Endocrinology Flashcards
What is the difference b/w Sulfonylureas & DPP-4 inhibitors ??
Both enhances Insulin secretion BUT - DPP-4 i enhances Glucose-dependent Insulin secretion (ie. it only works when BG is High)
- Sulfonylureas (+) Insulin secretion by (-) ATP-sensitive K+ channels in Beta cells => Insulin release regardless of glucose levels => increase risk of Hypoglycaemia
Which hormones control Ca2+ levels in the body ??
Primary 2 main hormones are
- PTH
- 1, 25- Dihydroxycholecalciferol (Calcitriol, the active form of Vit D)
Other hormones are
- Calcitonin (secreted from the Parafollicular cells (C-cells) of thyroid
- Thyroxine
- Growth hormone
How does Ca2+ hormonal regulation happen in our body ??
PTH
- Increase Ca2+ & decrease PO4-
- Increase bone Resorption
- Immediate action on Osteoblasts (produce Protein signals => activate Osteoclast => Resorption) to increase Ca2+ in ECF
- Increase Renal Tubule Ca2+ & decrease PO4- reabsorption
- Increase 1,25 (OH)2D in kidney => increase Bowel absorption of Ca2+
How does 1,25-Dihydroxycholecalciferol regulate Ca2+ metabolism ??
- Increase Plasma Ca2+ & PO4-
- Increase R tubule reabsorption & Gut absorption of Ca2+
- Increase Osteoclastic activity
- Increase Renal PO4- reabsorption in PCT
How does Calcitonin regulate Ca2+ levels ??
Secreted by C-cells of Thyroid
(-) Osteoclast activity
(-) Renal tubule Ca2+ absorption
7-Dehydrocholesterol (Skin) =sun(+)=> Cholecalciferol (Vit. D3) ==25-hydroxylase (from liver)==> 25(OH)Cholecalciferol (Calcidol) == Vit. D 1alpha Hydroxylase(+) (from Kidney)==> 1,25 Di(OH) Cholecalciferol (Calcitriol)
MCC of Primary Hyperparathyroidism ??
Solitary adenoma of Parathyroid
Rx. of Primary Hyperparathyroidism ??
Surgery ; Indications are
- Ca2+ > 1mg/dl above normal
- Hypercalciuria >400mg/ day
- Cr. clearance <30% compared with normal
- Episodes of life threatening Hyper Ca2+
- Nephroliathiasis
- < 50 yrs old
- Neuromuscular symptoms
- Reduced BMD of Femoral neck, lumbar spine or Distal radius > 2.5 Std. deviation below peak bone mass (T score < -2.5)
Rx. of Secondary Hyperparathyroidism ??
Medical therapy
Indications for Sx. are
- Bone pain
- Persistent PRURITIS
- Soft tissue Calcifications
Rx. of Tertiary Hyperparathyroidism ??
- Allow 12 months to elaspe following transplant as many cases will resolve
- IF Autonomously functioning PT gland => Sx. may be required
- Total Parathyroidectomy & Re-implantation of part of gland
What is Benign Familial Hypocalciuric Hyper Ca2+ ??
A D genetic disorder
Dx.- Genetic testing & concordant biochemistry (Urine Ca2+ : Cr clearance ratio < 0.01 - Distinguished from primary hyperparathyroidism
How to differentiate b/w Primary Hyperparathyroidism & B Familial Hypocalciuric HyperCa2+ ??
Urine Ca2+ : Cr clearance ratio
- Primary Hyperparathyroidism: > 0.01
- B Familial H H : < 0.01
What is the function of ADH ??
It is a Posterior Pituitary Hormone
- Inserts Aquaporin-2 channels in the CD of kidneys => H2O reabsorbed => Retention
Site of ADH synthesis ??
Supraoptic Nuclei of Hypothalamus => released by Posterior Pituitary
Factors causing increased secretion
- ECF osml increase
- Vol. decrease
- Pressure decrease
- Angiotensin-II
Factors causing Decreased secretion
- ECF osml. decrease
- Vol. Increase
- Temp. decrease
Importance of Adrenal Medulla ??
Integral to body’s acute stress response through the release of Adrenaline & NA
- Almost all of body’s Adrenaline & some of NA is produced by medulla
Composed of Chromaffin cells (modified Sympathetic Nerve cells); contain granules that store & release Catecholamines
Effects of Adrenaline & NA in various part of body ??
Metabolic Effect
- Catecholamines (+) breakdown of Glycogen ==> Glucose in liver
- Enhance breakdown of Fats & release FAs into blood stream
BP Regulation
- NA: constricts BVs, raises BP => redirecting blood to essential major organs during stress response
Role in Acute Stress response
- Rapid release of Catecholamines
What is the function of Prolactin hormone ??
Source: Anterior Pituitary
- (+) Breast development (Both initially & further Hyperplasia during Pregnancy)
- (+) Milk production
- Decreases GnRH pulsatility at the Hypothalamic level &
- To a lesser extent, (-) the action of LH on Ovary & Testes
How is Prolactin regulated in the body ??
It is under CONSTANT (-) by DA
Increases secretion
- TRH - Oestrogen.
- Pregnancy - Breastfeeding
- Sleep. - Stress
- Drugs: eg. metaclopramide, Antipsychotics
DECREASES Secretion
- Dopamine
- DA agonists
What is ANP ??
Mainly secreted by Myocytes of RA & Ventricles in response to increased blood volume
- 28 AA peptide hormone, which acts via cGMP
- Degraded by Endopeptidase
- Secreted by both the RA & LA (RA»LA)
Actions of ANP ??
- Natriuresis, ie., promotes excretion of Na+
- Lowers BP
- Antagonises A-II & Aldosterone actions
Name the hormones a/w hunger & satiety.
‘Ghrelin’ make you ‘Greedy’
- LEPTIN: decreases Appetite/ induce Satiety
- Ghrelin: Stimulates hunger
Features of Leptin & Ghrelin ??
Leptin
- Plays key role in Body wt. regulation
- Source: Adipose tissue => acts on satiety centre in Hypothalamus
- Leptin (+) release of MSH & CRH
- Low levels of Leptin (+) Neuropeptide Y (NPY)
Ghrelin
- Source: P/D1 cells lining the Fundus of stomach & EPSILON cells of Pancreas
- Levels Increases before meal & Decreases after meal
What is Endothelin ??
Potent, long-acting Vasoconstrictor & Bronchoconstrictor
- Secreted initially as Pro-hormone by vascular endothelium & later converted to ET-I by endothelin converting enzyme
- Acts via G-protein linked to Phospho lipase C => Ca2+ release
Name the following about endothelin
- Promotes release ??
- Inhibits release ??
- Raised levels seen in ??
PROMOTES release
- A-II, ADH
- Hypoxia, Mechanical shear forces
INHIBITS release
- Nitric oxide
- Prostacyclin
RAISED levels
- Primary PAH
- MI. - HF. - Asthma
- AKI
How does the Synthesis of Nitric oxide occurs ??
aka Endothelium derived Relaxation factor
- formed from L-Arginine & O2 by Nitric oxide synthase (NOS)
- Has a very short 1/2-life (seconds), inactivated by O2 free radicles
Effects of Nitric oxide in body ??
Acts on Guanylate cyclase leading to raised intracellular cGMP => decreases Ca2+ levels
- Vasodilation (mainly Venodilation)
- INHIBITS Platelet aggregation
Clinical relevance of Nitric Oxide ??
- Reduces NO production is implicated in Hypertrophic Pyloric S
- Lack of NO: Atherosclerosis
- In Sepsis, increased NO levels: Septic Shock
- Organic Nitrates (metabolism produced NO) is widely used to treat CVS diseases (eg Angina, HF)
- Sildenafil
What is GH source & functions ??
Anterior Pituitary (Somatotrophs comprise 50% of cells of anterior pituitary)
- Postnatal growth & devt.
- Actions on Protein, Carbohydrate & Fat metabolism ( increased lipolysis & gluconeogenesis)
What is MoA of GH ??
Acts on Transmemb. receptor for growth factor
- Binds to this receptor => Receptor Dimerization
- Acts directly on tissues & also Indirectly via IGF-1
What is the site production of IGF-1 ??
primarily by Liver
How is GH secretion regulated in the body ??
INCREASED Secretion
- GHRH (released in pulses by Hypothalamus)
- Fasting. - Exercise.
- Sleep (particularly Delta sleep)
DECREASED Secretion
- Glucose
- Somatostatin (itself is increased by somatomedins, circulating IGF-1 & 2)
Name the hormones produced by the layers of adrenal gland
Z Glomerulosa : MCs mainly Aldosterone
Z Fasciculata : GCs mainly Cortisol
Z Reticularis : Sex steroids; mainly Dehydroepiandrosterone (DHEA)
What is Renin & mention its actions ??
Enzyme released by JG cells in response to REDUCED Renal perfusion
- Renin HYDROLYSES Angiotensinogen ==> A-1
How is Renin hormone regulated ??
Factors (+) Renin
- Hypotension
- Hypo Na+
- Sympathetic nerve stimulation
- Catecholines
- Erect posture
Factors that reduce Renin
- Drugs: Beta-blockers, NSAIDs
What are the actions of Angiotensin-II ??
A-I ==ACE (in lungs)===> A-II
A-II functions are as follows
- Vasoconstriction => Raised BP
- Vasoconstriction of Efferent arteriole of glomeruli => Increased Filtration fraction (FF) to preserve GFR
- (+) Thirst (via Hypothalamus)
- (+) Aldosterone & ADH release
- Increases PCT Na+/H+ activity
What is the action of Aldosterone ??
Stimulated by
- Raised A-II, K+ & ACTH levels
- Causes retention of Na+ in exchange for K+/H+ in DCT
MCC of Hypercalcaemia ??
2 diseases causes 90% of HyperCa2+
Primary HyperPTH (MCC in Non-Hospitalized pts.)
Malignancy (MCC in Hospitalized pts.)
- PTHrP from tumour (Sq.CC of lungs)
- Bone metastates
- Myeloma (Osteoclastic bone resorption by local cytokines-IL1, TNF released by myeloma cells)
Other causes of Hyper Ca2+ ??
Sarcoidosis
Vit. D intoxication
Acromegaly
Thyrotoxicosis
Milk-Alkali syndrome
Drugs: Thiazides, Ca2+ containing antacids
Dehydration. Addison’s. Paget’s
TB & Histioplasmosis (Hyper Ca2+ due to prolonged Immobilization)
Rx. of Hypercalcaemia ??
Rehydration with NS (3- 4 lt./ day)
Bisphosphonates (Takes 2 days to work with max. effect by 7 days)
Other options are
Clacitonin (quicker effect than Bisphosphonates)
Sarcoidosis: STREOIDS
Furosemide: In pts. who can’t tolerate aggressive fluid rehydration (beware of Electrolyte imbalance)
Causes of Hyperkalaemia ??
AKI
Drugs: K+ sparing diuretics, ACEi, ARBs, Ciclosporin
Metabolic Acidosis
Addison’s
Rhabdomyolysis
Massive BT
Beta blockers (interfere with K+ transport into cells) in Renal Failure
UnFH & LMWH [by aldosterone secretion (-)]
Rx. of Hyperkalaemia ??
IV Calcium Gluconate (To stabilize the Cardiac membrane)
Short term K+ shift from ECF => ICF
- Insulin + Dextrose infusion
- Neb. Salbutamol
Removal of K+ from body
- Calcium Resonium (Enemas>Oral)
- Loop Diuretics
- Dialysis (If AKI + Persistent HyperK+)
Name the food rich in K+ ??
Salt substitutes (contains K+ instead of Na+)
Banana. Avocado
Oranges. Spinach
Kiwi fruit. Tomatoes
Pseudo-Hyper K+ ??
Haemolysis during Venipuncture
- Excessive Vacuum while drawing
- Prolonged tourniquet
- Fine needle gauge
Delay in processing of Blood specimen
Myeloproliferative disorders (Abnormally high Plt., WBCs, RBCs)
Familial causes
Why is Hyperkalaemia tends to be a/w Acidosis ??
As K+ levels rise, fewer H+ ions can enter cells
What is Liddle’s syndrome ??
A D condition
- causes HTN + Hypo[K+] Alkalosis
- Disordered Na+ channels in DCT => Increased Reabsorption of Na+
Rx.-
- Amiloride or Triamterene
Hallmarks of Barter’s ??
A R condition [SLC12A1 mutation]
- Defect: Na+/K+/2Cl- (similar to using a Loop diuretics)
- Normotension
- HypoK+
- HYPERCALCIURIA
- Polyuria, Polydipsia
- Presents in CHILDHOOD: eg FTT
Hallmark of Gitelman’s Syndrome ??
Defect in Thiazide sensitive Na+/Cl- transporter in the DCT [SLC12A3 mutation]
- Normotension
- Hypo K+
- HYPOCALCIURIA
- Hypo Mg2+
- Met. ALKALOSIS
Hallmarks of Type 1 RTA ??
DCT defect (Inability to generate acid urine- secrete H+)
- Causes: Idiopathic, RA, SLE, Sjogren’s, Amphotericin B toxicity, Analgesic Nephropathy
Complications
- Nephrocalcinosis
- Renal Stones
Hallmarks of Type 2 RTA ??
PCT defect (Decreased HCO3- Reabsorption)
- Causes: Idiopathic, Fanconi’s, Wilson’s, CYSTINOSIS, Outdates Tetracyclines, CA inhibitors (Acetazolamide, Topiramate)
Complications: Osteomalacia
Hallmarks of Type 4 RTA ??
Reduced Aldosterone ==> Reduced PCT [NH4-] excretion
- Causes: Hypoaldosteronism, Diabetes
Leads to HYPERKALAEMIA
Hallmarks of Type 3 RTA ??
Due to Carbonic Anhydrase 2 deficiency
- Results in Hypokalaemia
Extremely Rare
Causes of Pseudohyponatraemia ??
Hyperlipidaemia (increase in serum volume)
Blood from drip arm
Dx. of Hyponatraemia ??
By Urinary Na+ & Osmolarity levels
1) Urinary Na+ > 20 mmol/l
Na+ depletion (Renal loss): pts. are often hypovolaemic
- Diuretics: Thiazides, Loop
- Addison’s
- Diuretic stage of RF
Pat. often Euvolaemic
- SIADH (U Osml. > 500 mmol/kg)
- Hypothyroidism
2) Urinary Na+ < 20 mmol/l
Causes of Hypo Na+ with Urinary Na+ < 20 mmol/l ??
Na+ depletion, Extra renal loss
- Diarrhoea, Vomiting, Sweating
- Burns, Adenoma of Rectum
Water Excess (Hypervolaemic & Oedematous)
- 2ndary Hyperaldosteronism: HF, Liver cirrhosis
- Nephrotic syndrome
- IV Dextrose
- Psychogenic Polydipsia
Acute & Chronic Hypo Na+ ??
Develops over a period < 48hrs
Develops over a period > 48 hrs
- Mild: 130- 134 mmol/l
- Moderate: 120- 129 mmol/l
- Severe: < 120 mmol/l
HYPOVOLAEMIC HypoNa+ or Clinically Dehydrated
- Diuretic stage of RF, Diuretics
- Addisonian Crisis
EUVOLAEMIC HypoNa+
- SIADH
HYPERVOLAEMIC HypoNa+
- HF, Liver failure, Nephrotic
C/F of HypoNa+ ??
Mild HypoNa+ may be Asymptomatic
Early C/F
- Headache, Lethargy, N & V, Dizziness, Confusion, Muscle cramps
Late C/F
- Seizures, Coma, Resp. Arrest
Rx. of Chr. HypoNa+ without Severe C/F ??
HYPOVOLAEMIC Suspected
- Isotonic Saline 0.9% NaCl
Can be given as trial => If Na+ level rises => supports Dx.
- If Na+ levels falls => alternate Dx like SIADH
EUVOLAEMIC Suspected
- Fluid Restriction: 500-1000ml/day
- Consider medications: Democlocycline & Vaptans
HYPERVOLAEMIC Suspected
- Fluid Restriction: 500-1000ml/day
- Loop Diuretics & Vaptans
Rx. of Acute Hypo Na+ with Severe symptoms ??
< 120 mmol/L
- Hypertonic Saline (3% NaCl) is used to correct the Na+ levels more quickly than would be done in Chr. Hypo Na+
Hallmark of Hyper Na+ ??
Dehydration
Osmotic Diuresis eg.- Hyperosmolar Non-Ketotic Diabetic Coma
Diabetic Insipidus
Excessive IV Saline
Should be corrected with CAUTION
- Brain can lose Na+ & K+ rapidly, but lowering of other Osmolytes (specially H2O) occurs at a slower rate, predisposing to C- OEDEMA => Seizures, Coma & Death
- Correction rate: <= 0.5 mmol/hr
Causes of Hypophosphataemia ??
Alcohol excess, Acute Liver Failure
DKA, Refeeding syndrome
Osteomalacia
Primary HyperPTH
CONSEQUENCES
- RBC Haemolysis
- WBCs & Platelets dysfunction
- Muscle Weakness, Rhabdomyolysis
- CNS Dysfunction
Causes of Rise in ALP ??
Liver: Cholestasis, Hepatitis, Fatty Liver, Neoplasia
Paget’s Osteomalacia HyperPTH
Bone Metastases. Renal Failure
Physiological: Pregnancy, Growing children, Healing #
What causes
- Raised ALP + Raised Ca2+ ??
- Raised ALP + Low Ca2+ ??
- Bone Metastases & HyperPTH
- Osteomalacia & Renal Failure
Name the Acute Phase Proteins
IL-1, IL-6, IL-8 & TNF-alpha stimulates liver to produce these proteins
CRP
Procalcitonin
Ferritin. Haptoglobin
Fibrinogen
Alpha-1 Antitrypsin
Caeruloplasmin
Serum Amyloid A
Serum Amyloid P component
Complement
Hallmark of CRP ??
Synthesised by LIVER which binds to Phosphocholine in Bacterial cells & on cells undergoing Apoptosis
- By binding =activate=> Complement
- Also rise after a Surgery: > 150 at 48 hrs post-op. suggests evolving complications
During an Acute phase response, which protein’s synthesis are decreased ??
Negative Acute phase proteins
- Albumin
- Transthyretin (formerly aka Prealbumin)
- Transferrin
- Retinol binding protein
- Cortisol binding protein
Causes of Hyperuricaemia ??
Increased synthesis (rise in cell turnover)
- Lesch-Nyhan
- Myeloproliferative disorders
- Diet rich in Purines. - Exercise
- Psoriasis. - Cytotoxics
Decreased Excretion
- Drugs: Low-dose Aspirin, Pyrazinamide
- Pre-Eclampsia
- Alcohol. - Lead
- Renal Failure
What is DM ??
Chronic syndrome of impaired carbohydrate, protein & fat metabolism due to insufficient secretion of Insulin &/or Target-tissue Insulin resistance
Pathophysiology of Type 1 DM ??
Autoimmune disease => Antibodies against Beta cells of Pancreas
- HLA DR4>HLA DR3
Various antibodies such as
- Islet-Associated ANTIGEN 2 (IAA 2)
- Glutamic Acid Decarboxylase GAD Antibody
- Anti-ZnTransporter 8 Antibody
C/F of
- Type 1 DM ??
- Type 2 DM ??
Polyuria, Polydipsia, Wt. loss
May present with DKA
- Abd. Pain
- Vomiting
- Reduced Consciousness level
Picked incidentally on Routine Ix.
Polydipsia, Polyuria
Polyuria & Polydipsia are due to H2O being dragged out of the body due to osmotic effects of excess blood glucose => Glycosuria
What are the 4 main ways to check BG ??
Finger prick Bedside Glucose monitor
One off BG (Fasting or Post-P)
HbA1c
OGTT
Dx. is made by either Plasma glucose or HbA1c sample
Dx. criteria of DM ??
1) If pt. is SYMPTOMATIC
- FBG >= 7 mmol/L
- Random BG or After 75g OGTT >= 11.1 mmol/L. (OR)
2) If pt. is ASYMPTOMATIC
- Above criteria must be proved on 2 separate occasions. (OR)
3) HbA1c >= 48 mmol/L or 6.5% (but a value < 48 mmol/L does NOT exclude DM: cause it is not as sensitive as FBG)
What is
- Impaired FBG ??
- Impaired Glucose Tolerance ??
FBG of >= 6.1 but < 7.0 mmol/L
- Due to HEPATIC Insulin Resistance
FBG of < 7.0 mmol/L & OGTT 2 hr value >= 7.8 but < 11.1 mmol/L
- Due to MUSCLE Insulin Resistance
IGT pts. are more likely to develop T2DM & CVS disease than IFG pts.
People with IFG should be offered an OGTT to rule out dx. of DM
What is Pre-diabetes ??
FBG of 6.1 to 6.9 mmol/L (OR) HbA1c b/w 42 to 47 mmol/L (6.0% to 6.4%)
Normal HbA1c is <= 41 mmol/L (5.9%)
Rx. of Type 1 DM ??
ToC: BASAL-BOLUS Regimen
- Multiple daily injections of long acting Basal Insulin (eg.- Insulin Detemer or Glargine) + Rapid acting Insulin (eg.- Aspart) before meal
2x- daily PREMIXED INSULIN
- Indicated if BB regimen is CI
CSII (Continuous Subcutaneous Insulin Infusion)
METFORMIN can be considered in pts. with BMI >= 25 kg/m2
When is CSII indicated in Type 1 DM ??
Pts. with persistently HIGH HbA1c despite optimal injection regimens
Rx. BG target in Type 1 DM ??
5- 7 mmol/L upon WAKING
4- 7 mmol/L PRE-MEAL throughout the day
Post-Meal targets is individualised based on risk of Hypoglycaemia
HbA1c
- Aim for <= 48 mmol/L (6.5%) unless limited by Hypoglycaemia or other factors
- Measure every 3- 6 months
Rx. of Type 2 DM ??
Assess CVS risk factor (High risk QRISK >= 10% or Established CVD or Chr. HF)
- If Yes: METFORMIN & once established & titrated up as required, then add SGLT-2 i
- If No: only METFORMIN
IF Metformin is CI
- CVD (+)ve: SGLT-2 monotherapy
- No CVD: DPP-4 i/ Pioglitazone/ SUs & SGLT-2 can be used if NICE criterias are met
2nd line & 3rd line Rx. of T2 DM ??
SECOND Line
Add any 1 of the following to Metformin
- DPP-4 i or Pioglitazone or SUs or SGLT-2 (if NICE criterias met)
THIRD LINE
Add another drug from the list above
- eg.- Metformin + DPP-4 i + SUs (OR)
Start Insulin-based Rx
How to proceed when Triple Therapy (3rd line) is not effective ??
Switch one of the drugs for
GLP-1 mimetic IF
- BMI >= 35 kg/m2 & specific psychological or other medical probs a/w Obesity (OR)
- BMI < 35 & for whom Insulin Rx. will have occupational hazards or Wt. loss would benefit other Obesity-related comorbidities
Should only be continued IF
- HbA1c reduction of at least 11 mmol/L (1%) & Wt. loss of at least 3% of initial body wt. in 6 months
GLP-1 mimetic should only be added to Insulin under specialist care
How to start Insulin ??
Metformin should be continued
- Other OHAs, review the need
Start with Human NPH Insulin
- Isophane (Intermediate-acting) taken at Bed-time or 2x daily according to need
When to start Insulin in T2 DM ??
BBR (NPH or Long-acting analogs) when
- HbA1c exceeds 58 mmol/L (7.5%) despite maximal OHAs
- Continue Metformin & stop other OHAs if Complex Insulin regimen is initiated
When should another drug be added in DM ??
What is the HbA1c target for add on therapy ??
At HbA1c of >= 58 mmol/L (7.5%)
- If the BG is within this threshold (eg- 55 mmol/L, do not add another OHA)
For Lifestyle/ Metformin: Target is <= 48 mmol/L
Add-on therapy: <= 53 mmol/L
Frail/ Elderly: Relaxed, Case-dependent
[HbA1c should be checked every 3- 6 months until stable, then 6 monthly]
Cardiovascular risk management in T2DM ??
BLOOD PRESSURE
- In < 80yrs old: < 135/85 mmHg
- In > 80yrs old: < 145/85 mmHg
- ACEi or ARBs are 1st line in HTN
LIPID Management
- High intensity Statin (eg Atorva 20-80 mg) for primary or 2ndary prevention
- LDL Cholesterol targets: High Risk pts.: < 1.8 mmol/L & Very High Risk pts.: < 1.4 mmol/L
ANTI-PLATELETS
- For 2ndary prevention in pts. with established CVD
Renal Protection in T2DM ??
Regular RFT monitoring
- eGFR & ACR
Use SGLT-2 i for renal protection in Albuminuric CKD
Optimize BP control with ACEi/ ARBs
T2DM Rx. during Ramadan ??
Adjust Medication Timing & Dosing
- Split Metformin doses: 1/3rd pre-sunrise (Suhoor) & 2/3rd post-sunset (Iftar)
- Shift SUs to evening dose with Iftar
- No adjustments needed for Pioglitazone
Pts. with chronic conditions are exempt from fasting or may be able to delay fasting to shorter days of winter months
Foods recommended
- Suhoor: Long acting Carbohydrates
- BG moniter is given so that they can check their glucose levels
Types of Insulin ??
RAPID Acting (Onset: 15 min)
- Peak: 1-2 hrs, Duration: 3-5 hrs
- Insulin Lispro, Aspart, Glulisine
SHORT Acting (Onset: 30 min)
- Peak: 2-4 hrs. Duration: 5- 8 hrs
- Regular Insulin (Humulin R, Novolin R)
INTERMEDIATE Acting (Onset: 1-2 hrs)
- Peak: 4- 12 hrs, Duration: 4-12 hrs
- NPH Insulin
LONG Acting Insulin (Onset: 1- 2 hrs)
- Duration: 20- 24 hrs
- Insulin Glargine, Detemir
Hallmarks of Insulin ??
Preferred initial regimen in T1DM
- BBR
Insulin adjustments required in Infections & Stress conditions
S/E
- Lipodystrophy at injection site
- Hypoglycaemia, Wt. gain
Hallmark of Metformin ??
- (-)Hepatic Gluconeogenesis,
- Improves peripheral insulin sensitivity;
- Reduces Intestinal Glucose absorption
CI: eGFR < 30 ml/min; Acute or Chronic Met. Acidosis
S/E: GI upset- N and Diarrhoea;Lactic acidosis; Avoid in Acutely ill pt.
Hallmark of Sulfonylureas (SUs) ??
(+) Pancreatic Beta-cell Insulin release by blocking ATP-sensitive K+ channel
Gliclazide, Glimepiride, Glibenclamide
- Short acting (Gliclazide) preferred
S/E: Hypoglycaemia (MC with Long acting one); Wt. gain; Rare: Hypo Na+ & Bone marrow Suppression
CI: Pregnancy & Breastfeeding
Hallmarks of Thiazolidinediones ??
PPAR-Gamma agonists
- Increases Insulin Sensitivity in Fat, Muscles & Liver
- Promotes Adipogenesis & Fatty Acid storage
S/E: Wt. gain; Fluid retention; Risk of #, Increased risk of Bladder Ca
CI: HF (NYHA 3 or 4)
Monitor LFT & Minimal Hypoglycaemia
What is the rare S/E of Canagliflozin ??
Risk of Lower Limb Amputation
Hallmark of DPP-4 i (Gliptans)
(-) DPP-4 enzyme => Prolongs action of INCRETINS (GLP-1, GIP) => Enhance Glucose-dependant Insulin release
- Suppress Glucagon
Sitagliptan, Vildagliptan, Saxagliptan
S/E: Pancreatitis
CI: Pts. with Pancreatitis
Wt. Neutral
Useful in Older/ Frail pts. where Hypoglycaemia is a concern
Hallmarks of SGLT-2 i (Gliflozins) ??
(-) SGLT-2 in Renal Tubules
- Reduces Glucose reabsorption
- Increases Urinary Glucose excretion
Empa-, Dapa-, Cana- Gliflozin
Indication: T2DM, High CVD or Renal risk, HFrEF
S/E: UTI & Genital TI ; EUGLYCAEMIC Ketoacidosis
CI: eGFR < 45 ml/min
Cardio- & Nephro- Protective
Hallmark of GLP-1 Receptor Agonists ??
Mimics GLP-1 to (+) Insulin secretion, (-) Glucagon, Slow gastric emptying & Promote Satiety
S/E: N & V (MC), Diarrhoea, Pancreatitis (Rare), Medullary Thyroid CA (caution in FHx of MEN-2)
Hallmark of Tirzepatide ??
Dual GLP-1 & GIP receptor Agonist
- (+) Insulin secretion, (-) Glucagon & Improves metabolic outcomes
S/E: N & V; Hypoglycaemia (rare, when combined with Insulin or SUs)
Promotes Significant Wt. loss
Cardioprotective benefits seen
Examples of GLP-1 Receptor Agonists ??
Injectables: Liraglutide, Exenatide, Dulaglutide
Oral: Semaglutide (taken in empty tummy, 30 min before food)
GLP-1r Agonists can be continued if
- > 11 mmol/L (1%) fall in HbA1c levels in 6 months
- 3% wt. loss in 6 months
Exenetide is a/w Severe Pancreatitis
GI Autonomic Neuropathy ??
C/F
- Erratic BG control, Bloating & Vomiting
Chr. Diarrhoea: MC at Night
Rx.-
- Metoclopramide, Domperidone or Erythromycin
Peripheral Neuropathy Rx ??
PAGeD
Amitriptyline, Duloxetine, Gabapentin or Pregabalin
- Do NOT use these in combination
Rescue Therapy: TRAMADOL
Topical Capsaicin for localised neuropathic pain (Post-Herpatic N)
RF modification in DM ??
Lipids
- Start in pts. with QRISK > 10% (10 year CV risk)
PRIMARY Prevention (QRISK > 10% or T1 DM or CKD if eGFR < 60 ml/min):
- Atorva 20 mg
SECONDARY Prevention (IHD or Cerebrovascular disease or PAD)
- Atorva 80 mg
ANTI-PLATELETS
- Offered only if pt. has existing Cardiovascular disease
Hallmarks of Gestational DM ??
2nd MC medical disorder complicating pregnancy (after HTN)
Risk Factors
- BMI > 30 kg/m2
- PHx of Macrosomic baby >4.5 kg
- PHx of GDM
- 1st degree relative with DM
- Family origin with a high prevalence of DM (South Asian, Black Carribbean, Middle East)
Screening & Dx. of GDM ??
Test of Choice: OGTT (Early self-monitoring of BG is an alternative)
- Women with PHx of GDM: OGTT
asap after Booking & at 24-28 POG
- Women with RFs: OGTT at 24-28 wks
Diagnostic Criteria
- FBG: >= 5.6 mmol/L
- 2 hr Glucose: >= 7.8 mmol/L
Rx. of GDM ??
1) If FBG < 7 mmol/L: Trial of Diet & Exercise should be offered
- If target BG is not met in 1- 2 wks => Start METFORMIN
- If BG targets still not met: add Insulin- Short-acting only (to the existing regimen)
2) If FBG >= 7 mmol/L at Dx.: INSULIN is started directly
3) If FBG b/w 6.0 to 6.9 + Evedence of complications (Macrosomia/ Hydramnios) : INSULIN is started
4) If Metformin not tolerated + decline Insulin Rx : GLIBENCLAMIDE can be offered
Rx. of Pre-existing DM
Wt. loss if BMI > 27 kg/m2
Stop OHAs except Metformin
Start INSULIN
- Folate 5 mg/ day from Preconception to 12 wks POG
- Detailed ANOMALY Scan at 20 wks including 4 chamber view of heart & Outflow tracts
- Tight Glycaemic control
Treat RETINOPATHY as it can worsen during pregnancy
BG targets in DM during Pregnancy ??
FBG: 5.3 mmol/L
1 hr PP: 7.8 mmol/L
2 hrs PP: 6.4 mmol/L
Hallmark of MODY ??
T2 DM in < 25 yrs old
A D condition
MODY 3: 60% cases
- Defect in HNF-1 alpha gene
- a/w increased risk of HCC
MODY 2: 20% cases
- Defect in GF (Glucokinase) gene
MODY 5: (Rare)
- Defect in HNF-1 Beta gene
- a/w Liver & Renal cysts
Features of MODY ??
Ketosis is NOT a feature at presentation
Very Sensitive to SULFONYLYREAS
- Insulin is not usually necessary
Name some foods with
- High GI
- Medium GI
- Low GI
Glycaemic Index
- White Rice (87), Baked potato (85), White Bread (70)
- Couscous (65), Boiled New Potato (62), Digestive Biscuits (59), Brown Rice (58)
- Fruits & Vegetables, Peanuts
Glycosylated Hb features ??
HbA1c is produced by glycosylation of Hb at a rate proportional to the Glucose conc.
Lower-than-expected levels of HbA1c (due to reduced RBCs life span)
- SCD
- G6PD deficiency
- Hereditary Spherocytosis
HIGHER-than-expected levels of HbA1c (due to increased RBCs life span)
- B12 or Folate Deficiency, IDA
- Splenectomy
How is Average plasma glucose related to HbA1c ??
Ave. P. Glucose = (2*HbA1c) - 4.5
Causes of Hypoglycaemia ??
- Insulinoma (increased Proinsulin : Insulin ratio)
- Self administration of Insulin or SUs
- Liver Failure
- Addison’s
Alcohol (Exaggerated Insulin secretion) - [-OH] => affects Pancreatic Micro-circulation => Blood redistribution from exocrine to Endocrine part => Increased Insulin secretion
- Nesidioblastoma (Beta cell Hyperplasia)
Features of Hypoglycaemia ??
BG < 3.3 mmol/L cause AUTONOMIC C/F due to Glucagon & Adrenaline release
- Sweating, Shaking, Hunger, Anxiety, Nausea
BG < 2.8 mmol/L cause NEURO-GLYCOPENIC C/F due to inadequate Glucose supply to the brain
- Weakness, Vision changes, Confusion, Dizziness
Severe & Uncommon C/F
- Convulsions & Coma
Hallmark of Diabetic Foot Disease
Occurs 2ndary to 2 main factors
- NEUROPATHY: Loss of protective sensation, Charcot’s arthropathy, Dry skin
- PAD: Macro & Micro vascular complication
Features
- Neuropathy: Loss of sensation
- Ischaemia: absent foot pulses, reduced ABPI, intermittent claudication
- Complications: Calluses, ulcerations, Charcot’s arthropathy, cellulitis, Osteomyelitis, Gangrene
How to screen for Diabetic Foot disease ??
Screened on an ANNUAL Baasis
- Screening for ischaemia: Palpate both Dorsalis oedis & Poste. Tibial pulses
- Screening for Neuropathy: 10g Monofilament is used on various parts of the foot
Moderate/ High risk pts. should be followed up regularly by the Local Diabetic Foot Centre
Risk Stratification of Diabetic Foot pts. ??
LOW Risk: Only Callus
MODERATE Risk: Deformity/ Neuropathy/ Non-Critical limb ischaemia
HIGH Risk:
- Previous ulceration or
- Previous amputation
- On Renal R T or
- [Neuropathy + Non-Critical L I] or
- Neuropathy + Callus &/or Deformity
- Non-Critical L I + Callus &/or Deformity
Hallmarks of DKA ??
Complication of T1DM or 1st presentation of T1DM
- Uncontrolled LIPOLYSIS => excess FAs released => Ketone bodies
RFs: Infection, Missed Insulin, MI
C/F
- Abd. Pain, - Polyuria, - Polydipsia
- Dehydration
- Kussmaul breathing (Deep HyperV)
- Acetone breath (‘Pear drops’ smell)
Dx. Criteria of DKA ??
BG > 11 mmol/L or known DM
pH < 7.3
HCO3- < 15 mmol/L
Ketones > 3 mmol/L (OR) Urine Ketones ++ on dipstick
Rx. of DKA ??
Fluid Replacement
- DKA pts. are deplete around 5-8 lt.
- Isotonic NS used initially
INSULIN
- IV infusion at 0.1 U/kg/hr
- Once BG < 15 mmol/l, 5% Dextrose infusion is started
Correction of Electrolyte Imbalance
- S K+ is high despite low total body K+
- Falls quickly once Insulin Rx. started
- K+ is added to fluids
- If rate of K+ infusion is > 20 mmol/hr , Cardiac monitoring is required
LONG Acting Insulin continued & Short acting Insulin is stopped
Fluid regimen in DKA ??
0.9% NS 1L over 1st hour
0.9% NS 1L + KCl over next 2 hrs
0.9% NS 1L + KCL over next 2 hrs
0.9% NS 1L + KCl over next 4 hrs
0.9% NS 1L + KCl over next 4 hrs
0.9% NS 1L + KCl over next 6 hrs
SLOWER Infusion rate indicated in YOUNG pts. (18- 25) as they are higher risk of Cerebral Oedema
K+ replacement in DKA ??
K+ levels in 1st 24 hrs is
- > 5.5 mmol/L : Nil replacement
- 3.5- 5.5 : 40 mmol/L
- < 3.5 : Senior review as additional K+ needs to be given
How to identify DKA resolution ??
pH > 7.3
Blood Ketones < 0.6 mmol/L
HCO3- > 15.0 mmol/L
Ketonemia & Acidosis should be resolved in <= 24hrs if NOT => Senior review from Endocrinologist
Above criteria met + pt. is eating & drinking, Switch to SC Insulin
Diabetes Specialist Nurse review before discharge
Complications of DKA ??
Gastric Stasis
Thromboembolism
Arrhythmias 2ndary to Hyper[K+] or Iatrogenic Hypo[K+]
- Iatrogenic: Incorrect Fluid therapy => Cerebral Oedema, Hypo[K+], Hypoglycaemia
ARDS & AKI
Why does Children/ Young adult’s fluid correction is monitored with at most care ??
Highly vulnerable to Cerebral Oedema following Fluid Resuscitation
- Often needs 1:1 nursing to monitor CNS signs- Headache, Irritability, FND, Visual probs
- Usually occurs 4- 12 hrs following commencement of Rx. but can present at any time
- Any suspicion: CT head + Senior review
Hallmarks of HHS ??
Medical emergency, Elderly with T2DM, extremely difficult to manage
- Hyperglycaemia => Osmotic Diuresis , Severe Dehydration & Electrolyte imbalance
- Severe Volume depletion => significantly raised Serum Osml. typically > 320 mosml/kg => Blood Hyperviscosity
Even though HHS pts. are Severely volume depleted, they might not look dehydrated. Why ??
Hypertonicity leads to preservation of Intravascular volume
C/F of HHS ??
- Fatigue, Lethargy, N & V
- CNS: Altered Sensorium, Headaches, Papilloedema, Weakness
- HYPERVISCOSITY: MI, Stroke, Peripheral Arterial Thrombosis
- CVS: Hypotension, Tachycardia, Dehydration
Dx. of HHS ??
- Hypovolaemia
- Marked Hyperglycaemia > 30 mmol/L without significant Ketonaemia or Acidosis
- Significantly raised S Osmolarity > 320 mosml/kg
Mixed DKA & HHS can occur
Rx. of HHS ??
1) Normalise OSMOLALITY (Gradual)
- Key parameter to monitor
2) Replace Fluid & Electrolyte losses
- Fluid replacement alone will cause a gradual decline in BG & Osml.
- Insulin Rx. prior to adequate fluid replacement => CV collapse as H2O moves out of Intravascular space => decline in Intravascular volume
Ketone is measured before the need of Insulin is assessed
- IF Ketonaemia (+): Beta-hydroxy butyrate > 1 mmol/L; indicates relative HypoInsulinaemia & Insulin is started (eg.- Mixed DKA/HHS)
- Fixed rate IV Insulin infusion given at 0.05 U/kg/hr
Fluid Replacement in HHS ??
Fluid loss in HHS is around 100- 220 ml/g ; 10- 22 lt. in 100kg man
Rate of Rehydration is assed by
- Initial severity
- Pre-existing co-morbidities (HF, CKD, Elderly)
1st line fluid: IV 0.9% NS
- This is Hypotonic => very effective in restoring Normal S Osml.
- Achieve a (+)ve balance of 3-6 lt. by 12 hrs & remaining replacement fluid in next 12 hrs
- Rx. Aim: Replace 50% estimated fluid loss in 1st 12 hrs & rest in the following 12 hrs (if co-morbidities present limit correction speed)
- If S Osml. not declining despite (+)ve balance with 0.9%NS switch to 0.45% NS
How to calculate S. Osml ??
2*[Na+] + Glucose + Urea
Monitoring Rx. in HHS ??
Reduction of S. Osml. will cause a shift of H2O into Intracellular space
- This Inevitably results in rise in Na+
- Normally, Fall in BG of 5.5 mmol/L results in a 2.4 mmol/L rise in Na+
- IF this rise is > 2.4 for each 5.5 fall in BG, this suggests INADEQUATE Fluid replacementy
- Rise in Na+ is a concern if Osml. is NOT declining concurrently
- Safe rate of fall of BG: 4- 6 mmol/hr
- Fall of Na+ should not exceed 10 mmol/L in 24 hrs
Target BG: b/w 10- 15 mmol/L
Complete normalization of Electrolyte & Osml. takes up to 72 hrs
Dx. & Rx. of Insulinoma ??
High Insulin, Raised Proinsulin : Insulin ratio
- High C-Peptide
Supervised, prolonged fasting (72hrs)
CT Pancreas
Treatment
- Surgery
- Diazoxide & Somatostatin if Sx CI
Hallmark of Remnant Hyperlipidaemia ??
Fredrickson type 3 Hyperlipidaemia or Broad-Beta disease or Dysbetalipoproteinaemia
- Mixed Hyperlipidaemia (Raised Ch. & TGs levels)
- a/w APO-E2 Homozygosity
- High incidence of IHD & PVD
Impaired removal of INTERMEDIATE Density Lipoprotein from the blood by the Liver
Rx. of Hypoglycaemia ??
In the COMMUNITY
- Oral Glucose 10- 20 g in liquid, gel or tablet form
- Alternate: GlucoGel or DextroGel
- A HypoKit can be prescribed (Glucagon vial for IM/ SC at home)
In HOSPITAL Setting
- Alert: Quick acting Carbohydrate (as above)
- Unconscious/ Unable to swallow: IM or SC Glucagon injection
- Alternate: IV 20% Glucose solution
Hallmarks of Insulinoma ??
Neuroendocrine Tumour & MC Pancreatic Endocrine tumour
Site: Islet of Langerhans cells
- 10% malignant, 10% multiple
- 50% have MEN-1
Early morning hypoglycaemia or just before meals eg.- Diplopia, Weakness
- Raised body wt.
Abnormalities seen in Metabolic syndrome ??
It is a cluster of abnormalities
- INSULIN RESISTANCE
- IGT
- Central Obesity
- Reduced HDL Ch. levels
- Elevated TGs
- HTN
Key pathogenesis factor: Insulin Resistance
Other associated features include
- Raised Uric Acid levels
- NAFLD, PCOS
Dx. of Familial Hypercholesterolaemia ??
SIMON-BROOME Criteria
In Adults: TC > 7.5 & LDL-C > 4.9
In Children: TC >6.7 & LDL-C > 4.0
For definitive FH
- Tendon Xanthoma in pts. (OR)
- 1st or 2nd degree relatives (OR)
- DNA evidence of FH
For Possible FH
- FHx of MI in < 50yrs in 2nd degree relative (OR)
- < 60 yrs in 1st degree relative (OR)
- FHx of raised Ch. levels
Rx. of Familial Hyper Ch. ??
Referral to specialist Lipid Clinic
- 1st line: High dose Statins
- 1st degree relative have a 50% chance of having the disorder, so should be offered screening
- Statins should be discontinued in women 3 months before conception
MoA of Statins ??
Selectively & Competitively (-) HMG-CoA Reductase => decreases Ch. biosynthesis in Liver => Increases no. of Hepatic LDL receptors on Cell surface => Enhanced uptake & Catabolism of LDL
S/E: Myalgia, less frequently- Myositis or Rhabdomyolysis
What is Familial Hypercholesterolaemia ??
A D condition; results in High levels of LDL Ch.
- Due to mutations in the gene which encodes LDL-receptor protein
When to Suspect this ??
- Total Ch. > 7.5 mmol/L &/or
- Personal or FHx of Premature CAD (event when < 60yrs in an index person or 1st degree relative)
Children of affected parents
- If 1 parent : Test Child by age 10yrs
-If Both parents: Test by 5 yrs of age
Features & Rx. of Remnant Hyperlipidaemia ??
- Yellow Palmar Crease
- Palmar Xanthomas
- Tuberous Xanthomas
Treatment - 1st line: FIBRATES
Secondary causes of Hyperlipidaemia ??
HYPER- TGs predominant
- DM type 1 & 2, - Obesity
- Alcohol. - Liver disease
- Chr. Renal Failure
- Drugs: Thiazides, Non-selective Beta blockers, Unopposed Oestrogen
HYPER- Ch. predominant
- Nephrotic syndrome
- Cholestasis
- Hypothyroidism
Types of HMG-CoA Reductase i ??
LIPOPHILLIC Statins
- Atorva-, Lova-, Simva-, Fluva-, Pitava-
HYDROPHILLIC Statin
- Pravastatin
- Rosuvastatin
Lipophillic statins are widely distributed in various tissue but Hydrophillic statins are Liver specific
- S/E of statins are MC with Lipophillic
Hallmark of Fibrates ??
Specially used in Hyper TGs
- Activates PPAR-Alpha receptors => Increase in LPL activity => Reduce TGs
- Peroxisome proliferator-activated r
S/E:
- GIT s/e are common
- Increased risk of Thromboembolism
Hallmark of Ezetimibe ??
(-) intestinal absorption of Ch. by blocking Neimann-Pick C1-Like 1 (NPC1L1) protein transporter on Intestinal & Hepatic cells
- Decreases delivery of intestinal Ch. to liver
Indications
- Primary Heterozygous-Familial & Non-Familial Hyper Ch.
Prescription of Ezetimibe ??
Monotherapy
- Primary Hyper Ch. in adults in whom Statins are CI or can’t tolerate it
Co-Admistered with Initial Statin Rx.
- Primary Hyper Ch. in adults who have started Statin therapy when
— TC or LDL-C not well controlled either after proper dose titration of initial Rx. or because dose titration is limited by intolerance to initial statin therapy
— Change from initial Statin therapy to an alternative statin is being considered
Hallmark of Bempedoic acid ??
Adenosine Triphosphate Citrate Lyase (ACL) Inhibitor
Indications
- Primary Hyper Ch (Heterozygous Familial & Non- Familial)
- Mixed dyslipidaemia
- Pts. unable to reach LDL-C goal with max. tolerated dose of statin
- Statins are not tolerated or CI
Hallmark of PCSK9 Inhibitors ??
Proprotein Convertase Subtilisin/ Kexin Type 9
There are 2 FDA approved drugs
- Alirocumab (Praluent) SC
- Evolocumab (repatha) SC
- Both are available as Pre-filled pen
Indications
- Hyper Ch & Mixed Dyslipidaemia
- Homozygous Familial Hyper Ch
- Established Atherosclerotic CVS disease
MoA of PCSK9 Inhibitor ??
PCSK9 (-) stop the protein from working => more LDL r are available on liver cells => lower Blood Ch
- Normally PCSK9 protein breaks down LDL receptors => less receptor available & Blood Ch rises
Prescription
- Used in combination with Statin or Statin with other lipid-lowering therapies in pats. unable to reach
- LDL-C goals with max. tolerated dose of Statin or Alone or in combination with other lipid-lowering Rx. in pts. who are Statin intolerant or Statin is CI
Causes of Hypothyroidism ??
Hashimoto’s thyroiditis (MCC)
- Autoimmune, a/w T1DM, Addison’s, Pernicious anaemia
- Can cause transient thyrotoxicosis in acute phase
- 5x- 10x MC in Women
Subacute thyroiditis (De Quervain’s)
- a/w painful goitre & raised ESR
Reidel’s thyroiditis
- Painless goitre
- Fibrous tissue replace normal tissue
Postpartum Thyroiditis
Drugs: Lithium, Amiodarone
Iodine deficiency
- MCC in developing world
Causes of Hyperthyroidism ??
1) Grave’s disease (MCC)
- Typical thyrotixicosis features + Thyroid eye disease
2) Toxic Multinodular Goitre
- Autonomously functioning thyroid nodule => secretes excess thyroxine
3) Drugs: AMIODARONE
4) ACUTE Phase of
- Subacute (De Quervain’s) thyroiditis
- Post-Partum Thyroiditis
- Hashimoto’s
C/F of Hypothyroidism ??
Wt. gain, Lethargy, Cold Intolerance
Skin: Dry, Cold, Yellowish skin
- Non-Pitting oedema (hands & face)
- Dry, Coarse scalp hairs, loss of lateral eyebrows
Constipation
Menorrhagia
CHS: Decreased DTRs, Carpel Tunnel Syndrome
C/F of Hyperthyroidism ??
Wt. loss, Manic, Restlessness, Heat Intolerance
CVS: Palpitations, Arrhythmias (AF)
Skin: Increased sweating
- Periorbital Myxoedema: Erythematous, oedematous lesions above lateral malleoli
- Thyroid Acropachy: Clubbing
Diarrhoea
Oligomenorrhoea
CNS: Anxiety, Tremors
What are the antibodies a/w thyroid diseases ??
Anti-TPO antibody
TSH receptor Antibody
TG Antibodies
There is significant overlap but
- TSH r Antibody: Grave’s
- Anti-TPO Antibody: Hashimoto’s
Features seen ONLY in Grave’s but not in other causes of Thyrotoxicosis ??
1) EYE Signs (30% cases)
- Exophthalmos
- Ophthalmoplegia
2) Pretibial Myxoedema
3) Thyroid Acropachy (TRIAD)
- Digital Clubbing
- Soft tissue swelling of hands & feet
- Periosteal New bone formation
Ix. of Grave’s disease ??
TSH r stimulating Antibody (90%)
Anti-TPO antibodies (75%)
Thyroid Scintigraphy
- Diffuse, Homogenous, increased uptake of Radioactive Iodine
Rx. of Graves ??
Initial Rx (control of c/f)
- PROPRANOLOL (blocks adrenergic effects)
Refer to 2ndary Care for ongoing Rx
Carbimazole is considered in Primary care if pts. c/f are NOT controlled with Propranolol
1st line: Anti-Thyroid drugs
ATD Titration Regimen
- CARBIMAZOLE started at 40mg, reduced gradually to maintain Euthyroidism;
- Taken for 12-18 months
‘Block & Replace’ is Alternate Rx.
- Carbimazole 40mg & Thyroxine is added when pt. becomes Euthyroid
- Taken for 6- 9 months
ATD has fewer S/E than B & R
RADIOIODINE Rx.
Hallmark of Radioiodine Rx. ??
Used in pts. who relapse to ATD therapy or are Resistant to primary ATD Rx.
Absolute CI
- Pregnancy (avoid for 4- 6 months after Rx)
- < 16 yrs old
Relative CI: Thyroid Eye disease
Maj. of pts. will require Thyroxine Rx. by 5 yrs after RI Rx.
Hallmark of Toxic Multinodular Goitre ??
Plummer’s Disease
Autonomously functioning Thyroid nodules => Hyperthyroidism
- Nuclear Scintigraphy: PATCHY Uptake
ToC: RADIOIODINE Therapy
Hallmark of Thyroid Eye Disease ??
Autoimmune response against an Autoantigen, possibly TSH r => Retro-Orbital Inflammation => GAGs & Collagen deposition in the Muscles
SMOKING (most imp. RFs for devt. of Thyroid eye disease)
RadioIodine Rx. can aggravate inflam. of Thyroid eye disease
Features & Rx. of Thyroid Eye disease ??
Exophthalmos, Conjunctival Oedema
Optic Disc Swelling
Ophthalmoplegia
Inability to close eyelids => Sore, dry eyes ==> Exposure Keratopathy
Treatment
- Topical Lubricants
- Steroids
- Radiotherapy
- Surgery
What are the indications of Urgent review by Ophthalmologists in pts. with Thyroid Eye disease ??
- Unexplained deterioration in Vision
- Awareness of change in intensity or quality of colour vision in 1 or both eyes
- H/o Eye suddenly ‘popping out’ (Globe subluxation)
- Obvious Corneal Opacity
- Cornea still visible when eyelids are closed
- Disc swelling
Hallmarks of Thyroid Storm ??
Iatrogenic Thyroxine excess do NOT usually result in thyroid storm
RFs
- Thyroid or Non-Thyroidal Sx
- Trauma, Infection
- Acute Iodine load (CT contrast)
C/F
- Fever > 38.5 C
- Tachycardia, HTN, HF
- N & V; Confusion & Agitation
- Abnormal LFTs- Jaundice clinically
Treatment
- PCM, Treat the Ppt. event
- IV Propranolol
- Methimazole or PTU
- Lugol’s Iodine
- Dexamethasone: 4mg IV qds =(-)=> T4 to T3 conversion
Hallmarks of Hashimoto’s Thyroiditis ??
Chronic Autoimmune Thyroiditis
- a/w Hypothyroid
- Transient Thyrotoxicosis seen in acute phase
- 10x MC in women
A/W: Coeliac’s, T1DM, Vitiligo
O/E: Firm, Non-tender
Anti-TPO (+)ve also Anti-TG antibodies
Which lymphoma is Hashimoto’s a/w ??
MALT Lymphoma
Hallmarks of Subacute Thyroiditis ??
De Quervain’s Thyroiditis
- Subacute GRANULOMATOUS Thyroiditis
- Occurs after a VIRAL Infection
- Presents with Hyperthyroidism
Thyroid Scintigraphy
- Globally REDUCED I-131 uptake
Rx.: Self-limiting
- Thyroid pain: Aspirin, NSAIDs
- STEROIDS in more severe cases particularly if Hyperthyroidism (+)
Phases of Subacute Granulomatous Thyroiditis ??
Phase-1 (3- 6 wks):
- Hyperthyroid, Painful goitre
- Raised ESR
Phase-2 (1- 3 wks): Euthyroid
Phase-3 (wks- months): Hypothyroid
Phase-4 : Thyroid str. & function goes back to normal
Features of Subclinical Hyperthyroidism ??
Normal Free T4 & T3 levels + TSH < 0.1 mu/l
Causes
- MNG (particularly in Elderly females)
- EXCESS Thyroxine may give a similar biochemical result
Treatment
- TSH levels must be persistently low to warrant intervention
- Therapeutic level Low-dose ATD for 6 months (to induce remission)
Hallmarks of Subclinical Hyperthyroidism ??
Causes
- MNG in elderly females
- EXCESS Thyroxine
Effects
- CVS- Atrial Fib.
- Osteoporosis
- Increased risk of Dementia
Features of Subclinical Hypothyroidism ??
Raised TSH & T3, T4 normal
No obvious C/F
Treatment
1) TSH b/w 4- 10mU/L + Free T4 within normal range
- If < 65yrs + C/F of HypoT: LevoT trial => if NO improvement => Stop LevoT
- Older pts. (> 80yrs old): Watch & Wait, usually avoid hormonal Rx
- Asymptomatic: Observe & Repeat TFT in 6 months
2) TSH > 10 mU/L + Free T4 in normal range
- < 70yrs: LevoT started even if Asymptomatic
- Older people (> 80yrs old): Watch & Wait, hormone Rx. is generally avoided
Features of Non-Thyroidal Illness ??
Sick Euthyroid Syndrome
- TSH, T3, T4 all are LOW
- In maj. TSH is in Normal range (inappropriate as T3 & T4 are low)
Reversible upon recovery from systemic illness => NO Rx.
Features of Reidel’s Thyroiditis ??
Dense Fibrous tissue replacing the Normal thyroid parenchyma
- O/E: Hard, Fixed, Painless goitre
- Middle aged female
- a/w Retroperitoneal Fibrosis
Hallmark of Congenital Hypothyroidism ??
Affects 1 in 4000 babies
- If NOT dx. & treated within 1st 4 wks => Irreversible Cognitive Impairment
C/F
- Prolonged Neonatal Jaundice
- Delayed mental & physical milestones
- Short stature
- Puffy face, Macroglossia
- Hypotonia
Babies screened at 5- 7 days with Heel Prick test
Features of Pendred’s syndrome ??
A R condition; characterised by
- B/L SNHL
- Mild Hypothyroidism
- Goitre
Defect in ORGANIFICATION of I- => Dyshormonogenesis
- Thyroid C/F are mild & pts. are often Euthyroid
- Progressive Hearing loss, delay in academic progression
Dx. & Rx. of Pendred’s Syndrome ??
TFTs are Normal
PERCHLORATE Discharge test aids Dx
Gene testing: PDS gene on Chr 7
Audiometry & MRI: Characteristic 1.5 turns in the Cochlea (normal 2.5)
Treatment
- Thyroid Hormone Replacement
- Cochlear Implant
Why should pts. with Pendred syndrome avoid contact sports ??
Head trauma can worsen SNHL
[IM pts. should also avoid for 4 to 6 wks due to risk of Splenic rupture)
Features of Carbimazole ??
Blocks TPO from Coupling & Iodinating the Tyrosine residues on TGs => reduce T hormone synthesis
PTU as well as this central MoA, it also has a Peripheral action
- (-) 5-deiodinase which reduces peripheral T4 to T3 conversion
S/E: Agranulocytosis
- Crosses Placenta (but can be used in low doses during pregnancy)
Thyroid disease in Pregnancy ??
In pregnancy, there is an increase in TBG levels; this causes an
- INCREASE in Total Thyroxine levels
- Do NOT affect Free Thyroxine
Beta-HCG can activate TSH r => Transient Gestational HyperT
MCC of Thyrotoxicosis in Pregnancy is Grave’s disease
Rx. of Thyrotoxicosis in Pregnancy ??
1st Trimester: PTU
- Carbimazole is a/w increased risk of congenital abnormalities
At the beginning of 2nd Trimester
- switch back to CARBIMAZOLE
Maternal F T4 levels are kept at upper 1/3rd of normal range to avoid Fetal Hypothyroidism
RadioIodine therapy is CI
Hypothyroidism in Pregnancy ??
Thyroxine is SAFE
- TSH is measured in each Trimester & 6- 8 wks post-partum
INCREASE dose of Thyroxine-
- By 50% as early as 4- 6 wks POG
Breastfeeding is SAFE while on Thyroxine
Why should Thyrotrophin receptor stimulating antibodies checked at 30 to 36 wks POG ??
To determine the risk of Neonatal Thyroid Problems
Types of Thyroid Cancer ??
PAPILLART (70%)
- Often young female, good prognosis
FOLLICULAR (20%)
MEDULLARY (5%)
- Cancer of Parafollicular (C) cells, secrete Calcitonin, part of MEN-2
ANAPLASTIC (1%)
- Not responsive to Rx., Pressure c/f
LYMPHOMA (rare)
- a/w Hashimoto’s
Hallmark of Papillary CA ??
- Contains a mixture of Papillary & Colloidal filled follicles
- HP: Papillary projections & pale empty nuclei
- Seldom encapsulated
- LN metastasis predominant
- Blood spread is rare
Hallmarks of Follicular Adenoma
Present as SOLITARY Thyroid Nodule
Malignancy can only be excluded on formal HP assessment
Hallmarks of Follicular CA ??
Macroscopically encapsulated, Microscopically Capsular Invasion is seen- without this finding, the lesion is a Follicular Adenoma
Vascular Invasion predominates
Multifocal disease is rare
Hallmarks of Medullary CA ??
C-cells derived from Neural Crest & NOT thyroid tissue
S. Calcitonin levels are often raised
Familial form in 20% cases
LN & Blood metastasis recognised
Nodal disease is a/w poor prognosis
Hallmark of Anaplastic CA ??
Elderly Females (MC)
Local Invasion is a common feature
Rx.- Resection if possible
- Palliation may be achieved through Isthmusectomy & Radiotherapy
- Chemo is NOT effective
Skin disorders a/w Hypothyroidism ??
Dry (Anhydrosis), Cold, Yellow skin
Non-pitting oedema (eg- Hand, face)
Dry, coarse scalp hair, loss of lateral part of eyebrow
Eczema
Xanthomata
Pruritus
Skin disorders a/w Hyperthyroidism ??
Pretibial Myxoedema
- Erythematous, Oedematous lesions above the lateral malleoli
- Thyroid acropachy
- Scalp hair thinning
- Increased sweating
- Pruritus
Hallmark of Primary Hyperparathyroidism ??
Elderly female + Thirst + inappropriately normal or Raised PTH
Causes
- SOLITARY ADENOMA (MCC) 80%
- Hyperplasia (15%)
- Multiple adenoma (4%)
- Carcinoma (1%)
a/w HTN & MEN-1 & MEN-2
Features of Primary HyperPTH ??
Bones, stones, abd. groans & psychic moans
- Polydipsia, Polyuria
- Depression
- Anorexia, Nausea, Constipation
- PUD
- Pancreatitis
- Bone pain/ #
- Renal stones
- HTN
Ix. & Rx. of Primary HyperPTH ??
- Raised Ca2+ & Low PO4-
- PTH may be raised or Normal (inappropriate as Ca2+ is raised)
- Tc.-MIBI Subtraction scan
- X-Ray Skull: Pepperpot Skull
Definitive Rx.- Total PTectomy
Conservative Rx. - If Ca2+ < 0.25 mmol/L above upper limit & Pt. is > 50yrs & No evidence of End organ damage
Sx. CI: Cinacalcet (a Calcimimetic) - Mimics the action of Ca2+ on tissue by allosteric activation of Ca2+ sensing receptors
Hand X-ray features of HyperPTH ??
- Generalised Osteopenia
- Acro-Osteolysis: Erosions of Terminal Phalangeal tufts
- Sub-periosteal resorption of bone
Hallmarks of PseudoHypoPTH ??
A D condition
Target cell insensitivity to PTH due to mutation in a G-protein
- Type-1: Complete receptor defect
- Type-2: Cell receptor intact
Bloods:
- High PTH, Low Ca2+, High PO4-
Features of PseudoHypoPTH ??
Short 4th & 5th Metacarpals
Short stature
Cognitive impairment
Obesity
Round face
How to differentiate b/w Type 1 & Type 2 PseudoHypoPTH ??
PTH infusion => measure Urinary PO4- & cAMP
- Type-1: Neither of them rises
- Type-2: cAMP rises but Urine PO4- do not change
What is Hungry Bone Syndrome ??
Seen after PTectomy if HyperPTH has been long standing
High Pre-op PTH levels => constant (+) of Osteoclast activity=> Bone Demineralized => HyperCa2+
On PTectomy => PTH levels drop rapidly (due to short 1/2 life) => Osteoclast activity diminishes => Bone rapidly begins to Remineralize => Hungry Bone syndrome
Features of Hungry Bone Syndrome ??
X-ray: Changes similar to Metastatic Lytic lesions if left untreated
Effects on Ca2+ levels
- Hypocalcaemia
Hallmarks of Pituitary Adenoma ??
Benign tumour of Pituitary G
- Most cases are asymptomatic & is an Incidental Dx.
Classification based on
SIZE: Microadenoma (< 1cm) & Macroadenoma (> 1cm)
Hormone Status:
- Secretory/ Functioning adenoma: Produces a hormone in excess
- Non-Secretory adenoma: do NOT produce hormone in excess
MC types of Pituitary Adenomas ??
1) PROLACTINOMAS (MC type)
2) Non-Secreting Adenomas: next MC type
3) GH Secreting
4) ACTH Secreting
C/F of Pituitary Adenomas ??
1) Excess of a Hormone
- Prolactin excess: Amenorrhoea & Galactorrhoea
- ACTH excess: Cushing disease
- GH excess: Acromegaly
2) DEPLETION of a Hormone (due to Compression of normal functioning Pituitary gland)
- Non-Functioning tumours: Generalised Hypopituitarism
3) Stretching of the Dura (in/around pituitary fossa): Headaches
4) Compression of Optic Chiasma
- Bitemporal Hemianopia (nasal fibre
Ix. & Rx. of Pituitary Adenoma ??
Pituitary Blood Profile
- GH, Prolactin, ACTH, FH, LH, TFTs
Formal Visual Field Testing
MRI Brain with Contrast
Rx.-
- Hormonal Therapy: Bromocriptine 1st line for PLomas
- Surgery: Transsphenoidal Transnasal Hypophysectomy
- Radiotherapy
Hallmarks of Acromegaly ??
Causes:
- 95% cases are 2ndary to Pituitary Adenoma
- Ectopic GNRH or GH production by tumour eg.- Pancreas
Complications
- HTN, - DM
- Cardiomyopathy
- COLO-RECTAL Cancer
Features of Acromegaly ??
- Coarse facial appearance, Spade like hands, Increase in Shoe size
- Large tongue, Prognathism, Interdental spaces
- Excess Sweat & Oily skin: Sweat gland hypertrophy
- Pituitary Tumour C/F: Hypopituitarism ,Headache, Bitemporal Hemianopia
- Raised PL 1/3rd case: Galactorrhoea
- MEN-1 in 6% cases
Ix. done in Acromegaly ??
1st line: Serum IGF-1 levels
- If elevated confirm with Serial GH measurements (lack of suppression of GH < 1 ug/L following documented Hyperglycaemia during an OGTT
[Normally GH is suppressed to < 2 mu/L with Hyperglycaemia]
Monitoring: Serum IGF-1
MRI of Pituitary to show tumour
Rx. of Acromegaly ??
1st line: Trans-sphenoidal Sx
If Inoperable or Sx. unsuccessful
SOMATOSTATIN Analogue
- Directly (-) release of GH
- eg.- Octreotide
- Effective in 50- 70% cases
PEGVISOMANT
- GH receptor antagonist: (-) GH receptor dimerization
- SC administration once daily
- Very effective
- Do NOT shrink tumour; Sx needed
DA Agonists
- Bromocriptine
- Now not used commonly
EXTERNAL IRRADIATION
- used in Older pts. or
- Failed Sx. or Medical Rx.
Hallmark of Prolactin ??
Secreted by Anterior Pituitary gland
- DA is the primary PL releasing Inhibitory factor
- DA agonists (Bromocriptine) are used to control Galactorrhoea
Features of PL Excess
- Men: Impotence, Loss of Libido
- Women: Amenorrhoea
- Galactorrhoea in both M & F
Causes of raised Prolactin ??
Prolactinoma
Pregnancy
Oestrogens
Physiological: Stress, Exercise, Sleep
Acromegaly: 1/3rd pts.
PCOS
Primary Hypothyroidism: Because TRH (+) PL release
Drugs causing raised Prolactin ??
Metoclopramide, Domperidone
Phenothiazines
Haloperidol
Very rare: SSRIs, Opioids
Causes of SIADH ??
Malignancy
- Small Cell Lung Ca
- Also: Pancreas, Prostate
CNS: Stroke, SAH, SDH, Meningitis/Abscess/Encephalitis
Infections: TP, Pneumonia
Drugs:
- SUs (Glimepiride & Glipizide)
- SSRIs, TCAs, Carbamazepine
- Vincristine, Cyclophosphamide
Other Causes
- (+)ve End-Resp. Pressure [PEEP]
- Porphyrias
Rx. of SIADH ??
Excess ADH hoemone produced => excess H2O retention => HypoNa+ 2ndary to dilutional effect
Rx.-
- Slow correction of HypoNa+
- Fluid restriction
- Democlocycline: reduces response of Collecting Duct to ADH
- ADH r Antagonists
What is Insulin Stress Test ??
Used in the Ix. of HYPOPITUITARISM
- IV Insulin is given => GH & Cortisol levels measured
- Normal Pituitary: Both rises
Contraindications:
- Epilepsy
- IHD
- Adrenal Insufficiency
What is H2O deprivation test ??
It is designed to help evaluate pts. who have POLYDIPSIA
- Normal: Urine Osm- > 600 & Urine osm. Post DDAVP- > 600
- Psychogenic Polydipsia: U Osm- > 400 & U osm Post DDAVP: > 400
- Cranial DI: U Osm- < 300 & U Osm Post DDAVP- > 600
- Nephrogenic DI: U Osm < 300 & U Osm Post DDAVP- < 300
Hallmark of Primary Hyperaldosteronism ??
MCC: B/L Idiopathic Adrenal Hyperplasia (70%)
Conn’s syndrome
Features
HTN + Hypo[K+]
- Muscle weakness
Alkalosis
Ix. of Primary Hyperaldosteronism ??
1st line: Plasma Aldosterone : Renin ratio
- High Aldosterone & Low Renin [(-)ve feedback from Na+ retention]
Differentiate b/w U/L or B/L cause
- HRCT Abdomen & Venous Sampling
If CT is normal
- Adrenal Venous Sampling can be used to differentiate b/w U/L Adenoma & B/L Hyperplasia
Rx. of Primary Hyperaldosteronism ??
Adrenal Adenoma: SURGERY
B/L Adereno-Cortical Hyperplasia
- Aldosterone antagonists (Spironolactone)
What is Adrenal Insufficiency ??
Inadequate synthesis of Adrenal hormones- Cortisol & in some cases, Aldosterone due to dysfunction at Adrenals/ Pituitary/ Hypothalamus
Types
PRIMARY Adrenal I (PAI)
- Adrenal failure
- Addison’s is the MC form of PAI
- Other Causes: Infections, Adrenal haemorrhage, Metastatic Ca, CAH
SECONDARY Adrenal I (SAI)
- Decreased ACTH from Pituitary
- Chr. GC Therapy, Pituitary Tumour or Pituitary Sx.
TERTIARY Adrenal I (TAI)
- Decreased CRH from Hypothalamus
- Due to Prolonged suppression by Exogenous GCs
Pathophysiology of Adrenal Insufficiency ??
PAI
- Adrenal Cortex damage => Low Cortisol & Aldosterone, High ACTH
- Hyperpigmentation, Hypotension, Hypo[Na+] & Hyper[K+]
SAI & TAI
- Deficient ACTH (SAI) & CRH (TAI) production
- Aldosterone secretion is PRESERVED as it is primarily regulated by RAAS
- NO electrolyte abnormalities but Cortisol deficiency C/F like Fatigue, Weakness, Adrenal crisis under stress
C/F of Adrenal Insufficiency ??
PAI is more severe at presentation
C/F common to all forms of AI
- Fatigue, Lethargy
- Muscle weakness
- Wt. loss
- N & V
- Hypotension (Orthostatic)
C/F specific to PAI
- Hyperpigmentation [elevated ACTH also (+) MSH receptors]
- Hypo[Na+] & Hyper[K+]
- Salt craving (hallmark of Aldosterone deficiency)
SAI & TAI
- NO hyperpigmentation & electrolyte abnormality
Dx. of Adrenal Insufficiency
INITIAL Tests
1) 8 am Serum Cortisol test
- 150 nmol/L: Highly suggestive of AI
- 150- 300 nmol/L: Uncertain; further testing with ACTH Stimulation
- > 300 nmol/L: AI unlikely
2) SYNACTHEN Test (ACTH (+) test)
- Used to CONFIRM the dx. of AI & differentiate b/w PAI & SAI/TAI
- In PAI: Cortisol levels fail to rise after ACTH administration
- In SAI/TAI: Blunted response seen, but some Cortisol increase may occur
3) ACTH Levels:
- PAI: Elevated ACTH (due to lack of Cortisol (-)ve feedback
- SAI/TAI: Low or Normal ACTH
Other Ix. done in A I ??
S. Electrolytes
- In PAI only: Hypo[Na+] & Hyper[K+] due to aldosterone deficiency
Renin & Aldosterone levels: Useful in confirming Aldosterone deficiency in PAI
Rx. of Adrenal Insufficiency
GC Replacement
- 1st line: Hydrocortisone in divided dose
- 15- 25 mg/day (2 or 3 divided dose)\
- Largest dose: Morning & Smaller dose later in the day (to avoid INSOMNIA)
MC Replacement
- Necessary in PAI (eg. Addison’s)
- Fludrocortisone 50- 300 mcg/day
Sick day rules in Adrenal Insufficiency ??
2x or 3x the GCs dose during
- Illness, Sx., or Maj. stress to avoid Adrenal Crisis
- IM Hydrocortisone if pt. unable to take Oral medications (eg. N & V)
Long term monitoring in Adrenal Insufficiency ??
Regular Monitoring of
- BP, Electrolytes, Signs of GCs under- or over- replacement
Bone Density
- Assessed periodically due to risk of GC induced Osteoporosis
Hallmarks of Addison’s disease ??
MCC of Primary Hypoadrenalism in the UK accounting for 80% cases
- Both Cortisol & Aldosterone are reduced
Lethargy, Weakness, Anorexia, N & V, Wt. loss, SALT Craving
Hyperpigmentation (specially Palmar Crease)
Vitiligo, loss of Pubic hairs in women, Hypotension, Hypoglycaemia
Hypo[Na+] & Hyper[K+] may be seen
Other Causes of Hypoadrenalism ??
PRIMARY Cause
- TB, -HIV, -APLS
- Metastases (eg. Bronchial CA)
- Waterhouse-Friderichsen syndrome (Meningococcal Septicaemia)
SECONDARY Causes
- Pituitary Causes (eg- Tumors, Irradiation, Infiltration)
EXOGENOUS GC Therapy
Ix. of Addison’s disease ??
Definitive Ix.- Synacthen Test (ACTH Stimulation Test)
If Synacthen test NOT available=>
9 am S. Cortisol
- > 500 nmol/L: Addison’s unlikely
- < 100 nmol/L: Definitely abnormal
- 100- 500 nmol/L: Do Synacthen test
Electrolyte Abnormalities
Electrolyte abnormalities seen in Addison’s disease ??
Hyper[K+]
Hypo[Na+]
Hypoglycaemia
Met. Acidosis
Hallmark of Addisonian Crisis ??
Causes
- Sepsis or Surgery causes acute exacerbation of Chr. Insufficiency (Addison’s, Hypopituitarism)
- Adrenal Bleeding eg- Waterhouse F synd. (Fulminant Meningococcemia)
- Steroid withdrawal
Rx. of Addisonian Crisis or Adrenal Crisis ??
- Hydrocortisone 100mg IM or IV
- 1 lt. NS infusion over 30-60 min or with Dextrose if Hypoglycaemic
- Continue Hydrocort 6 hrly until pt. is stable
- NO Fludrocortisone (High Cortisol exerts Weak MC action)
- Oral Replacement: After 24 hrs & be reduced to maintenance dose over 3- 4 days.
Causes of Cushing’s Syndrome ??
ACTH Dependent Causes
- Cushing’s disease (80%): Pituitary tumour secreting ACTH => Adrenal Hyperplasia
- Ectopic ACTH production (5- 10%): Small Cell Lung Ca. is the MCC
ACTH Independent Causes
- Iatrogenic: Steroids
- Adrenal adenoma (5- 10%)
- Adrenal CA (rare)
- CARNEY Complex ( syndrome including Cardiac Myxoma)
- Micronodular Adrenal Dysplasia (very rare)
PSEUDO-Cushing’s
Causes of Pseudo-Cushing’s ??
- Mimics Cushing’s
- Often due to [-OH] excess or Severe Depression
- Cause FALSE (+)ve Dexamethasone Supression test or 24hr Urinary Free Cortisol
- Insulin Stress test may be used to differentiate
Hallmark of Cushing’s causes ??
Iatrogenic: Corticosteroids therapy
ACTH Dependent Causes
- Cushing’s Disease: P adenoma => ACTH secretion)
- Ectopic ACTH secretion 2ndary to Malignancy
ACTH Independent Causes
- Adrenal Adenoma
Ix. of Cushing’s Syndrome
1) 1st line: Overnight Dexamethasone Suppression Test
- Most sensitive test
- Cushing’s pts. do NOT have morning Cortisol spike suppressed
2) 24 hrs Urinary Free Cortisol
Localisation test in Cushing’s ??
1st line: 9 am & Midnight plasma ACTH (& Cortisol) levels
- ACTH suppressed: Non-ACTH dependent cause is likely (A Adenoma
High-Dose DM Suppresion Test
- Used to localise the pathology resulting in Cushing’s Synd.
Inference of High-Dose DM Suppression Test ??
Cushing’s Syndrome due to other causes (eg.- Adrenal Adenomas)
- Cortisol: NOT suppressed
- ACTH: Suppressed
Cushing’s Disease (ie. P Adenoma => ACTH secretion)
- Cortisol: Suppressed
- ACTH: Suppressed
Ectopic ACTH syndrome
- Cortisol: Not suppressed
- ACTH: Not suppressed
What is CRH stimulation test ??
If Pituitary source: Cortisol rises
If Ectopic/ Adrenal: NO change in Cortisol
Petrosal Sinus sampling of ACTH
- To differentiate b/w Pituitary & Ectopic ACTH secretion
How to differentiate b/w Pseudo-Cushing’s & True Cushing’s ??
Insulin Stress Test
How to differentiate b/w Pituitary & Ectopic ACTH secretion ??
Petrosal Sinus sampling of ACTH
What is Dynamic Pituitary Function Test ??
Used in cases of Primary Pituitary Dysfunction
- Given: Insulin, TRH, LHRH
- Measured: S. Glucose, Cortisol, GH, TSH, LH, FSH levels are recorded at regular intervals
PL levels are sometimes measured
- DA antagonist test: Normal response is 2x rise in PL. A Blunted response suggests- Prolactinoma
- Metoclopramide is used in Ix. of HyperPL
Normal Dynamic Pituitary Function Test characteristics ??
- GH levels rises > 20 mu/l
- Cortisol level rises > 550 mmol/l
- TSH level rises by > 2 mu/l from baseline
- LH & FSH should double
Hallmark of Pheochromocytoma ??
Catecholamine secreting tumour
- 10% are Familial & may be a/w MEN-2, NF & VHL syndrome
- B/L in 10%
- Malignant in 10%
- Extra-adrenal in 10%
Features of Pheochromocytoma ??
Typically Episodic
- HTN (90%, may be sustained)
- Headache, - Palpitations
- Anxiety, - Sweating
IxoC: 24hr Urinary Metanephrine levels (97% Sensitive)
- 24hr Urinary Catecholamines (86% sensitive)
Rx.-
- ToC: SURGERY
Pt. should be 1st stabilised with drugs
- Alpha blockers (eg. Phenoxybenzamine) given BEFORE a
- Beta blocker (Propranolol)
What is Polyglandular Autoimmune Syndrome (PAS) ??
Cluster of at least >= 2 endocrine diseases in a pt. attributed to Autoimmunity
- LYMPHOCYTE Infiltration causes organ specific damage
TYPES (PAS-2 is Commonest)
- PAS-1: Multiple Endocrine Deficiency Autoimmune Candidiasis (MEDAC)
- PAS-2: Schmidt’s Syndrome (MC)
- X-linked Immune Dysregulation Poly Endocrinopathy & Enteropathy (IPEX)
- Iatrogenic Poly-endocrinopathy due to use of Immunoregulatory agents in pts. with cancer
Features of PAS-1 ??
Onset: Children; M:F=3:4; Triad of
- Adrenal Insufficiency
- Chr. Hypoparathyroidism
- Chr. CANDIDIASIS
A R condition; Monogenic; AIRE1 gene mutation on Chr 21
A/W the following
- T1DM, - Pernicious anaemia
- Thyroid disorder, - IgA deficiency
- Alopecia, - Vitiligo
- Chr. Active Hepatitis
- Chr. Atopic Dermatitis
- KCS, - Hypogonadism
Features of PAS-2 ??
Onset: Childhood to adult; M:F=1:3
MC than PAS-1; At least 2/3 of
- Autoimmune Adrenal I
- Autoimmune Thyroid disease (Graves or Hypothyroidism)
- T1DM
Complex Polygenic Inheritance
Links to HLA DR3 & DR4
A/W the following
- Premature Ovarian deficiency
- Vitiligo, - Coeliac’s
- Hypoparathyroidism
- Chr. Atrophic Gastritis & B12 deficiency
Androgen Insensitivity Syndrome or Complete Androgen Insensitivity ??
46 XY [X linked recessive disorder]
- Defective Androgen receptor => End-organ resistance to Testosterone => Female Phenotypes & Male Genotype
- Rudimentary Vagina & Testes but No uterus
- Testosterone, Oestrogen & LH are all elevated
Features or Complete Androgen Insensitivity ??
- Primary Amenorrhoea
- Undescended testes => Groin swelling
- Breast develops: Conversion of Testosterone => Oestradiol
Dx.- Buccal Smear or Chr. Analysis
Rx.- - Raise child as Female
- B/L Orchidectomy
- Oestrogen therapy
5-Alpha Reductase deficiency ??
46 XY [A R condition]
- Inability of Males to convert Testosterone to DHT
- Ambiguous genitalia at Newborn
- Hypospadiasis is common
- Virilization at puberty
Male Pseudohermaphroditism ??
46 XY
- Has Testes but external genitilia are female’s or ambiguous
- May be 2ndary to AIS
Female Psudohermaphroditism ??
46 XX
- Has Ovaries but external genitalia are Male’s (virilized) or ambiguous
- May be 2ndary to CAH
True Hermaphroditism ??
46 XX or 47 XXY
- Both Ovarian & Testicular tissue are present
Hormone levels in Sex hormone disorders ??
Primary Hypogonadism (Klinefelter’s)
- LH: High & Testosterone: Low
Hypogonadotrophic hypogonadism (Kallman’s syndrome)
- LH: Low & T: Low
AIS
- LH: High & T: Normal/High
Testosterone secreting syndrome
- LH: Low & T: High
Features of Klinefelter’s syndrome ??
47 XXY
- Taller than average
- Lacks 2ndary Sexual character
- Small, Firm testes; - Infertile
- Gynaecomastia: increased breast Ca risk
- Elevated Gonadotrophin levels
Dx.: Chromosomal Analysis
Hallmark’s of Kallman’s Syndrome ??
Recognised due to delayed puberty 2ndary to hypogonadotrophic hypogonadism
- X-linked Recessive trait
Failure of GnRH-secreting neurons to migrate to hypothalamus
Defect in Olfactory neurons-
- Hyposmia or Anosmia
Features of Kallman’s syndrome ??
- Delayed Puberty, - ANOSMIA
- Hypogonadism, Cryptorchidism
- Sex hormone levels are LOW
- LH, FSH are inappropriately low /normal
- Pts. are typically of normal or above average height
Dx.- Cleft lip/Palate & Visual/Hearing defects are seen in some pts.
Hallmarks of CAH ??
A R disorders
- Affects ADRENAL Steroid Biosynthesis
Due to Low Cortisol levels => Anterior Pituitary secretes High levels of ACTH =(+)=> Adrenal Androgens synthesis => virilize Female infants
Types & features of CAH ??
21-Hydroxylase Deficiency (90%)
- Female: Genitalia virilised
- Males: Precocious puberty
- 60- 70% pts. have a Salt-losing crisis at 1- 3 wks. of age
11-Beta Hydroxylase Deficiency (5%)
- Female: Genitalia Virilised
- Males: Precocious Puberty
- HTN + Hypo[K+]
17-Hydroxylase Deficiency (Rare)
- Females: Non-Virilising
- Boys: Inter-sex
- HTN
Hallmarks of Gynaecomastia ??
Abnormal amount of Breast tissue in Males
- Due to Increased Oestrogen : Androgen ratio
- Differentiate Gynaecomastia from Galactorrhoea (due to action of PL on Breast tissue)
GRADES-
- 1: Small enlargement, No excess Skin
- 2a : Moderate enlargement + No excess Skin
- 2b : Moderate enlargement + Extra skin
- 3 : Marked enlargement + Extra Skin
Causes of Gynaecomastia ??
Puberty (Normal)
Kallman’s, Klinefelter’s
Testicular Failure eg- Mumps
Liver disease
Testicular Ca eg.- Seminoma secreting hCG
Ectopic tumour secretion
Hyperthyroidism
Haemolysis
Drugs
Drugs causing Gynaecomastia ??
MCC: Spironolactone
Cimetidine
Digoxin
Cannabis
Finasteride
GnRH agonists (Goserelin, Buserelin)
Oestrogen, Anabilic steroids
Very Rare Causes
- TCAs, - Isoniazid, - CCBs
- Heroin, - Busulfan, - Methyldopa
Phases of Menstrual Cycle ??
Menses : 1- 4th day
Follicular [Proliferative] : 5- 13th day
Ovulation : 14th day
Luteal [Secretory] : 15- 28th day
Hallmark of Follicular Ovarian Phase & Proliferative Endometrial Phase ??
- No. follicle develops => only One follicle will become Dominant around Mid-Follicular phase
- Proliferation of Endometrium
FSH rises (devt. of follicles) => secretes Oestradiol; When Egg has matured => secretes enough Oestradiol to =(+)=> LH surge => Ovulation
Cervical Mucus- - After Menses: Thick & Pluged Ext. Os
- Prior to Ovulation : Clear, Acellular, Low Viscosity
- ‘Stretchy’- “Spinnbarkeit”
BB Temp.- Falls prior to Ovulation (Oestradiol influence)
Hallmarks of Luteal Ovarian Phase & Secretory Endometrial Phase ??
Corpus Luteum
Endometrium: Changes to Secretory lining under Progesterone influence
C Luteum => secretes Progesterone rises through Luteal phase => If no fertilization => CL degenerates => P falls & Oestradiol levels rise in Luteal
Cervical Mucus
- Thick, Scanty & Tacky (due to P)
BB Temp.- Rises post ovulation in response to higher P levels
Hallmarks of Primary Amenorrhoea ??
No Menses by 15 yrs + normal 2ndary Sex. characters (OR) by 13 yrs without 2ndary sex. characteristics
CAUSES
- MCC: Gonadal dysgenesis (Turner’s)
- Testicular Feminization
- Congenital Genital tract malformed
- Functional Hypothalamic Amenorrhoea (eg.- 2ndary to Anorexia)
- CAH
- Imperforate Hymen
Hallmarks of 2ndary Amenorrhoea ??
Menses stop for 3- 6 months in Women with previous normal & regular menses (OR) 6- 12 months in women with H/o Oligomenorrhoea
CAUSES (exclude Pregnancy)
-Hypothalamic Amenorrhoea (2ndary to Stress, Excess Exercise)
- Hyperprolactinaemia
- Premature Ovarian Failure
- Thyrotoxicosis, - PCOS
- Sheehan’s,
- Asherman’s (IU adhesions)
HYPOTHYROIDISM can also cause Amenorrhoea
Ix. done in Amenorrhoea ??
EXCLUDE Pregnancy
Gonadotrophins
- Low levels : Hypothalamic cause
- High levels : Ovarian problem
- Raised if Gonadal Dysgenesis (eg.- Turner’s)
Prolactin
Androgen levels
- Raised levels can be seen in PCOS
Oestradiol
FBC, U&E, Coeliac’s screen, TFTs
Rx. of Amenorrhoea
PRIMARY Amenorrhoea
- Ix. & Rx of root cause
- Primary Ovarian Insufficiency due to Gonadal dysgenesis (Turner’s): HRT
SECONDARY Amenorrhoea
- EXCLUDE Pregnancy, Lactation & Menopause (in >= 40 yrs old)
- Treat the underlying cause
Hallmarks of PCOS ??
Ovarian Dysfunction
- Hyperinsulinaemia & High levels of LH is common in PCOS
- Overlaps with Metabolic Syndrome
Subfertility or Infertility
Oligo- or Amenorrhoea
Hirsutism, Acne (Hyperandrogenism)
Obesity
Acanthosis nigricans (Insulin R)
Ix. done in PCOS ??
Pelvic USS: Multiple cysts in Ovaries
PL is normal or elevated
Testosterone is normal or elevated
SHBG is low or normal
Raised LH:FSH (classic feature is no longer useful
Check of Impaired Glucose Tolerance
Dx. of PCOS ??
Rotterdam Criteria [2/3 must be (+)]
- Infrequent/ No Ovulation (presents as infrequent/no menses)
- Hyperandrogenism (Hirsutism, Acne (OR) elevated Total/Free Testosterone levels)
- Polycystic Ovaries on USS (>= 12 follicles of 2-9 mm) in one or both ovaries (OR) Increased Ovarian Volume > 10 cm3
Rx. of PCOS ??
Wt. Loss
COCPs (If Contraception needed)
Hirsutism & Acne
- 1st line: COCPs
- 2nd line: Topical Eflornithine
- Spironolactone, Flutamide, Finasteride used under specialists
INFERTILITY
- Wt. Loss
- Clomephene (risk of Multiple pregnancies)
- Metformin: alone or combined with Clomephene specially in Obese pts.
- Gonadotrophins
COCPs used in PCOS ??
3rd Generation COCPs (OR)
- Due to Fewer S/E
Co-Cyprindol
- Anti-androgen
Both has risk of VTE
Hallmarks of Premature Ovarian Failure ??
Menopausal C/F + Elevated Gonadotrophins in < 40 yrs old
C/F
- Climacteric c/f: Hot flushes, Night sweats
- Infertility
- 2ndary Amenorrhoea
Raised FSH & LH
- FSH > 40 IU/l
- Elevated FSH should be shown in 2 blood sample 4- 6 wks apart
Low Oestradiol
- eg.- < 100 pmol/l
Causes of Premature Ovarian Failure ??
IDIOPATHIC (MCC)
- FHx may be (+)ve
B/L Oophorectomy
Radio & Chemo therapy
Infection (eg.- Mumps)
Autoimmune disorders
Resistant Ovary Synd.- FSH receptor abnormalities
Rx.-
- HRT or COCPs until 51 yrs (average age of menopause)
Hallmark of Ovarian Cancer ??
5th MC malignancy in Females
- Peak: 60 yrs & carries poor prognosis due to late Dx.
Epithelial origin (90%): with 70-80% cases due to Serous CA
Site of Origin: Distal F tubes
RFs
- FHx of BRCA1 or BRCA2 mutation
- Multiple Ovulations: Early menarche, Late Menopause, Nulliparous
Multiple pregnancies & COCPs are protective
C/F & Ix. done in Ovarian Ca ??
Notoriously Vague C/F
- Abd. distension & Bloating
- Abd. & Pelvic Pain
- Urinary C.F eg- Urhency
- Early Satiety, - Diarrhoea
Ix.
Initial Test: CA-125
- If >= 35 IU/L => Urgent USS of Abd. & Pelvis
CA-125 should NOT be used for screening
Dx. & Rx. of Ovarian Ca ??
Diagnostic Laparotomy
Rx.- Surgery + Chemo (Platinum based)
Prognosis: 80% have advanced disease at presentation
Other conditions where CA-125 is elevated ??
Ovarian cancer
Endometriosis
Menstruation
Benign Ovarian Cysts
Hallmarks of Uterine Fibroids ??
Smooth muscle tumours of Uterus
- Seen in 20% White & 50% Black women in later Reproductive years.
- MC in Afro-Caribbean Women
- Rare before puberty, develops in response to Oestrogen
Dx.- TV-USS
Features of Fibroids ??
- May be Asymptomatic
- Menorrhagia: Can cause IDA
- Lower Abd. Pain: Cramping, common during Menses
- Bloating
- Urinary C/F: Frequency (with large fibroids)
- Subfertility
- POLYCYTHAEMIA 2ndary to EPO production by the fibroid
Rx. of Fibroids ??
Asymptomatic: NO Rx. + periodic review to monitor size & growth
Rx. of Menorrhagia
LNG-IUS : Useful if Contraception is also required
- Can’t be used if Uterine cavity distorted
NSAIDs, Tranexemic Acid, COCPs
Oral or Injectable Progestogen
Rx. to Shrink/ Remove Fibroids
Medical:
- GnRH agonists: Shrinks but useful for short term Rx
- Ulipristal Acetate: used in the past
Surgical:
Uterine Artery Embolization
Surgical Rx. of Fibroids ??
Complications of Fibroids ??
Myomectomy: can be performed Abdominally, Laparoscopically or Hysteroscopically
Hysteroscopic Endometrial Ablation
Hysterectomy
Regress after Menopause
Complications
- Sub-fertility & IDA
- RED Degeneration- Haemorrhage into tumour: commonly occurs during Pregnancy
Hallmark of Cervical Ca ??
50% occurs in women < 45 yrs of age
- Incidence rate highest in 25- 29 yrs
Types
- Squamous C Ca (80%)
- Adenocarcinoma (20%)
Features
- Detected during Routine Cervical Screening
- Abnormal Vag. Bleed: Postcoital, Intermenstrual or PM Bleed
- Vaginal Discharge
RFs of Cervical Cancer ??
HPV 16, 18 & 33 (most imp.)
- 16 & 18 produces oncogene E6 & E7
- E6 (-) p53 Tumour Suppressor gene
- E7 (-) RB suppressor gene
Other RFs
- Smoking, - HIV
- Early 1st Coitus, - High Parity
- Many Sexual Partners
- Low SES
- COCPs
Hallmark of Endometrial Ca ??
MC in PM Women; but 25% cases are seen before Menopause
Features
- PM Bleed (classic symptom)
- Intermenstrual Bleed in Pre-M women
- Pain & Discharge (unusual)
RFs of Endometrial Ca ??
Obesity, Nulliparity
Early Menarche & Late Menopause
Unopposed Oestrogen
- Adding Progesterone reduces risk
DM, PCOS, HNPCC
Tamoxifen
Ix. & Rx. of Endometrial Ca ??
PM bleed + >= 55 yrs
- Refer via Suspected Ca Pathway
1st line: TV-USS
- Normal endometrial thickness (< 4mm) has High (-)ve Predictive value
Hysteroscopy with Biopsy
Rx.-
- Local disease: TAH + B/L S-O
- High risk disease: TAH + B/L S-O + Post-Op. Radiotherapy
- Progesterone Therapy (if Sx. is CI)
Protective features of Endometrial Ca ??
COCPs & Smoking
Hallmark of Neuroblastoma ??
One of the top 5 causes of Ca in children, accounts for 7-8% of childhood malignancies
- Site: Neural crest tissue of Adrenal Medulla (MC site) & SNS
- Median age of onset: 20 months
Features of Neuroblastoma ??
Abdominal mass or Lump on Chest
Pallor, Wt. loss
Bone Pain, Limp
Hepatomegaly
Paraplegia
Proptosis
Ix.- Raised VMA & Homovanillic Acid (HVA) levels
- Calcification on Abd. X-ray
- Biopsy
Hallmarks of Galactosaemia ??
A R condition; due to absence of
- Galactose-1-Phosphate Uridyl Transferase
- Results in Intracellular accumulation of Galactose-1-Phosphate
Features-
- Jaundice, - FTT, - Hepatomegaly
- Cataracts, - Fanconi Syndrome
- Hypoglycaemia after exposure to Galactose
Dx.- Urine Reducing Substances
Rx.- Galactose free diet
If milk is given => Unmetabolised milk sugars build up & damage Liver, Eyes, Kidneys & Brain
How is Urinary Incontinence classified ??
Overactive Bladder/Urge Incontinence
- Detrusor Overactivity
- Urge to Urinate is quickly followed by uncontrollable leakage ranging from few drops to complete voiding
STRESS Incontinence
- Urine leak while Coughing/ Laughing
MIXED Incontinence:
- Both Urge & Stress
OVERFLOW Incontinence
- Bladder outlet obstruction eg Prostatomegaly
FUNCTIONAL Incontinence
Ix. done in Urinary Incontinence ??
Bladder dairies for 3 days
Vaginal examination to exclude Pelvic organ prolapse & ability to initiate voluntary contraction of pelvic floor muscles (Kegel exercise)
Urine dipstick & Culture
Urodynamics studies
What is Functional Incontinence ??
Comorbid physical conditions impair the pts. ability to go to a bathroom in time
Causes: Dementia, Sedating drugs & Injuries/ Illness => decreased Ambulation
Rx. of Urge Incontinence ??
Bladder Retraining ( for >= 6 wks; gradually increase interval b/w voiding)
Bladder Stabilising Drugs
- 1st line: Anti-Muscuranics
- Immediate release: Oxybutynin, Tolterodine
- Once daily: Darifenacin
- Immediate release is avoided in Frail elderly pts.
MIRABEGRON (Beta-3-agonist)
- Used if anti-cholinergic S/E is a concern in elderly, frail pts.
Rx. of Stress Incontinence ??
Pelvic Floor Muscle Training
- 8 contractions; 3x/day for 3 months
Sx.- Retropubic Mid-Urethral Tape procedure
Sx. declined: Duloxetine
- Combined NE & Serotonin reuptake inhibitor
- Increase synaptic conc. of NE & Serotonin in Pudendal nerve => increased (+) of urethral striated muscles within the sphincter enhanced
Causes of
- Predominant HypreCh. rather than HyperTGs ??
- Predominant HyperTGs ??
Nephrotic Synd.
Cholestasis
Hypothyroidism
DM, Alcohol
Bendrofluazide (Increases both Ch. & TGs)
Obesity-
- Elevated TGs
- Low HDL-C
- Slightly elevated LDL-C
Non-Functioning Pituitary Adenoma
Generally Dx. due to their compressive C/Fb(eg. Visual probs.)
- May manifest with Pan-Hypopituitarism due to compression of normally functioning pituitary
ToC: Trans-sphenoidal Sx.
2ndary Hypothyroidism + Hypogonadism + Headache (Dural stretching) + Elevated PL +/- Blurring of vision
Non-Functioning Pituitary adenoma
Thyroid Ca a/w RET oncogene ??
Medullary (in MEN 2)
Papillary
Drugs causing Nephrogenic DI ??
Single best useful test to find the cause of HypoCa2+ ??
Lithium, Democlocycline,
OFLOXACIN, Orlistat
PTH levels
Initial test to assess diabetic neuropathy ??
Test sensation using 10g Monofilament
Any Critical illness (eg. severe pneumonia) TFT values ??
TFT in RTH (Resistance to Thyroid Hormone)
TSH normal/low; T4: low; T3: low
Non-thyroidal Illness syndrome aka Euthyroid Sick Syndrome
TSH: High; T3: High; T4: Normal
