Endocrine

Question 1

What is the aetiology and pathogenesis of DM type 1 and DM type 2?

Answer 1

1. DM is a spectrum of metabolic disorders characterised by chronic hyperglycaemia due to insulin deficiency, insulin resistance, or a combination of both.
2. DM1 results from the autoimmune destruction of pancreatic β-cells, occurring in genetically susceptible individuals, and probably triggered by environmental antigens.
   
   • There is association with other organ specific immune diseases e.g. autoimmune, thyroid, Addison’s, pernicious anaemia.
3. DM2 is a polygenic disorder triggered by environmental factors, notably central obesity, in genetically susceptible individuals. The hyperglycaemia is characterised by a combination of reduced insulin (relative to glucose levels) and insulin resistance. The β-cell mass is reduced about 50% at normal time of diagnosis.

Question 2

Compare and contrast T1 and T2 DM.

Answer 2

A C-peptide test is often used to help tell the difference between type 1 and type 2 diabetes. With type 1 diabetes, your pancreas makes little to no insulin, and little or no C-peptide. With type 2 diabetes, the body makes insulin, but doesn’t use it well. This can cause C-peptide levels to be higher than normal

Question 3

How does diabetes present?

Answer 3

Acute presentation:

• Polyuria; due to osmotic diuresis - glucose exceeds renal reabsorptive capacity [the transporters are full so glucose is excreted; water follows the glucose passively]
• Thirst (polysipsia) due to fluid and electrolyte loss.
• Weight loss due to fluid depletion and breakdown of fat and muscle secondary toinsulin deficiency.
• Ketoacidosis follows if left untreated. [body breaks down fat as fuel as insulin amount is insufficient]

Subacute presentation

may have all of the above symptoms but also:

• Lack of energy.
• Visual problems.
• Candida infection of glans or vulva

Question 4

How is diabetes diagnosed?

Answer 4

One of 4 tests can be used to establish a firm diagnosis of diabetes:

• Fasting plasma glucose (FPG)
  
  • >6.9 mmol/L (>125 mg/dL)
• Random plasma glucose
  
  • ≥11.1 mmol/L (≥200 mg/dL) with diabetes symptoms such as polyuria, polydipsia, fatigue, or weight loss
• 2-hour post-load glucose
  
  • ≥11.1 mmol/L (≥200 mg/dL) on a 75 g oral glucose tolerance test
• HbA1c
  
  • ≥48 mmol/mol (≥6.5%).

+ The diagnosis should be verified by repeat testing, preferably with the same diagnostic test, but diagnostic levels of 2 different criteria are also acceptable (e.g., a combination of an elevated HbA1c and elevated FPG).

Some variability in HbA1c results is possible as a result of such factors as increased red blood cell turnover (e.g., sickle cell anaemia), factors related to ancestry, or laboratory variation.

Question 5

How can you tell the difference between T1 and T2 DM?

Answer 5

• Elevated plasma or urine ketones in the presence of hyperglycaemia
  
  • suggests type 1 diabetes, but is occasionally seen at presentation in a patient with type 2 diabetes.
• The diagnosis of type 1 diabetes is often obvious from the clinical presentation, but can be confirmed through additional testing.
• Low C-peptide levels and presence of one or more autoimmune markers are consistent with a diagnosis of type 1 diabetes.
• Autoimmune markers include autoantibodies to glutamic acid decarboxylase (GAD), insulin, islet cells, islet antigens (IA2 and IA2-beta), and the zinc transporter ZnT8.
• If C-peptide levels are very low or undetectable relative to the plasma glucose and anti-GAD antibodies are positive in such a patient, a diagnosis of type 1 diabetes can be made.
• Type 1 diabetes can occur at any age but usually is diagnosed in younger (age <35 years), thinner patients, and has a more rapid onset and often more severe symptoms.
• Around one third of patients with newly diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA). But, DKA may also occur in type 2 diabetes, particularly if there is an underlying infection. [will need to break down for fat for energy to get rid of infection]
• Urine ketones should be checked if patients are symptomatic of hyperglycaemia (polyuria, polydipsia, weakness) and volume depletion (dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock) at diagnosis or throughout course of disease.
• The best evidenced C-peptide test is the glucagon stimulation test (GST), but non-fasting ‘random’ blood C-peptide has been shown to correlate with fasting C-peptide and post-GST samples in subjects with well-defined type 1 or type 2 diabetes. Development of absolute insulin deficiency is a key feature of type 1 diabetes, which results in low (<0.2 nanomol/L) or undetectable levels of plasma C-peptide. A GST or non-fasting ‘random’ blood C-peptide level >1 nanomol/L suggests type 2 diabetes. C-peptide results must be interpreted in clinical context of disease duration, comorbidities, and family history.

Question 6

What are the secondary causes of hyperglycaemia or diabetes?

Answer 6

Diabetes is usually primary, however it can be secondary to other conditions:

• Pancreatic: total pancreatectomy, chronic pancreatitis and haemochromatosis.
• Endocrine: acromegaly and Cushing’s syndrome.
• Drugs: thiazide diuretics or corticosteroids.

Question 7

What are DDx for polyuria?

Answer 7

Polyuria is defined as urine output >2.5 - 3L in 24hrs:

Polydipsia: increased thirst leading to increased fluid intake (>3L/day).

• Solute diuresis: hyperglycaemia with glycosuria.
  
  • Osmotic diuresis is the increase of urination rate caused by the presence of certain substances in the small tubes of the kidneys.
• Diabetes insipidus.
• CKD.

Question 8

What is the aetiology of diabetic ketoacidosis?

Answer 8

Diabetic ketoacidosis results from untreated insulin deficiency and is seen in: undiagnosed DM1, interruption of insulin therapy, stress of other illness.

Most cases are preventable, and the most common mistake is to reduce insulin if a patient is not eating or vomiting, when they in fact may need more.

Question 9

What is the pathophysiology of DKA?

Answer 9

Ketoacidosis is a state of uncontrolled catabolism due to insulin deficiency:

• Unrestrained increase in hepatic gluconeogenesis.
• High circulating glucose cause osmotic diuresis and subsequent dehydration.
• Peripheral lipolysis raises Free Fatty Acid levels, which are metabolised in the liver to acidic ketones, causing metabolic acidosis.
• These processes are accelerated by release of catecholamines glucagon and cortisol in response to dehydration and stress of illness.

Question 10

What are the signs and symptoms of DKA?

Answer 10

Profound dehydration secondary to water and electrolyte loss from the kidney (osmotic diuresis) and exacerbated by vomiting:

• Eyes sunken.
• Tissue turgor reduced.
• Low BP.
• Kussmaul’s respiration–deep rapid breathing, compensatory mechanism for metabolic acidosis.
• Breath smells of ketones (like pear drops).
• Some disturbance of consciousness is common; 5% are in a coma.
• Occasionally abdominal pain.

Question 11

What are the investigations for DKA?

Answer 11

Diagnosis based on demonstration of hyperglycaemia in combination with acidosis and ketosis:

• Hyperglycaemia: blood glucose >11mmol/L
• Ketonaemia: blood ketones >3mmol/L, best measured using a finger prick and near patient meter which measures β-hydroxybutyrate.
• ABG: Acidosis: blood pH <7.3 and/or bicarbonate <15mmol/L, venous sample will be asimilar to arterial. Acidosis is high anion gap.
• Urine Stix show heavy glycosuria and ketonuria.
• Urea and electrolytes: Urea and creatinine is often raised as a result of dehydration.
• Low total body K+ due to osmotic diuresis, but serum K+ is raised.
• FBC: may show a raised WCC w/o infection.
• Further investigations are aimed a finding a precipitating cause: blood culture, CXR, urine MC+S, ECG and cardiac proteins.

Question 12

What is the emergency management of DKA?

Answer 12

Phase 1:

• Fluid replacement: 0.9% NaCl with 20mmol KCl/L.
• 1L in 30mins, then 1h, 2h, 4h,6hrs.
• Insulin: soluble insulin 6 units/h by IV infusion, OR 20 units IM stat with 6 units IM hourly. Aim for fall in blood glucose approx. 5mmol/h titrate insulin accordingly.
• If: BP <80mmHg, give plasma expander e.g. colloid.
• pH <7.0 give 500mL of NaHCO (sodium bicarbonate)

Phase 2 when blood glucose falls to 10-12mmol/L:

• Change infusion of fluid to 1L 5% dextrose plus 20mmol KCl 6-hourly.
• Continue insulin titrating dose based on blood glucose e.g. IV 3 units/h glucose 15mmol/L => 2units/h when glucose 10mmol/L etc.

Phase 3:

Once stable and able to eat and drink normally transfer to QDS s/c insulin regimen based on blood glucose.

Special measures:

• Broad-spectrum ABX if infection likely.
• Bladder catheter if no urine passed after 2h.
• NG tube if drowsy or protracted vomiting.
• Consider Central Venous Pressure measurement if previous cardiac or renal disease.
• Consider s/c prophylactic heparin in comatose, elderly or obese patients.

Monitoring:

• Vital signs, fluid given - urine output ratio hourly.
• Finger prick glucose hourly for 8h.
• Laboratory glucose and electrolytes 2-hourly for 8h, then 4-6 hourly, adjusting K+according to results.

Question 13

What is a hyperosmolar hyperglycaemic state?

Answer 13

Life-threatening emergency characterised by hyperglycaemia, hyperosmolality and mild or no ketoacidosis.

This is typical of uncontrolled DM2, often undiagnosed, and most commonly precipitated by infection, especially pneumonia.

Although insulin levels are reduced, they are sufficient to inhibit hepatic ketogenesis, but cannot control gluconeogenesis (generation of glucose from certain non-carbohydrate carbon substrates), which is unrestrained.

Question 14

How do patients in hyperosmolar hyperglycaemic states present?

Answer 14

Patients present with:

• Profound dehydration due to osmotic diuresis.
• Decreased level of consciousness, which is directly related to the degree of elevation of plasma osmolality.
• Without ketosis.

Question 15

What is the management for patients in a hyperosmolar hypoglycaemic state?

Answer 15

Ix and Rx are the same as ketoacidosis except that a lower rate of insulin infusion is necessary–3U/h, as these patients are extremely sensitive to insulin. The rate may be doubled after 2-3h if glucose is falling too slowly.

Hyperosmolar state predisposes to stroke, MI or arterial thrombosis, and prophylactic

s/c heparin is given.

Question 16

What are the different laboratory findings in DKA or hyperosmolar hypoglycaemic state?

Answer 16

Question 17

What hypoglycaemic agents are there?

Answer 17

• Biguanide–Metformin
• Suphonylureas
• Incretins
• Glitazones

Question 18

How does metformin work?

Answer 18

• Reduces glucose production by the liver and sensitises target tissues to insulin.
• First line treatment after failure to control diabetes using diet alone.
• Only oral agent shown to reduce CVD risk in diabetics.
• SE: anorexia and diarrhoea.
• Contraindicated: severe heart failure, liver or renal disease due to development of lactic acidosis.

used after lifestyle modification (e.g. diet, weight control and exercise) are ineffective in T2DM control

Question 19

How do sulphonureas work?

Answer 19

Promotes insulin secretion.

*used if HbA1C rises to 58mmol/mol (4th line in dual therapy) or used in combination as triple therapy (1st and 2nd line with DPP4 inhibitor/gliptins e.g. sitagliptin, blocks dpp-4 destroying incretin hormone or in use with pioglitazone)

Glibenclamide best, but contraindicated in elderly or renal failure due to long duration of action and renal excretion.

Tolbutamide is shorter acting and metabolised by the liver, so a better choice.

SE: hypoglycaemia.

Meglatinides are also insulin secretagogues [similar manner to sulphonureas]. With rapid onset and short duration, they administered just before a meal. [weaker binding affininty and faster dissociation from SulfonureaR1 binding site]

Question 20

How are incretins used in diabetes management?

Answer 20

• Mimic effect of GIP and GLP-1 that are released from the pancreas and promote
• insulin release after an oral glucose load.
• GLP-1 also prolongs gastric emptying and leads to a decrease in body weight.
• Exenatide and liraglutide are long acting GLP-1 analogues given by s/c injection,
• and used as an alternative to insulin, mainly in obesity.

Question 21

how do Glitazones’ (thiazolidinediones) help diabetes?

Answer 21

• Bind to and activate PPAR-γ, a nuclear receptor that regulates large numbers of genes including those controlling glucose and lipid metabolism.
• Reduce hepatic glucose production and enhance peripheral glucose uptake.
• SE: weight gain, fluid retention, and heart failure, anaemia, osteoporosis.
• Contraindicated in heart failure

Question 22

How is diabetes monitored at home and in hospital?

Answer 22

At home:

• Finger prick blood testing and reagent strips. Regular profiles: QTD 2/7 per week, and to keep a diary.
• Urine testing using Stix is inaccurate for glucose, but useful for ketones if patient unwell.

In clinic/hospital:

• Glycosylated Hb (HbA1c) useful measurement of average glucose levels during the life of the Hb.
• Non-DM 20-42mmol/mol.
• Target DM 48-59mmol/mol, pursuing lower values may cause hypoglycaemia, and reduces QOL.
• Glycosylated plasma proteins (e.g. fructosamine) are less reliable than HbA1c, butare useful in haemaglobinopathies.

Question 23

what are the indications for insulin therapy?

Answer 23

DM1:

• any patient <40y/o and/or any one who has been ketoacidotic.

DM2:

• Only given after failure of diet and oral hypoglycaemics to control glucose levels.
• Given with metformin, initially one dose at night, then more throughout the day if necessary.
• Multiple injections and pumps (continuous s/c insulin infusion) are being used in younger DM2 patients

Question 24

What is the management pathway in T2DM?

Answer 24

Question 25

What are the vascular complications of diabetes?

Answer 25

Patients with diabetes have a reduced life expectancy: cardiovascular (70%), CKD (10%) and infections (6%) are the most common cause of premature death in treated patients.

Complications are directly related to the degree and duration of hyperglycaemia, and are thus reduced by diabetic control.

The pathogenic mechanisms that lead to damage are ill defined, however there are cellular consequences of hyperglycaemia that may play a role:

Non-enzymatic glycosylation of proteins e.g. Hb, tubulin, LDL and collagen, which accumulate cause injury and inflammation via complement and cytokines.

Polyol pathway: metabolism of glucose leads to accumulation of sorbitol and fructose causing changes in vascular permeability, capillary structure and cellproliferation.

Microvascular occlusion due to vasoconstrictors leads to endothelial damage

Formation of Reactive Oxygen Species, and GF stimulation–VEGF and TGF-β [inflammation inc in kidney/podocytes/glomerulosclerosis]

Question 26

What are the macrovascular complications of diabetes?

Answer 26

• Diabetes is a risk factor for atherosclerosis, and is additive with other risk factors for large vessel disease (smoking, HTN and hyperlipidaemia), and can result in IHD, stroke, and Peripheral Vascular Disease.

Risk is reduced by good diabetic control, and also modulating risk factors:

• Aggressive control of HTN (target <130/80mmHg).
• Cessation of smoking.
• Treatment with a statin, regardless of serum cholesterol.
• ACEI or angiotensin II receptor antagonist with ACEI intolerance.
• Low-dose aspirin as well

Question 27

What are the microvascular complications of diabetes?

Answer 27

In contrast to macrovascular disease, microvascular disease is specific to diabetes.

Small vessels are affected through out the body, but the retina, renal glomerulus and nerve sheath are most in danger.

Diabetic retinopathy, nephropathy and neuropathy tend to manifest 10-20yrs after diagnosis in young patients, but present earlier in older patients, probably because they had unrecognised diabetes for longer

Question 28

What happens to the diabetic eye?

Answer 28

33% of young diabetics develop eye problems, and 5% are blind after 30yrs of DM.

Diabetes affect the eye in several ways:

• Diabetic retinopathy with lesions in the retina and iris.
• Cataracts develop earlier.
• Temporary blurred vision also occurs in acute hyperglycaemia due to reversible osmotic changes.
• External ocular palsies: 3rd and 6th most commonly affected.

Diabetic retinopathy is the most common cause of blindness in <65yrs. At diagnosis 30% have early retinal damage–background retinopathy. The development and progression is accelerated by: poor glycaemic control, HTN and smoking.

Retinopathy is divided into non-proliferative and proliferative based on the presence of neovacularisation. Proliferative retinopathy develops due to damage of the retinal vessels and the resultant retinal ischaemia, which also occurs in non-proliferative retinopathy.

Most patients are asymptomatic until late, irreversible stages. Any diabetic requires annual assessment, and those with retinopathy are referred to an ophthalmologist.

Question 29

What happens in diabetic kidney?

Answer 29

Nephropathy secondary to glycaemic glomerular damage manifests 15-25yrs after diagnosis.

It starts with thickening of the basement membrane, but then progresses to glomerulosclerosis:

Microalbuminuria: increase in urinary albumin but not detectable on dipstick.

Progresses to intermittent albuminuria, then persistent proteinuria with frank nephrotic syndrome.

At this stage of proteinuria, plasma creatine is normal, but only 5-10yrs from end-stage kidney disease.

Aggressive control of BP <130/80 with ACEI or AR2A is most important factor in limiting disease progression.

Ischaemic arteriolar lesions with hypertrophy and hyalinization can damage both afferent and efferent arterioles in the kidney. The appearances are similar to that of hypertensive disease but are not necessarily related to BP in diabetics.

Infective lesions may occur, due to UIs. A rare complication is renal papillary necrosis, in which renal papillae are shed in the urine and may cause ureteral obstruction.

Question 30

What happens in diabetic neuropathy?

Answer 30

Isolated mononeuropathies are thought to result from occlusion of the vasa nervorum–the small arteries that provide blood supply to the peripheral nerves, while more diffuse neuropathies may arise from accumulation of fructose and sorbitol (polyol pathway) in peripheral nerves, which disrupts the structure and function of the nerve.

Symmetrical (mainly) sensory neuropathy: the most common neuropathy and affecting the feet first (rarely hands), and is often unrecognised.

Early signs: loss of vibration, pain (deep before superficial) and temperature in feet.

Later stages: ‘walking on cotton wool’, losing balance while walking in the dark or washing face due to impaired proprioception.

Complications include:

Unrecognised trauma e.g. a blister due to ill-fitting shoe that becomes an ulcer.

Charcot’s joints: abnormal stress and repeated minor trauma usually prevented by pain may develop into neuropathic arthropathy in ankle and knee’s.

Motor neuropathy: leads to wasting of the small muscles of the hand, and a distorted foot with a high arch and clawing toes.

Mononeuritis and multiple mononeuropathies:

when one or multiple individual nerves are affected including involvement of a spinal root. Onset is abrupt and painful, and is more likely to occur at common sites of external pressure e.g. carpal tunnel. Most common cranial mononeuropathies are 3rd and 6th nerves supplying extraocular muscles, causing unilateral pain, ptosis and diplopia, with sparing of papillary function.

Acute painful neuropathy: the patient describes burning or crawling pains in the lower limbs. Symptoms are typically worse at night, and pressure from bedclothes intolerable. Treatment is good diabetic control, tricyclics, gabapentin and carbamazepine.

Diabetic amyotrophy: usually asymmetrical, painful wasting of quadriceps muscle, with diminished or absent reflexes.

Autonomic neuropathy is irreversible and managed symptomatically:

CVS: resting tachycardia, loss of sinus arrhythmia, postural hypotension, and peripheral vasodilation with a warm foot and bounding pulse.

GIT: diarrhoea and gastroparesis leading to intractable vomiting.

Bladder: incomplete emptying followed by painless distended bladder.

Male erectile dysfunction.

Question 31

What happens in diabetic foot?

Answer 31

Foot problems are a major cause of morbidity and mortality in diabetics, with infection,ischaemia, and neuropathy all contributing to necrosis. May present with:

• Neuropathy: reduced sensation to vibration, temperature and pinprick.
• Charcot arthropathy. (weakening of bones in foot –> fracture–> foot shape change)
• Signs of vascular disease: thin skin, absence of hair, bluish discolouration, reduced skin temperature and absent pulses.

Many diabetic ulcers are preventable so patients need to learn principles of good footcare: well fitting, lace-up shoes, regular chiropody, no ‘bathroom surgery’, daily inspection of feet and early advice for any damage, and avoidance of heat e.g. radiators or hot baths.

Management:

• Swabbing of ulcers for culture and early ABX treatment.
• Good local wound care, and if necessary surgical debridement of ulcers.
• Evaluation for PVD: Doppler pulses and femoral angiography if indicated.
• Reconstructive vascular surgery for localised areas of arterial occlusion.

Question 32

What are the signs and symptoms of hypoglycaemia?

Answer 32

Classical presentation is with fasting hypoglycaemia. Symptoms are due to neuroglycopenia and stimulation of sympathetic nervous system:

• Sweating.
• Palpitations.
• Diplopia.
• Weakness.
• Progression to confusion.
• Abnormal behaviour.
• Fits then coma.

Causes:

• Drug induced:
  
  • Insulin or sulphonylureas.
  • Quinine.
  • Pentamidine.
  • Propranolol.
  • Salicylate overdose.
• Islet cell tumour of pancreas (insulinoma) produces inappropriately high circulating insulin levels.
• Non-pancreatic tumours (hepatoma, sarcoma) through secretion of IGF
• Endocrine causes (Addison’s disease) impaired counter regulation to the action of insulin.
• Fulminant liver failure due to failure of hepatic gluconeogenesis.

Excess alcohol:

• Enhanced insulin response to carbohydrate.
• Inhibition of hepatic gluconeogenesis.

After gastric surgery:

• Rapid gastric emptying.
• Mismatch of food and insulin.

Factitious hypoglycaemia: surreptitious self-administration of insulin or sulphonylureas, often in a non-diabetic.

Question 33

What is the acute management of hypoglycaemia?

Answer 33

Immediate diagnosis and treatment are essential. Blood glucose always done insuspected hypoglycaemic.

Treatment:

• Immediately: rapidly absorbed carbohydrate i.e. non-diet fizzy drink or GlucoGel given orally.
• Unconscious patient: IV dextrose 50mL 50% flushed with normal saline.
• IM glucagon to rapidly mobilise hepatic glycogen if difficult to find IV route for glucose.
• Oral glucose once patient revives.
• 10% dextrose drip to prevent relapse.

NB hyper and hypoglycaemia may have the same presentation in a diabetic patient. Always some sugar to rule out hypo first.