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Phase 2A > Endocrinology Part 2 > Flashcards

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
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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
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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

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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

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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

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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

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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
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8
Q

What are the 3 areas of risk factors for thyroid autoimmunity?

A
  1. Genes
    - HLA, target organ, T cell response, immunoglobulin, cytokine
  2. Endogenous factors
    - sex hormone, glucocorticoid, prolactin, birthweight, pregnancy
  3. Environmental factors
    - diet, infection, drugs, toxin, stress
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9
Q

What would happen during the postpartum period?

A
  • Autoimmune thyroiditis
  • Grave’s thyrotoxicosis
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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)

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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
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12
Q

What is Graves’ disease caused by?

A

thyroid stimulating antibodies that may cross the placenta

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13
Q

Talk about goitre.

A
  • Palpable & visible thyroid enlargement
  • Variety of causes
  • Commonly sporadic or autoimmune
  • Endemic in iodine-deficient areas
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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
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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

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16
Q

What are the 3 common causes of hyperthyroidism?

A
  • Graves’ disease (75- 80% of all cases)
  • Toxic multinodular goitre
  • Toxic adenoma
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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)
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18
Q

What are the drugs that can induce hyperthyroidism?

A
  • Iodine
  • Amiodarone
  • Lithium
  • Radiocontrast agents
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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
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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

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21
Q

What test is used to confirm biochemical hyperthyroidism?

A

Thyroid function tests (TFTs)

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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

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23
Q

What are the supporting investigation other than TFT for confirming the diagnosis of hyperthyroidism?

A
  1. Thyroid antibodies: TPO, Tg, TRAb
  2. Isotope uptake scan
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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.

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25
Q

What are the treatment for hyperthyroidism?

A

Antithyroid drugs (course or long-term)

Radioiodine (131) I

Surgery (partial, subtotal thyroidectomy)

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26
Q

What are the antithyroid drugs out there?

A

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

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27
Q

What are the poor prognostic factors for hyperthyroidism?

A
  • severe biochemical hyperthyroidism
  • large goitre
  • TRAb +ve at end of course of ATD
  • male sex
  • young age of disease onset
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28
Q

What are the side effects of thionamide?

A

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

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29
Q

Talk about iodine.

A

Iodine essential for thyroid hormone production

I actively transported by Na/I symporter into thyroid follicular cells

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30
Q

Talk about iodine 131.

A
  • 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
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31
Q

How does radioiodine work in hyperthyroidism?

A
  • Emission of beta particles results in ionization of thyroid cells
  • Direct damage to DNA and enzymes
  • Indirect damage via free radicals
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32
Q

What are the early and long-term effects of 131 Iodine?

A

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

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33
Q

What are the different types of surgery for hyperthyroidism?

A

Near total thyroidectomy for Graves’ disease and MNG

Near total thyroidectomy / lobectomy for toxic adenoma

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34
Q

What is hypothyrodism?

A

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
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35
Q

What are the drugs that can induce hypothyroidism?

A

Iodine, inorganic or organic
iodide
iodinated contrast agents
amiodarone
Lithium
Thionamides
Interferon - alpha

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36
Q

What are the causes of hypothyroidism in neonate/child?

A

Neonatal hypothyroidism
Thyroid agenesis (absent)
Thyroid ectopia
Thyroid dyshormonogenesis
Others
Resistance to thyroid hormone
Isolated TSH deficiency

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37
Q

What are the clinical features in hypothyroidism?

A
  • Fatigue
  • Wt gain
  • Cold intolerance
  • Constipation
  • Menstrual disturbance
  • Muscle cramps
  • Slow cerebration
  • Dry, rough skin
  • Periorbital oedema
  • Delayed muscle reflexes
  • Carotenaemia
  • Oedema
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38
Q

Talk about primary and secondary/tertriary hypothyroidism?

A

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

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39
Q

What are the treatment for hypothyroidism?

A

Treatment of choice
- synthetic L-thyroxine (T4)
Older treatments - dessicated thyroid (pig and beef extracts) - inconsistent from batch to batch
? T3 / T4 combination

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40
Q

Talk about monitoring treatment in hypothyroidism.

A

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

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41
Q

Is goitre usually benign or malignant?

A

Benign!

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42
Q

subacute thyroiditis usually after what type of illnesses?

A

viral illness

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43
Q

Swollen extraocular muscle in the eyes during hyperthyroidism can cause?

A

Compression of the optic nerves and bulging of the eyeballs

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44
Q

What type of drug do we use when it comes to patients with hyperthyroidism during pregnancy for the first trimester only?

A

propylthiouracil (PTU)

Carbimazole is the drug used during the rest of pregnancy.

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45
Q

Talk about iodine-contained drug and thyroid problems.

A

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

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46
Q

Puffy face, is it hyper or hypothyrodism?

A

Hypothyroidism

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47
Q

What type of thyroid problems will be triggered by viral infection?

A

De Quervain’s (subacute)thyroiditis, a painful swelling of thethyroid gland

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48
Q

What are the metabolic changes in pregnancy?

A
  • Increased erythropoetin, cortisol, noradrenaline
  • High cardiac output
  • Plasma volume expansion
  • High cholesterol and triglycerides
  • Hyperventilation
  • Pro thrombotic and inflammatory state
  • Insulin resistance
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49
Q

What are the Gestational Syndromes.

A
  • Pre-Eclampsia
  • Gestational Diabetes
  • Obstetric cholestasis
  • Gestational Thyrotoxicosis
  • Transient Diabetes Insipidus
  • Lipid disorders
  • Postnatal depression
  • Postpartum thyroiditis
  • Postnatal autoimmune disease
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50
Q

Talk about foetus thyroid gland development.

A

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

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51
Q

Talk about glycoprotein hormone.

A

Glycoprotein hormone consists of 2 subunits, a common alpha unit, a distinct beta subunit. Eg: TSH, LH, FSH, hCG

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52
Q

Talk about hypothyroidism in pregnancy?

A

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

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53
Q

What is the aetiology of hypothyroidism?

A

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

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54
Q

How does hypothyroidism affect pregnancy?

A

Inadequate treatment:
Gestational hypertension and pre-eclampsia
Placental abruption
Post-partum haemorrhage

If untreated:
Low birth weight
Preterm delivery
Neonatal goitre
Neonatal respiratory distress

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55
Q

What to do when there is hypothyroidism in pregnancy?

A

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

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56
Q

What is the difference between overt and subacute hypothyroidism?

A

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.

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57
Q

Talk about targetted screening in hypothyroidism?

A
  • 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
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58
Q

Talk about hyperthyroidism in pregnancy.

A
  • 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
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59
Q

For hyperthyroidism, how does the disease effect pregnancy?

A

If inadequately treated:
- IUGR (intrauterine growth restriction)
- Low birth weight
- Pre-ecclampsia
- Preterm delivery
- Risk of stillbirth
- Risk of miscarriage

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60
Q

For hyperthyroidism, how does pregnancy affect the disease?

A
  • Tends to worsen in the first trimester
  • Improves latter half of pregnancy
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61
Q

Talk about the management in hyperthyroidism in pregnancy.

A
  • 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

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62
Q

Talk about autoantibodies in hyperthyroidism in pregnancy.

A
  • 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
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63
Q

Talk about Fetal Thyrotoxicosis.

A

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

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64
Q

Talk about gestational diabetes in pregnancy.

A
  • 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

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65
Q

Differential thyrotoxicosis in pregnancy between Grave disease and Gestational thyrotoxicosis.

A

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: -

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66
Q

Talk about post-partum thyrotoxicosis.

A

Prevalence 7 %
High risk women are
Type 1 diabetics
Graves disease in remission
Chronic viral hepatitis
Measure TSH 3 months post partum

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67
Q

Drugs that usually interfere the thyroid gland.

A

Commonly:
Amiodarone
Lithium
Interferon
Immune therapies (oncology, rheumatology)

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68
Q

Talk about Amiodarone and Thyroid function.

A

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)

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69
Q

Talk about Amiodarone Induced Hypothyroidism. (AIH)

A

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

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70
Q

Talk about the 2 types of Amiodarone Induced Hypothyroidism.

A

AIT type 1
Latent pre-existing
Low iodine areas
Iodine induced excess
Thyroid hormone release
Jode-Basedow phenomenon

AIT Type 2
Normal Thyroid
Destructive

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71
Q

Talk about Amiodarone and the thyroid: key points

A
  • 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
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72
Q

Talk about immune therapy and the thyroids.

A

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

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73
Q

Talk about Ipilimumab and Nivolumab.

A

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

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74
Q

Talk about Ipilimumab.

A

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

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75
Q

Talk about Ipilimumab Hypophysitis.

A
  • 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
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76
Q

What are the brain structures above the pituitary gland?

A

Optic Chiasm and hypothalamus, then pituitary stalk

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77
Q

Where is vasopressin and oxytocin made?

A

Made in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), then transported to the posterior pituitary gland in the axoplasm of the neurons

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78
Q

Talk about arginine vasopressin (AVP)/ ADH.

A
  • 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

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79
Q

Talk about the proportion of fluid in an average 70kg adult man.

A
  • 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)
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80
Q

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?

A

Na+, Cl-, HCO3-

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81
Q

Vasopressin binds to whic h receptor on the renal collecting duct principle cells?

A

V2 receptor (vasopressin- 2 receptor)

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82
Q

Talk about the mechanism of action of vasopressin.

A
  • 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
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83
Q

What is the term for concentration in plasma?

A
  • 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
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84
Q

What is the normal osmolality?

A

282 - 295 mOsmol/kg

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85
Q

What are the diseases associated with the posterior pituitary gland?

A
  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
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86
Q

Talk about AVP/ ADH deficiency and resistance

A
  • 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

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87
Q

Causes of AVP deficiency (cranial Diabetes Insipidus)?

A

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
Q

Talk about AVP resistance (nephrogenic diabetes insipidus)

A
  • 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
Q

Talk about water deprivation test.

A

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
Q

Talk about the management of AVP deficiency (Cranial DI)

A
  • 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
Q

Talk about the management of AVP resistance (nephrogenic DI)

A
  • try and avoid precipitating drugs
  • congenital DI - very difficult
    > free access to water
    > very high dose desmopressin
92
Q

What is one of the advanced approach in diagnosing diabetes insipidus?

A

Measurement of copeptin

93
Q

Talk about hyponatraemia.

A
  • 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
Q

What are the three different levels of symptomatic hyponatraemia?

A
  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
Q

The brain undergoes volume adaptation in response to gradual-onset hyponatraemia.

A
  • 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
Q

What are the different types of classifications of hyponatraemia?

A

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
Q

Talk about the general and specific appraoch for hyponatraemia

A

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
Q

Talk about the assessment and management of hyponatraemia.

A
  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

  1. 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
Q

Talk about the syndrome of antidiuresis (SIAD)

A
  • 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
Q

What are the causes of SIAD?

A
  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
Q

Talk about treatment goal for SIAD.

A
  • 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
Q

Talk about management of SIAD

A

*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
Q

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?

A

osmotic demyelination

104
Q

What is osmotic demyelination syndrome (ODS)?

A
  • White areas in the middle of the
    pons
  • Massive demyelination of
    descending axons
  • May take up to 2 weeks to
    manifest
105
Q

What are the Risk Factors for Osmotic
Demyelination Syndrome (ODS)?

A
  • 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
Q

What are the other management of ODS?

A

Selective V2 receptor oral
antagonist - ‘tolvaptan’
-competitive antagonist to AVP
-cause a profound ‘aquaresis’
-licensed for SIAD
-expensive tablet

107
Q

Talk about the structure/anatomy of the anterior and posterior pituitary gland.

A
  • Anterior lobe: glandular
    tissue, accounts for 75% of
    total weight.
  • Posterior: nerve tissue &
    contains axons that
    originate in the
    hypothalamus.
108
Q

What are the different types of pituitary mass lesion?

A
  • 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
Q

Talk about the development of the pituitary galnd.

A

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
Q

Talk about craniopharyngioma.

A

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
Q

Talk about Rathke’s Cyst.

A
  • 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
Q

Talk about meningioma.

A

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
Q

Talk about Lymphocytic Hypophysitis.

A
  • 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
Q

Talk about the imaging presentation of Lymphocytic Hypophysitis.

A
  • Hypointense on T1 imaging
  • Hyperintense on T2 imaging
  • Stalk enlargement
  • Pituitary enlargement
115
Q

Talk about Non-Functioning Pituitary Adenoma (NFPA) or Silent Pituitary Adenoma
(SPA).

A
  • 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
Q

Talk about non-functioning pituitary adenoma (NFPA).

A
  • 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
Q

What are the impacts of pituitary dysfunction and what are the possible investigation methods?

A
  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
Q

What are the local mass effects out there?

A
  1. Cranial nerve palsy and temporal lobe epilepsy
  2. Visual field defects
  3. CSF rhinorrhoea
  4. Headaches
119
Q

How do you measure the visual field defect?

A

using the red tip needle <3

120
Q

What is the type of visual field defect that will present when there is chiasmal compression from pituitary tumour?

A

Bitemporal hemianopia

121
Q

What are the different type of hormonal secretion from anterior pituitary gland?

A
  1. TSH
  2. MSH (Melanocyte- stimulating hormone)
  3. ACTH (adrenocortiocotropin)
  4. Prolactin
  5. Growth Hormone
  6. Gonadotropins (like for FSH and LH)
122
Q

Talk about non-functioning tumour at the pituitary gland.

A
  • No specific test but absence of hormone
    secretion
  • Test normal pituitary function
  • Trans-sphenoidal surgery if threatening
    eyesight or progressively increasing in size
123
Q

Why is testing pituitary function complex?

A

– 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
Q

What are the different type of hormone presentation in Testing Pituitary-Thyroid Axis.

A
  • 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
Q

What are the different type of hormone presentation in Testing Gonadal Axis: Men.

A
  • 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
Q

What are the different type of hormone presentation in Testing Gonadal Women: Female.

A
  • 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
Q

Testing the HPA axis.

A
  • 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
Q

Testing GH/IGF1 axis.

A
  • 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
Q

Talk about prolactin levels.

A
  • 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
Q

Talk about investigation of the different types of diabetes insipidus using water deprivation test.

A

So at 16 hours, provide 2 microgram of desmopressin.

Cranial DI will respond but nephrogenic DI will not.

131
Q

Talk about dynamic testing of the pituitary gland hormone.

A

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
Q

Talk about Radiologic Evaluation: MRI for pituitary gland.

A
  • 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
Q

Talk about Radiologic Evaluation: CT for the pituitary gland.

A
  • 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
Q

Talk about the different presentation of pituitary hormone deficiency.

A
  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
Q

Talk about treatment for ACTH deficiency.

A

Current Hydrocortisone Replacement Therapy:
Inadequate & non-circadian

Challenge: gut length and
transit time

Solution: microparticulates
Microparticulate: Modified-Release HC

136
Q

Talk about Thyroxine replacement.

A
  • 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
Q

Talk about growth hormone replacement.

A
  • < 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
Q

Talk about testosterone replacement.

A
  • 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
Q

Talk about oestrogen replacement.

A
  • 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
Q

Talk about desmopressins.

A
  • Different formulations: subcutaneously, orally, intra-nasally, sub-lingually
  • Adjust according to symptoms
  • Monitor sodium levels
141
Q

What does acromegaly actually mean in words?

A

acros - extremity
megale - great

142
Q

What is the pathogenesis of acromegaly?

A

Growth hormone - IGF-1 (insulin-like growth factor- 1)

143
Q

Talk about the epidemiology of acromegaly

A
  • Mean age at diagnosis is 44 years
  • Mean duration of symptoms is 8 yrs
    (range 7 to 11yrs)
144
Q

What are the different types of acromegaly comorbidities?

A
  1. Hypertension and heart diseases
  2. Sleep apnoea
  3. Cerebrovascular events and headache
  4. Arthritis
  5. Insulin-resistant diabetes
145
Q

What are the types of diagnosis methods for acromegaly?

A
  1. Clinical features
  2. Growth Hormone
  3. IGF-1 (Insulin-like Growth Factor-1)
146
Q

What are the presenting clinical features of acromegaly?

A
  • Acral enlargement
  • Arthralgias
  • Maxillofacial changes
  • Excessive sweating
  • Headache
  • Hypogonadal symptoms
147
Q

What are the criteria for diagnosis of acromegaly?

A

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
Q

What are the objectives of therapy in acromegaly?

A
  • 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
Q

What are the treatment options for acromegaly.

A
  • Pituitary surgery
  • Medical therapy
  • Radiotherapy
150
Q

Talk about transsphenoidal pituitary surgery.

A

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
Q

Talk about the surgery as primary therapy for acromegaly.

A
  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
Q

What are the possible complications of pituitary surgery?

A

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
Q

Talk about radiotherapy in pituitary surgery (acromegaly and prolactinoma??)

A

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
Q

Talk about pituitary radiotherapy.

A

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
Q

Talk about medical therapy for acromegaly

A
  • Dopamine agonists – cabergoline
  • Somatostatin analogues
  • Growth Hormone receptor antagonist

(Dopamine and Somatostatin both inhibits the production of growth hormone)

156
Q

Talk about dopamine agonist in treating acromegaly.

A
  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
Q

Talk about somatostatin analogues.

A
  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
Q

What is an example of a growth hormone receptor antagonist?

A

Pegvisomant

half-life >70 hours
* subcutaneous administration
Ø serum GH cannot be used as
a disease marker
Ø cross-reacts in GH assays

159
Q

acromegaly summary?

A

*significant morbidity and mortality
*often insidious onset
*effective treatment essential
*pituitary surgery mainstay of therapy
*medical management improving

160
Q

Talk about prolactinoma.

A

Incidence 10 per 100,000
Women&raquo_space; men
Prevalence 90 per 100,000
Lactotroph cell tumour of the pituitary

161
Q

What are the clinical features of prolactinoma?

A

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
Q

What is prolactinoma?

A

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
Q

Talk about Hyperprolactinaemia.

A

> 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
Q

What is the management of prolactinoma?

A

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
Q

Talk about prolactinoma summary.

A
  • Cause of infertility and hypogonadism
  • Galactorrhoea
  • Careful drug history
  • Mainstay of management is medical
166
Q

Why is diabetes a public health issue?

A

> 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
Q

Why is type 2 diabetes a public health issue?

A

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
Q

Amount of people in England with diabetes?

A

3.8 million

169
Q

Talk about the trend in diabetes prevalence.

A

Primary prevention: incidence of condition decreases

Secondary prevention: % of incident cases diagnosed increases

Tertiary prevention: survival from diagnosis increases

170
Q

Relate the relationship between the risk of diabetes and BMI

A

The higher the BMI, the higher the risk for diabetes

171
Q

How can we reduce the impact of type 2 diabetes?

A

> identifying people at risk of diabetes
preventing diabetes (“Primary” prevention)
diagnosing diabetes earlier (“Secondary” prevention)
effective management and supporting self-management (“Tertiary” prevention)

172
Q

What are the Lifestyle and environmental factors that increase the risk of diabetes?

A
  • Sedentary job, sedentary leisure activities
  • Diet high in calorie dense foods/low in fruit and vegetables, pulses and wholegrain
  • “Obesogenic” environment
173
Q

Talk about the obesogenic environment

A

> 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
Q

What are the “steep slope”, “ineffective brakes” and “accelerator” of the weight gain train?

A

Obesogenic environment = steep slope

Knowledge, prejudice, physiology = ineffective brakes

Vicious cycles of mechanical dysfunction, psychological impact, ineffective dieting, low socioeconomic status = accelerators

175
Q

What are the mechanisms that maintain overweight?

A

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
Q

What are the known risk factors that may already be recorded in a clinical record?

A

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
Q

Is screening test the same for pre-diabetes and diabetes?

A

yes

178
Q

What are the currently available screening test for IGT (Impaired Glucose Tolerance) and IFT (Impaired Fasting Glucose)?

A
  • 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
Q

What are the effective interventions required in preventing diabetes?

A

Sustained increase in physical activity
Sustained change in diet
Sustained weight loss

180
Q

Talk about NICE guideline

A

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
Q

What are the 3 approaches in diagnosing diabetes earlier?

A

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
Q

Talk about the screening for Type 2 diabetes.

A
  • 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
Q

What are the things that NICE Guideline are focusing on diabetes?

A
  • Focus on risk assessment followed by blood tests (HbA1c; FBG)
  • Focus on cost-effective weight loss, diet and physical activity interventions
184
Q

Why is NHS England investing in type 2 diabetes prevention?

A

> 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
Q

How is NHS England investing in type 2 diabetes prevention?

A

“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
Q

Talk about Supporting Self-care for Diabetes.

A

> 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
Q

What is the public health role for diabetes healthcare?

A

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
Q

What are the components of unmet need in diabetes in the public health?

A

> 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
Q

What is the definition of diabetes?

A

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
Q

What are the presenting features of diabetes?

A
  • 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
Q

What are the suggestive features that the diabetes is Type 1 diabetes?

A
  • 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
Q

What are the clinical features of newly diagnosed Type 1 diabetes?

A
  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
Q

What are the suggestive features of Type 2 diabetes?

A

> 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
Q

Can Type 1 diabetes occur at any age?

A

Yes!

Commonest age at diagnosis, 5-15y, but can occur at any age

Relatively rare (prevalence of 3/1000 among children and adolescents)

195
Q

Talk about the genetic probability of Type 1 Diabetes.

A

> 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
Q

Talk about gene in children diagnosed of DM1.

A
  • 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
Q

What are some examples of autoimmune diseases?

A
  1. Hashimoto’s hypothyroidism
  2. Addison’s
  3. Coeliac disease
198
Q

What happens if the diagnosis of type 1 DM is missed?

A

DKA (Diabetic Ketoacidosis might happen)

199
Q

Talk about fat metabolism and the formation of ketone bodies in DM.

A
  • 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
Q

Talk about ketoacidosis.

A
  • 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
Q

What is the definition of Diabetic Ketoacidosis? (DKA)

A
  1. Hyperglycaemia (plasma glucose usually <50 mmol/l)
  2. Raised plasma ketones (urine ketones > 2+)
  3. Metabolic acidosis – plasma bicarbonate < 15 mmol/l
202
Q

What are the causes of Diabetic Ketoacidosis (DKA)?

A
  • Intercurrent illness
    > infection
    > myocardial infarct
  • Treatment errors – stop/reduce insulin dose
  • Previously undiagnosed diabetes
  • Unknown
203
Q

What si the triad of diabetic ketoacidosis (DKA)?

A

> Hyperglycaemia
Ketones
Acidosis

204
Q

What are the clinical features of DKA (the signs and symptoms)?

A

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
Q

Talk about the biochemical diagnosis of DKA.

A

> 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
Q

What is the management for DKA?

A
  • 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
Q

What are the complications of DKA?

A
  • 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
Q

What are the aims of treatment in Type 1 Diabetes?

A
  • 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
Q

What are the microvascular complications of DM1?

A
  • Around 30% in the UK will develop diabetic nephropathy
    > CV mortality withno 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
Q

What is the treatment of Type 1 DM?

A

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
Q

Talk about the specific features of DM1 symptoms on:
- Inappropriately high insulin levels confer a high risk of hypoglycaemia

A
  • 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
Q

Talk about the different spectrum of hypoglycaemia.

A

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
Q

What is SMBG snapshot?

A

Self-monitoring Blood Glucose Snapshot

214
Q

Talk about the benefits and risks of tight glucose control.

A

Tigh glucose control can decrease the risk of retinopathy but increase the risk of hypoglycaemia.

215
Q

What is the dilemma for those with Type 1 Diabetes Mellitus?

A

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

Phase 2A (11 decks)

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