Endocrinology Flashcards
Adrenocortical axis
Hypothalamus
I
CRH
I
Anterior Pituitary
I
ACTH
I
Adrenal gland
I
CortisolPrimary adrenal insufficiency
Pathophysiology and examples
- Adrenal glands themselves are damaged, resulting in a reduction in secretion of cortisol and aldosterone
- Most common cause is autoimmune
- Example: Addisons
Secondary adrenal insufficiency
Pathophysiology and examples
- Result of inadequate ACTH stimulating the adrenal glands, resulting in low cortisol release
- Due to loss or damage of the pituitary gland
- Examples: pituitary surgical removal, infection, loss of blood flow, radiotherapy
- Sheehan’s syndrome: massive blood loss during childbirth leads to pituitary gland necrosis
Tertiary adrenal insufficiency
Pathophysiology and examples
- Result of inadequate CRH release by the hypothalamus
- Usually the result of long term oral steroids (>3 weeks) causing suppression of hypothalamus
- When exogenous steroids are suddenly withdrawn, the hypothalamus does not ‘wake up’ fast enough and endogenous steroids are not adequately produced
What is released by the anterior pituitary gland?
- Thyroid stimulating hormone (TSH)
- Adrenocorticotropic hormone (ACTH)
- Follicle stimulating hormone (FSH) and luteinising hormone (LH)
- Growth hormone (GH)
- Prolactin
What is released by the posterior pituitary gland?
- Oxytocin
- Antidiuretic hormone (ADH)
Diabetes
What is secreted by alpha cells
Glucagon
Diabetes
What is secreted by beta cells
Insulin
Diabetes
What is secreted by D-cells
Somatostatin
Diabetes
What is secreted by PP/F cells
Pancreatic polypeptides
Where are alpha- and beta- cells?
Islets of Langerhans in the pancreas
Basic pathology of T1DM
Autoimmune disorder where the insulin-producing beta cells of the islets of Langerhans in the pancreas are destroyed by the immune system
This results in an absolute deficiency of insulin resulting in raised glucose levels
Patients tend to develop T1DM in childhood/early adult life and typically present unwell, possibly in diabetic ketoacidosis
Basic pathology of T2DM
This is the most common cause of diabetes in the developed world. It is caused by a relative deficiency of insulin due to an excess of adipose tissue. In simple terms there isn’t enough insulin to ‘go around’ all the excess fatty tissue, leading to blood glucose creeping up.
Diagnosis of diabetes
Symptomatic AND one of:
- Fasting glucose > 7.0 mmol/L
- Random glucose > 11.1 mmol/L (or after 75 g OGTT after 2 hrs)
Asymptomatic:
- Above criteria but on two separate occasions
HbA1c:
- > 48 mmol/mol = diagnostic
Diabetes
Why do you get polydipsia and polyuria
Osmotic effect of water being ‘dragged’ out of body due to excess blood glucose being excrete in the urine (glycosuria)
What can cause a misleading HbA1c result?
Increased red cell turnover
DKA
Features
- Abdominal pain
- Polyuria, polydipsia, dehydration
- Kussmaul respiration (deep hyperventilation)
- Acetone-smelling breath (‘pear drops’ smell)
T1DM
Use of HbA1c
- Not as useful in patients with possible/suspected diagnosis of T1DM as it may not accurately reflect a recent rapid rise in serum glucose
T1DM
C-peptide
- Levels are typically LOW in T1DM
Diabetes
Autoantibodies
- Antibodies to glutamic acid decarboxylase (anti-GAD): 80% T1DM
- Islet cell antibodies (ICA, against cytoplasmic proteins in the beta cells): 70-80% T1DM
- Insulin autoantibodies (IAA): 90% of young children with T1DM and 60% of older patients
- Insulinoma-associated-2 autoantibodies (IA-2A)
T1DM
Classic presentations
- Ketosis
- Rapid weight loss
- Age of onset below 50 years
- BMI below 25 kg/m²
- Personal and/or family history of autoimmune disease
How to differentiate T1DM and T2Dm if in doubt?
- Autoantibodies
- C-peptide
T2DM
Use of HbA1c
- > 48 diagnostic of T2DM
- < 48 does not necessarily exclude T2DM
Conditions where HbA1c may not be used for diagnosis
- Haemoglobinopathies
- Haemolytic anaemia
- Untreated iron deficiency anaemia
- Suspected gestational diabetes
- Children
- HIV
- Chronic kidney disease
- People taking meds causing hyperglycaemia (e.g. corticosteroids)
Impaired fasting glucose
A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting glucose (IFG)
Impaired glucose tolerance
Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
People with IFG should then be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that the person doesn’t have diabetes but does have IGT
Hypertensive management in diabetes
Targets
Age < 80 yrs:
- Clinic 140/90
- ABPM 135/85
Age > 80 yrs
- Clinic 150/90
- ABPM 145/85
Hypertensive management in diabetes
1st line
- ACE-I/ARB due to renoprotective effect in diabetes
- ARB preferred for black African or African-Caribbean diabetic patients
- Further management reverts back to that of non-diabetic patients
Beta-blockers in diabetes
- The routine use of beta-blockers in uncomplicated hypertension should be avoided, particularly when given in combination with thiazides
- They may cause insulin resistance, impair insulin secretion and alter the autonomic response to hypoglycaemia.
T1DM
HbA1c target
48 mmol/mol or lower
T1DM
HbA1c
How often should it be measured
Every 3-6 months
T1DM
Patient monitoring
- Measure BM QDS at least
- Before each meal and before bed
- More often if high frequency of hypoglycaemia episodes, e.g. illness, sport, planning pregnancy, whilst breastfeeding
T1DM
Blood glucose targets
5-7 mmol/l on waking and
4-7 mmol/l before meals at other times of the day
T1DM
Types of insulin
- Offer multiple daily injection basal–bolus insulin regimens, rather than twice‑daily mixed insulin regimens, as the insulin injection regimen of choice for all adults
- Twice‑daily insulin detemir is the regime of choice. Once-daily insulin glargine or insulin degludec is an alternative.
- Offer rapid‑acting insulin analogues (insulin aspart, insulin lispro, and insulin glulisine) injected immediately before meals, rather than rapid‑acting soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 diabetes
T1DM
When might you consider adding Metformin?
If BMI > 25 kg/m
T2DM
HbA1c targets
It’s worthwhile thinking of the average patient who is taking metformin for T2DM, you can titrate up metformin and encourage lifestyle changes to aim for a HbA1c of 48 mmol/mol (6.5%), but should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%).
Once on a second drug, aim for 53 mmol/mol (7%).
If on any drug with risk of hypoglycaemia, e.g. lifestyle advice and sulfonylurea –> aim for 53 mmol/mol
T2DM
Dietary advice
- Encourage high fibre, low glycaemic index sources of carbs
- Low-fat dairy products
- Oily fish
- Discourage foods marketed specifically at diabetes
- Initial target weight loss in obesity = 5-10%
Diabetes and ramadam
- They should try and and eat a meal containing long-acting carbohydrates prior to sunrise (Suhoor)
- Patients should be given a blood glucose monitor to allow them to check their glucose levels, particularly if they feel unwell
- For patients taking metformin the expert consensus is that the dose should be split one-third before sunrise (Suhoor) and two-thirds after sunset (Iftar)
- Expert consensus also recommends switching once-daily sulfonylureas to after sunset. For patients taking twice-daily preparations such as gliclazide it is recommended that a larger proportion of the dose is taken after after sunset
- No adjustment is needed for patients taking pioglitazone
DM
General sick day rules
- Increased BM monitorign frequency
- Increased fluid intake (3 litres in 24 hrs)
- Sugary drinks if unable to eat
- Box of ‘sick day supplies’
- Access to mobile phone
DM
Sick day rules on oral hypoglycaemics
If taking oral hypoglycaemics:
- Continue taking
- Stress response with increase cortisol and push sugars high even without oral itnake
- Though stop metformin if very dehydrated (renal impairment risk)
DM
Sick day rules on insulin
- DO NOT STOP (risk of DKA)
- Continue normal regime but check blood more frequently
- Check ketone levels and if raised along with glucose then give corrective dose of insulin (total daily insulin divided by 6 - max dose 15 units)
DM
Sick day rules
Factors indicating possible admission
- Underlyinf illness requirign admission, e.g. MI
- Inability to keep fluids down (> few hours)
- Persistent diarrhoea
- Significant ketosis in insulin dependent diabetic despite additional insulin
- BM > 20 despite additional insulin
- Unable to manage adjustments to usually diabetes management
- Lack of support at home (lives alone, at risk of becoming unconscious)
Diabetes and driving - criteria for HGV licence
- There has not been any severe hypoglycaemic event in the previous 12 months
- The driver has full hypoglycaemic awareness
- The driver must show adequate control of the condition by regular blood glucose monitoring*, at least twice daily and at times relevant to driving
- The driver must demonstrate an understanding of the risks of hypoglycaemia
- Tere are no other debarring complications of diabetes
Diabetic foot disease
Causes x2
- Neuropathy: resulting in loss of protective sensation, e.g. not noticing a stone in the shoe. Also Charcot’s arthropathy or dry skin.
- Peripheral arterial disease: DM is a RF for both macro and microvascular ischaemia
Diabetic foot disease
Presentation
- Neuropathy - loss of sensation
- Ischaemia - absent foot pulses, reduced ABPI, intermittent claudication
Diabetic foot disease
Complications
- Calluses
- Ulceration
- Charcot’s arthropathy
- Cellulitis
- Osteomyelitis
- Gangrene
Diabetic foot disease
Screening
- Annually (at least)
- Screening for ischaemia: palpate dorsalis pedis pulse and posterior tibialis pulse
- Screening for neuropathy: a 10 g monofilament is used on various parts of sole of the foot
Diabetic foot diease
Low risk
- No RFs except callus alone
Diabetic foot disease
Moderate risk
One of:
- Deformity
- Neuropathy
- Non-critical limb ischaemia
Diabetic foot disease
High risk
One of:
- Previous ulceration
- Previous amputation
- On renal replacement therapy
- Neuropathy and non-critical limb ischaemia together
- Neuropathy in combination with callus and/or deformity
- Non-critical limb ischaemia in combination with callus and/or deformity
Diabetic foot disease
Management
Moderate to high risk should be followed up regularly by local diabetic foot centre
DKA
Management
- FLUIDS
- If kid -> give fluids for 1 hr first before insulin
- IV insulin (0.1 unit/kg/hr) of 5% dextrose
- Correction of electrolyte disturbance (often high K+ to start but will drop with insulin so monitor and consider replacement)
- Long-acting insulin should be continued !!! Short-term insulin should be stopped !!!
DKA
Resolution parameters
- pH >7.3 and
- Blood ketones < 0.6 mmol/L
- Bicarbonate > 15.0mmol/L
- Both the ketonaemia and acidosis should have resolved within 24 hours –> senior review from an endocrinologist if not
- If above criteria met and patient is eating/drinking –> switch to SC insulin
- Review by DM nurse prior to discharge
DKA
Complications
- Gastric stasis
- Thromboembolism
- Arrhythmias secondary to hyperkalaemia/ iatrogenic hypokalaemia
- Iatrogenic due to incorrect fluid therapy (cerebral oedema (children + young adults particularly vulnerable, head CT if suspected), hypokalaemia, hypoglycaemia)
- AKI
- Acute respiratory distress syndrome
Diabetes insipidus
Pathophysiology
Two types
- Decreased secretion of ADH from pituitary (cranial DI)
OR - Insensitivity to ADH (nephrogenic DI)
Causes of cranial DI
- Idiopathic
- Post head injury
- Pituitary surgery or radiotherapy
- Brain infections - meningitis/encephalitis/TB
- Craniopharyngiomas
- Infiltrative: histiocytosis X, sarcoidosis
- DIDMOAD (DI, DM, optic atrophy, deafness - Wolframs syndrome)
- Haemochromatosis
Causes of nephrogenic DI
- Genetic (affect vasopression ADH receptor)
- Electrolytes: hypercalcaemia, hypokalaemia
- Lithium - desensitises the kidney’s ability to respond to ADH in collecting ducts
- Tubulo-interstitial disease: obstruction, sickle-cell, pyelonephritis
DI
Features
- Polyuria
- Polydipsia
- HYPERnatraemia
- Dehydration
- Postural hypotension
DI
Investigations
- High plasma osmolality
- Low urine osmolality (> 700 mOsm/kg excludes DI)
- Water deprivation test!
DI
What is the water deprivation test?
- Also know as desmopressin stimulation test
- Initially avoid taking fluids for 8 hrs
- Urine osmolality measured
- Synthetic ADH (desmopressin) administered
- 8 hrs later urine osmolality measured again
Water deprivation test
Results in cranial DI
- Kidneys can still respond to ADH, but aren’t getting any
- Initially urine osmolality will remain low as continues to be diluted by excessive water, but after desmopressin –> urine osmolality is high
Water deprivation test
Results in nephrogenic DI
- Unable to respond to ADH
- Therefore urine osmolality ill remain low even after desmopressin
What is primary polydipsia?
Excessive consumption of fluids leading to polydipsia and polyuria
Water deprivation test
Results in primary polydipsia
- Urine osmolality will be high even before desmopressin is given
Management of DI
- Treat underlying cause
- Mild cases can be managed conservatively
Cranial DI:
- Desmopressin
Nephrogenic DI:
- Thiazides
- Low salt/protein diet
- Sometimes higher doses of desmopressin under close monitoring
Thyroid hormones
Functions
- Food metabolism
- Protein synthesis
- Increased sympathetic action, e.g. CO and HR
- Heat production
- Needed for growth and development
Unique features of Grave’s disease
All due to presence of TSH receptor antibodies
- Diffuse goitre (without nodules)
- Graves eye disease
- Bilateral exophthalmos
- Pretibial myxoedema
Unique features of toxic multinodular goitre
- Goitre with firm nodules
- Most > 50 yrs
- Second most common cause
What time of lump is a solitary toxic thyroid nodules likely to be? Management
Benign adenoma
Surgical removal
What is De Quervain’s thyroiditis?
- Viral infection with fever, neck pain and tenderness, dysphagia and hyperthyroidism
- Hyperthyroidism phase is followed by a hypothyroid phase as TSH levels fall due to negative feedback
- Self-limiting -> supportive Tx with NSAIDs and beta-blockers
Radioactive iodine therapy
What does it involve
- Drink single dose of radioactive idone
- Taken up by thyroid gland and emitted radiation destroys a proprortion of thyroid cells
Radioactive iodine therapy
Recovery
- Remission can take 6 months
- Patients can be left with hypothyroidism and require thyroxine
Radioactive iodine therapy
Contraindications and ‘rules’
- Must not be pregnant, do not get pregnant within 6 months
- Must avoid close contact with children and pregnant women for 3 weeks
- Limit contact with anyone for several days following the dose
Thyroid eye disease
Pathophysiology
- Autoimmune response agasint an autoantigen, possibly the TSH receptor –> retro-orbital inflammation
- Inflammation results in glycosaminoglycan and collagen deposition in muscles
Thyroid eye disease
Features
- Eu-, hypo- or hyper- thyroid at time of presentation
- Exopthalmos
- Conjunctiuval oedema
- Optic disc swelling
- Ophthalmoplegia
- Inability to close the eyelids –> may lead to sore, dry eyes
- If severe and untreated, may result in exposure keratopathy
Thyroid eye disease
Prevention
- Stop smoking
- Radioiodine may increase inflammatory symptoms, prednisolone helps reduce the risk
Thyroid eye disease
Management
- Topical lubricants
- Steroids
- Radiotherapy
- Surgery
Thyroid eye disease
Need for urgent review when?
- Unexplained deterioration of vision
- Awareness of change in intensity or quality of colour vision in one/both eyes
- Hx of eye suddenly ‘popping out’
- Obvious corneal opacity
- Cornea still visible when eyelids closed
- Disc swelling
Thyroid cancer
Papillary
- 70%
- Young females
- Spread: lymph nodes, lung
- Excellent prognosis
- Surgery
Thyroid cancer
Follicular
- 20%
- Middle-aged
- Spread: blood to bone, lungs
Thyroid cancer
Medullary
- 5%
- Cancer of parafollicular (C) cells
- Secrete CALCITONIN (tumour marker)
- Part of MEN-2
Thyroid cancer
Anaplastic
- 1%
- Not responsive to Tx
- Can cause pressure symptoms
Thyroid cancer
Lymphoma
- Associated with Hashimoto’s thyroiditis
- More prevalent in females
- STRIDOR
What is MEN-2?
Multiple endocrine neoplasia type 2
- Medullary thyroid cancer: 98% to 100% with MEN2A are affected
- Pheochromocytoma, a typically benign (noncancerous) tumor of the adrenal glands: 50% with MEN2A affected
- Parathyroid adenoma (a benign tumor) or hyperplasia, meaning increased size of the parathyroid gland: 5% to 10% with MEN2A affected
Management of papillary and follicular cancer
- Total thyroidectomy
- Followed by radioiodine (I-131)
- Yearly thyroglobulin levels to detect early recurrent disease
Causes of gynaecomastia
- Physiological in puberty
- Testicular cancers (secrete oestrogen, hCG) - leydig cells, seminomas
- Liver cirrhosis and failure
- Hyperthyroidism
- Haemodialysis
- Other hCG secreting hormones (SCLC)
Drug causes:
- Spironolactone (most common cause)
- Cimetidine
- Digoxin
- Cannabis
- Finasteride
- GnRH agonists (GOSERELIN) - used in prostate cancer
- oestrogens, anabolic steroids
Complications of Transphenoidal surgery
- Hypopituitarism
- Diabetes insipidus
- Haemorrhage
- CNS injury
- Meningitis
Normal TSH levels
0.5-5.5
Normal free T4 levels
9-18
Normal total T4 levels
70-140
Hypercalcaemia
At what level would you consider Tx with bisphosphonates?
> 3
What might be considered in a diabetic with erratic blood glucose control, bloating and vomiting?
Pathophysiology and management
Gastroparesis (due to neuropathy of the vagus nerve, causing abnormal gut movement)
Manage with metoclopramide, domperidone or erythromycin
Causes of hypoglycaemia
EXPLAIN
- Exogenous drugs (typically sulfonylureas or insulin)
- Pituitary insufficiency
- Liver failure
- Addison’s disease
- Islet cell tumours (insulinomas)
- Non-pancreatic neoplasms
Glucocorticoid SEs
Endocrine
- impaired glucose regulation
- increased appetite/weight gain
- hirsutism
- hyperlipidaemia
Cushing’s syndrome
- moon face
- buffalo hump
- striae
Musculoskeletal
- osteoporosis
- proximal myopathy
- avascular necrosis of the femoral head
Immunosuppression
- increased susceptibility to severe infection
- reactivation of tuberculosis
Psychiatric
- insomnia
- mania
- depression
- psychosis
Gastrointestinal
- peptic ulceration
- acute pancreatitis
Ophthalmic
- glaucoma
- cataracts
- suppression of growth in children
- intracranial hypertension
- neutrophilia
Mineralocorticoid SEs
- Fluid retention
- Hypertension
Thyroid storm
Precipitating events
- Thyroid or non-thyroid surgery
- Trauma
- Infection
- Acute iodine load, e.g. CT contrast media
Thyroid storm
Features
- Fever > 38
- Tachycardia
- Confusion and agitation
- N+V
- HTN
- HF
- Abnormal liver function - jaundice may be seen
Thyroid storm
Management
- Beta blockers
- Propylthiouracil / Methimazole
- Hydrocortisone
- Dexamethasone
Thyroid eye disease
severity of eye disease
NOSPECS
Best to Worst
N: No signs/symptoms
O: Only signs (e.g. upper lid retraction)
S: Signs and symptoms (including soft-tissue involvement)
P: Proptosis
E: Extra-ocular muscle involvement
C: Corneal involvement
S: Sight loss due to optic nerve involvement
What do you need to test for in those with acromegaly and why?
DM, because growth hormone is anti-insulin and this leads to a state of insulin resistance and eventually diabetes
What is the leading cause of death in those with acromegaly?
- CVS disease secondary to increase in heart muscle size, HTN and insulin resistance
What are the white patches called seen in hypothyroidism?
Vitiligo
From which anatomical structure does the thyroid gland originate from before embryological descent?
Foramen caecum
When do the foetal thyroid follicles and T4 develop?
at week 10
Hypothyroidism
What might you see on and FBC?
- Macrocytic anaemia
Pernicious anaemia
Grave’s Disease
Three aspects that define Graves
- Thyroid eye disease (ophthalmoplegia, exophthalmos, extra-ocular muscle swelling)
- Pretibial myxoedema (mucin deposits)
- Thyroid acropachy (clubbing, swollen fingers, toe swelling, periosteal new bone formation)
Urine and plasma osmolalities seen in diabetes insipidus? (high/low)
- urine = low
- plasma = high
Explain how the water deprivation test allows for diagnosis of diabetes insipidus?
Normal response of the body is to concentrate urine and decrease urine output.
However, in DI, there is continued production of large volumes of urine with low osmolality
What can repeated hypoglycaemic episodes lead to?
A lack of awareness of hypoglycaemia by the body and the initial autonomic symptoms may not occur
Advice for preventing hypos
- Regular finger-prick checking
- Never miss a meal
- Keep emergency supply of glucose on person
- Change insulin appropriately in response to change in diet, activity, illness
Describe the oral glucose tolerance test
- Patient fasts overnight
- Drink containing 75 g glucose in 300 ml water is given
- Blood glucose is measured prior to drink and then at 2 hours
- Diabetes if > 11.1mmol/L at 2 hrs
- Patient advised not to drink coffee or smoke in fasting period
DKA
Bedside test to check for it once already done BM?
Urine dipstick for ketones
DKA
Management
- Fluid replacement (aggressively)
- Insulin sliding scale
- Potassium replacement
DKA
Explain pathophysiologu
- Insulin deficiency produces glucose production in the liver
- Lipolysis occurs
- Fatty acids are broken down to form ketone bodies
- This produces a metabolic acidosis
- This usually occurs in starvation periods, as breaking down ketones is less efficient
What is the by product of ketone breakdown?
Acetone
What is the hyperventilation in DKA known as?
Kussmaul’s respiration
Advice for those on glucocorticoids
- Never stop them suddenly
- Carry steroid card
- Medic alert bracelet
- Change dose (double) when unwell
- Carry emergency ampoule of hydrocortisone for when oral route not advisable
Complication of parathyroid surgery?
- Hypoparathyroidism
- Laryngeal nerve palsy
What is the first type of sense to diminish in diabetic neuropathy?
Vibration
What might you see in the foot of someone with diabetic neuropathy?
- Charcot’s joint
- Painless ulcers
- High arched foot with clawing toes
- Diminished reflexes
Other types of neuropathy that can occur in diabetes? (other than peripheral)
- Autonomic neuropathy
- Diabetic amyotrophy
- Mononeuropathy
- Acute painful neuropathy
Hypothyroidism
Pregnancy
- Thyroxine is safe in pregnancy and breastfeeding
- Increased dose during pregnancy (by up to 50% as early as 4-6 weeks in)
- Serum TSH measured in each trimester and 6-8 weeks post-partum
Hyperthyroidism
Pregnancy
Drug choice
Propylthiouracil is used in the first trimester of pregnancy in place of carbimazole, as the latter drug may be associated with an increased risk of congenital abnormalities. At the beginning of the second trimester, the woman should be switched back to carbimazole
What is the most common thyrotoxicosis in pregnancy?
Graves Disease
What are the risks of untreated thyrotoxicosis in pregnancy?
- Risk of fetal loss
- Maternal heart failure
- Premature labour
Hyperthyroidism
Pregnancy
TFT levels
- Should be kept in upper third of normal range to avoid foetal hypothyroidism
Hyperthyroidism
Pregnancy
Monitoring
- Thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks gestation
- Helps to determine risk of neonatal thyroid problems
What is the risk of over-treatment with thyroxine?
- Osteoporosis
- Hyperthyroidism
- Worsening of angina
- Atrial fibrillation
Interactions with levothyroxine and how to get around it?
- Iron, calcium carbonate
- Absorption of levothyroxine is reduced
- Give at least 4 hrs apart
1st line insulin regime in newly diagnosed T1DM?
Basal–bolus using twice‑daily insulin detemir
If C-peptides are present, which type of diabetes is it?
T2DM
