Pancreas and Insulin

The normal blood glucose in the body is 4-6mM and is controlled by pancreatic hormones insulin and glucagon.
It is important to control these as certain organs like the brain can only use glucose as a respiratory substrate.
- Normally glucose à broken down by glycolysis à enters Krebs cycle à oxidative phosphorylation.
- Cells can also metabolize fat à produces reduced FAD/NAD which enter oxidative phosphorylation.

But some organs like the brain cannot break down fat and instead use ketone bodies which are made in the liver.
- Acetyl CoA + Acetyl CoA à Acetoacetyl CoA àHMG-CoA à Acetyl CoA + Acetoacetyl CoA

These ketone bodies are an alternative fuel source – They are Acetone, Acetoacetate and B-hydroxybutyrate.

Insulin release:
- This is a peptide hormone which is synthesized in the b-cells in the islets of
Langerhans in the pancreas.

- When blood glucose increases, more glucose enters the cells through
GLUT2 channels à more glycolysis occurs à increase in cell ATP

- ATP binds to K channels (which is attached to sulphonylurea receptor)

ATP

closing them à leads to cell depolarisation

- Voltage gated Ca channels open à increase in exocytosis of insulin.

2+

There are many factors which affect insulin release in the body:
i) Cephalic phase – parasympathetic stimulation (using Ach) of Beta-cells promotes anticipatory
insulin release before consuming a meal
ii) Blood glucose – insulin levels rise if [glucose] > 5mM
iii) Incretins – GIP and GLP-1 are stomach hormones released in response to oral glucose. These
stimulate insulin release and inhibit glucagon.
- These are broken down by enzyme dipeptidyl peptidase 4 (DPP-4)
iv) Sympathetic stimulation – it inhibits insulin release, allowing blood glucose to increase in exercise.

Insulin actions:
Insulin exerts its effect by binding to the insulin receptor – a tyrosine kinase linked receptor.
- Acts through messenger Akt2 which aims to reduce blood glucose and increase storage as glycogen and fat.

Muscle:
- Promotes glucose uptake by translocation of GLUT4 to
membrane + glucose metabolism and glycogenesis
- Stimulates amino acid uptake and protein synthesis

Fat:
- Promotes glucose uptake and conversion to fat
- Inhibits fat breakdown and promotes fat uptake

Liver:
- Promotes glycogenesis and fat synthesis
- Inhibits gluconeogenesis and glycogen breakdown.
à Glucagon:
On the other hand, glucagon is produced by the a-cells in the islets of Langerhans. It works to ­ blood glucose
and fatty acids, acting as the main catabolic hormone of the body
Release: Produced by the pancreas when concentration of insulin and glucose in the bloodstream falls too low.
- Stimulated by hypoglycaemia and adrenaline but inhibited by insulin and hyperglycaemia

Actions: Promotes gluconeogenesis + glycogenolysis in the liver raising free blood glucose
- Decreases fatty acid synthesis + promotes lipolysis in liver and adipose for use by skeletal muscle.
Thyroid gland
This is an endocrine gland in the neck. It is made of two lobes joined together by an isthmus. It is made up
of two types of cells which control metabolic rate and calcium levels in the body.

a) Parafollicular cells – secrete Calcitonin, which antagonizes effects of PTH

- Decreases plasma [Ca ] by decreasing bone breakdown by inhibiting
2+

osteoclasts whilst promoting osteoblasts

b) Follicular cells – produce thyroid hormones, triiodothyronine (T ) and 3

thyroxine (T ) – tyrosine based hormones partially composed of iodine.

4

- Mainly produces T which is 5x less active than T – 85% of T is made from

4 3 3

peripheral conversion of T 4

Thyroid hormone synthesis:

Hypothalamus releases thyrotropin releasing hormone
(TRH) which stimulates Thyroid stimulating hormone (TSH) and prolactin Thyroglobulin
from anterior pituitary. Thyroid
Peroxidase
Thyroid hormone is made in follicles by the iodination of tyrosine residues Iodinated
from a precursor called thyroglobulin, using the enzyme thyroid peroxidase. thyroglobulin
- This is iodinated with 2 iodides to give T which can then be deiodinated to
4

T by the enzyme 5’-deiodinase

3
T4

Control of synthesis is from the hypothalamus via the HPT axis. De-iodinase
- T exerts short and long negative feedback loops self-regulating release.
3 T3

Thyroid hormone actions:

Thyroid hormones travel in the blood bound to thyroxine binding globulin.
- T converted to T by enzyme deiodinase àT has a half-life of 7 days, but T is only 1 day
4 3 4 3

- These bind thyroid hormone receptors in the nucleus of all cells,

which initiates transcription of specific genes to exert many
different effects:

Metabolic – Increase basal metabolic rate of all tissues

- Increase body sensitivity to catecholamines (e.g. adrenaline)
- Increase absorption in the gut and uptake of cells
Cricoid
- Increase glucose and fat breakdown + free fatty acids
Cartilage
Cardiovascular – Increase rate/strength of heartbeat + breathing
- Increase heat generation and body temperature

Development – Facilitate growth rate with growth hormone

- Facilitate normal brain development in fetus and early life

Sexual function – Maintain sexual function, sleep and thought Parathyroid

Glands
Parathyroid gland
The Parathyroid Glands are 4 tiny glands that are located behind the thyroid in the anterior mediastinum.

Function: Maintain the body’s calcium and phosphate levels

- This is achieved through the secretion of Parathyroid Hormone (PTH)

Release: Secreted in response to decreased plasma Ca 2+

Actions: PTH acts on the bone and the kidney.

- Increases [Ca ] by stimulating bone resorption by osteoclasts and reabsorption by kidney.
2+

- Causes a net decrease in PO by increasing phosphate excretion by kidney despite bone resorption.
4
3-
Adrenal Gland
The adrenal gland is split into the adrenal medulla and the cortex, which itself is subdivided into 3 sections.
The glands are found above the kidneys and are supplied by superior, middle and inferior adrenal arteries.

Medulla – This is at the centre of each adrenal gland.

- Made up of chromaffin cells producing noradrenaline (20%) and adrenaline (80%)
- Driven by sympathetic preganglionic fibres which synapse in medulla
- Considered a specialised sympathetic ganglion which releases secretions into the blood.

Cortex – This is the outermost layer of the adrenal gland which is split into 3 zones:
i) Zona glomerulosa
This is the outermost zone of the adrenal cortex.
- This is responsible for the production of aldosterone, a mineralocorticoid, which is made
by the enzyme aldosterone synthase.
- This is part of the renin-angiotensin system and acts to increase blood pressure by increasing reabsorption
of sodium from the kidneys.

ii) Zona fasciculata

This is situated between the zona glomerulosa and reticularis.
- It is the largest layer of the adrenal cortex.
- Responsible for producing glucocorticoids like cortisol through the HPA axis.

Cortisol synthesis is stimulated by the release of corticotrophin-releasing factor

from the hypothalamus.
- Stimulates production of ACTH from anterior pituitary gland
- This acts on the adrenal cortex to directly stimulate cortisol synthesis and some
mineralocorticoid release.

Cortisol exerts its effects by binding the glucocorticoid receptor within nuclei and
causing transcription of specific genes.

Metabolic actions: Immune Actions:

i) Counters insulin – increases i) Decreases T and B cell proliferation
gluconeogenesis and decreases uptake ii) Decreases production of inflammatory
by fat/muscle increasing blood glucose cytokines IL-12 and TNFa
iii) Increases production of anti-
ii) Increases protein breakdown and inflammatory cytokines IL-10
reduces protein synthesis iv) Switches from Th1àTh2 response

Other actions: Cortisol also changes one’s mood and suppresses reproductive function.
- Inhibits bone formation and collagen synthesis in the skin and stimulates gastric acid secretion

Because the steroid has these actions, prolonged exposure to steroids has a number of side effects:
- Infection, due to immunosuppression - Muscle wasting due to protein catabolism
- Poor wound healing - Thinning of the skin
- Osteoporosis, due to osteoblast inhibition - Weight gain
- Hyperglycaemia (steroid-induced diabetes) - Cataracts and Glaucoma

Steroid use also suppresses the HPA due to its negative feedback actions, so sudden withdrawal is avoided.
This is because it can lead to adrenal insufficiency, as patients cannot synthesise their own steroids.

iii) Zona reticularis

This is the innermost layer of the adrenal cortex, which produces precursor androgens including DHEA and
androstenedione from cholesterol.
- These precursors can be converted in the adrenal cortex or are released into the blood stream where they
are taken up by testes/ovaries and made into testosterone and estrogen.
- ACTH partially regulates adrenal androgen secretion and so is seen as a permissive factor.
Pituitary gland
The pituitary gland is one of the most important endocrine glands in the body. It interacts with the
hypothalamus which stimulates the production of hormones from the pituitary. It is split into 2 parts:

• Posterior pituitary
This is a down-growth of the brain contained within the blood brain barrier which releases 2 hormones:
a) ADH – controls the water content on the body by influencing water reabsorption from collecting duct.
- Binds V1 receptors on artieroles (vasoconstriction) + V2 receptors on collecting duct
N.B. Ethanol inhibits ADH secretion, explains why you need to urinate (“Break the seal”)

b) Oxytocin – responsible for the milk ejection reflex; acts in the mammary glands to release milk
- Uterine contractions; important for cervical dilation before birth and labour contractions

• Anterior pituitary
This lies outside the blood brain barrier and is made up of hormone producing cells.
It is stimulated by hormones released into the portal blood circulation and then it
releases hormones into the blood stream.

i) TSH – thyroid stimulating hormone acts on thyroid gland resulting in release

of T and T
3 4

ii) ACTH – acts on adrenal cortex to cause release of glucocorticoids and

mineralocorticoids.

iii) Prolactin – Secretion is stimulated by PRF (prolactin releasing factor)

- Secretion is inhibited by tuberoinfundibular (TIDA) dopamine neurones
- Causes enlargement of mammary glands during pregnancy
- Stimulates mammary glands to produce milk and plays an important role in
maternal behaviour.
- Contributes to pulmonary surfactant synthesis and neurogenesis

iv) FSH/LH – These sex hormones act on the testes and ovaries
- This results in sexual maturation by forming testosterone and oestrogen.
- Regulated by GnRH secretion from the hypothalamus which is produced in quantities during puberty.

Males: FSH binds Sertoli cells whereas LH binds Leydig cells.

- In puberty, FSH stimulate primary spermatocytes to undergo meiosis, to form secondary spermatocytes.
- LH increases testosterone which responsible for secondary characteristics and sperm production.

Females: FSH initiates follicular growth whereas LH triggers ovulation.

v) Growth hormone
This is a hormone which is secreted by somatotrophs in response to hypoglycaemia, low free fatty acids
and high amino acids.
- Secretion stimulated by GnRH produced by the hypothalamus
- Secretion inhibited by somatostatin produced by delta cells of pancreas – this inhibits GH and TSH from
the pituitary and release of VIP + glucagon + insulin from pancreas.

It has many effects both on metabolism and growth:

Metabolic – Stimulates gluconeogenesis and lipolysis

- Reduces glucose uptake from fat and muscle raising blood [glucose]
- Increases protein synthesis and conversion of T à T
4 3

Growth – It acts by stimulating production of IGF-1 in the target tissues.

- It stimulates osteoblast and chondrocytes to promote bone growth.
- Insulin is a permissive factor – hence you do not grow in starvation.
 DRUGS AFFECTING BLOOD SUGAR

a) Drugs which reduce blood glucose

• Insulins – These are versions of normal insulin which are given by subcutaneous injection.

There are many different forms of insulin, which have different half-lives:
Rapid o Insulin glulisin + insulin aspart + insulin lispro – these are rapidly acting

Regular o Regular insulin – this is a recombinant form of human insulin.

- Must deliver to patients using an insulin syringe, as in normal syringe there are 100units/ml

Intermediate o Neutral Protamine Hagedorn – this is intermediate acting. It is a suspension of insulin-zinc

complexes with protamine which slows absorption.

Long o Ultralente insulin + Detemir + Glargine – long acting. They have changes to the amino acid
sequence which delays absorption

Side effects:
- Overdose can result in hypoglycemia
- Hypokalemia
- Weight gain + lipodystrophy (fat build up) at the injection site

• Metformin
This reduces gluconeogenesis and increases peripheral insulin sensitivity.
- Also acts to decrease the intestinal absorption of glucose
- It does not depend of functioning b-cells as it exerts most its effects at the liver
- Taken as a tablet and safe to use if breastfeeding
- Metformin is good in that it rarely causes hypoglycemia or weight gain on its own.

Side effects:
- Lactic acidosis in renal failure patients due to decreased drug excretion or in liver failure patients
- GI upset --> if this occurs, switch to the modified release tablet

• Sulphonylureas – These drugs bind to the SUR1 receptor on K channels on the beta-cells closing
ATP

them, mainly increasing insulin release and also increasing tissue insulin sensitivity

1 generation:
st

o Tolbutamide – this is a short acting sulphonylurea

o Chlorpropamide – long acting which used in the treatment of Neurogenic diabetes insipidus
as it potentiates ADH action at V2 receptors.
- However, it is long acting and has highest chance of hypoglycemia, produces SIADH and
has disulfiram-like reactions with alcohol.

2nd generation:
o Glipizide – this is an intermediate acting drug.

3 generation:
rd

o Glimepiride – this is a long acting sulphonylurea.

These drugs are very useful in treating type II diabetes but are not effective against type 1 diabetes.

Side effects:
- Hypoglycemia – proportional to how long the drug acts for
- Weight gain
- Not used in pregnancy as can cross the placenta
- Some can cause SIADH leading to hyponatreamia
- People develop tolerance due to downregulation of sulphonylurea receptors.
• Meglitinides – Repaglinide
These drugs also block K channels causing an increase in insulin secretion.
ATP

- It is a very fast acting drug which is used to limit post-prandial hyperglycemia

- Also used in people with sulpha-drug allergies

Side effects: Hypoglycemia + Weight Gain

• Thiazolidinediones – Pioglitazone + Rosiglitazone (-glitazone)

These PPAR-y agonists increase tissue sensitivity to insulin and activate hormone adiponectin
- They also act on muscle and fat to increase glucose uptake and lipogenesis
- Therefore they reduce plasma glucose but do not cause hypoglycemia.

Side effects: Exacerbate congestive heart failure due to fluid retention

- Osteoporosis - Bladder Cancer - Weight Gain

• Alpha-glucosidase inhibitors – Acarbose + Miglitol

These inhibit amylase and glucoside enzymes which break down starch in the intestines
- Therefore, act to reduce the absorption of glucose into the bloodstream

Side effects: Flatulence --> Not used in IBD or Liver cirrhosis

• Incretins – Exenatide + Liraglutide

These are synthetic versions of GLP-1 which reduce appetite, taken by subcutaneous injection
- Acts by increasing insulin secretion, decreasing glucagon secretion and decreasing appetite

Side effects: Sickness + Pancreatitis - Also cause weight loss

• DPP-4 inhibitors – Sitagliptin, Saxagliptin (-gliptin)

-These inhibit the DPP-4 enzyme which breaks down the incretins GLP-1 and GIP

Side effects: Indirectly cause sickness + pancreatitis - Also cause weight loss

• Amylin analog – Pramlintide

This is a polypeptide stored and secreted by B-cells which acts with insulin to reduce blood sugar
- Treats type 1 and 2 diabetes by slowing gastric emptying and decreasing glucagon secretion.

• SGLTI (selective sodium glucose transporter 2 inhibitor) – Empagliflozin (-gliflozin)

- Blocks glucose reabsorption in the kidneys to promote excretion of excess glucose in urine

Side effects: Genital infections/UTI due to increased glucose in urine + Diabetic Ketoacidosis

b) Drugs which increase blood glucose

• Glucagon
This is a hormone which is made by the alpha cells of the pancreas and is gluconeogenic
- It used to rescue people from hypoglycaemic crisis acting to increase the serum glucose concentration
- Has minimal side effects

• Diazoxide
This is a potassium channel opener that binds and opens ATP-sensitive K channels in the b-cells
+

causing hyperpolarization --> inhibits insulin release.

- Used to treat hypoglycemia secondary to an insulinoma
- Also used as a potent vasodilator used in hypertensive emergency
DRUGS AFFECTING THYROID
The levels of thyroid hormone must be carefully balanced within the body as an excess/shortage of thyroid
hormone can have significant problems. There are drugs which both increase and decrease thyroid levels.

a) Pro-thyroid drugs
These drugs are synthetic analogues which aim to mimic the effects of normal thyroid hormone.

• Levothyroxine
This is a synthetic sodium salt of T (thyroxine) that maintains normal T and T levels.
4 4 3

- It is the first drug of choice in hypothyroidism.

• Liothyronine
This is a recombinant form of T which is used to treat hypothyroidism.
3

Side effects: Can produce hyperthyroidism --> nervousness, anxiety and headache
- Induce arrhythmias and angina in patients with underlying cardiovascular disease.

b) Anti-thyroid drugs
These drugs aim to reduce the effects of an excess of thyroid hormone in the body, either by inhibiting
the synthesis of thyroid hormone, or blocking its release.

• Thioamides
These interfere with the coupling of iodide ions to thyroglobulin by inhibiting the peroxidase enzyme,
and so inhibit the synthesis of thyroid hormone.

o Propylthiouracil (PUT)
- Also inhibits the conversion of T à T by inhibiting 5’- deiodinase.
4 3

- Can be used during pregnancy and is short acting

- Associated with hepatic toxicity

o Methimazole
- Works only by inhibiting the peroxidase enzyme and is long acting
- Cannot be used during pregnancy as it causes aplasia cutis (congenital absence of skin)
- Sometimes sold as a pro-drug called Carbamizole

Side effects: Associated with agranulocytosis and aplastic anaemia

- Therefore, these drugs need constant monitoring with blood tests to measure FBC

• Anion inhibitors – Thiocyanate, perchlorate, fluoborite (-ate)

These are small anions which are similar to iodide, and competitively inhibit the transport of iodide
ions by the thyroid gland à inhibit thyroid hormone synthesis

Side effects: Severely toxic causing aplastic anaemia – therefore discontinued

• Iodide
In high concentrations, iodide inhibits many steps in thyroid hormone synthesis/release
- Also helps to reduce the size of the thyroid gland
- This is known as the Wolff-Chaikoff effect – temporary inhibition of peroxidase enzyme
- It is commonly used before thyroid surgery to decrease thyroid tissue size and decrease vascularity,

Side effects: Angioedema + metallic taste + hypersensitivity reactions

• Radioactive iodine ( I)
131

This is transported and gets concentrated in the thyroid gland and emits toxic beta-particles.
-Used to kill thyroid follicular cells non-surgically as a treatment for hyperthyroidism

Side effects: Overdose can produce hypothyroidism

DRUGS AFFECTING CACLIUM HOMEOSTASIS
These drugs aim to mimic/antagonize the endogenous hormone PTH to maintain calcium homeostasis.
- The regulation of calcium is especially important as calcium phosphate is a large component of bones:
- In osteoporosis, bone turnover increases so that bone resorption is greater than bone formation, due to
increased activity of osteoclasts.

a) Increase plasma [Ca ] 2+

• Teriparatide
This is a recombinant version of parathyroid hormone which is a full PTH agonist
- Intermittent exposure results in net bone formation --> used to treat osteoporosis
Side effects: Hypercalcemia + osteosarcoma

• Calcipotriol
This is a synthetic form of active vitamin D made by the kidney (1,25-DHCC).
- Vitamin D usually acts to increase calcium reabsorption from the kidney and small intestine.
- In reality, this drug actually has few effects on Calcium homeostasis
- Instead it is used as a topical cream to treat skin disorders like psoriasis.

• Calcium/cholecalciferol
This is a combination of calcium salt and vitamin D .
3

- Used to increase serum Ca in hypocalcaemia + Vitamin D deficiency

2+

- Used to treat calcium deficiencies in the elderly and osteoporosis.

b) Decrease plasma [Ca ] 2+

• Bisphosphonates – Alendronate + Etidronate (- dronate)

These are analogues of pyrophosphate (P-O-P) that bind directly to hydroxyapatite (inorganic salts) and
stop the resorption of bone by osteoclasts.
- They are first line drugs both in the prevention and treatment of osteoporosis and hypercalcemia

Side effects:
- Corrosive oesophagitis if patients do not take the drug with water and remain upright for 30 minutes
- Atypical stress fractures (especially of the proximal femoral shaft)

• Calcitonin
This is released by the parafollicular C-cells of the thyroid gland
- Interacts with osteoclasts to stop reabsorption of calcium from bone
- It reduces hypercalcemia due to Paget disease and hyperparathyroidism
- It is used as a marker of Medullary Carcinoma: a thyroid cancer that presents with localized
amyloidosis due to polymerization of pro-calcitonin into b-sheets.

• Denosumab
This is a monoclonal antibody which blocks the action of RANK ligand
- RANK ligand usually ligand binds to RANK receptor and promotes osteoclast activity
- This therefore reduces osteoclast activity --> treats osteoporosis
- Used in post-menopausal women who are intolerant to other drugs or have renal failure.
+ -
• Cinacalcet Ca 2+
CaSR PTH
The parathyroid gland senses calcium via protein CaSR +
- This drug activates CaSR which reduces the serum PTH Cinacalcet
- Acts to decreased plasma Ca to treat hyperparathyroidism.
2+

N.B. It is important to remember that several drugs indirectly affect Calcium homeostasis too:
- Thiazide diuretics --> reduce renal Ca excretion
2+

- Loop diuretics --> increase renal Ca excretion

2+

- Glucocorticoids increase bone resorption and stop absorption in intestine --> net decrease in calcium
- Oestrogens impair action of PTH --> used in the treatment of osteoporosis
DRUGS AFFECTING POSTERIOR PITUITARY GLAND

a) ADH (Vasopressin) affecting drugs

• Desmopressin
An ADH mimic that is the most effective treatment for neurogenic diabetes insipidus
- It has higher activity on V2 receptors in collecting tubule rather than V1 receptors
- Not effective for nephrogenic form of diabetes insipidus
- Also used for nocturnal enuresis by reducing night-time urine production
- Treats Von Willebrand disease as it stimulates production of Factor VIII

• Terlipressin
This is an ADH mimic with a higher affinity for V1 receptors.
- It causes vasoconstriction of arterioles especially supplying the gut.
- Used to treat noradrenaline resistant hypotension and portal hypertension.

• Vaptans – Conivaptan + Tolvaptan

These are antagonists of ADH receptors, which are used to treat SIADH
- Conivaptan blocks both V1a and V2 receptors non-specifically to treat SIADH
- Tolvaptan is a selective V2 receptor antagonist to treat SIADH

b) Oxytocin drugs
• Oxytocin – Used for the induction and maintenance of labour as stimulates uterine contraction
- Also stimulates milk ejection from the breast
- First line drugs to control postpartum uterine bleeding

Side effects: As very similar to ADH, can cause water reabsorption + hypertension

DRUGS AFFECTING ANTERIOR PITUITARY GLAND

a) Drugs influencing Prolactin

Prolactin secretion is also affected by drugs used on the central nervous system which affect dopaminergic
activity. These will include antipsychotics + Antidepressants + Anxiolytics

As prolactin secretion is inhibited by Dopaminergic neurones, drugs which try to decrease prolactin
secretion often try to stimulate the dopaminergic system.

• Bromocriptine + Cabergoline
These are dopamine D agonists which can act within the central nervous system
2

- They are used to inhibit prolactin secretion in prolactin-secreting tumours and galactorrhoea

b) Drugs influencing Growth Hormone

• Somatotropin
These is a synthetic version of growth hormone which is administered via injection
- Used to stimulate growth in replacement therapy in people with GH deficiency and Turner syndrome

• GH antagonists – Pegvisomant
This is a GH antagonist that is used specifically for the treatment of acromegaly.
- It opposes the actions of growth hormone but will not help to shrink the pituitary tumour.

• Somatostatin analogs – Octreotide + Lanreotide (longer-acting analog)

- These mimic the role of somatostatin to inhibit growth hormone release
- Used to treat acromegaly
- Also used to counter diarrhea through the inhibition of GI secretions, slowing of GI motility and
inhibition of gallbladder secretion.
- Used to treat VIP-secreting tumours like gastrinoma, glucagonoma

Side effects: Vitamin B Deficiency due to decreased release of intrinsic factor

12
 DRUGS AFFECTING THE ADRENAL CORTEX
The most important drugs used are corticosteroids which aim to mimic or block the effects of the natural
glucocorticoid (cortisol) and mineralocorticoid (aldosterone).
- In illness, patients usually double the corticosteroid dose but keep mineralocorticoid dose the same

a) Mineralocorticoid mimics
These primarily affect the kidney, regulating salt and water balance and increasing Na retention +

- They are used in replacement therapy to maintain electrolyte and fluid balance in hypoaldosteronism

• Fludrocortisone
This is used for long-term mineralocorticoid replacement.
- Used in Addison’s disease and congenital adrenal hyperplasia

Side effects: Sodium retention leading to hypertension + hypokalaemia

b) Glucocorticoid mimics
These drugs have a variety of uses:
- Used for replacement therapy for primary/secondary insufficiency
- Anti-inflammatory actions to settle down the immune system in hypersensitivity disorders
- Immunosuppression for autoimmune diseases
- Reduction on intracranial pressure in tumours and infections

There are several different types of corticosteroids which mimic the effects of cortisol.

• Short-acting – Hydrocortisone (1 drug of choice for replacement therapy)

st
Less gluc
ENC
Y • Intermediate acting - Prednisolone More Min ocorticoid
POT eralocort
icoid
• Long-acting - Dexamethasone

Side effects:
- Adrenal suppression - Hyperglycaemia including steroid-induced
- Hypertension diabetes and weight gain
- Peptic ulcer – increase gastric acid secretion - Poor wound healing
- Muscle breakdown - Cataracts and glaucoma
- Osteoporosis - Steroid-induced psychosis

It is advisable to take steroids in the morning as they have an awakening effect which can lead to insomnia.
- Patients stopping long-term glucocorticoid therapy must be weaned of the drug slowly, to allow for
adrenal recovery and prevent them from going into an Addisonian crisis.
(1)

1.
Barbot M, Ceccato F, Scaroni C. Diabetes Mellitus Secondary to Cushing’s Disease. Front Endocrinol (Lausanne). 2018;9.
doi:10.3389/fendo.2018.00284
Endocrine tests and investigations

i) Capillary blood glucose

This refers to a one-off blood test which measures the circulating glucose level in your blood.
- It is important to know whether the patient is fasting or non-fasting when interpreting the results.
- If fasting à Normal range = 3.9-7.1mM

Impaired Fasting Glucose (IFG) = fasting glucose sample >6.1mM but <7.0mM

ii) Oral Glucose Tolerance Test (OGTT)

This is a test which measures the body’s ability to metabolise a glucose load. It specifically tests the ability
of the pancreas to release insulin and how responsive the tissues are to this hormone.
- A fasting blood glucose is taken followed by a 75g glucose load.
- The blood glucose is then repeated 2 hours later.

Impaired Glucose Tolerance (IGT) = OGTT > 7.8mM but <11.1mM

iii) HbA1c
This is a measure of the glycosylated haemoglobin in the bloodstream.
- HbA1c is proportional to glucose concentration in the blood.
- It is used to measure the average blood glucose over the past 2-3 months.
- It is used to measure glycaemic control in those with DM every 3-6 months until stable then 6 monthly.

The level of HbA1c is dependent on blood glucose but also affected by RBC lifespan, therefore:
- Conditions which ¯RBC life span give a lower than expected HbA1c e.g. haemolytic anaemias.
- Conditions which ­the RBC life span give a higher than expected HbA1c e.g. megaloblastic anaemia,
iron deficiency anaemia, or splenectomy.
- May also get a raised HbA1c from people taking medication that causes hyperglycaemia e.g. steroids.

iv) Thyroid Function Tests

These principally measure free T and T as well as TSH.
4 3

- If hyperthyroidism suspected à Ask for suspected T , T and TSH. All have decreased TSH due to negative
3 4

feedback with raised T 4

- If hypothyroidism suspected à Ask for only T and TSH. TSH is raised with low T
4 4

Condition TSH T4

Primary Hyperthyroidism ¯ ­
Primary Hypothyroidism ­ ¯
Secondary Hypothyroidism (rare) ¯ ¯
Sick Euthyroid syndrome ¯/normal ¯
Subclinical Hypothyroidism ­ Normal
Poor thyroxine compliance ­ Normal
Steroid Therapy ¯ Normal

Other tests:
- Thyroid antibodies – antithyroid peroxidase or antithyroglobulin antibodies seen in autoimmune disease

- TSH receptor antibody – increased in Graves’ disease

- Serum thyroglobulin – useful in monitoring treatment of carcinoma

- Ultrasound scan – distinguishes cystic from solid nodules

- Isotope scan – used to detect the cause of hyperthyroidism and to detect thyroid nodules/metastases
Diabetes
This is a condition which results from a lack of, or reduced effectiveness of endogenous insulin. There are two
main types of diabetes mellitus, as well as some other rarer causes.

• Type 1 Diabetes
This is insulin deficiency due to an autoimmune destruction of pancreatic B-cells
- T lymphocytes attack islets, with autoantibodies against insulin present
- It is associated with HLA-DR3 and HLA-DR4
- The disease usually manifests in adolescence, sometimes after a viral infection.

Symptoms: Hyperglycemia – low insulin leads to decreased glucose uptake by fat and muscle
- Weight loss, low muscle mass – unopposed glucagon leads to lipolysis and glycogenolysis
- Polyuria, polydipsia and glycosuria

Management:
1) Insulin therapy – twice-daily insulin detemir is the regime of choice (2x long-acting)
- 2 line, once-daily insulin glargine or insulin detemir
nd

2) Monitor HbA1c every 3-6months – target of <48mM

3) Self-monitoring glucose – test this 4 times/day, before and after each meal + before sleep
- More frequency monitoring in illness, sport, pregnancy and breastfeeding
- Target = 5-7mM (Waking) 4-7mM (before meals)
4) Metformin – consider adding if BMI > 25kg/m 2

5) Glucagon kit – given to all patients in case of hypoglycaemic crisis

There are several complications which are associated with Type 1 diabetes, which can be life threatening:

Ø Diabetic ketoacidosis
This is an emergency which is characterized by severe hyperglycaemia and severe acidosis, seen in diabetes.
- Due to the body being in starvation like state and excessive ketone body production.

Symptoms –Drowsiness + dehydration + Unexplained vomiting

- Ketotic breath, coma
- Deep breathing (Kussmaul hyperventilation)

Diagnosis – Acidaemia (Venous pH <7.3 or HCO3- >15mM)

- Hyperglycaemia (glucose >11mM) or known diabetic
- Ketones >3mM or >2 on a urine dipstick

Management – Use the ABC approach

i) Start fluid infusion 1L 0.9% saline
ii) Add insulin – IV infusion at 0.1 unit/kg/hour
- If on insulin, continue long-acting insulin, stop short-acting
iii) Monitor blood glucose and ketones hourly
iv) Dextrose solution – once [glucose] < 15mM, add 5% dextrose to prevent hypoglycaemia
v) Monitor Potassium – insulin forces K into cells, so give potassium to reduce hypokalaemia
+

Complications:
- Arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
- Cerebral oedema --> seen more in children/young adults, occurs 4-12 hours usually after treatment
--> Gives headache, confusion, visual disturbances due to raised ICP

Ø Impaired Hypoglycaemia Awareness

Long standing hyperglycaemia can lead to neuropathy of the autonomic nervous system.
- This is the leading cause of impaired hypoglycaemic awareness in diabetic patients
- Awareness is also reduced by usage of b-blockers
 • Type 2 diabetes
This is end-organ insulin resistance which is the most common form of diabetes.
- Arises in middle aged, obese adults due to decreased number insulin receptors.
- Later insulin deficiency develops due to b-cells exhaustion

Causes: Obesity, lack of excessive + alcohol excess

- Stronger genetic influence than type 1 – high in Asians, men and the elderly

Symptoms: Initially clinically silent, but then similar symptoms to Type 1 in later disease

Diagnosis:
The diagnosis of diabetes mellitus can be made using plasma glucose or a HbA1c sample . 1

- Plasma glucose or HbA1c must show evidence of diabetes of two separate occasions if asymptomatic:

1) Fasting glucose > 7.0 mmol/L If patient is asymptomatic, then these have to be
2) Random glucose/OGTT > 11.1mmol/L shown on two separate occasions
3) HbA1c > 48mmol/mol (6.5%)

Management: NICE 2015 guidelines for management . 2

DIET
1) If HbA1c rises to 48mM
>48mM
- Lifestyle modifications – diet, weight control + exercise

2) If HbA1c stays above 48mM METFORMIN

- Commence Metformin – aim for HbA1c < 48mM
>58mM
3) If HbA1c rises >58mM
METFORMIN
- Add sulphonylurea or DPP–4 inhibitor + 1 of + DPP-4i
or Thiazolidinedione or SGLT-2 inhibitor Or SGLT-2i
Or Sulphonylurea
+ 2 of
4) If HbA1c stays >58mM Or Thiazolidinedione
- Add 3 drug (metformin + 2 of previous)
rd

>58mM (persistent)
5) If not effective/tolerated and BMI>35 kg/m 2

METFORMIN
- Try metformin + Sulphonylurea + GLP1 mimic + INSULIN
6) If still not controlled à commence insulin therapy (but continue metformin)

In addition to Type 1 and 2 diabetes, there are a few variant types of diabetes.
o Latent autoimmune diabetes of adults (LADA) – a form of type 1 DM, but with slower progression
to insulin dependence in later life.

o Maturity Onset Diabetes of the Young – autosomal dominant mutation in HNF1A gene
- Leads to poor production of insulin, causing T2DM symptoms in much younger patients
Treatment - Sulphonylureas

o Gestational diabetes – transitory form caused by pregnancy associated hormonal changes

o Prediabetes – Used for patients who do not meet the criteria but are likely to develop condition soon
- HbA1c of 42-47mmol/mol or Fasting Glucose of 6.1-69mM

o Secondary diabetes – this can be due to conditions that affect blood glucose and/or insulin:
- Pancreatitis – damage to insulin producing cells.
- Hyperthyroidism – thyroid hormone excess
- Acromegaly – GH excess - Cushing’s disease – cortisol excess

1
https://cks.nice.org.uk/diabetes-type-2#!diagnosisSub
2
https://www.nice.org.uk/guidance/ng28/chapter/Key-priorities-for-implementation
One of the biggest problems is that there are several complications associated with these conditions:

Ø Non-enzymatic glycosylation (NEG) of macrovessels – this leads to atherosclerosis

- Causes cardiovascular disease – MI is 4x more common in diabetes and stroke 2x common
- Causes peripheral vascular disease – leading cause of non-traumatic amputations.
- If foot pulses cannot be felt, use Doppler pressure measurements. Ensure regular chiropody to remove
callus to reduce risk of ulcers

Ø Non-enzymatic glycosylation (NEG) of microvessels – leads to hyaline arteriosclerosis

- Causes Nephropathy – nephrotic syndrome characterized by Kimmelstiel-Wilson nodules in glomeruli
- Gives microalbuminuria (when the urine dipstick is negative for protein but the urine albumin:creatinine
ratio is >4mg/mmol)
- Diabetic patients get annual screening to measuring morning albumin:creatinine ratio

Ø Diabetic retinopathy – glucose enters Schwan cells, the lens and retinal blood vessels damaging them
- Results in osmotic damage
- Leads to Cataracts + Rubeosis iridis (new vessels on iris leading to glaucoma)
- Diabetes is the leading cause of blindness in the developed world.

Ø Diabetic peripheral neuropathy - This is loss of sensation which often occurs in the feet
- Patient shows loss of sensation in “stocking” distribution + numbness/tingling
- Also leads to neuropathic deformity e.g. claw toes, Charcot Joint
- Pain is felt, worse at night à 1 line treatment is Duloxetine
st

Ø Diabetic Autonomic Neuropathy

- Causes decreased lower oesophageal sphincter pressure giving GORD (3)
- Can lead to chronic diarrhoae worse at night Charcot Joint
- Gastroparesis --> Bloating and vomiting, alleviated with prokinetic antimimetics

Ø Hyperosmolar Hyperglycaemic State – This is where hyperglycaemia results in osmotic diuresis, severe
dehydration and electrolyte deficiencies.
- High glucose leads to osmotic diuresis with loss of sodium and potassium
- Gives severe volume depletion giving raised serum osmolality (>320mosmol/kg), making blood viscous

Symptoms:
General malaise --> Fatigue, nausea + vomiting
Neurological --> Low consciousness, headaches, papilloedema
Haematological --> MI and peripheral thrombosis (due to hyperviscosity)
Cardiovascular --> Tachycardia + Hypotension (similar to hypovolaemic shock)

Diagnosis:
1) Hypovolaemia
2) Marked Hyperglycaemia (>30 mmol/L) without much ketones or acidosis
3) Significantly raised serum osmolarity (> 320 mosmol/kg)

Management - manage in HDU.

- 1st fluid resuscitation – IV 0.9% sodium chloride solution

- 2nd normalise blood glucose – only give insulin if ketones are high, as fluids will naturally reduce glucose
- If no ketones avoid insulin, as it leads to a rapid decline in glucose and serum osmolality increasing risk
of central pontine myelinosis or cardiovascular collapse

- 3rd replace potassium as required – prevents arrhythmias.

DKA is similar is HHS, so it is important to

differentiate between them.

HHS has higher glucose, less ketones and occurs

much slower (days) than DKA (hours)

3.
J. Terrence Jose Jerome / CC BY (https://creativecommons.org/licenses/by/3.0)
 Ø Hypoglycaemia:
This is the most common endocrine emergency characterized by plasma glucose <3mM.

Causes: Diabetic - Insulin or sulphonylurea treatment e.g. increased activity missed meal, overdose.

Non-Diabetic – The causes of non-diabetic hypoglycaemia are remembered by acronym (EXPLAIN).

The cause can be found by taking drug history , excluding liver failure and monitoring.
EX = Exogenous drugs A= Addison’s
P=Pituitary insufficiency I= Insulinoma
L=Liver failure N=Non-pancreatic neoplasms

Symptoms - Autonomic – sweating, anxiety, tremor, dizziness

Neurological – Confusion, drowsiness, can be confused with a stroke

Treatment - If conscious, 15-20g of fast carbohydrate snack (orange juice) and recheck glucose after 10 min
- If conscious but not cooperative à put glucose gel between teeth and gums
- If unconscious à start glucose IV (10% and 200mL/15min) or glucagon 1mg IM (not in malnourished)
- Once blood glucose >4mM, give long acting carbohydrate e.g. slice of toast.

• Insulinoma
This is a benign pancreatic islet cell tumour which is sporadic or commonly seen with MEN-1
Symptoms – fasting hypoglycaemia with mental status change that is relieved by administration of glucose
Whipple’s triad --> Symptoms associated with fasting/exercise
--> Recording hypoglycaemia with symptoms
--> Symptoms relieved by glucose

Diagnosis – Give insulin and measure C-peptide levels

- This is because exogenous insulin usually inhibits C-peptide production, but not in an insulinoma
- You will therefore find low serum glucose levels in the presence of high insulin and C-peptide

Treatment – Surgical excision

• Paediatric Diabetes – This usually presents as type 1 diabetes, which occurs after a viral infection
Risk Factors: Family history, Genetic susceptibility (associated with HLA-DR3/4)
Symptoms: Increased thirst + urination (wetting the bed), extreme hunger, weight loss, fatigue (insidious symptoms)
- Sudden decline in performance at school - Girls can get genital yeast infection
Diagnosis: Same diagnostic criteria as Diabetes Mellitus in adults – however HbA1c is not appropriate for diagnosis
Management: Insulin therapy and continuous glucose monitoring

• Gestational Diabetes – This is the 2nd most common complication after hypertension
- During pregnancy, the placenta secretes cortisol and progesterone which give insulin resistance causing diabetes
Risk factors: BMI >30, previous gestational diabetes, family history of diabetes + previous big baby > 4.5kg

Symptoms: Increases chance of preeclampsia for mother but also leads to complications for foetus:
- Babies can be large for gestational age (macrosomia) meaning need for caesarean section
- Can also be small with intrauterine growth retardation
- Higher risk of being born with hypoglycaemia, jaundice and polycythaemia

Screening – If previous gestational diabetes, give OGTT at booking scan and at 24-28 weeks if 1st test is normal
- Any woman with risk factors offered OGTT at 24-28 weeks

Diagnosis – Positive if fasting glucose > 5.6mM or 2-hour glucose >7.8mM

Management – See woman in joint diabetes/antenatal clinic within 1 week.

- If fasting glucose < 7, trial diet and exercise à 2nd add metformin à3rd add insulin
- If > 7mM, start insulin ASAP

If the woman already has diabetes herself:

1) Encourage weight loss if BMI > 27
2) Stop oral medication (except metformin) and start insulin
3) Start folic acid 5mg/day from pre-conception to 12 weeks gestation
4) Take early anomaly scan at earlier than 20 weeks if possible with 4 chamber view of heart (Fetal echo)
5) Treat retinopathy as this can worsen during pregnancy
Thyroid Disease
Thyroid conditions involve under/activity of the gland. To determine cause, number of test you can do. Thyroid
function should be checked in people with AF + diabetes + hyperlipidemia + patients on amiodarone/lithium

a) Hypothyroidism (myxoedema)
This is a condition marked by a lack of thyroid hormone which is fairly common. If treated, the prognosis
is excellent, but the problem is the it gives non-specific symptoms which are very subtle.
- Features are based on decreased BMR and decreased sympathetic activity

Symptoms: Signs:
- Increased weight with normal appetite - Slow reflexes and ataxia
- Cold intolerance with no sweating - Cold dry hands
- Bradycardia - Ascites/oedema
- Decreased mood - Hypercholesterolemia
- Constipation - Heavy Periods (menorrhagia)
- Tiredness and lethargic - Absent Reflexes
- Poor memory/cognition - Carpal Tunnel Syndrome

Whilst these are the general signs of a lack of thyroid hormone, there are a number of different causes:
• Hashimoto thyroiditis – most common cause in regions where iodine levels are adequate
- Due to autoimmune destruction of thyroid gland, associated with HLA-DR5
- It is associated with other autoimmune conditions e.g. – Type I diabetes, Addison’s.
- Antithyroglobulin and antithyroid peroxidase antibodies present
- Gives chronic inflammation with germinal centres and Hurthle cells
- More common in postmenopausal women (60-70) and presents with firm non-tender goitre

• Primary Atrophic Hypothyroidism

- A diffuse lymphocyte infiltration of thyroid leading to atrophy, hence does not give a goitre

• Riedel fibrosing thyroiditis – chronic inflammatory disease with fibrosis of thyroid gland
- Gives hypothyroidism with a hard, nontender thyroid gland

• Iodine deficiency – this is needed to make thyroid hormone (most common cause worldwide)

• Drugs – Antithyroid drugs e.g. lithium + amiodarone (can cause either hypo/hyperthyroidism)

• Secondary Hypothyroidism – This is secondary to low TSH due to hypopituitarism, very rare

• Subclinical Hypothyroidism – This occurs when T levels are normal amidst raised TSH levels
4

- It is common (10% of people above 55 years) with risk of progression to hypothyroidism

- Advisable to recheck TSH after 2-4 months to confirm that levels are actually raised
- Only treated in TSH > 10 or thyroid antibodies or other autoimmune disease present

• Sick Euthyroid Syndrome – This is a condition which usually occurs in acute systemic illness
- Theoretically everything TSH, T and T is low but the TSH can be within the normal range
4 3

- T are especially low in these types of patients

3

- Changes are reversible with recovery from illness and usually no treatment is needed

Hypothyroidism treatment: Levothyroxine - hormone replacement therapy to replace T 4

- Iron supplements reduce absorption of levothyroxine so give these 2 hours apart

Ø Myxoedema Coma – This is one of the biggest complications of untreated hypothyroidism is a:

- This is the ultimate hypothyroid state before death, resulting from severe absence of thyroid hormone

Symptoms: Exceptionally hypothyroid features --> Hypothermia + Bradycardic + Coma + Seizures

- Low BP + low glucose + hyporeflexia
Treatment – Give IV liothyronine (T ) + Hydrocortisone (+ fluids/glucose if required)
3
b) Hyperthyroidism
This is a condition marked by increased levels of circulating thyroid hormone.
- It leads to increase in basal metabolic rate (due to increased synthesis of Na/K-ATPase)
- Increased sympathetic nervous system activity (due to increased B -adrenergic receptors)
1

Symptoms: Signs:
- Weight loss despite increase appetite - Fast pulse/atrial fibrillation
- Heat intolerance and sweating - Warm moist skin
- Tachycardia + palpitations - Thin hair
- Tremor/anxiety - Staring gaze with eyelid lag
- Diarrhoea - May be goitre
- Decreased muscle mass with weakness - Hypocholesterolaemia
- Bone resorption with hypercalcemia - Low/absent periods
- Hyperglycaemia

Whilst these are the general signs of excess thyroid, there are a number of different causes:
• Graves’ disease – An autoimmune condition which is the most common cause of hyperthyroidism
- Autoimmune IgG antibody stimulates the TSH receptor increasing thyroid release
- TSH stimulating antibodies seen in 90% and anti-thyroid peroxidase antibodies also present
- Usually occurs in women of childbearing age (30-50 years)

Specific symptoms:
- Diffuse goitre as constant TSH stimulate leads to thyroid hyperplasia
- Pretibial myxoedema – shin fibroblasts express TSH receptor causing inflammation
- Exophthalmos (bulging of eyes) – fibroblasts behind orbit express the TSH receptor
- Stimulation leads to increased inflammation and oedema, seen in 30% of patients
- If inflammation involves the cornea, becomes very concerning.
- Stopping smoking aids eye symptoms

Diagnosis: TFT shows high T , low TSH. High glucose and hypocholesterolaemia
4

• Multinodular goitre – This is an enlarged thyroid gland with multiple nodules, seen in elderly
- Regions become TSH-independent giving hyperthyroidism
Diagnosis - Nuclear scintigraphy shows a patchy uptake
Treatment - Radioiodine therapy

• Toxic adenoma – This is a solitary nodule producing excess thyroid hormone.

- Iodine scan shows nodule is “hot” (hormone producing) and rest of gland suppressed

• Ectopic thyroid tissue – in metastatic follicular thyroid cancer, metastasis can produce T /T
3 4

• Subacute (De Quervian) Thyroiditis - A subacute granulomatous thyroiditis after a viral infection
- Presents as a tender thyroid with a goitre giving a transient hyperthyroidism (stage 1)
- Patient then becomes euthyroid (stage 2) before hypothyroidism (Stage 3)
- Self-limiting and function eventually returns to normal
Diagnosis – Thyroid scintigraphy shows globally reduced iodine-131 (+ Raised ESR)

Hyperthyroidism treatment - We first try to stabalise the heart and then treat the cause.
i) Beta-blockers – e.g. Propranolol gives control of symptoms due to high sympathetic activity
ii) Antithyroid medication – Methimazole + PUT iii) Radioiodine
iv) Thyroidectomy – risk of recurrent laryngeal nerve injury + people become hypothyroid after

Ø Hyperthyroid Crisis (Thyroid Storm) - One of the biggest complications of hyperthyroidism

- High levels of T ultra-sensitise the body to the sympathetic system resulting in serious symptoms
4

Causes – Thyroid surgery, trauma, acute iodine load (e.g. CT contrast)

Symptoms – Heat generation (T >38.5), Tachycardia, Confusion, Hypertension + Heart failure
Treatment – IV propranolol + Propylthiouracil + Dexamethasone (stops T à T ) + Iodine solution
4 3
c) Thyroid cancer
Thyroid nodules are more likely to be benign. Malignant cancers are characterized by iodine uptake test
and are cold, showing decreased uptake and then require biopsy performed by fine needle aspiration (FNA).

• Papillary carcinoma (MOST COMMON)

This is the most common thyroid carcinoma, usually in young females.
- Exposure to radiation in childhood is risk factor
- Made of papillae lined by cells with clear “Orphan Annie eye” nuclei + papillary projections
- The patient is completely euthyroid however

Management - Total thyroidectomy --> followed by radioiodine to kill residual cells

- Yearly thyroglobulin levels to detect recurrent disease

• Follicular carcinoma (2 MOST COMMON)

ND

A malignant proliferation of follicular cells producing thyroid hormone, seen in middle age
- Appears to be encapsulated, but microscopically capsular invasion in seen which differentiates in from
a follicular adenoma
- Metastasises early via the blood to the bones and lungs
- Can produce exogenous thyroid hormone giving symptoms of hyperthyroidism

Management - Total thyroidectomy --> followed by radioiodine to kill residual cells

- Yearly thyroglobulin levels to detect recurrent disease

• Medullary carcinoma (3 MOST COMMON)

RD

A Malignant proliferation of C cells which secrete calcitonin

- Familial cases are seen due to multiple endocrine neoplasia MEN2A (glands) and 2B (involves oral
mucosa) associated with mutations in the RET oncogene
- Calcitonin gets deposited in tumour as amyloid and may give hypocalcaemia
- Metastasises to both lymph nodes and through blood

Management – Thyroidectomy + lymph node clearance

• Anaplastic carcinoma (LEAST COMMON)

An undifferentiated malignant tumour usually seen in elderly females
- Causes local invasion of structures giving pressure symptoms
- Not responsive to treatment, so palliation is offered with surgery and radiotherapy

d) Congenital thyroid conditions

• Thyroglossal duct cyst
This is a cystic remnant of the thyroglossal duct.
- Thyroid tissue develops at the base of the tongue and travels down along duct to neck
- Although it usually degenerates, it can persist and dilate
- Presents as a neck mass in the anterior triangle which moves upwards with tongue protrusion due to
the residual connection with the back of the tongue
- Can become painful if infected

Management - Surgical excision

• Lingual thyroid
This is the presence of thyroid tissue at the base of tongue
- Can interrupt with swallowing/breathing if large or asymptomatic
 Parathyroid Conditions
a) Depletion of PTH
• Hypoparathyroidism – A condition due to an impairment in PTH secretion
- Primary – due to autoimmune damage, congenital DiGeorge syndrome
- Secondary – due to radiation, surgery or low Mg (needed for synthesis)
2+

Symptoms –Resemble hypocalcaemia raising excitability of nerve and muscle:

- Tetany --> muscle twitching, cramping and spasm
- Gives numbness and tingling around mouth (circumoral)
- Trousseau sign – inflating cuff above systolic BP --> muscle contraction due to increase excitability
- Chvostek sign – tap on zygomatic bone --> twitching of facial muscle as it is more excitable.

Diagnosis – Blood test shows ¯PTH and ¯Ca , but ­PO

2+
4
3-

Management – Calcium supplements + Alfacalcidol (synthetic Vitamin D ) 3

• Pseudohypoparathyroidism – this occurs due to a failure of the organs to respond to PTH

- Can be autosomal dominant – characterized by short stature with short 4 and 5 digits, round face th th

- Alternate form is pseudopseudohypoparathyroidism – same features but with normal biochemistry

Diagnosis – Blood test shows ¯Ca , but ­PO and ­PTH
2+
4
3-

- During infusion of PTH, urinary cAMP and PO do not rise unlike in hypoparathyroidism.
4
3-

Management – Calcium supplements + Alfacalcidol (synthetic Vitamin D3)

b) Excess of PTH
• Primary Hyperparathyroidism – Excess PTH due to a disorder of the parathyroid gland itself
Causes: 80% due to parathyroid adenoma, also due to parathyroid hyperplasia or parathyroid carcinoma

Symptoms – It often feels asymptomatic, but there are signs related to high serum calcium:
- Bones --> Ectopic calcification (e.g. cornea) and bone pain (due to bone resorption)
- Stones --> Renal stones and renal failure
- Groans --> Abdominal pain, vomiting, constipation and weakness
- Psychic Moans --> Confusion + irritability + Depression

Diagnosis – Blood test ­PTH (can be normal), ­Ca , ­urinary cAMP, ­ALP
2+
- ¯ PO 4
3-

- Urine Calcium: creatinine clearance ratio > 0.01

- X-ray --> osteitis fibrosa cystica of phalanges + “pepper-pot” skull appearance

Treatment – If Ca < 0.25mM above normal limit and no organ damage, conservatively give fluids
2+

- If moderate to severe, surgical total parathyroidectomy or cinacalcet if unsuitable for surgery.

• Secondary Hyperparathyroidism – This is excess PTH due to a disease extrinsic to gland

- The most common cause is chronic renal failure.
- Renal insufficiency gives decreased phosphate excretion so PO binds serum Ca 4
3- 2+

- Less free calcium stimulates parathyroid glands to secrete excess PTH

Diagnosis – Blood test shows ­PTH + ­ALP + ­PO 4 - ¯Ca and ¯Vitamin D
3- 2+

Treatment – Vitamin D supplements, else surgery if bone pain/pruritus/ectopic calcifications

• Tertiary hyperparathyroidism – This occurs after prolonged secondary hyperparathyroidism, causing

glands to act autonomously after undergoing hyperplasia, which is seen in chronic renal failure
- Lead to increased Ca from unlimited PTH secretion
2+

- ­PTH, ­Ca , ­urinary cAMP, ­ALP

2+
- ¯ PO and ¯Vitamin D 4
3-

• Malignant hyperparathyroidism
Parathyroid-related protein is produced by some squamous cell lung, breast and renal carcinomas
- This protein mimics PTH resulting in increased calcium
Treatment - Need to treat the underlying cancer
Adrenal Gland Conditions
a) Adrenal medulla
• Pheochromocytoma – This is an adrenaline producing tumour of the chromaffin cells
- Follows rule of 10s – 10% are bilateral, 10% familial, 10% malignant and 10% located outside adrenal
medulla in the bladder wall or organ of Zuckerandl by aortic bifurcation.
- Most are unilateral on the right
- Associated with MEN 2A/B, Neurofibromatosis type 1
- Also linked to von Hippel-Lindau disease – an autosomal dominant hereditary condition associated
with tumors arising in multiple organs

Symptoms: Triad of episodic headache, sweating and tachycardia (palpitations), with hypertension

Diagnosis – Increased plasma Metanephrine level

- Increased 24-hr urine Metanephrines + Vanillylmandelic acid
- Abdominal CT/MRI scan to locate tumour

Management – First stabilise the patient with medical therapy:

-1 line is alpha-blocker phenoxybenzamine, 2 line is labetalol (if heart disease or tachycardia)
st nd

- Surgical excision to remove tumour is the definitive treatment

b) Adrenal cortex
• Hypercortisolism (Cushing’s syndrome)
This is a clinical state produced by chronic cortisol excess and loss of the normal feedback mechanism
of the HPA axis and circadian rhythm of cortisol secretion (normally highest in morning).

ACTH-independent causes: (gives low ACTH à adrenal atrophy)

- Exogenous steroids – most common cause, gives bilateral adrenal atrophy, steroids suppress ACTH
- Primary adrenal adenoma/hyperplasia or carcinoma – leads to atrophy of uninvolved adrenal gland

ACTH-dependent causes: (gives high ACTH à adrenal hyperplasia)

- Cushing’s disease – bilateral adrenal hyperplasia from an ACTH secreting pituitary adenoma
- Ectopic ACTH production – from small cell carcinoma of lung giving bilateral adrenal hyperplasia.

Pseudo-Cushing’s: (mimics symptoms and obscures test results)

- Chronic alcohol abuse or severe depression
- Insulin stress test is used to diagnose these and distinguish from Cushing’s disease

Symptoms: Signs:
- Muscle weakness and breakdown - Abdominal striae- thinning of skin
- Osteoporosis - Poor wound healing
- Immune suppression - Central obesity, buffalo hump
- Hypertension - Moon faced shape
- Hyperglycemia (diabetes) + weight gain

Diagnosis – First you want to confirm the diagnosis, then you can do tests to localise the lesion.
- 1 line: Overnight dexamethasone testà give dexamethasone at 11pm + measure cortisol at 8am
st

- Normally cortisol is suppressed, but no suppression seen in Cushing’s syndrome.

- 2 line: 24hr urinary free cortisol.
nd

Once you have diagnosed Cushing’s syndrome want to locate the cause.
- Measure plasma ACTH --> if high it indicates pituitary or ectopic source.
- If ACTH-dependent --> do 48hr high-dose dexamethasone suppression test
- Will distinguish between pituitary tumour and ectopic ACTH tumour
- Dexamethasone would supress pituitary ACTH, but not ACTH from ectopic source.
- If pituitary Cushing’s disease à pituitary MRI If ectopic source à CT chest/abdo/pelvis

Treatment – Stop steroids if iatrogenic, surgical removal if tumour

Complications: Nelson Syndrome – in Cushing’s treated with bilateral adrenalectomy, loss of -ve
feedback gives raised ACTH causing enlargement of pituitary adenoma + pigmentation of skin
• Hyperaldosteronism – This refers to excess aldosterone production existing in two types:

o Primary hyperaldosteronism – excess production independent of the renin-angiotensin, causing

increased sodium and water retention.
- Characterized by high aldosterone and low renin (as high BP inhibits renin)
Causes: Conn syndrome – aldosterone producing adenoma (most common)
- Sporadic adrenal hyperplasia

o Secondary hyperaldosteronism – due to activation of renin-angiotensin system

- Characterized by high aldosterone and high renin
Causes: Poor renal perfusion e.g. renal artery stenosis, heart failure, diuretics

Symptoms – Often asymptomatic but gives signs of hypokalaemia --> weakness, cramps, alkalosis
- Increased Na expands blood volume --> hypertension

Diagnosis: Measure Aldosterone: Renin Ratio à then CT abdomen + adrenal vein sampling

Treatment – Conn’s syndrome à laparoscopic surgery to remove adenoma

- Hyperplasia à K sparing diuretics e.g. spironolactone/amiloride
+

• Adrenal insufficiency – This is the failure of the adrenal gland to produce cortisol and aldosterone

o Primary insufficiency (­ACTH) – called Addison’s disease and is due to failure of gland itself
- TB is the most common cause worldwide
- Also due to autoimmune destruction (most common cause in UK) gives chronic insufficiency
- Waterhouse-Friderichsen syndrome à haemorrhagic necrosis of adrenal glands classically in
young children with N miningitidis infection.

o Secondary insufficiency (¯ACTH) – This is caused by a factor extrinsic to the adrenal glands
- Most common cause is iatrogenic due to long term steroid therapy and adrenal suppression
- Also due to pituitary disease leading to lack of ACTH

Symptoms:
- Lack of cortisol --> hypotension, muscle weakness
- Lack of aldosterone --> dehydration, hypovolemia, hyponatremia, hyperkalaemia
- Metabolic acidosis
- ­ACTH --> causes hyperpigmentation due to increase melanocyte stimulating hormone

Diagnosis - 1 line ACTH stimulation test (Short Synacthen test)

st

- Measure cortisol before + 30 minutes after giving Tetracosactide/Synacthen (ACTH analogue)

- If cortisol does not increase, shows that patient has primary adrenal insufficiency

2 line – Measure 9am serum cortisol, if lower than 100nM, then highly suggestive of Addison’s
nd

Treatment
- Replace steroids – hydrocortisone In illness, double hydrocortisone dose, but
- Replace aldosterone - fludrocortisone keep fludrocortisone constant!

• Addisonian crisis
Causes: Failure to take steroid tablets, increased stress due to infection
Symptoms: Shock (increased HR, vasoconstriction, hypotension, weak/confused/coma)
- ­K , ¯Na , ¯glucose, metabolic acidosis
+ +

Treatment – if crisis is suspected, treat before biochemical results come

i) Give hydrocortisone 100mg IM or IV (fludrocortisone not required immediately!!!)
ii) Fluids – 1 litre saline over 30-60mins (with dextrose is hypoglycaemia)
iii) Change to oral steroids after 72 hours
 Pituitary Gland Conditions

a) Posterior pituitary gland

• Diabetes insipidus (DI) – Production of much dilute urine (>3L/day) due to poor water reabsorption.
Desmopressin i) Central DI – This is a failure of the pituitary gland to produce ADH
Responsive Causes: Idiopathic (50%), congenital defect in ADH gene DIDMOAD + trauma/tumour

Desmopressin ii) Nephrogenic DI – This is an impaired renal response to ADH

Unresponsive Causes: Inherited genes, low K , high Ca , Drugs (e.g. lithium, demeclocycline)
+ 2+

iii) Dipsogenic DI – This is producing large amounts of urine due to drinking too much water

Symptoms – These resemble those of losing water giving hypernatremia

- Polyuria + polydipsia (e.g. kids drinking bathwater) with risk of life-threatening dehydration
- Dilute urine and low specific gravity à a high urine osmolality (> 700mOsm/kg) excludes DI

Diagnosis – ­ Plasma Osmolality, ¯Urine Osmolality

- Water deprivation test --> this tests ability of the kidney to concentrate urine
--> Patient empties bladder and is then deprived of water for 8 hours
--> Weighed hourly and urine collected every 2h – measure volume and osmolarity
--> After 8h, if urine osmolarity <600mOsmol/kg (dilute), give desmopressin
--> If osmolarity does not increase after 4h, then nephrogenic, otherwise neurogenic

Treatment - Central DI à Desmopressin

- Nephrogenic DI à Treat the cause + Bendroflumethiazide diuretic – acts as an anti-diuretic

• SIADH syndrome – This is a disease which leads to excessive ADH secretion

Causes: Often due to ectopic ADH production (e.g. small cell lung carcinoma)
- CNS trauma + Drugs (SSRIs, opiates, TCAs)

Symptoms – Hyponatremia (low serum Na and low osmolarity) and low volume urine
+

- This leads to neuronal swelling and cerebral oedema giving rise to seizures, headache

Diagnosis – Concentrated urine Na > 20mM, and >100mOsmol/kg with hyponatraemia (Na <125mM)
+ +

Management – Water restriction

- Demeclocycline – an antibiotic which also reduces the sensitivity of the collecting duct to ADH
- ADH receptor antagonists – Vaptan drug family

b) Anterior pituitary gland

• Hypopituitarism – This is decreased secretion of anterior pituitary hormones.
- Most commonly affected hormone is GH à FSH/LH à TSH à ACTH à Prolactin

Causes – These occur at 3 levels

- Hypothalamus – Kallman’s syndrome, tumour
- Pituitary stalk – Trauma, Carotid artery aneurysm
- Pituitary gland – Adenoma + apoplexy (bleeding of adenoma, haemorrhage of gland)

o Sheehan syndrome – during pregnancy, the gland doubles in size but blood supply hardly increases
- Blood loss during parturition gives ischaemia and infarction of pituitary gland
- Patients get fatigued + have poor lactation

o Empty Sella syndrome – arachnoid mater and CSF herniate into Sella compressing the pituitary

o Kallman Syndrome – failure of development of GnRH neurons derived from olfactory epithelium
- Gives anosmia (lack of smell) + cleft lip + colour blindness
- Low LH/FSH and low sex hormones cause delayed puberty and hypogonadism
- Height is usually normal or above average
 Symptoms: Hypopituitarism gives many symptoms due to the effect on the corresponding hormones.
Tests: Different tests are carried out to work out which hormones are affected e.g. LH/FSH, IGF-1
Treatment – Hormone replacement therapy

• Pituitary adenoma – This is a benign tumour of the anterior pituitary cells.

- It can be a microadenoma (<1cm) or macro (>1cm)
- Can also be functional (hormone-producing) or non-functional (silent)
- Most common tumour is prolactin secreting à non-functional à GH secreting à ACTH secreting

i) Non-functional tumours – these often present with mass effect due to structural compression
- Can cause bitemporal hemianopia --> compression of the optic chiasm
- Visual disturbances --> pressure on cavernous sinus pressing CN III, IV and VI
- Can cause hypopituitarism --> compression of normal pituitary tissue
- Early morning headaches, worse when lying down

ii) Functional tumours – these present with the features based on the type of hormone produced
- Usually prolactin, GH and ACTH producing - the others are very rare

Tests – Pituitary blood profile (GH, prolactin, ACTH, FH, LH and TFTs)
- MRI provides visualization of pituitary gland enlargement
- Formal visual field testing

Management – if it affects hormones, treat accordingly

- Surgery – transphenoidal hypophysectomy or radiotherapy (residual/recurrent adenomas)

• Craniopharyngioma: (1)
- A benign tumour of the epithelial remnants of Rathke’s pouch
- This sits between the pituitary gland and the 3 ventricle rd

- It presents as a supratentorial mass in a child or young adult, often leading to

compression of the optic chiasm

Symptoms: (Children) Gives growth failure, and compression of structures

- Bitemporal hemianopia (lower quadrants worse)
(Adults) Amenorrhoea, loss of libido, DI, hyperphagia
Imaging- CT/MRI shows calcifications (as if derived from “tooth like tissue”)
Management – Surgical removal, but usually recurs after resection

• Hyperprolactinemia – This is the most common hormone disturbance on the pituitary

Causes: Most often due to a pituitary adenoma increasing production
- Also due to reduced inhibition e.g. dopamine antagonists (Haloperidol, Domperidone)
- Pregnancy and raised oestrogen - Polycystic Ovary syndrome
- Acromegaly (1/3 of patients)
- Primary hypothyroidism à as TRH stimulates prolactin release

Symptoms: As well as direct effects on lactation, raised prolactin inhibits GnRH which decreases
testosterone and estrogen giving secondary effects like osteoporosis.

Females Males
Amenorrhea – absence of menstruation Erectile dysfunction
Infertility – due to Inhibition of GnRH Loss of libido
Galactorrhoea Galactorrhoea

Diagnosis – MRI visualisation of pituitary gland

Management – 1 choice is dopamine agonists to reduce secretion e.g. Bromocriptine/Cabergoline

st

- 2 line is surgery
nd

1.
Hellerhoff / CC BY (https://creativecommons.org/licenses/by/3.0)
• Acromegaly
- This is a condition caused by increased secretion of growth hormone from the pituitary
- Most often due to a pituitary adenoma

Symptoms: GH stimulates bone and soft tissue growth through IGF-1

- (Children) – gigantism due to increased bone growth
- (Adults) – enlarged hands, tongue, jaw and feet (increase shoes size)
- Acroparathesia – tingling in the extremities
- Pituitary tumour features (headache + hyperprolactinaemia)
- Excessive sweating and oily skin, due to sweat gland hypertrophy

Complications - Growth of visceral organs leads to cardiomyopathy

- Hypertension
- Secondary diabetes mellitus as GH induces gluconeogenesis
- Colorectal cancer

Diagnosis:
- 1 line is to check if Serum IGF-1 level is raised
st

- Confirmation test is Oral glucose tolerance test à Normally GH supressed to <2mu/L with glucose
- In acromegaly there is no suppression of GH
- MRI pituitary fossa to visualise tumour

Management:
- 1 line is transphenoidal surgery
st

- Octreotide – somatostatin analogue, used as adjunct to surgery

- Pegvisomant – GH receptor antagonist, given by subcutaneous injection
- Can use radiotherapy in older patients of if the methods above fail

(2)

2.
Philippe Chanson and Sylvie Salenave (https://creativecommons.org/licenses/by/2.0
 Multiple Gland Conditions
This is a group of genetic conditions which affect multiple glands and tissues.

• Multiple Endocrine Neoplasia

This is an inherited autosomal dominant condition that leads to multiple hormone producing tumours
in endocrine glands. Divided into three types:
- Type 1 (Wermer Syndrome) is due to a mutation in the MEN1 tumour suppressor gene,
- Type 2 is due to a RET oncogene (receptor tyrosine kinase) mutation and is split into 2 types.
- For type 1, the most common presentation is hypercalcaemia due to parathyroid hyperplasia

MEN Type I MEN Type II

Parathyroid hyperplasia (95%), A – Medullary thyroid cancer
without altering hormone
secretion. + Phaeochromocytoma

Pituitary prolactinoma/GH + Parathyroid hyperplasia

tumour
- Most of these are B – Medullary thyroid cancer
prolactinomas, then GH
secreting tumours. + Phaeochromocytoma

Pancreas: + Tall, thin Marfan’s body type

insulinoma/gastrinoma + Dry eyes or lack of tears
- Can lead to Zollinger-Ellison + Delayed puberty
syndrome
It usually manifests before a child is 10.

Treatment – Treat the affected glands, usually by surgical excision

• Sjogren’s syndrome
An autoimmune disorder which is characterised by lymphocyte infiltration and fibrosis of exocrine
glands, usually lacrimal and salivary glands
- Primary – this occurs more in females (90%) around 40-50 years old
- Secondary – due to rheumatoid arthritis or other connective tissue disorders

Symptoms:
– Major risk is development of non-Hodgkin Lymphoma
- Dry eyes (keratoconjunctivitis sicca) - Joint and muscle pain
- Dry mouth (xerostomia) - Renal tubular acidosis
- Raynaud’s Phenomenon - Sensory neuropathy

Diagnosis:
- Rheumatoid factor + ANA positive
- anti-Ro (SSA) antibodies in 70% - anti-La (SSB) antibodies in 30%
- Schirmer’s test – uses filter paper to measure tear formation in eyes --> shows low production

Management:
- 1 line is symptom control à artificial tears drops and saliva stimulants (pilocarpine)
st

- If severe with arthralgia, immunosuppressants (hydroxychloroquine)