Endocrinology Flashcards
What is empagliflozin
Glifozin class
sodium glucose co-transporter-2 (SGLT-2) inhibitor
induces glucose excretion via the kidney
Reduces Major Adverse Cardiac Event risk
i.e. reduces cardiac death and CCF
What is liraglutide
GLP-1 - glucagon like peptide 1
potentiates insulin release
inhibits glucagon release
slows gastric emptying
have a BMI of 35 kg/m2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or
have a BMI lower than 35 kg/m2and:
for whom insulin therapy would have significant occupational implications or
weight loss would benefit other significant obesity‑related comorbidities
REDUCES MACE
Whats is the therapeutic range of glicazide
25-160mg
little evidence of increased effect beyond 160mg dose - flat dose response curve beyond this
What is Diabetic Amyotrophy
Aetiology unclear
Poor diabetic control results in LMN lesions below sacral plexus sensory motor neuropathy -proximal weakness -neuropathic pain -loss of reflex arc -flaccid plantars -loss of tone bilaterally
Treatment:
TIGHTER CONTROL
TRANSITION TO INSULIN
RECOVERY = 3-4 MONTHS
ONLY 50% GO BACK TO BASELINE
What causes false positives in dexamethasone suppression tests?
Dex is metabolised by the cytochrome p450A system
Induction of the enzyme will lead to greater breakdown of dex and a failure to exert an effect on central ACTH production
i.e. Appearance of failed suppresion = ? ectopic ACTH
NB Ectopic ACTH is most commonly from bronchial tumour
p450 INDUCERS = SCRAP GP Sulponylureas - gliclazide /tolbutamide Carbemazepine Rifampicin Alcohol phenytoin
griseofulvin
phenobarbitol
When is insulin initiated in DM2
At the second intensification of treatment
1. Start metformin and titrate 2 Dual therapy (metformin +... sulphonylurea - gliclazide - potentiate insulin release DPP4 i - gliptins - increase GLP-1 and GIP halflife SGLT-2i - empagliflozin urinary excretion pioglitazone - (TZD PPAR-y) 3 triple therapy metformin +SU + sitagliptin metformin + SU + pioglitazone metformin + SU + SGLT-2 metformin + pioglitazone + SGLT-2 metformin + SU + GLP-1
4 Insulin + METFORMIN / GLP-1
Describe how to managed type 2 diabetes
Principal : Education Diet control Exercise yearly screening - opth / podiatry Agree on HbA1c target
HbA1c >48 = MONOTHERAPY
Start metformin and titrate
increase insulin sensitivity
HbA1c >58 = DUAL THERAPY = AIM <53
FIRST INTENSIFICATION
a) Metformin and a gliptin (DPP4-i)
(sitagliptin - increase GLP-1 and GIP halflife)
or
b) Metformin and sulfonylurea -
(gliclazide - potentiate insulin release)
or
c) Metformin and SGLT-2 inhibitor - gliflozin class
(empagliflozin - induce glucose urinary excretion)
or
d) Metformin and TZD - PPAR-y agonist
(pioglitazone - drive FFA storage and increase CHO use)
HbA1c remains >58 = TRIPLE THERAPY AIM <53
SECOND INTENSIFICATION
METFORMIN + SULPHONYLUREA+
a) TZD pioglitazone - PPAR-y agonist
b) DPP4i sitagliptin - increase GLP-1 and GIP halflife
or
METFORMIN + PIOGLITAZONE+
c) SGLT-2 inhibitor - empagliflozin - increase cho in urine
d) Trial GLP-1 with triple therapy
metformin pioglitazone liraglutide
e) INSULIN + metfomrin
f) INSULIN + GLP-1
Review:
Continue liraglutide if HbA1c has fallen and weight loss 3% in 6 months
Consider insulin + GLP-1 - specialist review
How do the Gliptins (DPP4-i) help in blood glucose control and when should they be considered?
Gliptins are DPP4 - i (Dipeptidyl peptidase-4 inhibitor)
They inhibit DPP4
This results in a longer halflife of circulaiton GLP-1 and GIP which together
1. increase incretin stimualted insulin production
2. suppress glucagon release
Use:
Second line agent in combination with metformin if metformin alone doese not lower HbA1c <58
Describe what happens in relation to normal GLP-1 and GIP
- meal ingestin
- incretin release
- production of GLP-1 and GIP
- DPP-4 breaks these two proteins down - GLP and GIP act on B islets to stimulate insulin release
- increased cellular glucose uptake via glut-4 - GLP-1 acts on A cells to inhibit production of glucagon
- reduced hepatic neogenesis and glycogenolysis
How do TZDs work and what is an example of one?
When are they used?
Thiazalidinediones - aka glitazones e.g. PIOGLITAZONE
Second line agent to be used in combination with metformin for blood glucose lowering
MOA:
Pioglitazone binds the nuclear receptor PPAR-y
Cobinding to retinoid receptor X this induces transcription of proteins that INCREASE FREE FATTY ACID STORGE
This shifts cellular metabolic dependency to carbohydrates and away from fatty acids and ketons
Thus the cell must increase expression of glut-4 / glut-2 and increase absorption of glucose lowering circulating glucose levels
When is metformin contraindicated
EGFR <30
need dose adjustment <45
AKI
Lactic acidosis
If metformin is not tolerated / contraindicated what should initial management of DM2 begin with
1) education
diet / lifestye / compliance / HbA1c monitoring and FU
2) initiate monotherapy
TZD - pioglitazone ppar-y agonist
DPP4i - the gliptins which increase GLP-1 and GIP halflife
Sulphonylurea - gliclazide - potentiate insulin release
SGT
AIM HbA1c <48 or <53 if on sulphonylurea
3) dual therapy
Pioglitazone + SGLT-2 i (emplagliflozin)
Pioglitazone + sulphonylurea
Sulphonylurea +DPP4 - i
4) triple therapy or insulin
pioglitazone + SU + SGLT-2
sulphonyl urea + DPP4 i + SGLT-2i
Pioglitazone + GLP-1 + SGLT-2
5) insulin + metformin
6) insulin + GLP-1
When is a pioglitazone contra-indicated
heart failure or history of heart failure
hepatic impairment
diabetic ketoacidosis
current, or a history of, bladder cancer
uninvestigated macroscopic haematuria.
What oral antidiabetic agents do you know and how do they work
Metformin - monotherapy
weight loss
no risk of hypoglycaemia
increases insulin sensitivity - GLUT-4 transcription
Sulphonylurea - glicalzide
risk of hypo
potentiates insulin release
weight gain is common
DPP4i - sitagliptin
suppress appetite due to greater GLP-1 and GIP circulation
risk of pancreatitis and drug reaction
Thiazalidinediones - pioglitazone
PPAR-y agonist together with RXR protein increase FFA storage and push energy metabolism to favour CHO
GLP-1 like agonist - liraglutide
mimic action of GLP-1 on B islets potentiating insulin release and on a cells suppressing glucagon release
can promote weight loss but due to risk of hypo should be carefully monitored especially if on insulin currently
SGLT-2 - empagliflozin
Potentiates increase in urinary glucose excretion - blocks PCT reabsorption.
How is insulin initiated?
For DM2 insulin should be continued alongside metformin
-Start intermediate acting insulin BD (NPH / ISOPHANE /
independent / can self administer
-Start long acting - levemir / glargine / detemir
Reducing to once daily injection if needs carer support
unable to self administer
risk of hypoglycaemia
poor compliance
-Start mixed / biphasic insulin preparation if the HbA1c is >75 on review
How does post partum thyroiditis present?
3-7 months post partum
Weight gain post partum
low mood
fatigue
anti-TPO antibodies present in 30-52%
40% will develop permanent hypothyroidism - majority of these are TPO positive
Mx:
low dose thyroxine 50mcg and withdraw after 6 months to measure recovery
How does Kallman syndrome present?
ISOLATED GONADOTROPHIN DEFICIENCY
Infertility Anosmia Lost libido Gonadal deficiency absent secondary sexual chars
LOW LH
LOW TESTOSTERONE
NORMAL FSH (high in kleinfelter)
Mx:
Need GnRH or pulsed gonadotrophin therapy
Testosterone replacement - will not resolve fertility
How does Kleinfelter syndrome present?
XXY chromosomal disorder
androgen deficiency - limited testosterone production and high fsh and lh
Present early: poor sexual development small or undescended testicles gynaecomastia infertility learning disabilities
Associated:
DM2
breast Ca
tall
Mx:
Androgen replacement
What are causes of raised prolactin
- pregnancy
- COCP
- prolacintoma - prolactin >1000
Prolactinoma may present with: erectile dysfunction lactation on minimal stimualtion vaginal dryness lost libido amenorrhoea
Prolactin suppresses FSH and LH production
Mx:
Dopamine agonist - suppreses prolactin
BROMOCRIPTINE / ROPINIROLE / CABERGOLINE / PERGOLIDE
nb side effect of cabergoline and pergolide = pericarditis
MRI pit fossa
SURGERY
What are side effects and contraindications to pioglitazone
Pioglitazone is a TZD which acts on PPAR-y stimualting FFA storage and shifting metabolic focus to glucose metabolism
It has notable side effects including fluid retention and bone demineralisation
It actively improves hepatic steatosis
What is deQuervains Thyroiditis?
How does it present?
What might blood tests show?
Inflammatory post viral or inter-viral thyroiditis that causes
- Painful thyroid gland
- Transient period of hyperthyroidism secondary to damage to thyroid follicles
- rendering of a euthyroid state
- new hypothyroidism which is mostly transient
Management
- conservative
- NSAID
- small proportion will remain hypo and need
- beta blockade for hyperthyroid phase
What is Hashimotos Thyroiditis
Autoimmune hypothyroidism
Anti TPO abs
Painless hard goitre
What is Reidels Thyroiditis?
Euthyroid Goitre
Woody fibrosis
Risk of Tracheal compression
How is Acromegally diagnosed?
1. History Dentures not fitting Shoes dont fit Shovel hands Frontal bossing Wide spaced teeth from maxilla hyper trophy Coarse hair finger measurement Temporal field defect = optic chiasm adenoma weight gain new onset DM2 / insulin resistane
- IGF-1 screening
3.OGTT
IGF-1 / GH / glucose at time = 0
75g glucose oral
Measure GH / glucose at 30 60 90 120 150 180
Glucose bolus should stimulate insulin production and suppress IGF and GH.
Failure to suppress = Likely macroadenoma
What is DI?
How many types are there?
5 types of DI
Basis is a failure to concentrate urine resulting in polydipsia and polyuria.
-Central DI is due to an ADH deficiency ages of 10 and 20 and occurs in males and females = Idiopathic Tumours cranial surgery or HI
- Nephrogenic DI is due to ADH insensitivity
- Dipsogenic DI is due to abnormal thirst mechanisms in the hypothalamus
-Gestational DI occurs only during pregnancy.
Placenta produces vessopressinase - breaks down arginine vassopressin
If excessive can lead to DI
Treat with desmopressin - not vassopressin as this will be broken down
Also caused by gestational Toxemias - imparied hepatic clearance of normal vessopressinase therefore less active ADH and more urine produced and excreted
-Psychogenic polydipsia may also manifest as DI but unlike DI will respond to a water deprivation test
Diagnosis:
Serum and urine osm
Urine Na
water deprivation test - measure urine output over 24 hours + remeasure urine and serum osm to see if urine is concentrated. In central and nephrogenic, gestational it will not. Dipsogenic and psychogenic it will.
Typically the urine will be very dilute (low urine osm compared to serum osm) and production can exceeed 20L/day
Mx:
Central and Gestational = ADH replacement - vassopressin
Gestational: desmopressin
Nephrogenic - treat underlying cause or use indapamide / bendroflumethiazide
What are the water deprivation and vassopressin challenges and what are they used for
Used to diagnose and distinguish the forms of Diabetes Insipidus and rule out primary polydipsia
1L fluid restriction put in place for 24 hours
- measure the changes in body weight, urine output, and urine composition when fluids are withheld to induce dehydration.
- The body’s normal response to dehydration is to conserve water by concentrating the urine. Those with DI continue to urinate large amounts of dilute urine in spite of water deprivation. I
- In primary polydipsia, the urine osmolality should increase and stabilize at above 280 Osm/kg with fluid restriction, while a stabilization at a lower level indicates diabetes insipidus.
- Stabilization = increase in urine osmolality is less than 30 Osm/kg per hour for at least three hours.[
Desmopressin stimulation
- drink fluids or water only when thirsty to avoid cerebral oedema
- If desmopressin reduces urine output and increases urine osmolarity, the hypothalamic production of ADH is deficient, and the kidney responds normally to exogenous vasopressin (desmopressin).
- If the DI is due to renal pathology, desmopressin does not change either urine output or osmolarity (since the endogenous vasopressin levels are already high).
How does a phaeochromocytoma present?
TYPICAL:
HTN + Paroxysms of headache + palpitations + sweating
MEN2A and MEN2B
Also less commonly - Acute heart failure
-cateholaine induced cardiomyopathy
Most commonly:
Adrenal medullary tumour
Often bilateral
If not - preganglionic often
If cannot be located on CT = 131 MIBG scan to localise source of metanephrin production
ALSO: Acute heart failure Flushing Tachycardia syncopal / pre-syncopal hypotensive / hypertensive confusion
MX:
24 hour urinary catecholamines / metanephrins
adrenal androgens
renin:aldosterone ratio for HTN
RX:
Surgery
Alpha blockade first - PHENOXYBENZAMINE
If b blockade first can be sent into hypertensive crisis
What are the multiple endocrine neoplasia syndromes
Cause:
2 hit hypoth - genetic and somatic in MEN1 gene
Transcripts found in all body systems
MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant
Carcinoid tumours are also associated
MEN I (3 Ps) - Pituitary, Pancreatic, Parathyroid, MEN IIa (2Ps, 1M) - Pheochromocytoma, Medullary Thyroid Ca + Parathyroid MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma
How is gestational Grave’s disease managed?
Thyroxine does not cross the placental barrier Other will be experiencing symptoms of GD - hypertension - palpitations - headache - flushing and anxiety - sweating - thyroid acropatchy - exophthalmos - smooth goitre - painless
MX:
Abs = ANTI-THYROID ANTIBODY POSITIVE
Thyroid receptor stimulating antibodies
TSH neg
RX:
No need to block and replace
Instead block and monitor T4 levels aiming to keep in upper 2/3 of normal range
USE CARBIMAZOLE LATE - LESS HEPATOTOXICITY IN PREGNANCY
PROPYLTHIOURACIL CAN BE USED IN EARLY PREGNANCY BUT NOT IN LATE
How does Paget’s disease cause deformity?
osteitis deformans
Paget’s disease is described in four stages
1 - Increased Osteoclastic activity VIA RANK-L - loss lamellar bone
2 - Mixed osteoclastic – osteoblastic activity
3 - Osteoblastic activity - lay down trabecular bone - weak - and replace marrow with highly vascularised trabecullar bone
Eventually the whole struture becomes decellularised = BURNED OUT PAGETS
4 - Malignant degeneration - 1% osteosarcoma
Overall this leads to
1) lytic lesions / wedge fractures / spont fractures / osteolytica circumspecta of the skull
2) MSCC / hip fractures
3) malignant osteosarcoma in a minority
4) pancytopenia
MX: BONE SCAN SKELETAL SURVEY BISPHOSPHONATES 6 MONTHLY ALP LEVELS
Goal of therapy is to normalise bone turnover and ALP is a marker of this
typical bloods at presentation
NORMAL CALCIUM and PHOSPHATE
RAISED ALP
NORMAL LFTS OTHERWISE without history of ALD / hepatitis / psc / pbc and no jaundice
What is the function of the adrenal gland
- ZONA GFR=ACT
The functions of the adrenal gland can be split into 3 anatomically distinct regions of the cortex
1. Zona glomerulosa = ALDOSTERONE REABSORB SALT AND EXCRETE POTASSIUM reduces renin production (initial stimulus) 2. Zona fasciculata = CORTISOL GLUCOSE / METABOLISM / INFLAMMATION 3. Zona reticularis = TESTOSTERONE FERTILITY / LIBIDO Peripheral tissues Testosterone to DIHYDROTESTOSTERON via 5a reductase Testosterone to oestrogen via AROMATASE
What is CONN SYNDROME and how is it different to LIDDLE SYNDROME?
How is it diagnosed?
What causes it?
How is it treated?
Principally Conn and Liddle are very similar
Both result in the effects of hyperactivation of the NA/K DCT exchanger
HYPERTENSION
HYPOKALAEMIA
HYPERNATRAEMIA / NORMAL / NORMAL HIGH
METABOLIC ALKALOSIS
HOWEVER
CONN
= HYPERSECRETION OF ALDOSTERONE
-Renin suppressed
-High Aldosterone
-acidified urine - activation of Na+/H+ exchanger
-metabolic alkalosis
=Primary hyporeninaemic hyperaldosteronism
Constant secretion of aldosterone from zona glomerulosa of adrenal cortex either due to a ZG hyperplasia or adenoma
= Hyporeninaemic hyperaldosteronism with hypernatremic, hypokalemic, metabolic alkalosis.
LIDDLE = HYPERACTIVATION OF DCT SODIUM/K+ EXCHANGER -Renin and Aldosterone suppressed -urine acidified -metabolic alkalosis
Actions:
DCT and CD = sodium absorption / K+ excretion
DCT H+ / Na+ exchanger = acidifies urine / absorbs sodium
CONSEQUENCES:
Plasma volume expansion results due to osmosis
BP rise = > Atrial stretch + JMA reduces renin
ANP = natriuretic and decreases sodium reabsorption - no effect on K+ channels
JMA = reduces renin = reduces ang1/ang2
Result = correction of hypernatraemia - high normal
hyporeninism
hypokalaemia
metabolic alkalosis (loss of H+)
DIAGNOSIS:
HYPOKALAEMIA - esp if occurs while on ACEi
-Normally ACEi would reduce ANG II and so reduce aldosterone production leading to retention of potassium rather than a low potassium
-renin:alodesterone ratio
MX:
SPIRONOLACTONE / EPILERONONE FOR CONNS
Salt restricted diet
AMILORIDE FOR LIDDLE
-spiro has no effect as defect is with the channel itself - not the upstream receptor
