Endocrinology Part 2 Flashcards
1
Q
What is the commonest endocrine disorders?
A
Thyroid disease
- Female preponderance 5-10 fold
- Hyperthyroidism 2.5% prevalence
- Hypothyroidism 5%
- Goitre 5-15%
- Thyroid dysfunction affects many organ systems
2
Q
Talk about thyroid autoimmunity.
A
- Clinically significant diseases
- Wide spectrum
- Altered thyroid function to extrathyroidal manifestations
- Focal thyroiditis and/or positive TPO and thyroglobulin antibodies
- Postpartum thyroiditis
- Autoimmune hypothyroidism
> Hashimoto’s thyroiditis
> Atrophic thyroiditis - Graves’ disease
> Thyroid associated ophthalmopathy
3
Q
Why are autoimmune thyroid diseases important?
A
First autoimmune diseases to be described
2% of women will get Graves’ disease or autoimmune hypothyroidism (5-10 times the frequency in men)
5% will have postpartum thyroiditis, and up to 20% will have positive thyroid antibodies
Associated with other serious autoimmune disorders
4
Q
What are the thyroid antibodies out there?
A
Thyroglobulin and thyroid peroxidase (TPO) antibodies found in almost all patients with autoimmune hypothyroidism
Also present in 75% Graves’ patients
Low levels present in healthy individuals at risk of thyroid or other autoimmune disease
5
Q
Talk about Mechanism of thyroid cell destruction?
A
Cytotoxic (CD8+) T cell-mediated
Thyroglobulin and TPO antibodies may cause secondary damage, but alone have no effect
Uncommonly antibodies against the TSH-receptor may block the effects of TSH
6
Q
What is the antibody that causes Graves’ disease?
A
thyroid stimulating antibodies (TSA)
Originally called long acting thyroid stimulators (LATS)
Now called thyroid stimulating antibodies - these are the cause of Graves’ disease
Some TSH-R antibodies do not stimulate the receptor; instead they block the effects of TSH - these (rarely) can cause hypothyroidism
7
Q
What are the predisposition (risk factors) of thyroid autoimmunity?
A
- Genetic and environmental factors in varying proportion
- Being female is biggest risk factor, and onset of disease common postpartum
- HLA-DR3 and other immunoregulatory genes contribute (25% monozygotic twins concordant)
- Environmental factors include stress, high iodine intake, smoking
8
Q
What are the 3 areas of risk factors for thyroid autoimmunity?
A
- Genes
- HLA, target organ, T cell response, immunoglobulin, cytokine - Endogenous factors
- sex hormone, glucocorticoid, prolactin, birthweight, pregnancy - Environmental factors
- diet, infection, drugs, toxin, stress
9
Q
What would happen during the postpartum period?
A
- Autoimmune thyroiditis
- Grave’s thyrotoxicosis
10
Q
What are the autoimmune diseases associated with thyroid autoimmunity?
A
Type 1 diabetes mellitus
Addison’s disease*
Pernicious anaemia*
Vitiligo
Alopecia areata
Coeliac disease/ dermatitis herpetiformis
Chronic active hepatitis
Rheumatoid arthritis/ SLE/ Sjogren’s syndrome
Myasthenia gravis (Graves’ disease)
11
Q
Talk about Thyroid associated ophthalmopathy.
A
- Present in most Graves’ and some autoimmune hypothyroidism patients
- Swelling in extraocular muscles, thus causing bulging of the eyeball, not necessary symmetrical bulging, can be unilateral bulging
- Most likely due to an autoantigen in the extraocular muscle that cross-reacts with, or is identical to, a thyroid autoantigen
- Current favourite candidate is the TSH receptor
12
Q
What is Graves’ disease caused by?
A
thyroid stimulating antibodies that may cross the placenta
13
Q
Talk about goitre.
A
- Palpable & visible thyroid enlargement
- Variety of causes
- Commonly sporadic or autoimmune
- Endemic in iodine-deficient areas
14
Q
Talk about sporadic non-toxic goitre.
A
- Commonest endocrine disorder
8.6% prevalence thyroid enlargement - Euthyroid
- Goitre: diffuse, multinodular, solitary nodule, dominant nodule
- Differentiate benign from malignant
15
Q
Talk about hyperthyroidism.
A
Definition: excess of thyroid hormones in blood
3 mechanisms for increased levels:
a. overproduction thyroid hormone
b. leakage of preformed hormone from
thyroid
c. ingestion of excess thyroid hormone
16
Q
What are the 3 common causes of hyperthyroidism?
A
- Graves’ disease (75- 80% of all cases)
- Toxic multinodular goitre
- Toxic adenoma
17
Q
What are the causes of hyperthyroidism?
A
- Congenital (neonatal) hyperthyroidism
- Non-autoimmune hereditary hyperthyroidism
- Subacute thyroiditis
- Silent thyroiditis
- Postpartum thyroiditis
- Iodine-induced hyperthyroidism
- Hyperemesis gravidarum
- Molar pregnancy (hCG)
- Thyrotoxicosis factitia
- Metastatic differentiated thyroid Ca
- Struma ovarii
- Pituitary resistance to thyroid hormone
- Pituitary adenoma (TSHoma)
18
Q
What are the drugs that can induce hyperthyroidism?
A
- Iodine
- Amiodarone
- Lithium
- Radiocontrast agents
19
Q
What are the clinical features of hyperthyroidism?
A
- Wt loss
- Tachycardia
- Hyperphagia
- Anxiety
- Tremor
- Heat intolerance
- Sweating
- Diarrhoea
- Lid lag + stare
- Menstrual disturbance
20
Q
What are the disease-specific signs of hyperthyroidism?
A
GRAVES’ SPECIFIC:
- Diffuse goitre
- Thyroid eye disease (infiltrative)
- Pretibial myxoedema
- Acropachy
MNG SPECIFIC:
- Multinodular goitre
ADENOMA SPECIFIC
- Solitary nodule
21
Q
What test is used to confirm biochemical hyperthyroidism?
A
Thyroid function tests (TFTs)
22
Q
In thyroid function test, what happen to the level of T3 and T4 and TSH during primary and secondary hyperthyroidism?
A
In primary hyperthyroidism:
1. Increase T3 and T4
2. Suppressed TSH
In secondary hyperthyroidism:
1. Increase T3 and T4
2. Inappropriately high TSH
23
Q
What are the supporting investigation other than TFT for confirming the diagnosis of hyperthyroidism?
A
- Thyroid antibodies: TPO, Tg, TRAb
- Isotope uptake scan
24
Q
Talk about thyroid function in destructive thyroiditis?
A
Initially the thyroid release thyroxine, thats why T3 and T4 level is high, and then euthyroid (normal thyroid function), then the T3 and T4 are low, and then it will go back to normal level (rises)
During the whole process, the TSH is intially low (normal), then it rises to push the T3 and T4 back to normal.
25
What are the treatment for hyperthyroidism?
Antithyroid drugs (course or long-term)
Radioiodine (131) I
Surgery (partial, subtotal thyroidectomy)
26
What are the antithyroid drugs out there?
Thionamides-
carbimazole, propylthiouracil (PTU),
methimazole
Decrease synthesis of new thyroid hormone
PTU also inhibits conversion T4 -> T3
Do not treat underlying cause of hyperthyroidism
BUT
Immune modifying effects are seen (decrease IL-6) and reduction in antibody titres
...........................................................................
TITRATION regimen (12-18months)
BLOCK AND REPLACE regimen with T4 (6-12mths) for Graves’ disease
OR
short course to render euthyroid before 131I and surgery
OR
long-term treatment in patients unwilling to have131I or surgery
27
What are the poor prognostic factors for hyperthyroidism?
- severe biochemical hyperthyroidism
- large goitre
- TRAb +ve at end of course of ATD
- male sex
- young age of disease onset
28
What are the side effects of thionamide?
Generally well tolerated
Common side effect:
rash
Less common:
arthralgia
hepatitis
neuritis
thrombocytopenia
vasculitis
Usually occur within first few months
Resolve after stopping drug
AGRANULOCYTOSIS
most serious side effect
occurs in 0.1% to 0.2%
manifests as sore throat, fever, mouth ulcers
MUST warn patients before starting ATD
STOP if patients develops symptoms and check FBC
29
Talk about iodine.
Iodine essential for thyroid hormone production
I actively transported by Na/I symporter into thyroid follicular cells
30
Talk about iodine 131.
- One of 20 isotopes of I (127I stable)
- Ideal for ablation
- Emits large beta particles of moderate energy beta particles non penetrating and deliver 90% of energy within a 1-2 mm zone to follicular cells
- Some gamma ray emission
- Half-life 8.1 days
31
How does radioiodine work in hyperthyroidism?
- Emission of beta particles results in ionization of thyroid cells
- Direct damage to DNA and enzymes
- Indirect damage via free radicals
32
What are the early and long-term effects of 131 Iodine?
Early:
- necrosis follicular cells
- vascular occlusion
- occur over weeks to months
Long-term:
- shorter cell survival
- impaired replication cells
- atrophy and fibrosis
- chronic inflammation resembling
-Hashimoto’s
- late hypothyroidism
33
What are the different types of surgery for hyperthyroidism?
Near total thyroidectomy for Graves’ disease and MNG
Near total thyroidectomy / lobectomy for toxic adenoma
34
What is hypothyrodism?
Thyroid hormones levels abnormally low
3 types
PRIMARY (>99%)
- absence / dysfunction thyroid gland
- most cases due to Hashimoto’s thyroiditis
SECONDARY / TERTIARY
- pituitary / hypothalamic dysfunction
35
What are the drugs that can induce hypothyroidism?
Iodine, inorganic or organic
iodide
iodinated contrast agents
amiodarone
Lithium
Thionamides
Interferon - alpha
36
What are the causes of hypothyroidism in neonate/child?
Neonatal hypothyroidism
Thyroid agenesis (absent)
Thyroid ectopia
Thyroid dyshormonogenesis
Others
Resistance to thyroid hormone
Isolated TSH deficiency
37
What are the clinical features in hypothyroidism?
- Fatigue
- Wt gain
- Cold intolerance
- Constipation
- Menstrual disturbance
- Muscle cramps
- Slow cerebration
- Dry, rough skin
- Periorbital oedema
- Delayed muscle reflexes
- Carotenaemia
- Oedema
38
Talk about primary and secondary/tertriary hypothyroidism?
For primary hypothyroidism:
- low T3 and T4
- increase TSH
- T4/ T3 may be low normal in mild hypothyroidism
- positive titre of TPO antibodies in Hashimoto’s
For secondary/tertiary hypothyroidism:
- TSH inappropriately low for reduced T4 / T3
levels
39
What are the treatment for hypothyroidism?
Treatment of choice
- synthetic L-thyroxine (T4)
Older treatments - dessicated thyroid (pig and beef extracts) - inconsistent from batch to batch
? T3 / T4 combination
40
Talk about monitoring treatment in hypothyroidism.
In primary hypothyroidism
dose titrated until TSH normalises
T4 half-life is long - check levels 6-8 weeks after dose adjustment
In secondary / tertiary hypothyroidism
TSH will always be low
T4 is monitored
41
Is goitre usually benign or malignant?
Benign!
42
subacute thyroiditis usually after what type of illnesses?
viral illness
43
Swollen extraocular muscle in the eyes during hyperthyroidism can cause?
Compression of the optic nerves and bulging of the eyeballs
44
What type of drug do we use when it comes to patients with hyperthyroidism during pregnancy for the first trimester only?
propylthiouracil (PTU)
Carbimazole is the drug used during the rest of pregnancy.
45
Talk about iodine-contained drug and thyroid problems.
Iodine-contained drug can either produce hypo or hyperthyroidism (there is Wolff–Chaikoff effect), don't usually prescribe iodine as a treatment, but do check with them during history taking whether they took any iodine-contained drugs before that might possibly cause hypo or hyperthyroidism
46
Puffy face, is it hyper or hypothyrodism?
Hypothyroidism
47
What type of thyroid problems will be triggered by viral infection?
De Quervain's (subacute) thyroiditis, a painful swelling of the thyroid gland
48
What are the metabolic changes in pregnancy?
- Increased erythropoetin, cortisol, noradrenaline
- High cardiac output
- Plasma volume expansion
- High cholesterol and triglycerides
- Hyperventilation
- Pro thrombotic and inflammatory state
- Insulin resistance
49
What are the Gestational Syndromes.
- Pre-Eclampsia
- Gestational Diabetes
- Obstetric cholestasis
- Gestational Thyrotoxicosis
- Transient Diabetes Insipidus
- Lipid disorders
- Postnatal depression
- Postpartum thyroiditis
- Postnatal autoimmune disease
50
Talk about foetus thyroid gland development.
Fetal thyroid follicles and thyroxine synthesis occurs at 10 weeks
Fetal thyroid axis matures at 15-20 weeks
Maternal T4 0-12 weeks regulates neurogenesis, migration and differentiation then fetal T4
51
Talk about glycoprotein hormone.
Glycoprotein hormone consists of 2 subunits, a common alpha unit, a distinct beta subunit. Eg: TSH, LH, FSH, hCG
52
Talk about hypothyroidism in pregnancy?
Prevalence during pregnancy 2-3 %
Overt hypothyroidism 0.3-0.5 % in pregnancy
Subclinical hypothyroidism 2-3 %
Signs and symptoms:
- Usually predate the pregnancy
- Weight gain, cold intolerance, poor concentration, poor sleep pattern, dry skin, constipation, tiredness
53
What is the aetiology of hypothyroidism?
Primary:
- autoimmune
- Hashimotos'
- Atrophic thyroiditis
- Prior surgery or radio-Iodine ablation
- Drugs - Lithium and amiodarone
- Iodine deficiency
- Congenital
Transient:
- Post-partum thyroiditis
- Subacute thyroiditis
Secondary:
- Hypopituitarism
54
How does hypothyroidism affect pregnancy?
Inadequate treatment:
Gestational hypertension and pre-eclampsia
Placental abruption
Post-partum haemorrhage
If untreated:
Low birth weight
Preterm delivery
Neonatal goitre
Neonatal respiratory distress
55
What to do when there is hypothyroidism in pregnancy?
Pre-existing:
Preconception counselling
ideal pre-conception TSH <2.5 mIU/L
Increase dose by 30 %
Arrange TFT early pregnancy and titrate
Women require a dose increase in their thyroxine during pregnancy
If new presentation of overt in pregnancy aim to normalise asap
start thyroxine 50-100mcg measure TFT at 4-6 weeks
56
What is the difference between overt and subacute hypothyroidism?
Overt thyroid disease means that both the TSH levels and the thyroid hormone levels are abnormal, while subclinical disease is defined by abnormal TSH levels only — the thyroid hormone levels are normal.
57
Talk about targetted screening in hypothyroidism?
- Age >30
- BMI >40
- Miscarriage preterm labour
- Personal or family history
- Goitre
- Anti TPO
- Type 1 DM
- Head and neck irradiation
- Amiodarone, Lithium or contrast use
58
Talk about hyperthyroidism in pregnancy.
- Prevalence in pregnancy is 0.1-0.4 %
- Female Population 2%
- 85-90% due to Graves disease
- Less common toxic adenoma or multi-nodular goitre, gestational thyrotoxicosis, trophoblastic neoplasia, TSH-oma
59
For hyperthyroidism, how does the disease effect pregnancy?
If inadequately treated:
- IUGR (intrauterine growth restriction)
- Low birth weight
- Pre-ecclampsia
- Preterm delivery
- Risk of stillbirth
- Risk of miscarriage
60
For hyperthyroidism, how does pregnancy affect the disease?
- Tends to worsen in the first trimester
- Improves latter half of pregnancy
61
Talk about the management in hyperthyroidism in pregnancy.
- Symptomatic treatment: B-blockers are safe eg propranolol 10-20 mg tds
- Anti-thyroid medication
> PTU or Carbimazole
> prevent thyroid peroxidase enzyme coupling and iodinating tyrosine residues on thyroglobulin reduce T3 and T4
- RAI is contraindicated during pregnancy
- Surgical interventions- if intolerant optimal timing 2nd trimester
Anti-thyroid medications in pregnancy
Carbimazole:
Increased risk of congenital abnormalities
Aplasia cutis
Choanal atresia
Intestinal anomalies
Propylthiouracil (PTU):
Rare hepatotoxicity
62
Talk about autoantibodies in hyperthyroidism in pregnancy.
- TSH-R antibodies (TRAB/TBII)
- Are measured at 22-26 weeks
- Can cross the placenta
- If raised 2-3 fold or present:
fetal/neonatal thyrotoxicosis risk increased and surveillance needed
- Who to test:
Current Graves’, past Graves’, previous neonate with Graves’, etc
63
Talk about Fetal Thyrotoxicosis.
Transplacental transfer of TSH-R antibodies
Occurs in 0.01 % of cases
Management options: anti-thyroid medication
Associated with:
> IUGR
> Fetal goitre
> Fetal tachycardia
> Fetal hydrops
> Preterm delivery
> Fetal demise
64
Talk about gestational diabetes in pregnancy.
- Limited to the first half of the pregnancy
- Raised FT4, low/suppressed TSH
- Absence of thyroid autoimmunity
- Associated with hyperemesis gravidarum
- 5-10 cases/1000 pregnancies
- Multiple gestation
- Hydatidaform mole
- Hyperplacentosis
- Choriocarcinoma
Issues:
- Benefits of treating
- Hyperemesis gravidarum
- Extreme- Wernicke’s encephalopathy
- electrolyte imbalance low K and IUGR
- Thyrotoxicosis risks
65
Differential thyrotoxicosis in pregnancy between Grave disease and Gestational thyrotoxicosis.
Grave disease:
- Symptoms predate pregnancy: ++
- Symptoms during pregnancy: +/++
- Nausea and Vomiting: -/+
- Goitre with bruit, thyroid eye disease: +
- TSH-R antibody: +
Gestational thyrotoxicosis:
- Symptoms predate pregnancy: -
- Symptoms during pregnancy: -/+
- Nausea and Vomiting: ++++
- Goitre with bruit, thyroid eye disease: -
- TSH-R antibody: -
66
Talk about post-partum thyrotoxicosis.
Prevalence 7 %
High risk women are
Type 1 diabetics
Graves disease in remission
Chronic viral hepatitis
Measure TSH 3 months post partum
67
Drugs that usually interfere the thyroid gland.
Commonly:
Amiodarone
Lithium
Interferon
Immune therapies (oncology, rheumatology)
68
Talk about Amiodarone and Thyroid function.
Dirty drug
Potent anti-arrhythmic- AF
37 % iodine by weight
200mg tablet 75 mg iodide
Lipid soluble
Long elimination half life
14-18 % get abnormalities
Amiodarone Induced Hypothyroidism (AIH) or Amiodarone Induced Thyrotoxicosis (AIT)
69
Talk about Amiodarone Induced Hypothyroidism. (AIH)
Susceptibility
Inhibitory effect on thyroid hormone synthesis
Inability of gland to escape Wolf-Chaikoff effect
Accelerate Hashimotos trend
Reduction in thyroid hormone synthesis
Downregulation of peripheral receptors
70
Talk about the 2 types of Amiodarone Induced Hypothyroidism.
AIT type 1
Latent pre-existing
Low iodine areas
Iodine induced excess
Thyroid hormone release
Jode-Basedow phenomenon
AIT Type 2
Normal Thyroid
Destructive
71
Talk about Amiodarone and the thyroid: key points
- Amiodarone -Iodine rich often used to treat
- Atrial fibrillation
- SE: pulmonary, GI, ophthalmic, neurologic, dermatologic, thyroid
- Incidence AIT 3 % M > F
- AIH 22 % F > M
- Prognosis
- Dronedarone does not contain Iodine
72
Talk about immune therapy and the thyroids.
a) Immune checkpoint inhibitors
CTLA-4 and PD-1 inhibitors
Ipilimumab and Nivolumab ➜ melanoma
b) Thyrosine kinases inhibitors
Sunitinib
c) Immune reconstitution therapy
Alemtuzumab ➜ multiple sclerosis
73
Talk about Ipilimumab and Nivolumab.
Ipilimumab:
Licenced for advanced melanoma
Mode of action: monoclonal antibody, activates immune system by inhibiting CTLA-4 which normally downregulates immune system
Target CTLA-4 – keeps T Cell active to destroy cancer cells
Nivolumab:
Licensed for advanced melanoma, renal cell carcinoma
Mode of action: monoclonal antibody that blocks PD-1 activity and promotes antitumor immunity
74
Talk about Ipilimumab.
Associated endocrinopathies- new entity
Most common:
- Hypophysitis 0-17 %
- Hypothyroidism (thyroiditis related) 2.7 %
- Hyperthyroidism (thyroiditis related) 0.3 %
- Primary Adrenal Insufficiency 2.1 %
More frequent with increased usage given overall survival benefit
Strategies for early detection
75
Talk about Ipilimumab Hypophysitis.
- Headache and fatigue common presentation
- Can occur as early as 3 weeks but most 11 weeks*
- Males>Females (unlike lymphocytic hypophysitis)
- Diagnosis with low levels of pituitary hormones (ACTH, TSH, LH, FSH)
> Thyroiditis and primary adrenal insufficiency ACTH and TSH are high
- If doubt take bloods and give steroids
- Discuss with Endocrine
- MRI pituitary
- Visual fields
- Recovery may occur over time
76
What are the brain structures above the pituitary gland?
Optic Chiasm and hypothalamus, then pituitary stalk
77
Where is vasopressin and oxytocin made?
Made in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), then transported to the posterior pituitary gland in the axoplasm of the neurons
78
Talk about arginine vasopressin (AVP)/ ADH.
- binds to G-protein coupled 7 transmembrane domain receptors
> V1a - vasculature
> V2 - renal collecting tubules - reabsorption of water
> V1b - pituitary
Release controlled by:
1. osmoreceptors in hypothalamus - day to day
2. baroreceptors in brainstem and great vessels - emergency
79
Talk about the proportion of fluid in an average 70kg adult man.
- 60% of the body weight (42L) is water
- 1/3 (14L) is extracellular fluid
- 2/3 (28L) is intracellular fluid
- For extracellular fluid, 1/4 (3L) is intravascular fluid, 3/4 (11L) is interstitial fluid)
80
The intra and extracellular fluid compartments differ in their ionic composition. Which are the ions that are commonly more in extracellular fluid compared to intracellular fluid?
Na+, Cl-, HCO3-
81
Vasopressin binds to whic h receptor on the renal collecting duct principle cells?
V2 receptor (vasopressin- 2 receptor)
82
Talk about the mechanism of action of vasopressin.
- Vasopressin binds to the
vasopressin V2 receptors
- This stimulates an
intracellular cascade
- Aquaporin-2 proteins are synthesised and
inserted into the apical membrane,
increasing the permeability of the
renal collecting duct
- Water is reabsorbed from the renal collecting duct and returned to the blood
stream, decreasing the plasma osmolality
83
What is the term for concentration in plasma?
- osmolality
- measured by an osmometer- by freezing point
> Concentration per kilo
> size of particle not important, number is important - i.e one molecule of larger protein albumin same effect as Na+
> sodium, potassium, chloride, bicarbonate, urea and glucose present at high enough concentrations to affect osmolality
> alcohol, methanol, polyethylene glycol or manitol - exogenous solutes that may affect osmolality
84
What is the normal osmolality?
282 - 295 mOsmol/kg
85
What are the diseases associated with the posterior pituitary gland?
1. Lack of vasopressin = AVP deficiency (cranial diabetes insipidus)
* Uncommon but life threatening
2. Resistance to action of vasopressin = AVP resistance (nephrogenic diabetes
insipidus)
* Not common but life threatening
3. Too much vasopressin release when it should not be released = syndrome of antidiuretic hormone secretion – SIAD – (also from ectopic source – e.g. carcinoma of
lung)
* Really common, and can be life threatening
* NB – other causes of hyponatraemia MUST be identified – different management
86
Talk about AVP/ ADH deficiency and resistance
* polyuria
* polydypsia
* no glycosuria
NB – primary polydipsia or ‘overdrinking’ is very common and causes diagnostic confusion
Diagnosis
* measure urine volume - DI unlikely if urine volume <3L/day
* check renal function and serum calcium
* biochemistry
> inappropriately dilute urine for plasma osmolality
> serum osmo >300 AND urine osmo<200 consistent with DI
> normonatraemia or hypernatraemia
> water deprivation test
> hypertonic saline infusion and measurement of AVP
87
Causes of AVP deficiency (cranial Diabetes Insipidus)?
Acquired:
* Idiopathic
* Tumours - craniopharyngioma, germinoma, metastases,
‘never’ anterior pituitary tumour
* Trauma
* Infections – TB, encephalitis, meningitis,
* Vascular – aneurysm, infarction, Sheenan’s, sickle cell
* Inflammatory - neurosarcoidosis, Langerhans’s histiocytosis,
Guillain Barre, Granuloma
Primary/ Genetic:
* DIMOAD (wolfram syndrome)
* Autosomal dominant
* Rarely autosomal recessive
Developmental:
* septo-optic dysplasia
88
Talk about AVP resistance (nephrogenic diabetes insipidus)
* Familial – rare
– X-linked – V2 receptor defect
– Autosomal - aquaporin 2 defect
* Acquired – either reduction in medullary
concentrating gradient or antagonism of effects of
AVP
– Osmotic diuresis (eg diabetes mellitus)
– Drugs – e.g. Lithium, demeclocycline, tetracycline
– Chronic renal impairment
– Post obstructive nephropathy
– Metabolic – hypercalcaemia/hypokalaemia
– Renal infiltration – e.g amyloid
89
Talk about water deprivation test.
Provide 2 microgram of desmopressin and observe the plasma osmolality and urine osmolality in AVP resistance and AVP deficiency
Hypertonic saline infusion and measurement of AVP an alternative
90
Talk about the management of AVP deficiency (Cranial DI)
* treat any underlying condition
* desmopressin – high activity at V2 receptor
> tablets 100-600 micrograms/day
> nasal spray 10-20 micrograms/day
> injection 1-2 micrograms/day
91
Talk about the management of AVP resistance (nephrogenic DI)
* try and avoid precipitating drugs
* congenital DI - very difficult
> free access to water
> very high dose desmopressin
92
What is one of the advanced approach in diagnosing diabetes insipidus?
Measurement of copeptin
93
Talk about hyponatraemia.
* Common
* Symptomatic vs Asymptomatic
* Most often caused by excess water
rather than salt loss
Definition: serum sodium < 135 mmol/l
Biochemical Severe: serum sodium < 125 mmol/l
Normal serum sodium 135-144mmol
Investigation and management are frequently poor
94
What are the three different levels of symptomatic hyponatraemia?
1. No or mild symptoms
2. Moderate symptoms
- headache
- irritability
- nausea/vomiting
- mental slowing
- unstable gait/ falls
- confusion/ delirium
- disorientation
3. Severe symptoms
- stupor/ coma
- convulsions
- respiratory arrest
95
The brain undergoes volume adaptation in response to gradual-onset hyponatraemia.
- normal brain
- water gain- immediate effect of hypotonic state ( brain expand)
- Loss of sodium, potassium and chloride (low osmolality) ( rapid adaptation)
- Loss of organic osmolytes (low osnolality) (slow adaptation)
96
What are the different types of classifications of hyponatraemia?
15-22% of all hospitalised patients
1. Biochemical
* Mild 130-135mmol/l
* Moderate 125-129mmol/l
* Severe <125mmol/l
2. Symptoms
* Mild
* Moderate
* Severe
3. Aetiology
* Hypovolaemic
* Euvolaemic
* Hypervolaemic
4. Acuity of onset
* Acute < 48 hours
* Chronic > 48 hours
97
Talk about the general and specific appraoch for hyponatraemia
General
* Stop hypotonic fluids
* Review drug card – long list - PPI etc.
Specific
* Plasma and Urine Osmolality
* Urinary Na+
* glucose
* TFT’s
* +/- Assessment of Cortisol
* Assessment of underlying causes eg chest imaging
98
Talk about the assessment and management of hyponatraemia.
1. Fluid overloaded (Do fluid restrict)
- cirrhosis/ liver faliure
- CCF
- inappropriate IV fluids
2. Normovolaemic (Do fluid restrict)
- Serum + Urine Osmolalities
- Spot Urine Sodium
- TSH normal
- Cortisol > 430 nmol/L
SIAD
3. Dehydrated (Do saline replacement)
a) Low urine Na
*Vomiting and diarrhoea
*Burns
*Pancreatitis
*Sodium depletion
after diuretics
b) Urine Na > 40mmol/l
*Diuretics
*Addison’s (or
occasionally
pituitary failure)
*Cerebral salt wasting
*Salt wasting
nephropathy
99
Talk about the syndrome of antidiuresis (SIAD)
* common in clinical practice - 25% of all hyponatraemia
BUT not the only cause………………
* Too much AVP, when it should not be being secreted
* Low osmolality
* Plasma sodium is low
* Urine is inappropriately concentrated
* Water retention - ECF volume increased mildly
* Increase GRF - less Na reabsorption in PCT
* thus - urine Na+ usually >30mmol/l
* normal thyroid and adrenal function
Clinically: NORMAL CIRCULATING VOLUME
No Oedema
100
What are the causes of SIAD?
1. CNS disorder
- Head injury
Meningitis
Encephalitis
Brain tumour
Brain abscess
Cerebral haemorrhage/thrombosis
Guillain-Barre syndrome
Acute intermittent porphyria
2. Tumours
- Carcinoma (especially lung)
- lymphoma
- leukaemia
- thymoma
- sarcoma
- mesothelioma
3. Respiratory causes
- pneumonia
- TB
- severe asthma
- pneumothorax
- positive-pressure ventilation
- emphysema
4. Drugs
- carbamazapine, clofibrate, chlorpropramide
, thiazides, phenothiazines, MAO inhibitors,
, cytotoxics, desmopressin, vasopressin,
, oxytocin, Selective serotonin reuptake
inhibitors, PPI’s
101
Talk about treatment goal for SIAD.
* ensure correct diagnosis
* allow/facilitate increase in serum Na+
* treat any underlying condition
* identify and stop any causative drug (if possible)
* in acute setting - daily U+E - hospital
* in chronic setting - weekly to monthly U+E - hospital/GP
* frequent co-morbidity
* Na+>130 mmol/l - usually no need for urgent intervention
102
Talk about management of SIAD
*Diagnose and treat underlying condition
*fluid restriction <1L/24 hour
*sometimes demeclocycline/ vaptan
*if Na+ <115 mmol/l AND fitting hypertonic N/Saline on ITU
*<8mmol/l increase in Na+ per 24 hour if chronic
*Potential risk of central pontine myelinolysis
103
The brain undergoes volume adaptation in
response to gradual-onset hyponatraemia. What is the worst outcome if there is imporper therapy due to rapid correction of the hypotonic state?
osmotic demyelination
104
What is osmotic demyelination syndrome (ODS)?
* White areas in the middle of the
pons
* Massive demyelination of
descending axons
* May take up to 2 weeks to
manifest
105
What are the Risk Factors for Osmotic
Demyelination Syndrome (ODS)?
* Serum Na+ <105mmol/L
* Hypokalaemia
* Chronic excess alcohol
* Malnutrition
* Advanced Liver disease
* >18mmol/L Na+ increase in 48 hour
LIMITS (not targets) for NA+ rise
* High risk <8mmol/l in any 24 hour period
* Normal <10-12mmol/l in any 24 hour period
106
What are the other management of ODS?
Selective V2 receptor oral
antagonist - ‘tolvaptan’
-competitive antagonist to AVP
-cause a profound ‘aquaresis’
-licensed for SIAD
-expensive tablet
107
Talk about the structure/anatomy of the anterior and posterior pituitary gland.
* Anterior lobe: glandular
tissue, accounts for 75% of
total weight.
* Posterior: nerve tissue &
contains axons that
originate in the
hypothalamus.
108
What are the different types of pituitary mass lesion?
* Non-Functioning Pituitary Adenomas (silent)
* Endocrine active pituitary adenomas
* Malignant pituitary tumors: Functional and
non-functional pituitary carcinoma
* Metastases in the pituitary (breast, lung,
stomach, kidney)
* Pituitary cysts: Rathke's cleft cyst, Mucocoeles,
Others
* Developmental abnormalities: Craniopharyngioma
(occasionally intrasellar location), Germinoma, Others
* Primary Tumors of the central nervous system: Perisellar meningioma, Optic glioma, Others
* Vascular tumors: Hemangioblastoma, Others
* Malignant systemic diseases: Hodgkin's disease, NonHodgkin lymphoma, Leukemic infiltration, Histiocytosis X
* Granulomatous diseases: Neurosarcoidosis, Wegner's
granulomatosis, Tuberculosis, Syphilis
* Vascular aneurysms (intrasellar location)
109
Talk about the development of the pituitary galnd.
The infundibulum forms the hypothalamus and the neural lobe residual lumen for the posterior pituitary gland.
the Rathke's pocket/pouch degenerate and form the intermediate anterior lobe of pituitary gland.
110
Talk about craniopharyngioma.
Arise from squamous epithelial remnants of Rathke’s pouch
– Adamantinous: cyst formation and calcification
– Squamous papillary: well circumscribed
* Benign tumour although infiltrates surrounding structures
* Peak ages: 5 to 14 years; 50 to 74 years
* Solid, cystic, mixed, extends into suprasellar region
* Raised ICP, visual disturbances, growth failure, pituitary
hormone deficiency, weight increase
111
Talk about Rathke’s Cyst.
* Derived from remnants of Rathke’s pouch
* Single layer of epithelial cells with mucoid,
cellular, or serous components in cyst fluid
* Mostly intrasellar component, may extend
into parasellar area
* Mostly asymptomatic and small
* Present with headache and amenorrhoea,
hypopituitarism and hydrocephalus
112
Talk about meningioma.
Commonest tumour of the region after pituitary adenoma
* Complications of radiotherapy
* Associated with visual disturbance and
endocrine dysfunction
* Usually present with loss of visual acuity,
endocrine dysfunction and visual field defects
* T1 MRI images similar to grey matter,
hypointense to the pituitary and enhance with contrast
A meningioma is a primary central nervous system (CNS) tumor. This means it begins in the brain or spinal cord. Overall, meningiomas are the most common type of primary brain tumor. - google
113
Talk about Lymphocytic Hypophysitis.
* Inflammation of the pituitary gland due to an autoimmune reaction
– Lymphocytic adenohypophysitis
– Lymphocytic infindibuloneurohypophysitis
– Lymphocytic panhypophysitis
* Incidence 1 per 9 million based on pituitary surgery
* LAH commoner in women - 6:1
* Age of presentation of LAH women: 35 years; men: 45 years
– Pregnancy or postpartum
114
Talk about the imaging presentation of Lymphocytic Hypophysitis.
* Hypointense on T1 imaging
* Hyperintense on T2 imaging
* Stalk enlargement
* Pituitary enlargement
115
Talk about Non-Functioning Pituitary Adenoma (NFPA) or Silent Pituitary Adenoma
(SPA).
* Pituitary adenomas account for <10 – 15% of primary intracranial tumours
* NFPA account for 14 - 28% of clinically
relevant pituitary adenomas and 50% of
pituitary macroadenomas - Preop
* Most SPA express gonadotropins or subunits - Postop
* 23% of SPA are classified as null cell adenomas
116
Talk about non-functioning pituitary adenoma (NFPA).
* Diagnosed between 20 and 60 years of age in 78% of cases
* 50% of NFPA are incidenalomas
* 50% of macroadenomas have visual
disturbances and 50% have headaches
* Signs of aggressiveness
– Large size
– Cavernous sinus invasion
– Lobulated suprasellar margins
117
What are the impacts of pituitary dysfunction and what are the possible investigation methods?
1. Tumour mass effects
2. Hormone excess
3. Hormone deficiency
Investigations:
* Hormonal tests
* If hormonal tests abnormal or tumour
mass effects perform MRI pituitary
118
What are the local mass effects out there?
1. Cranial nerve palsy and temporal lobe epilepsy
2. Visual field defects
3. CSF rhinorrhoea
4. Headaches
119
How do you measure the visual field defect?
using the red tip needle <3
120
What is the type of visual field defect that will present when there is chiasmal compression from pituitary tumour?
Bitemporal hemianopia
121
What are the different type of hormonal secretion from anterior pituitary gland?
1. TSH
2. MSH (Melanocyte- stimulating hormone)
3. ACTH (adrenocortiocotropin)
4. Prolactin
5. Growth Hormone
6. Gonadotropins (like for FSH and LH)
122
Talk about non-functioning tumour at the pituitary gland.
* No specific test but absence of hormone
secretion
* Test normal pituitary function
* Trans-sphenoidal surgery if threatening
eyesight or progressively increasing in size
123
Why is testing pituitary function complex?
– Many hormones: GH, LH/FSH, ACTH, TSH and ADH
– May have a deficiency of one or all and may be borderline
– Circadian rhythms and pulsatile
Guiding principle:
- If the peripheral target organ is working normally the pituitary is working
124
What are the different type of hormone presentation in Testing Pituitary-Thyroid Axis.
* Primary Hypothyroid - Raised TSH low Ft4
* Hypopituitary - Low Ft4 with normal or low TSH
* Graves disease (toxic) - Suppressed TSH high Ft4
* TSHoma (very rare) - High Ft4 with normal or high TSH
* Hormone resistance - High Ft4 with normal or high TSH
> Measure Ft4 in pituitary disease
125
What are the different type of hormone presentation in Testing Gonadal Axis: Men.
* Primary Hypogonadism - Low T raised
LH/FSH
* Hypopituitary - Low T normal or low
LH/FSH
* Anabolic use - Low T and suppressed LH
* Measure 0900h fasted T and LH/FSH in
pituitary disease
126
What are the different type of hormone presentation in Testing Gonadal Women: Female.
* Before puberty - Oestradiol very low/undectable with low LH and FSH although FSH slightly higher than LH
* Puberty - Pulsatile LH increases and oestradiol increases
* Post menarche - Monthly menstrual cycle with LH/FSH, mid-cycle surge in LH and FSH and levels of oestradiol increase through cycle
* Primary ovarian failure (includes menopause) - High LH and FSH with FSH greater than LH and low oestradiol
* Hypopituitary - Oligo or amenorrhoea with low oestradiol and normal or low LH and FSH
127
Testing the HPA axis.
* Circadian Rhythm
* Measure 0900h cortisol and
synacthen
* Primary AI: Low cortisol, high
ACTH, poor response to Synacthen
* Hypopituitarism: Low cortisol, low
or normal ACTH, poor response to
synacthen
128
Testing GH/IGF1 axis.
* GH is secreted in pulses with
greatest pulse at night and low or undetectable levels between pulses
* GH levels fall with age and are
low in obesity
* Measure: IGF-I and GH
stimulation test
– Insulin stress test
– Glucagon test
– Other
129
Talk about prolactin levels.
* Prolactin under negative control of
dopamine
* Prolactin is a stress hormone
* Measure prolactin or cannulated
prolactin (3 samples over an hour
to exclude stress of venepuncture
* Prolactin may be raised because of:
– Stress
– Drugs: antipsychotics
– Stalk pressure
– Prolactinoma
130
Talk about investigation of the different types of diabetes insipidus using water deprivation test.
So at 16 hours, provide 2 microgram of desmopressin.
Cranial DI will respond but nephrogenic DI will not.
131
Talk about dynamic testing of the pituitary gland hormone.
Dynamic stimulation/suppression testing may be useful in select cases to further evaluate pituitary reserve and/or for pituitary hyperfunction
* Dexamethasone suppression testing – Cushing’s
* Oral glucose GH suppression test - Acromegaly
* CRH stimulation – Cushing’s
* TRH stimulation – TSHoma
* GnRH stimulation – gonadotrophin deficiency
* Insulin-induced hypoglycemia – GH/ACTH deficiency
* Glucagon test – GH deficiency
132
Talk about Radiologic Evaluation: MRI for pituitary gland.
* Preferred imaging study for the pituitary
* Better visualization of soft tissues and vascular structures
than CT
* No exposure to ionizing radiation
* T1-weighted images produce high–signal intensity images of fat. Structures such as fatty marrow and orbital fat show up
as bright images.
* T2-weighted images produce high-intensity signals of structures with high water content, such as cerebrospinal fluid and cystic lesion
133
Talk about Radiologic Evaluation: CT for the pituitary gland.
* Better at visualizing bony structures and calcifications within soft tissues
* Better at determining diagnosis of tumors with calcification, such as germinomas, craniopharyngiomas, and meningiomas
* May be useful when MRI is contraindicated, such as in patients with pacemakers or metallic implants in the brain or eyes
* Disadvantages include:
– less optimal soft tissue imaging compared to MRI
– use of intravenous contrast media
– exposure to radiation
134
Talk about the different presentation of pituitary hormone deficiency.
1. GH deficiency
> Short stature
> Abnormal body composition
> Reduced Muscle Mass
> Poor Quality of Life
> Rx: Growth Hormone
2. LH/ FSH deficiency
> Hypogonadism
>Reduced Sperm Count
>Infertility
>Menstruation Problems
> Rx: Testosterone in males; oestradiol ±
progesterone in females
3. TSH deficiency
Hypothyroidism
Rx: Levothyroxine
4. ACTH deficiency
Adrenal Failure Decreased Pigment
Rx: Hydrocortisone
5. ADH deficiency
Diabetes Insipidus
(ADH deficiency -
Decreased water absorption in
kidney resulting in polyuria &
polydipsia)
Rx: DDAVP
135
Talk about treatment for ACTH deficiency.
Current Hydrocortisone Replacement Therapy:
Inadequate & non-circadian
Challenge: gut length and
transit time
Solution: microparticulates
Microparticulate: Modified-Release HC
136
Talk about Thyroxine replacement.
* Dose 1.6 micrograms/kg/day
* Aim to achieve levels to mid to upper half of
reference range
* Check level before levothyroxine dose
* Higher doses usually required in patients on
oestrogens or in pregnancy
137
Talk about growth hormone replacement.
* < 60 years – start 0.2 – 0.4mg/day
* > 60 years – start 0.1 – 0.2 mg/day
* Aiming for mid-range IGF1 levels
* Measure IGF1 6 weeks after dose start and
change
* Improves lipid profiles, body composition and bone mineral density
138
Talk about testosterone replacement.
* Different types of formulations: gels,
injections, oral
* Follow Testosterone levels, Full Blood Count
and Prostate Specific Antigen
* Improve bone mineral density, libido, sexual
function, energy levels and sense of well
being, muscle mass and reduce fat
139
Talk about oestrogen replacement.
* Oral oestrogen or combined
oestrogen/progestogen formulations (also
transdermal, topical gels, intravaginal creams)
* Alleviate flushes and night sweats; improve
vaginal atrophy
* Reduce risk of cardiovascular disease,
osteoporosis and mortality
140
Talk about desmopressins.
* Different formulations: subcutaneously, orally, intra-nasally, sub-lingually
* Adjust according to symptoms
* Monitor sodium levels
141
What does acromegaly actually mean in words?
acros - extremity
megale - great
142
What is the pathogenesis of acromegaly?
Growth hormone - IGF-1 (insulin-like growth factor- 1)
143
Talk about the epidemiology of acromegaly
* Mean age at diagnosis is 44 years
* Mean duration of symptoms is 8 yrs
(range 7 to 11yrs)
144
What are the different types of acromegaly comorbidities?
1. Hypertension and heart diseases
2. Sleep apnoea
3. Cerebrovascular events and headache
4. Arthritis
5. Insulin-resistant diabetes
145
What are the types of diagnosis methods for acromegaly?
1. Clinical features
2. Growth Hormone
3. IGF-1 (Insulin-like Growth Factor-1)
146
What are the presenting clinical features of acromegaly?
- Acral enlargement
- Arthralgias
- Maxillofacial changes
- Excessive sweating
- Headache
- Hypogonadal symptoms
147
What are the criteria for diagnosis of acromegaly?
Acromegaly excluded if:
1. random GH <0.4 ng/ml and normal IGF-I
2. If either abnormal proceed to:
75 gm Glucose tolerance test (GTT)
3. Acromegaly excluded if:
IGF-I normal
and
GTT nadir GH <1 ng/ml
148
What are the objectives of therapy in acromegaly?
* restoration of basal GH and IGF-I to normal levels
* relief of symptoms
* reversal of visual and soft tissue changes
* prevention of further skeletal deformity
* normalization of pituitary function
149
What are the treatment options for acromegaly.
* Pituitary surgery
* Medical therapy
* Radiotherapy
150
Talk about transsphenoidal pituitary surgery.
Used as primary treatment for all types of pituitary adenoma except prolactinoma
Problems making surgery harder
* Large size
* Invasiveness
Life-long monitoring needed for
most patients
151
Talk about the surgery as primary therapy for acromegaly.
1. Microadenoma (<1 cm)
Surgical cure rate ~90%
2. Macroadenoma (>1 cm)
Surgical cure rate <50%
Two important determinants of success of surgery:
> size of tumour
> the surgeon
152
What are the possible complications of pituitary surgery?
Transsphenoidal surgery requires dedicated surgeon.
> Anaesthetic complications
> Carotid artery surgery
> CNS injury
> Haemorrhage
> Nasal septum perforation
> Post-operative epistaxis (nosebleed)
> Post-operative sinusitis
> Hypopituitarism
> DI
> Death
153
Talk about radiotherapy in pituitary surgery (acromegaly and prolactinoma??)
Ø Conventional
* multi-fractional
* 40 years experience
* mass of data
Ø Stereotactic
* single fraction
* less radiation to surrounding tissues
> gamma knife
> LINAC
> proton beam
154
Talk about pituitary radiotherapy.
Problems of radiotherapy
* Loss of pituitary function in the long-term
* Potential damage to local structures – e.g.
eye nerves
* Control of tumour growth / excess hormone
secretion not always achieved
Life-long monitoring needed for all patients
Sheffield is the National Centre for
Stereotactic Radiosurgery :D
155
Talk about medical therapy for acromegaly
* Dopamine agonists – cabergoline
* Somatostatin analogues
* Growth Hormone receptor antagonist
(Dopamine and Somatostatin both inhibits the production of growth hormone)
156
Talk about dopamine agonist in treating acromegaly.
1. Goals:
– Control GH
– Control IGF-I
– Improve well-being
2. Control (normal IGF-1)
– bromocriptine 10%
– Cabergoline 37%
* more potent
* fewer side effects
* twice weekly
3. Advantages:
- No hypopituitarism
- Oral administration
- Rapid onset
4. Disadvantages
- Relatively ineffective
- Side effects
Particularly useful in GH/prolactin co-secreting tumors
* occasional dramatic tumour shrinkage
* control of GH secretion
157
Talk about somatostatin analogues.
1. Goals:
– Control GH
– Control IGF-I
– Clinical improvement
2. Control (normal
IGF-I):
* IGF-I controlled 65%
* GH controlled 60%
* tumor shrinkage
3. Determinants of
efficacy
* GH level
* Tumor size
* SMS receptor expression
4. Disadvantages:
- injectable
- side effects
158
What is an example of a growth hormone receptor antagonist?
Pegvisomant
half-life >70 hours
* subcutaneous administration
Ø serum GH cannot be used as
a disease marker
Ø cross-reacts in GH assays
159
acromegaly summary?
*significant morbidity and mortality
*often insidious onset
*effective treatment essential
*pituitary surgery mainstay of therapy
*medical management improving
160
Talk about prolactinoma.
Incidence 10 per 100,000
Women >> men
Prevalence 90 per 100,000
Lactotroph cell tumour of the pituitary
161
What are the clinical features of prolactinoma?
Local effect of tumour – macro-adenoma
* headache
* visual field defect (bi-temporal hemianopia)
* CSF leak (rare)
Effect of prolactin
* menstrual irregularity/amenorrhoea
* infertility
* galactorrhoea
* low libido
* low testosterone in men
162
What is prolactinoma?
Prolactinoma is a noncancerous tumor of the pituitary gland. This tumor causes the pituitary gland to make too much of a hormone called prolactin. The major effect of a prolactinoma is decreased levels of some sex hormones — namely, estrogen and testosterone. A prolactinoma isn't life-threatening.
163
Talk about Hyperprolactinaemia.
> Macroprolactinoma – can be massive
> Microprolactinoma – virtually always stay small
> Non-functioning pituitary tumour – compression of pituitary stalk – prolactin <4000 mIU/L
> Antidopaminergic drugs – don’t measure prolactin in patients on these, but a careful drug history needed!
164
What is the management of prolactinoma?
Unlike other pituitary tumours management
is medical rather than surgery
Dopamine agonists – cabergoline,
bromocriptine, quinagolide
* Remarkable shrinkage usual with
macroadenoma – sight saving
* Microadenoma - usually respond to
small doses of cabergoline just once
or twice per week
165
Talk about prolactinoma summary.
* Cause of infertility and hypogonadism
* Galactorrhoea
* Careful drug history
* Mainstay of management is medical
166
Why is diabetes a public health issue?
> Mortality – common underlying cause of death, under-reported on death certificates
> Disability – blindness, renal failure, amputation (neuropathy and peripheral vascular disease)
> Co-morbidity – other physical and mental health conditions (eg obesity, depression)
> Reduced quality of life – chronic condition; long-term self management and monitoring
167
Why is type 2 diabetes a public health issue?
A major and highly topical public health issue because it is PREVENTABLE and yet..
1) Increasing in prevalence and affecting younger age groups
2) Lack of effective global, national or local policy that has influenced trends in population obesity and sedentary lifestyles that are driving the global “epidemic” of type 2 diabetes
3) Major inequalities in prevalence and outcomes with higher prevalence in BME communities and poorer outcomes in deprived communities
168
Amount of people in England with diabetes?
3.8 million
169
Talk about the trend in diabetes prevalence.
Primary prevention: incidence of condition decreases
Secondary prevention: % of incident cases diagnosed increases
Tertiary prevention: survival from diagnosis increases
170
Relate the relationship between the risk of diabetes and BMI
The higher the BMI, the higher the risk for diabetes
171
How can we reduce the impact of type 2 diabetes?
> identifying people at risk of diabetes
> preventing diabetes (“Primary” prevention)
> diagnosing diabetes earlier (“Secondary” prevention)
> effective management and supporting self-management (“Tertiary” prevention)
172
What are the Lifestyle and environmental factors that increase the risk of diabetes?
- Sedentary job, sedentary leisure activities
- Diet high in calorie dense foods/low in fruit and vegetables, pulses and wholegrain
- “Obesogenic” environment
173
Talk about the obesogenic environment
> Physical environment: eg TV remote controls, lifts, “car culture”
> Economic environment: eg cheap TV watching, expensive fruit and veg
> Sociocultural environment: eg safety fears, family eating patterns
174
What are the "steep slope", "ineffective brakes" and "accelerator" of the weight gain train?
Obesogenic environment = steep slope
Knowledge, prejudice, physiology = ineffective brakes
Vicious cycles of mechanical dysfunction, psychological impact, ineffective dieting, low socioeconomic status = accelerators
175
What are the mechanisms that maintain overweight?
Physical/physiological - more weight = more difficult to exercise (arthritis, stress incontinence) and dieting -> metabolic response
Psychological - low self-esteem and guilt, comfort eating
Socioeconomic - reduced opportunities employment, relationships, social mobility
176
What are the known risk factors that may already be recorded in a clinical record?
Age, sex, ethnicity, family history
Weight, BMI, waist circumference
History of gestational diabetes
Hypertension or vascular disease
Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG)
177
Is screening test the same for pre-diabetes and diabetes?
yes
178
What are the currently available screening test for IGT (Impaired Glucose Tolerance) and IFT (Impaired Fasting Glucose)?
- HbA1c
- Random capillary blood glucose
- Random venous blood glucose
- Fasting venous blood glucose
- Oral glucose tolerance test (venous blood glucose 2 hours after oral glucose load)
Threshold for further testing – capillary or random test result > 5.5 or 6 mmol/l
Diagnostic range for IGT: 7.8 – 11.0 mmol/l
Diagnostic range for IFG: 6.1 – 6.9 mmol/l
Diagnostic threshold for diabetes (WHO criteria): FBG ≥ 7.0 or 2 hr Glu ≥ 11.1 mmol/l
179
What are the effective interventions required in preventing diabetes?
Sustained increase in physical activity
Sustained change in diet
Sustained weight loss
180
Talk about NICE guideline
In 2017 NICE issued a update to 2012 guidance based on economic modelling
Added advice to PRIORITISE interventions for those with HbA1c = 44–47 mmol/mol OR fasting plasma glucose 6.5–6.9 mmol/l
Added recommendation to use metformin if BMI >35 + HbA1c increasing OR lifestyle intervention not possible + HbA1c increasing
“Preventing type 2 diabetes: population and community-level interventions in high-risk groups and the general population”
Focus on ethnic minority and socio-economically deprived communities at increased risk
Focus on culturally appropriate interventions (for both diet and activity)
181
What are the 3 approaches in diagnosing diabetes earlier?
Raising awareness of diabetes and possible symptoms in the community
Raising awareness of diabetes and possible symptoms in health professionals
Using clinical records to identify those at risk and/or using blood tests to screen before symptoms develop
182
Talk about the screening for Type 2 diabetes.
- Current practice is to screen as part of CHD prevention (NHS Health Check – every 5 yrs from 40 to 74yrs)
- Screening at review of hypertension management
- Other risk groups MAY be screened
- 30% of adult at risk population may have blood glucose measurement even without systematic screening
183
What are the things that NICE Guideline are focusing on diabetes?
- Focus on risk assessment followed by blood tests (HbA1c; FBG)
- Focus on cost-effective weight loss, diet and physical activity interventions
184
Why is NHS England investing in type 2 diabetes prevention?
> Trials show that changes in diet, weight loss and increased physical activity reduces risk of progression from impaired glucose tolerance
> Pilot programme suggests it is feasible to identify high risk individuals who would benefit from lifestyle change by screening so they can be offered interventions
185
How is NHS England investing in type 2 diabetes prevention?
“Healthier You: The NHS Diabetes Prevention Programme”
Programme of lifestyle education, weight loss support, and group physical exercise
From 2016, 20,000 places available in 27 areas (including Sheffield)
National roll out by 2020, with 100,000 referrals available annually
186
Talk about Supporting Self-care for Diabetes.
> Self-monitoring – helpful for some, particularly if on insulin, but not all
> Diet - Support for changing eating patterns
> Exercise - Support for increasing physical activity
> Drugs - Support for taking medication
> Education – professionals/expert patients
> Peer support – Health Champions/ Health Trainers
187
What is the public health role for diabetes healthcare?
Healthcare systems can play an important public health role in reducing inequalities in access, experience and outcomes for diabetes, even if they cannot change the population prevalence.
188
What are the components of unmet need in diabetes in the public health?
> Primary: under-recognition of illness by individuals and people around them
> Secondary: identified as ill but treatment not available
> Inadequate quality of in-service provision
> Insufficient assets for recovery or ongoing self-management
189
What is the definition of diabetes?
Symptoms and random plasma glucose > 11.1 mmol/l
Fasting plasma glucose > 7.0 mmol/l
HbA1c > 48 mmol/mol
No symptoms - OGTT (75g glucose) fasting > 7 or 2h value > 11.1 mmol/l
190
What are the presenting features of diabetes?
- Thirst
osmotic activation of hypothalamus
- Polyuria
osmotic diuresis
- Weight loss and fatigue
lipid and muscle loss due to
unrestrained gluconeogenesis
- Hunger
Lack of useable energy source
- Pruritis vulvae and balanitis
Vaginal candidiasis
Chest / skin infections
- Blurred vision
Altered acuity due to uptake of glucose/water into lens
191
What are the suggestive features that the diabetes is Type 1 diabetes?
- Onset in childhood / adolescence
- Lean body habitus
- Acute onset of osmotic symptoms
- Prone to ketoacidosis
- High levels of islet autoantibodies
Can occur at any age, the spectrum of presentation depends on the rate of b-cell destruction
192
What are the clinical features of newly diagnosed Type 1 diabetes?
1. Weight loss
2. Short history (weeks) of severe symptoms
3. Moderate or large urinary ketones
Any 2 of these three features indicate Type 1 diabetes and are an indication for immediate insulin treatment at ANY age
193
What are the suggestive features of Type 2 diabetes?
> Usually presents in over-30s
> Onset is gradual
> FH is often positive
> Almost 100% concordance in identical twins
> Diet, exercise and oral medication can often control hyperglycaemia; insulin may be required later in the disease
194
Can Type 1 diabetes occur at any age?
Yes!
Commonest age at diagnosis, 5-15y, but can occur at any age
Relatively rare (prevalence of 3/1000 among children and adolescents)
195
Talk about the genetic probability of Type 1 Diabetes.
> if a mother has the condition, the risk of developing it is about 2%
> If a father has the condition, the risk of developing it is about 8%
> if both parents have the condition, the risk of developing it is up to 30%
> if a brother or sister develops the condition, the risk of developing it is 10%
(rising to 15% for a non-identical twin and 40% for an identical twin).
196
Talk about gene in children diagnosed of DM1.
- If a family member has diabetes then the index case is less unwell compared to sporadic cases
- Less autoimmunity in familial vs sporadic cases
- Parents diagnosed 13% of the time after the birth of the index child
- Offspring of affected fathers are more unwell than those of affected mothers, with longer duration of symptoms, more than twice as likely to present in ketoacidosis.
197
What are some examples of autoimmune diseases?
1. Hashimoto's hypothyroidism
2. Addison's
3. Coeliac disease
198
What happens if the diagnosis of type 1 DM is missed?
DKA (Diabetic Ketoacidosis might happen)
199
Talk about fat metabolism and the formation of ketone bodies in DM.
- Reduced insulin leads to fat breakdown and formation of glycerol (a gluconeogenic precursor) and free fatty acids
- Free fatty acids (FFA)
> Impair glucose uptake
> Are transported to the liver, providing ‘energy’ for gluconeogensis
> Are oxidised to form ketone bodies (beta hydroxy butyrate, acetoacetate and acetone)
200
Talk about ketoacidosis.
- Absence of insulin and rising counterregulatory hormones leads to increasing hyperglycaemia and rising ketones
- Glucose and ketones escape in the urine but lead to an osmotic diuresis and falling circulating blood volume
- Ketones (weak organic acids) cause anorexia and vomiting
- Vicious circle of increasing dehydration, hyperglycaemia and increasing acidosis eventually lead to circulatory collapse and death
201
What is the definition of Diabetic Ketoacidosis? (DKA)
1. Hyperglycaemia (plasma glucose usually <50 mmol/l)
2. Raised plasma ketones (urine ketones > 2+)
3. Metabolic acidosis – plasma bicarbonate < 15 mmol/l
202
What are the causes of Diabetic Ketoacidosis (DKA)?
- Intercurrent illness
> infection
> myocardial infarct
- Treatment errors – stop/reduce insulin dose
- Previously undiagnosed diabetes
- Unknown
203
What si the triad of diabetic ketoacidosis (DKA)?
> Hyperglycaemia
> Ketones
> Acidosis
204
What are the clinical features of DKA (the signs and symptoms)?
Symptoms:
- develop over days
- polyuria and polydipsia
- nausea and vomiting
- weight loss
- weakness
- abdominal pain (confused with surgical abdomen)
- Drowsiness / confusion
Signs:
- hyperventilation (Kussmaul breathing)
- dehydration (average fluid loss 5-6 litres)
- hypotension
- Tachycardia
- coma
205
Talk about the biochemical diagnosis of DKA.
> hyperglycaemia (<50 mmol/l)
> K+ – high on presentation despite total body K+ deficit (due to acute shift of K out of cell with acidosis), subsequently fall with insulin and rehydration, anticipate fall in K+
> HCO3- <15 mmol/l
> urea and creatinine - raised due to pre-renal failure
> urinary ketones dipstix >2+ ketones
blood ketones >3.0
206
What is the management for DKA?
- rehydration (3L first 3 hrs)
- insulin (inhibits lipolysis, ketogenesis, acidosis, reduces hepatic glucose production, increase tissue glucose uptake)
- replacement of electrolytes (K+)
- treat underlying cause
- Treatment must be started without delay
- Follow DKA protocol in hospital
207
What are the complications of DKA?
- cerebral oedema (deterioration in conscious level)
> children more at risk
- adult respiratory distress syndrome
- thromboembolism – venous and arterial
- aspiration pneumonia (in drowsy/comatose patients)
- death
208
What are the aims of treatment in Type 1 Diabetes?
- Relieve symptoms and prevent ketoacidosis
- Prevent microvascular and macrovascular complications
- On average, people with Type 1 diabetes lose 8 years of life (mostly from cardiovascular disease)
209
What are the microvascular complications of DM1?
- Around 30% in the UK will develop diabetic nephropathy
> CV mortality with no nephropathy x2, but with nephropathy x30
- Those with nephropathy tend to develop proliferative retinopathy and severe neuropathy with major effect on quality of life
210
What is the treatment of Type 1 DM?
To restore the physiology of the beta cell
1. Insulin treatment
- Twice daily mixture of short/medium acting insulin
- Basal bolus, (once or twice daily medium acting insulin plus pre meal quick acting insulin)
2. Ability to judge CHO intake
3. Awareness of blood glucose lowering effect of exercise
All combined to keep blood glucose close to normal (and so prevent diabetic complications)
211
Talk about the specific features of DM1 symptoms on:
- Inappropriately high insulin levels confer a high risk of hypoglycaemia
- Acute deprivation of glucose within the brain leads to cerebral dysfunction (loss of concentration, confusion, coma)
- Physiological defences to hypoglycaemia :
> Release of glucagon, adrenaline
> Symptoms of:
- Sweating, tremor, palpitations (autonomic activation)
- Loss of concentration, ‘hunger’
may be overwhelmed by the glucose lowering effect of insulin
212
Talk about the different spectrum of hypoglycaemia.
Glucose level
4.6 mM- inhibition of insulin secretion
3.8 mM- counter-regulatory hormone release (glucagon and adrenaline)
3.8-2.8 mM- autonomic symptoms
sweating, tremor, palpitations
<2.8 mM - neuroglycopenic symptoms
confusion, drowsiness, altered behaviour, speech difficulty, incoordination
<1.5 mM - severe neuroglycopenic
convulsions, coma, focal neurological deficit - ie hemiparesis
213
What is SMBG snapshot?
Self-monitoring Blood Glucose Snapshot
214
Talk about the benefits and risks of tight glucose control.
Tigh glucose control can decrease the risk of retinopathy but increase the risk of hypoglycaemia.
215
What is the dilemma for those with Type 1 Diabetes Mellitus?
Setting higher glucose targets will reduce the risk of hypoglycaemia but increase the risk of diabetic complications
Setting lower glucose targets will reduce the risk of complications but increase the risk of hypoglycaemia
