Endocrine

Question 1

Define diabetes mellitus

Answer 1

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

Question 2

What types of complications are associated with diabetes

Answer 2

Hyperglycemia results in serious micro-vascular e.g. retinopathy (disease of the retina), nephropathy (deterioration of kidney function) and neuropathy (damage of peripheral nerves) or macrovascular e.g. strokes, renovascular disease, limb ischaemia and heart problems.

Question 3

What are normal levels of blood glucose

Answer 3

Between 3.5-8mmol/L under all conditions

Question 4

What is the main organ involved in glucose homeostasis and what is its role

Answer 4

The liver is the principal organ of glucose homeostasis:

• Stores & absorbs glucose as glycogen - in post-absorptive state
• Performs gluconeogenesis from fat, protein and glycogen
• If blood glucose is HIGH then the liver will make glycogen (convert
  glucose to glycogen) in a process called glycogenesis - in the long term the liver will make triglycerides (lipogenesis)
• If blood glucose is LOW then the liver will split glycogen (convert
  glycogen to glucose) in process called glycogenolysis - in the longer
  term the liver will make glucose (gluconeogenesis) from amino acids/lactate

Question 5

How much glucose is produced everyday

Answer 5

About 200g of glucose is produced and utilised each day. More than 90% is derived from liver glycogen and hepatic gluconeogenesis and the remainder from renal gluconeogenesis.

Question 6

Where is glucose utilised

Answer 6

• The brain is the MAJOR CONSUMER of glucose and its function depends on
  an uninterrupted supply of this substrate
• Tissues such as muscle and fat have insulin-responsive glucose
  transporters and absorb glucose in response to postprandial (post-meal) peaks in glucose and insulin

Question 7

Why is the brain so reliant on just glucose and no other energy forms

Answer 7

• This is because the brain CANNOT use free fatty acids to be converted to ketones which can then be converted to Acetyl-CoA and used in the Kreb’s cycle for energy production, since free fatty acids CANNOT CROSS the
  BLOOD BRAIN BARRIER
• Glucose uptake by the brain is OBLIGATORY and is not dependent on insulin, and the glucose used is oxidised to CO2 and H2O

Question 8

How is glucose utilised in muscles

Answer 8

Glucose taken up by muscle is stored as glycogen or metabolised to lactate or CO2 and H2O

Question 9

How is glucose utilised in adipose tissue

Answer 9

• Fat uses glucose as a substrate for triglyceride synthesis
• Lipolysis of triglyceride releases fatty acids + glycerol - the glycerol is then used as a substrate for hepatic gluconeogeneis

Question 10

What are the 2 main hormonal regulators of blood glucose levels

Answer 10

Insulin and glucagon

Question 11

What are some of the roles of insulin

Answer 11

• 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)

Question 12

What is meant by bisphasic insulin release

Answer 12

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.

Question 13

What are some roles of glucagon

Answer 13

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

Question 14

What are some other counter-regulatory hormones that are also involved in regulating blood glucose levels

Answer 14

• Adrenaline, Cortisol and Growth Hormone
• These increase glucose production in the liver and reduce its utilisation in fat and muscle

Question 15

How is insulin formed

Answer 15

• Insulin is coded for on CHROMOSOME 11 produced in the BETA CELLS of
  the ISLETS of LANGERHANS of the PANCREAS:
  • 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)
  • After secretion, insulin enters the portal circulation and is carried to the
    liver, its prime target organ

Question 16

What are the main roles of insulin in a fed and fasting state

Answer 16

• In the fasting state - its main action is to regulate glucose release by the liver
• In the post-prandial state - its main action is to promote glucose uptake by fat and muscle

Question 17

Cell membranes are not inherently permeable to glucose so how does glucose get into the cells

Answer 17

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

Question 18

How many types of GLUT are there what are their functions

Answer 18

• GLUT-1:
  Enables basal NON-INSULIN-STIMULATED glucose uptake into many cells
• GLUT-2:
  Found in BETA-CELLS of the pancreas
  Transports glucose into the beta-cell - enables these cells to SENSE GLUCOSE LEVELS
  It 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
• GLUT-3:
  Enables NON-INSULIN-MEDIATED glucose uptake into BRAIN, NEURONS & PLACENTA
• GLUT-4:
  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

Question 19

What is the role of the insulin receptor in glucose transport

Answer 19

• This is a glycoprotein, coded for on the short arm of chromosome 19, which straddles the cell membranes of many cells
• When insulin binds to the receptor it results in the activation of tyrosine kinase and initiation of a cascade response - one consequence of which is
  the migration of the GLUT-4 transporter to the cell surface and increased
  transport of glucose into the cell

Question 20

Diabetes can be primary or secondary to other conditions. What conditions might diabetes be secondary to

Answer 20

• Pancreatic pathology e.g. total pancreatectomy, chronic pancreatitis, haemochromatosis
• Endocrine disease e.g. Acromegaly and Cushing’s disease
• Drug induced commonly by thiazide diuretics and corticosteroids
• 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

Question 21

What are the types of primary diabetes

Answer 21

• Type 1 DM
  The type 1 diabetic is young, has insulin deficiency with no resistance and immunogenic markers
• Type 2 DM
  Common in all populations enjoying an affluent lifestyle and is also increasing in frequency - particularly in adolescents

Question 22

Where is Type 1 DM most prevalent

Answer 22

Most prevalent in Northern European countries, particularly Finland and the incidence is increasing in most populations

Question 23

Define T1DM

Answer 23

Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterised by hyperglycaemia due to an absolute deficiency of insulin. This is caused by an autoimmune destruction of beta cells of the pancreas.

Question 24

Describe the epidemiology of T1DM

Answer 24

• 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

Question 25

Describe the aetiology of T1DM

Answer 25

• AUTOIMMUNE - Auto-antibodies forming against insulin and islet beta cells - INSULITIS
• Idiopathic - Uncommon form that is characterised by absence of antibodies
• Genetic susceptibility - HLA-DR3-DQ2 or HLA-DR4-DQ8
• Association found with enterovirus

Question 26

What are risk factors for T1DM

Answer 26

• 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
  • Pernicious anaemia
• Environmental factors:
  
  • Dietary constituents
  • Enteroviruses such as Coxsackie B4
  • Vitamin D deficiency
  • Cleaner environment may increase type 1 susceptibility

Question 27

Describe the pathophysiology of T1DM

Answer 27

• 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:
  
  • 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)
• Patient MUST have INSULIN since they are prone to diabetic ketoacidosis:
  
  • This is due to reduced glucose supply to cells due to lack of insulin which drives the formation of ketone bodies for use as a form of energy. Ketone bodies are strong acids and lower the pH of the blood. This has many effects e.g. impairing Hb ability to bind O2, acute kidney injury etc
• Eventual complete Beta cell destruction results in the absence of serum C-peptide
• Present VERY LATE often with only 10% of beta cells remaining

Question 28

What are the clinical manifestations of T1DM including signs and symptoms

Answer 28

Pt generally leaner than pt with T2DM.

• Signs
  
  • BMI typically < 25 kg/m2
  • Glycosuria (presence of reducing sugars in the urine)
  • Ketonuria (high levels of ketones in your urine)
  • Failure to thrive in children: dropping off height and weight centiles
  • Glove and stocking sensory loss
  • Reduced visual acuity
  • Diabetic retinopathy
  • Diabetic foot disease:
    
    • Reduced peripheral pulses
    • Calluses
    • Ulceration
    • Charcot join
• Symptoms
  
  • Polydipsia (excessive thirst)
  • Polyuria (excessive urination)
  • Nocturia (need to get up at night regularly to urinate)
  • Weight loss
  • Lethargy
  • Recurrent infections - e.g. pt complaining of balanitis or pruritis vulvae due to repeat candida infections
  • Evidence of complications: Blurred vision or parasthesia

Question 29

What are the primary investigations for suspected T1DM

Answer 29

Primary investigations:

• Random blood glucose:taken at any time of day and ≥11mmol/L is diagnostic
• Fasting blood glucose:≥7.0 mmol/L
  • 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 test:>11mmol/L two hours after a 75g oral glucose load. 7.8-11mmol/L suggests pre-diabetes.
• HbA1C:measures amount of glycated haemoglobin. ≥48 mmol/mol suggests hyperglycaemia over the preceding 3 months

Question 30

What other investigations may be done in suspected T1DM

Answer 30

• C-peptide:NICE advise this should only be measured in atypical presentations, e.g. age > 50, or BMI > 25kg/m2.
• Autoantibodies:only conducted if atypical features are present, and if positive, suggests autoimmune beta-cell destruction. Autoantibodies against the following may be found:
  
  • Glutamic-acid decarboxylase (GAD)
  • Insulin
  • Islet cell
  • Islet antigens
  • Zinc transporter (ZnT8)
• VBG:if concerned aboutDKA, e.g. systemically unwell or vomiting, this will reveal a metabolic acidosis

Question 31

What are the diagnostic criteria for T1DM

Answer 31

NICE guidelines stipulate a diagnosis should be made taking into accountclinical featuresand evidence of hyperglycaemia, e.g.random glucose ≥ 11.1 mmol/L. Additionally, NICE state that type 1 diabetics will usually have one of the following:

• Ketosis
• Rapid weight loss
• Age of onset < 50 years
• BMI < 25 kg/m2
• Personal and/or family history of autoimmune disease

Question 32

What are the differential diagnosis for T1DM

Answer 32

• Monogenic diabetes: maturity onset diabetes of the young (MODY) - should be suspected in cases of diabetes in non-obese, young patients (adolescence or young adult) with family history of diabetes in two or more successive generations.
  
  • C peptide will be present, autoantibodies will be absent
• Neonatal diabetes: diabetes diagnosed under 6 months of age.
  
  • Genetic testing with majority of mutations in the genes encoding the adenosine triphosphate-sensitive potassium channel and the insulin gene.
• Latent autoimmune diabetes in adults (LADA): Typical age of onset of diabetes is over 30 years old. Patients are usually non-obese and respond initially to lifestyle modifications and oral agents. Production of insulin gradually decreases (between 6 months and 5 years), such that treatment with insulin is required.
  
  • Low to normal initial C-peptide level.
  • Can be positive for at least 1 of the 4 antibodies commonly found in type 1 diabetic patients.
• Type 2 diabetes: Older age and slow onset, obesity, a strong family history, absence of ketoacidosis, and initial response to oral anti-hyperglycaemic drugs are typical of type 2 diabetes.
  
  • C peptide present, autoantibodies absent

Question 33

What is the 1st line management for T1DM

Answer 33

Multidisciplinary approach

Lifestyle:

• Educate patient on disease and risk
• Maintain lean weight, stop smoking and take care of feet (to reduce gangrene
  risk)
• Patients should be educated regarding carbohydrate counting. This is a technique which allows the insulin dose to be matched to intake
• NICE recommend that dietary advice should be tailored to the patient’s personal needs and culture

Insulin therapy (refer to other notes tab for types of insulin):

Basal-bolus regimen: the first-line regimen of choice, whereby a long-acting insulin is given regularly (basal) and supplemented with a rapid-acting insulin before each meal (bolus)

• Basal:Levemir (Detemir) is the first line basal insulin given twice-daily. Lantus (Glargine) once-daily is an alternative
• Bolus:Humalog (Lispro) or Novorapid (Aspart) are examples

Question 34

What are further steps in the management plan for T1DM

Answer 34

• Mixed insulin regimen:a mixture of a short or rapid-actingandintermediate-acting insulin. It is given twice daily and used in those who cannot tolerate multiple injections as part of a basal-bolus regimen
• Continuous insulin infusion:indicated if the patient has disabling hypoglycaemia or persistently hyperglycaemic (HbA1c>69mmol/mol) on multiple injection insulin therapy

Question 35

What are complications of insulin therapy

Answer 35

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

Question 36

What monitoring needs to be done for patients with T1DM

Answer 36

Patients require regular follow-up to monitor HbA1c levels and assess for complications of diabetes.

- HbA1c:measure every 3-6 months with a target of≤48 mmol/mol
- NICE advises that the target can be tailored based on personal daily activities, aspirations, the likelihood of complications, comorbidities, occupation and history of hypoglycaemia - Self-monitoring:should be tested at least4 times a day, including before meals and before bed; more frequent monitoring may be required during periods of illness. Targets are as follows:
- On waking:5–7 mmol/L
- Other times of the dayincluding before meals: 4–7 mmol/L
- Bedtime:this target should be personalised and depends on the timing of the last meal

On an annual basis (more frequently if required), patients should receive a diabetic review. This includes assessment of injection site problems, retinopathy, nephropathy, diabetic foot problems (e.g. neuropathic problems), cardiovascular risk factors and thyroid disease.

• Retinopathy:annual screening
• Nephropathy:renal function (eGFR) and albumin:creatinine ratio (ACR)
• Diabetic foot problems:full examination including footwear, monofilament assessment of neuropathy, vascular assessment +/- dopplers.
• Cardiovascular risk factors:primary/secondary prevention strategy with optimisation of blood pressure, lipids, weight, smoking and others
• Thyroid disease:screening blood test

Question 37

What are the main complications with regards to T1DM patients

Answer 37

• DKA
• Hypoglycaemia - complication of insulin treatment, especially insulin doses without a meal.
• Diabetic kidney disease - involves glomerular mesangial sclerosis leading to proteinuria and progressive decline in glomerular filtration.
• Retinopathy
• Peripheral or autonomic neuropathy
• Cardiovascular disease - increased risk of atherosclerosis, hyaline arteriolosclerosis etc
• Summary of micro- and macrovascular complications

Question 38

What is the prognosis for T1DM patients

Answer 38

Overall, cardiovascular disease is the leading cause of death in these patients. With good control of blood glucose levels, the risk of complications can be reduced. Life-expectancy is reduced by 13 years but this is dependent on glucose control.

Question 39

What is latent autoimmune diabetes and what are its clinical cues

Answer 39

• 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

Question 40

What are the main types of insulin and how should they be taken

Answer 40

Short acting soluble insulins -

• 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

Short acting insulin analogues -

• Human insulin analogues (insulin aspart, insulin lispro, insulin glulisine) have a faster onset and a shorter duration than 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

Longer acting insulin -

• Insulin premixed with retarding agents (either protamine or zinc) precipitate crystals
• Can be intermediate (12-24 hrs) or long-acting (more than 24hrs)

Question 41

What is the definition for T2DM

Answer 41

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and less severe insulin deficiency.

Question 42

Describe the epidemiology of T2DM

Answer 42

• Common in 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
• M>F

Question 43

Describe the aetiology of T2DM

Answer 43

• 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

Question 44

What are the risk factors for T2DM

Answer 44

• Family history - genetics. 75% risk if both parents have T2DM
• Increasing age
• Obesity and poor exercise - can trigger DMT2 in genetically susceptible individuals
• Ethnicity - Middle Eastern, South-east Asian and Western pacific
• Obesity
• Hypertension
• Dyslipidemia - especially with low high-density lipoprotein (HDL) and/or high triglycerides
• Gestational Diabetes
• Polycystic ovary syndrome
• Drugs: corticosteroids, thiazide diuretics

Question 45

Describe the pathophysiology of T2DM

Answer 45

Repeated exposure to glucose and insulin makes the cells in the body resistant to effects of insulin, therefore requiring more insulin to cause glucose uptake into cells. + decreased GLUT4 expression. Pancreatic beta cells become fatigued and damaged by producing so much insulin. Result: chronic hyperglycaemia with increased insulin demand from depleted beta cell population.

Question 46

Describe the clinical manifestations of T2DM including signs and symptoms

Answer 46

Pt generally overweight compared to pt’s with T1DM

• Signs
  
  • Acanthosis nigricans - characterised by blackish pigmentation at the nape of the neck and in the axillae
  • Glove and stocking sensory loss
  • Reduced visual acuity
  • Diabetic retinopathy
  • Diabetic foot disease
    
    • Reduced peripheral pulses
    • Calluses
    • Ulceration
    • Charcot joint
• Symptoms
  
  • Weight loss
  • Polyuria
  • Polydypsia
  • Lethargy
  • Recurrent infections
  • Evidence of complications e.g. blurred vision or paresthesia

Question 47

What are the 1st line investigations for potential case of T2DM

Answer 47

Primary investigations:

• Random blood glucose:taken at any time of day and ≥11mmol/L is diagnostic
• Fasting blood glucose:≥7.0 mmol/L
  
  • 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 test:>11mmol/L two hours after a 75g oral glucose load. 7.8-11mmol/L suggests pre-diabetes.
• HbA1C:measures amount of glycated hemoglobin. ≥48 mmol/mol suggests hyperglycaemia over the preceding 3 months

Question 48

What further investigations would be done for a potential T2DM patient

Answer 48

• Fasting lipids:patients with diabetes often have dyslipidaemia
• U&Es:reduced eGFR may be seen due to diabetic nephropathy
• Urine albumin:creatinine ratio:diabetic nephropathy leads to protein leaking through the glomerular basement membrane

Question 49

What is the diagnostic criteria for T2DM

Answer 49

Diagnosing T2DMrequires an elevated plasma glucose sample and/or HbA1c on one occasion if symptomatic or two occasions if asymptomatic.

The WHO diagnostic criteria also contain apre-diabetic phase which comprisesimpaired fasting glucose (IFG)andimpaired glucose tolerance (IGT). Both of these confer an increased risk of developing diabetes mellitus.

• Patients with IFG: raised fasting glucose andnormalOGTT
• Patients with IGT: raised OGTT, and may or may not have a raised fasting glucose

Question 50

What are the differential diagnosis for T2DM

Answer 50

• Pre-diabetes
• T1DM
• LADA - can be mistaken due to late onset
• Monogenic diabetes - MODY
• Ketosis-prone diabetes - idiopathic diabetes. Unprovoked ketosis or ketoacidosis. Some patients may have type 2 presentation.
• Gestational diabetes

Question 51

What are the first line management steps for T2DM

Answer 51

Lifestyle:

Target HbA1c with lifestyle management is48 mmol/mol(6.5%). Metformin should be commenced if HbA1crises above this.

• High fibre, low glycaemic index sources of carbohydrates
• Include low-fat dairy products and oily fish
• Control intake of trans and saturated fats, and limit sucrose-containing foods
• Discourage the use of foods marketed specifically for people with diabetes
• Aim for an initial weight loss of 5-10%

Anti-diabetic medications:

There are a number of choices with metformin used first line.

• Metformin
  
  • First-line agent and target HbA1c with metformin is48 mmol/mol(6.5%). Iflevel rises above this, the dose should be increased
  • Dual therapy (with a second anti-diabetic drug) should be commenced if HbA1Crises above58 mmol/mol(7.5%) despite maximal dose (1g BD)
  • If not tolerated, monotherapy with an alternative anti-diabetic should be used and then further anti-diabetic agents added in as the HbA1c rises above 58mmol/mol (7.5%)

Question 52

What further management steps are used for T2DM

Answer 52

Triple therapy and insulin:

• If the HbA1C is >58 mmol/mol(7.5%)despite dual therapy, either triple therapy can be commenced,or insulin treatment can be considered
• If triple therapy fails, metformin with a sulfonylurea and GLP-1 mimetic may be used if any of the following apply:
  
  • BMI ≥ 35 kg/m2andspecific psychological or other medical problems associated with obesity
  • BMI < 35 kg/m2for whom insulin therapy would have significant occupational implications
  • BMI < 35 kg/m2andweight loss would benefit other significant obesity‑related comorbidities
• NICE suggest commencing anintermediate-acting insulin with metformin, with the need for all other anti-diabetic agents to be reviewed. A long-acting insulin may be used as an alternative.

Controlling other factors:

• Ramipril for BP control
• Statins for hyperlipidaemia control
• Orlistat - to promote weight loss in pt’s who are obese

Question 53

What are complications of T2DM treatment

Answer 53

• Hypoglycaemia - due to insulin or antidiabetic drugs such as sulfonylurea
• Injection site - lipohypertrophy
• Side effects of metformin: anorexia, diarrhoea, nausea, abdominal pain

Question 54

What are examples of anti-diabetics

Answer 54

• Metformin
  
  • Reduces rate of gluconeogenesis in the liver
  • Increases cells sensitivity to insulin
  • Helps with weight issues
  • Reduces CVS risk in diabetes
• Sulfonylureas
  
  • 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
• Dipeptidyl peptidase-4 inhibitor (DPP-4i)
• Pioglitazone
• Sodium–glucose cotransporter 2 inhibitor (SGLT-2i)

Question 55

What monitoring needs to be done for T2DM patients

Answer 55

• HbA1c: measure every 3-6 months until the HbA1c is stable on unchanging therapy, after which it can be measured 6 monthly. The targets are dependent on the treatment and summarised in diagram on notion, however, NICE states that these can be tailored on a case by case basis
• Self-monitoring: not routine and only indicated in the following circumstances:
  • On insulin therapy
  • Evidence of hypoglycaemic episodes
  • At risk of hypoglycaemia whilst operating machinery or driving
  • Pregnant or planning pregnancy

Question 56

What are complications with T2DM

Answer 56

Macrovascular –> cardiovascular (ischaemic HD, Heart failure and peripheral vascular disease) and cerebrovascular (stroke)

Microvascular –> Neuropathy (Mononeuropathy, polyneuropathy - glove and stocking, amyotrophy - proximal painful lower limb muscle wasting, autonomic neurpathy - gastroparesis erectile dysfunction and postural hypotensions)
Renal (diabetic nephropathy and CKD)
Retinopathy

Carpal tunnel syndrome

open-angle glaucoma

Cataracts

Hyperosmolar hyperglycaemic state

Question 57

What is the prognosis for T2DM

Answer 57

Survival depends on glucose control and management of cardiovascular risk factors. Adults with type 2 diabetes are twice as likely to die of stroke or myocardial infarction compared to those without diabetes.

Question 58

Define diabetic ketoacidosis

Answer 58

Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes that is potentially fatal and requires prompt medical attention for successful treatment. It is characterised by absolute insulin deficiency and is the most common acute hyperglycaemic complication of type 1 diabetes mellitus.

Question 59

Describe the epidemiology of DKA

Answer 59

• It is estimated that there are more than 20,000 cases per year in the UK
• It is suspected that 4% of patients with T1DM develop DKA each year and up to 14% of diabetes related hospital admissions are the result of DKA.
• The condition is also being increasingly recognised in type 2 diabetes mellitus. This isn’t common as there is residual beta cell function and so some insulin presence.
• DKA at diagnosis was more common in children aged below 10 years, and in non-white than in white people.

Question 60

Describe the risk factors for DKA

Answer 60

• Infection
• Undiagnosed diabetes
• Inadequate insulin or non-adherence to insulin therapy
• Myocardial Infarction
• Physiological stress: e.g. trauma or surgery
• Other co-morbidities: e.g. hypothyroidism and pancreatitis
• Drugs that affect carbohydrate metabolism: e.g. corticosteroids, diuretics and salbutamol

Question 61

Describe the pathophysiology of DKA

Answer 61

Diabetic ketoacidosis (DKA) is a metabolic state which occurs as a complication oftype 1 diabetes(and rarely T2DM). DKA is considered a medical emergency associated with the triad of significanthyperglycaemia,acidosisandketonaemia, resulting in dehydration and electrolyte imbalances.

The lack of insulin means the body is unable to utilise glucose. This leads to accumulation of glucose within the blood resulting in hyperglycaemia. As glucose cannot be used there is an increase in hepatic glucose production through the breakdown of glycogen stores (glycogenolysis) and increased formation of glucose from other substrates (gluconeogenesis).

This is coupled with an increase in counter-regulatory hormone release (e.g. cortisol, glucagon, growth hormone), which exacerbates the hyperglycaemia and drives the production of alternative energy sources.

The lack of utility of glucose leads to the break down of fats (lipolysis) that increases serum free fatty acids. Fatty acids can be used as an alternative energy source through ketogenesis.

This increases the levels of ketone bodies (acetone, beta-hydroxybutyrate and acetoacetate) within the blood leading to ketonaemia. The main ketone body within DKA is 3-beta-hydroxybutyrate. Ketone bodies are weak acids, which can lead to significant acidosis and severe illness in increasing quantities.

As DKA progresses, the raisedplasma glucose leads to osmotic diuresis and profound hypovolaemia that is exacerbated by vomiting. This can lead to major electrolyte derangements, reduced consciousness and eventually death if not managed urgently.

Question 62

What are the clinical manifestations of DKA including signs and symptoms

Answer 62

• Signs
  
  • Fruity smell of acetone on breath
  • Dehydration
    
    • Mild: only just detectable
    • Moderate: dry skin and mucus membranes; reduced skin turgor
    • Shock: tachycardia, hypotension (late), drowsiness, reduced urine output
  • Kussmaul respiration: deep, labored breathing trying to reverse the metabolic acidosis
  • Hypotension
  • Abdominal tenderness
  • Reduced consciousness/ coma
• Symptoms
  
  • Abdominal pain
  • Leg cramps
  • Headache
  • Nausea and vomiting
  • Polyuria
  • Polydipsia
  • Weight loss
  • Inability to tolerate oral fluids
  • Lethargy
  • Confusion

Question 63

What are the first line investigations for potential DKA

Answer 63

Primary investigations:

• Laboratory glucose: > 11.0 mmol/L
• Venous/arterial blood gas: quickest way to ascertain pH and HCOlevels. ABG may be used as the initial blood gas sample for diagnosis, but later samples should be venous if possible - pH < 7.3 or bicarbonate < 15 mmol/L
• Ketone testing: capillary blood ketone ≥ 3 mmol/L or urinary ketones+++ or above

Question 64

What are further investigations that may be done for potential DKA

Answer 64

To confirm DKA, DKA precipitants and monitor complications:

• Urine dip:glycosuria and ketonuria
• U&Es:electrolyte derangement and acute kidney injury due to dehydration
• FBC and CRP:raised inflammatory markers may suggest underlying infection as a precipitant
• LFTs
• Troponin
• Infection screen: if an infection is the suspected trigger
• ECG
• Imaging: chest xray

Question 65

What is the diagnostic criteria for DKA

Answer 65

For a diagnosis to be made, hyperglycaemia, acidosis, and ketonaemia must be present.

As per NICE, it is possible to have DKA with normal blood glucose levels, particularly in children and young people on insulin therapy. Furthermore, low blood ketone levels (< 3 mmol/L) do not always exclude DKA.

Glucose > 11mmol/L or known diabetes mellitus

HC03 <15 mmol/L and/or venous pH < 7.3

Ketonaemia (greater than or equal to 3mmol/L) or 2+ ketones o dipstick

Question 66

What are the differential diagnosis for DKA

Answer 66

• Hyperosmolar hyperglycaemic state - Patients are typically older than patients with DKA and are usually patients with type 2 diabetes.
• Lactic acidosis - The presentation is identical to that of DKA. In pure lactic acidosis, the serum glucose and ketones should be normal and the serum lactate concentration should be elevated.
• Starvation ketosis - Starvation ketosis results from inadequate carbohydrate availability resulting in physiologically appropriate lipolysis and ketone production.
• Alcoholic ketoacidosis - these are people with long-standing alcohol use disorder for whom ethanol has been the main caloric source for days to weeks. The ketoacidosis occurs when for some reason alcohol and caloric intake decreases.
• Salicylate poisoning - Salicylate intoxication produces an anion gap metabolic acidosis usually with a respiratory alkalosis.
• Ethylene glycol/methanol intoxication - Methanol and ethylene glycol also produce an anion gap metabolic acidosis without hyperglycaemia or ketones.
• Uraemic acidosis - elevated serum urea and creatinine with normal plasma glucose. The pH and anion gap are usually mildly abnormal.

Question 67

What is the 1st line management in DKA

Answer 67

• ABC’s
• IV fluids (0.9% saline) are priority as patients with DKA are fluid deplete by 5-8 litres. Duration of infusion will differ. For example, slower fluid replacement may be required in younger patients (18 to 25 years old) due to the increased risk of cerebral oedema, as well as those with heart failure.
• Insulin infusion: 0.1 units/kg/hr. Once glucose level < 14 mmol/L: add 10% glucose. Do notstop long-acting insulin
• Potassium replacement (KCl):In DKA, even if serum potassium levels are normal, total body potassium is low. Insulin therapy and correction of acidosis causes a further reduction in serum potassium, hence replacement and monitoring are key.

If potassium levels in first 24hrs ore greater than 5mmol/L nil potassium replacement in mmol/L of infusion solution.

If potassium levels are 3.5-5.5 then 40mmol/L of infusion solution

If less than 3.5 then consider HDU/ITU replacement via a central line

Question 68

What are follow up managements for DKA patients

Answer 68

Anticoagulation: patients are at increased risk of VTE

Question 69

What monitoring must be done for DKA patient

Answer 69

Glucose, pH, bicarbonate, ketone levels, and electrolytes should be closely monitored throughout, 1-2 hourly

Question 70

What complications might occur for DKA patients

Answer 70

• Hypokalaemia - K+ moves out of cell, as H+ moves into cell. The lack of insulin means more K+ is lost from the cell. This may also cause arrhythmias
• Hypoglycaemia
• Cardiovascular: Venous
  thromboembolism
• Renal:acute kidney injury
• Iatrogenic (due to treatment):Cerebral oedema, pulmonary oedema, central pontine myelinolysis, hypokalaemia, hypoglycaemia; due to inappropriate fluid replacement
• Gastrointestinal: gastric stasis
• Non-anion gap hyperchloraemic acidosis - this occurs due to urinary loss of ketoanions needed for bicarbonate regeneration, and also increased reabsorption of chloride secondary to intensive administration of chloride-containing fluids.

Question 71

What is the prognosis for DKA patients

Answer 71

Fortunately, mortality has decreased in the UK from 8% to < 1%. In children and young adults, cerebral oedema is the most common cause of death. In adults, the most common causes of death include severe hypokalaemia, ARDS, and co-morbid conditions such as pneumonia, sepsis and acute myocardial infarction.

Question 72

What is the definition of Hyperosmolar hyperglycaemic state (HHS)

Answer 72

Hyperosmolar hyperglycaemic state (HHS) is characterised by profound hyperglycaemia, hyperosmolality and volume depletion in the absence of significant ketoacidosis, and is a serious complication of diabetes (T2DM).

Question 73

Describe the epidemiology of HHS

Answer 73

• The incidence of HHS is not precisely known but is thought to make up less than 1% of diabetes-related hospital admissions
• Usually occurs in the elderly but is increasingly recognised in younger patients.
• The average age of presentation is 60 years old and it is associated with a 15-20% mortality.
• HHS is often the first the presentation of type 2 diabetes mellitus in up to 20-30% of cases.

Question 74

What are risk factors/precipitants of HHS

Answer 74

• Infection
• Myocardial infarction
• Stroke
• Poor medication compliance
• Vomiting
• High-dose steroids - can increase blood glucose

Question 75

Describe the pathophysiology of HHS

Answer 75

Decreased insulin levels which are sufficient to inhibit hepatic ketogenesis (DKA cannot occur as it isn’t absolute insulin deficiency) but insufficient to inhibit hepatic glucose production (> hyperglycaemia). Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium. Severe volume depletion leads to hyperosmolality.

Question 76

What are the clinical manifestations of HHS

Answer 76

• Signs
  
  • Reduced GCS - reduced consciousness/ coma
  • Dehydration - tachycardia and hypotension, dry mucous membranes, reduced skin turgor
  • Could be confused for a stroke - e.g. hemiparesis
  • Seizures
• Symptoms
  
  • Generalised weakness
  • Leg cramps
  • Lethargy
  • Confusion
  • Hallucinations
  • Headache
  • Visual disturbances
  • Polyuria
  • Polydipsia
  • Nausea, vomiting and abdominal pain: possible, but more common in DKA

Question 77

What are the 1st line investigations for HHS

Answer 77

The key investigations for management of HHS include a laboratory glucose, urea & electrolytes blood test (electrolyte derangement and AKI due to dehydration), ABG/VBG (hyperglycaemia without a metabolic acidosis) and a blood or urinary ketone level.

Question 78

What further investigations may be done for HHS

Answer 78

• Urine dip:glycosuria
• Serum osmolality:if laboratory testing is not available, use the formula:
  
  • 2Na++ glucose + urea
• FBC and CRP:raised inflammatory markers may suggest underlying infection as a precipitant

Question 79

What is the diagnostic criteria for HHS

Answer 79

Hyperglycaemia: greater than or equal 30mmol/L without significant hyperketonaemia (<3mmol/L) and without acidosis (pH>7.3, bicarbonate >15mmol/L)

Hyperosmolaloty: >320 mosmol/KG

Hypovolaemia

Question 80

What are the differential diagnosis for HHS

Answer 80

• DKA
• Lactic acidosis
• Alcohol ketoacidosis
• Ingestion of toxic substances
• Paracetamol overdose
• Salicylate overdose
• Seizures
• Stroke

Question 81

What is the first line management for HHS

Answer 81

• ABC’s
• IV fluid (0.9% saline)- results in reduction in osmolality and glucose. Insulin not always required

Question 82

What is the follow up management for HHS

Answer 82

• Insulin - not first line as pt with T2DM are insulin sensitive and there are risks of rapid correction. Insulin given if hyperglycaemia not fixed by IV fluid infusion.
• Potassium replacement - patients are potassium deplete, as seen in DKA
• Anti-coagulation - low molecular weight heparin for full duration of admission to reduce risk of VTE.

Question 83

What monitoring is required with HHS

Answer 83

• Serum osmolalityis the most important parameter (to which glucose and sodium are the main contributors);fluid replacement aloneis usually sufficient to reduce osmolality
• Rapid changes to osmolality must be avoided to preventcentral pontine myelinolysisandcardiovascular collapse
• If laboratory osmolarity testing is not available, use the formula2Na++ glucose + urea
• Maintain an accurate fluid balance chart and initiallyplotosmolalityhourly
• Rising sodiumis only a concern if the osmolality isNOTdeclining concurrently
• The rate of fall of plasma sodiummust not exceed10 mmol/L in 24 hours
• Plasma glucose aim:a reduction of4-6 mmol/houris considered safe, with an overall goal of10-15 mmol/L

Question 84

What complications may arise with HHS

Answer 84

• Cardiovascular: venous thromboembolism,arrhythmias (hyper/hypokalaemia), myocardial infarction
• Neurological:stroke and seizures
• Renal:acute kidney injury
• Iatrogenic (due to treatment): cerebral oedema or central pontine myelinolysis; due to rapid correction of osmolality.Cardiovascular collapsemay occur if insulin is administered prior to adequate fluid replacement.

Question 85

What is the prognosis with HHS

Answer 85

HHS has significantly higher mortality than DKA, with estimates at 5-20% in HHS compared to <1% for DKA. This is predominantly due to the fact that HHS develops over days and is associated withprofound dehydrationandsignificant electrolyte abnormalities.

Furthermore, HHS can be complicated byvascular complicationssuch as MI, peripheral arterial thrombosis and stroke due to hyper-viscosity. In addition, neurological manifestations such asseizuresare more common in HHS than DKA.

Question 86

What is the follow up if a GP suspects diabetic eye disease

Answer 86

The GP should immediately refer patients to thelocal eye screening unitupon diagnosis and the patient should be seen within 3 months.

Annual screeningshould take place thereafter if no changes are found.

A referral to an ophthalmologist is warranted if there is evidence of pre-proliferative or proliferative retinopathy, or evidence of maculopathy.

Question 87

What is the criteria for an emergency review by an ophthalmologist for suspected diabetic eye disease

Answer 87

An emergency review by an ophthalmologist is required if any of the following are present:

• Acute reduction in acuity
• Rubeosis iridis
• Vitreous haemorrhage
• Retinal detachment

Question 88

How is risk assessed for diabetic foot disease

Answer 88

The risk of diabetic foot disease should be assessed on diagnosis, and at least annually thereafter by the GP. Assessing risk involves a full examination of both feet, assessing theneurovascular status including an ankle-brachial pressure index. NICE stipulate a10g monofilamentmust be used to assess sensation.

Patients deemed low risk can bescreened annually. Referral to thelocal foot protection serviceis indicated if either moderate or high risk. This is a service led by podiatrists with MDT input from multiple specialities including vascular surgeons and diabetologists. The servicemust see moderate-risk patients within8 weeks, and high-risk patients within4 weeks.

Question 89

What is involved in renoprotective therapy with regards to diabetic nephropathy

Answer 89

Diabetes can cause chronic kidney disease (CKD), hence, patients should have theireGFRcheckedannually, as well as a urinaryalbumin:creatinine ratio.

Renoprotective therapy:

• ACEi:patients with diabetesand CKD should be started on anACE inhibitor(ACEi) due to its renoprotective effects
• Aim for a target BP of130/80 mmHgif CKD anddiabetes are both present
• Even if the patient has a normal BP, they should still be started on an ACEi if there is evidence of CKD

Question 90

How is cardiovascular risk decreased in diabetic patients

Answer 90

All patients should be given lifestyle advice, with a particular emphasis on smoking cessation.

Statin therapy:primary prevention with atorvastatin 20mg

• T1DM:should be considered in all patients and given ifanyof the following are present:
  
  • > 40 years
  • Diabetes for > 10 years
  • Diabetic nephropathy
  • Other cardiovascular risk factors
• TD2M:as for non-diabetics, calculate the QRISK2 score and, if ≥10%, commence therapy

Anti-hypertensive therapy:

• ACEiis first-line, irrespective of age
• Target BP:140/90 mmHg in patients without CKD, or 130/80 mmHg in patients with CKD

Question 91

Describe the basic anatomy of the thyroid

Answer 91

• Endocrine structure located in the neck
• Located in the anterior neck between C5-T1 vertebrae
• Divided into two lobes which are connected by an isthmus
• Straddles the trachea
• Secretes hormone directly into the blood thus highly vascularised

Question 92

Describe hypothyroidism (myxoedema) and its aetiology

Answer 92

• Underproduction of thyroid hormone
• Causes:
  
  • Primary hypothyroidism (reduced T4 and thus T3):
    
    • Primary atrophic hypothyroidism (PAH)
    • Hashimoto’s thyroiditis
    • Iodine deficiency
    • Post-thyroidectomy/radioiodine/anti-thyroid drugs
    • Lithium/amiodarone
  • Secondary hypothyroidism (reduced TSH from anterior pituitary):
    
    • Hypopituitarism

Question 93

Describe the formation of monoiodotyrosine and diiodotyrosine

Answer 93

• Within the thyroid gland are numerous follicles each composed of an enclosed sphere of follicular cells surrounding a core containing a protein-rich material called the colloid.
• Synthesis begins when circulating iodide is actively cotransported with Na+ ions across the basolateral membranes of the follicular cells - this is known as iodide trapping, the Na+ is pumped back out of the cells via Na+/K+- ATPases
• The negatively charged iodide ions then diffuse to the apical membrane of the follicular cells and are transported into the colloid
• The colloid of the follicles contains large amounts of a protein called thyroglobulin
• Once inside the colloid iodide is rapidly oxidised to iodine which then bind to tyrosine residues on the thyroglobulin molecules (produced by the follicular cells) under the action of the enzyme thyroid peroxidase
• The tyrosine may either bind to one iodine molecule - in which case its called a monoiodotyrosine (T1)
• The tyrosine may bind to two iodine molecules - in which case its called a diiodotyrosine (T2)

Question 94

Describe the production of and control/stimulation of T3 and T4

Answer 94

• When the thyroid is stimulated to produce thyroid hormone, the T1 and T2 molecules are cleaved from their tyrosine backbone (but are still attached to the thyroglobulin) and join to create T3 (T1 + T2) or T4 (T2 + T2)
• For thyroid hormone to be secreted into the blood, extensions of the colloid-
  facing membranes of the follicular cells engulf portions of the colloid (with its iodinated thyroglobulin) by endocytosis
• TSH (from pituitary) stimulates the movement of T3 & T4 containing colloid
  into secretory cells
• The iodated thyroglobulin is then brought into contact with lysosomes in the cell interior
• Proteolysis of the thyroglobulin results in the release of T3 & T4 which then are able to diffuse out of the follicular cells into the interstitial fluid and from there into the blood
• There is sufficient iodinated thyroglobulin stored within follicles of the thyroid to provide thyroid hormone for several weeks even in the absence of dietary iodine - this is unique amongst endocrine glands
• The thyroid produces more T4 than T3 - T3 is more active and is produced
  peripherally from the conversion of T4. More T4 is produced but T3 is more active.

Question 95

Describe the effects of T3/T4

Answer 95

• The effects of T3/T4 are numerous:
  
  • BMR:increases the basal metabolic rate.
  • Metabolism:it hasanabolic effects at low serum levels andcatabolic effectsat higher levels.
  • Growth:increases release and effect of GH and IGF-1.
  • Cardiovascular:increases theheart rate and contractility through increasing sensitivity to catecholamines.

Question 96

Describe thyroid disease epidemiology and presentation

Answer 96

• Commonest endocrine disorder
• More common in females than males
• Hyperthyroidism has a 2.5% prevalence
• Hypothyroidism has a 5% prevalence
• Most common clinical presentation of thyroid disease is Goitre (5-15%):
  
  • A swelling of the thyroid gland that causes a palpable lump to form in the front of the neck
  • The lump will move up and down when you swallow
  • Mechanism is caused by TSH receptor stimulation which causes the thyroid to grow
  • Can be caused by BOTH hyperthyroidism and hypothyroidism
  • Hyperthyroidism: e.g. in graves’ there is excessive stimulation of the TSH receptor which stimulates the thyroid to produce more hormone and grow larger = goitre
  • Hypothyroidism: When pituitary detects low thyroid levels (due to iodine deficiency for example) it produces more TSH which in turn stimulates TSH receptors on the thyroid resulting in thyroid enlargement
  • Endemic in iodine deficient areas
  • Can be diffuse, nodular, solitary
    
    • Diffuse:
      
      • Physiological
      • Graves’ disease
      • Hashimoto’s thyroiditis
      • De Quervain’s
    • Nodular:
      
      • Multi-nodular
      • Adenoma/cyst
      • Carcinoma:
        
        • Papillary (70%), follicular (20%), anaplastic (<5%), lymphoma (2%) or medullary cell (5%)

Question 97

Define thyrotoxicosis and what are the 3 mechanisms for increased levels

Answer 97

• Excess of thyroid hormones in blood
• 3 mechanisms for increased levels:
  
  • Overproduction of thyroid hormone - hyperthyroidism
  • Leakage of preformed hormone from thyroid: can be caused if follicular cells are destroyed by either infection or autoimmune thereby releasing 2-3 months supply of hormone
  • Ingestion of excess hormone

Question 98

Describe hyperthyroidism and its aetiology

Answer 98

• Overproduction of thyroid hormone
• Causes:
  
  • Graves’ disease - most common cause
  • Toxic multi nodular goitre - produces high amounts of thyroid hormone
  • Toxic adenoma (benign) - a single nodule producing excess thyroid hormone
  • Ectopic thyroid tissue (metastases)- thyroid tissues not located in its usual position producing thyroid hormone
  • Exogenous (iodine/T4 excess)
  • De quervain’s thyroiditis (post-viral) - painful swelling of the thyroid gland due to viral infection. Usually self-limiting.

Question 99

What is the definition of hyperthyroidism

Answer 99

Hyperthyroidism is a common endocrine condition caused by an overactive thyroid gland causing an excess of thyroid hormone.

• Hyperthyroidism:overactive thyroid gland (i.e. increasedthyroid hormone production) causing an excess of thyroid hormone and thyrotoxicosis.
• Thyrotoxicosis**:refers to an excess of thyroid hormone, having an overactive thyroid gland is not a prerequisite (e.g.consumption of thyroid hormone).

Question 100

What is the definition of thyrotoxicosis

Answer 100

Thyrotoxicosis:refers to an excess of thyroid hormone, having an overactive thyroid gland is not a prerequisite (e.g.consumption of thyroid hormone).

Question 101

What is the epidemiology of hyperthyroidism

Answer 101

• The overall prevalence of hyperthyroidism is approximately 1.3% and increases to 4-5% in older women
• Affects 2-5% of all women at some time
• Mainly between 20-40yrs

Question 102

What are the primary causes of hyperthyroidism

Answer 102

• Graves’ disease most common cause worldwide. Underlying aetiology involves anti-TSH antibodies stimulating thyroid gland
• Toxic multinodular goitre. Iodine deficiency leads to compensatory TSH secretion and hyperstimulation leading to nodular goitre formation. These nodules can become TSH-independent and secrete thyroid hormones
• Toxic adenoma. A single autonomous functional nodule secreting thyroid hormone
• Subclinical hyperthyroidism. Normal TS/T4 but low TSH.
• Thyroiditis. In the intial stages including Hashimoto’s and De Quervain’s thyroiditis, there can be transient hyperthyroid state which is then followed by a hypothyroid state
• Drugs. Amiodarone can cause both hyper and hypothyroidism

Question 103

What are some secondary causes of hyperthyroidism

Answer 103

• Pituitary adenoma. TSH-secreting pituitary adenoma
• Ectopic tumour. Such as hCG-secreting tumours; e.g. choriocarcinoma
• Hypothalamic tumour. Results in excessive TRH secretion; a very rare cause of hyperthyroidism

Question 104

What are some other causes of hyperthyroidism

Answer 104

• Beta-HCG related. Beta-HCG is thought to mimic the action of TSH causing thyroid hormone synthesis and release. It occurs in states of elevated Beta-HCG e.g. pregnancy, choriocarcinoma.
• Ectopic thyroid tissue - thyroid tissue found elsewhere that produces thyroid hormone.

Question 105

What are risk factors for hyperthyroidsm

Answer 105

• Family history
• Auto-immune disease e.g. vitiligo, type 1 diabetes, Addison’s disease

Question 106

Describe the pathophysiology of hyperthyroidism

Answer 106

Hyperthyroidism describes increased levels of circulating thyroid hormone leading to raised metabolic rate and sympathetic nervous system activation.

Primary hyperthyroidisminvolves an excessive production of T3/T4 by the thyroid gland due to pathology affecting the thyroid gland itself.Secondary hyperthyroidismoccurs due to excessive stimulation of the thyroid gland by TSH, secondary to pituitary or hypothalamic pathology, or from an ectopic source such as a TSH-secreting tumour.

Primary hyperthyroidism is the most common subtype, whilst secondary hyperthyroidism is rare.

Question 107

What are the clinical manifestations of hyperthyroidism

Answer 107

• Signs
  
  • Postural Tremor
  • Palmar erythema
  • Hyperreflexia
  • Sinus tachycardia/ arrhythmia
  • Goitre
  • Lid lag and retraction
  • Specific to Graves’ disease:
    
    • Thyroid acropachy (thickening of the extremities)
    • Thyroid bruit
    • Pretibial myxoedema (localised lesions of the skin)
    • Eye signs
      
      • Exophthalmos (bulging of the eye)
      • Ophthalmoplegia (paralysis or weakness of the eye muscles)
• Symptoms
  
  • Weight loss
  • Anxiety
  • Fatigue
  • Reduced libido
  • Heat intolerance
  • Palpitations
  • Menstrual irregularity

Mnemonic - Thyroidism: tremor, heart rate increase, yawning, restless, oligomenorrhoea, irritability, diarrhoea, intolerance to heat, sweating, muscle wasting (weight loss).

-

Question 108

What are the first line investigations for hyperthyroidism

Answer 108

Thyroid function tests.

Decreased TSH and increased T4 means primary hyperthyroidism e.g. Graves’ disease.

Decreased TSH and same T4 levels means subclinical hyperthyroidism.

Increased TSH and increased T4 or same levels of TSH and increased T4 means secondary hyperthyroidism e.g. TSH-secreting pituitary adenoma.

Question 109

What follow up/ 2nd line investigations are done for hyperthyroidism

Answer 109

Antibodies: anti-TSH receptorantibodies are positive in 95% of patients with Graves’. Anti-TPO (thyroid peroxidase) and anti-thyroglobulin antibodies may also be positive

Question 110

What further investigations are done for hyperthyroidism

Answer 110

• Thyroid ultrasound:offered to patients with thyrotoxicosisifthey have a palpable thyroid noduleorin patients with normal thyroid function when malignancy is suspected
• Technetium radionuclide scan:usually performed if anti-TSH antibodies are negative. ShowsdiffuseuptakeinGraves’ disease, unlike in toxic adenoma or toxic multinodular goitre
• Glucose:hyperthyroidism is associated with hyperglycaemia
• ECG: hyperthyroidism is associated with atrial fibrillation

Question 111

What are the differential diagnosis for hyperthyroidism

Answer 111

• Usually is clinically obvious
• Differentiation of mild cases from anxiety can be difficult, look for:
  
  • Eye signs e.g. lid lag & stare
  • Diffuse goitre
  • Proximal myopathy & wasting

Question 112

What is the 1st line management for hyperthyroidism

Answer 112

1st line – Antithyroid drugs, e.g., carbimazole (blocks thyroid peroxidase, reducing thyroid levels. Agranulocytosis common side effect – presents with sore throat.) Propylthiouracil if pregnant. Block-replace: give carbimazole + levothyroxine simultaneously (less risk of iatrogenic hypothyroidism). Radioactive iodine treatment (emits beta particles and destroys thyroid tissue). Thyroidectomy (risks: recurrent laryngeal nerve palsy, hypothyroidism, hypoparathyroidism.) Beta-blockers treat symptoms

Question 113

What is second line treatment for hyperthyroidism

Answer 113

• Second line antithyroid medication if Carbimazole not used = Propylthiouracil, but this is associated with hepatotoxicity. In pregnancy, propylthiouracil is used in the first trimester and this is switched to carbimazole thereafter as per NICE
• Surgery:total or hemithyroidectomy
  • Optimisation with antithyroid drugs is vital, aiming forpre-operative euthyroidism
  • Indicated in those at high risk of recurrent hyperthyroidism or when other options fail
  • Hemithryoidectomy is preferred for a single thyroid nodule

Question 114

What are potential complications in hyperthyroidism management

Answer 114

• Surgery complications - risk of hypothyroidism, hypoparathyroidism, and recurrent laryngeal nerve palsy resulting in a hoarse voice, trachael compression from post-operative bleeding
• Anti-thyroid drugs - agranulocytosis and neutropenia or hepatotoxicity

Question 115

What are potential complications for a hyperthyroidism patient

Answer 115

• Cardiovascular: heart failure, atrial fibrillation
• Musculoskeletalosteoporosis, proximal myopathy
• Thyrotoxic crisis/ thyroid storm - rapid T4 increase. Medical emergency!
  
  • Features include hyperpyrexia, tachycardia, extreme restlessness
    and eventually delirium, coma and death
  • Treated with large doses of carbimazole, propranolol, potassium iodide, IV hydrocortisone to stop conversion of T4 to T3
• Iatrogenic (due to treatment):
  
  • Agranulocytosis and neutropaenic sepsis: secondary to carbimazole
  • Hepatotoxicity: secondary to propylthiouracil
  • Congenital malformations: carbimazole in first trimester
  • Foetal goitre and hypothyroidism: any antithyroid medication in pregnancy at high doses

Question 116

What is the prognosis for hyperthyroidism

Answer 116

Prognosis depends on the underlying cause and severity. Patients may well become hypothyroid during the course of their management and require levothyroxine to achieve a euthyroid status.

Question 117

Define Graves’ disease

Answer 117

Graves’ disease is the most common cause of hyperthyroidism worldwide. It is an autoimmune induced excess production of thyroid hormone

Question 118

Describe the epidemiology of Graves’ disease

Answer 118

• This is the MOST COMMON CAUSE of hyperthyroidism (2/3rds of cases)
• More common in FEMALES than males
• Typically presents at 40-60yrs (appears earlier if maternal family history)

Question 119

Describe the aetiology of Graves’ disease

Answer 119

• 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 goiter
• Persistent high levels predict a relapse when drug treatment is stopped
• Similar auto antigen can also result in retro-orbital inflammation - graves opthalmopathy

Question 120

What are risk factors of Graves’ disease

Answer 120

• Family history
• Female
• Autoimmune disease
• Stress
• High iodine intake
• Radiation
• Tobacco use

Question 121

Describe the pathophysiology of Graves’ disease

Answer 121

Involves anti-TSH antibodies causing increased thyroid hormone production through stimulation of the TSH receptor. Of note, anti-TSH antibodies react with orbital antigens in fat and connective tissue, causing retro-orbital inflammation which leads to thyroid eye disease.

Question 122

What are the clinical manifestations of Graves’ disease

Answer 122

• Signs and symptoms
  
  • Thyroid acropachy - clubbing, swollen fingers and periosteal bone formation
  • Thyroid bruit - continuous sound heard over thyroid mass
  • Pretibial myxoedema - raised, purple-red symmetrical skin lesions over the anterolateral aspects of the shin
  • Eye signs
    
    • Exophthalmos - protruding eye
    • Ophthalmoplegia - paralysis or weakness of eye muscles

Question 123

What are the 1st line investigations for Graves’ disease

Answer 123

• 1st lineTFT’s: raised T3 and T4, reduced TSH.

All other aspects of investigation and management are the same as generic hyperthyroidism

Question 124

What is toxic multinodular goitre

Answer 124

• 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

Question 125

Describe the features of solitary toxic adenoma

Answer 125

• Cause of about 5% of cases of hyperthyroidism
• Prolonged remission is rarely induced by drug therapy

Question 126

Describe the features of De Quervains thyroiditis

Answer 126

• 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

Question 127

What drugs may cause drug induced hyperthyroidism

Answer 127

• 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

Question 128

Define thyrotoxic crisis

Answer 128

Also known as a ‘thyroid storm’, a thyrotoxic crisis is a life-threatening complication of hyperthyroidism and is most commonly seen in patients with Graves’ disease or toxic multinodular goitre.

Question 129

Describe the aetiology of thyrotoxic crisis

Answer 129

It is classified as an endocrine emergency and it often occurs secondary to a precipitating factor such as infection or trauma in patients with known hyperthyroidism. However, it may also be the first manifestation of undiagnosed hyperthyroidism.

Question 130

Describe the clinical manifestations of thyrotoxic crisis

Answer 130

• Signs
  
  • Hyperpyrexia: often > 40°C
  • Tachycardia: often > 140 BPM, with or without atrial fibrillation
  • Reduced GCS - consciousness
• Symptoms
  
  • Nausea and vomiting
  • Diarrhoea
  • Abdominal pain
  • Jaundice
  • Confusion, delirium or coma

Question 131

What are the investigations for thyrotoxic crisis

Answer 131

• TFTs: elevated T3 and T4 levels, suppressed TSH levels
• ECG: tachycardia; may demonstrate atrial fibrillation
• Blood glucose: perform in all patients with reduced consciousness

Question 132

What is the management for thyrotoxic crisis

Answer 132

• Conservative: IV fluids, NG tube insertion (if vomiting), tepid sponging, paracetamol, ITU admission
• Antithyroid drugs: propylthiouracil is generally preferred, but carbimazole is an alternative
• Corticosteroid: IV hydrocortisone or methylprednisolone
• Beta-blocker: propranolol PO, or IV over 10 minutes
• Oral iodine: Lugol’s iodine is offered > 1 hour after propylthiouracil (some trusts advise giving it at 4 hours) - blocks the peripheral conversion of T4 to T3
• Sedation: if required, use chlorpromazine
• Plasma exchange or thyroidectomy: in refractory patients

Question 133

What is the prognosis of thyrotoxic crisis

Answer 133

Even if promptly treated, it has a mortality of 10-20%.

Question 134

Define hypothyroidism

Answer 134

Hypothyroidism is a common endocrine condition caused by a deficiency in thyroid hormone.

Hypothyroidism is a pathological state reflecting a reduction in circulating T3 and T4. Hypothyroidism is classified as primary, secondary and congenital. 95% of cases are primary, with secondary and congenital causes being rare.

Question 135

Describe the epidemiology of hypothyroidism

Answer 135

• It is estimated that the prevalence of any cause of hypothyroidism is 1-2%, with Hashimoto’s thyroiditis being the most common cause in the developed world. Iodine deficiency is the most common cause worldwide.
• Female gender: 5-8x more likely to develop than men
• Middle-aged: peak age is 30-50 years old in Hashimoto’s thyroiditis

Question 136

Describe the aetiology of hypothyroidism

Answer 136

Primary hypothyroidism (low thyroglobulin and thyroid peroxidase antibodies): autoimmune Hashimoto’s disease, atrophic thyroiditis, iodine deficiency, drug-induced (anti-thyroid drugs, amiodarone, lithium), iatrogenic: thyroidectomy, radioiodine treatment.
Secondary hypothyroidism (very rare): not enough TSH due to hypopituitarism, hypothalamic disorders
Transient hypothyroidism: withdrawal of thyroid suppressive therapy, post-partum thyroiditis.

Question 137

What are risk factors for hypothyroidism

Answer 137

• Family history
• History of autoimmunity
• Genetic disorders: Turner and Down syndrome
• Chest or neck irradiation
• Thyroidectomy or radioiodine

Question 138

Describe the pathophysiology of hypothyroidism

Answer 138

Hypothyroidism is a pathological state reflecting a reduction in circulating T3 and T4. 95% of cases are primary, with secondary causes being rare.

Primary hypothyroidismis due to pathology affecting the thyroid gland itself, such as an autoimmune disorder (e.g. Hashimoto’s thyroiditis) or iodine deficiency.

Secondary hypothyroidismis usually due to pathology affecting thepituitarygland (e.g. pituitary apoplexy) or a tumour compressing the pituitary gland. It may also be caused byhypothalamicdisorders and certain drugs.

Congenital hypothyroidismoccurs due to an absent or poorly developed thyroid gland (dysgenesis), or one that has properly developed but cannot produce thyroid hormone (dyshormonogenesis).

Question 139

What are the clinical manifestations of hypothyroidism

Answer 139

• Signs
  
  • Dermatological: hair loss, loss of lateral aspect of the eyebrows (Queen Anne’s sign), dry and cold skin, coarse hair
  • Bradycardia
  • Goitre
  • Decreased deep tendon reflexes
  • Carpal tunnel syndrome
  • Hoarse voice
• Symptoms
  
  • Myxoedema - seen in autoimmune hypothyroidism
  • Fluid retention - oedema, pleural effusions, ascites
  • Weight gain
  • Cold intolerance
  • Lethargy
  • Dry skin
  • Constipation
  • Menorrhagia: followed later by oligomenorrhoea and amenorrhoea

Question 140

What are the 1st line investigations for hypothyroidism

Answer 140

Thyroid function tests (TFTs) - decreased T3/T4 and increased TSH in primary disease.

Question 141

What are the follow up investigations for hypothyroidism

Answer 141

Antibodies:Anti-TPO is associated with Hashimoto’s thyroiditis in 95% of cases
Inflammatory markers:raised in de Quervain’s thyroiditis

Question 142

What are other investigations to consider in hypothyroidism

Answer 142

• Ultrasound:not routinely carried out but may be useful if there is a goitre or focal nodule and malignancy is suspected in patients with normal thyroid function
• Radionuclide scan: not routinely carried out. Uses a small dose of a radioactive chemical (isotope) called a tracer that can detect cancer, trauma, infection or other disorders.
• Fasting lipids: hypothyroidism is associated with hypercholesterolemia
• Serum glucose and HbA1c:hypothyroidism is associated with hypoglycaemia. Also, Hashimoto’s thyroiditis is associated with T1DM
• FBC and serum B12 level: autoimmune thyroid disease is associated with a higher risk of pernicious anaemia
• Coeliac serology: to assess for coeliac disease if autoimmune thyroid disease is suspected. Thyroid disease is more common in patients with coeliac disease.

Question 143

What is the management plan for hypothyroidism

Answer 143

The aims of treatment are to resolve signs and symptoms and to maintain serum TSH and FT4 levels within or close to the normal reference range (0.5-2.5 mU/L). All patients with secondary hypothyroidism require urgent referral to an endocrinologist.

• 1st line
  
  • Levothyroxine (T4):offer with regular review of symptoms and TSH every 3 months. Once TSH is stable (on 2 occasions at least 6 months apart), review TSH annually
    
    • T4 starting dose: 50-100 mcg OD for most patients
    • Lower T4 starting dose: 25 mcg OD titrated slowly if > 50 years, severe hypothyroidism or a history of ischaemic heart disease
  • Advise that symptoms may lag behind treatment changes for several weeks or months
  • Review dose every8-12 weekswhen dose is changed
  • Interactions: iron and calcium carbonatereducelevothyroxine absorption so should be given ≥ 4 hours apart

Question 144

What are important considerations to take with regards to pregnancy and postpartum hypothyroidism patients

Answer 144

• If TFTs are abnormal, advise delaying conception and using contraception until stabilised on levothyroxine
• Inform the woman that there is anincreased demand for levothyroxinein pregnancy, with the dose usually increased by at least 25-50 mcg and aiming for a low-normal TSH
• Post-partum thyroiditis: the hypothyroid state may require levothyroxine, with most patients’ thyroid function normalising by 12 months of the birth

Question 145

What complications may arise in hypothyroidism patients

Answer 145

• Cardiovascular:
  hypercholesterolaemia is associated with ischaemic heart disease
• Neurological:carpal tunnel syndrome, peripheral neuropathy, proximal myopathy
• Myxoedema coma:rare but potentially fatal outcome of untreated/undertreated hypothyroidism. Presents with confusion, hypothermia, hypoglycaemia, hypoventilation, and hypotension
• Thyroid lymphoma:patients with Hashimoto’s thyroiditisare at increased risk of lymphoma, usually diffuse large B cell lymphomas
• Thyroxine side-effects:
  • Hyperthyroidism
  • Atrial fibrillation
  • Osteoporosis
  • Angina

Question 146

What is the prognosis for hypothyroidism

Answer 146

Hypothyroidism, if well managed with levothyroxine, will not present any issues for the individual and euthyroid status can be achieved. However, if left untreated, hypothyroidism slowly develops and worsens and predisposes to the above complications.

Question 147

What are the features of subclinical hypothyroidism and what is the management

Answer 147

• Subclinical hypothyroidism:
  
  • Normal T3/T4with increased TSH
  • Can be caused by any of the above
  • Management
    
    • TSH > 10 mU/L and normal T4(on two occasions):consider levothyroxine
    • TSH < 10 mU/L and normal T4(on two occasions):consider a 6 month trial of levothyroxine if symptomaticandless than 65 years old
    • In all other cases observation is indicated

Question 148

Define Hashimoto’s thyroiditis

Answer 148

The most common cause of hypothyroidism in the West. Antithyroid antibodies is the cause for this type of hypothyroidism

Question 149

Describe the epidemiology of Hashimoto’s thyroiditis

Answer 149

• It is estimated to affect between 0.5% and 2% of the population.
• More common in FEMALES than males
• Incidence increases with age

Question 150

What are the risk factors for Hashimoto’s thyroiditis

Answer 150

• Female sex
• Associated with other autoimmune disease e.g. T1DM
• Associations with Turner’s and Down’s syndrome

Question 151

Describe the pathophysiology of Hashimoto’s thyroiditis

Answer 151

Autoimmune inflammation of thyroid gland. This is associated with anti thyroid peroxidase (TP) antibodies and anti-thyroglobulin antibodies. There may also be anti-TSH receptor antibodies leading to degeneration of thyroid gland.

(Thyroid peroxidase converts iodide into iodine and is essential for thyroid hormone production. As is thyroglobulin)

It exists in two forms:

• Goitrous:characterised by a firm and rubbery goitre
• Atrophic:characterised by an atrophic gland

Initially it causes goitre, after which there is atrophy of the thyroid gland

Question 152

Define thyroid cancer

Answer 152

Cancers of the thyroid gland: Four types account for more than 98% of thyroid malignancies: papillary, follicular, anaplastic, and medullary.

Question 153

Describe the epidemiology of thyroid cancer

Answer 153

• Thyroid cancer is the most common endocrinological malignancy
• Not generally common, but are responsible for 400 deaths annually in the UK
• More common in women than men, generally
• Most likely to be diagnosed between the ages of 45 to 54 years.

Question 154

Describe the clinical manifestations of thyroid cancer

Answer 154

• Palpable thyroid nodule in most cases
• Occasionally (5%) they present with cervical lymphadenopathy or with lung,
  cerebral, hepatic or bone metastases
• Thyroid gland may increase in size, become hard and may be irregular in shape
• Tracheal deviation
• Neck enlargement
• Dysphagia
• Hoarseness of voice
• Dyspnoea

Question 155

Describe the 1st line investigations for thyroid cancers

Answer 155

• Fine needle biopsy - To distinguish between benign or malignant nodules
• TFTs - To check if hyperthyroid or hypothyroid (TSH, T3 & T4) - needs to be treated before carcinoma surgery
• Ultrasound of neck - Can differentiate between benign or malignant
• Laryngoscopy - paralysed vocal cord is highly suggestive of malignancy

Question 156

Describe papillary thyroid cancers

Answer 156

• These cancers are derived from the follicular cells - they secrete thyroglobulin and take up radioiodine
• They can spread via lymphatic invasion to cervical nodes and neck
• They are slow growing

Question 157

Describe the epidemiology and risk factors of papillary thyroid cancers

Answer 157

• Most frequent (around 80%)
• F>M
• Peak incidence 30s-50s
• Risk factors
  
  • Radiation exposure
  • Mutation RET and BRAF

Question 158

Describe the management and prognosis of papillary thyroid cancers

Answer 158

• Management
  
  • Lobectomy (or total thyroidectomy with lymph node removal)
  • High risk patients may receive radioiodine to catch the cancer that may not have been resected
  • TSH suppression with thyroid hormone replacement (TSH is a growth factor for the cancer)
• Prognosis
  
  • Associated with best prognosis (10 year survival >95%)

Question 159

Describe a follicular thyroid cancer

Answer 159

• Derived from follicular cells - secretes thyroglobulin and takes up radioiodine
• Hurthle cells (a subtype of follicular cells) seen
• Early metastases
• Can spread via vascular invasion: locally invasive, invades thyroid capsule
• Distal spread more common than papillary

Question 160

Describe the epidemiology and risk factors of follicular thyroid cancers

Answer 160

• 10% of thyroid cancers
• F>M
• Peak in 40s-60s

Risk factors:
Mutations in RAS

Question 161

Describe the management and prognosis of follicular thyroid cancers

Answer 161

• Management
  
  • Lobectomy (or total thyroidectomy with lymph node removal)
  • High risk patients may receive radioiodine to catch the cancer that may not have been resected
  • TSH suppression with thyroid hormone replacement
• Prognosis
  
  • More aggressive than papillary

Question 162

Describe a medullary thyroid cancer

Answer 162

• Derived from para-follicular cells (aka C-Cells responsible for calcitonin production) - do not secrete thyroglobulin and does not take up radioiodine
• Associated with early metastasis

Question 163

Describe the epidemiology and risk factors of medullary thyroid cancers

Answer 163

• Epidemiology
  
  • 5% of thyroid cancers
  • Sporadic (80%) - F>M, peak in 40s-60s
  • Familial (20%) - F:M, peak onset at early age
• Risk factors
  
  • Family with MEN 2A and 2B
  • Mutation in RET

Question 164

Describe the management and prognosis of medullary thyroid cancers

Answer 164

• Management
  
  • Lobectomy (maybe total thyroidectomy with lymph node removal)
  • Thyroid hormone replacement for normal TSH (no TSH suppression)
• Prognosis
  
  • More aggressive than follicular

Question 165

Describe anaplastic thyroid cancers

Answer 165

• Also known as undifferentiated carcinoma due to poor differentiation
• Very aggressive
• Spread: infiltrative to local structures, soft tissue of neck, widespread metastases, early mortality

Question 166

Describe the epidemiology of anaplastic thyroid cancers

Answer 166

• 3% of thyroid cancers
• M>F
• Peak in 60s to 80s

Question 167

Describe the management and prognosis of anaplastic thyroid cancers

Answer 167

• Management
  
  • Does not respond to radioactive iodine
  • If possible a total thyroidectomy is done
  • Combined chemotherapy and radiation - may be palliative
• Prognosis
  
  • Worst prognosis

Question 168

Describe a thyroid lymphoma and the management plan

Answer 168

• Generally a B cell-type non-Hodgkin’s lymphoma. It generally arises in the setting of pre-existing Hashimoto’s thyroiditis.
• Management
  • Primary thyroid lymphoma is treated with a combination of radiation and chemotherapy. The most common chemotherapy regimen is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone).

Question 169

What are the differential diagnosis of thyroid cancers

Answer 169

• Goitre
• Benign thyroid nodule

Question 170

What are the complications of thyroid cancers

Answer 170

• Complications
  
  • Airway obstruction
  • Surgery related:
    
    • Hypoparathyroidism
    • Recurrent laryngeal nerve damage
    • Bleeding
  • TSH suppression related:
    
    • Atrial fibrillation
    • Bone mineral loss
  • Radioiodine related:
    
    • Secondary tumours
    • Dryness of mouth

Question 171

What hormone does the hypothalamus release

Answer 171

Corticotropin-releasing hormone (CRH) released from the hypothalamus

Question 172

What is the role of Corticotropin-releasing hormone (CRH)

Answer 172

CRH stimulates the anterior pituitary to release adrenocorticotrophic hormone (ACTH)

Question 173

What is the role of ACTH (adrenocorticotrophic hormone)

Answer 173

ACTH stimulates release of mineralocorticoids, glucocorticoids and gonadocorticoids (androgens) from the adrenal gland

Question 174

Describe the structure of the adrenal gland

Answer 174

Adrenal gland is located above the kidney (retroperitoneal) and is split into adrenal medulla and adrenal cortex. The cortex is further subdivided into zona glomerulosa, zona fasciculata, zona reticularis. Each layer is responsible for the secretion of a different hormone.

Question 175

What hormones do each layer of the adrenal gland release

Answer 175

• Zona glomerulosa - secretes mineralocorticoids e.g. aldosterone
• Zona fasciculata - secretes glucocorticoids e.g. cortisol
• Zona reticularis - secretes gonadocorticoids (androgens) - these are weak hormones
• Medulla - is under sympathetic control and secretes catecholamines e.g. adrenaline and noradrenaline

NOTE: the zona glomerulosa - that secretes aldosterone is NOT UNDER CONTROL of the hypathalamo-pituitary axis (it responds to angiotensin II, low sodium and high potassium) - meaning pathology of the hypothalamus or pituitary will NOT EFFECT ALDOSTERONE SECRETION - only pathology of the kidney will.

Question 176

What are the actions of the following hormones:
- Aldosterone
- Cortisol
- Gonadocorticoids
- Adrenaline and noradrenaline

Answer 176

• Aldosterone - works on kidney to increase blood volume, increase BP. May also cause hypernatraemia.
• Cortisol - suppresses immune system, inhibits bone formation, increases metabolism - protein catabolism & lipolysis, gluconeogenesis, increases alertness.
• Gonadocorticoids - production of oestrogen and testosterone. Main role is controlling libido.
• Adrenaline and noradrenaline - gluconeogenesis, glycogenolysis, lipolysis, increase BP.

Question 177

Define Cushing syndrome

Answer 177

Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause.

Question 178

Describe the epidemiology of Cushing’s syndrome

Answer 178

• Cushing’s syndrome is uncommon, with an estimated 1-10 cases per million in the population
• It most commonly affects people aged 20 to 50 years
• Occurs 3 times more commonly in women than in men

Question 179

Describe the aetiology of Cushing’s syndrome

Answer 179

• Iatrogenic - due to exogenous steroid use
• Cushing’s disease - a pituitary adenoma secreting excess ACTH
• Primary disease - e.g. adrenal adenoma or adrenal hyperplasia - secreting excess cortisol
• Paraneoplastic Cushing’s- cancer producing ectopic ACTH e.g. from small cell lung cancer or neuroendocrine tumours
• Carney complex - a genetic disorder with multiple benign tumours, e.g. cardiac myxoma
• Micronodular adrenal dysplasia - rare cause

Question 180

What are the risk factors for Cushing’s syndrome

Answer 180

• Long term steroid use
• Pituitary adenoma
• Adrenal adenoma
• Small cell lung cancer
• Neuroendocrine tumours

Question 181

What are the clinical manifestations of Cushing’s syndrome

Answer 181

• Signs
  
  • Hypertension
  • Moon face
  • Buffalo hump
  • Central adiposity
  • Violaceous striae
  • Muscle wasting and proximal myopathy
  • Ecchymoses and fragile skin
  • Acne
• Symptoms
  
  • Bloating and weight gain
  • Mood change
  • Tiredness
  • Easy bruising
  • Increase susceptibility
  • Menstrual irregularity
  • Reduced libido

Question 182

What are the 1st line investigations for Cushing’s syndrome

Answer 182

Afterexcluding exogenous glucocorticoid use, the first step is toconfirm hypercortisolismwhich can be done with any of the following:

• 24-hour urinary free cortisol
• Overnight dexamethasone suppression test:most sensitive; shows failure of cortisol suppression
• Low dose dexamethasone suppression test:shows failure of cortisol suppression
• Late-night salivary cortisol -helps to demonstrate a loss of the normal circadian pattern.

Question 183

What is the gold standard investigation for Cushing’s syndrome

Answer 183

Most commonly performed:

• 24-hour urinary free cortisol
• Overnight dexamethasone suppression test

Question 184

What tests are done to confirm the cause of Cushing’s sydrome

Answer 184

Once hypercortisolism is confirmed, the source must belocalised:

• 9am ACTH:
  
  • Ifelevated: suggests anACTH-dependentcause and warrants ahigh dose dexamethasone suppression test
  • Iflow: suggests anACTH-independentcause and warrants aCT adrenalsto look for adrenal pathology
• High dose dexamethasone suppression test (DST):suppression of cortisol occurs in Cushing’s disease (pituitary adenoma), butnotin an ectopic ACTH source

Question 185

What further investigations need to be considered in Cushing’s syndrome

Answer 185

If a DST isinconclusive:

• CRH stimulation test:
  
  • Pituitary source: cortisol rises
  • Ectopic or adrenal source: no change in cortisol
• Petrosal sinus sampling of ACTH: to differentiate between pituitary and ectopic ACTH source

Final localisation tests:

• MRI pituitary:if Cushing’s disease (pituitary adenoma)is suspected
• CT chest, abdomen and pelvis: if an ectopic source is suspected

Question 186

What are differential diagnosis for Cushing’s syndrome

Answer 186

• Obesity
• Metabolic syndrome

Question 187

What is the management for Cushing’s syndrome

Answer 187

Iatrogenic – stop treatment if possible, e.g., oral steroids.
Cushing’s disease: transsphenoidal resection to remove pituitary adenoma
Adrenal adenoma – adrenalectomy
Ectopic ACTH – remove neoplasm.
Cortisol synthesis inhibition – metyrapone, ketoconazole

Question 188

What monitoring needs to be done for Cushing’s syndrome

Answer 188

Recurrence of adrenocorticotrophic hormone-dependent Cushing syndrome is common, with at least a 5% to 26% risk of recurrence at 5 years. Patients who have achieved remission should be screened periodically (every 6-12 months) for recurrence of disease.

Question 189

What complications arise with Cushing’s syndrome

Answer 189

Complications associated with action of cortisol -

• Osteoporosis
• Increased susceptibility to infection
• Diabetes mellitus
• Hypertension

Treatment related -

• Hypopituitarism
• Adrenal insufficiency
• Nelson syndrome after bilateral adrenalectomy - enlarged pituitary, development of adenomas.
• Hypothyroidism
• Growth hormone deficiency
• Hypogonadism

Question 190

What is the prognosis for Cushing’s syndrome

Answer 190

The prognosis depends on the underlying cause. Adrenal adenomas and pituitary microadenomas are associated with a favourable outcome. Those with adrenal carcinomas have poor outcomes. The prognosis in ectopic ACTH production depends on the underlying malignancy, but many are aggressive and grow rapidly.

Question 191

Describe the circadian pattern

Answer 191

Corticotropin releasing hormone (CRH) and hence cortisol are released according to the circadian rhythm (light-dark determines this) and in stress

• Highest levels in the morning 7-9am
• Lowest at midnight

Question 192

Describe features and causes of pseudo-Cushing’s

Answer 192

• Cushingoid features and abnormal cortisol levels butnotassociated with HPA pathology
• Common causes include alcohol excess, severe depression, obesity, pregnancy
• Results in afalse positivedexamethasone suppression test and 24h urinary free cortisol
• Differentiated using an insulin stress test

Question 193

Describe the 24hr urinary free cortisol test

Answer 193

Take > 2 measurements (cortisol is bound to albumin, when capacity is reached then will spill out to urine)

Question 194

Describe the overnight dexamethasone suppression test

Answer 194

Dexamethasone should, in the healthy patient, send negative feedback to the pituitary and hypothalamus resulting in ↓ ACTH and thus reduced cortisol.

• 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

Question 195

Describe the role of growth hormone and how it is controlled

Answer 195

Growth hormone (GH) is secreted in a pulsatile fashion under the control of two hypothalamic hormones:

• Growth hormone releasing hormone (GHRH) stimulates GH secretion
• Somatostatin (SST) inhibits GH secretion

GH is also inhibited by high glucose and dopamine

Ghrelin (synthesised in the stomach) also stimulates release of GH

GH exerts its actions either:

• Indirectly through the induction of insulin-like growth factor (IGF-1), which is
  synthesised in the liver and other tissues
• Directly on tissues such as the liver, muscle, bone or fat to induce metabolic
  changes

Question 196

Define acromegaly and gigantism

Answer 196

Acromegaly is a condition caused by an excess of growth hormone (GH) most commonly related to a pituitary adenoma.

Gigantism refers to excess GH production before fusion of the epiphyses of the long bones

Question 197

Describe the epidemiology of acromegaly

Answer 197

• Acromegaly is a rare disease with a prevalence of < 0.1%
• Acromegaly is often recognised in middle-aged men or women but can occur at any age.
• The disease is equally distributed between both sexes.

Question 198

Describe the aetiology of acromegaly

Answer 198

• Pituitary adenomas account for > 90% of cases of acromegaly.
• Other causes of acromegaly are very rare. They are related to excess secretion of GHRH or GH:
  • Ectopic release of GH: May be seen in neuroendocrine tumours.
  • Ectopic release of GHRH: Related to tumours including carcinoid and small cell lung cancer.
  • Excess hypothalamic release of GHRH: Related to hypothalamic tumours.

Question 199

What are risk factors for acromegaly

Answer 199

• MEN-1:pituitary adenomas, primary hyperparathyroidism, and pancreatic neuroendocrine tumours; MEN-1 is present in 6% of cases
• McCune-Albright syndrome

Question 200

Describe the pathophysiology of acromegaly

Answer 200

Acromegaly describes a state of excessive growth hormone (GH) production.A pituitary somatotroph adenomais responsible in over 95% of cases, but acromegaly can rarely occur due to ectopic secretion from a GHRH or GH producing-tumour, such as a pancreatic tumour.

Excessive GH causessoft-tissue growth resultingin the classical appearance seen in the disease. Additionally, if sufficiently large, a pituitary adenoma can causebitemporal hemianopia, and significant compression can lead to panhypopituitarism.

Question 201

What are the clinical manifestations for acromegaly

Answer 201

Acromegaly typically has an insidious onset and is often diagnosed late.

• Signs
  
  • Bitemporal hemianopia: due to compression of optic chiasm by pituitary tumour
  • Facial features:
    
    • Prominent jaw and supra-orbital ridge
    • Coarse facial appearance
    • Prognathism: protrusion of the lower jaw
    • Splaying of teeth
    • Macroglossia: large tongue
  • Spade like hands
  • Sweaty palms and oily skin
  • Hypertension
  • Organomegaly
• Symptoms
  
  • Visual disturbance
  • Headaches
  • Obstructive sleep apnoea
  • Rings and shoes are tight
  • Polyuria and polydispia due to
    T2DM
  • Tingling in hands: carpal tunnel
    sydrome
  • Hyperprolactinaemia: raised
    prolactin seen in over 20% of
    cases - features include
    galactorrhea, dysmenorrhoea,
    hypogonadism, decreased libido
    and infertility.

Question 202

What are the 1st line investigations for acromegaly

Answer 202

It is important to note that GH levels are not diagnostic of acromegaly as levels vary throughout the day, as well as being associated with episodic bursts.

• 1st line
  
  • Serum insulin-like growth factor 1 (IGF-1):elevated in acromegaly
    
    • As per Endocrine Society guidelines, this is thefirst-lineinvestigation for suspected acromegaly and, if elevated or inconclusive, an OGTT should be conducted to confirm the diagnosis; also used for monitoring
  • Oral glucose tolerance test (OGTT):
    
    • Physiologically, a glucose load should cause suppression of GH
    • In acromegaly, there isfailure of GH suppression2 hours post 75g glucose load (lack of suppression of GH to < 1 μg/L)

Question 203

What are further investigations to consider for acromegaly

Answer 203

• Other
  
  • Pituitary MRI: visualisation of the tumour; recommended in patients following biochemical confirmation
• Investigations to consider
  
  • Visual perimetry:formal assessment of visual fields. This has important implications for driving
  • Pituitary hormone screen:prolactin, LH, FSH, ACTH, TSH to monitor for panhypopituitarism; prolactin israisedin over 20% of patients
  • CT chest, abdomen, and pelvis:if an ectopic source of GH is suspected
  • GHRH levels: Elevated levels indicate excess production from a hypothalamus tumour or ectopic source.
  • Octreoscan & DOTATATE PET: Further scans that can be used to locate tumours that may produce GH/GHRH.

Question 204

What are differential diagnosis for acromegaly

Answer 204

Acromegaloidism or pseudo-acromegaly

Question 205

What is first line management for acromegaly

Answer 205

Surgery:trans-sphenoidal resection of the pituitary. Surgery isfirst-lineas acromegaly can have significant systemic complications

Question 206

What is the second line of management for acromegaly

Answer 206

• Medical:for patients unsuitable for surgeryor if there are persistent symptoms after surgery
  
  • Dopamine agonists:used in mild disease; cabergoline is first-line (bromocriptine is an alternative) and has 30% efficacy
  • Somatostatin analogues:used in moderate to severe disease to directly inhibit GH release (e.g. octreotide); has an efficacy of 35-60%
  • GH antagonist:pegvisomant is also used in severe disease but, in reality, is often avoided due to cost; once-daily subcutaneous injection. Very effective and reduces IGF-1 in up to 95% of patients, but does not reduce tumour size so surgery is still required

Question 207

What is the third line management in acromegaly

Answer 207

Radiotherapy:reserved for patients who have failed medical and surgical treatment, or in elderly patients unsuitable for surgery

Question 208

What monitoring is required for acromegaly patients

Answer 208

Patients with acromegaly will require lifelong monitoring of growth hormone and insulin-like growth factor 1 (IGF-1) levels.

Once the initial treatment interventions (surgical, medical, and radiotherapy, as required) have remediated or significantly improved the disease state, regular monitoring of disease-related parameters is recommended.

Medical complications of acromegaly also require ongoing monitoring and treatment e.g. regular screening for colorectal cancer

Question 209

What are potential complications with acromegaly

Answer 209

• Cardiac:cardiomyopathy, heart failure, hypertension
• Respiratory:obstructive sleep apnoea
• Neurological:carpal tunnel syndrome, proximal myopathy
• Endocrine: T2DM (insulin resistance due to GH excess), panhypopituitarism
• Gastrointestinal: colorectal cancer
• Organomegaly: organ dysfunction
• Osteoarticular complications: arthritis

Question 210

What is the prognosis of acromegaly

Answer 210

The aim of treatment is biochemical normalisation of IGF-1 and random serum GH levels. Surgical treatment is curative, however, patients still need regular monitoring of GH and IGF-1 levels with life expectancy near normal in treated disease.

Acromegaly appears to be associated with an increased mortality. Much of this risk is related to the obstructive sleep apnea and cardiovascular complications. Studies have reported average survival reduction of up to 10 years in patients with acromegaly.

Question 211

How do acromegaly and gigantism compare

Answer 211

Both acromegaly and gigantism are characterised by excessive growth hormone (GH) secretion. Excess GH secretion in children (before fusion of the growth plates) is known as gigantism. Both conditions are most commonly caused by a pituitary adenoma (95% of cases).

GH secretion occurspriorto fusion of the epiphyseal (growth) plates, resulting inincreased overall height. This does not occur in acromegaly as the growth plates have fused in adults.

Compression by the pituitary adenoma can cause a reduction in the function of other parts of the pituitary, resulting in panhypopituitarism.Reduced LSH/FSHfrom the anterior pituitary affectspubertyandgonadal developmentin children for gigantism.

Question 212

Define hyperaldosteronism and Conn’s syndrome

Answer 212

Excess levels of aldosterone. The causes for this can be primary (independent of RAAS) or secondary (dependent on RAAS)

Conn’s syndrome refers to primary hyperaldosteronism.

Results in increased sodium and thus water retention (resulting in increased BP).

Question 213

Describe the epidemiology of hyperaldosteronism

Answer 213

• Primary hyperaldosteronism was originally thought to be rare, with a prevalence of <1%, but recent evidence suggests that it may be more common than initially thought.
• Common in middle-aged adults

Question 214

Describe the aetiology of primary hyperaldosteronism

Answer 214

• Primary hyperaldosteronismDescribes adrenal dysfunction causingraised aldosteronelevels withdecreased reninlevels due to negative feedback from sodium retention. Causes include:
  • Adrenal hyperplasia: idiopathic bilateral hyperplasia is the most common cause (⅔), can also be unilateral
  • Adrenal adenoma: classically termedConn’s syndrome
  • Adrenal carcinoma: extremely rare
  • Familial hyperaldosteronism: rare

Question 215

Describe the aetiology of secondary hyperaldosteronism

Answer 215

• Secondary hyperaldosteronismDescribes inappropriate activation of the RAAS, therefore patients haveraised aldosterone and raised reninlevels. Causes include:
  • Renal artery stenosis
  • Heart Failure: arterial hypovolemia due to reduced oncotic pressure causes reduced renal perfusion

Question 216

What are risk factors for hyperaldosteronism

Answer 216

• Family history of early onset hypertension
• Family history of primary hyperaldosteronism

Question 217

Describe the normal physiology of RAAS system

Answer 217

Juxtaglomerular cells in the afferent arteriole of the kidney detect low blood pressure and release renin. Renin converts angiotensin (secreted by the liver) to angiotensin I. Angiotensin converting enzyme ACE converts angiotensin I to II in the lungs. Angiotensin II stimulates aldosterone release from adrenal glands.
Excess aldosterone > acts on distal tubule = increased sodium reabsorption, water retention and potassium excretion in kidneys > hypertension and hypokalaemia

Question 218

What are the clinical manifestations of hyperaldosteronism

Answer 218

• Signs
  
  • Refractory hypertension
  • Hypokalaemia - increased K+ secretion by kidneys
  • Metabolic alkalosis - increased H+ secretion by kidneys
• Symptoms
  
  • Lethargy
  • Mood disturbance
  • Paresthesia and muscle cramps
  • Polyuria and nocturia

Question 219

What are the first line investigations for hyperaldosteronism

Answer 219

Aldosterone/renin ratio: first-line diagnostic test. Will show high aldosterone, with low renin in cases of primary hyperaldosteronism and high aldosterone and high renin in cases of secondary hyperaldosteronism.

CT imaging should be performed if there is a raised ratio.

Question 220

What are further investigations for hyperaldosteronism

Answer 220

• Serum U&Es:hypokalaemia and hypernatraemia may be seen
  
  • Patients may have normal sodium levels due to the ‘aldosterone-escape’ mechanism
  • Water is absorbed alongside sodium which increases the hydrostatic pressure within peri-tubular capillaries causing sodium to leak back into the tubule
• Blood gas - to look for alkalosis
• High-resolution CT abdomen:useful to exclude carcinoma; if CT suggests an adenoma or hyperplasia, perform bilateral adrenal venous sampling
• Adrenal venous sampling:to determine if there is unilateral or bilateral disease, and if the mass is functional
  
  • Adrenal vein sampling measures the amount of corticosteroid secreted from each adrenal gland
  • In a non-functional mass, imaging will show an abnormality but corticosteroid levels will be normal; removal would not be necessary in this instance
• In cases of secondary hyperaldosteronism - doppler/ CT angio/ MRA to look for renal artery stenosis

Question 221

What are differential diagnosis for hyperaldosteronism

Answer 221

• Other forms of hypertension e.g.
  
  • Essential hypertension
  • Secondary hypertension
  • Liddle syndrome

Question 222

What is 1st line management for hyperaldosteronism

Answer 222

• Laparoscopic adrenalectomy:for unilateral
  adrenal hyperplasia or adenoma
• Spironolactone: for bilateral adrenal hyperplasia or adenoma; spironolactone is an aldosterone antagonist

Question 223

What is the 2nd line management for hyperaldosteronism

Answer 223

• In unilateral disease where surgery is inappropriate, treat with spironolactone
• ENaC inhibitor: Amiloride, a potassium-sparing diuretic, may be used if aldosterone antagonists are not tolerated.
• Other
  In secondary hyperaldosteronism - percutaneous renal artery angioplasty to resolve the renal artery stenosis

Question 224

What monitoring is done for hyperaldosteronism patients

Answer 224

• Patients who have undergone unilateral adrenalectomy - BP, plasma electrolytes, and aldosterone and renin levels should be monitored every 6 to 12 months for clinical and biochemical evidence of recurrence (if cured postoperatively) or worsening (if improved but not cured) of PA.
• Patients receiving aldosterone medications - Electrolytes and renal function should be monitored regularly (e.g., every 3 to 6 months), watching for development of hyperkalaemia, hyponatraemia, and uraemia. CT of the adrenals should be performed annually at first and, if no nodular growth is seen, every 3 to 4 years, indefinitely.
• Patients with familial hyperaldosteronism type I (FH-I) - Hypertension is readily controlled by administering glucocorticoids in low doses. Control can be assessed by clinic, home, and ambulatory BP monitoring, and by periodic (e.g., yearly) echocardiography.

Question 225

What complications may arise for a hyperaldosteronism patient

Answer 225

• Secondary to long-standing hypertension: ischaemic heart disease, stroke, hypertensive nephropathy and chronic kidney disease
• Iatrogenic - hyperkalaemia

Question 226

What is the prognosis for patients with hyperaldosteronism

Answer 226

Patients with primary hyperaldosteronism have increased mortality and cardiovascular morbidity compared to age and sex-matched controls. Surgical management leads to a cure in 50% of patients and the rest will have improvement of symptoms and blood pressure.

Question 227

What is aldosterone escape

Answer 227

• Aldosterone escapeThe volume expansion prompted by increased water reabsorption results in an ‘escape’ phenomenon. This is a diuresis that occurs in response to the water and sodium retention caused by raised aldosterone. The exact mechanisms are unclear but appear to involve:
  • Pressure natriuresis
  • Atrial natriuretic peptide release
  • Changes to reabsorption in the distal tubule

Question 228

Define a pituitary adenoma

Answer 228

Tumours of the pituitary gland

• Can be non-functional (causing compressive symptoms) or functional (e.g. Prolactinoma, Acromegaly and Cushing’s)
• Can be microadenomas or macroadenomas

Question 229

Define the epidemiology of pituitary adenomas

Answer 229

• Pituitary adenomas are the third most common intra-cranial neoplasms in adults, accounting for about 10% of all intra-cranial tumours.
• The prevalence of pituitary adenoma varies from 19 to 28 cases per 100,000 in the UK
• Prevalence increases with age - there is a peak in incidence between the ages of 30 to 60 years

Question 230

What are the risk factors of a pituitary adenoma

Answer 230

• MEN-1
• Carney complex
• Familial isolated pituitary adenomas - rare

Question 231

What is the pathophysiology of a pituitary adenoma

Answer 231

Usually macroadenomas and can secrete a variety of hormones depending on the cell of origin

A number of cell lines may be affected:
- Mammotrophs:Results in hyperprolactinaemia caused by a prolactinoma.
- Somatotrophs:Acromegaly occurs due to excess growth hormone.
- Corticotrophs:Results in the release of excess cortisol (Cushing’s syndrome) through excess production ofACTH.

Question 232

What are the clinical manifestations of a pituitary adenoma

Answer 232

Symptoms will vary depending on cells affected and mass effects of the tumour

Prolactinoma
- Galactorrhoea
- Irregular menses
- Lack of libido
- Erectile dysfunction

Cushing’s related symptoms

Acromegaly related symptoms

Compressive effects
- Headache
- Visual disturbances - bitemporal hemianopia
- Palsy of cranial nerves III, IV, VI
- Diabetes insipidus
- May even present as hypopituitarism

Question 233

What are the investigations for a pituitary adenoma

Answer 233

Those with a known family history (first and second-degree relatives) may be screened. Screening tends to be annual, typically from the ages of 5 to 65 (and may continue after this time, but less frequently).

• Hormonal tests:
  
  • Prolactinoma:raised prolactin
  • Acromegaly:raised IGF-1 and failure of growth hormone suppression following oral glucose tolerance test
  • Other:the remaining hormones should also be screened as mass effect can lead to hypopituitarism.
• Imaging:
  
  • MRI is 1st line
  • PET-CT
  • CT
• DNA testing -MEN1: mutation testing should be offered to patients and their relatives

Question 234

What are the differential diagnosis for pituitary adenoma

Answer 234

• Rathke’s cleft cyst: an abnormal fluid-filled (cyst) sac that usually is found between the anterior and posterior pituitary glands.
• Craniopharyngioma: a rare type of noncancerous (benign) brain tumor that begins near the brain’s pituitary gland and can affect the function of the pituitary gland and other nearby structures in the brain.
• Meningioma: a tumor that forms on membranes that cover the brain and spinal cord just inside the skull.
• Hypophysitis: a rare condition which involves the acute or chronic inflammation of the pituitary gland or pituitary stalk.
• Infection

Question 235

What is the management for a pituitary adenoma

Answer 235

The treatment of pituitary adenomas is dependent on the cell line affected and whether it is a macro or microadenoma.

Functioning tumours
- Prolactinomas:first-line management is with dopamine agonists such as bromocriptine
- Acromegaly/ Cushing’s:transsphenoidal resection is first-line

Non-functioning tumours
- Surgical resection:conducted when mass effect is observed

Other treatment involves radiation for residual tumour

Question 236

What are potential complications for pituitary adenoma patients

Answer 236

• Hyperpituitarism
• Hypopituitarism - may be due to compressive effects or iatrogenic
• Conditions related to hypopituitarism e.g. hypothyroidism
• Surgery related complications - such as mortality, meningitis, cerebrospinal fluid rhinorrhoea

Question 237

What is the prognosis for pituitary adenomas

Answer 237

Patients with clinically non-functional pituitary adenomas (CNFPAs) generally have a good prognosis. The 10-year progression-free survival for pituitary adenoma is 80% to 94%.

Micro-adenomas do well with observation.

Macro-adenomas have a propensity to grow, and even when diagnosed as asymptomatic, need very close monitoring.

Patients with CNFPAs may be at increased risk of death, especially secondary to cardiovascular disease.

Patients with pituitary adenomas have been shown to have a lower quality of life (QoL) before and after pituitary surgery compared with people without pituitary adenomas.

Question 238

Define Addisons disease

Answer 238

Addison’s disease (primary adrenal insufficiency) is caused by destruction or dysfunction of the adrenal cortex.

Results in mineralocorticoid (aldosterone), glucocorticoid (cortisol) and gonadocorticoid (androgens) deficiency

Question 239

What is the epidemiology of Addisons Disease

Answer 239

• In Europe, the overall prevalence has increased from 40-70 cases per million in the 1960s to more than 140 cases per million in developed countries.
• More common in women

Question 240

Describe the aetiology of Addisons disease

Answer 240

• Autoimmune adrenalitis - most common in western world. Autoantibodies target the adrenal gland and the enzymes involved in steroid synthesis. One of the main targets for autoimmune destruction is the enzyme 21-hydroxylase.
• Infection - TB (most common worldwide), HIV, Meningococcal infection
• Congenital cause - congenital adrenal hyperplasia causes impaired cortisol synthesis
• Medication
  
  • Long term steroid use (causes reduced ACTH via negative feedback)
  • Etomidate, Mitotane, Aminoglutethimide (reduce cortisol production) - drugs usually used to treat Cushing’s syndrome
• Rare causes
  
  • Adrenal hemorrhage/ infarction
  • Malignant invasion
  • Infiltration of adrenal glands
    
    • Hemochromatosis
    • Amyloidosis

Question 241

What are risk factors for Addisons disease

Answer 241

• Female gender
• Autoimmune conditions
• Autoimmune polyendocrinopathy syndrome
• Adrenal haemorrhage
• Warfarin which may predispose to adrenal haemorrhage
• TB
• HIV

Question 242

Describe the pathophysiology of Addisons disease

Answer 242

Addison’s disease refers tochronic primary adrenal insufficiency(hypoadrenalism) resulting in reduced adrenocortical hormones, including mineralocorticoids (zona glomerulosa), glucocorticoids (zona fasciculata), and androgens (zona reticularis).

Corticosteroids (glucocorticoids and mineralocorticoids) are involved in renal excretion of potassium and acid as well as sodium reabsorption. Hence, adrenal insufficiency results in ametabolic acidosiscoupled with hyperkalaemia and hyponatraemia.

In developed countries, such as the UK, most cases (80%) are caused byautoimmune destructionof the adrenal glands. These patients are at risk of developing other autoimmune conditions such as vitiligo or thyroid disease, and on occasion, forms part of an autoimmune polyendocrinopathy syndrome (APS).

Due to there not being any negative feedback, there are higher levels of CRH and ACTH.

Question 243

What are the clinical manifestations of Addisons disease

Answer 243

• Signs
  
  • Hyperpigmentation (caused by increased levels of ACTH) - especially in palmar creases and buccal mucosa
  • Vitiligo - due to loss of androgens
  • Loss of pubic hair in women
  • Hypotension and postural drop
  • Associated autoimmune conditions
  • Tachycardia
• Symptoms
  
  • Lethargy and generalised weakness
  • Loss of libido
  • Nausea and vomiting
  • Cachexia - weight loss and muscle wasting
  • Dehydration
  • Salt-cravings
  • Collapse and shock (Addisonian crisis)

Question 244

What are the 1st line investigations for Addison disease

Answer 244

8 - 9 am cortisol: NICE suggests using this first-line in primary care

• <100 nmol/L: highly suggestive of Addison’s; NICE advise admission to hospital
• 100 - 500 nmol/L: refer the patient for an ACTH stimulation test
• > 500 nmol/L: Addison’s is unlikely; this result would be expected in normal people

Question 245

What are other primary investigations for Addison disease

Answer 245

• 8 am ACTH:increased due to loss of negative feedback from cortisol
• Adrenal antibodies:anti-21-hydroxylase suggests autoimmune aetiology
• U&Es:mineralocorticoid deficiency causeshyponatraemiaandhyperkalaemia

Question 246

What is the gold standard investigation for Addison’s disease

Answer 246

ACTH stimulation test (short Synacthen test): Plasma cortisol is measured before and 30 minutes after giving Synacthen 250μg IM (ACTH analogue)

• Failure of an adequate rise in cortisolpost-Synacthen (with peak cortisol levels < 500 nmol/L at 1 hour) suggests Addison’s disease

Question 247

What are other investigations to consider with Addison’s disease

Answer 247

• Aldosterone/renin ratio:decreased in Addison’s disease due to reduction in mineralocorticoid production
• CT adrenal:atrophied glands in Addison’s disease; can also identify if malignancy is the cause

Question 248

What are the differential diagnosis in Addison’s disease

Answer 248

• Haemochromatosis due to hyperpigmentation
• Hyperthyroidism due to weight loss and tachycardia
• Anorexia nervosa due to weight loss

Question 249

What is the first line management in Addison’s disease

Answer 249

• 1st lineCorticosteroid replacement:
  - Hydrocortisonein 2-3 doses divided throughout the day with a total dose of 20-30 mg for glucocorticoid replacement. Dose divisions vary in shift-workers with different sleep cycles; the largest dose is always given upon waking
  - Fludrocortisoneis recommended once daily for mineralocorticoid replacement (50-300 micrograms)

Question 250

What are further management steps in Addison’s disease

Answer 250

• Androgen replacement - mainly in women
• Patient education:
  • Patients should be advised regarding medication compliance and not missing doses
  • Advise patients to wear a MedicAlert bracelet or carry steroid cards in case of an Addisonian crisis
  • Advise patients todoubletheir glucocorticoid dose (hydrocortisone) if they develop an intercurrent illness
  • When travelling, patients should take extra medication plus an emergency hydrocortisone injection kit

Question 251

What monitoring needs to be done for Addison’s disease patients

Answer 251

Patients should be evaluated annually to judge adequacy of glucocorticoid and mineralocorticoid replacement. Dose can be adjusted depending on presentation of patients at review.

Monitoring also key due to complications associated with Addison’s disease.

Question 252

What are complications for Addison’s disease patients

Answer 252

• Secondary Cushings due to excess hormone replacement
• Osteopenia and osteoporosis
• Secondary hypertension
• Addisonian crisis - drop in glucocorticoid levels usually due to non-compliance with medication

Question 253

What is the prognosis for Addison’s disease patients

Answer 253

Addison’s disease is a lifelong illness. 40% of patients will experience an adrenal crisis. Overall, the mean age at death is 75.7 years (for females) and 64.8 years (for males), which is 3.2 and 11.2 years less than the estimated life expectancy.

Question 254

Define an Addisonian crisis

Answer 254

Addisonian crisis, also known as an adrenal crisis, is a state of acute insufficiency of adrenocortical hormones. It most often occurs on a background of established Addison’s disease due to precipitating factors such as poor medication compliance, infection, trauma, surgery, and myocardial infarction.

Question 255

Describe the epidemiology of Addisonian crisis

Answer 255

In those with Addison’s disease, 40% of patients will experience one crisis

Question 256

Describe the aetiology of an Addisonian crisis

Answer 256

• Steroid withdrawal: any patient on long term steroids should not abruptly withdraw their medication
• Severe dehydration
• Sepsis or surgery: resulting in acute exacerbation of pre-existing adrenal insufficiency (e.g. Addison’s disease)
• Meningococcal infection:meningococcal sepsis can lead to adrenal haemorrhage (Waterhouse-Friderichsen syndrome)

Question 257

Describe the pathophysiology of an Addisonian crisis

Answer 257

Drop in level of corticosteroids.

Corticosteroids (glucocorticoids and mineralocorticoids) are involved in renal excretion of potassium and acid as well as sodium reabsorption. Hence, adrenal insufficiency results in a metabolic acidosis coupled with hyperkalaemia and hyponatraemia. In a crisis, there is also accompanying haemodynamic instability due to sodium and, therefore, fluid loss.

Question 258

What are the clinical manifestations of an Addisonian crisis

Answer 258

• Signs
  
  • Hypotension
  • Hypovolemic shock
  • Reduced GCS - consciousness
  • Confusion
  • Pyrexia - increased temperature
• Symptoms
  
  • Nausea and vomiting
  • Abdo pain
  • Trigger e.g. infection or MI

Question 259

What are the investigations for an Addisonian crisis

Answer 259

• 12-lead ECG:hyperkalaemic changes include flat P waves, short QT interval, broad QRS, ST depression, and tented T waves
• VBG:can be conducted quickly and will reveal metabolic acidosis with hyponatraemia and hyperkalaemia. Patients may also be hypoglycaemic
• U&E’s: hyponatraemiaandhyperkalaemia; acute kidney injury may be present due to hypovolaemia causing pre-renal injury
• FBC and CRP:leukocytosis and raised inflammatory markers may suggest an underlying infection as the precipitant
• TFTs:hypothyroid states may mimic an Addisonian picture

Question 260

What is the management for an Addisonian crisis

Answer 260

• IV fluids: for resuscitation (e.g. normal saline); consider dextrose if hypoglycaemic
• Corticosteroid:hydrocortisone100 mg IV (IM is an alternative) and a further dose 6 hours later may be given. Oral replacement usually starts after 24 hours, with a reduction to maintenance over 3-4 days
• Fludrocortisone isnotrequired in the acute stage as hydrocortisone exerts an effect at the mineralocorticoid receptor
• Treat the underlying cause e.g. infection

Question 261

What is the prognosis of an Addisonian crisis

Answer 261

There are poor outcomes if treatment is delayed, with a risk of death due to hypovolaemic shock. Mortality is almost 100% if untreated

Question 262

Define secondary adrenal insufficiency

Answer 262

Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH).

Adrenal suppression refers to decreased cortisol production as a result of negative feedback on the hypothalamic-pituitary-adrenal axis, caused by excess glucocorticoids. The consequence is decreased production of both corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone from the pituitary gland, leading to a decrease in serum cortisol levels.

Question 263

Describe the aetiology of secondary adrenal insufficiency

Answer 263

• Iatrogenic - commonest cause. Due to long term steroid use leading to suppression of the HPA axis
• Hypothalamic pituitary disease - resulting in reduced ACTH production
• Removal of pituitary tumour - the remaining ACTH-secreting cells in the pituitary gland may be sluggish in their recovery, resulting in a period of adrenal suppression

Question 264

Describe the pathophysiology of secondary adrenal insufficiency

Answer 264

• Decreased levels of ACTH resulting in decreased glucocorticoid (CORTISOL)
• Mineralocorticoid production remains intact

Question 265

Describe the clinical manifestations of secondary adrenal insufficiency

Answer 265

Similar presentation to Addison’s disease however no hyperpigmentation as there is no excess ACTH.

• Signs
  
  • Vitiligo - due to loss of androgens
  • Loss of pubic hair in women
  • Hypotension and postural drop
  • Associated autoimmune conditions
  • Tachycardia
• Symptoms
  
  • Lethargy and generalised weakness
  • Loss of libido
  • Nausea and vomiting
  • Cachexia - weight loss and muscle wasting
  • Dehydration
  • Salt-cravings
  • Collapse and shock (Addisonian crisis)

Question 266

What are the investigations for secondary adrenal insufficiency

Answer 266

Same as with Addison’s disease

• ACTH levels are low and mineralocorticoid production is intact in secondary hypoadrenalism - can be used to differentiate from Addison’s

ACTH stimulation test (short Synacthen test): Plasma cortisol is measured before and 30 minutes after giving Synacthen 250μg IM (ACTH analogue)

• Failure of an adequate rise in cortisolpost-Synacthen (with peak cortisol levels < 500 nmol/L at 1 hour) suggests Addison’s disease

Question 267

What is the management for secondary adrenal insufficiency

Answer 267

• Adrenals will recover if long-term steroids are slowly weaned off - but this is
  a long and difficult process
• ORAL HYDROCORTISONE - replacement of glucocorticoids

Question 268

What is the prognosis for secondary adrenal insufficiency

Answer 268

Adrenal insufficiency secondary to corticosteroid treatment has a generally good prognosis. Time to recovery depends on dose and/or potency of glucocorticoid used and treatment length. Signs and symptoms of Cushing’s syndrome will disappear with time as the inciting medication is stopped.

Question 269

Define SIADH (syndrome of inappropriate Antidiuretic hormone secretion

Answer 269

The syndrome of inappropriate anti-diuretic hormone (SIADH) results from excess ADH secretion.

ADH excess, as the name suggests, results in reduced diuresis - water excretion and urinary output are reduced. This leads to an increase in total body water and hyponatraemia.

Question 270

Describe the production, storage and release of ADH

Answer 270

Antidiuretic hormone (ADH) is produced by the magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus.

It is stored and released by the posterior pituitary in response to rising plasma osmolality or decreasing blood volume. It may also be referred to as arginine vasopressin (AVP) or simply vasopressin.

Question 271

What is the role of ADH

Answer 271

ADH acts on the distal convoluted tubule and collecting duct to increase water reabsorption independent of sodium. ADH stimulates the insertion of aquaporin-2 channels onto the luminal membrane, allowing the free entry of water. ADH also causes vasoconstriction of arterioles.

Question 272

Describe the epidemiology of SIADH

Answer 272

• Hyponatraemia is the most common electrolyte disorder encountered in clinical practice
• The prevalence of hyponatraemia in the community is around 8% and increases with age (approximately 12% in people aged 75 or older)

Question 273

Describe the aetiology of SIADH

Answer 273

• Neurological
  
  • Meningitis, encephalitis or cerebral abscess
  • Intracranial haemorrhage, e.g. subarachnoid or subdural haemorrhage
  • Stroke
  • Trauma
• Malignancy
  
  • Small cell carcinoma of the lung most commonly
  • Other cancers, e.g. breast cancer, and head and neck tumours, are rarer causes
• Infections
  
  • Pneumonia
  • Tuberculosis
  • HIV
• Endocrine
  
  • Hypothyroidism
  • Hypopituitarism
• Drugs (remember mnemonic CARDISH - chemo, antidepressants, recreational drugs, diuretics, inhibitors e.g. ACEI & SSRIs, sulfonylurea, hormones e.g. desmopressin)
  
  • SSRIs and TCAs
  • Proton pump inhibitors
  • Carbamazepine
  • Cyclophosphamide
  • Sulfonylureas (glimepiride and glipizide)

Question 274

What are risk factors for SIADH

Answer 274

• Age >50
• Pulmonary conditions
• Malignancy
• Medicine associated with SIADH induction
• CNS disorder

Question 275

Describe the pathophysiology of SIADH

Answer 275

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) describesincreased antidiuretic hormone(ADH)releasefrom the posterior pituitary or an ectopic source.

ADHis responsible for free water reabsorption by acting on the collecting ducts of the kidney, resulting inwater retention by increased insertion of aquaporin 2, butnotthe reabsorption of solutes. This increases blood volume and decreases serum osmolarity.

Increased ADHresults in increased free water retention, subsequent dilution of the blood and a decrease in solutes in the blood.

Increase in blood volume leads to stretching of heart muscle and release of ANP and BNP (natriuretic peptide). This inhibits renin release and activity, and therefore the RAAS system. This promotes natriuresis (excretion of sodium). This leads to sodium and water excretion, which promotes further ADH activity.

This cycle continues. Overtime, the kidneys will adapt. The number of aquaporin channels will decrease to compensate for the amount of ADH present. This will now lead to diuresis as well as natriuresis. This is why there is there is a euvolaemic state rather than a hypervolaemic state, coupled with hyponatraemia.

Overall, patients will have high urine Na+ levels and low serum Na+ levels. They will be euvolaemic due to compensatory mechanisms.

Question 276

What are the clinical manifestations of SIADH

Answer 276

The clinical features seen in SIADH depend on the degree of hyponatraemia and the rate of change in serum sodium levels (acute or chronic). A large proportion of cases will be asymptomatic with clinical features developing with either severe hyponatraemia or following a rapid fall in the sodium level.

• Key Presentations
  Hyponatraemic and euvolaemic (no features of hyper- or hypovolaemia)
• Symptoms
  Mild(130-135 mmol/L):
  • Nausea, vomiting, headache, lethargy, anorexia
  Moderate(125-129 mmol/L):
  - Weakness, muscle aches, confusion, ataxia, asterixisSevere(< 125 mmol/L):
  - Reduced consciousness, seizures, myoclonus, respiratory arrest

Question 277

What are the investigations for SIADH

Answer 277

There is no single test that conclusively diagnoses SIADH. Instead, diagnosis relies upon suggestive biochemistry results and the clinical context.

Blood tests
Renal function: gives a serum sodium that confirms hyponatraemia. May also show a low serum urea consistent with mild volume expansion.

Serum osmolality: a low serum osmolality is seen, less than 280 mOsm/kg.

Urinary tests:

Urinary osmolality: a high urine osmalality is seen, greater than 100 mOsm/kg.

Urine sodium: typically a high urinary sodium is seen, greater than >40 mmol/L.

Question 278

What are the diagnostic criteria for SIADH

Answer 278

• Low plasma osmolality: < 275 mOsm/kg
• High urine osmolality: > 100 mOsm/kg
• High urine sodium: > 30 mmol/L
• Clinical euvolaemia
• Exclusion of glucocorticoid deficiency or hypothyroidism(rare)

Question 279

Describe the acute management for SIADH

Answer 279

• Acute management: <48 hrs onsetAcute hyponatraemia must be treated urgently due to the risk of cerebral oedemaand herniation
  • Hypertonic (3%) saline is preferred - slow infusion to avoid complications
  • Furosemide (diuretic) - in patients who have fluid overload. Causes an increase in water, Na+, Ka+ and Cl- excretion. (Note: KCl should be replaced)

Question 280

Describe the chronic management for SIADH

Answer 280

1st line- Restrict fluid (to correct hyponatraemia) + treat underlying cause
For chronic SIADH: 2nd - Tolvaptan (V2 receptor antagonist), 3rd – sodium chloride and furosemide

Question 281

What are the complications with SIADH

Answer 281

• Cerebral oedema: hyponatraemia lowers the osmolality of the blood causing an osmotic shift of water into brain tissue with subsequent oedema and risk of herniation
• Central pontine myelinolysis:rapid correction of sodium can cause osmotic demyelination, particularly in chronic hyponatraemia (slow correction is vital)
  • Manifests as tremors, dysarthria, quadriplegia, ophthalmoplegia, seizures and extrapyramidal symptoms
  • May result in ‘locked-in syndrome’, where patients are awake but unable to verbally communicate or move
  • Diagnosis is confirmed with MRI

Question 282

What is the prognosis for SIADH

Answer 282

If the underlying cause is found and treated successfully, SIADH typically resolves. If the underlying condition persists, SIADH is difficult to manage, secondary to difficulty complying with necessary fluid restriction or medicines.

Question 283

What is potassium homeostasis dependent upon

Answer 283

Potassium homeostasis is multifactorial and depends on intake, absorption, distribution, and excretion. Important hormonal factors that reduce serum potassium include insulin (causes an intracellular shift of potassium), adrenaline (beta-receptor stimulation causes intracellular shift), and aldosterone (promotes potassium excretion).

Question 284

Define hyperkalaemia

Answer 284

A serum level >5.5 mmol/L is considered to be hyperkalaemia

A serum level > 6.5mmol/L = MEDICAL EMERGENCY!

Question 285

Describe the aetiology of hyperkalaemia

Answer 285

• Decreased excretion:
  
  • Acute kidney injury (AKI) or oliguric renal failure (where there is very small amount of urine produced) - COMMON
• Drugs:
  
  • Potassium-sparing diuretics e.g. spironolactone - COMMON
  • ACE inhibitors (interfere with RAAS) e.g. ramipril - COMMON
  • NSAIDs - COMMON
  • Ciclosporin
  • Heparin
  • Beta-antagonists: inhibit cellular entry of potassium
  • Digoxin: inhibitor of Na+/K+ ATPase causing reduced cellular entry of potassium
• Addison’s disease - reduced aldosterone causes reduced potassium excretion
• Redistribution of K+ - intracellular to extracellular:
  
  • Diabetic ketoacidosis - insulin resistance - insulin controls Na+/K+ pump - pumping sodium out of cell in exchange for K+. With insulin resistance, the K+ leaves the cell.
  • Metabolic acidosis - to compensate H+ is pumped into cell from the blood, in exchange of K+
  • Tissue necrosis or lysis
  • Rhabdomyolysis - muscle breakdown releases potassium
• Death of muscle fibres and release of their contents, including K+, into bloodstream caused by a traumatic CRUSH INJURY e.g. from a car accident or building collapse
  
  • Tumour lysis syndrome
  • Severe burns
• Increased load:
  
  • Potassium chloride
  • Transfusion of stored blood

Question 286

Describe the pathophysiology of hyperkalaemia

Answer 286

Increased blood potassium leads to disruption in the transmembrane potential difference. Hyperkalaemia depolarises the cells however persistent depolarisation will deactivate the sodium channels and sodium will not enter the cells, causing them to become refractory to stimulation. Cells will not respond to electrical signals and remain depolarised. This can cause fatal cardiac arrhythmias by: prolonging membrane depolarisation, slower myocardial conduction and shortening of the repolarisation time.

Question 287

Describe the clinical manifestations of hyperkalaemia

Answer 287

• Signs
  
  • Tachycardia (arrhythmia)
  • Fast irregular pulse
  • ECG differences - tall tented T waves, small P waves, wide QRS
• Symptoms
  
  • Muscle weakness
  • Lightheadedness
  • Muscle cramps
  • Paresthesia (tingling in skin)
  • Palpitations
  • Chest pain

Question 288

What are the clinical investigations for hyperkalaemia

Answer 288

• 12-lead ECG:hyperkalaemic changes include flat P waves, short QT interval, broad QRS, ST depression, and tented T waves
• U&Es:confirm high serum potassium levels
• Lithium heparin sample:rule out pseudohyperkalaemia. This is where thrombus formation and haemolysis within a normal EDTA tube can cause a falsely elevated potassium concentration; e.g. when the tourniquet is too tight or blood is left sitting too long
• VBG:check for acidosis which may be causing the hyperkalaemia

Question 289

What are the differential diagnosis for hyperkalaemia

Answer 289

• Could be artefactual - repeat tests if pt has no symptoms
  
  • Haemolysis e.g. from vigorous venepuncture or due to K+ release from abnormal RBCs in some blood disorders e.g. leukaemia
  • Contamination with K+ EDTA anticoagulant in FBC bottles
  • Thrombocythaemia (increased platelets) - K+ leaks out of platelets during clotting
• DKA
• Hyperosmolar hyperglycaemic state
• Chronic kidney disease

Question 290

Describe the management for hyperkalaemia

Answer 290

Management Severe/ECG changes: 1st line – IV 10ml 10% calcium gluconate to stabilise myocardium. 2nd – insulin/dextrose to drive K+ intracellularly. Other: nebulised salbutamol
Stable/no ECG changes: 1st line – insulin/dextrose. Other: nebulised salbutamol
Stop exacerbating drugs (e.g., ACE inhibitors), treat underlying cause, lower body potassium (calcium resonium, loop diuretics)

Question 291

What are complications of hyperkalaemia

Answer 291

Cardiac arrhythmias and arrest: severe hyperkalaemia is associated with broadening of the QRS complex and can cause potentially life-threatening ventricular tachycardia or ventricular fibrillation, and subsequent cardiac arrest

Question 292

What is the prognosis for hyperkalaemia

Answer 292

The prognosis of patients with hyperkalaemia ultimately depends on the underlying cause. Untreated moderate and severe hyperkalaemia is associated with the development of potentially life-threatening arrhythmias so must be treated expediently.

Question 293

Define hypokalaemia

Answer 293

Potassium is an essential body cation, which has a normal plasma concentration of 3.5-5.5 mmol/L. Hypokalaemia is defined as a plasma potassium concentration < 3.5 mmol/L.

Hypokalaemia can be further divided as follows:

• Mild:3.0-3.4 mmol/L
• Moderate:2.5-2.9 mmol/L
• Severe:< 2.5 mmol/L or symptomatic

Question 294

Describe the epidemiology of hypokalaemia

Answer 294

• Hypokalaemia is a common electrolyte abnormality in secondary care affecting up to 20% of inpatients.
• Potassium concentration is highly variable depending on age, sex, ethnicity and socioeconomic status.

Question 295

What is the range for normal plasma potassium levels

Answer 295

3.6-5.2 mmol/L

Question 296

Describe the aetiology of hypokalaemia

Answer 296

• Inadequate intake
  
  • Eating disorders: bulimia, anorexia nervosa, alcoholism
  • Poor diet
  • Systemic illness and dental problems
  • Inadequate potassium in feed or fluid replacement (IVF, NG feed, TPN)
• Increased excretion
  
  • Renal tubular failure
  • Diuretics (thiazide-like & loop)
  • Mineralocorticoid excess e.g.
    
    • Cushing’s syndrome
    • Conn’s syndrome
    • Nephrotic syndrome - leaky kidneys resulting in increased aldosterone secretion and thus K+ loss
    • Steroid use causing mineralocorticoid excess
  • Genetic causes include:
    
    • Bartter’s syndrome:Refers to a group of autosomal recessive conditionscharacterised by hypokalaemia, alkalosis, and hypotension or normotension, related to genetic variants in genes encoding proteins in the loop of Henle.
    • Gitelman’ssyndrome:Is an autosomal recessive condition characterised by hypokalaemia, hypomagnesaemia, alkalosis, and hypotension or normotension, related to a genetic variant in a gene encoding the thiazide-sensitive sodium chloride transporter.
    • Liddle’ssyndrome:Is an autosomal recessive condition characterised by hypokalaemia and hypertension, related to genetic variants in genes encoding the subunits of the epithelial sodium channel.
  • Gastrointestinal: diarrhoea, vomiting, pyloric stenosis, villous adenoma, laxative abuse
  • Skin: burns, erythroderma, hyperhidrosis
• Shift from extracellular to intracellular K+
  
  • Alkalosis - H+ moves out of cell and is swapped for K+ as a compensatory mechanism
  • Insulin excess - Na+/K+ pump, more K+ moves into cell
  • Activation of beta-adrenergic receptors (e.g. salbutamol) enhance movement of K+ intracellularly.

Question 297

Describe the pathophysiology of hypokalaemia

Answer 297

K+ key for maintaining resting cell membrane potential

Low levels of K+ can affect smooth, skeletal and cardiac muscles due to diminished contraction

• Cardiac - arrhythmias and cardiac arrest
• Smooth muscle - constipation
• Skeletal muscle - weakness, cramps and flaccid paralysis
• Respiratory muscles - respiratory depression

Question 298

Describe the clinical manifestations of hypokalaemia

Answer 298

• Signs
  
  • Arrhythmias
  • Muscle paralysis and rhabdomyolysis (severe)
  • Hypotonia - decreased muscle tone
  • Hypoflexia - muscles less responsive to stimuli
• Symptoms
  
  • Fatigue
  • Generalised weakness
  • Light headedness
  • Muscle cramps and pain
  • Tetany
  • Palpitations
  • Constipation

Question 299

What is the 1st line investigations for hypokalaemia

Answer 299

The diagnosis of hypokalaemia is based on a laboratory sample of plasma potassium:

• Mild:3.0-3.4 mmol/L
• Moderate:2.5-2.9 mmol/L
• Severe:< 2.5 mmol/L or symptomatic

Question 300

What are other investigations for hypokalaemia

Answer 300

• ECG - Prolonged PR, ST segment depression, flattening of T wave, U wave present
• Urine osmolality
• Urinary electrolytes (sodium & potassium)
• Full blood count
• U&Es, bone profile, magnesium
• VBG/ABG (can assess acid/base, bicarbonate & chloride)
• CK (creatinine kinase) - sign of muscle damage

Question 301

What is the management for mild to moderate hypokalaemia

Answer 301

• Treat underlying cause
• Review medication
  
  • If taking a diuretic, replace with a potassium sparing diuretic
• Other electrolyte abnormalities, magnesium in particular, should be identified and replaced. Hypokalaemia difficult to treat until Mg2+ levels have been normalised.
• Potassium replacement -
  
  • Oral route preferred
  • e.g. SANDO-K (potassium chloride with potassium bicarbonate), two tablets, three times a day for mild hypokalaemia and two tablets, four times a day for moderate hypokalaemia.

Question 302

What is the management for severe hypokalaemia

Answer 302

• IV replacement with 40 mmol of KCL in 1 litre of normal saline. The maximal rate on a normal ward is 10 mmol of potassium an hour. A repeat blood test should be sent after each bag of replacement.
• In rare cases it may be necessary to give more concentrated replacement (e.g. 40 mmol KCL in 500ml of normal saline or 10 mmol KCL in 100 mls of normal saline) or more rapid replacement. This should only be done under the guidance of a senior physician in compliance with local guidelines, normally in an HDU/ITU setting.
• Do not give K+ if oliguric
• Never give K+ as a fast stat bolus dose

Question 303

What are complications with hypokalaemia

Answer 303

Cardiac - arrhythmias and cardiac arrest

Question 304

Define diabetes insipidus

Answer 304

Diabetes insipidus (DI) is a metabolic disorder characterised by an absolute or relative inability to concentrate urine, resulting in the production of large quantities of dilute urine.

It is due to the patient’s inability to make ADH or respond to ADH. This leads to polydipsia, polyuria, and hypotonic urine.

Question 305

Describe the epidemiology of diabetes insipidus

Answer 305

• DI is uncommon, although the exact prevalence is difficult to estimate.
• There are no differences in prevalence between sexes or among ethnic groups.
• Inherited causes for both central and nephrogenic DI account for less than 10% of all cases.

Question 306

Describe the aetiology of diabetes insipidus

Answer 306

• Nephrogenic - pathology affecting the kidney
  
  • Drugs e.g. Lithium, Demeclocycline
  • Genetic - AVR2 gene X chromosome
  • Intrinsic kidney disease
  • Post-obstructive uropathy - urine can’t flow due to obstruction and so refluxes back into kidney
  • Electrolyte imbalances - mainly hypokalaemia and hypercalcaemia
• Cranial - ADH not produced or secreted
  
  • Idiopathic
  • Congenital defects in ADH gene
  • Brain tumours
  • Head injuries
  • Brain malformations
  • Hypophysitis
  • Hypophysectomy
  • Infections e.g. meningitis, encephalitis, TB
  • Infiltration e.g. sarcoidosis
  • Brain surgery
  • Radiotherapy

Question 307

What are risk factors for diabetes insipidus

Answer 307

• Pituitary surgery
• Craniopharyngioma
• Brain injury
• Congenital pituitary abnormalities
• Medication e.g. lithium
• Autoimmune disease - some cases linked to antibodies against ADH secreting cells
• Family history
• CNS infections
• Pregnancy - associated with a number of changes in salt and water regulation. A transient central DI may develop as a consequence of a decreased osmotic threshold for thirst and ADH release, and a decrease in plasma osmolality. Also associated with increase in metabolic clearance of ADH.

Question 308

Describe the pathophysiology of diabetes insipidus

Answer 308

• Central DI results from any condition that impairs the production, transportation, or release of ADH.
• Nephrogenic DI results from conditions that impair the renal collecting ducts’ ability to respond to ADH.

Both central and nephrogenic DI are characterised by impaired renal water re-absorption, resulting in the production of excessive, hypotonic (dilute) urine (polyuria). This is accompanied by significant thirst and increased drinking (polydipsia), as central osmo-sensing and peripheral baro-sensing drive central thirst and thirst-dependent behaviours to maintain circulating volume and osmolar status.

Question 309

Describe the clinical manifestations of diabetes insipidus

Answer 309

• Signs
  
  • Postural hypotension
  • Hypernatraemia
• Symptoms
  
  • Polyuria
  • Polydipsia
  • Dehydration

Question 310

What are the 1st line investigations for diabetes insipidus and the gold standard investigations

Answer 310

• 1st line
  
  • U&E - hypernatraemia found
  • Serum glucose - exclude DM
  • Urine osmolality - low urine osmolality found
  • Serum osmolality - high serum osmolality found
  • Water deprivation test (desmopressin suppression test) - avoid taking fluid or foods 8 hrs before test. Then urine osmolality is measured followed by giving desmopressin. 8 hrs later urine osmolality is measured again. Allows us to differentiate between cranial and nephrogenic diabetes insipidus
    
    • Cranial - ADH not being made but kidney’s still able to respond. So when desmopressin is given, urine osmolality should increase. In nephrogenic causes, desmopressin will not have an effect on urine osmolality after synthetic desmopressin administration.
• Gold standard
  Water deprivation test (desmopressin suppression test)

Question 311

What are other investigations for diabetes insipidus

Answer 311

MRI - for cranial DI. Test anterior pituitary function.

Question 312

What are the differential diagnosis for diabetes insipidus

Answer 312

• Primary polydipsia - normal ADH, but excessive thirst and excessive urine production. In the water deprivation test, patient’s with primary polydipsia will already have high urine osmolality prior to desmopressin administration.
• Diabetes mellitus - due to polyuria and polydipsia
• Hypercalcaemia

Question 313

What is the 1st line management for diabetes insipidus

Answer 313

Cranial DI: desmopressin
Nephrogenic: maintenance of adequate fluid intake. Treat underlying cause. Thiazide diuretics (Bendroflumethiazide). Thiazides reduce the rate that kidneys filter blood which reduces amount of urine passed over time.

Question 314

What other management may be used for diabetes insipidus

Answer 314

NSAIDs - can be used in nephrogenic DI. Prostaglandins locally inhibit ADH action. NSAID’s lower urine volume and plasma Na+ by inhibiting prostaglandin synthase.

Question 315

What is the emergency management for diabetes insipidus

Answer 315

• Urgent plasma U&E, serum and urine osmolality
• IV fluid to keep up with urine output. If severe hypernatraemia, do not lower Na+ rapidly. Risk of cerebral oedema with rapid correction!
• IM desmopressin

Question 316

What monitoring is required for diabetes insipidus

Answer 316

Patients require regular follow-up with monitoring of serum electrolytes to assess sodium status.

For patients with central DI, follow-up imaging is recommended if initial scans were unable to detect pathology, as pituitary, para-pituitary, or stalk lesions may not manifest on initial scanning.

In patients with nephrogenic DI for whom polyuria is significant, bladder dysfunction may develop. If unrecognised, this may lead to renal impairment. These patients need periodic renal and bladder ultrasonography and regular assessment of serum creatinine.

Question 317

What is the prognosis for diabetes insipidus

Answer 317

Outcome and outlook depend on the underlying aetiology, type of DI, and associated comorbidities.

• While DI is often a lifelong condition, central DI following pituitary surgery or traumatic brain injury may be transient.
• Nephrogenic DI secondary to hypercalcaemia or hypokalaemia commonly resolves following treatment of the underlying electrolyte disorder. While nephrogenic DI secondary to medication may resolve following agent discontinuation, this is often not the case in those with nephrogenic DI secondary to lithium.
• DI developing in pregnancy typically resolves following delivery.

Question 318

Define hypercalcaemia

Answer 318

Hypercalcemia refers to a higher than normal calcium levels in the blood, generally over 10.5 mg/dL.

Question 319

Describe the aetiology of hypercalcaemia

Answer 319

• Acidosis: promotes less binding between albumin and calcium. This causes less bound calcium and more free ionised calcium
• Osteoclastic bone resorption due to:
  
  • Hyperparathyroidism
  • Malignant tumours: secrete parathyroid hormone-related protein or PTHrP, a hormone that mimics the effect of parathyroid hormone which stimulates the osteoclasts and cause osteoblasts to die
• Excess vitamin D: increased calcium absorption from GI tract
• Sarcoidosis: due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages
• Thyrotoxicosis: thyroid hormones known to cause bone resorption
• Milk-alkali syndrome: ingestion of large amounts of calcium and absorbable alkali, with resulting hypercalcemia.
• Medications
  
  • Thiazide diuretics increases calcium reabsorption in the distal tubule of the kidney
  • Lithium
• Familial benign hypocalciuric hypercalcaemia: defect in calcium sensing receptor

Question 320

Describe the pathophysiology of hypercalcaemia

Answer 320

High levels of ionised calcium affect a variety of cellular processes, in particular, electrically active neurons.

With high levels of extracellular calcium, voltage-gated sodium channels are less likely to open up, which makes it harder to reach depolarisation, and makes the neuron less excitable.

• This causes slower or absent reflexes
• The sluggish firing of neurons also leads to slower muscle contraction, which causes constipation and generalised muscle weakness.
• In the central nervous system, hypercalcaemia causes confusion, hallucinations, and stupor.

Too much calcium in the blood causes hypercalciuria. This leads to a loss of excess fluid in the kidneys causing an individual to get dehydrated.

Question 321

What are the clinical manifestations of hypercalcaemia

Answer 321

• Abdominal pain
• Vomiting
• Constipation
• Dehydration
• Polydipsia
• Polyuria
• Absent reflexes
• Muscle weakness
• Weight loss
• Depression
• Confusion
• Hallucinations
• Stupor
• Hypertension
• Pyrexia

Question 322

Describe the investigations for hypercalcaemia

Answer 322

• Bloods: high calcium. Also check parathyroid hormone, vitamin D, albumin, phosphorus, and magnesium levels.
  
  • In malignancy, there is low albumin, low chloride, alkalosis, low potassium, high phosphate, high ALP
  • Hyperparathyroidism: high PTH
• 24 hr urinary Ca2+ excretion: raised
• Electocardiogram: tachycardia, AV block, shortening of the QT interval, and sometimes in the precordial leads the appearance of an J wave
• Imaging
  
  • Chest X-ray
  • Isotope bone scan

Question 323

What are the differential diagnosis for hypercalcaemia

Answer 323

Hyperalbuminaemia (pseudohypocalcaemia): causes there to be a higher concentration of protein-bound calcium, while free ionised calcium concentrations stay the same. This can occur when individuals are dehydrated, concentrating albumin.

Question 324

What is the management for hypercalcaemia

Answer 324

• Increase urinary calcium excretion
  
  • Rehydration: increases filtering of Ca2+
  • Loop diuretics: inhibit calcium reabsorption in the loop of Henle
• Decrease calcium absorption from GI tract
  
  • Glucocorticoids
• Prevention of bone resorption
  
  • Biphosphonates
  • Calcitonin
• Chemotherapy may help in malignancy

Question 325

What are the complications of hypercalcaemia

Answer 325

• Kidney stones: due to dehydration combined with hypercalciuria
• Renal failure
• Ectopic calcification e.g. cornea
• Cardiac arrest

Question 326

Describe the storage and types of calcium that exist in the body

Answer 326

• Most of the calcium exists in bones, in the form of hydroxyapatite (99%)
• The remaining calcium is either intracellular (0.01%) or extracellular (0.99%)
  • Intracellular calcium levels remain low as high levels cause the cell to undergo apoptosis
  • Extracellular calcium can be diffusible or not diffusible.
    • Diffusable:
      
      • Free-ionised calcium: involved in cellular processes e.g. neuronal action potentials, contraction of skeletal, smooth, and cardiac muscle, hormone secretion, and blood coagulation.
      • Complexed calcium: positively charged calcium is ionically linked to negatively charged molecules e.g. oxalate. Not involved in cellular processes.
    • Non-diffusable: calcium is bound to negatively charged proteins e.g. albumin. Also uninvolved in cellular processes.

Question 327

Describe the production and role of parathyroid hormone

Answer 327

Changes in the body’s levels of extracellular calcium are detected by the calcium-sensing receptor in parathyroid cells. There are four parathyroid glands situated in four corners of the thyroid gland. The parathyroid glands, specifically the chief cells in the glands, produce parathyroid hormone in response to hypocalcaemia (low blood calcium).

The parathyroid hormone causes:

• The bones to release calcium
• The kidneys to reabsorb more calcium so it’s not lost in the urine (as well as excrete more phosphate)
• The kidneys to synthesise calcitriol/ active Vitamin D. Active Vitamin D then goes on to cause the gastrointestinal tract to increase calcium absorption.

Question 328

Define hypocalcaemia

Answer 328

Hypocalcemia refers to lower than normal calcium levels in the blood, generally less than 8.5 mg/dL.

Question 329

Describe the aetiology of hypocalcaemia

Answer 329

With increased phosphate:

• Chronic kidney disease: lack of reabsorption of Ca2+, lack of active vitamin D
• Hypoparathyroidism: e.g. due to removal of or autoimmune destruction PT glands, DiGeorge syndrome
• Pseudohypoparathyroidism
• Acute rhabdomyolysis: large numbers of cells die and release phosphate. The phosphate binds to the ionised calcium and forms calcium phosphate, making it insoluble and effectively decreasing the total amount in blood.
• Hypomagnesaemia: magnesium is needed for PTH secretion

With normal or low phosphate:

• Vitamin D deficiency: leads to less Ca2+ absorption from GI tract
• Osteomalacia
• Acute pancreatitis: free fatty acids end up binding to ionised calcium, which is insoluble and precipitates.
• Over-hydration
• Respiratory alkalosis: high pH (alkalosis) causes more binding between albumin and calcium, which results in less free ionised calcium

Question 330

Describe the pathophysiology of hypocalcaemia

Answer 330

Low levels of ionised calcium affect a variety of cellular processes e.g.

• With low levels of extracellular calcium, voltage-gated sodium channels are less stable and more likely to open up, which allows the cell to depolarise more easily, and makes the neurone more excitable. This can trigger tetany.

Question 331

What are the clinical manifestations of hypocalcaemia

Answer 331

SPASMODIC:

• Spasms (Trousseau’s sign): blood pressure cuff occludes the brachial artery, and that pressure on the nerve is enough to make it fire, which results in a muscle spasm that makes the wrist and metacarpophalangeal joints flex.
• Perioral numbness/ paraesthesiae
• Anxious, irritable, irrational
• Seizures
• Muscle tone increases: colic, wheeze and dysphagia
• Orientation impaired and confusion
• Dermatitis
• Impetigo herpetiformis (severe pustular psoriasis occurring in pregnancy)
• Chvosteks sign (facial muscles twitch after the facial nerve is lightly finger tapped); choreoathetosis, cataract (if chronic hypocalcaemia), cardiomyopathy

Question 332

What investigations are done for hypocalcaemia

Answer 332

• Bloods: low calcium. Also check for parathyroid hormone, vitamin D, albumin, phosphorus, and magnesium levels.
• Electrocardiogram: may show prolonged QT, prolonged ST segment, and arrhythmias e.g. torsade de pointes and atrial fibrillation.

Question 333

What are the differential diagnosis for hypocalcaemia

Answer 333

Hypoalbuminaemia (pseudohypocalcaemia): there is a loss of bound calcium but free ionised levels remain the same

Question 334

What is the management for hypocalcaemia

Answer 334

• Calcium supplements e.g. calcium gluconate
• Vitamin D supplementation e.g. alfacalcidol, if appropriate
• If alkalosis, correct alkalosis

Question 335

Define hyperparathyroidism

Answer 335

Hyperparathyroidism refers to a condition where there is an overproduction of parathyroid hormone.

Question 336

Describe the pathophysiology of primary hyperparathyroidism

Answer 336

Caused by uncontrolled parathyroid hormone produced directly by a tumour of the parathyroid glands (independent of calcium levels). This leads to hypercalcaemia.

Most often, primary hyperparathyroidism is caused by a single parathyroid adenoma which happens either because of a genetic mutation in a single cell or because of an inherited disorder e.g. multiple endocrine neoplasia.

Rarely, primary hyperparathyroidism is caused by hyperplasia or by a parathyroid carcinoma.

Question 337

Describe the pathophysiology of secondary hyperparathyroidism

Answer 337

Insufficient vitamin D or chronic renal failure leads to low absorption of calcium from the intestines, kidneys and bones. This causes hypocalcaemia. This is usually due to kidney issues as the kidney can’t filter out the phosphate or make active vitamin D.

The parathyroid glands reacts to the low serum calcium by excreting more parathyroid hormone. Over time the total number of cells in the parathyroid glands increase as they respond to the increased need to produce parathyroid hormone. The glands become more bulky.

The serum calcium level will be low or normal but the parathyroid hormone will be high.

Question 338

Describe the pathophysiology of tertiary hyperparathyroidism

Answer 338

This happen when secondary hyperparathyroidism continues for a long period of time. It leads to hyperplasia of the glands. The baseline level of parathyroid hormone increases dramatically.

Then when the cause of the secondary hyperparathyroidism is treated the parathyroid hormone level remains inappropriately high. This high level of parathyroid hormone in the absence of the previous pathology leads to high absorption of calcium in the intestines, kidneys and bones and causes hypercalcaemia.

Question 339

Describe the impact of hypercalciuria

Answer 339

This is because there is just too much calcium to be reabsorbed by the kidneys. Excess loss of calcium in urine can lead to dehydration.

Question 340

What are the clinical manifestations of hyperparathyroidism

Answer 340

‘Stones, thrones, bones, groans, and psychiatric overtones’

• Stones: kidney stones or gallstones
• Thrones: refers to the toilet, polyuria that results from impaired sodium and water reabsorption.
• Bones: bone pain
• Groans: refers to symptoms of constipation, nausea and vomiting
• Psychiatric overtones: depressed mood, fatigue, psychosis and confusion

Question 341

Describe the investigations for hyperparathyroidism

Answer 341

• Bloods: high levels of parathyroid hormone; testing for blood levels of calcium, phosphate, and vitamin D to confirm the type of hyperparathyroidism.
• 24 hr urinary calcium: raised
• ALP: raised from bone activity
• OtherImaging e.g.
  - DEXA scan for osteoporosis
  - Can show osteitis fibrosa cystica

Question 342

What are the differential diagnosis for hyperparathryoidism

Answer 342

Malignant hyperparathyroidism: parathyroid related protein produced by some squamous cell lung cancers, breast and renal cell carcinomas. This can mimic PTH and lead to hypercalcaemia.

Question 343

What is secondary management for hyperparathyroidism

Answer 343

• Correcting the vitamin D deficiency
• Phosphate binders
• Renal transplant to treat renal failure
• Sometimes parathyroidectomy

Question 344

What is tertiary management for hyperparathyroidism

Answer 344

• Surgical removal of parathyroid tissue

Question 345

What are complications with hyperparathyroidism

Answer 345

• Secondary hyperparathyroidism can cause:
  
  • Renal osteodystrophy: bone resorption
• Secondary and tertiary hyperparathyroidism can cause:
  
  • Calcification in blood vessels and soft tissues: the high levels of phosphate cause it to stick to any available calcium, forming bone-like crystals.
• Bone resorption:
  
  • Bone fractures
  • Osteoporosis
  • Osteopenia
• Nephrolithiasis
• Iatrogenic
  
  • Hypoparathyroidism
  • Recurrent laryngeal nerve damage

Question 346

What detects changes in the body’s level of extracellular calcium

Answer 346

Calcium-sensing receptor in parathyroid cells. There are 4 parathyroid glands situated in 4 corners of the thyroid gland. The parathyroid glands, specifically the chief cells in the glands, produce parathyroid hormone in response to hypocalcaemia.

Question 347

Role of parathyroid hormone

Answer 347

• The bones to release calcium
• The kidneys to reabsorb more calcium so it’s not lost in the urine (as well as excrete more phosphate)
• The kidneys to synthesise calcitriol/ active Vitamin D. Active Vitamin D then goes on to cause the gastrointestinal tract to increase calcium absorption.

Question 348

Where are neuroendocrine cells found

Answer 348

Neuroendocrine cells are found in tissues throughout the body, particularly in the epithelial layer of gastrointestinal organs and the lungs.

Question 349

What are the roles of neuroendocrine cells

Answer 349

• They receive signals from nerve cells and, in response, they release hormones into the blood.
• Neuroendocrine cells release a variety of hormones including amines, like serotonin and histamine; polypeptides, like bradykinin, a vasodilator; and prostaglandins which are also powerful vasodilators.
• The production of these hormones can also be regulated by other hormones e.g. somatostatininhibits the release of a number of hormones from neuroendocrine cells
• When serotonin does get released from neuroendocrine cells, it enters the liver through the portal vein. In the liver, some of the serotonin is metabolised to 5-hydroxyindoleacetic acid which is eliminated from the body through the urine. The remaining serotonin is not metabolised, and this remains in the systemic circulation where it has various effects.

Question 350

What are the roles of serotonin

Answer 350

• In the gastrointestinal tract, serotonin increases motility and peristalsis
• In the vasculature, platelets take up the serotonin and later use it to constrict blood vessels, particularly after injury
• In the connective tissue of the heart, it stimulates fibroblasts which make lots of collagen.

Question 351

Define a carcinoid tumour

Answer 351

Carcinoid tumour refers to a tumour of the neuroendocrine cells, resulting in excessive release of certain hormones.

Question 352

Describe the pathophysiology of a carcinoid tumour

Answer 352

Neuroendocrine cells mutate and divide uncontrollably, leading to a carcinoid tumour. Most of the time this occurs in the gastrointestinal tract.

The cancerous neuroendocrine cells produce and secreting large amounts of hormones. Tumours can secrete:

Bradykinin, tachykinin, serotonin, substance P, VIP, gastrin, insulin, glucagon, ACTH, parathyroid and thyroid hormones.

Counterintuitively, they also express more somatostatin receptors on their surface.

Carcinoid tumours tend to be slow growing. Common primary sites include:

Appendix, small or large intestines, rectum, stomach, pancreas, liver, lungs, ovaries, testis, and the thymus.

Sometimes tumours can metastasise. A common site for this is the liver.

Question 353

What are common primary sites for a carcinoid tumour

Answer 353

Appendix, small or large intestines, rectum, stomach, pancreas, liver, lungs, ovaries, testis, and the thymus.

Question 354

Describe the pathophysiology of carcinoid syndrome

Answer 354

Associated with hepatic involvement.

Carcinoid syndrome occurs when there is a buildup of hormones produced by the neuroendocrine cells as the liver is no longer able to metabolise them.

• Increased histamine and bradykinin: can cause vasodilation leading to flushing
• Increased histamine: can cause itching
• Increased serotonin: can cause thickening of fibrosis, particularly in the heart valves leading to heart dysfunction, like tricuspid regurgitation and pulmonary stenosis; and bronchoconstriction leading to asthma, shortness of breath, and wheezing.Also reduces the amount of tryptophan available to the body to make niacin, vitamin B3. Reduced levels of niacin can cause pellagra, a disease which causes symptoms like inflamed skin and mental confusion.

Question 355

Describe the clinical manifestations of carcinoid tumour and carcinoid syndrome

Answer 355

• Diarrhoea
• Shortness of breath
• Flushing
• Itching
• Hepatic metastases: may cause RUQ pain

Symptoms are worsened by alcohol and stress: stimulate the neuroendocrine cells.

Question 356

What are the investigations for carcinoid tumour and carcinoid syndrome

Answer 356

• 24 hr urine 5-hydroxyindoleacetic acid: show increased levels
• Chest X-ray/ chest or pelvis MRI/ CT: to identify location
• Plasma chromogranin A: reflects tumour mass
• Ostreoscan: injected radiolabelled somatostatin analogue, octreotide, to bind to the increased number of somatostatin receptors on tumour cells.
• Other
  
  • Echocardiogram and brain natriuretic peptide: to look for carcinoid heart disease

Question 357

What is the management for carcinoid tumour and carcinoid syndrome

Answer 357

• Decreasing emotional stress and alcohol consumption
• Somatostatin analogues: e.g. octreotide, inhibit hormone release
• Surgical resection
• Debulking embolisation or radiofrequency ablation of hepatic metastases: can help with symptoms

Question 358

What are complications with carcinoid tumours and carcinoid syndrome

Answer 358

• GI tumours can cause: appendicitis, intussusception, or obstruction
• Carcinoid crisis: tumour outgrow blood supply or is handled too much during surgery. This causes mediators to flood out causing life-threatening vasodilation, hypotension, tachycardia, bronchoconstriction and hyperglycaemia. Treated with high dose octreotide, supportive measurements and management of fluid balance.

Question 359

What is the prognosis for carcinoid tumours and carcinoid syndrome

Answer 359

5-8 years survival. 3 years if metastases present

80% of tumours metastasise!

Question 360

Define phaeochromocytoma

Answer 360

Phaeochromocytoma is a rare tumour (usually benign) arising from chromaffin cells in the adrenal medulla resulting in the overproduction of catecholamines.

Rule of 10s:

• 10% extra-adrenal (paraganglioma): the most common extra-adrenal site is the organ of Zuckerkandl located at the bifurcation of the aorta.
• 10% bilateral
• 10% malignant
• 10% familial

Question 361

Describe the epidemiology of phaeochromocytoma

Answer 361

• The typical presentation is between 30-50 years of age
• Phaeochromocytomas are rare and account for only 0.05% of hypertensive individuals

Question 362

Describe the risk factors of phaeochromocytoma

Answer 362

• MEN 2A:phaeochromocytoma, medullary thyroid cancer, primary hyperparathyroidism
• MEN 2B:phaeochromocytoma, medullary thyroid cancer, marfanoid habitus, mucosal neuromas
• Von-Hippel-Lindau syndrome:phaeochromocytoma, renal cell carcinoma, cerebellar hemangioblastoma
• Neurofibromatosis 1:phaeochromocytoma and skin changes, e.g. café-au lait spots and neurofibromas

Triggers include:

• Stress
• Physical exertion
• Certain foods that contain tyramine

Question 363

Describe the pathophysiology of phaeochromocytoma

Answer 363

• Adrenaline is produced by the “chromaffin cells” in the adrenal medulla of the adrenal glands. A phaeochromocytoma is a tumour of the chromaffin cells that secretes unregulated and excessive amounts of catecholamines.
• Adrenaline is a “catecholamine” hormone and neurotransmitter that stimulates the sympathetic nervous system and is responsible for the “fight or flight” response. In patients with a phaeochromocytoma the adrenaline tends to be secreted in bursts giving periods of worse symptoms followed by more settled periods.
• Phaeochromocytoma’s typically form in one of the adrenal glands, but rarely can be in both and sometimes can even develop in other parts of the body where chromaffin cells are found like the carotid arteries in the neck, the bladder, and the abdominal aorta. If they arise from an extra-adrenal source, they are referred to as a paraganglioma.
• In approximately 10% of cases, phaeochromocytoma is associated with familial conditions such as:
  • MEN 2: caused by a mutation in the RET gene, a protooncogene
  • Neurofibromatosis 1: caused by a mutation in the gene NF1 that encodes for a tumour suppressor protein called neurofibromin
  • Von-Hippel-Lindau disease: a mutation in the VHL gene which codes for the von Hippel-Lindau tumour suppressor protein.

Question 364

Describe the clinical manifestations of phaeochromocytoma

Answer 364

• Signs
  
  • Hypertension: present in 90% of cases and usually refractory to treatment
  • Tachycardia
  • Paroxysmal atrial fibrillation
  • Hypertensive retinopathy
• Symptoms
  
  • Episodic headaches
  • Palpitations
  • Anxiety
  • Sweating

Question 365

What are the primary investigations in phaeochromocytoma

Answer 365

• 24 hr urinary metanephrine collection: metanephrine is a breakdown product of catecholamines, urinary and serum metanephrines are the first-line investigation; will both beelevated (97% sensitivity)
• Plasma-free metanephrines
• CT abdomen and pelvis:if there is biochemical evidence of a phaeochromocytoma, then CT imaging can be performed to look at the adrenals

Question 366

What other investigations would be done for phaeochromocytoma

Answer 366

• PET scan:used if metastatic disease is suspected and is generally preferred over scintigraphy
• I-123 MIBG scintigraphy:radionucleotide incorporates itself into the phaeochromocytoma so helps localise metastatic tissue if suspected
• Chromogranin A: may be used in combination with 24 hr urinary metanephrine collection for follow-up

Question 367

What are the first line management steps for phaeochromocytoma

Answer 367

• Peri-operative:initial alpha blockade (e.g. phenoxybenzamine)followed bybeta-blockade (e.g. propranolol)
  
  • Alpha-blockademust be offered for at least 7-14 days pre-operatively to allow for blood pressure and heart rate normalisation
  • Beta-blockadeis usually required for additional blood pressure control and management of tachyarrhythmias
  • Commencing a beta-blockerbeforean alpha-blocker can lead to unopposed alpha stimulation, subsequent vasoconstriction and a hypertensive crisis
• Surgical:definitive management with laparoscopic adrenalectomy

Question 368

What is the second line management for phaeochromocytoma

Answer 368

Medical: patients not suitable for surgery should be treated with long term anti-hypertensive agents

Question 369

What are the complications for phaeochromocytoma

Answer 369

• Hypertensive crisis: patients can present with severe hypertension and evidence of end-organ damage e.g. cerebral haemorrhage, encephalopathy, arrhythmias, myocardial infarction, and renal failure. Requires IV anti-hypertensive therapy e.g. labetalol
• Metastatic spread: commonly to lymph nodes, liver, bones, and lungs.

Question 370

What is the prognosis for phaeochromocytoma

Answer 370

Generally associated with an excellent prognosis.

Localised phaeochromocytomas have a 95% 5-year survival rate