Rest of endocrine Flashcards
1
Q
In primary hypogonadism (men) testosterone and LH/FSH would be:
A
Testosterone would be low.
LH/FSH would be raised.
2
Q
In hypopituitarism (men) testosterone and LH/FSH would be:
A
Testosterone is low.
LH/FSH can be normal or low.
3
Q
In anabolic testosterone use (men) testosterone and LH/FSH would be:
A
Testosterone would be low.
LH/FSH suppressed.
4
Q
What type of blood test would be required in pituitary disease for men?
A
09:00h fasted T and LH/FSH test
5
Q
What would a pre-puberty blood panel look like for a woman (gonadal axis)?
A
Oestradiol low/undetectable
Low LH and FSH (FSH>LH)
6
Q
What would the blood test for a woman at puberty look like (gonadal axis)?
A
Pulsatile LH secretion increases
Oestradiol increases
7
Q
What would the blood test for a post menarche woman look like (gonadal axis)?
A
Monthly menstrual cycle:
LH and FSH surge in the middle of the cycle
Oestradiol levels increase throughout the cycle
8
Q
What would the blood test for a woman with primary ovarian failure look like (including menopause)?
A
Oestradiol would be low.
LH and FSH would be high (FSH>LH).
9
Q
What would the blood test for a woman with hypopituitary disease would look like?
A
Oligo- or amenorrhoea with low oestradiol.
Normal or low LH and FSH.
10
Q
What time do we measure cortisol levels?
A
09:00h in the morning and synachthen.
11
Q
Primary AI:
A
Cortisol: low
ACTH: high
Response to synachthen test: poor
12
Q
Hypopituitarism in AI:
A
Cortisol: low
ACTH: low or normal
Response to synachthen test: poor
13
Q
When is the greatest pulse of GH secreted?
A
At night – followed by low or undetectable levels between pulses.
14
Q
In what conditions does GH level fall?
A
With ageing and in obesity.
15
Q
How do we measure the GH/IGF-1 axis?
A
Measuring IGF-1 and GH stimulation test:
> Insulin stress test
> Glucagon test
> Other
16
Q
What is unique about measuring prolactin levels?
A
It is under negative control of dopamine.
It is a stress hormone.
17
Q
Why prolactin levels may be raised?
A
Stress
Drugs: antipsychotics
Stalk pressure
Prolactinoma
18
Q
How to measure prolactin?
A
Can measure prolactin or cannulated prolactin (3 sampled over an hour to exclude stress of venepuncture).
19
Q
Nephrogenic DI
A
= Vasopressin resistance (there is hormone secretion but no response)
20
Q
Cranial DI
A
= Vasopressin deficiency (no ADH is being made or secreted)
21
Q
What test is used to investigate vasopressin deficiency/resistance?
A
Water deprivation test with desmopressin.
22
Q
What other molecule can be measured to confirm Dx of DI?
A
Copeptin
23
Q
Primary polydipsia is confirmed if stimulated copeptin levels are:
A
> 4.9 pmol/L
24
Q
What dynamic testing is used in Cushing’s?
A
Dexamethasone suppression testing.
CRH stimulation.
25
What dynamic testing is used in acromegaly?
Oral glucose GH suppression test.
26
What dynamic testing is used in TSHoma?
TRH stimulation.
27
What dynamic testing is used in gonadotrophin deficiency?
GnRH stimulation
28
What dynamic testing is used in GH/ACTH deficiency?
Insulin induced hypoglycaemia.
29
What other dynamic testing can be used in GH deficiency?
Glucagon test.
30
What is the preferred imaging study for the pituitary?
MRI
31
Why is MRI chosen to study the pituitary?
Better visualisation of soft tissues and vascular structures than CT.
No exposure to ionising radiation.
32
T1-weighted images produce high-signal intensity images of what?
Fat – Structures such as fatty marrow and orbital fat show up as bright images.
33
T2-weighted images produce high-intensity signals of what structures?
Structures that have high water content (CSF and cystic lesions).
34
CT imaging gives better visualisation of what?
Bony structures and calcifications within soft tissues.
35
What type of tumours are better Dx with CT?
Tumours with calcification such as germinomas, craniopharyngiomas and meningiomas.
36
In what patient groups would CT be useful?
PT with pacemakers or metallic implants in the brain or eyes.
37
What are some of the disadvantages of CT?
Suboptimal soft tissue imaging compared to MRI.
Use of IV contrast is required.
Exposure to radiation.
38
GH deficiency results in:
Short stature.
Abnormal body composition.
Reduced muscle mass.
Poor quality of life.
39
Rx of GH deficiency?
Exogenous GH.
40
LH/FSH deficiency results in what?
Hypogonadism
Reduced sperm count
Infertility.
Menstruation problems.
41
Rx of LH/FSH deficiency?
Rx of LH/FSH deficiency?
Testosterone in males.
Oestradiol and progesterone in females.
42
TSH deficiency results in what?
Hypothyroidism.
43
Rx of TSH deficiency?
Levothyroxine
44
ACTH deficiency results in what?
Adrenal failure and decreased pigmentation
45
Rx of ACTH deficiency?
Hydrocortisone.
46
ADH deficiency results in what?
Vasopressin deficiency = DI
47
Rx of ADH deficiency?
DDAVP
48
What is a challenge in drug delivery?
The gut length and transit time. This was overcome by using modified release microparticulates
49
Thyroxine replacement therapy?
Dose 1.6 micrograms/kg/day.
Aims to achieve the mid to upper half reference range.
Higher doses are required in pregnancy and in patients on oestrogen.
50
GH replacement therapy?
<60 years – start 0.2-0.4 mg/day
>60 years – start 0.1-0.2 mg/day
Aiming for mid-range IGF1
Measure IFG1 6 weeks after dose start and adjust.
Improves lipid profiles, body composition and bone mineral density.
51
Testosterone replacement therapy?
Different formulations (gels, injections, oral.
Follow testosterone levels, FBC, PSA.
Improve bone mineral density, libido function, energy levels, sense of well-being, muscle mass and reduce fat.
52
Oestrogen replacement therapy?
Oral oestrogen or combined oestrogen/progesterone formulations (transdermal, topical gels, intravaginal creams).
Alleviate flushes and night sweats, improve vaginal atrophy.
Reduce risk of CVD, osteoporosis and mortality.
53
Desmopressin therapy?
Desmopressin therapy?
Different formulations: SC, PO, intra-nasally, SL
Adjust dose according to symptoms.
Monitor sodium levels
54
What are the consequences of excess growth hormone production?
Excess growth hormone goes to the liver where it gets transformed into IGF-I which affects cartilage and bone growth.
Two forms depending on onset of age (gigantism or acromegaly).
55
What is the incidence of acromegaly?
3.3 per a million
56
What is the mean age at diagnosis?
44 years. (38-69)
57
What is the mean duration of symptoms?
8 years. (7-11).
58
What are the co-morbidities with acromegaly?
Hypertension and heart disease.
Sleep apnea.
Insulin-resistant diabetes.
Arthritis.
Cerebrovascular events and headaches.
59
What is the impact of acromegaly on survival?
Overall survival is reduced by ~10 years.
26-50% die before 50 years.
64-89% die before 60 years.
Both diabetes and cardiac disease have a significant impact.
60
How is acromegaly diagnosed?
Presence of clinical features.
GH levels.
IGF-I levels.
61
What are the common presenting features of acromegaly?
Acral enlargement.
Arthralgias.
Maxillofacial changes.
Excessive sweating.
Headache.
Hypogonadal symptoms.
62
What test is used to diagnose acromegaly?
75g oral glucose tolerance test.
63
When is acromegaly excluded?
If random GH <0.4 ng/mL and IGF-I is normal.
If IGF-I is normal and GTT nadir (low point), GH <1 ng/ml.
64
What are the objectives of therapy?
Restoration of basal GH and IGF-I to normal levels.
Relief of symptoms.
Reversal of visual and soft tissue changes.
Prevention of further skeletal deformity.
Normalisation of pituitary function.
65
What are the options for treatment of acromegaly?
Pituitary surgery.
Medical therapy.
Radiotherapy.
66
Transsphenoidal surgery is used for all types of pituitary adenomas except for what?
Prolactinoma.
67
What makes the transsphenoidal surgery challenging?
Large size of the tumour.
Invasiveness.
68
What is the differentiating point for microadenomas vs. macroadenomas?
10mm.
Microadenoma <10 mm and the surgical cure rate is ~90%.
Macroadenoma >10 mm and the surgical cure rate is <50%.
69
What are the two important determinants of success of a surgery?
The size of the tumour.
The surgeon
70
What are the complications of pituitary surgery?
There is a long list, but the two important ones are hypopituitarism and death.
71
What are the different types of radiotherapies?
Conventional (multi-fractional).
Stereotactic (single fraction, less radiation to surrounding tissues).
72
What are the examples of stereotactic radiotherapy?
Gamma knife.
LINAC.
Proton beam.
73
Sheffield is the National Centre for what?
Stereotactic Radiosurgery.
74
What are the problems with radiotherapy?
Loss of pituitary function in the long term.
Potential damage to local structures (eye nerves).
Control of tumour growth/excess hormone secretion is not always achieved.
Life-long monitoring needed for all patients.
75
What two factors determine the efficacy of conventional radiotherapy?
GH level.
The extension of the tumour.
76
What are the disadvantages of conventional radiotherapy?
Delayed response.
Hypopituitarism.
Rare secondary tumours.
Rare visual defects.
77
What medical therapies are used for the treatment of acromegaly?
Dopamine agonists – cabergoline.
Somatostatin analogues.
GH receptor antagonist.
78
What are the goals of dopamine agonists therapy?
Control GH.
Control IGF-I.
Improve well-being.
79
What are the advantages of Cabergoline over bromocriptine?
More potent.
Fewer side effects.
Twice weekly dosage.
80
What are the advantages of dopamine agonist therapy?
No hypopituitarism.
Oral administration.
Rapid onset.
81
What are the disadvantages of dopamine agonist therapy?
Relatively ineffective.
Side effects.
82
Dopamine agonists are particularly useful in what tumours?
GH + prolactin co-secreting tumours.
Occasional dramatic tumour shrinkage.
Control of GH secretion.
83
Describe the function of human somatostatin:
Inhibits multitude of hormones.
Half-life is short ~3 minutes.
Rebound.
Binds all 5 receptor subtypes.
84
Synthetic version of somatostatin analogues.
More specific.
Half-life is extended 100 mins.
No rebound.
Examples: Octreotide and Lanreotide
85
What are the goals of somatostatin analogues?
Control GH.
Control IGF-I.
Clinical improvement.
86
Somatostatin analogues control what?
IGF-I 65%.
GH 60%.
Tumour shrinkage.
87
What are the determinants of efficacy in somatostatin analogues?
GH level.
Tumour size.
SMS receptor expression.
88
What are the disadvantages of somatostatin analogues?
Injectable.
Side effects.
89
Describe Pegvisomant:
GH analogue.
191 AAs.
9 AA substitution.
4-5 PEG moieties.
Half-life >70 hours.
SC administration.
90
What are the disadvantages of Pegvisomant use?
Serum GH cannot be used as disease marker.
Cross reacts in GH assays.
91
What is the incidence of prolactinoma?
10 per 100.000
92
Which gender is more affected by prolactinomas?
Women >> men.
93
What is the prevalence of prolactinomas?
90 per 100.000.
94
What is a prolactinoma?
Lactotroph cell tumour of the pituitary.
95
What are the local effects of the tumour (macroadenoma)?
Headache.
Visual field defect – bitemporal hemianopia.
CSF leak (rare).
96
What are the effects of prolactin?
Menstrual irregularity/amenorrhoea.
Infertility.
Galactorrhoea.
Low libido.
Low testosterone in men.
97
Hyperprolactinaemia can be caused by:
Macroprolactinoma (can be massive).
Microprolactinoma (virtually always stay small).
Non-functioning pituitary tumour – compression of the pituitary stalk (prolactin <4000 mlU/L).
Antidopaminergic drugs.
Other causes (stress, hypothyroidism, PCOS, drugs, renal failure, chest wall injury).
98
Management of prolactinomas?
Medical rather than surgical.
Dopamine agonists (cabergoline, bromocriptine, quinagolide).
Remarkable shrinkage usually with macroadenomas (sight saving).
Microadenomas usually respond to small doses of cabergoline (1x, 2x a week).
99
There are different definitions of Diabetes, discuss this.
Symptomatic presentation and random plasma glucose is greater than or equals to 11.1 mmol/L.
Fasting plasma glucose is greater than or equals to 7.0 mmol/L.
HbA1c is greater than or equals to 48 mmol/mol.
No symptoms – OGTT (75g glucose), fasting levels are greater than or equals to 7 or 2 hour value is greater than or equals to 11.1 mmol/L.
100
What are the presenting features of diabetes?
Thirst: osmotic activation of the hypothalamus.
Polyuria: osmotic diuresis.
Weight loss and fatigue: lipid and muscle loss due to unrestrained gluconeogenesis.
Hunger: lack of useable energy source.
Pruritis vulvae and balanitis: vaginal candidiasis + chest and skin infections.
Blurred vision: altered acuity due to uptake of glucose/water into lens.
101
What are the more common symptoms in type 1?
Lethargy
Stupor
Weight loss
Kussmaul breathing
Smell of acetone
Nausea
Vomiting
Abdominal pain
102
What are the suggestive features of type 1?
Onset in childhood/adolescence.
Lean body habitus.
Acute onset of osmotic symptoms.
Prone to ketoacidosis.
High levels of islet autoantibodies.
103
Does type 1 only occur in childhood or adolescence?
No, it can occur at any age, the spectrum of presentation depends on the rate of beta-cell destruction.
104
What happens to the beta cells before the onset of diabetes?
They are exposed to repeated damage.
105
What are the clinical features of newly diagnosed T1DM?
Weight loss + short history of severe symptoms + moderate or large urinary ketones.
Two must be present for Dx.
Insulin Rx at ANY age.
106
What are the suggestive features of T2DM?
Usually present in over 30s.
Onset is gradual.
FH is often positive.
Almost 100% concordance in identical twins.
Diet, exercise and oral medication can often control hyperglycaemia; insulin may be required later.
107
What is the commonest age of onset of T1DM?
5-15 years but can occur at any age.
108
What is the prevalence of T1?
3/1000 among children and adolescents.
109
How many people are living with T1 in the UK?
370.000
110
Many genes are associated with T1, what are the risks for developing it if…
Mother has the condition = 2%.
Father has the condition = 8%.
Both parents have it = 30%.
Brother/Sister develops it = 10%.
Non identical twins = 15%.
Identical twins = 40%.
111
What are the Abs associated with T1 (more common in children)?
Anti-GAD
Pancreatic islet cell Ab
Islet antigen-2 Ab
ZnT8
112
Some Abs are associated with other autoimmune diseases, which are these?
Hypothyroidism.
Addisons.
Coeliac disease.
113
Fat are the consequences of a missed T1 diagnosis?
Reduced insulin leads to fat breakdown and formation of glycerol (a gluconeogenic precursor) and free fatty acids
114
What are the problems with free fatty acids?
Impair glucose uptake.
Used in gluconeogenesis to provide energy.
Oxidised to form ketone bodies (beta hydroxy butyrate, acetoacetate and acetone).
115
Describe ketoacidosis.
Absence of insulin and rising counterregulatory hormones lead to increasing hyperglycaemia and rising ketones.
Glucose and ketones escape in the urine, which leads to an osmotic diuresis and falling circulating blood volume.
Ketones (weak organic acids) cause anorexia and vomiting.
Vicious circle of increasing dehydration, hyperglycaemia and increasing acidosis eventually lead to circulatory collapse and death.
116
The definition of DKA is:
Hyperglycaemia (plasma glucose <50 mmol/L).
Raised plasma ketones (urine ketones >2+).
Metabolic acidosis (plasma bicarb <15 mmol/L)
117
What are the causes of DKA?
Intercurrent illness (infection, MI).
Treatment errors (stop/reduce insulin dose).
Previously undiagnosed diabetes.
Unknown.
118
What is the triad of DKA?
Hyperglycaemia
Ketones
Acidosis
119
Describe the symptoms of DKA:
Develop over days.
Polyuria and polydipsia.
Nausea and vomiting.
Weight loss.
Weakness.
Abdominal pain (confused with surgical abdomen).
Drowsiness/confusion.
120
What are the signs of DKA?
Hyperventilation – Kussmaul breathing.
Dehydration (average fluid loss 5-6 litres).
Hypotension.
Tachycardia.
Coma.
121
How is potassium affected in DKA?
High on presentation despite total body potassium deficit (due to acute shift of K out of cell with acidosis).
Subsequently fall with insulin and rehydration, anticipate fall in potassium.
122
How are urea and creatinine affected in DKA?
Both raised due to pre-renal failure.
123
Ketones in the blood during DKA are:
>3.0
124
What is the management of DKA?
Rehydration (3L first 3hrs).
Insulin.
Replacement of electrolytes (potassium).
Treat underlying cause.
Treatment must be started without delay.
125
What are the complications of DKA?
Cerebral oedema (deterioration in conscious level). Children more at risk.
Adult respiratory distress syndrome.
Thromboebolism (venous and arterial).
Aspiration pneumonia (in drowsy/comatose patients).
Death.
126
What are the aims of the treatment of T1?
Achieve weight gain.
Relieve symptoms and prevent ketoacidosis.
Prevent microvascular and macrovascular complications.
Prevent the loss of 8 years of life due to premature death.
127
What are the microvascular complications of diabetes?
Nephropathy. (CV + nephropathy 30x).
Retinopathy.
Neuropathy.
128
What is the Rx for T1DM?
Insulin treatment (twice daily mixture of short/medium acting insulin).
Basal bolus (once or twice daily medium acting insulin plus pre meal quick acting insulin).
Ability to judge CHO intake.
Awareness of blood glucose lowering effect of exercise.
129
What is the risk of high insulin levels?
High risk of hypoglycaemia.
Acute deprivation of glucose within the brain leads to cerebral dysfunction.
130
What are the physiological defences to hypoglycaemia?
Release of glucagon, adrenaline.
Symptoms of sweating, tremor, palpitations, loss of concentration (hunger).
131
What happens if glucose levels are at 4.6 mM?
Inhibition of insulin secretion.
132
What happens if glucose levels are at 3.8 mM?
Counter-regulatory hormone release (glucagon and adrenaline).
133
What happens if blood glucose levels are between 3.8-2.8 mM?
Autonomic symptoms (sweating, tremor, palpitations).
134
What happens if blood glucose levels are <2.8 mM?
Neuroglycopenic symptoms (confusion, drowsiness, altered behaviour, speech difficulty, incoordiation).
135
What happens in blood glucose levels are <1.5 mM?
Severe neuroglycopenic symptoms (convulsions, coma, focal neurological deficit, i.e. hemiparesis).
136
DAFNE (Dose Adjustment for Normal Eating) reduces the incidence of what?
DKA and severe hypos.
137
Setting higher glucose targets will the reduce the risk of what?
Hypoglycaemia but increase the risk of diabetic complications.
138
Setting lower glucose targets will reduces the risk of what?
Complications but increase the risk of hypos.
139
What is an example of a monogenic diabetes?
MODY – Maturity-onset diabetes of the young.
Commonest type, diagnosed <25 years.
140
What is the inheritance pattern of MODY?
Autosomal dominant.
141
Is MODY insulin dependent?
It is a non-insulin dependent form.
142
What is the pathophysiology in MODY?
Singe gene defect altering beta cell function
143
What is the appearance of individuals with MODY?
Non-obese.
144
What transcription factors are involved in MODY?
HNF: hepatic nuclear factor mutations alter insulin secretion, reduce beta cell proliferation.
145
Describe the HNF1A mutation (MODY 3):
Very sensitive to sulphonylurea treatment – often does not require insulin.
146
Describe the HNF4A mutation (MODY 1):
Family history, young age of onset, non-obese, sulphonylurea Rx.
Macrosomia (>4.4.kg at birth).
Neonatal hypoglycaemia.
147
Glucokinase gene (GCK) mutation (MODY 2):
GCK is a glucose-sense of beta cells and is the rate determining step in glucose metabolism, controlling the release of insulin.
Higher set point but still tight glycaemic control.
Mild diabetes, no treatment required.
148
Which patients might be MODY?
Parent are affected by diabetes.
Absence of islet autoantibodies.
Evidence of non-insulin dependence. (Good control on low dose insulin, no ketosis, measurable C-peptide).
Sensitive to sulphonylurea.
149
What is C-peptide?
It is the by-product when pro-insulin is cleaved into its active form.
C-peptide has a longer half-life 30 mins.
T1DM C-peptide is negative within 5 years (due to complete autoimmune beta cell destruction).
T2DM and MODY C-peptide persists.
150
Describe: Permanent Neonatal Diabetes
Diagnosed <6 months (usually de novo, 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 = beta cells unable to secrete insulin.
Sulphonylureas close the ATP dependent potassium channels
151
Describe maternally inherited diabetes and deafness (MIDD):
Mutation in mitochondrial DNA.
Loss of beta cell mass.
Similar presentation to type 2.
Wide phenotype.
152
Describe lipodystrophy:
Selective loss of adipose tissue.
Associated with insulin resistance, dyslipidaemia, hepatic steatosis, hyperandrogenism, PCOS.
153
Describe the acute inflammatory disease of the exocrine pancreas:
Usually transient hyperglycaemia due to increased glucagon secretion.
154
Describe chronic pancreatitis:
Due to too much alcohol consumption.
Alters secretions, formation of proteinaceous plugs that block ducts and act as a foci for calculi formation.
Stop alcohol consumption and treat with insulin.
155
Describe hereditary haemochromatosis:
Autosomal recessive disease. Triad of cirrhosis, diabetes and bronzed hyperpigmentation.
Excess iron deposited in liver, pancreas, pituitary, heart and parathyroids.
Most need exogenous insulin therapy.
156
What two molecules can form deposits in the pancreas?
Amyloidosis/cystinosis.
157
Describe pancreatic neoplasia:
Common cause of CA death.
4-5 resections per week at STH.
Requires Sc insulin.
Prone to hypoglycaemia due to loss of glucagon function.
Frequent small meals, enzyme replacement.
Insulin pumps.
158
Cystic fibrosis and diabetes:
CF transmembrane conductance regulator gene on chromosome 7.
Regulates chloride secretion.
Viscous secretions lead to duct obstruction and fibrosis.
Incidence I 25-50% in adults.
Ketoacidosis rare.
Insulin treatment is required.
As CF survival is better – microvascular complications are increasing.
159
How does insulin help patients with CF?
Improves body weight, reduces infections, improves lung function and quality of life.
160
Describe the endocrine causes of diabetes – acromegaly.
Excessive secretion of GH.
Similar to T2.
Insulin resistance rises, impairing insulin action in liver and peripheral tissues.
161
Describe the endocrine causes of diabetes – Cushings syndrome.
Increased insulin resistance, reduced glucose uptake into peripheral tissues.
Hepatic glucose production increased through stimulation of gluconeogenesis via substrates (proteolysis and lipolysis).
162
Describe the endocrine causes of diabetes – Pheochromocytoma.
Catecholamine, predominantly epinephrine excess.
Increased gluconeogenesis.
Decreased glucose uptake.
163
Give an example of a drug that leads to drug-induced diabetes:
Glucocorticoids increase insulin resistance.
Thiazides / protease inhibitors (HIV) / antipsychotics can all lead to insulin resistance (the mechanism is not clearly understood).
164
How does less insulin affect the blood vessels and glucose delivery?
Less insulin induced vasodilation in muscle leading to reduced glucose delivery to muscle beds, reducing opportunity of muscle to clear glucose from the blood.
165
Describe the cortisol circadian rhythm:
Starts to rise at around midnight with reaching the peak at 8-9 in the morning then continuously fall during the day.
166
Describe the circadian system:
A clock set to local time – light is the primary zeitgeber (changes in the quantity and quality of light at dawn and dusk).
Eye to SCN in the hypothalamus.
167
Is melatonin high or low during the day?
It is low in the day and high at night.
168
How does the central clock control the peripheral clocks?
Via second messengers – glucocorticoids.
169
Describe primary adrenal insufficiency (Addison’s disease) (93-140/M).
Problem with the adrenal gland itself.
Autoimmune adrenalitis >60% cases
Autoimmune polyglandular syndrome (APS) type 1 10-15% of cases.
Congenital adrenal hyperplasia (CAH) 1:15000 live births.
Adrenoleukodystrophy.
Mets, haemorrhage, infection
TB infection or amyloid infiltration.
170
Describe secondary adrenal insufficiency - hypopituitarism (150-280/M).
Pituitary macroadenoma / cranio.
Apoplexy.
Hypophysitis (checkpoint inhibitors).
Mets, infiltration, infection.
Radiotherapy.
Congenital.
171
Describe tertiary adrenal insufficiency – Suppression of HPA.
Steroids: oral, inhaler, creams.
172
How is AI diagnosed? (High level of suspicion).
History.
Signs.
Biochemistry.
173
What does the history in AI look like?
Symptoms: fatigue, weight loss, poor recovery from illness, adrenal crisis, headache.
Past history: TB, post-partum bleed, CA
Family history: autoimmunity, congenital disease
Treatment; ANY steroid, etomidate, ketoconazole.
174
What are the signs of AI?
Pigmentation and pallor.
Hypotension.
175
What does the biochemistry reveal in AI?
Low sodium, high potassium (SIADH like picture).
Eosinophilia.
Borderline elevated TSH.
176
What time are cortisol levels measured?
09:00 cortisol and ACTH.
Cortisol is >450-500 nmol/L = AI is unlikely.
Cortisol is <100 nmol/L = AI likely.
ACTH > 22 pmol/L = primary.
ACTH < 5 pmol/L = secondary.
177
Renin and aldosterone are elevated in which type of AI?
Elevated renin in primary AI.
178
What does the Synacthen test measure?
ACTH stimulation to see how well the adrenal gland makes cortisol.
250 microgram is administered IV 0’ and 30’.
If results are >450-500 nmol/L = AI unlikely.
179
What are the investigations in primary AI?
Adrenal antibodies.
Very long chain fatty acids.
17-OHP.
Imaging.
Genetic.
180
What are the investigations in secondary AI?
Any steroids?
Imaging.
Genetic.
181
Describe the management of adrenal crisis.
Take bloods if possible, for cortisol and ACTH levels.
Immediate hydrocortisone 100mg IV, IM, (SC).
Fluid resuscitation (1L N/Saline 1 hour).
Hydrocortisone 50-100mg IV/IM 6 hourly or 200mg/24hour.
In primary AI – fludrocortisone 100-200 microgram (when HC < 50mg).
When stable wean to normal replacement over 24-72h:
-50mg orally TDS
-20mg orally TDS
-10mg orally TDS
182
What are the sick day rules in AI?
Always carry 10 x 10mg tablets hydrocortisone.
If unwell with fever or flu like illness or in doubt = double the dose of steroids.
If vomiting = emergency injection of hydrocortisone 100mg IM (SC).
If unable to have injection = take hydrocortisone 20mg 6 hourly and repeat if vomit.
Go to ER.
183
What should all patients with AI carry?
Steroid emergency card.
184
Describe glucocorticoid replacement.
Daily production of cortisol 5-6 mg/m^2 BSA.
Hydrocortisone 15-25mg in 2-3 divided doses.
First dose on waking, second midday, third 17:00h.
HC can be 10/10/5 or 10/5/5 or 10/5/2.5.
Prednisolone (3-5mg/d) administered orally once or twice daily in patients with reduced compliance.
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When to check cortisol levels during treatment?
If malabsorption or rapid clearance is suspected.
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Can doe be adjusted during treatment?
Yes, dose can be adjusted according to symptoms and signs of under and over replacement.
?5mg if stressed/exercise.
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What is the dosage of mineralocorticoid treatment?
Usual dose 50-300 microgram once or twice daily.
Start with 100-150 microgram.
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What renin levels do we aim for in mineralocorticoid treatment?
Upper half of normal range
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What are monitored in mineralocorticoid treatment?
Urea and electrolytes + BP + salt craving.
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Give two examples of increasing or decreasing the dose of mineralocorticoid treatments?
Increase if sweating due to exercise or hot climate.
Reduce BUT DO NOT STOP in hypertension.
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Describe androgen replacement therapy.
Trial of DHEA in women with low libido and low energy levels.
DHEA provides normal body hair in young women with AI.
Dose 25-50mg daily.
Can measure DHEA levels and watch out for signs or symptoms of excess androgens.
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What are the challenges of treating AI in paediatrics?
Different dosages may be needed.
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Describe Alkindi treatment for children with AI:
Age appropriated dosing for the growing child.
HC granules in capsules for opening.
Taste masked to hide bitterness. Well tolerated and no adrenal crises.
Can be administered either directly to the mouth or sprinkled onto soft food or yoghurt.
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What are the outcomes of AI in adults?
Current glucocorticoid regimens cannot replicate physiology.
Standard mortality rate increased between 1.5 to 3.0.
Worse metabolic profile with increased GC dose.
Impaired quality of life.
Lowest dose = best quality of life.
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Describe the current HC therapy?
It is inadequate – three times a day. Too much drug initially then drops to too little.
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What are the benefits of Efmody tablets?
Delay release through pH coating (6.8) because of the gut length and transit time it was needed. Microparticulates in capsules.
Twice daily Efmody mimics the physiological release of cortisol.
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Why are exogenous glucocorticoids dangerous?
They can cause adrenal atrophy and also suppress the HPA axis.
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Describe salivary cortisol testing.
Non-invasive.
Stress-free sampling.
Can be performed at home.
Relatively cheap and easy.
Measure by LC-MS/MS (Liquid chromatography – mass spectrometry).
199
What are the objectives of diabetes treatment:
Reducing the risk of:
- CV morbidity and mortality
- CKD
- Microvascular complications
Weight reduction:
- Increasing physical activity
- Decreasing dietary fat
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What are the pillars of CVD and risk managements in DM?
Lifestyle modification and diabetes education.
Glycaemic control.
BP management.
Lipid management.
Agents with CV and Kidney benefit.
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The risk of diabetic complications increases with mean HbA1c, these include:
Diabetic retinopathy (DR).
Nephropathy.
Severe non-proliferative or proliferative DR.
Neuropathy.
Microalbuminuria.
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What is the driving force of hyperglycaemia in T2DM?
Hepatic insulin resistance.
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What are the 4 treatment options for controlling excess blood glucose in T2DM?
- Sensitising (Metformin and pioglitazone) = helping the body to respond better to its own insulin.
- Stimulate secretion (Sulphonylureas, DDP-4 inhibitors, GLP-1 receptor agonists) to stimulate the pancreas to secrete more insulin.
- Replace insulin by injecting insulin to promote the uptake/storage in liver and muscle.
- Excrete = remove excess glucose load (insulin independent) by SGLT2 inhibitors.
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What are the potential sequences of antihyperglycaemic therapy?
Lifestyle changes + monotherapy.
Dual therapy.
Triple therapy.
Combination injectable therapy.
205
What are incretins?
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.
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What do incretins do?
Promotes satiety and reduces appetite.
On the alpha cells: decrease postprandial glucagon secretion.
On the liver: reduced glucagon = reduced hepatic glucose output.
On the stomach: helps regulate gastric emptying.
On the beta-cells: enhances glucose-dependent insulin secretion.
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Describe DPP-4 inhibitors
Dipeptidyl-peptidase 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 hypo, body weight unchanged).
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DPP-4 inhibitors work by….
Orally available.
Small increase in endogenous GLP-1.
Little effect on gastric emptying.
Do not cause nausea and vomiting.
No effect on weight.
Effects are mediated by multiple receptors.
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GLP-1 analogues work by….
Injectable only.
Large increase in GLP-1 level.
Induces delay in gastric emptying.
Likely to induce nausea and vomiting.
Induces weight loss.
Effects mediated by GLP-1 receptor.
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What are examples of SGLT-2 inhibitors?
Empaglifozin, Dapaglifozin, Canaglifozin.
211
SGLT-2i and thrush in diabetes:
More common in women than men.
More often mycotic than bacterial.
Easily managed = SGLT-2i should be continued.
Co prescribed at initiation – self treat if any symptoms of candidiasis.
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What are the variations of bariatric surgery?
Roux-en-Y bypass.
Sleeve gastrectomy.
213
List the diabetic complications:
Stroke
CVD
DPN
PVD
Diabetic nephropathy
Diabetic retinopathy
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What are the clinical consequences of diabetic neuropathy?
Painful neuropathic symptoms.
Autonomic neuropathy and its manifestations (orthostatic hypotension).
Insensitivity (foot ulceration).
215
What is the typical sensory loss in DPN?
Glove and stocking. Starts in the toes and gradually marches proximally. Once lower limb is established it affects the upper limb.
216
Besides hyperglycaemic risk factors, what are the other risk factor for DPN?
Hypertension.
Smoking.
BMI.
Triglycerides.
Total cholesterol.
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What are the treatment options for Diabetic Painful Neuropathy?
Good glycaemic control.
Tricyclic antidepressants/SSRIs.
Anticonvulsants (Gabapentin).
Opioids.
IV lignocaine.
Psychological interventions.
218
What percentage of DM sufferers develop foot ulceration?
15% during their lifetime.
LL amputations occur is 15x more likely.
219
Describe the cause of diabetic amputation:
Neuropathy or vascular disease – trauma – ulcer – failure to heal – infection (osteomyelitis) – amputation.
220
What are the two principal factors for high-risk diabetic foot?
Peripheral neuropathy.
Peripheral vascular disease.
221
Describe motor nerve damage in peripheral neuropathy:
Causes weakness in the intrinsic muscles of the feet, leading to contraction of the muscles and clawed toes.
222
People with neuropathy do not feel pain, as a result of this they can develop?
Callus at the site of most pressure points.
223
What is a consequence of autonomic nerve damage?
People lose their ability to perspire so the skin dries out and becomes cracked. These cracks can be common portals for infections.
224
What are the screening tests for diabetic peripheral neuropathy?
Test sensation (10 g Semmes Weinstein monofilament, neurotips).
Vibration perception (tuning fork, biothesiometer).
Ankle reflexes.
225
Describe peripheral vascular disease?
Decreased perfusion due to macrovascular disease at more distal sites. 15-40 times more likely to have LL amputation.
226
What is the difference in PVD in people with and 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 therefore seen from the knee to ankle rather than the pelvis to knee.
227
What are the symptoms of PVD?
Intermitted claudication (worse on walking upstairs or uphill and relived by rest).
228
What are the signs of PVD?
Diminished or absent pedal pulses.
Coolness of the feet and toes.
Poor skin and nails.
Absence of hair on feet and legs.
229
What investigation methods are used in PVD?
Doppler pressure studies.
Duplex arterial imaging/MRA.
These are used to identify and confirm disease, predict healing or determine the need for surgical intervention.
230
What are the treatment options of PVD?
Quit smoking.
Walk through pain.
Surgical intervention – angioplasty.
231
What is currently being done to reduce the risk of amputation?
Screening to identify risk.
Education and providing orthotic shoes.
MDT foot clinic.
Pressure relieving footwear, podiatry, revascularisation, ABX.
232
Describe the national eye screening programme:
Early detection.
Eligibility >12 years old.
2 field retinal photography.
Screeners grade photographs.
233
Describe the pathogenesis of leakage (DR):
Basement membrane thickening.
Pericyte loss.
Reduces junctional contact with endothelial cells.
Leakage.
234
Describe the pathogenesis of ischaemia (DR):
Pericyte loss, endothelial cells respond by increasing turnover > thickening of the basement membrane = ischaemia.
Glial cells grow down capillaries and lead to occlusion.
Ischaemia and occlusion = proliferation.
235
Describe DR gradin from R0-R3:
R0 = none
R1 = background
R2 = pre-proliferative
R3 = proliferative
236
Describe DR grading from M, P, U:
M: maculopathy
P: photocoagulation
U: unclassfiable
237
What are used in glycaemic control?
HbA1C (risk reduction – not elimination)
Piglitazones
Semaglutide
Closed loop system
238
What other factors need to be controlled for glycaemic control?
BP.
Lipids (Statins, fenofibrate).
Smoking.
239
Glycaemic control in pregnancy.
Digital surveillance arm of the screening service (Diagnosis, 16-20 weeks, 28 weeks gestation, 6/12 post partum).
Optimise control.
Normal birth.
Tropicamide.
240
Laser therapy for DR?
Only proven treatment.
Benefits > risks.
Aim is to stabilise changes.
Treatment does not improve sight.
241
Photocoagulation can be:
Focal/grid to macula.
Peripheral scatter.
242
What are the risks of laser treatment?
>50% difficulty with night vision.
1 in 5 lose peripheral vision.
3% stop driving because of tunnel vision.
Temporary drop in acuity.
Vitreous haemorrhage.
243
Effectiveness of laser treatment?
>90% of severe sight loss prevented by laser for early proliferative retinopathy.
Laser of macular changes prevents 0%.
244
Describe diabetic nephropathy.
Characterised by progressive kidney fibrosis resulting in loss of function.
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.
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What is the CKD definition?
Abnormality of kidney structure and/or function for >3 months with implications for health.
Decreased eGFR <60ml/min/1.73 m^2.
Albuminuria A2-A3 <30 mg/g.
246
What pathways are involved in DKD?
Metabolic.
Haemodynamic.
Inflammatory.
247
Spot collection values for albuminuria for males and females (mg/mmol creatinine):
Normoalbuminura <2.5 and <3.5
Microalbuminuria 2.5-25 and 3.5-35
Macroalbuminuria >25 and >35.
248
Describe the CKD classification scale:
Grade 1 = kidney damage with reduced eGFR 90->105
Grade 2 = mild CKD with GFR 60-89.
Grade 3 = moderate CKD with GFR 30-59.
Grade 4 = Severe CKD with GFR 15-29.
Grade 5 = ESFR with GFR <15 or dialysis.
249
What is the different in microalbuminuria in T1 and T2?
T1: develops 5-10 yrs of diagnosis
T2: can be present at the time of Dx.
250
Why do 20% of patients with albuminuria have normal GFR?
Better BP/BG control and RAAS blockade.
251
What are the Rx options of DN?
Blood pressure control.
Glycaemic control.
RAAS blockade: max tolerated ARB and ACEi.
Add SGLT-2i, NS-MRAs and GLP-1 RA.
Cholesterol control.
Proteinuria control.
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