Wk9 - Endocrinology Flashcards
Define DM
“A metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both.”
Presentation of DM
Hyperglycaemmia:
Glycosuria - Depletion of Energy Stores
Tired, weak, weight loss, difficulty concentrating, irritability
Glycosuria - Osmotic Diuresis
Polyuria, polydipsia, thirst, dry mucous membranes, reduced skin turgor, postural hypotension
Glucose Shifts - Swollen Ocular Lenses
Blurred vision
Insulin deficiency & complications:
Ketone Production -
Nausea, vomiting, abdominal pain, heavy/rapid breathing, acetone breath, drowsiness, coma
Depletion of Energy Stores (ie. Muscle) - Weakness, polyphagia, weight loss, growth retardation in young
Complications (T2DM) - Macrovascular, Microvascular, Neuropathy, Infection
WHO criteria for DM
Fasting plasma glucose of >=7.0 mmol/L
Random plasma glucose of >=11.1 mmol/L
One abnormal values diagnostic if symptomatic
Two abnormal values if diagnostic if asymptomatic
HbA1c 6.5% or 48 mmol/mol
Diabetes should not be diagnosed on the basis of glycosuria or a BM stick
OGTT only required for diagnosis if IFG or GDM
Classifying primary diabetes
1) Type 1 DM
Immune pathogenesis
Severe insulin deficiency
2) Type 2 DM
Combination of insulin resistance and insulin deficiency
Diagnosis of DM
Plasma ketone metres (Beta-hydroxybutyric acid)
Islet autoantibodies:
Markers of autoimmune process associated with T1DM
Present in 80% of T1DM if combination of glutamic acid decarboyxylase (GAD) and insulinoma-associated antigen -2 (IA2) measured (<1% of MODY)
Some patients with phenotype of T2DM have positive antibodies (progress more quickly to insulin). Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before, especially in obese)
C-peptide:
Secreted in equimolar concentrations to insulin
Useful marker of endogenous insulin secretion
Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before especially in obese)
Can be measured in blood or urine (urine c peptide/creatinine ratio)
Pathogenesis of type 1 DM
Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion.
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans.
Occurs in genetically susceptible subjects and is probably triggered by one or more environmental agents.
Reports have linked each of the following factors to an increased risk of T1DM (no associations have been verified and many have been contradicted):
●Viral infections, particularly enterovirus infections
●Immunizations
●Diet, especially exposure to cow’s milk at an early age
●Higher socioeconomic status
●Obesity
●Vitamin D deficiency
●Perinatal factors such as maternal age, history of preeclampsia, neonatal jaundice and low birth weight (reduced risk)
Disease progression of T1DM
Genetic risk
Immune activation - beta cells are attacked
Immune response - development of a single autoantibody…..
Epidemiology of T1DM
Lifetime risk of developing T1DM:
No family history – 0.4 percent
Offspring of an affected mother – 1 to 4 percent
Offspring of an affected father – 3 to 8 percent
Offspring with both parents affected – reported as high as 30 percent
Non-twin sibling of affected patient – 3 to 6 percent
Dizygotic twin – 8 percent
Monozygotic twin – 30 percent within 10 years of diagnosis of the first twin, and 65 percent concordance by age 60 years 5% of DM.
Pathogenesis of T2DM
90% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency
Common with a prevalence that rises markedly with increasing levels of obesity
Most likely arises through a complex interaction among many genes and environmental factors
Epidemiology of T2DM
Prevalence varies remarkably among ethnic groups living in the same
39% have at least one parent with the disease
Lifetime risk for a first-degree relative of a is 5 -10 times higher than that of age- and weight-matched without family history of diabetes.
Environment explains why Pima Indians in Mexico are less than one-fifth that in United States Pima Indians (6.9 versus 38 percent).
Pathogenesis and epidemiology of T2DM
1-2% of DM (often unrecognised)
Caused by change in a single gene (monogenic). Autosomal dominant (50% chance of inheriting)
6 genes have been identified accounting for 87% of UK MODY (HNF1-A around 70%)
3 main features:
- Often <25yrs onset
- Runs in families from one generation to next
- Managed by diet, OHAs, insulin (not always)
Pathogenesis and epidemiology of GDM
Carbohydrate intolerance with onset, or diagnosis, during pregnancy
Studies show that appropriate interventions reduce adverse outcomes in pregnancy
Risk factors include high body mass index, previous macrosomic baby or gestational diabetes, or family history of, or ethnic prevalence of, diabetes
All women with risk factors should have an OGTT at
24 to 28 weeks. Internationally agreed criteria for gestational diabetes using 75 g OGTT:
Fasting venous plasma glucose ≥ 5.1 mmol/l, or
One hour value ≥ 10 mmol/l, or
Two hours after OGTT ≥ 8.5 mmol/l
Recall causes of secondary DM
Secondary Diabetes
1) Genetic Defects of beta-cell function
2) Genetic defects in insulin action
3) Disease of exocrine pancreas
- Pancreatitis/Carcinoma/CF/Haemochromatosis
4) Endocrinopathies
- Acromegaly/Cushings/Phaeochromocytoma
5) Immunosuppressive agents
- Glucocorticoids/Tacrolimus/Ciclosporin
6) Anti Psychotics – Cloazpine/Olanzipine
7) Genetic syndromes associated with DM
- Down’s Syndrome Friedreich’s Ataxia, Turner’s
- Myotonic Dystrophy, Kleinfelter’s Syndrome.
Pathophysiological basis of insulin secretion
Insulin is produced in beta cells which constitute 75% of the islets of Langerhans of the pancreas
Insulin, as well as C peptide, are released by exocytosis into the portal venous system which leads it directly to the liver (50%)
The principal stimulant of insulin secretion is glucose
With a basal secretion of approximately 40 microgram/h under fasting conditions, there are increases of secretion linked to meals
The aim of the treatments by exogenous insulin is to approach the physiological curve of secretion.
Human vs analogue insulin ….
-
Insulin pens
More convenient and easier to transport than traditional vial and syringe
Repeatedly more accurate dosages
Easier to use for those with impairments in visual and fine motor skills
Less injection pain (as polished and coated needles are not dulled by insertion into a vial of insulin before a second insertion into the skin)
Can be used without being noticed
Continuous Subcutaneous Insulin infusion (CSII)
CSII or ‘pump therapy’ can potentially provide significant improvement in glycaemic control and quality of life for some people with Type 1 diabetes.
Pumps have the potential to make it easier to achieve glucose control with less danger of severe and incapacitating hypoglycaemia. However, the efficacy of this compared to SMBG is still debatable.
Specific but infrequent complications of CSII therapy include reactions and occasionally infections at the cannula site, tube blockage and pump malfunction.
CSII therapy is expensive, incurring costs for batteries, reservoirs, infusion sets, insulin, lancets, test strips and glucometers.
Curative treatment for T1DM
Islet cell transplant - harvest islets from pancreas and then inject them - immunosuppressive drugs needed
Pancreatic transplant
Physiological hierachy of hypoglycaemia
4.6 mmol/l - inhibition of insulin release - general malaise: headache, nausea
3.8 mmol/l - release of counterrgulatory hormones glucagon and adrenaline – onset of autonomic symptoms (most occur ~3 mmol/l) - sweating, palpitations, shaking, nausea, anxiety, hunger
BUT 70-80% of readings at this level no symptoms
2.5 -2.8 mmol/l - impairment of cognitive function and concentration, inability to perform complex tasks - confusion, drowsiness, odd behaviour, speech difficulty, incoordination, weakness, visual change, dizziness, tiredness
<2mmol/l – EEG changes, seizures
<1.5 mmol/l - coma, convulsions
Severity scale of hypoglycaemia
MILD: autonomic
MODERATE: autonomic and neuroglycopaenic
MODERATE: autonomic and nueroglycopaenic
SEVERE: autonomic and neuroglycopaenic
Hypos and driving
CBG> 5mmol/l before driving (5 TO DRIVE), carry CHO, identifiers
If between 4-5 mmol/l – eat before driving
2 hours at a time
Do not drive if feeling hypo or CBG <4 mmol/l
If hypo: 1 hour before driving (from onset) and CBG>5
Group 1 entitlement: on insulin
Adequate hypo awareness
Notify if >1 severe hypo whilst awake in 12 months or most recent <3months when filling form
CBG monitoring evidence
Not a danger to the public
Acuity and visual fields OK
Group 1 entitlement: tablets risk of hypos e.g. sulphonylureas
Hypo guidance as above
CBG diary for driving
Group 2 entitlement: IRDM
Full hypo awareness and understanding of risks
No severe hypos in 12 months
CBG monitoring evidence: 3 months of recordings
Not a danger to the public
Acuity and visual fields OK
Group 2 entitlement: tablets risk of hypos
No severe hypos in 12 months
Full hypo awareness and understanding of risks
CBG checks at least twice daily and more often for driving
Definition of DKA
Features and diagnosis of DKA
Defintion:
- DKA is an acute metabolic complication of diabetes that is potentially fatal and requires prompt medical attention for successful treatment.
- It is characterised by absolute insulin deficiency and is the most common acute hyperglycaemic complication of type 1 DM
Clinical diagnosis with diagnostic criteria
Mainly T1DM but now recognise ketosis prone T2DM
4.6 to 8 episodes per 1000 people with diabetes
Mortality: fallen from 7.96% to 0.67% in UK. 5% worldwide
Mortality in young: cerebral oedema 70-80% deaths
Mortality in adults: severe hypokalaemia, ARDS, illness causing
decompensation
1) Metabolic acidosis: venous bicarbonate < 18mmol
H+ > 45 mEq/L
pH < 7.3
2) Plasma glucose: > 13.9mmol/l
3) Urinary / plasma ketones: ≥2+ urinary / >3mmol/L
Metabolic acidosis, hyperglycaemia and ketonuria or ketonaemia
Pathophysiology od DKA
Absolute or relative insulin deficiency
+
Increase in stress hormones
–>
- Lipolysis: FFAs: ketogenesis
- Gluconeogenesis: severe hyperglycaemia
- Osmotic diuresis + acidosis: dehydration
Clinical features of DKA
Osmotic Symptoms Weight Loss Breathlessness – Kussmaul respiration Abdominal pains, especially in children Leg cramps Nausea and vomiting Confusion
Precipitating factors of DKA
ACute illness (MI, trauma, pancreatitis)
NEw-onset DM
Insulin omission
Infections (pneumonia and UTIs are most common)
Steroids CSII pump failure Substance abuse Deliberate omission of insulin dose - weight management, avoidance of hypo, escaping domestic situation, depression, attention seeking Eating disorder
Typical key losses in DKA
DKA treatment
Complications of DKA
Key losses: 6-8L of water Sodium Chloride Potassium
Treatment:
Always consider and treat the precipitant
Fluid: restoration of circulatory volume: crystalloid (saline solution)
Clearance of ketones: 10% dextrose
Potassium
Insulin
Complications: hypoglycaemia, hypokalaemia (associated with cardiac arrhythmias)
Definition of HHS
Features and diagnosis of HHS
HHS is characterised by profound hyperglycaemia, hyperosmolality and volume depletion in the absence of significant ketoacidosis
Hypovolaemia
Very high blood glucose > 30mmol/L
Serum osmolality >320mOsmol/l
Bicarbonate usually > 15mmol/l
Absence of significant ketones
Ketoacidosis not present
May proceed to coma: watch GCS
Precipitating factors for HHS
Infection - 60%
Poor compliance - 30%
Drugs
Treatment of HHS
Treat the precipitant
Fluid
0.9% sodium chloride
Aim for a positive fluid balance of 3-6L by 12 hours
Only switch to 0.45% sodium chloride if osmolality not falling despite
positive fluid balance
Rate of fall in sodium should not exceed 10mmol in 24 hours
Insulin
Rate of fall no more than 5mmol/L/hr
Only start when glucose not falling with fluid alone
Low dose insulin 0.05units/kg/hr
Other
LMWH
Foot protection
Microvascular, foot and macrovascular ocmplications of diabetes
Retinopathy (eyes):
A leading cause of blindness in the working population in the developed world
First microvascular complication for patients with diabetes
Nephropathy (kidneys):
Will affect 30-40% of patients with diabetes;
23% of patients starting dialysis have diabetes as the primary case, but poorer survival on it
Neuropathy/foot disease:
Life-time risk for a foot ulcer is 25%
80% of non-traumatic amputations occur in patients with diabetes
Cardiovascular disease (CVD):
Increased risk of CVD
Duration of diabetes and female gender increase risk
Management of microvascular, foot and macrovascular ocmplications of diabetes
Retinopathy (eyes):
Annual photographic retinal screening with triggers for ophthalmology referral
Nephropathy (kidneys):
Annual monitoring of renal function and urinary albumin excretion, referral to renal team if nephropathy progesses e.g. CKD4; macroalbuminuria
Neuropathy/foot disease:
Annual foot-screening (minimum) with risk stratification and referral to podiatry/vascular as appropriate e.g. progressive neuropathy, structural change, ischaemia
Cardiovascular disease (CVD):
Keep BP <130/80, lower if nephropathy
Statin therapy if T2DM and age >40 regardless of DM duration and baseline cholesterol. Consider in T1DM especially if complications
MOA of metformin
Side effects of biiguanides
Metformin is part of the biguanide class
MOA:
Increases the activity of AMP-dependent protein kinase (AMPK)
This inhibits gluconeogenesis
Decreases insulin resistance.
Side effects: Diarrhoea Nausea Vomiting Taste disturbances Lack of apetite Risk of lactic acidosis in patients with renal failure
Not recommended in pregnancy and renal failure
MOA of sulphonylureas
Side effects
MOA of sulphonylureas (e.g. Cliclazide, Glimepiride):
Stimulates B cells of the pancreas to produce more insulin
Increases cellular glucose uptake and glycogenesis; reduces gluconeogensis
Gliclazide is short acting (12 hours approx)
Glimepiride is long acting)
Side effects: Hypoglycaemia Rashes Nausea Vomiting Stomach pain Indigestion Weight gain
Renally excreted so accumulates with renal failure
Avoid alcohol
Hypopitiutarism
Failure of (anterior) pituitary function
Can affect single hormonal axis or all hormones (panhypopituitarism)
Leads to secondary gonadal/thyroid/adrenal failure
Need multiple hormone replacement
Causes of hypopituitarism
Tumours (most common) Radiotherapy Infarction / haemorrhage (apoplexy) - Associated headache / visual disturbance - Assoc PPH (Sheehan’s syndrome) Infiltration (eg sarcoid) Trauma Lymphocytic hypophysitis
Anterior pituitary hromone replacement
Deficiency Replacement ACTH - hydrocortisone TSH - thyroxine FSH/LH - testosterone (males) - oestrogen (females) GH - growth hormone PRL - no replacement
Causes of high prolactin
Prolactinomas
Physiological
Lactation / pregnancy
Drugs (that block dopamine)
Tricyclics / antiemetics / antipsychotics
“stalk” effect
Due to loss of inhibitory dopamine
Macro vs micro adenoma
Macro >1cm
Micro <1cm
Pituitary tumours - types
Non-functioning (majority) - dont produce any hormones
Functioning Prolactin (prolactinoma) GH (acromegaly) ACTH (Cushing’s disease) TSH (TSHoma)
Others
Craniopharyngioma, pituitary cancer, Rathke’s cyst
Problems associated with non-functioning pituitary tumours
Commonest (25 % of all pit tumours)
No hormonal release
But cause problems Visual field defects Headache Stops other pituitary hormones working Eye movement problems
Investigation and treatment of non-functioning pituitary tumour
Investigation Imaging Visual field assessment Prolactin Other pituitary hormones
Treatment
Surgery
RT
Medical management unhelpful
Clinical features of prolactinoma
Pituitary tumours releasing prolactin
Micro < 1 cm
Macro > 1 cm
Clinical features Galactorrhoea Headaches Mass effect Visual field defect
Amenorrhoea / erectile dysfunction
(Gonadotrophic hormones are the ones first affect)
Prolactinomas diagnosis & treatment
Serum prolactin
Usually > 6000
MRI pituitary
Test remaining pituitary function
Gonadal function and thyroid hormones most affected
Medical
Dopamine agonists
eg cabergoline / bromocriptine / quinagolide
Surgery
VF compromise
Failure of medical therapy
Prolactinomas in pregnancy
Pituitary gland gets bigger in pregnancy
Dopamine agonists contraindicated
[prolactin] unhelpful
Can’t do serial MRI in pregnancy
Monitor visual fields if macroprolactinoma
Features of acromegaly
Pituitary tumour secreting Growth Hormone
Post puberty ie after growth plates fused
Gigantism
Features Sweats and headaches Alteration of facial features Increased hand and feet size Visual impairment Cardiomyopathy Inc. Inter-dental space
Diagnosis of acromegaly
Rare
20 new cases per year in Scotland
Usually macroadenoma
Diagnosis
Glucose tolerance test:
- Glucose should suppress GH so if present, GH will still be high regardless of oral administration of glucose
- Measure IGF-1 as has long half-life and is more useful than a random GH
Then MRI
Acromegaly treatment
First line- surgery
Often tumour can’t be fully removed
Drugs
- Somatostatin analogue: Octreotide; Before and after surgery
- Dopamine agonist
- GH receptor agonist: Pegvisomant ; £££
Radiotherapy
- Residual tumour / ongoing symptoms
Gene mutation causes Acromegaly
AIP gene
What is cushings disease?
Diagnosis
Pituitary tumour releasing ACTH
One of the causes of Cushing’s syndrome
wt gain / thin skin / easy bruising / BP / osteoporosis
Diagnosis- try to suppress it
- Dexamethasone suppression testing
Treatment of cushings disease
Surgery first line
If surgery fails / inappropriate / refused Bilateral adrenalectomy Medical therapy Ketoconazole / metyrapone Radiotherapy
Signs and symptoms of cushings disease
Buffalo hump Hypertension Moon face, with red (plethoric) cheecks Increased abdo fat Easy bruising...
Features of TSHoma
Pituitary tumour releasing TSH
Rare
Causes high TSH and high fT4
Clinical features and differential diagnosis of diabetes insipidus
ADH deficiency- central or cranial Clinical features polydipsia chronic excessive thirst accompanied by excessive fluid intake polyuria urine output > 3 L/day Differential diagnosis Nephrogenic diabetes insipidus Psychogenic polydipsia
Investigation:
Water deprivation test - deprived of fluids for 8 hours and plasma and urine osmolality measured every 2-4 hours. Then give synthetic ADH (desmopressin). If cranial DI, the urine osmolality will increase after given desmopressin; There will be no change in urine osmolality with nephrogenic DI.
Causes of central diabetes insipidus
deficiency of ADH idiopathic trauma pituitary tumour pituitary surgery pregnancy familial other Wegeners, sarcoidosis, histiocytosis X, lymphocytic panhypophysitis
Diagnosis and treatment of diabetes of diabetes insipidus
Diagnosis
Try to stimulate its release
Water deprivation test
Assess ability to concentrate urine with ADH
Treatment
Underlying cause
DDAVP
Spray, tablets or injection
Defining hypoglycaemia
Patients without DM: biochemical threshold of plasma glucose less than 4 mmol/L1
In non-DM- documented plasma glucose <3.0 mmol/L (some protocols 2.2 mmol/L)
Symptoms of hypoglycaemia
Autonomic symptoms: sweating, palpitations, pallor, tremors, nausea, irritability, hunger1,2
Neuroglycopenic symptoms: inability to concentrate, confusion, drowsiness, personality change, slurred speech, incoordination, weakness, dizziness, vision impairment, headache, seizures, coma1,2
Generally in patients with diabetes, autonomic symptoms occur before neuroglycopenic symptoms
Investigations of hypoglycaemia
Post Prandial Investigations
Ideally mixed meal test up to 5 hours
OGTT can be misleading
72 hour fast: Provoke the homeostatic response that keeps blood glucose concentrations from falling to concentrations that cause symptoms in the absence of food
Glucagon, Adrenaline> GH/Cortisol are the most important components.
Complete at plasma glucose at 2.5 mmol/L, 72 hours have elapsed or when plasma glucose is < 3 if Whipple’s triad previously documented
Young, lean, healthy, women may have plasma glucose ranges of 2.2 – 3.0 or even lower after prolonged periods of fasting, without symptoms
Glucose Insulin C peptide SU screen (Beta hydroxybutyrate) low in Insulinoma (Pro Insulin) low with exogenous Insulin Insulin Antibodies (can be taken at any time)
Imaging:
CT, MRI, EUS
Arterial Calcium Stimulaiton Test: Distinguishes focal (Insulinoma) from diffuse disease(nesidioblastosis/islet cell hypertrophy)
Causes of spontaneous hypoglycaemia
Pancreatic
Insulinoma
Non Insulinoma Pancreatogenic hypoglycaemia (NIPH) - Nesidioblastosis
MEN1
Non Islet Cell Tumour Hypoglycaemia
IGF II secreting tumours (Mesenchymal tumours, Carcinomas of the liver, stomach and adrenals)
Lymphoma, Myeloma, Leukaemias
Metastatic Cancer
Autoimmune Hypoglycaemia
Autoimmune Insulin Syndrome
Anti Insulin Receptor
Reactive Hypoglycaemia
Post Gastric Surgery
Alcohol Provoked Reactive Hypoglycaemia
Drug Induced: Insulin Indomethacin Sulfonylurea Lithium Repaglinide Levofloxacin Salicylates Heparin Quinine Trimethoprim Haloperidol Pentamidine Beta Blockers Disopyramide
Dietary Toxins:
Alcohol
Mushrooms causing acute liver failure
Organ Failure:
Severe Liver Disease
End Stage Renal Disease & Renal Dialysis
Congestive Cardiac Failure
Endocrine Disease:
Hypopituitarism
Adrenal Failure
Hypothyroidism
Inborn errors of metabolism
Miscellaneous: Sepsis Starvation Anorexia Nervosa Total parenteral nutrition Severe excessive exercise
What is Whipple’s triad?
Symptoms consistent with hypoglycaemia
Low plasma glucose concentration
Relief of those symptoms after the plasma glucose level is raised
Anatomy of adrenal gland
Glomerulosa: Aldosterone –> salt
Fasciculata: Cortisol –> sugar
Reticularlis: Androgens –> sex hormone production
Substarte = cholesterol
Adrnela medulla have chromograffin cells –> catecholamines
Revision: Regulation of renin-angiotensin system
Renin major regulator of aldosterone production
Activated in response to blood pressure
Leads to production of Ang II which causes direct (vasoconstriction) and indirect (aldosterone) methods of BP elevation
What can hypertension and hypokalaemia signify?
Could potentially be primary aldosteronism
- depending on rest of the clinical context
Tests for suspicion of primary aldosteronism
Aldosterone (would be high)
Renin (would be low)
APR
Features of primary aldosteronism
Commonest ‘secondary’ cause of hypertension-
40% adenoma; 60% bilateral hyperplasia
Hypokalaemia present in less than 50% of cases (but is an important clinical sign)
Aldosterone-renin-ratio (ARR) best screening tool
If increased, then consider further testing
Confirmation of aldosterone excess - first Tx
Stop medications if possible
Definitely stop β blockers and MR antagonists
Alternative drugs include α-blockers/verapamil/ hydralazine
Saline suppression test:
2L saline over 4 hours
4h aldosterone >270 pmol/l highly suspicious
(Wanting to suppress aldosterone level. if does not decrease suggests abnormality)
Management of Primary aldosteronism
Surgical - Unilateral laparoscopic adrenalectomy - Only done if adrenal adenoma - Cure of hypokalaemia - Cures hypertension in 30-70% cases Medical - Use MR antagonists (spironolactone or eplerenone)
Clinical features of cushings syndrome
Weight gain Hirsutism Psychiatric Proximal myopathy Plethora Hypertension Bruising Striae Inc. abdo fat Moon face Buffalo hump
Diagnosing cushings syndrome
Is Cortisol elevated?
Perform two of the following:
24 hr Urinary free cortisol
Urine cortisol: creat ratio x 3
Dexamethasone suppression test
Either overnight or low dose test over 48 hours
Plasma cortisol should be undetectable in normal circumstances
Late night salivary cortisol
Should be undetectable or very low in normals
Imaging:
CT (looking for adrenal adenoma)
Causes of cushings syndrome
ACTH dependent:
- Pituitary adenoma (68%) Cushing’s Disease
- Ectopic ACTH 12%
- Ectopic CRH <1%
ACTH independent:
- Adrenal adenoma 10%
- Adrenal carcinoma 8%
- Nodular hyperplasia 1%
Using HPA Axis
Congenital adrenal hyperplasia
Autosomal recessive disorder
Range of genetic disorders relating to defects in steroidogenic genes
Most common
CYP21 (21α hydroxylase) –> stops production of cortisol and aldosterone
Female
ambiguous genitalia (present earlier than boys)
Boys
Adrenal crisis (Hypotension, hyponatraemia)
Early virilisation
Treated with mineralocorticoid and glucocorticoid replacement
Features of phaechromocytoma
Phaeochromocytoma: tumour of adrenal medulla
Paraganglioma
extra-adrenal tumour - neural crest cells eg sympathetic ganglia
Rare, 2-8/million cases per year
Symptoms/ signs:
Hypertension (intermittent in 50%)
Episodes of headache, palpitations, pallor and sweating
Also tremor, anxiety, nausea, vomiting, chest or abdo pain
Crises last 15 minutes
Often well in between crises
Up to 25% of cases associated with genetic condition MEN VHL SDHB & SDHD mutations Neurofibromatosis
15-20% malignant
5 year survival <50%
80-85% benign
recurrence rate <10% and 5 year survival 96%
Pre-operative treatment of phaeochromocytoma
Alpha-blockade initially:
- Phenoxybenzamine or doxazosin
- Aim for SBP< 120 mm/Hg if possible
- Postural drop
Then beta blocker if tachycardic
- Labetolol or bisoprolol
Encourage salt intake
Adrenal insufficiency
Inadequate adrenocortical function
Primary insufficiency:
Addison’s disease
Autoimmune destruction
Clinical features: Anorexia, weight loss Fatigue/lethargy Dizziness and low BP Abdominal pain, vomiting, diarrhoea Skin pigmentation (due to high levels of ACTH)
Diagnosis of adrenal insufficiency
‘Suspicious biochemistry’: - dec. Na, inc. K - hypoglycaemia SHORT SYNACTHEN TEST Measure plasma cortisol before and 30 minutes after iv ACTH injection Normal: baseline >250nmol/L, post ACTH >480 ACTH levels Should be (causes skin pigmentation) Renin/aldosterone levels Inc. renin Dec. aldosterone
Adrenal autoantibodies
Primary vs Secondary Amenorrhoea
Primary:
Never had a period
Genitourinary abnormalities:
- Congenital absence of uterus, cervix or vagina (Rokitansky syndrome,
Androgen insensitivity syndrome)
Chromosomal abnormalities:
- Turners syndrome
Secondary hypogonadism (pituitary/ hypothalamic causes):
- Kallmans syndrome
- Pituitary disease
- Hypothalamic amenorrhoea (Low BMI, stress, illness)
Secondary: - No periods for 6 months Uterine - Ashermans syndrome Ovarian - PCOS - Premature ovarian failure Pituitary - Prolactinoma - Pituitary tumour Hypothalamic - Weight loss, stress, drugs e.g. opiates
Other causes of amenorrhoea
Physiological
- Pregnancy
- Lactation
Iatrogenic
- OCP or other hormonal contraceptives
Thyroid dysfunction
Hyperandrogenism
- Cushing’s syndrome
- CAH
- Adrenal or ovarian tumour
What is hirsutism
“Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens”
Causes of hirsutism
Ovarian - PCOS (95%), Androgen secreting tumour
Adrenal - Congenital adrenal hypertrophy, androgen secreting tumours
Idiopathic - normal invstigations
Presentation of PCOS
Classic presentation is with symptoms of
anovulation (amenorrhoea, oligomenorrhoea, irregular cycles)
Associated with symptoms of
hyperandrogenism (hirsutism, acne, alopecia)
However spectrum of presentation includes anovulatory women without hirsutism and hirsute women with mainly regular cycles
Typically presents during adolescence
Affects >5% women of reproductive age
Commonest cause of anovulatory infertility (80%)
Typical endocrine features are raised testosterone and LH
Also associated with metabolic abnormalities and increased risk of type 2 diabetes
3 features of pathophysiology of PCOS
Gonadotrophins
Androgens]Insulin resistance
Pathophysiology of PCOS - gonadotrophins
Increased LH concentration
Increased LH receptors in PCOS ovaries
Support ovarian theca cells
Increased ovarian androgen production
Decreased FSH
Low constant levels result in continuous stimulation of follicles without ovulation
Decreased conversion of androgens to oestrogens in granulosa cells
Pathophysiology of PCOS - Androgens
Increased androgen production (especially of androstenedione) from theca cells under influence of LH Disordered enzyme action Ovarian enzyme expression Peripheral conversion Decreased SHBG Produced in liver, binds testosterone Only free testosterone is biologically active Hyperandrogenism Hyperinsulinaemia
PAthophysiology of PCOS - insulin resistance
Overweight/obese women with PCOS are more symptomatic - more amenorrhoea and hisutism
Increased insulin in response to glucose load
Increased insulin resistance
Cause Vs Association?
Insulin stimulates theca cells of ovaries
Insulin reduces hepatic production of SHBG
Increased circulating androgens
Investigations of PCOS
Confirm profile of PCOS: - Testosterone - Andrestenedione - DHEAS - SHBG - FSH/LH Assess for other features: - Type 2 diabetes - Abnormal lipids Exclude other pathologies
Treatment of PCOS
Metformin for PCOS:
Not useful for treatment of infertility
Not very effective for treatment of hirsutism
May have a place in management of women at high risk of developing diabetes
Hirsutism - corticosteroids?
Main strategy: Weight loss & lifestyle advice - can improve ovulation rate and fertility
Male gonadal function
Testosterone Production (Leydig Cells) Steroid hormone Circulates bound to SHBG & albumin Free testosterone is active Activated to more potent form in target tissues
Growth
- Sex organs
- Skeletal muscle
- Epiphyseal plates fusion
- Larynx growth
- 2° characteristics
Other Effects
- Erythropoesis
- Behaviour
Adult
- Muscle mass
- Mood
- Bone mass
- Libido
- Body shape
Fertility
- Libido
- Erectile Function
- Spermatogenesis
Spermatogenesis (Spermatocytes, Leydig & Sertoli Cells)
Spermatocytes – mature into Spermatozoa
Leydig Cells – secrete Testosterone to promote sperm development
Sertoli Cells
Blood-testis barrier
Remove damaged spermatocytes
Secrete androgen binding protein
Control of gonadal function
-
Clinical features of hypogonadism
Child/Young adult:
- Slow growth in teens - No pubertal spurt
Small testes and phallus
Lack of secondary development
Adult:
- Depression/low mood - Poor libido - Erectile problems - Poor muscle bulk/power - Sparse body/body hair - Gynaecomastia - Gynoid weight gain - Great head hair - Short phallus - Small testes - abn. consistency
Testing for Hypogonadism
Testosterone:
- Early morning
- Free testosterone (N > 200)
- Total testosterone (N > 16)
- SHBG (sex hormone binding hormone)
LH & FSH
- Help determine possible pituitary cause
Fertility? Semen analysis: 1-3 days after last ejaculation 2-5 ml volume 20 x 106 sperm/ml 50% progressive motility ≥ 30% normal morphology
What is Kallmann’s syndrome
Commonest form of isolated gonadotrophin deficiency
Failure of cell migration of GnRH cells to hypothalamus from Olfactory placode
Associated with aplasia/hypoplasia of olfactory lobes – giviing anosmia or hyposmia
Also may be assoc. with deafness, renal agenesis, cleft lip/palate
May have micropenis ± cryptorchidism
Familial with variable penetration X-linked – Absence of KAL gene (KAL1) Autosomal Dominant (KAL2) Autosomal Recessive (KAL3) Other genetic causes of IHH exist (e.g Kisspeptin/GPR54 mutations)
Features seen with Kallmann’s syndrome
Childhood
Poor growth
Undescended testes
Adolescence Poor growth Small testes Micropenis Delayed/absent puberty features
Adult Slow, but adequate growth Small testes Small phallus Hypogonadal features
Klinefelter’s syndrome
Commonest genetic cause of male hypogonadism (1 in 500 male births)
XXY (but other sex chromosome variations exist)
Clinically manifests at puberty
Inc. LH & FSH – but seminiferous tubules regress & Leydig cells do not function normally
Wide clinical variation in phenotype due to hormonal response to LH surges Delayed puberty Suboptimal genital development Reduced 2° male sexual characteristics Persistent gynaecomastia Azospermia Behavioural issues/learning difficulties Androgen replacement ± psychological support ± fertility counselling
Hypogonad treatment
Androgen Replacement Therapy
Oral
IM
Topical
Fertility Treatment
hCG
Recombinant LH & FSH
GnRH pumps
Side effects of androgen replacement
Mood issues (aggression/behaviour change) Libido issues Increased haematocrit Possible prostate effects Acne, sweating Gynaecomastia
Functions of calcium
Muscle contraction (stabilisation of membrane potentials) Bone growth and remodelling Second messenger signalling (secretion of hormones e.g. insulin)
Distribution of calcium
1-2 kilos in adult humna body
Skeleton 99%:
Intracellular 0.01% e.g. ER, mitochondria
Extracellular 0.99%: 45% ionised (free), 55% bound (albumin, lactate, phosphate)
Total calcium (ionised and bound) ranges from 2.2.-2,6 mmol/L Ionised calium regulated by PTH and vitamin D
Parathyroid glands
Usually 4 glands (2-6) Posterior aspect of thyroid gland 10% are ectopic Weigh 30-50mg Supplied by inferior thyroid artery (caution during thyroid surgery)
Action of PTH
Basic action is to raise blood calcium
Kidney:
Reabsorption of calcium at distal tubule
Internalises sodium-phosphate co-transporters at proximal tubule
Inhibits Na+/H+ leading to bicarbonate wasting
Bone:
Increased number and activity of osteoclasts in continuous PTH exposure
Intermittent exposure increases anabolic activity of osteoblasts
Gut:
Stimulates synthesis of active form of Vit D in kidney (1,25 dihydroxy cholecalciferol)
Thereby increases calcium absorption from the gut.
Secretion of PTH
Stored in chief cells of parathyroid glands
Secretion controlled by the calcium sensing receptor (CaSR)
Rising calcium –> CaSR activated –> inhibits transcription of PTH gene and causes PTH secretion inhibited
Rising calcium –> clacium sensing proteases activated –> PTH broken down/inactivated
Loss of function mutations associated with familial hypocalciuric hypercalcaemia
Calcimimetic drugs target the CaSR and inhibit PTH secretion
Calcium sensing receptor
Kidney
Increases urinary calcium and magnesium excretion
Increases sodium, potassium and chloride excretion
Thyroid
Expressed in C-cells
Stimulates calcitonin secretion
Also expressed in brain, intestine and bone where role less well understood.
Vitamin D
Action of Vit D
Steroid hormone i.e. needs to bind to a nuclear receptor (vitamin D receptor)
Acts to increase serum calcium levels
Process of activation…
Action:
Increases calcium and phosphate absorption from gut - inc. muscle strength
Bone mineralisation and mobilises calcium stores - reduces insulin resistance
Immunomodulation (B and T cells) - interacts with RAAS, role in prevention of CVD
25-OHD3 is generally accepted for functional measurement of Vit D status as it is the most abundant and stable metabolite.
Beware 25-OHD3 measurement in renal disease!
Symptoms of hypercalcaemia
If mild, often asymptomatic
Once calcium >3mmol/L symptoms are common
Confsion, depression, fatigue, coma
Muscle weakness, bone pain, oestoporosis
Shrtening of QTc, bradycardia, hypertension
Polyuria, nephrogenic DI, stones, nephrocalcinosis
Anorexia, nausea, constipation, pancreatitis
Aetiology of hypercalcaemia
PTH-mediated (i.e. elevated/ normal PTH):
Primary hyperparathyroidism
Familial syndromes e.g. MEN-1 and MEN-2
Familial hypocalciuric hypercalcaemia
PTH-dependent (i.e. undetectable PTH): Malignancy Granulomatous disorders Vitamin D toxicity Drugs: - Thiazides - Lithium - Calcium supplements! Adrenal insufficiency Milk-alkali syndrome Immobilisation
Hypercalcaemia - invetigations
Calcium and PTH levels History and examination Chest x-ray FBC/ESR TFTs Myeloma screen Synacthen test Vit D
Hypercalcaemia due to malignancy
Commonest cause of hypercalcaemia in hospitalised patients
Solid organ tumours and haematological malignancies
Causes hypercalcaemia through increased bone resorption and calcium release through 3 possible mechanisms:
1) Osteolytic metastases and myeloma
2) Tumour secretion of PTHrP
Binds to PTH receptor and stimulates bone resorption and renal calcium reabsorption
Can be measured directly
e.g. squamous cell lung cancer; oesophageal cancer; renal cell carcinoma; breast cancer
3) Tumour production of 1,25 dihydroxycholecalciferol
By activated macrophages
Occurs in lymphoma
Other conditions associated with independent hypercalcaemia (other than malignancy)
Vitamin D Toxicity
Increased bone resorption and gut absorption
Ingestion of high doses of calcitriol (e.g. hypoparathyroid or renal disease)
Resolves within 48 hrs of stopping offending agent
Endogenous production of 1,25 dihydroxycholecalciferol
E.g. lymphoma; sarcoid, Wegeners granulomatosis
Extra-renal activation of cholecalciferol
Usually responsive to steroid treatment
Adrenal insufficiency
Increased proximal tubule calcium reabsorption; increased bone resorption
Milk-Alkali syndrome
Hypercalcaemia, metabolic alkalosis, renal insufficiency
Due to ingestion of calcium and antacids
Management of hypercalcaemi
Stop offending / contributing medications
Rehydration!
Normal saline
3-4 litres in first 24 hours unless contraindicated
+ / - loop diuretic
Promote calciuria
Bisphosphonates Inhibit bone resorption E.g. zoledronic acid 4mg IV Takes effect within 24-48 hrs Last several weeks
Steroids
Effective in haematological malignancy; vitamin D intoxication; granulomatous disease
Features of primary hyperparathryoidism
Affects up to 1 in 500 general population
Female preponderance (postmenopausal)
85% isolated parathyroid adenoma
14% parathyroid hyperplasia-often assoc with familial conditions e.g. MEN etc
<1% parathyroid carcinoma
End-organ damage? Bone - Osteoporosis (peripheral cortical bone) - Other radiological changes e.g. bone cysts; subperiosteal resorption Kidneys - Renal calculi - Nephrocalcinosis - Renal impairment Other, e.g. pancreatitis
Primary hyperparathyroidism - investigations
1) Confirm diagnosis
- Drugs
- UEs
- PTH
- Urine calcium: creatinine ratio (differentiate from FHH where usually <0.01)
- Vit D (deficiency can cause elevated PTH)
2) End organ damage?
- DEXA
- KUB/renal US
3) Other conditions?
- Consider MEN-1 or MEN-2 if <40 years old or history of hyperparathyroidism in 1st degree relative
4) If surgery indicated
Localise abnormal gland:
- 2 separate techniques – Sestamibi and ultrasound neck
- Minimally invasive neck exploration
Management of primary hyperparathryoidism
Parathyroidectomy?
Calcium > 3.0 mmol/L; hypercalciuria; osteoporosis; age under 50 years; intractable symptoms; renal stones.
Observation
If no end-organ damage or unfit for surgery
Annual bone profile; renal function; urinary calcium
DEXA and renal US every 3 years
Medical treatment
Only indicated if not fit for surgery
Bisphosphonates preserve bone mass but little effect on calcium
Calcium sensing receptor agonists (Cinacalcet)
30mg BD
Reduces serum (not urine!) calcium
Doesn’t prevent end-organ damage
Complications of parathyroidectomy
Mechanical
Vocal cord paresis
Haematoma causing tracheal compression
Metabolic
Transient hypocalcaemia (suppression of remaining glands)
May require oral calcium / vit D supplementation
“hungry bones” (don’t overly need to know)
Uncommon
Occurs in patients who have significant bone disease pre-op or very elevated PTH.
Sudden withdrawal of PTH leads to imbalance between bone formation and resorption – marked net increase in uptake of calcium, phosphate and magnesium by bone
Requires calcium and vitamin D supplementation
Vitamin D deficiency
Poor sunlight exposure (i.e. elderly or housebound)
Malabsorption
Gastrectomy
Enzyme inducing drugs e.g. anticonvulsants
Renal disease (impaired hydroxylation of 250H Calcitriol)
Osteomalacia
Classically associated with very low levels of vitamin D
Failure to ossify bones in adulthood as a result of Vit D deficiency
Hypo-mineralisation of trabecular and cortical bone
Presents insidiously with bone pain; proximal myopathy; hypocalcaemia
Low calcium; low phosphate; high alk phos; Low Vit D; elevated PTH.
Treatment for Vit D deficiency
Cholecalciferol (D3)
Restore body stores
Correct metabolic disturbance
Heal bony abnormalities
800-1600 units per day
Or, single large dose of Ergocalciferol / D2 (150,000-300,000 units)
Biochemistry may not settle for several months
Alfacalcidol (i.e. active Vit D)
In renal impairment
In hypoparathyroidism (cannot activate Vit D in gut)
Not measured by traditional lab Vit D assay (25-OHD3)
Higher risk of hypercalcaemia
Causes of thyrotoxicosis
Primary – i.e. driven by the thyroid
- Graves’ disease – due to thyroid stimulating immunoglobulin antibodies – TSH receptor antibodies that bind to and stimulate the TSH receptor.
- Toxic Multinodular Goitre
- Toxic Adenoma
- Rarer Causes (metastatic thyroid cancer, ectopic thyroid tissue)
Secondary (1 and 3 are rare!)
- TSH secreting pituitary adenoma – ‘TSHoma’ TSH remains detectable or high, despite high fT4 or fT3
- Gestational Thyrotoxicosis – see below high levels of human chorionic gonadotrophin in 1st trimester
- Thyroid Hormone Resistance Syndrome – pattern of elevated fT4 and fT3 due to peripheral resistance to action with detectable TSH.
How does insulin deficiency lead to diabetic ketoacidosis?
DKa occurs as a result of insulin deficiency and counter regulatory catabolic hormone excess e.g. Glucagon
Insulin deficiency results in excess mobilisation of free fatty acids from adipose tissue which provides the substrate for ketone production from the liver.
Ketones (B hydroxyl butyrate, acetoacetate, acetone) are excreted by the kidneys and buffered in the blood initially but eventually this system fails and acidosis develops.]Hyperglycaemia also occurs as the liver produces glucose from lactate and alanine which are generated by muscle proteinolysis.
Reduced peripheral glucose utilisation associated with Insulin deficiency exacerbates hyperglycaemia.
The osmotic diuresis produced by hyperglycaemia and ketonuria causes hypovolaemia
What are the possible causes of diabetic kektoacidosis, other than a new presentation of T1DM?
(from CBL notes)
Non compliance with insulin Inappropriate alterations in insulin Infection Myocardial infarction Pregnancy
Lifestyle advice when giving diagnosis of T2DM
Diet including advice on weight loss
Exercise - increase in activity level should be encouraged, exercise improves insulin sensitivity
Lifestyle - especially on advice on how to stop smoking
Management strategies for GDM
Patients are managed with diet, self monitoring of blood glucose and, if required, metformin or insulin
Symptoms of thryotoxicosis
Weight Loss Increased appetite Tremor Oligomenorrhoea Polyuria Weakness, fatigue Diarrhoea Insomnia, anxiety Change in heat preference – cold not hot.
How do you define hyperthyroidism and thyrotoxicosis?
Thyrotoxicosis is the syndrome resulting from excessive free thyroxine (fT4) and or free tri-iodothyronine (fT3).
Hyperthyroidism refers to thyroid over activity resulting in thyrotoxicosis.
Thyrotoxicosis can thus occur without hyperthyroidism – e.g. when stored hormone is released from a damaged gland (e.g. sub acute thyroiditis) or when excess hormone replacement is prescribed.
What are the causes of primary thyrotoxicosis?
Primary - i.e. driven by the thyroid
- Graves disease - due to thyroid stimulating immunoglobulin antibodies - TSH receptor antibodies that bind to and stimulate the TSH receptor.
- Toxic Multinodular Goitre
- Toxic Adenoma]4. Rarer causes (metastatic thyroid cancer, ectopic thyroid tissue)
Secondary (1 and 3 rare)
- TSH secretinf pituitary adenoma - ‘TSHoma’ TSH remians detectable or high, despite high fT4 or fT3
- Gestational Thyrotoxicosis - see below high levels of human chorionic gonadotrophin in 1st trimester
- Thyroid Hormone Resistance Syndrome - pattern of elevated fT4 and fT3 due to peripheral resistance to action with detectable TSH
What investigations can help delineate the substrate of thyrotoxicosis?
Antibodies +/- nuclear medicine scan.
Thyroid Autoantibodies
Markers of autoimmune thyroid disease
Anti TPO antibodies. Antithyroid microsomal antibodies have been identified as antithyroid peroxidise (Anti TPO) antibodies. Present in 45-80% of Graves’ disease and 80-95% of Hashimoto’s disease/atrophic thyroiditis.
Anti TSH Receptor antibodies (TRABs) are difficult to measure – but are the most reliable test for diagnosing Graves’ disease and indeed are the cause of Graves’ disease. They are important in 2 situations in pregnancy
1) To determine the cause of thyroid disease in pregnancy – βhCG causes specificity spillover at the TSH receptor due to homology with TSH and when βhCG levels are high causes a transient gestational thyrotoxicosis
2) To assess the risk of neonatal thyrotoxicosis.
Nuclear imaging in the diagnosis of thyrotoxicosis
Thyroid scintigraphy scanning with technetium-99m or Iodine -131 is useful when antibody testing is negative, a nodule is palpable, or thyrotoxicosis without hyperthyroidism is suspected. Important patterns –
1) Diffuse uptake with suppression of background activity = Graves’
2) Irregular Uptake – Multi Nodular Goitre
3) Hot Nodule – Toxic Adenoma
4) Reduced uptake- thyroiditis eg viral.
This is an important investigation in that patients with multinodular goitre or hot nodules are less likely than those with Grave’s to have a sustained remission with anti thyroid drugs alone.
Treatment of Graves Disease
Anti thyroid drugs Beta blockers (eg propranolol) can be used to improve symptoms whilst anti-thyroid medication becomes effective.
Carbimazole and Propylthiouracil (PTU) inhibit iodide organification by thyroid peroxidise reducing T3 and T4 production. They also reduce TSH receptor stimulating antibody levels. Carbimazole usually used, PTU if pregnancy planned or pregnant. Patients should always be warned about the symptoms of infections and rashes. Fever, mouth ulcers or a sore throat may herald incipient agranulocytosis and hence patients must know to stop treatment and have an urgent FBC checked. There are 2 regimens used:
1) A reducing regimen where higher doses are started at initiation of treatment (e.g. 40 mg of Carbimazole) then as the patient becomes euthyroid the dose is reduced, maintaining a euthyroid state.
2) Block and Replace – Commence with blocking medication e.g. 40mg of Carbimazole – then when patient is euthyroid add in Thyroxine. Smoother biochemical control, ideal where there is concern of hypothyroidism with thyroid eye disease. Avoid in pregnancy.
Radioactive Iodine (131I) Contraindicated in pregnancy, lactation, and in patients with active thyroid eye disease. May be socially unacceptable eg to mothers due to the restrictions on prolonged close contact with small children afterwards. 131I acts slowly – may induce hypothyroidism requiring life long thyroxine therapy. Can induce a transient thyroiditis. Treatment of choice for toxic MNG – except large MNG or those with significant retrosternal extension causing obstructive symptoms, who may require surgery. Also often used in patients who have remission after a course of medical therapy.
Surgery
Subtotal/total thyroidectomy – Is indicated where 131I is contraindicated or unacceptable to the patient or where there is a large goitre as above. Hypothyroidism, hypocalcaemia, recurrent laryngeal nerve palsy are important considerations.
What factors increase the risk of developing Graves’ opthalmopathy?
Smoking Male sex Age Radioactive iodine treatment Signs of thyroid eye disease
Treatment of Graves’ opthalmopathy?
Grittiness – artificial tears
Eyelid – tape eyelids at night to avoid corneal damage, surgery if risk of exposure keratopathy
Proptosis – steroids, radiotherapy may need orbital decompression
Optic neuropathy - steroids, radiotherapy may need orbital decompression
Ophthalmoplegia – prisms in the acute phase, orbital decompression, orbital muscle surgery.
What are the possible causes of hypothyroidism?
Autoimmune Hashimoto's thyroiditis Destructive thyroiditis Secondary to hypothalamic or pituitary failure Idiopathic atrophic hypothyroidism Iodine deficiency Following treatment for thyrotoxicosis
Treatment of primary hypothyroidism
Thyroid hormone replacement – Levothyroxine usually starting at 50-100mcg (25mcg where there is a concern of ischaemic heart disease) and titrating in 25mcg increments aiming for a normal TSH. There may be a time lag from TSH being in the normal range to clinical improvement.
What is Myxoedema? Myxoedema coma?
Myxoedema is severe hypothyroidism in which there is accumulation of hydrophilic mucopolysaccharides in the ground substance of the dermis and other tissues leading to the thickened facial features and doughy induration of the skin. In myxoedema:
Dull, expressionless face, sparse hair, periorbital puffiness, macroglossia
Pale, cool, skin which is rough and doughy
Pericardial effusion
Megacolon/ intestinal obstruction
Cerebellar ataxia
Prolonged relaxation phase of deep tendon reflexes
Peripheral neuropathy
Myxoedema Coma
Uncommon, reduced conciousness and hypothermia common – not necessarily with coma. Heart failure, hypotension, hyponatraemia and hypoventilation also occur. Treatment is supportive with intravenous fluids, slow rewarming, ventilation and intravenous T3 followed by oral or nasogastric T4 once improving.
What are the 2 drugs used to treat Graves’ disease?
Describe their mechanism of action
Carbimazole and Propylthiouracil (PTU) - inhibit iodide organification by thyroid peroxidase reducing T3 and T4 production. They also reduce TSH receptor stimulating antibody levels.
Carbimazole is usually used, PTU if pregnancy planned or is pregnant (as carbimazole freely crosses the placenta)
MOA of GLP1 agonists
E.g. Exanatide, Liraglutide
MOA:
GLP1 is a hormone that is released after meals to increase insulin secretion.
GLP1 agonist increases insulin secretion, decreases glucagon secretion and decreases hunger
Good for control of T2DM in patients with excess weight
Side effects: Hypoglycaemia Nausea Vomiting Diarrhoea
Autoimmune polyendocrine syndrome type 2
Triad of Addison’s, Al thyroiditis and T1DM
More common in feamles
Presents in adult hood
Polygenic - HLA DQ + DR allele association; DR3 DQB1, DR4 DQB1
Association: Pernicious anaemia Primary hypogonadism Myasthenia Gravis Coeliac disease Alopecia
Hoe does insulin deficiency lead to diabetic ketoacidosis?
DKA occurs as a result of insulin deficiency and counter regualtory catabolic hormone excess e.g. glucagon.
Insulin deficiency results in excess mobilisation of free fatty acids (FFAs) from adipose tissue (lipolysis) which provides the substrate for ketone production from the liver.
Ketones (B hydroxyl butyrate, acetoacetate, acetone) are excreted by the kidneys and buffered in the blood initially but eventually this system fails and acidosis develops.
Hyperglycaemia also occurs as the liver produces glucose from lactate and alanine which are generated by muscle proteinolysis.
Reduced peripheral glucose utilisation assoictaed with insulin deficiency exacerbates hyperglycaemia.
The osmotic diuresis produced by hyperglycaemia and ketonuria causes hypovolaemia.
What are the possible causes of diabetic ketoacidosis, other than a new presentation of T1DM?
Non compliance with insulin Inappropriate alterations in insulin Infection Myocardial Infarction Pregnancy
What elements do you consider to be key to an education package prior to discharge after diagnosis of T1DM
1 Never stop Insulin – it is required for survival
2 Use of Insulin device, injection technique, injection sites, rotation of injection sites
3 Out line of the basics of the chosen Insulin regimen
4 Sick day rules – how to manage acute illness with potentially increased Insulin requirements, monitoring of BMs and urine ketones
5 Hypoglycaemia – recognising symptoms – precipitants and how to adjust insulin
6 Smoking
7 Alcohol
8 Driving regulations and informing the DVLA
9 Exercise
10 Diabetes U.K. – local contacts and website address
11 Contact with Diabetes Nurse Specialist and follow up
12 Principals of long term control – the association of good glycaemic control with lower risks of microvascular and macrovsacular complications.
13 Planning a pregnancy.
BP lowering in patients with T2DM
Target diastolic is <=80 mm Hg
Target systolic BP is <=130 mm Hg
Should be commenced on:
an ACEi (or ARB) or
A calcium channel blocker or
A thiazide diuretic
Beta blockers and alpha blockers should not normally be used
