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Phase 2a Lauren > Endocrinology - Alison's > Flashcards

Endocrinology - Alison's Flashcards

1
Q

Define diabetes mellitus.

A

Syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both

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2
Q

Consequences of hyperglycaemia?

A

Hyperglycaemia results in serious microvascular (retinopathy, nephropathy, neuropathy) or macrovascular (strokes, renovascular disease, limb ischaemia and above all heart disease) problems

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3
Q

What are optimum levels of blood glucose?

A

Blood glucose levels should be between 3.5-8.0mmol/L under all conditions

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4
Q

Explain the role of the liver in glucose homeostasis?

A
  • Stores & absorbs glucose as glycogen
  • Performs gluconeogenesis from fat, protein & glycogen
  • If BG HIGH = produce glycogen = glycogenesis - long term makes triglycerides (lipogenesis)
  • If BG LOW = glycogen splitting into glucose = glycogenolysis.. long term makes glucose from amino acids/lactate (gluconeogenesis
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5
Q

How much glucose is produced and used per day?

A

~200g

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6
Q

Where is glucosed derived?

A 
90% = liver glycogen & hepatic gluconeogenesis
10% = renal gluconeogenesis
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7
Q

Why is the brain the major glucose consumer?

A
  • The brain cannot use free FAs to be converted to ketones which can be converted into Acetyl-CoA and used in Kreb’s as free FAs CANNOT CROSS BLOOD BRAIN BARRIER
  • Brain glucose uptake is OBLIGATORY and not insulin dependant. Glucose is oxidised to CO2 & H2O
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8
Q

Where are insulin-responsive glucose transporters and their effect?

A

Muscle and fat

Absorb glucose in response to postprandial (post-meal) peaks in glucose and insulin

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9
Q

What happens to glucose taken up by muscle?

A

Stored as glycogen or metabolised to lactate or CO2 and H2O

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10
Q

What does fat use glucose for?

A

Triglyceride synthesis

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11
Q

Explain the process of lipolysis?

A

Lipolysis of triglyceride releases fatty acids + glycerol - the glycerol is then used as a substrate for hepatic gluconeogeneis

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12
Q

Describe the action of insulin?

A

-Suppresses hepatic glucose output - decreases glycogenolysis & gluconeogenesis
- Increases glucose uptake into insulin sensitive tissues:
Muscle - glycogen & protein synthesis
Fat - fatty acid synthesis
Suppresses:
Lipolysis
Breakdown of muscles (decreased ketogenesis)

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13
Q

Explain biphasic insulin release?

A

Biphasic insulin release:
B-cells can sense the rising glucose levels and aim to metabolise it by releasing insulin - glucose levels are the major controlling factor in insulin release
First phase response is the RAPID RELEASE of stored insulin
If glucose levels remain high then the second phase is initiated, this takes longer than the first phase due to the fact that more insulin must be synthesised

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14
Q

Describe the action of glucagon?

A

-Increases hepatic glucose output - increases glycogenolysis & gluconeogenesis
-Reduces peripheral glucose uptake
-Stimulates peripheral release of gluconeogenic precursors e.g. glycerol & amino acids
Stimulates:
Lipolysis
Muscle glycogenolysis & breakdown (increased ketogenesis)

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15
Q

What are the other counter-regulatory hormones to glucagon?

A
  • Adrenaline, Cortisol and Growth Hormone

- These increase glucose production in the liver and reduce its utilisation in fat and muscle

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16
Q

Where is insulin coded for?

A

Chromosome 11

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17
Q

Where is insulin produced?

A

Beta cells on the islets of langerhans of the pancreas

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18
Q

Explain how insulin is cleaved from proinsulin?

A
  • Proinsulin is the precursor of insulin
  • It contains the Alpha & Beta chains of insulin which are joined together by a C PEPTIDE
  • When insulin is being produced, the proinsulin is cleaved from its C peptide and is then used to make insulin which is then packaged into insulin secretory granules
  • Thus when there is insulin release there will also be a high level of C peptide in the blood from the cleavage of the proinsulin from it
  • Synthetic insulin DOES NOT have C peptide - thus the presence of C peptide in the blood determines whether release is natural (then C peptide will be present) or synthetic (then C peptide will not be present)
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19
Q

How much insulin is extracted and degraded in the liver?

A

~50%

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20
Q

How does glucose get across membranes?

A

Cell membranes are not inherently permeable to glucose

A family of specialised glucose-transporter (GLUT) proteins carry glucose through the membrane and into cells

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21
Q

What do GLUT1 receptors do?

A

Enables basal NON-INSULIN-STIMULATED glucose uptake into many cells

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22
Q

What do GLUT2 receptors do?

A
  • Found in BETA-CELLS of the pancreas
  • Transports glucose into the beta-cell - enables these cells the SENSE GLUCOSE LEVELS
  • Is a low affinity transporter that is, it only allows glucose in when there is a high concentration of glucose i.e. when glucose levels are high and thus WANT insulin release
  • In this way via GLUT2 beta-cells are able to detect high glucose levels and thus release INSULIN in response
  • Also found in the renal tubules and hepatocytes
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23
Q

What do GLUT3 receptors do?

A

Enables NON-INSULIN-MEDIATED glucose uptake into BRAIN NEURONES & PLACENTA

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24
Q

What do GLUT4 receptors do?

A

Mediates much of the PERIPHERAL ACTION of INSULIN
It is the channel through which glucose is taken up into MUSCLE and ADIPOSE TISSUE cells following stimulation of the insulin receptor by INSULIN binding to it

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25
Q

What is an insulin receptor and what is it’s role?

A

A glycoprotein, coded for on the short arm of chromosome 19, which straddles the cell membranes of many cells
-insulin binds = activation of tyrosine kinase and initiation of a cascade response = migration of the GLUT-4 transporter to the cell surface and increased transport of glucose into the cell

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26
Q

What are causes of secondary diabetes?

A

-Pancreatic pathology e.g. total pancreatectomy, chronic pancreatitis, haemochromatosis
-Endocrine disease e.g. acromegaly and Cushing’s disease
-Drug induced
-Maturity onset diabetes of youth (MODY):
Autosomal dominant form of type 2 diabetes - single gene defect altering beta cell function
Tends to present <25 yrs with a positive family history

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27
Q

What drugs can cause secondary diabetes?

A
  • Thiazide diuretics
  • Beta-blockers
  • Immunosuppressives e.g. ciclosporin and tacrolimus (used in UC and skin)
  • Thyroid hormone
  • Corticosteroids
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28
Q

What are the most common causes of premature death in diabetes patients?

A

Cardiovascular problems - 70%
Chronic kidney disease - 10%
Infections - 6%

Directly related to hyperglycaemia

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29
Q

What are macrovascular complications of diabetes?

A
  • Atherosclerosis - so more likley to have stroke, ischaemic heart disease, peripheral vascular disease etc
  • Peripheral vascular disease - Affects distal vessels. 15-40 times more likely to have lower limb amputation. Symptoms include intermittent claudication and rest pain
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30
Q

What are the microvascular complications of diabetes?

A
  • Retinopathy
  • Nephropathy
  • Neuropathy

Manifest 10-20 years after diagnosis in young patients

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31
Q

What is diabetic retinopathy?

A
  • Microaneurysms (seen as tiny red dots) form due to poorly controlled diabetes causing intramural pericyte death and thickening of the basement membrane.
  • Haemorrhages (seen as blots) form due to breach of the microaneurysms causing leakage of fluid into the retina which is cleared by veins but leaves behind protein and lipid deposits causing hard exudates (yellowish deposists)
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32
Q

What is the treatment for diabetic retinopathy?

A
  • Early detection and treatment can reduce risk of blindness - Theres a National eye screening program
  • Laser therapy, it doesn’t improve sight but stabilises deterioration and prevents progression, but risks include loss of night vision and the loss of peripheral vision
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33
Q

What is diabetic nephropathy?

A
  • Thickening of basement membrane to glomerular damage due to poor glycaemic control leads to microalbuminuria - this gives an early warning sign of an impending renal problem.
  • May induce transient nephrotic syndrome
  • May progress to end stage kidney disease and require dialysis and transplant
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34
Q

How do you detect diabetic nephropathy?

A

This is undetectable by conventional dipstick - result shows negative for protein. But urine albumin:creatinine ratio > 3 will indicate microalbuminuria

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35
Q

How do you treat diabetic nephropathy?

A

Treat BP aggressively with ACE inhibitors or angiotensin receptor blockers

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36
Q

What is the commenest form of diabetic neuropathy?

A

Commonest form is distal symmetrical neuropathy

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37
Q

What are features of diabetic neuropathy?

A
  • Pain - Allodynia, paraesthesia, burning pain (worse at night)
  • Autonomic - Postural hypotension, Gatsroparesis, Diarrhoea, Constipation, Incontinence, Erectile dysfunction
  • Insensitivity - ‘Glove and stocking’ sensory loss, can lead to foot ulceration, infection, amputations and falls
  • Diabetic amyotrophy - painful asymmetrical wasting of quadriceps, diminished knee reflex
  • Mononeuritis - Isolated palsies mainly to extraoccular muscles (III and VI). There’s a characteristic feature of diabetic CN III lesion of sparing of the pupillomotor fibres so there is a retained pupillary reflex
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38
Q

What is the treatment/management for diabetic neuropathy?

A

Treatment - Good glycaemic control

Management - Foot screening, teach patients to care for feet and check daily

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39
Q

Why are infections more likely in diabetic patients?

A

Poorly controlled diabetes impairs the function of leucocytes

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40
Q

Define diabetes mellitus Type 1?

A

Disease of insulin deficiency usually caused by autoimmune destruction of beta cells of the pancreas

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41
Q

What is latent autoimmune diabetes in adults (LADA)?

A
  • A ‘slow burning’ variant with slower progression to insulin deficiency occurs in later life
  • May be difficult to differentiate from type 2 diabetes (which also presents in later life) - clinical clues include; leaner build, rapid progression to insulin therapy following an initial response to other therapies and the presence of circulating islet autoantibodies)
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42
Q

What is the aetiology of diabetes T1?

A

Autoimmune - Auto-antibodies forming against insulin and islet beta cells - Insulitis
Idiopathic
Genetic susceptibility - HLA-DR3-DQ2 or HLA-DR4-DQ8

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43
Q

What is the pathophysiology of diabetes T1?

A
  • Results from autoimmune destruction by autoantibodies of the pancreatic insulin-secreting Beta cells in the Islets of Langerhans
  • Causing insulin deficiency and thus the continued breakdown of liver glycogen (producing glucose and ketones) leading to glycosuria and ketonuria as more glucose is in the blood
  • In skeletal muscle and fats there is impaired glucose clearance
  • Eventual complete Beta cell destruction results in the absence of serum C-peptide
  • Present VERY LATE often with only 10% of beta cells remaining
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44
Q

Why are patients with DM T1 present thirsty?

A

In skeletal muscle and fats there is impaired glucose clearance:
Blood glucose is increased - when it reaches 10mmol/L body can no longer absorb glucose - you become thirsty and get polyuria (as body attempts to remove excess glucose)

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45
Q

Why are patients with DM T2 prone to diabetic ketoacidosis?

A
  • Reduced supply of glucose (since there will be a significant decline in circulating insulin) and an increase in fatty acid oxidation (due to an increase in circulating glucagon)
  • The increased production of Acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidise them. Ketone bodies are relatively strong acids (pH 3.5), and their increase lowers the pH of blood
  • IMPAIRS THE ABILITY OF HAEMOGLOBIN TO BIND TO OXYGEN - note if a patient is in diabetic ketoacidosis, the excess ketones in the blood will result in their BREATH SMELLING OF PEAR DROPS (KETONES)
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46
Q

What are the risk factors for DM T1?

A

-Northern European - especially Finnish
-Family history - HLA-DR3-DQ2 or HLA-DR4-DQ8 in > 90%
-Associated with other autoimmune disease:
Autoimmune thyroid
Coeliac disease
Addison’s disease (excess cortisol)
Pernicious anaemia
-Environmental factors:
Dietary constituents
Enteroviruses such as Coxsackie B4
Vitamin D deficiency
Cleaner environment may increase type 1 susceptibility

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47
Q

What is the epidemiology for DM T1?

A
  • Typically manifests in childhood, reaching a peak incidence around the time of puberty - but can present at any age
  • Usually younger - < 30yrs
  • Patient is usually lean
  • Increased in those of Northern European ancestry, especially in Finland
  • Incidence is increasing in most populations - particularly children
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48
Q

Define DM T2?

A

Results from a combination of insulin resistance and less severe insulin deficiency

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49
Q

What is the aetiology of DM T2?

A
  • Decreased insulin secretion +/- increased insulin resistance
  • Associated with obesity, lack of exercise, calorie and alcohol excess
  • No immune disturbance
  • No HLA disturbance but there is a stronger genetic link
  • Polygenic disorder
  • More common in MALES than females
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50
Q

What conditions is DM T2 associated with?

A

Central obesity, hypertension, hypertriglyceridaemia, a decreases high-density lipoprotein (HDL) cholesterol, disturbed homeostatic variables and modest increases in a number of pro-inflammatory markers
-accumulation of intracellular triglycerides in muscle and liver and a high proportion have non-alcoholic fatty liver disease

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51
Q

What is the physiology of DM T2?

A
  • Insulin binds normally to its receptor on the surface of cells in DMT2 just like in healthy people - thus insulin resistance develops post-receptor
  • At the time of diagnosis the Beta cell mass is reduced to about 50% of normal
  • Almost all patient show amyloid deposition in the islets of the pancreas at autopsy derived from a peptide known as amylin or islet amyloid polypeptide which is co-secreted with insulin
  • Levels are higher due to increased glucose production from the liver (due to the inadequate suppression of gluconeogenesis) and reduced glucose uptake by peripheral tissues (insulin resistance)
  • Hyperglycaemia and lipid excess are toxic to beta cells (glucotoxicity) and this is thought to result in further beta cell loss and further deterioration or glucose homeostasis
  • It typically progresses from a preliminary phase of impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) - this is a UNIQUE WINDOW FOR LIFESTYLE INTERVENTION to prevent FULL DMT2 progression
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52
Q

What are the values classifying impaired glucose tolerance?

A

Fasting plasma glucose < 7mmol/L - Oral glucose tolerance of 2hrs glucose > 7.8mmol/L but < 11mmol/L

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53
Q

What are the values classifying impaired fasting glucose?

A

Fasting plasma glucose > 6.1mmol/L but < 7mmol/L

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54
Q

What are the risk factors for DMT2?

A

-Family history - genetics
-Increasing age
-Obesity and poor exercise - can trigger DMT2 in genetically susceptible individuals
-Ethnicity - Middle Eastern, South-east Asian and Western pacific
-Environment:
There is an association between low weight (as a result of poor nutrition) at birth and at 12 months of age with glucose intolerance later in life
Thought to be caused because poor-nutrition early in life impairs beta cell development and function - predisposing to diabetes later in life
Low birth weight has also been shown to predispose to heart disease and hypertension

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55
Q

What is the epidemiology of DM T2?

A
  • Common is all populations enjoying an affluent lifestyle - has increased in incidence due to the ageing population and increasing obesity in the Western world
  • Older - usually >30 yrs of age - but teenagers are starting to get it
  • Often overweight around the abdomen
  • More prevalent in South Asian, African and Caribbean ancestry
  • Middle eastern and Hispanic Americans also more at risk
  • Hypertension is present in 50% of patients with DMT2 and a higher proportion of African and Caribbean patients
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56
Q

What is the difference in presentation of DMT1 and DMT2?

A
  • type 1 tend to be leaner and present with more marked polydipsia, polyuria, weight loss and ketosis
  • type 2 the patient tends to be overweight in the abdominal area and also presents with polydipsia, polyuria and weight loss and ketosis (only when very advanced with absolute insulin deficiency) but less marked
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57
Q

Signs of diabetes mellitus?

A

-Ketonuria is often present in young people and may progress to ketoacidosis if these early symptoms are not recognised and treated:
Occur primarily in DMT1 and very advanced DMT2 (i.e. when there is absolute insulin deficiency)
-Patients may have breath smelling of ketones (pear-drops)
-Evidence of weight loss and dehydration may be present
-Older patients may present with established complications and the presence of the characteristic retinopathy is DIAGNOSTIC in diabetes
-Patients with severe insulin resistance (i.e. DMT2) may have acanthosis nigricans - characterised by blackish pigmentation at the nape of the neck and in the axillae

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58
Q

What is the classic triad of symptoms for a patient with DMT1?

A

2-6week history
-Polyuria and nocturia:
Since glucose draws water into the urine by osmosis - not enough glucose can be reabsorbed as kidneys have reached the renal maximum reabsorptive capacity
This results in high levels of glucose in tubule urine and thus lots of water resulting in polyuria and nocturia
-Polydipsia (thirst):
Due to the loss of fluid and electrolytes from excess glucose and thus water being in the urine
-Weight loss:
Due to fluid depletion and the accelerated breakdown of fat and muscle secondary to insulin deficiency

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59
Q

What are the symptoms of subacute presentation (months-years) of DM?

A
  • Onset may be over several months or years, particularly in older patients
  • Polyuria, polydipsia and weight loss are typically present but tend to be less marked
  • Patients may complain of such symptoms as lack of energy, visual blurring (due to glucose-induce changes in refraction) or pruritus vulvae or balantis that is due to Candida infection
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60
Q

What do you look for in asyptomatic patients with DM?

A
  • In these individuals, the only symptoms detected may just by glycosuria and raised blood glucose with no other symptoms of ill-health
  • More common in older people, who have a raised renal threshold for glucose
  • When present, glycosuria is NOT DIAGNOSTIC for diabetes but indicates the need for further investigations
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61
Q

What investigations are undertaken for patients with suspected DM?

A

-Random plasma glucose
-Fasting plasma glucose
For both tests one abnormal value is DIAGNOSTIC in symptomatic individuals
Two abnormal values are required in asymptomatic individuals
For borderline cases:
-Oral glucose tolerance tests (OGTT)
-Haemoglobin A1c:
-Screen urine for microalbuminuria - to asses for kidney disease
FBC, U&Es, liver biochemistry, fasting blood sample for cholesterol and triglycerides
Raised blood pH to look for metabolic acidosis (high H+ and low HCO3-, due to ketoacidosis) - seen in DMT1 and advanced DMT2

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62
Q

What values indication diabetes diagnosis in oral glucose tolerance test?

A

-Fasting > 7mmol/L = DIABETES DIAGNOSIS
-2 hrs after glucose > 11.1 mmol/L = DIABETES DIAGNOSIS
-Can also detect impaired glucose tolerance (IGT) - a risk factor for future diabetes and cardiovascular disease:
Fasting < 7mmol/L
2 hrs after glucose 7.8-11.0mmol/L

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63
Q

What values indication diabetes diagnosis in HbA1c?

A
  • Measures amount of glycated haemoglobin - thus tells us blood glucose concentration
  • HbA1c > 6.5% normal (48mmol/mol) = DIABETES DIAGNOSIS
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64
Q

What values indication diabetes diagnosis in random plasma glucose?

A

> 11.1mmol/L = DIABETES DIAGNOSIS

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65
Q

What values indication diabetes diagnosis in fasting plasma glucose?

A

> 7mmol/L = DIABETES DIAGNOSIS

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66
Q

What are complication of DM?

A
  • Staphylococcal skin infection
  • Retinopathy found during visit to optician
  • Polyneuropathy causing tingling and numbness in the feet
  • Erectile dysfunction
  • Arterial disease resulting in MI or peripheral gangrene
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67
Q

What are non-pharmacological treatment/management of both DMT1 and DMT2?

A

-MDT approach
-Educate patient on disease and risks
-Maintain lean weight, stop smoking and take care of feet (to reduce gangrene risk)
-Encourage regular physical activity and reduction in bodyweight in the obese - both of which improve glycaemic control in DMT2
-Good glycemic control with good diet:
Low in sugar
High in starchy carbohydrates with low glycaemic index e.g. pasta
High in fibre
Low in fat

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68
Q

What are pharmacological treatment/management of both DMT1 and DMT2?

A
  • Treatment of hypertension with ACE-inhibitors e.g. RAMIPRIL
  • Treatment of hyperlipidaemia with statins e.g. SIMVASTATIN - risk factors for long term complication
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69
Q

What are pharmacological treatment/management of DMT1?

A

-Insulin is always indicated in a patient who has been in ketoacidosis and is usually required in lean patients who present under the age of 40
-For good control is it VITAL to educate to self-adjust doses
-Ensure they:
Can phone for support (24/7 nurse)
Can modify diet wisely and avoid binge drinking
Partner can abort hypoglycaemia e.g. sugary drinks
-Synthetic (recombinant) human insulin is used and administered via SUBCUTANEOUS INJECTION into abdomen, thighs or upper arm
-Change injection site to prevent areas of lipohypertrophy (fatty lumps)

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70
Q

What are the three main types of insulin?

A
  • Short acting (soluble insulins)
  • Short acting insulin analogues
  • Long acting insulin
71
Q

What are the features of short-acting insulins?

A

Start working within 30-60 minutes and last for 4-6 hours
Given 15-30 minutes before meals in patients on multiple dose regimens and by continuous IV infusion in labour, during medical emergencies, at the time of surgery and in patients using insulin pumps

72
Q

What are the features of short-acting insulin analogues?

A

Human insulin analogies (insulin aspart, insulin lispro, insulin glulisine) have a fast onset and a short duration that the soluble insulin but overall DO NOT IMPROVE DIABETIC CONTROL
Have a reduced carry-over effect compared to soluble insulin and are used with the evening meal in patients who are prone to nocturnal hypoglycaemia

73
Q

What are the features of long-acting insulins?

A
  • Insulin premixed with retarding agents (either protamine or zinc) precipitate crystals
  • Can be intermediate (12-24 hrs) or long-acting (more than 24hrs)
  • The protamine insulins are also known as isophane or NPH insulins
  • The zinc insulins are also known as lente insulins
  • Insulin glargine is a structurally modified insulin that precipitates in tissues and is then slowly released from the injection site
74
Q

What are the complications of insulin treatment?

A

Hypoglycaemia - most common (also caused by SULFONYLUREA)
Injection site - lipohypertrophy
Insulin resistance - mild and associated with obesity
Weight gain - insulin makes people feel hungry

75
Q

What are the first line treatments of DMT2?

A
  • Lifestyle & dietary changes are ESSENTIAL!
  • Dietary factors e.g. low sugar, high in starch carbohydrates with low glycaemic index e.g. pasta, high in fibre, low in fat (esp. sat. fat)
  • Nutrient load should be spread throughout the day (three main meals with snacks in between and at bedtime) - which reduces swings in blood glucose
  • Blood pressure control e.g. RAMIPRIL
  • Hyperlipidaemia control e.g. STATINS
  • Exercise
  • Weight loss if obese - associated with improved diabetic control
  • Can give ORLISTAT in obesity which is an intestinal lipase inhibitor and reduces the absorption of fat from the diet - it promotes weight loss
76
Q

What are the second line treatments for DMT2?

A

-Used in association with diet & lifestyle changes when this alone has failed to control hyperglycaemia
-Initially give a biguanide eg Metformin
-If HbA1c > 53mmol/L 16 weeks later then add a sulfonylurea e.g. ORAL GLICLAZIDE:
-If at 6 months the HbA1c > 57mmol/L consider adding:
Insulin, glitazone, sulfonylurea receptor binding, GLP

77
Q

How do biguanides eg. metformin work?

A

-Reduces rate of gluconeogenesis in the liver
-Increases cells sensitivity to insulin
-Helps with weight issues
-Reduces CVS risk in diabetes
S/E; anorexia, diarrhoea, nausea, abdominal pain, NOT HYPOGLYCAEMIA
-Contraindicated in heart failure, liver disease or renal disease, since can induce lactic acidosis

78
Q

How do sulfonylureas eg. gliclazide work?

A

-Promotes insulin secretion
-These are ineffective in patients without a functional beta-cell mass
-Avoided in pregnancy
-Effect wears off as beta-cell mass declines
S/E; hypoglycaemia (must monitor glucose), promote weight gain (so best avoided in the overweight!!)
-Should be used with care in people with liver disease and those with renal impairment should use sulfonylurea’s primarily excreted by the liver
-The safest drug in the very elderly is ORAL TOLBUTAMIDE since it has a very short duration of action

79
Q

In DMT1 when is diabetic ketoacidosis usually seen in?

A

Previously undiagnosed diabetes
Interruption of insulin therapy
The stress of intercurrent illness e.g. surgery or infection

80
Q

What is the pathophysiology of diabetic ketoacidosis?

A
  • insulin deficiency = uncontrolled catabolism
  • high circulating glucose = osmotic diuresis by kidnets and dehydration & loss of electrolytes
  • plasma osmolality rises and renal perfusion falls
  • peripheral lipolysis = more FFAs broken into Acetyl-CoA turned into ketones
  • high ketones = metabolic acidosis
  • vomit = more loss
  • rep compensation = hyperventilation
  • pH drops = enzymes less efficient
  • stress hormones accelarate process
  • fatal if untreated
81
Q

Risk factors of diabetic ketoacidosis?

A
  • Stopping insulin therapy
  • Infection e.g. UTI
  • Surgery
  • MI
  • Pancreatitis
  • Undiagnosed diabetes
82
Q

Signs of diabetic ketoacidosis?

A
  • Pear drop breath - The excess ketones are excreted in the urine but also appear in the breath, producing a distinctive smell (pear drops)
  • Kussmaul’s respiration (deep rapid breathing) may be present - sign of respiratory compensation by hyperventilating
  • Some disturbance of consciousness is common but only 5% present with coma
  • Body temperature is often subnormal even in the presence of infection
83
Q

Symptoms of diabetic ketoacidosis?

A
  • Vomiting - which exacerbates fluid and electrolyte loss, causing profound dehydration
  • Eyes are sunken, tissue turgor is reduced and the tongue is dry - in severe cases of dehydration
  • Gradual drowsiness, vomiting and dehydration in type 1 diabetic (very rarely in type 2 diabetic)
  • A few patients have abdominal pain - which is so severe it can sometimes be confused for a surgical acute abdomen
84
Q

Investigations for diabetic ketoacidosis?

A

-Hyperglycaemia - blood glucose > 11mmol/L
-Raised plasma ketones > 3mmol/L - measured using a finger prick sample and near–patient meter that measure —-Beta-hydroxybutyrate (major ketone)
-Acidaemia - blood pH < 7.3
-Metabolic acidosis with bicarbonate < 15mmol/L
-Urine stick testing shows heavy glycosuria and ketonuria
-Urea and creatinine are often raised as a result of dehydration
-Total body K+ is low as a result of osmotic diuresis - but serum K+ is often raised due to the absence of insulin which allows K+ to shift out of cells
-FBC may show raised white cell count even in the absence of infection
Blood cultures, CXR and urine microscopy and culture to look for infection
-ECG and cardiac enzymes to look for MI

85
Q

Treatment of diabetic ketoacidosis?

A

-Immediate ABC mangement
-Replace the fluid loss with 0.9% saline
-Restore electrolyte loss (K+)
-Restore acid-base balance over 24hrs - normally done by kidneys once circulating volume has been restored
-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
-Complications of management:
Hypotension - increase circulating volume with saline to treat this
Coma - insert naso-gastric tube to prevent aspiration
Cerebral oedema - from rapid lowering of blood glucose and thus osmolality of blood
Hypothermia
-Late complications include pneumonia and deep-vein thrombosis (DVT) - occur especially in comatose or elderly patient

86
Q

Define hyperosmolar hyperglycaemic state

A
  • This is a life-threatening emergency characterised by marked hyperglycaemia, hyperosmolality and mild or no ketosis
  • This is the metabolic emergency characteristic of uncontrolled type 2 diabetes mellitus
87
Q

What is the pathophysiology of hyperosmolar hyperglycaemic state?

A

Endogenous insulin levels are reduced but are still sufficient to inhibit hepatic ketogenesis but insufficient to inhibit hepatic glucose production

88
Q

What are risk factors of hyperosmolar hyperglycaemic state?

A
  • Infection - most common precipitating cause - particularly pneumonia
  • Consumption of glucose rich fluids
  • Concurrent mediation such as thiazide diuretics or steroids
89
Q

What is the epidemiology of hyperosmolar hyperglycaemic state?

A

Patients present in middle or later life often with previously undiagnosed diabetes

90
Q

What are the signs of hyperosmolar hyperglycaemic state?

A

-Severe dehydration (secondary to osmotic diuresis)
-Decreased level of consciousness - which is directly related to the elevation of plasma osmolality
-Hyperglycaemia
-Hyperosmolality - which may predispose to stroke, MI or arterial insufficiency of the lower limbs
-No ketones in blood or urine
Stupor or coma
-Bicarbonate is NOT LOWERED

91
Q

What are the investigations for hyperosmolar hyperglycaemic state?

A
  • Hyperglycaemia - blood glucose > 11mmol/L
  • Urine stick testing shows heavy glycosuria
  • Plasma osmolality is extremely high
  • Total body K+ is low as a result of osmotic diuresis - but serum K+ is often raised due to the absence of insulin which allows K+ to shift out of cells
92
Q

What is the treatment and management for hyperosmolar hyperglycaemic state?

A
  • These patients are more sensitive to insulin so give a lower rate of infusion
  • Fluid replacement with 0.9% saline
  • Low molecular weight heparin e.g. SC ENOXAPARIN to reduce risk of thromboembolism, MI, stroke and arterial thrombosis which patient is at increased risk of due to hyperosmolality
  • Restore electrolyte loss (K+)
  • Risk of cerebral oedema - from rapid lowering of blood glucose (with insulin - that they are extremely sensitive to) and thus osmolality of blood
93
Q

What is hypoglycaemia?

A

Defined as plasma glucose < 3mmol/L

94
Q

What is the aetiology of hypoglycaemia?

A

-In diabetics:
Due to insulin or sulphonylurea treatment - commonest cause:
E.g. with increased activity, missed meal, accidental or nonaccidental overdose

-In non-diabetics - EXPLAIN:
Ex -Exogenous drugs - insulin, oral hypoglycaemic, alcohol binge with no food
P - Pituitary insufficiency
L - Liver failure
A - Addison’s disease
I - Islets cell tumour (insulinoma) & immune hypoglycaemia
N - Non-pancreatic neoplasm e.g. fibrosarcomas and haemangiopericytomas

95
Q

What is the presentation of hypoglycaemia?

A

Autonomic:
Sweating, anxiety, hunger, tremor, palpitations, dizziness

Neuroglycopenic:
Confusion, drowsiness, visual trouble, seizures, coma
Rarely there are focal symptoms such as transient hemiplegia, mutism, personality change, restlessness and incoherence

96
Q

What are the investigations for hypoglycaemia?

A

-Fingerpick blood during attack (on filter-paper at home) - and then can be sent for analysis
-Take drug history and exclude liver failure
-Bloods - glucose, insulin, C-peptide, plasma ketones
-If hypoglycaemic hyperinsulinaemia:
-Due to insulinoma, sulfonylurea or insulin injection (no C-peptide in serum) or congenital
-If low insulin, no excess ketones:
-Due to non-pancreatic neoplasms or anti-insulin receptor antibodies
-If low insulin, increased ketones:
Alcohol, pituitary insufficiency, Addison’s disease

97
Q

What is the treatment/management of hypoglycaemia?

A
  • If episodes are often then advise many small high-starch meals
  • In diabetics re-educate on insulin use and safety!!

Pharmacological

  • Oral sugar and long-acting starch e.g. toast
  • If cannot swallow then give 50% Glucose IV
  • Or IM Glucagon if no IV access
98
Q

What are important structures located near the thyroid gland?

A

• Recurrent laryngeal nerve • Superior laryngeal nerve • Parathyroid glands • Trachea • Common carotid artery • Internal jugular vein

99
Q

What is T3?

A

Triiodothyronine = more active

100
Q

What is T4?

A

Thyroxine = less active than T3 but more is produced

101
Q

How are the thyroid molecules produced?

A
  • Iodine cotransported with Na+ into follicular cells (iodine trapping). Na pumped back out Na+/K+/ATPases
  • iodine transported into colloid (protein rich core)
  • Oxidised into iodine
  • Binds to tyrosine residues using thyroid peroxidase
  • monoiodotyrosine = 1 iodine T1
  • diiodotyrosine = 2 iodine T2
  • When stimulated they are cleaved: T1 + T2 = T3, T2 + T2 = T4
  • TSH stimulates movement of T3 & T4
  • iodated + lysosomes = proteolysis = T3 & T4 released
102
Q

What are the causes of hyperthyroidism?

A
  • Grave’s disease
  • Toxic multiodular goitre
  • solitary toxic adenoma
  • De Quervains’ thyroiditis
  • Drug induced
103
Q

How does grave’s cause hyperthyroidism?

A
  • Serum IgG antibodies, specific for Graves’ disease, known as TSH receptor stimulating antibodies (TSHR-Ab) bind to TSH receptors in the thyroid
  • Thereby stimulating thyroid hormone production (T3 & T4) - essentially they behave like TSH
  • Resulting in excess secretion of thyroid hormones and hyperplasia of thyroid follicular cells resulting in hyperthyroidism and diffuse goitre
  • Persistent high levels predict a relapse when drug treatment is stopped
  • Similar auto antigen can also result in retro-orbital inflammation - graves opthalmopathy
104
Q

How does toxic multinodular goitre cause hyperthyroidism?

A
  • Nodules that secrete thyroid hormones
  • Seen in elderly and in iodine-deficient areas
  • Commonly occurs in older women and drug therapy rarely produces prolonged remission
105
Q

How does solitary toxic adenoma cause hyperthyroidism?

A

Cause of about 5% of cases of hyperthyroidism

Prolonged remission is rarely induced by drug therapy

106
Q

How does de quervains’s thyroiditis cause hyperthyroidism?

A

Transient hyperthyroidism sometimes results from acute inflammation of the thyroid gland, probably due to viral infection
Typical for there to be globally reduced uptake on technetium thyroid scan
Usually accompanied by fever, malaise and pain in the neck
Treat with aspirin and only give prednisolone for severely symptomatic cases

107
Q

How do drugs cause hyperthyroidism?

A

AMIODARONE - anti-arrhythmic drug:
Can cause both hyperthyroidism (due to the high iodine content of amiodarone) and hypothyroidism (since it also inhibits the conversion of T4 to T3)
Iodine
Lithium

108
Q

What are the risk factors for hyperthyroidism?

A
  • Female
  • Genetic - HLA-B8, DR3 and DR2
  • E. coli and other gram-NEGATIVE organisms contain TSH-binding sites so may initiate pathogenesis via ‘molecular mimicry’
  • Smoking
  • Stress
  • High iodine intake
  • Autoimmune disease:
  • Vitiligo (pale white patches -on skin)
  • Addison’s disease
  • Pernicious anaemia
  • Myasthenia gravis
  • Type 1 DM
109
Q

What is the epidemiology of hyperthyroidism?

A
  • Graves occurs more commonly in females typically between the ages of 40-60
  • Other causes of hyperthyroidism again mainly occurs in women but between the ages of 20-40
110
Q

What is the presentation of graves?

A
  • Results in retro-orbital inflammation and swelling of the extrocular muscles
  • Eye discomfort, grittiness, increased tear production, photophobia, diplopia, reduced acuity
  • Exophthalmos - appearance of protruding eye and proptosis - eye protrudes beyond orbit
  • Conjunctival oedema
  • Corneal ulceration
  • Ophthalmoplegia - paralysis of eye muscles
  • Graves dermopathy - only in -Graves (Rare) - Pretibial myxoedema which is raised, purple-red symmetrical skin lesions over the anterolateral aspects of the shin
  • Thyroid acropachy - clubbing, swollen fingers and periosteal bone formation
111
Q

What are the signs of hyperthyroidism?

A
  • Hands - Palmar erythema, warm moist skin and fine tremor
  • Diffuse goitre
  • Lid lag & ‘stare’ - can occur in any hyperthyroidism
  • Hyperkinesis - muscle spasm
  • Warm - vasodilator peripheries
  • Proximal myopathy & muscle wasting
  • Lymphadenopathy and splenomegaly can occur
112
Q

What are the symptoms of hyperthryoidism?

A
  • Palpitations
  • Diarrhoea
  • Weight loss & increased appetite
  • Oligomenorrhea (infrequent periods) +/- infertility
  • Heat intolerance i.e. sweating a lot - will be wearing fewer clothes than normal
  • Irritability/behavioural change
  • Anxiety

Elderly:

  • Atrial fibrillation
  • Other tachycardias and/or heart failure

Children:

  • Excessive height or excessive growth rate
  • Behavioural problems like hyperactivity
113
Q

What is the differential for hyperthyroidism?

A

Usually no other differentials would fit the presentation, sometimes milds cases just need to differentiated from anxiety

114
Q

What are the investigations for hyperthyroidism?

A

-Thyroid function tests (TFTs):
Serum TSH is suppressed: Due to negative feedback produced by hyperthyroidism
T4 & T3 raised - DIAGNOSTIC:
-T4 is almost always raised
-T3 is more sensitive
In secondary hyperthyroidism e.g. pituitary resistance or pituitary secreting adenoma - TSH will be very elevated and not suppressed since the fundamental problem is with the pituitary
-Thyroid peroxidase (TPO) and thyroglobulin antibodies - Present in 80% of Graves’ but are all found in normal hyperthyroidism
-Ultrasound of thyroid - Helps to differentiate Graves’ from toxic adenoma

Graves’ specific tests:

  • TSH receptor stimulating antibodies (TSHR-Ab) raised - DIAGNOSTIC of GRAVES’
  • Mild neutropenia
  • Eyes are examined via CT/MRI of orbit (For Graves)
115
Q

What are the complications of hyperthyroidism?

A

-Thyroid crisis or thyroid storm:MEDICAL EMERGENCY!
Rare, life threatening condition in which there is a rapid deterioration of thyrotoxicosis (RAPID T4 INCREASE)
Features include hyperpyrexia, tachycardia, extreme restlessness and eventually delirium, coma and death
Usually precipitated by stress, infection, surgery or radioactive iodine therapy in an unprepared patient
Treated with LARGE DOSES of:
ORAL CARBIMAZOLE
ORAL PROPRANOLOL
ORAL POTASSIUM IODIDE (to block acutely the release of thyroid hormone from gland)
IV HYDROCORTISONE (to inhibits peripheral conversion of T4 to T3)

116
Q

What is the graves specific treatment of hyperthyroidism?

A
  • Conservative treatment includes smoking cessation and sunglasses
  • Treated with IV Methylprednisolone and surgical decompression or eyelid surgery
117
Q

What are the pharmacological managements of hyperthyroidism?

A
  • Beta-blockers eg. propanalol
  • Anti-thyroid drugs
  • Radioactive iodine
118
Q

What are the main anti-thyroid drugs?

A

-PROPYLTHIOURACIL (PTU) stops the conversion of T4 to T3
-ORAL CARBIMAZOLE which blocks thyroid hormone biosynthesis and also has immunosuppressive effects (which will affect Graves’ disease process)
-2 strategies:
–Titration e.g. ORAL CARBIMAZOLE for 4 wks then reduce doses according to thyroid function tests (TFTs; TSH, T3 & T4)
–Block-replace therapy e.g. ORAL CARBIMAZOLE + THYROXINE (T4) which has less risk of developing hypothyroidism
-Half of those with Graves’ relapse on discontinuation of drug treatment after 2 yrs
-Main side effect is AGRANULOCYTOSIS - results in a severely low white blood cell count (leukopenia) - most commonly neutropenia:
If they get sore throat, mouth ulcers and fevers then STOP DRUG ASAP
-Other S/E; rash (common), arthralgia, hepatitis and vasculitis (in bold less common)

119
Q

What are the important features of radioactive iodine?

A
  • RADIOACTIVE I(131) is given
  • Contraindicated in pregnancy and breast feeding
  • Can be given to all ages
  • Stop antithyroid drugs 4 days before giving iodine
  • Iodine is essential for thyroid hormone production so is readily taken up by the thyroid gland
  • Here it accumulates and results in local irradiation and tissue damage with return to normal thyroid function over 4-12 weeks
  • S/E; discomfort in the neck and hyperthyroidism initially
120
Q

What are the surgical managements of hyperthyroidism?

A
  • Indicated for those with large goitre, poor response to drugs and have drug side-effects
  • Subtotal thyroidectomy only in those who have been rendered euthyroid (normal functioning thyroid gland)
  • Total thyroidectomy only in those with large goitre or suspicion of malignancy (toxic adenoma) in a nodule and also for Graves’
  • Stop antithyroid drugs 10-14 days before and give potassium iodide to reduce vascularity of the gland
  • Patients become hypothyroid
121
Q

What are the complications of surgical management of hyperthyroidism?

A

Tracheal compression from postoperative bleeding - Laryngeal nerve palsy resulting in hoarse voice - Transient hypocalcaemia - due to removal of parathyroid gland too

122
Q

What is hypothryroidism?

A

Underactivity of the thyroid gland may be primary, from disease of the thyroid gland, or much less commonly, secondary to hypothalamic or pituitary disease (secondary hypothyroidism)

123
Q

What is the pathophysiology of Autoimmune/Atrophic Hypothyroidism?

A
  • The most common cause of hypothyroidism
  • Associated with antithyroid autoantibodies leading to lymphoid infiltration of the gland and eventual atrophy and fibrosis - since there is atrophy there is NO GOITRE
  • Associated with other autoimmune disease e.g. pernicious anaemia and vitiligo
124
Q

What is the pathophysiology of hashimoto’s thyroiditis?

A
  • Form of autoimmune hypothyroidism
  • Most common in middle age & in women aged 60-70yrs
  • Produces atrophic changes & regeneration = GOITRE FORMATION due to lymphocytic and plasma cell infiltration
  • Gland is usually firm and rubbery but may range from soft to hard
  • Thyroid peroxidase = enzyme essential for the production and storage of thyroid hormone
  • Thyroid peroxidase antibodies (TPO-Ab) are present in HIGH TITRES
  • Patients may be hypothyroid or euthyroid (normal thyroid function)
  • LEVOTHYROXINE THERAPY may shrink the goitre, even when the patient is not hypothyroid
125
Q

What is the pathophysiology of post-partum thyroiditis?

A
  • Usually a transient phenomenon observed following pregnancy
  • May cause hyperthyroidism, hypothyroidism or the two sequentially
  • Thought to result from modifications to the immune system necessary in pregnancy and histologically is a lymphocytes thyroiditis (AUTOIMMUNE)
  • Normally self-limiting but when conventional antibodies are found there is a high chance of this proceeding to permanent hypothyroidism
  • Can be misdiagnosed as postpartum depression - why TFTs are essential!
126
Q

What is the pathophysiology of the ioatrogenic (caused by treatment/examinations) hypothyroidism?

A
  • Thyroidectomy - for treatment of hyperthyroidism or goitre
  • Radioactive iodine treatment or external neck irradiation for head and neck cancer
127
Q

What drugs induced pathophysiology?

A
  • Carbimazole
  • Lithium
  • Amiodarone: Can cause both hyperthyroidism (due to the high iodine content of amiodarone) and hypothyroidism (since it also inhibits the conversion of T4 to T3)
  • Interferon
128
Q

What is the pathophysiology behind iodine deficiency hypothyroidism??

A
  • Dietary iodine deficiency - results in goitre
  • Patients are euthyroid or hypothyroid, depending on the severity of iodine deficiency
  • Mechanism is thought to be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing iodine deficiency
  • Iodine deficiency is a problem in the Netherlands, Wester pacific, India, SE Asia, Russia and part of Africa
129
Q

What are the risk factors of hypothyroidism?

A
  • Autoimmune hypothyroidism is associated with other autoimmune disease e.g. DMT1, Addisons’, pernicious anaemia
  • Associated with Turner’s (only affects females, only have one X chromosome as opposed to the normal XX) & Down’s (trisomy 21) syndrome, cystic fibrosis, primary biliary cirrhosis and ovarian hyper-stimulation
130
Q

What is the epidemiology of hypothyroidism?

A
  • Worldwide = iodine deficiency
  • The most common cause of primary hypothyroidism in areas with no iodine deficiency is autoimmune/atrophic hypothyroidism
  • More common in FEMALES than males
  • Incidence increases with age
131
Q

What are the signs of hypothyroidism?

A

BRADYCARDIC

  • Reflexes relax slowly - best seen on achilles with them kneeling on a chair
  • Ataxia (cerebellar)
  • Dry, thin hair/skin
  • Yawning/drowsy/coma
  • Cold hands +/- temperature drop
  • Ascites
  • Round puffy face
  • Defeated demeanour
  • Immobile +/- Ileus (temporary arrest of intestinal peristalsis)
  • Congestive cardiac failure
132
Q

What are the symptoms of hypothyroidism?

A
  • Hoarse voice
  • Goitre
  • Constipation
  • Cold intolerant
  • Weight gain
  • Menorrhagia
  • Myalgia, weakness
  • Tired, low mood, dementia
  • Myxoedema - accumulation of mucopolysaccharide in SC tissue
133
Q

What are symptoms of children with hypothyroidism?

A

May not show the classic features but often have a slow growth velocity, poor school performance and sometimes an arrest in puberty

134
Q

What are the symptoms of young women with hypothyroidism?

A

May not show obvious signs. Hypothyroidism should be excluded in all people with oligomenorrhea/ amenorrhoea, menorrhagia, infertility or hyperprolactinaemia

135
Q

What are the symptoms of elderly with hypothyroisism?

A

Hard to differentiate clinical features from normal ageing - should exclude hypothyroidism in those with cognitive impairment

136
Q

What are the investigations for those with hypothyroism?

A
  • THyroid function tests (TFTs)
  • Thyroid antibodies and organ specific antibodies
  • Blood tests
137
Q

What are you looking for in thyroid function tests for hypothyroidism?

A
  • Serum TSH high (confirm primary hypothyroidism) - increases in an attempt to make thyroid work again
  • -In secondary hypothyroidism the TSH is inappropriately low for the low T4/T3 - since issues is in the pituitary
  • Serum free T4 low - DIAGNOSTIC for HYPOTHYROID STATE
138
Q

What antibodies are you looking for in Hashimotos?

A

TPO-Ab (Thyroid peroxidase antibody)

139
Q

What are you looking for on a blood test for hypothyroidism?

A
  • Anaemia:
  • -Usually normochromic and normocytic
  • -May be macrocytic (sometimes due to pernicious anaemia)
  • -Or microcytic (in women, due to menorrhagia or undiagnosed coeliac disease)
  • Raised serum aspartate transferase levels from muscle and/or liver
  • Increase serum creatinine kinase levels associated with myopathy
  • Hypercholesterolaemia
  • Hyponatraemia due to an increase in ADH and impaired free water clearance
140
Q

What are the treatments and managements for hypothyroidism?

A

Lifelong thyroid hormone replacement e.g. ORAL LEVOTHYROXINE (T4)

  • -In patients with ischaemic heart disease use with caution and start on lower dose
  • -Aim is normal TSH conc. which will be achieved by levothyroxine - but don’t give too much so as to completely suppress TSH as this carries risk of AF and osteoporosis

Monitoring treatment:

  • Primary hypothyroidism:
  • -Dose is titrated until TSH normalises
  • -Check T4 levels 6-8 weeks after dose adjustment
  • Secondary hypothyroidism:
  • -TSH will always be low
  • -T4 is monitored
141
Q

What are the complications of lifelong thyroid hormone replacement therapy?

A

Myxoedema coma:

  • Severe hypothyroidism (REDUCED T4) that may rarely present with confusion and coma - particularly in elderly
  • Typical features include hypothermia, cardiac failure, hypoventilation, hypoglycaemia and hyponatraemia
  • MEDICAL EMERGENCY and given IV/ORAL T3 & glucose infusion as well as gradual rewarming
142
Q

What are the types of thyroid carcinoma?

A 
Papillary (70%): 
Follicular (20%): 
Anaplastic (<5%): 
Lymphoma (2%) 
Medullary cell (5%)
143
Q

What is papillary thyroid carcinoma?

A

70% of thyroid carcinomas

  • Most common, well differentiated
  • Young people, local spread and good prognosis
  • Arise from thyroid epithelium
144
Q

What is follicular thyroid carcinoma?

A

20% of thyroid carcinomas

  • Middle age, spread to lung/bone, usually good prognosis
  • Well differentiated, arise from thyroid epithelium
145
Q

What is anaplastic thyroid carcinoma?

A

<5% of thyroid carcinomas

  • Very undifferentiated and arise from thyroid epithelium
  • Aggressive, local spread but poor prognosis
146
Q

What is medullary cell thyroid carcinoma?

A

5% of thyroid carcinomas

Arise from calcitonin C cells of thyroid gland

147
Q

What is the pathophysiology of thyroid carcinomas?

A

-Minimally active hormonally
-Over 90% secrete thyroglobulin which can be used as a tumour marker after thyroid ablation
-Carcinomas derived from thyroid epithelium may be:
Differentiated - papillary or follicular
Undifferentiated - anaplastic

148
Q

What are risk factors of thyroid carcinomas?

A

-Radiation

149
Q

What is the epidemiology of thyroid carcinomas?

A
  • Not common, but are responsible for 400 deaths annually in the UK
  • More common in FEMALES than male
150
Q

What are the signs of thyroid carcinomas?

A
  • Thyroid nodule - Present in 90%
  • Cervical lymphadenopathy - May also metastasis to lung, cerebral, hepatic or bone metastases
  • If thyroid gland increases in size, becomes hard and is irregular in shape - think carcinoma
151
Q

What are the symptoms of thyroid carcinoma?

A

Dysphagia or hoarseness of voice - due to tumour compression on surrounding structures i.e. oesophagus and laryngeal nerve

152
Q

What is a differential diagnosis of thyroid carcinoma?

A

Goitre

153
Q

What are the investigations of thyroid carcinoma?

A
  • Fine needle aspiration cytology biopsy - To distinguish between benign or malignant nodules
  • Blood test - to check TFTs (TSH, T4 & T3) - To check if hyperthyroid or hypothyroid - needs to be treated before carcinoma surgery
  • Ultrasound of thyroid - Can differentiate between benign or malignant
154
Q

What are the treatment and management of thyroid carcinoma?

A
  • Thyroid LOVES iodine = readily take up radioactive iodine which in turn will locally irradiate and destroy cancer - providing very little radiation damage to other surrounding structures
  • Lots of LEVOTHYROXINE (T4) to keep TSH reduced as this is a growth factor for the cancer!
  • Chemotherapy = reduce risk of spread & treats micro-metastases that have been undetected
  • Papillary and follicular carcinomas:
  • -Total thyroidectomy
  • -Ablative radioactive iodine
  • Anaplastic carcinomas and lymphomas:
  • -DO NOT responde to radioactive iodine
  • -External radiotherapy provides brief respite - mainly palliative
  • Medullary carcinoma:
  • -Thyroidectomy and lymph node removal
155
Q

What is Cushing’s syndrome?

A

General term which refers to chronic excessive and inappropriate elevated levels of circulating CORTISOL whatever the cause - Alcohol excess mimics this

156
Q

What is Cushing’s disease?

A

Specifically refers to excess glucocorticoids resulting from inappropriate ACTH (adrenocorticotrophic hormone) secretion from the pituitary due to tumour

157
Q

What is cortisol?

A

Cortisol is released from the zona fasciculata of the adrenal cortex

158
Q

What are the functions of cortisol?

A
  • Increased carbohydrate and protein catabolism (breakdown)
  • Increased deposition of fat and glycogen
  • Na+ retention
  • Increased renal K+ loss
  • Diminished host response to infection
159
Q

When is corticotropin releasing hormone (and hence cortisol) released?

A

According to circadian rhythm & in stress

  • Highest at 7/9am
  • Lowest at mignight
160
Q

What is the pathophysiology of Cushing’s disease/syndrome?

A
  • Oral steroids VERY COMMON
  • Spontaneous endogenous = rare
  • -80% = raised ACTH, most common is pituitary adenoma (Cushing’s disease)

-Alcohol, depression, obesity, pregnance = high cortisol

161
Q

What are the ACTH dependent causes of Cushings’s?

A
  • Cushing’s disease - most common ACTH-dependent cause:
  • -Bilateral adrenal hyperplasia from an ACTH-secreting pituitary adenoma (benign) (usually a microadenoma)
  • -Equal prevalence in both men and women
  • -Peak age is 30-50 yrs

Ectopic ACTH production:

  • -a ACTH producing tumour elsewhere
  • -Especially small cell lung cancer and carcinoid tumours

ACTH treatment for e.g. asthma

162
Q

What are the ACTH independent causes of Cushing’s?

A

(↓ ACTH due to negative feedback from raised cortisol):

  • Adrenal adenoma (benign)/cancer - tumour of the adrenal that releases cortisol
  • Iatrogenic such as administration of a glucocorticoid e.g. PREDNISOLONE

-Excess cortisol can either result from excess ACTH which in turn stimulates excess cortisol release or from neoplasms in the adrenals which in turn stimulate the zona fasciculata to release more cortisol

163
Q

What is the presentation of Cushing’s?

A
  • Obese - central fat distribution
  • Plethoric complexion (ruddy and swollen) with moon face
  • Mood - depression, lethargy, irritable, psychosis
  • proximal weakness
  • gonadal dysfunction
  • Protein catabolic effect of cortisol - muscle atrphy, thin skin, purple striae on abdomen
  • Acne
  • High BP
  • children not grow up, just out
  • infections
  • osteoporosis
  • hyperglycaemia
164
Q

Differential of Cushing’s?

A

Pseudo-Cushing’s syndrome - caused by alcohol excess, resolves after 1-3 weeks of alcohol abstinence

165
Q

Investigations of Cushing’s?

A
  • Drug history STEROIDS
  • Random plasma cortisol
  • 1st line test
  • 2nd line test
166
Q

What are you looking for on the random plasma cortisol?

A

If high then proceed to 1st line test

May mislead as illness, time of day and stress (e.g. due to venepuncture) will influence results

167
Q

What is the first line test for Cushing’s?

A
  • Dexamethasone should, in the healthy patient, send negative feedback to the pituitary and hypothalamus resulting in ↓ ACTH and thus reduced cortisol
  • Overnight dexamethasone suppression test:
  • -Oral dexamethasone 1mg at 00:00
  • -Measure serum cortisol at 8AM
  • -Normally there will be cortisol suppression < 50nmol/L
  • -In Cushing’s syndrome there will be no suppression

Urine free cortisol over 24hrs is an alternative:
-Take > 2 measurements (cortisol is bound to corticosteroid binding globulin, when capacity is reached then will spill out to urine)

168
Q

What is the second line test for Cushing’s?

A

If there’s no supression

  • Perform 48hr dexamethasone supression test
  • If above +ve, do plasmsa ACTH

-If ACTH = 0 = adrenal tumour likely = CT/MRI/adrenal vein sampling

-If ACTH detectable = ectopic
production = high dose dexamethason suppression/corticotropin releasing hormone test

-If test shows that cortisol doesn’t respond to CRH then look for ectopic source of ACTH - IV contract CT, MRI, CXR

169
Q

What is the treatment and management of iatrogenic Cushing’s?

A

Stop steroids

170
Q

What is the treatment and management Cushing’s disease?

A

-Surgical selective removal of pituitary adenoma - trans-sphenoidal approach

Bilateral adrenalectomy (remove both adrenal glands):

  • If source unlocatable or recurrence post-op
  • Complication: Nelson’s syndrome: - Increase skin pigmentation due to significantly increased ACTH from an enlarging pituitary tumour as the adrenalectomy will remove the negative feedback - Will respond to pituitary radiotherapy
171
Q

What is the treatment and management of Cushing’s caused by adrenal adenoma??

A

Adrenalectomy

172
Q

What is the treatment and management of Cushing’s caused by adrenal carcinoma?

A

Adrenalectomy (doesn’t cure cancer) so radiotherapy and adrenolytic drugs e.g. MITOTANE

173
Q

What is the treatment and management of Cushing’s caused by ectopic ACTH?

A
  • Surgery if tumour is located and hasn’t spread
  • Drugs that inhibit cortisone synthesis e.g. METYRAPONE, KETOCONAZOLE and FLUCONAZOLE are used pre-op or if awaiting effects of radiation

Phase 2a Lauren (15 decks)

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