Endocrinology Part 3 Flashcards
1
Q
What is MODY?
A
Maturity-onset diabetes of the young- MODY
- Commonest type of monogenic diabetes (~1% diabetes)
- Diagnosed <25y
- Autosomal dominant
- Non-insulin dependent
- Single gene defect altering beta cell function
- Tend to be non-obese
2
Q
Talk about transcription factors in MODY.
A
Hepatic nuclear factor (HNF) mutations alter insulin secretion, reduce beta cell proliferation.
3
Q
What are the different types of MODY?
A
- HNF1A mutation (MODY 3)
- Very sensitive to sulphonylurea treatment (tablet), so often do not need insulin (~80%) - HNF4A mutation (MODY 1)
- FH, young age of onset, non-obese, Sus, AND
- Macrosomia (>4.4kg at birth)
- Neonatal hypoglycaemia - Glucokinase gene (GCK) mutation (MODY 2)
- GCK is the glucose-sensor of beta cells, rate determining step in glucose metabolism, controlling the release of insulin
- Higher set point, but still tight glycaemic control
- Mild diabetes, no treatment required
4
Q
MODY is usually misdiagnosed as what type of diabetes?
A
Diabetes type 1 or young onset Type 2 diabetes
5
Q
Compared MODY with Type 1 DM and Type 2 DM.
A
MODY: non-insulin depedence, +/- obesity, diagnosis < 25 yo, 1 parent affected
Type 1 DM: insulin dependence, +/- obesity, diagnosis < 25 yo, 0-1 parent affected
Type 2 DM: non-insulin dependence, +++ obesity, unusual before 25 yo, 1-2 parent affected
6
Q
Which patients might be MODY?
A
- Parent affected with diabetes
- Absence of islet autoantibodies
- Evidence of non-insulin dependence
- Good control on low dose insulin
- No ketosis
- Measurable C-peptide
- Sensitive to sulphonylurea
7
Q
Talk about C-peptide in different type of diabetes.
A
- Not present in synthetic insulin
- C-peptide longer half-life, 30 vs 3 mins
- In Type 1 diabetes, C-peptide is negative within 5 years (due to complete autoimmune beta cell destruction)
- Type 2 and MODY, C-peptide persists
8
Q
Talk about permanent neonatal diabetes.
A
- Diagnosed <6 months (usually de novo):
> Signs:
> Small babies, epilepsy, muscle weakness - Mutations encode Kir6.2 and SUR1 subunits of the beta cell ATP sensitive potassium channel
- Rising ATP closes the channel as a result of hyperglycaemia, depolarising the membrane and insulin is secreted
- Mutations prevent closure of the channel, and thus beta cells unable to secrete insulin
- Sulphonylureas close the KATP channel
9
Q
What is maternally inherited diabetes and deafness (MIDD)?
A
- Mutation in mitochondrial DNA
- Loss of beta cell mass
- Similar presentation to Type 2
- Wide phenotype
10
Q
What is lipodystrophy?
A
- Selective loss of adipose tissue
- Associated with insulin resistance, dyslipidaemia, hepatatic steatosis, hyperandrogenism, PCOS
11
Q
What are some examples of diseases of the exocrine pancreas?
A
- Inflammatory (acute and chronic pancreatitis)
- Hereditary Haemochromatosis
- Deposition (Amyloidosis / cystinosis)
- Pancreatic Neoplasia
- Cystic Fibrosis
12
Q
Talk about inflammatory (pancreatitis)
A
Acute – usually transient hyperglycaemia, due to increased glucagon secretion
Chronic pancreatitis:
- Alcohol
- Alters secretions, formation
of proteinaceous plugs that
block ducts and act as a foci
for calculi formation
- Stop alcohol, treat with insulin
13
Q
Talk about Hereditary Haemochromatosis.
A
Autosomal recessive – triad of cirrhosis, diabetes and bronzed hyperpigmentation
Excess iron deposited in liver, pancreas, pituitary, heart and parathyroids
Most need insulin
14
Q
What are the 2 deposition diseases that are commonly seen in the pancreas?
A
Amyloidosis / cystinosis
15
Q
Talk about pancreatic neoplasia.
A
- Common cause of cancer death
- 4-5 resections per week at STH
- Require sc insulin
- Prone to hypoglycaemia due to loss of glucagon function
- Frequent small meals, enzyme replacement
- Insulin pumps
16
Q
Talk about cystic fibrosis.
A
- Cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7q22
- Regulates chloride secretion
- Viscous secretions lead to duct obstruction, and fibrosis
- Incidence is 25 to 50% in adults
- Ketoacidosis rare
- Insulin treatment required
- CF survival better, so microvascular complications increasing
- Insulin improves:
> Body weight
> Reduces infections
> Lung function
> Improves quality of life, and ?survival
17
Q
What are some examples of endocrine causes of diabetes?
A
- potentially reversible
> Acromegaly
> Cushing syndrome
> Pheochromocytoma
18
Q
Talk about acromegaly induced diabetes.
A
- Excessive secretion of growth hormone
- Similar to Type 2
- Insulin resistance rises, impairing insulin action in liver and peripheral tissues
19
Q
Talk about Cushings syndrome-induced diabetes.
A
- Increased insulin resistance, reduced glucose uptake into peripheral tissues
- Hepatic glucose production increased through stimulation of gluconeogenesis via increased substrates (proteolysis and lipolysis)
20
Q
Talk about pheochromocytoma-induced diabetes.
A
Pheochromocytoma:
Pheochromocytoma is a type of neuroendocrine tumor that grows from cells called chromaffin cells. These cells produce hormones needed for the body and are found in the adrenal glands. If you have a pheochromocytoma, the tumor releases hormones that may cause high blood pressure, headache, sweating and symptoms of a panic attack.
- Catecholamine, predominately epinephrine excess
- Increased gluconeogenesis
- Decreased glucose uptake
21
Q
Talk about drug-induced diabetes.
A
Glucocorticoids increase insulin resistance
Thiazides / protease inhibitors (HIV) / antipsychotics – mechanisms not clearly understood
Less insulin induced vasodilatation in muscle leading to reduced glucose delivery to muscle beds, reducing opportunity of muscle to clear glucose from the blood
22
Q
Describe the HPA axis
A
Hypothalamus - Pituitary Gland (ACTH) - Adrenal - Cortisol
23
Q
What is the time period for the acrophase (peak) and nadir phase (lowest point) for cortisol circadian rhythm?
A
Acrophase (peak)
- 0832h (0759h - 0905h)
Nadir phase (lowest point)
- 0018h (2339h – 0058h)
24
Q
What is circadian system?cr
A
Circadian rhythms are physical, mental, and behavioral changes that follow a 24-hour cycle. These natural processes respond primarily to light and dark and affect most living things
25
What is the primary 'zeitgeber' of the body clock/ circadian rhythm?
(zeitgeber - a rhythmically occurring natural phenomenon which acts as a cue in the regulation of the body's circadian rhythms.)
Light - changes in the quantity and quality of light at dawn or dusk
eye - then feedback to the suprachiasmatic nuclei in the brain
26
Central body clock controls peripheral body clock.
true/ false?
True
Suprachiasmatic Nuclei - Muscle, heart, lung, brain, hormones, liver, kidney, stomach
Glucocorticoids are a secondary messenger from central to peripheral clocks
27
Talk about adrenal insufficiency.
* Primary – Addison’s Disease (93-140/M)
− Autoimmune adrenalitis >60% of cases
− APS type 1 10-15% of cases
− CAH 1:15000 live births
− Adrenoleukodystrophy
− Mets, haemorrhage, infection
− Infection (TB), infiltration (Amyloid)
* Secondary – Hypopituitarism (150-280/M)
− Pituitary macroadenoma/Cranio
− Apoplexy
− Hypophysitis
− Mets, infiltration, infection
− Radiotherapy
− Congenital
* Tertiary – Suppression of HPA
− Steroids, oral, inhaler, creams
28
What are the diagnosis for adrenal insufficiency?
* History
− Symptoms: fatigue, weight loss, poor recovery from illness, adrenal crisis, headache
− Past History: TB, post partum bleed, cancer
− Family History: Autoimmunity, congenital disease
− Treatment: Any steroids! Etomidate, Ketoconazole
* Signs
− Pigmentation and pallor
− Hypotension
* Biochemistry
− Low Na, high K
− Eosinophilia
− Borderline elevated TSH
29
Talk about the biochemical investigation for adrenal insufficiency?
* 0900 Cortisol and ACTH
− Cortisol > 500 nmol/l AI unlikely
− Cortisol < 100 nmol/l AI likely
− ACTH > 22 pmol/l primary
− ACTH < 5 pmol/l secondary
* Renin / Aldo
− Elevated renin in primary
* Synacthen Test
− 250ug IV measure 0’ & 30’
− > 500-550 nmol/l AI unlikely
What is a synacthen test? A synacthen test uses a special chemical (synacthen) to test how well the adrenal glands make cortisol. It involves stimulating the adrenal glands and then checking to see if they respond.
30
Talk about the investigation for causes of adrenal insufficiency?
* Primary
− Adrenal antibodies
− Very long-chain fatty acids
− 17-OHP
− Imaging
− Genetic
* Secondary
− Any steroids???
− Imaging
− Genetic
31
Talk about the treatment for adrenal insuffiency.
* Goal: Mirror the normal physiological state
* Hydrocortisone (pharmaceutical name for cortisol) twice or three times daily at a dose to replace cortisol levels 15-25mg
* In primary adrenal insufficiency also replace aldosterone with fludrocortisone
32
Talk about adrenal crisis.
Common Presentation of adrenal insufficiency:
− Hypotension and cardiovascular collapse
− Fatigue
− Fever
− Hypoglycaemia
− Hyponatraemia and hyperkalaemia
In patients on treatment with glucocorticoids:
− Incidence 5-10 / 100 patient years
− Mortality 0.5 / 100 patient years
33
What is the management for adrenal crisis?
* Take bloods if possible for cortisol and ACTH
* Immediate hydrocortisone 100mg IV, IM, (SC)
* Fluid resuscitation (1L N/Saline 1 hour)
* Hydrocortisone 50-100mg IV/IM 6 hourly
* In primary start fludrocortisone 100-200ug (when HC <50mg)
* When patient stable wean to normal replacement over 24-
72h:
− 50mg orally TDS
− 20mg orally TDS
− 10mg orally TDS
* Sick day rules!!
34
Talk about "sick day rules" for adrenal insufficiency.
* Always carry 10 x 10mg tablets hydrocortisone
* If unwell with fever or flu like illness double dose of steroids
* If in doubt double dose of steroids
* If vomiting or increasingly unwell take emergency injection
of hydrocortisone 100mg IM (SC)
* If unable to have injection take hydrocortisone 20mg and repeat if vomit
* Go to emergency room / ring ambulance
* You cannot harm yourself in the short-term taking extra steroid
* Carry steroid card and medic-alert
35
What is the current Hydrocortisone therapy for adrenal insufficiency?
Current three times daily hydrocortisone therapy.
36
Talk about Adrenal Insufficiency: Increased morbidity and mortality.
- Standardised Mortality Ratio – 2.7
- Quality of Life - Impaired
- Cardiovascular risk - Increased
- Osteoporosis – Low BMD (Bone Mineral Density)
37
What is the current and new therapies for adrenal insuffiency?
- Hydrocortisone
– Chronobiology approach (Chronocort® in development) (microparticulate to tackle the challenge of gut length and transit time
38
What is diabetes mellitus?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
39
How can diabetes mellitus cause morbidity and mortality?
Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperglycaemic Hyperosmolar State)
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
Side effects of treatment- hypoglycaemia
40
Talk about impaired insulin secretion and insulin resistance.
1. Genes and environment
2a) impaired insulin secretion
2b) insulin resistance
3. impaired glucose tolerance
4. Type 2 diabetes
5. Progressive hyperglycaemia and high free fatty acids
41
What are the complications for diabetes mellitus type 2?
- Diabetic Retinopathy
- Diabetic Nephropathy
> Leading cause of
end-stage renal disease
- 2-4 fold increase in CV mortality and stroke
- 8/10 people with diabetes die from CVD
- DPN (Diabetic Peripheral Neuropathy)
> Leading cause of non-traumatic
lower extremity amputations
42
What are the 6 common CVD seen in patients with DM2?
- stable angina
- unstable angina
- non-fatal MI
- unheralded coronary death
- HF (heart failure)
- ischaemic stroke
43
Talk about the mechanism of CVD in diabetes patients.
Hyperglycaemia - subclinical atherosclerosis - atherosclerotic clinical events - acute and chronic coronary syndromes, stroke, peripheral artery disease
44
What are the different drugs at different sites for DM2?
1. GI Tract
- Delay gastric emptying
- Inhibition of glucagon release
- Inhibition of glucose absorption
- Stimulation of GLP-1 release
Drugs : pramlintide, alpha glucosidase inhibitor
2. Pancreatic beta cells
- Acute stimulation of insulin release
- stimulation of insulin biosynthesis
- inhibition of beta cells apoptosis
- stimulation of beta cell differentiation
Drugs: sulfonylurea, meglitinides, GLP1/DPP-IV inhibitors
3. Liver
- Inhibition of glucose production
- Increase in hepatic insulin sensitivity
Drugs: metformin
4. Muscle
- Increase in muscle insulin sensitivity
Drugs: Thiazolidinediones
5. Adipose tissue
- Suppression of NEFA release
- Fat redistribution (visceral to subcutaneous)
- Modulation of adipokine release
Drugs: Thiazolidinediones
45
Talk about the structure in Diabetes Care 2002?
1. Healthy eating, weight control, increased physical activity, diabetes education
2. metformin
3. SU/ TZD/ Glinides
4. Insulin
46
What are the lifestyle interventions for DM2?
1. Compliance
2. Lifestyle and patient education
3. 30 min exercise a day
4. Dietitian
5. Local education programmes (e.g. Desmond and Xpert)
Desmond : Diabetes Education and Self-Management for Ongoing and Newly Diagnosed people
Xpert: X-PERT is a six-week group education programme for patients with Type 2 Diabetes. It has been developed to help patients understand more about diabetes and how they can manage it through lifestyle changes. It is suitable for anyone newly diagnosed and those who have had diabetes for a while but want to learn more.
47
Talk about T2DM prevention.
Early treatment and prevention key to reducing T2DM burden
Intensive diet and exercise programmes can delay onset or prevent T2DM
Including use of metformin and TZDs
Difficult to maintain over long term and costly
Unwanted side-effects of medications
48
Talk about metformin in diabetes patients.
Metformin decreased risk of diabetes-related endpoints in overweight diabetes patients, associated with less weight gain and less hypoglycemia than insulin and sulfonylurea, it maybe first-line pharmacologic therapy of choice in these patients
49
What are the other options other than metformin for patients with T2DM?
- Sulphonylurea
- Incretin-based agents
- SGLT-2 inhibitors
- Insulin
50
Talk about incretins in T2DM.
Incretins are hormones secreted by intestinal endocrine cells in response to nutrient intake
Incretins influence glucose homeostasis via multiple actions including glucose-dependent insulin secretion, postprandial glucagon suppression, and slowing of gastric emptying
51
What is GLP1?
A type of incretin hormone
52
Talk about GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
- promote satiety and reduce appetite
- alpha cells: decrease postprandial glucagon secretion
- Liver: decrease glucagon reduces hepatic glucose output
- Stomach: help regulate glucose emptying
- Beta cells: Enhances glucose-dependent insulin secretion
53
What are the agents that prolong the activity of endogenous GLP-1?
DPP-IV Inhibitors (oral; once daily)
54
Talk about DPP4 inhibitor in T2DM.
Dipeptidyl-peptidase 4 (DPP-4) is an enzyme present in vascular endothelial lining which inactivates the incretin hormones GIP and GLP-1
DPP-4 Inhibitors are competitive antagonists of the DPP-4 enzyme - enhancing the effects of both GIP and GLP-1
> Glucose dependent reduction in fasting and postprandial glucose levels in addition to decreasing glucagon secretion. Low risk hypoglycaemia.
> Body weight unchanged
- Orally available
- Small increase in endogenous GLP-1
- Little effect on gastric emptying
- Do not cause nausea/ vomiting
- No effect on weight
- Effects are mediated by multiple receptors
55
Talk about GLP1 analogues.
- Injectable only
- Large increase in GLP-1 level
- Induces delay in gastric emptying
- Likely to induce nausea/ vomiting
- Induces weight loss
- Effects are mediated by GLP-1 Receptor
56
Talk about benefits, drawbacks and effect on weight on metformin, SU and TZD.
Metformin:
> Benefits: low risk of hypoglycaemia, BP reduction, possible cardioprotective benefits
> Drawbacks: Lactic acidosis (rare), caution indicated in older patients with CHF
> Weight neutral or slightly weight loss
SU:
> Benefits: Newer class entrant may have reduced CV risk
> Drawbacks: May increase risk of CV, hypoglycaemia
> Weight gain
TZDs:
> Benefits: low risk of hypoglycaemia, positive effects on biomarker
> Drawback: Increased CV risk, lipid abnormalities
> Weight gain
57
Talk about TZDs.
Both effective glucose lowering agents
Positive effects on the metabolic syndrome
Contraindicated in CCF(Congestive Cardiac Failure) , high risk of fractures, macula oedema
Pioglitazone: CV end points- ProActive
58
Talk about SGLT- 2 Inibitors
- Current treatments are act as insulin secretagogues or sensitisers
- Limitations
- Kidney key role in glucose homeostasis
59
What are some examples of SGLT-2 inhibitors?
Empaglifozin, Dapaglifozin, Canaglifozin
(at the proximal convoluted tubule)
60
Show how SGLT2 Inhibitors modulate a range of factors that are related to CV risk?
- decrease weight
- decrease visceral adiposity
- decrease oxidative stress
- decrease glucose
- decrease insulin
- decrease uric acid
- decrease albuminuria
- decrease blood pressure
- decrease arterial stiffness
- increase LDL and HDL
- decrease triglycerides
61
What are those drugs for DM that will cause weight gain and those that will not?
Weight gain
- Insulin
- SU
- DPP4-i
- Pioglitazone
No weight gain
- GLP1a (injection)
- SGLT 2i
62
SGLT-2i efficacy declines with increasing renal impairment
True/False?
True
63
Talk about SGLT2i examples with eGFR
In patients with eGFR > 45ml/min/1.73m2 canaglifosin (100mg) and empaglifosin can be used and effectively reduces Hba1c
In patients with eGFR > 60ml/min/1.73m2 dapaglifosin can be used and effectively reduces Hba1c
Avoid in eGFR < 30ml/min/1.73m2
SGLT-2i do not worsen kidney disease - going on canagliflozin trial eGFR as an end point to examine whether the drug slows progression of kidney disease
Recent research suggests that SGLT2 inhibitors similar to angiotensin-converting enzyme inhibitors.
64
SGLT-2i may cause intravascular volume depletion
True/False
True
Risk factors: renal impairment, diuretics, low systolic BP and elderly
Monitor patients for symptoms of hypotension after initiating treatment
Consider patients with co-morbid CCF – dose of diuretics may need to be reviewed
65
Talk about heredity in T2DM.
Positive family history confers 2.4 fold increased risk
Lifetime risk by 60yo of 38% one parent, 60% two parents
Concordance rate dizygotic twins 20%, monozygotic twins 58%
With IGT included increases to 88% in monozygotic twins
66
What are the factors promoting insulin resistance?
- Obesity
- Physical inactivity
> Inflammation
> Free Fatty Acids
> Hormones (Adiponectin)
- Viceral fat and ectopic fat (muscle and liver)
67
Talk about glucose metabolism and Type 2 diabetes.
A consequence of insulin resistance and progressive failure of insulin secretion (but insulin levels are always detectable)
Impaired insulin action leads to
> Reduced muscle and fat uptake after eating
> Failure to suppress lipolysis and high circulating FFAs
> Abnormally high glucose output after a meal
Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive
68
Talk about the Pathogenesis of Type 2 Diabetes.
1. Impaired insulin secretion
2a) Hepatic insulin resistance
2b) Muscle/fat insulin resistance
3a) Excessive glucose production
3b) Impaired glucose clearance
4. Hyperglycaemia
5. Glycosuria
69
What are the different types of diabetes?
- Type 1
- Type 2
> Includes gestational and medication-induced diabetes
- Maturity onset diabetes of youth (MODY)
- Pancreatic diabetes
- “Endocrine Diabetes” (acromegaly/Cushings)
- Malnutrition related diabetes
70
Talk about Regulation of CHO metabolism in non diabetic humans in the fasting state.
- All glucose comes from liver
> Breakdown of glycogen
> Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)
- Glucose is delivered to insulin independent tissues, brain and red blood cells
- Insulin levels are low
- Muscle uses FFA for fuel
- Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
71
Talk about Regulation of CHO metabolism in non diabetic humans after feeding.
- Physiological need to dispose of a nutrient load
- Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
- 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
- Ingested glucose helps to replenish glycogen stores both in liver and muscle
- High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
72
Talk about Insulin signalling and insulin resistance: Mobilization of GLUT4 to the Cell Surface.
1. Insulin bind
2. Intracellular signaling cascades
3. GLUT4 vesicle mobilization to plasma membrane
4. GLUT4 vesicle integration into plasma membrane
5. Glucose entry into cell via GLUT4
73
Peripheral Insulin Sensitivity Decreases With Intra-abdominal Fat
True/False
True
74
Summarise the pathophysiology of T1DM and T2DM.
- Type 1 diabetes
> Severe insulin deficiency due to autoimmune destruction of the cell (initiated by genetic susceptibility and environmental triggers)
- Type 2 diabetes
> Insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors
75
Diabetic neuropathy affects how many percentage of patients with diabetes?
30-50% of patients with diabetes
Diabetic peripheral neuropathy is probably the commonest complication of diabetes and starts in the toes and gradually marches proximally in a stocking distribution. Once it is well established in the lower limbs the upper limbs are affected.
Significant motor deficit is not common.
Painful symptoms are present in about a third.
Now there has been an alarming association between DPN and cardiovascular disease.
Mortality amongst our neuropathic patients is high and the cause of death is often cardiovascular disease.
76
What are the 3 major clinical consequences of diabetic neuropathy?
1. Painful neuropathic symptoms (burning)
> paraesthesia
> hyperaesthesia
> allodynia
> nocturnal-exacerbation
2. Autonomic neuropathy (orthostatic)
> Cardiac AN
> gastroparesis
> diarrhoea
> constipation
> incontinence
> Erectile Dysfunction
3. Insensitivity (foot ulceration)
> infection
> amputation
> falls
> Charcot foot
77
What are the risk factors of diabetic neuropathy (DN)?
- baseline glycaemic control
- change in glucose control over the 7 years duration of diabetes
- traditional markers of macrovascular disease and insulin resistance including:
> hypertension
> smoking
> BMI
> TG
> cholesterol
78
What are the treatment for Diabetic Painful neuropathy?
- Good glycaemic control
- Tricyclic antidepressants / SSRIs
- Anticonvulsants (carbamazepine, Gabapentin)
- Opiods (Tramadol, oxycodone)
- IV lignocaine
- Capsaicin
- Transcutaneous nerve stimulation / acupuncture / spinal cord stimulators
- Psychological interventions / hypnosis
79
What is the common consequence of peripheral neuropathy
Diabetic foot ulceration (DFU)
80
Talk about diabetic foot ulceration.
Common cause for hospital bed occupancy
Foot ulceration occurs in 15% of people with DM during their lifetime1
Lower limb amputations X 15 in people with DM
Mortality in those with DFU X 2
81
Talk about the cause of diabetic amputation.
- Neuropathy or vascular disease
- trauma
- ulcer
- failure to heal
- infection
- amputation
82
What are the two principal factors that contribute to the high-risk diabetic foot?
1. Peripheral neuropathy – damage to the nerves that serve the lower limbs and hands.
2. Peripheral vascular disease, which affects the larger vessels of the lower limbs.
In most people, a combination of peripheral neuropathy and peripheral vascular disease co-exists.
83
How can sensory nerve damage in diabetic patients lead to infection?
a person who attended a foot clinic for treatment of ulceration, completely unaware that they were walking with a thumb-tack stuck into their foot. Had the tack not been found, this injury could quite easily have become infected, leading to serious consequences.
84
Other than affecting the sensory nerves, what does peripheral neuropathy affect?
motor nerves of the feet.
This causes weakness in the intrinsic muscles of the feet, leading to contraction of the muscles and clawed toes.
As the toes claw back, the fat pads are pulled forward from under the metatarsal heads, increasing the pressure under these metatarsal heads and on the tips of the toes (common places for neuropathic ulceration).
85
Talk about localised callus in diabetic patients.
When an increase in pressure and discomfort occurs, people with normal sensation change their gait.
People with neuropathy do not feel pain and continue to walk in the same way.
This leads to a build up of callus at the site of most pressure.
Ultimately this hard, localized callus can cause the tissue underneath to breakdown forming ulceration.
As a preventive measure, all callus should be removed.
It is particularly important to note that bleeding callus is indicative of possible ulceration and should be removed immediately.
86
Talk about autonomic nerve damage in diabetic patients.
Damage to the autonomic nervous system accompanies significant peripheral neuropathy.
Normally, feet perspire, keeping the skin moist and supple.
In autonomic neuropathy, people lose the ability to perspire; the skin dries out and becomes cracked.
These cracks are a very common portals for infection.
87
What are the diabetic peripheral neuropathy screening tests?
- Test sensation
> 10 gm monofilament
> neurotips
- Vibration perception
> Tuning fork
> biothesiometer
- Ankle reflexes
88
Talk about peripheral vascular disease in patients with diabetes.
Peripheral vascular disease causes a decrease in perfusion, due to macrovascular disease.
Interestingly, diabetes-related peripheral vascular disease is slightly different from that suffered by people without diabetes.
In people with diabetes, the tibial and peroneal arteries are often more involved than the femoral/aortic-iliac vessels.
More of the disease is therefore seen from the knee to ankle rather than the pelvis to knee.
Curiously, the pedal arteries often remain patent in people with diabetes. This is important because it allows a bypass graft to be anastamosed at that level.
89
What is the clinical presentation/symptom of diabetic peripheral vascular disease?
1. Intermittent claudication
2. Rest pain
Symptoms include intermittent claudication – pain in the calf that is brought on by walking, especially upstairs or up a hill, and is relieved by rest.
It can be very uncomfortable but, unlike angina, it is not dangerous to continue walking through the pain threshold; indeed, this is recommended in treatment.
Rest pain is experienced pain in the lower limbs, even at rest.
This is very serious and very uncomfortable.
Surgical intervention is required to relieve the symptoms.
90
What are the signs on the foot that can be observed when there is vascular disease?
- Diminished or absent pedal pulses
- Coolness of the feet and toes
- Poor skin and nails
- Absence of hair on feet and legs
91
What are some non-invasive test/evaluation for peripheral vascular disease in diabetic patients?
- Methods
> Doppler pressure studies (ABI)
> duplex arterial imaging/MRA
- Rationale
> identify and confirm disease
> predict healing or determine need for surgical intervention
92
Talk about Doppler Ultrasound in diabetic peripheral vascular disease.
pressure at brachial, pedal and toe arteries
Ankle Brachial Index (ABI)
<0.9 abnormal
0.9 to 1.0 normal
>1.3 non-compressible
Doppler ultrasound is used to measure the Ankle Brachial index (ABI) – an estimate of the lower limb blood flow. In this test, the systolic blood pressure of the brachial artery is divided into the systolic blood pressure of the pedal arteries.
The ratio should be 0.9 to 1.0. A low result indicates that care needs to be exercised before using sharp debridement or dressings that debride. It also indicates that a formal vascular assessment is required.
A note of caution: people with diabetes often have calcified, stiff arteries that are difficult to compress. This leads to an abnormally high ABI result that does not give accurate indication of the degree of peripheral vascular disease.
93
Talk about the treatment for peripheral vascular disease.
- Quit smoking
- Walk through pain
- Surgical intervention
94
How to prevent amputation gradually in pts with diabetic peripheral vascular disease?
- Screening to identify risk
- Education and providing orthotic shoes
- MDT foot clinic
- Pressure relieving footwear, podiatry, revascularisation, antibiotics
95
Talk about Multidisciplinary Foot Service in diabetic patients.
Most amputations start with ulcers
MDT foot ulcer management includes:
Wound care
Offloading
Revascularisation
Infection control.
Cure rate of a diabetic foot ulcer in 12 to 20 weeks was only 24% (National)
Innovations that promote rapid and complete ulcer healing and reduce the need for expensive surgical procedures will impact costs substantially.
96
Talk about the the devices for offloading in diabetic foot.
- removable boots
- ortho wedge
- post-op shoe
- crow boot
- traditional tcc
> Smart shoe insole systems adjunct to offloading interventions in the management of plantar ulcers.
> Hypothesis: use of this system accelerates healing of diabetic foot ulcers by using biofeedback to change behaviour
97
Talk about autonomic neuropathy in diabetic patient.
Autonomic neuropathy is caused by damage to the nerves that supply the body structures that regulate functions such as blood pressure, heart rate, bowel and bladder emptying, and digestion.
- postural hypotension
- Arrhythmia
- Silent ischaemia
- Sudden death
- Urine retention
- Erectile dysfunction
- Gastroparesis
- Constipation
- Diarrhoea
- Gustatory sweating
98
Talk about mononeuropathy in diabetic patients.
Cranial nerves:
Third nerve – closed eye
Sixth nerve – pupil directed nasally
Seventh nerve - Bell’s palsy
olfactory (CN I),
optic (CN II),
oculomotor (CN III),
trochlear (CN IV),
trigeminal (CN V),
abducent (or abducens; CN VI),
facial (CN VII),
vestibulocochlear (CN VIII),
glossopharyngeal (CN IX),
vagus (CN X),
accessory (CN XI),
hypoglossal (CN XII).
99
Talk about diabetic retinopathy.
- DR most common cause of blindness in working population (not in UK)
- Early detection and treatment can reduce risk of blindness
Risk factors:
> Long duration diabetes
> Poor glycaemic control
> Hypertensive
> On insulin treatment
> Pregnancy
100
Talk about eye screening for diabetic retinopathy in diabetic patients.
- Effective way of detecting early DR
- DoH set up the National Screening Programme
- Eligibility: >11 yrs old
- Once registered patients receive an invitation letter
- 2 field retinal photography
- Screeners grade photographs and reports sent to GP
101
What are the different types of pathogenesis in diabetic retinopathy?
- leakage
- occlusion
- micro aneurysm
- ischaemia
102
Talk about Micro Aneurysm pathogenesis in diabetic retinopathy.
- Pericyte loss and smooth muscle cell loss
- MA’s
- MA’s adjacent to or upstream of capillary non-perfusion
103
Talk about leakage pathogenesis in diabetic retinopathy.
- Basement membrane thickening
- Pericyte loss
- reduces junctional contact with endothelial cells
- LEAKAGE
104
Talk about ischaemia pathogenesis in diabetic retinopathy.
Pericyte loss, endothelial cells respond by increasing turnover > thickening > ISCHAEMIA
Glial cells grow down capillaries > OCCLUSION
Ischaemia/Occlusion > Proliferation
105
Talk about the grading system of diabetic retinopathy.
R0: None
R1: Background
R2: Pre-proliferative
R3: Proliferative
M: Maculopathy
P: Photocoagulation
U: Unclassifiable
R1: (Background)
Microaneurym(s)
Retinal haemorrhages
Retinal exudates
R2: (Pre-proliferative)
Venous beading
Venous loop or reduplication
Intraretinal microvascular abnormalities (IRMA)
Multiple deep, round or blot haemorrhages
R3: (Proliferative)
New vessels on disc
New vessels elsewhere
Pre-retinal or vitreous haemorrhage
Pre-retinal fibrosis +/- tractional retinal detachment
Maculopathy:
- Exudate within 1 disc diameter (DD) of the centre of the fovea
- Circinate or group of exudates within the macula
Photocoagulation:
- Focal/grid to macula
- Peripheral scatter
106
Talk about laser therapy in diabetic retinopathy.
- Only proven treatment for DR
- The benefits outweigh the risks
- Aim is to stabilise changes
- Treatment does not improve sight
- OP treatment over one or more visits
107
Talk about risks of laser treatment.
- Over half notice difficulty with night vision
- One in five lose peripheral vision
- 3% stop driving because of tunnel vision
- May notice temporary drop in acuity if intensive laser
- Vitreous haemorrhage
108
How successful is laser treatment?
If treatment is given at the correct stage it is very effective
Over 90% of severe sight loss prevented by laser for early proliferative retinopathy
Laser of macular changes prevents 60%
109
Diabetic is the main cause of ESRD.
True/False
True
End-Stage Renal Disease
110
Talk about diabetic nephropathy.
- Hallmark is development of proteinuria
- Followed by progressive decline in renal function
- Major risk factor for CVD
- Risk factors are poor BP and BG control
Marked renal extracellular basement membrane accumulation resulting in extreme mesangial expansion and GBM thickening are present in the vast majority of T1DM patients who develop overt diabetic nephropathy (DN) manifesting as proteinuria, hypertension, and declining GFR
111
Talk about the pathophysiology of diabetic nephropathy.
- Glomerular changes
- Increase in glomerular injury
- Filtrations of protein
- Diabetic nephropathy
112
Talk about definition and classification of diabetic nephropathy.
Diabetic nephropathy is generally defined as a rise in urinary albumin excretion (UAE) and reduced renal function, as reflected by raised plasma creatinine concentration, reduced calculated creatinine clearance or decreased glomerular filtration rate (GFR)
Male:
Normalalbuminuria- <2.5
Microalbuminuria- 2.5-25
Macroalbuminuria- >25
Female:
Normalalbuminuria- <3.5
Microalbuminuria- 3.5-35
Macroalbuminuria- >35
113
Talk about CKD classification. (Chronic Kidney Disease)
Grade 1: Kidney damage with reduced eGFR (90->105)
Grade 2: Mild CKD (60-89)
Grade 3: Moderate CKD (30-59)
Grade 4: Severe CKD (15-29)
Grade 5: ESRD (<15 or dialysis)
114
Why does every diabetic patient get a glucometer and none get home bp monitor?
The reason is bp therapy can safely be administered without home monitoring while tight glycemic control requires glycemic monitoring.
115
Talk about treatment for diabetic nephropathy.
Blood pressure control
Glycemic control
ARB / ACEi
Proteinuria control
Cholesterol control
*ARB: Angiotensin Receptor Blocker
*ACEi: Angiotensin Converting Enzyme inhibitors
