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
What is polyglandular syndrome
3 types of AUTOIMMUNE polyglandular syndromes
HYPOS of EVERYTHING
1) PGS 1 = WHITAKER SYNDROME AIRE GENE MUTATION - aut recessive addisons hypoparathyroidism -candidiasis
2)PGS 2 = SCHMIDTS - most common PGS (HLA-DQ2, HLA-DQ8 and HLA-DR4 linked) addisons hypothyroid DM1 \+/- coeliac and myaesthenia / graves and hashimotos - low sodium (no aldosterone) - low T4 / high TSH - elevated FG >7 / random >11
3) X linked PGS 3 - FOXP3 mutation - loss of tolerance
AI thyroiditis and other assorted AI conditions
What is PGS1 associated with?
Whitaker syndrome
AIRE mutation
ADDISONS
HYPOPARATHYROID
CANDIDA
What is PGS2 associated with?
SCHMIDTS syndrome
HLA linked
DM1
ADDISONS
HYPOTHYROID
COELIAC / MYAESTHENIA / pernicious anaemia
What is PGS3 associated with?
X linked IPEX syndrome = mutation in FOXP3
Responsible for T cell tolerance mechanisms
multiple AI pathologies arise due to lack of screening in thymus / lack of Il-10 and tgfb secretion by CD25+ Tregs
How does postpartum hyperthryoidism present?
how is it diagnosed
Causes hyperthyroidism and low TSH
TSH R ab +VE
TPO ab +ve
follows similar course to deQuervains
thyrotox–>euthyroid –>hypothyroid (may be permanent)
How is Insulinoma diagnosed?
Fasting for 15hrs
C peptide and pro-insulin titre measured
glucose measured
Normal response is insulin suppressed and normal glucose levels maintained due to glucagon and glycogenolysis
Glucose <2.5 and insulin >5 (majority is proinsulin) = insulinoma
72hr fast = 98% sensitivity
ALL MEN
Associations:
MEN I (3 Ps) - Pituitary, Pancreatic Insulinomas or glucagonoma, Parathyroid,
MEN IIa (2Ps, 1M) - Pheochromocytoma, Medullary Thyroid Ca + Parathyroid
MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuromaMEN 1 = classic 3 Ps - phaeo / pancreatic insulinoma or glucagonoma / parathyroid cancer
What is he pentagastrin stimulation test and when is it used?
What does it do? - SYNTHETIC GASTRIN
stimulates gastrin / gastric acid / calcitonin and intrinsic factor release
binds CCK-R
Used to diagnose
1. Carcinoid syndrome to induce flushing / drive serotonin response in borderline individuals
2. diagnose meckels
3. diagnose medullary thyroid cancer = Men 2a and Men 2b
typically a hard mass is found on the neck and may be associated with signs of phaeochromocytoma
PENTAGASTRIN - CALCITONIN STIMULATION TEST
Pentagastrin given
-cause calcitonin levels to rise significantly above the normal or basal range
-calcitonin normally inhibits PTH - thus in MTC expect low calcium levels.
-After a total thyroidectomy for medullary thyroid carcinoma, the pentagastrin-stimulated calcitonin release can be used to detect residual parafollicular cell C-cells.
What is medullary thyroid cancer?
Malignancy of calcitonin parafocllicular C cells - secreting cells of thyroid and associated with raised calcitonin levels
How is PCOS diagnosed
Rotterdam criteria - need 2/3 Oligo / amenorrhoea hyperandrogenism - raised DHT / low oestrogen - coarse hair / facial hair cysts on USS - >12 follicles in each or 1 ovary over 2mm
Associated:
adrenal hyperplasia, hypothyroidism, and hyperprolactinemia.
Present: weight gain irregular menstruation - heavy / oligo / amen hirsutism polydipsia / polyurea if early DM2 infertility
What is the normal ratio of TP : globulins
60:40
globulins combine all binding globulins / immunoglobulins / enzymes in plasma
How does myeloma present?
Hypercalcaemia WITHOUT hypophosphataemia
- bone pain
- low mood and depression
- renal stones
- abdominal pain and constipation
+ spontaenous fracture
+ proetinureia
Diagnosis:
Serum free K and L light chain electrophoresis
will be either IgM / IgA / IgG dominant process
B cell myeloma
Mx:
Steroid - pred 40
pamidronate
chemotherapy
How do bisphosphonates work
Bind to hydroxyapetite and inhibit osteoclast activity
Can rapidly correct hypercalcaemia from bone turnover in myeloma
risk of AVN
What is necrobiosis lipodica?
Associated with DM1 and may repdate onset - 0.3-1% incidence
Characterised by area of skin atrophy and ulceration with pigmentation
Nona trophied areas should be treated with topical steroid
What is Von Hippel Lindau syndrome?
Haemangioblastoma
Renal cell cancer
Phaeochromocytoma
Syndrome characterised by cyst formation, -Haemangioblastomas
- cns ataxia / retina / spinal cord
RCC
- polycythaemia due to secondary increase in EPO
When switching from sliding scale to insulin how should it be prescribed
Insulin requirement whilst in hyperosmolar hyperglycaemic state will be greater than normal 24 hr requirement
Therefore count sum fo insluin over 24 hours on sliding scale
prescribe 2/3 dose split bd mix 30
What are common features observed in autonomic diabetic neuropathy?
Postural drops Gastroparesis peripheral sensory neuropathy proprioceptive feedback loss - charcot's joints achalasia
DDX:
AXR = dilated stomach
isotope motility study - assess gastric emptying
RX:
bed head elevation / compression stockings / education re: sitting up - FLUDROCORTISONE 50MCG start and titrate to max 400mcg /24 hr
Erythromycin 50 qds / metoclop / domperidone
senna
Where do Xanthoma typically present
Accumulation of lipid laden foam macrophages reflecting lipid metabolism
The defect makes the body unable to remove low density lipoprotein = ACCELERATED ATHEROMATOUS DISEASE
FAMILIAL HYPERCHOLESTEROLAEMIA = 1/500 Tendon Xantholamata + high cholesterol = PATHOGNEMONIC - Other causes of tendon deposition are very rare Achilles tendon Knuckles extensor hallucis longus triceps tendon tibial tubersotity Cholesterol >7.5mmol/l
Heterozygotes - CAD in 30s and MI 60s
Homozygotes - CAD in teens and MI 30s - Cholesterol >16
Treatment:
- atorvastatin - reduce LDL - promote HDL - improve TG clearance
- ezetimibe statin dual therapy or if statin not tolerated
- add in fibrate to reduce TG absorption
What does necrobiosis lipodica look like?
Associated with diabetes 0.3-1%
may predate / post date
atrophic skin changes associated with multifocal necrotic uclers with that are slow to heal
What is the most common arthropathy
Gout and Pseudo gout characterised by uric acid crystals and calcium pyrophosphate crystals within the joint space respectively
How does phenoxybenzamine work?
Alpha blocker - highly potent - non selective irreversible
used in treatment of phaeochromocytoma prior to b-blockade
Dose 10mg bd increased to 20mg qds. - 3 days continuous treatment before surgical intervention to ensure complete alpha blockade
What is characteristic of neurofibromatosis 1
autosomal dominant mutation of TSG NF1 Chr 17
NIH criteria need >2
- > 6 Cafe au Lait spots >15mm
- > 2 neurofibromas or one plexiform lesion - bag of worms. Neurofibromas are tumors of the peripheral nerves
- Axillary or Inguinal freckling
- Lisch nodules - iris brown hamartomas >2
- Optic Glioma (MOST COMMON TUMOUR)
- FMH
- pseudarthrosis - previous non healed fracture forms pseudojoint
- SCOLIOSIS
optic gliomas are treated with chemo
Associated with HTN
Renal Artery Stenosis
Phaeochromocytoma
Aortic Coarctation
RARE - SCHWANNOMA / MENINGIOMA
normal LE
What is characteristic of neurofibromatosis 2
Chr 22
Differs considerable from NF1 - mainly schwanomas
- scanty neurofibromas - S/C gliomas / schwannomas instead
- very scanty cafe au lait- <6
- NO Crowe’s sign - axillary freckling
- NO LISCH nodules on iris (hamartomas)
LEARNING DIFFICULTIES
ACOUSTIC NEUROMAS + SN DEAFNESS - BILATERAL
ATAXIA
NIH Diagnosis:
A) Bilateral acoustin neuromas on CN VIII on Ct or MRI
or
2 of:
-unilateral acoustic neuroma
-glioma / schwanomma / meningioma/neurofibroma
-FMH
Associated HTN:
phaeochromocytoma
Renal artery stenosis
Aortic Coarctation
Reduced LE due to compressive CNS lesions
McCune Albright syndrome may also present with neurofibromas - how is it different to NF1 / NF2?
Mutations in a G protein coupled receptor found in multiple body systems
- hyperactivation of many endocrine processes
- cafe au lait pigmentation whcih does not cross the midline
- cafe au lait spots that follow developmental lines =nape of neck and crease of buttocks
Path fractures
Precocious puberty: Commonest - estrogen-producing cysts =early menarch / rapid growth / early breast development BUT Less common in males = macroorchidism
Hyperthyroidism: 33%
Growth Hormone Excess: GNAS mutation ant.pit.
Cushing’s Syndrome: rare + in infancy
How does gonadal failure present in bloods
Low testosterone
high FSH
high LH
High GnRH
e.g. Kleinfelter XXY = gonadal failure - HIGH FSH / HIGH LH AND LOW TESTOSTERONE
DIff to Kallman where LH and testosterone are low (Gonadotrophin deficiency)
What triad defines Conns and Liddle Syndrome
HYPERTENSION
HYPOKALAEMIA
METABOLIC ALKALOSIS
How does Conns differ from Liddle syndrome - SPIRONOLACTONE / AMILORIDE TARGET
Conns is primary hyperaldosteronism - can be blocked with spironolactone
Liddle is constitutive activation of the aldosterone receptor target channel - NA/K+ exchanger. Spironolactone will have no effect but amiloride will block the channel
What is Gittelman syndrome? (TZD / INDAPAMIDE TARGET)
Aut Recessive mutation in thiazide-sensitive sodium-chloride symporter in DCT = transports K+ / Na / CL / Cal / Mag
Constitutively inactive
Results: -hypokalaemia -hypomagnesia -hypocalcaemia - METABOLIC ALKALOSIS The high lumenal K+ results in compensatory ativation of H+/K+ exchanger and net loss of H+
What is Bartters syndrome (FUROSEMIDE TARGET)
Aut Recessive mutation in furosemide sensitive thick ascending limb of th eloop of henle affecting the loop diuretic transporter Na+ 2cl- / K+ transporter
hypokalemia, metabolic alkalosis, and normal to low blood pressure and secondary hypomagnesia / hypocalcaemia
Normally works through active transport of Na+ and Cl-into medulla.
Water follows. lumen osm increases.
Diffusion of K+ back into nephron further increasing osm and +Ve charge
Mg2+ and Ca2+ transport relies on maintaining +ve charge in lumen i.e Mg2+ Ca2+ moves down ion gradient into cell from lumen
Therefore dysfunction of Na / K / CL transporter results in
- HYPOTENSION (NO H20 MOVEMENT)
-HYPOKALAEMIA
-HYPOMAG
-HYPOCAL
- METABOLIC ALKALOSIS
The high lumenal K+ results in compensatory ativation of H+/K+ exchanger and net loss of H+
How is Paget’s disease activity monitored
ALP 6 monthly
skeletal survey
limited evidence bisphosphonates slow progression
What paraneoplastic conditions arise in SCLC
SIADH
- Thirst
- Dilutional Hypontraemia
- dilute serum osm
- Can lead to salt wasting syndrome as well due to secondry renal medulla washout
- urinary sodium >20
- responds to fluid restriction
Ectopic ACTH
- cortisol - glycusouria and impaired FG / OGTT
- aldosterone - hypokalaemia + corrected hypernatraemia
- metabolic alkalosis
- HTN
hyporeninemic hyperaldosteronism
- will fail dexamethasone suppression test
Is prolactin elevated in thyroid disease?
prolactin is elevated in hypothyroidism
It is suppressed by dopamine - e.g. bromocriptine / cabergoline / percolide
What does lead poisoning cause
Aldosterone resistance
Also lead poisoning interstitial nephritis
also headaches
abdo pain
glycosuria
aminoacid uria
Mx:
penicillamine
DMSA
calcium disodium edetate
How does glucagonoma present and what is the incidence?
Rare
skin = NECROLYTIC MIGRATORY ERYTHEMA
impaired FG and OGTT
lethargy
weight loss
glycosuria
What picture is seen in SIADH?
ADH causes urinary concentration in the colelcting ducts via AQ2
It causes a net movement of water
Therefore EXPECT: Low serum osm (being diluted) <280 high urine osm (being concentrated >300 Dilutional hyponatraemia - becomes salt wasting Stable BP
worsened by given salt fluids
treat:
tolvaptan
fluid restriction
What is the aetiology of secondary hyperparathyroidisms?
CKD
insufficient a1 hydroxylase in kidney = less 25oh vit D
therefore less calcium absorbed from guy
greater calcium urinary losses
activation of PTH. Remains elevated as vit D conversion correction pathway is irreperable
treat with calcium supplementation
vit d supplementation
calcitonin
How does DeQuervains thyroiditis present?
How is it treated
Post viral thyroiditis - over release Vs over production
inflammatory attack of thyroid gland leading to degranulation of T3 and T4
No rise in TSH - suppressed
typical features of hyperthyroid
May then appear hypothyroid
may recover - may not
MX:
nsaid - pred if pain not improving
conservative
replacement if not recovering
How is Grave’s hyerpthyroidism treated?
Radioiodine uptake into nodules
increased uptake seen on isotope scan
How is Cushings disease diagnosed?
Low dose Dexamethasone suppression test
Aim is to suppress ACTH production and therefore Cortisol production.
Successful suppression results in cortisol <50 and rules it out
>50 = cushings disease
Progress to MRI pituitary ?ACTH secreting adenoma
In this case high ACTH would suggest pituitary
Low ACTH would suggest adrenal cushings
What is high dose dexamethasone suppression used for?
Differentiate Cushings disease from ectopic ACTH production
i.e.
How is overactive bladder managed?
botulinum toxin if failed anti-muscarinics (oxybutynin)
How is a diabetic foot ulcer managed?
Co-amoxiclav - 2 weeks
MRI to rile out osteomyelitis if deep ulceration
How is PCOS managed
Androgen effects - anti-androgen or oestrogens
COCP
co-cyprindrol
help to re-establish menstrual regularity
reduce hirsutism
metformin
can help regularise periods
Liraglutide - weight loss + glycaemic control
GLP-1 agonist
inhibits glucagon secretion
increases insulin production
increases satiety and promotes weight loss
takes up to 6 months to see an effect
ovaarian drilling
How is oesteoporosis managed?
bisphosphonates
alendronate / risedronate etc
Anti-Rank L
denosumab
How does osteomalacea present and how is it treated?
low vit D = High PTH = high turnover to restore calcium homeostasis
Fractures
proximal weakness
malaise
Treat with high dose cholecalciferol
How is Grave’s eye disease managed?
Eye disease may manifest before thyrotoxicosis and smooth goitre
Caused by deposition of hydrophillic glycosaminoglycans in retro-orbital tissue leading to exophthalmos
typically causes opthalmoplegia and vision loss over time
MAnagement:
high dose steroids
retuximab
extra orbital radiation - limited evidence
surgical decompression once disease quiescent
When can postural hypotension commonly occur?
How is it managed?
Parkinsonism MND SACD DM1 autonomic neuropathy Addisons pituitary failure alcohol induced neuropathy
- compression stockings
- permanent head tilt of bed
- fludricortisone
- pyridostigmine
How is thryoxine therapy instigated
subclincial hypothyroid and asymptomatic TPO negative
Repeat TFTs in 3 years
subclincial hypothyroid TPO positive
Annual TFTs
Subclinical hypothyroidism IF symptomatic
-Start 50mcg
Clinical hypothyroidism and symptomatic
- start 100mcg
How is acromegally treated?
Somatostatin analogues
- (primary therapy or while awaiting surgery)
Dopamine agonists - cabergoline / l doppa / bromocriptine / silegiline
-(particularly for prolactin cosecretion)
Pituitary Surgery
Post-operative radiotherapy
Stereotactic ‘gamma knife’ radiotherapy for recurrence
GH receptor antagonists for recurrence
-Pegvisomant is an analogue of human growth hormone that has been genetically modified to
be a growth hormone receptor antagonist.
• It binds to growth receptors on cell surfaces, where it blocks growth hormone binding and
decreases IGF-1.
• Licensed for use in patients with acromegaly who have had an inadequate response to
surgery and/or radiation therapy and in whom an appropriate medical treatment with
somatostatin analogues did not normalise IGF-1 concentrations or was not tolerated.
annual colonoscopic surveillance - RR adenocarcinoma
Which anti-hypertensives are recommended in diabetes and which are not?
Ramipiril recommended esp if proteinurea present
bendroflumethiazide not recommended due to adverse effects on glucose
- use amlodipine if already on ramipril
MTC screening
Depending on what type of gene mutation
RET = MEN 2 - moderate risk
screen from age 5 with calcitonin levels / uss / thyroid exam