.5 mmol/L):- IV REPLACEMENT 40mmol KCl in 1L of 0.9% NaCl (normal saline with added potassium chloride)
Complications of hypokalaemia
Cardiovascular- Chronic heart failure, Acute MI, arrythmias, Muscle – weakness, depression of deep tendon reflexes, Rhabdomyolysis
You are asked to review a 71-year-old man who is being treated on the ward for community-acquired pneumonia. He has been complaining of palpitations and muscle weakness. An ECG taken on the ward that morning shows peaked T waves and a PR interval of 0.22 seconds. A K+ level of 6.4mmol/L (3.5 – 5.3 mmol/L). What is the most appropriate immediate management option?IV calcium gluconate IV fluids Intravenous (IV) calcium resoniumIV insulin/dextrose infusion
IV calcium gluconate – severe hyperkalaemia with ECG changes
Define segnificant hyperkalaemia
Serum potassium value >5.5mmol/L
Causes of hyperkalaemia
Excessive exogenous potassium load (Increased Intake), Excessive endogenous potassium load (Increased Production), Redistribution (Shift from intracellular to extracellular fluid), Diminished potassium excretion (Decreased Excretion)
Presentation of Hyperkalaemia
Neuromuscular transmission, Muscle weakness and paralysis, Fast irregular pulse, Chest pain, Light headiness ECG:- Tall, tented T waves,- Small/loss of P waves, - Wide QRS complex, - Ventricular fibrillations,- sine wave (severe)
Diagnostic investigations for hyperkalaemia
Metabolic panelECGUrine electrolytes
Treatment of hyperkalaemia
If ECG changes:- stabilise cardiac membrane by IV CALCIUM GLUCONATE/CHLORIDE (DOES NOT LOWER SERUM POTASSIUM LEVELS) - If no cardiotoxic changes are seen in ECG, shift potassium into cells (ECF > ICF) by giving COMBINED INSULIN/DEXTROSE INFUSION with NEBULISED SALBUTAMOL - Remove potassium from body by giving Calcium resonium, loop diuretics, dialysis All patients with SEVERE hyperkalaemia (≥ 6.5 mmol/L) OR with ECG changes should have emergency treatment - 1st: IV CALCIUM GLUCONATE: to stabilise the myocardium - INSULIN/DEXTROSE INFUSION: short-term shift in potassium from ECF to ICF - other treatments such as nebulised salbutamol may be given to temporarily lower the serum potassium Further management includes: - stop exacerbating drugs e.g. ACE inhibitors - treat any underlying cause - lower body potassium (Calcium resonium, loop diuretics, dialysis)
What is Carcinoid syndrome
Carcinoid syndrome occurs due to release of SEROTONIN (5-hydroxytryptamine) and other VASOACTIVE PEPTIDES into the systemic circulation from a carcinoid tumour (type of neuroendocrine tumour that grows from neuroendocrine cells).
Causes of carcinoid syndrome
- SMALL INTESTINE MALIGNANCY (most common) * esp APPENDIX malignancy-LIVER most common site for metastasis of carcinoid tumours from ileumMost common in GI tract then:- lungs- liver- ovaries- thymus
Pathophysiology of Carcinoid syndrome
Neuroendocrine tumours normally secrete serotonin into the circulation. With GI tract tumours:hormones secreted> enters enterohepatic circulation> liver inactivates hormones> therefore no symptomsHowever, when liver metastases are present (liver tumour)-> hormone secretion -> released into circulation + liver dysfunction -> symptoms
Presentation of carcinoid syndrome
Flushing, diarrhoea, abdominal cramps, bronchospasm (wheezing, asthma), fibrosis (heart valve dysfunction, palpitations
Diagnostic investigations for carcinoid syndrome
1st line: Urinary 5-hydroxyindoleacetic acid test - ELEVATED levels Chest X-ray and Chest/pelvic MRI/CT - helps locate primary tumours
Treatment of Carcinoid syndrome
Surgery - resection of tumour is the only cure for carcinoid tumours do need to find primary tumourSomatostatin analogues (OCTREOTIDE) -blocks release of tumour mediators and counter peripheral effectsDebulking, embolization, or radiofrequency ablation (removing the tissue)for hepatic masses/metastases can decrease symptoms
Causes of Hypernatraemia
- DEHYDRATION - DIabetes mellitus- Nutritional issues
Management of Hypernatraemia
Typically due to dehydration- REHYDRATE Mild: - initally just regular water orally if mild - may give IV glucose 5%Severe:- If patient isn’t volume depleted/hypotensive IV GLUCOSE 5%- If volume depleted/hypotensive - IV 0.9% NaCl (baso just fluid resus)
Causes of Hyponatraemia
- Pseudohyponatraemia (low sodium but normal serum osmolality)- RENAL dysfunction- VOMITING/Diarrhoea- SIADH- Oedematous states- Inappropriate IV FLUID therapy- Addison’s- Psychogenic (excess water drinking)
Treatment of hyponataraemia
- If due to SIADH: fluid restriction- If due to Na+ depletion: IV 0.9% SALINE
Signs/symps of hyponatraemia
Headaches, nausea, siezures
Define Phaeochromocytoma
CATECHOLAMINE ()NAd, Adr) secreting Adrenal MEDULLARY tumour
Causes of phaeochromocytoma
Usually inherited. Associated with:- MULTIPLE ENDOCRINE NEOPLASIA 2a + 2b- NEUROFIBROMATOSIS I (tumours deposited along nerve myelin sheath)
Presentation of phaeochromocytoma
- HYPERTENSION (but rarer cause than conn’s)- PALLOR- V SWEATY- TACHYCARDIA
Diagnosis of phaeochromocytoma
Bloods:- RAISED PLASMA METANEPHRINES + NORMETANEPHRINES (breakdown products of NAd + Adr) - DIAGNOSTIC - metanephrines hava a longer 1/2 life than Adr so give more sensitive readings- urinary catecholamines- CT adrenals to image tumour
Treatment of phaeochromocytoma
- FIRST = ALPHA BLOCKERS (phenoxybenzamine)- then: Beta Blocker (Atenolol) - in this order to PREVENT REACTIVE VASOCONSTRICTION- EXCISE TUMOUR if surgery possible
Complication of phaeochromocytoma
HTN CRISIS (>180/120 BP) - could be caused by XR contrast, tricyclic antidepressants, opiates- treat with PHENTOLAMINE (alpha blocker)
Dx of renal artery stenosis
- Doppler US- CT angiogram- MR angiogram
