What is the pathogenesis of diabetic ketoacidosis?

  1. Insulin deficiency and glucagon excess – decreases peripheral utilization of glucose while increasing gluconeogenesis  – severe hyperglycaemia
  2. Hyperglycaemia causes osmotic diuresis and dehydration
  3. Insulin deficiency increases lipolysis and FFAs production.  FFAs are converted to ketone bodies by the liver.  If rate of ketone bodies production exceeds rate of utilization by peripheral tissues®ketonaemia and ketonuria.  Decreased urinary excretion of ketones leads to systemic metabolic ketoacidosis

Pass criteria:

  • 1 from each of these groups to pass

What are the long-term complications of diabetes?

  1. Macrovascular– coronary, peripheral vascular, cerebral and other large artery atherosclerosis, hypertension
  2. Microangiopathy- nephropathy, cerebral microangiopathy, peripheral neuropathy, autonomic neuropathy
  3. Diabetic ocular complications– retinopathy, cataracts, glaucoma

Pass Criteria:

  • Macrovascular and microvascular with 2 examples of each to pass or
  • Simple list of 6 to pass
  • Higher score for organization in groups

Describe the stages in the development of Type 1 Diabetes?

  • Genetic predisposition
  • Precipitating event
  • Autoimmune destruction of islet cells
  • Subclinical leading to overt DM



What is thyrotoxicosis?

  • Hypermetabolic state caused by elevated circulating levels of T3 and T4

What are the clinical features of thyrotoxicosis?

  • Cardiac – inc  HR, dysrhythmias, CCF
  • Neuromusc – tremor, prox myopathy
  • Ocular – wide staring gaze, lid lag, proptosis
  • CNS – anxiety, emotional lability, insomnia
  • Skin – warm, flushed, inc sweating
  • Heat intolerance
  • Thyroid storm – fever, tachycardia, arrhyth., may be fatal if not treated promptly

Pass Criteria:

  • Bold to pass

What are the main causes of thyrotoxicosis?

  • Diffuse toxic hyperplasia (Graves disease)
  • Toxic multinodular goitre
  • Toxic adenoma/carcinoma
  • Neonatal from maternal Graves dis
  • Non-hyperthyroidism – thyroiditis, etc

Pass criteria:

  • Bold PLUS 1 other



What is the pathogenesis of Type 1 Diabetes Mellitus?

  • Genetic predisposition
  • Precipitating event
  • Autoimmune destruction of islet cells
  • Subclinical leading to overt DM

Pass criteria:

  • 3 to pass

What environmental factors may contribute to the development of Type I Diabetes Mellitus?

  • Infections (group B coxsackieviruses; mumps; measles; CMV; rubella; EBV): may induce tissue damage and inflammation, leading to the release of B-cell antigens.  OR
  • the viruses produce antigens which mimic self-antigens with the immune response cross-reacting with self-tissue

Pass Criteria:

  • Pass – 2 out of 3 groups must include biogenic amines and example of each

How does genetic susceptibility contribute to the development of Type I DM?

  • Complex pattern of genetic associations: putative susceptibility genes mapped to at least 20 loci.
  • Most important is class II MHC (HLA) locus – 50% of total genetic susceptibility: on chromosome 6p21 (HLA-D)
  • 95% Caucasians with type I DM have HLA-DR3, DR4 or both. DQB1*0302 allele considered the primary determinant of genetic susceptibility.
  • Non-MHC genes: the first disease-associated non-MHC gene to be identified was insulin. Tandem repeats in the promoter region being associated with disease susceptibility.
    • mechanism of association is unknown: maybe the disease associated polymorphism  makes the protein less functional or stable OR may influence the level of expression of insulin in the thymus, so altering negative selection of insulin-reactive T cells
  • Another gene recently shown to be associated: encoding for the T-cell inhibitory receptor CTLA-4



How are pituitary adenomas classified?

Prompt: Name two cell types involved.

  • Classification based on hormone cell-type: prolactin cell, growth hormone cell (densely or sparsely granulated), thyroid stimulating cell, ACTH cell, gonadotroph cell (including silent and oncocytic), mixed GH-prolactin cell, Other plurihormonal cell, hormone negative

Pass criteria:

  • 2 cell types to pass.
  • If describe “functional” or “silent” adenomas – move to prompt

What clinical syndromes may they produce?

  • Prolactinoma: amenorrhea, galactorrhea, loss of libido, and infertility
  • Somatotroph (GH): gigantism or acromegaly
  • ACTH: Cushing’s syndrome
  • Gonadotroph: local effects (headaches, visual impairment, diplopia, pituitary apoplexy), hypogonadism (lethargy, loss of libido, amenorrhoea)




What defects in glucose handling characterise Type II Diabetes Mellitus?
Prompt: What are the mechanisms?

  1. Reduced insulin secretion from beta cells – altered glucose sensing mechanism, cellular overstimulation
  2. Reduced tissue responsiveness to insulin – reduced post receptor signaling, reduced insulin receptors

What are the main risk factors for the development of Type II diabetes mellitus?

  1. Obesity (most important) – present in 80%, truncal obesity higher risk,
  2. Genetic factors – not HLA linked, collection of multiple genetic defects, more important than Type I DM, concordance rates in identical twins 60-80%

Pass: At least one

What are the main adverse effects of acute, severe, sustained hyperglycaemia?

  1. Osmotic diuresis – hypovolaemia, risk of thrombosis
  2. Electrolyte losses – Na, K, PO4
  3. Hyperosmolarity – changes in conscious state

Pass: At least two


What are the main risk factors for the development of Type I Diabetes Mellitus?

Genetic factors – Northern European decent, familial groupings, identical twin concordance rate 70%, 6% in first degree relatives, linked to class II antigens of major histocompatability complex

Viral infections – cocksackie B, mumps, measles, CMV, rubella, EBV

Cows milk exposure prior to 4 months of age

Drugs – pentamidine
Pass: Genetic factors plus one other

What is the sequence of events that leads to Type I diabetes mellitus?
Prompt: How do the risk factors combine to cause Type I DM?

Genetic susceptibility

Exposure to environmental insult – exogenous antigen (viral), drugs

Auto immune response directed towards beta cells – molecular mimicry or altered expression of Beta cell antigens, 70-80% have auto islet antibodies

Beta cell destruction – reduced cell mass and insulin

Pass: At least 3

What are some of the long-term complications of chronic hyperglycaemia?

  1. Vascular – macro and microvascular, CVasc, renal, ocular
  2. Neuropathic
  3. Immune
  4. Renal- Kimmelstiel Wilson lesions
  5. Foetal
  6. Dermal – ulcers, necrobiosis
  7. Muscular – proximal myopathy


Pass: At least 3



What are the characteristic clinical findings of Grave's disease?

  1. Clinical hyperfunction
  2. Thyroid enlargement
  3. Infiltrative opthalmopathy
  4. Infiltrative dermopathy

Pass: Bold

What is the pathogenesis?

  1. Auto-immune: variety of antibodies
  2. Auto-antibodies to TSH receptors
  3. LATS — IgG mimics TSH, thyroid stimulating immunoglobulin


Pass: At least 2



What are the principal complications of Diabetes Mellitus?

PROMPT – What happens in the pancreas?

  • Vascular
    • Macro
      • Atherosclerosis
      • Coronary artery disease
      • Peripheral vascular disease
      • Renal artery stenosis
      • Hypertension
      • Cerebrovascular accident
    • Microangiopathic
      • Thickened basement membrane, increased permeability of capillaries to plasma proteins – nephropathy, retinopathy, neuropathy
  • Pancreatic Changes
    • Loss of islet cells (number and size)
  • Renal
    • Sclerosis
    • Basement membrane thickening
    • Glomerulosclerosis
  • Ocular
    • Proliferative and non-proliferative
    • Heamorrhages
    • Exudates
    • Neovascularisation
    • Detachment
    • Glaucoma
  • Neuropathy

Pass Criteria:

  • Bold + 3 of 7 clinical complications

Outline some of the differences in patients with Type 1 and Type 2 diabetes.

Type 1 Type 2
Onset – childhood, <18 Onset – usually adult
Normal or under weight Obese
Decrease in insulin Increased blood insulin
Circulating islet autoantibodies No islet autoantibodies
Polyuria, polydipsia, polyphagia +/- ketoacidosis May have HONC
Genetic linkage No genetic linkage
Dysfunction in T cell resulting in islet Ab Insulin resistance
  • Type 1:
    • Typically young <18 years, usually abrupt onset due to exhaustion of B cell reserve – often with a precipitating illness increasing demands on pancreas e.g. infection
  • Type 2:
    • Often >40 years, obese
    • Often asymptomatic and incidental finding on routine followup or bloods
    • May have DKA or HONC with dehydrating precipitant
    • Often a longer cause illness due to residual pancreas

Pass Criteria:

  • Age group and severity of illness + at least 2 symptoms or syndromes associated with each type
  • Age + 2 clinical + 1 pathology to pass



What is the pathogenesis of Type 2 Diabetes Mellitus?

  • Insulin resistance
    • Decreased ability of the peripheral tissues to respond to the secreted insulin
    • Secondary to either genetic predisposition or obesity/lifestyle factors
  • Quantitative and qualitative beta cell dysfunction
    • Manifests as inadequate insulin secretion in the face of insulin resistance and hyperglycaemia
    • Initial beta cell hyperplsaia maintains normoglycaemia with increased levels of insulin secretion
    • Early and subsequently late failure manifests as impaired glucose tolerance and diabetes
    • Genetic predisposition to B-cell failure

Pass Criteria:

  • Bold to pass

What are the complications of diabetes?

  1. Macrovascular
    • Coronary, peripheral vascular, cerebral and other large vessel atherosclerosis
    • Hypertension
  2. Microangiopathy
    • Nephropathy
    • Peripheral neuropathy
    • Autonomic neuropathy
    • Cerebral microangiopathy
  3. Diabetic ocular complications
    • Retinopathy
    • Cataracts
    • Glaucoma
  4. Increased susceptibility to infections
  5. HONK, DKA, hypoglycaemia, hyperglycaemia

Pass Criteria:

  • Two from  1 and 2
  • One from 3


Name some clinical manifestations of diffuse toxic hyperplasia of the thyroid
Prompt: Graves' disease

  • Cardiac
    • Tachycardia
    • Palpitations
    • Heart failure
  • Eye
    • Staring
    • Lid lag
    • Proptosis
  • Gastrointestinal
    • Malabsorption
    • Diarrhoea
  • Neurological
    • Tremor
    • Anxiety
    • Poor concentration

Pass Criteria:

  • 4 clinical features to pass.