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Jeremy Chui

Michael Phipps Phase 3A

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Topics

•  Introduction to Endocrinology •  Diabetes •  Disorders of the Thyroid Gland •  Cushing’s Syndrome •  Disorders of Growth Hormone •  Conn’s Syndrome •  Addison’s Disease •  Disorders of ADH •  Disorders of Calcium Metabolsim •  Disorders of Potassium •  Neuroendocrine Tumours

The endocrine organs


The Endocrine System

1. Pituitary Gland 2. Thyroid Gland 3. Pineal Gland 4. Thymus 5. Adrenal Gland 6. Pancreas 7. Ovary 8. Tes;s

hKp://upload.wikimedia.org/wikipedia/commons/9/9d/Illu_endocrine_system_New.png

Diabetes


Diabetes Type 1 •  Insulin deficiency from autoimmune destruction of insulin secreting

pancreatic beta cells

•  Autoimmune association with HLA DR3 / DR4

•  Features : weight loss, persistent hyperglycaemia, ketonuria

•  Presence of : islet cell antibodes + antiglutamic acid decarboxylase antibodies

•  Classic picture : polydipsia, polyuria, weight loss, ketosis


Diabetes Type 2 •  Increased insulin resistance

•  Impaired glucose tolerance

–  fasting plasma glucose < 7 mmol / l

–  OGTT 2hr glucose ≥ 7.8 but ≤ 11.1 mmol / l

•  Obesity, Lack of exercise, Calorie / alcohol excess, Older patients

•  Symptoms of hyperglycaemia (or asymptomatic) + raised venous glucose

–  Fasting ≥ 7 mmol / l

–  Random ≥ 11 mmol / l


Type 1 D Tx •  Subcutaneous insulin

–  ultra fast acting

–  isophane insulin

–  pre mixed insulin with ultra fast-acting component

–  long acting recombinant human insulin analogues


Type 2 D Tx •  Biguanide (metformin) : increased insulin sensitivity + helps weight

•  If HbA1c > 7% at 16wks : sulfonylurea (inc insulin secretion) e.g. gliclazide

•  If HbA1c > 7.4% at 6m : insulin / glitazone (inc insulin sensitivity)

•  Sulfonylurea receptor binders - nateglinide (inc beta cell insulin release)

•  Glucagon-like peptide analogues - sitagliptin (augments insulin release)

•  Alpha glucosidase inhibitors - acarbose (dec breakdown of starch to sugar)


Diabetes Complica;ons •  Vascular disease : MI 4x more common, stroke 2x more common

•  give statins (simvastatin)

•  Nephropathy : microalbuminuria

•  A2a blocker (candesartan), inhibits RAA, dec albumin excretion

•  Cataracts : osmotic change in lens by acute hyperglycaemia

•  Rubeosis iridis : new vessel on iris > glaucoma


Diabetes re;nopathy •  Background retinopathy

•  microaneurysms (dots)

•  haemorrhages (blots)

•  hard exudates (lipid deposits)

•  Pre-proliferative retinopathy : cotton wool spots

•  Proliferative retinopathy : new vessel formation

•  Maculopathy

•  Decreased visual acuity

•  Capillary endothlial change > vascular leak > microaneurysms > capillary exclusion > local hypoxia + ischaemia > new vessel formation


Diabe;c neuropathy •  Ischaemia : critical toes, absent dorsalis pedis pulses

•  Peripheral neuropathy : injury / infection over pressure points

•  Neuropathy :

•  pes cavas, claw toes, loss of transverse arch, rocker bottom sole

•  patchy sensory loss

•  glove & stock distribution

•  absent knee jerks


Diabe;c neuropathy •  Symmetric sensory polyneuropathy (glove & stock)

•  Mononeuritis multiplex : CN III, CN VI

•  Amyotrophy : painful wasting of quadriceps + pelvifemoral muscles

•  Autonomic neuropathy

•  postural hypotension, dec cerebrovascular autoregulation, gastroparesis, urine retention, erectile dysfunction, diarrhoea


Hyperosmolar hyperglycaemic non-‐keto;c coma •  Type 2 DM

•  Hx ≥ 1 week

•  marked dehydration

•  glucose > 35 mmol / l

•  Acidosis absent

•  Patients often old, first time presenting

•  Occlusive events :

•  focal CNS signs, chorea, DIC, DVT, leg ischaemia

•  Tx : heparin, rehydrate, replace K+ loss, insulin (after 1 hour)


Diabe;c ketoacidosis •  Mechanism!

•  Low insulin

•  Dec cellular uptake of glucose

•  Dec production of pyruvate by glycosis

•  Acetyl CoA generated by fat breakdown to make up deficit

•  Excess 2C acetyl CoA relative to C4 acid in TCA cycle

•  Excess converted to ketone bodies

•  Inc acetone = fruity smelling breath

Disorders of the thyroid gland


Thyroid Physiology

HYPOTHALAMUS

PITUITARY

THYROID

Thyrothropin Releasing Hormone

Thyroid S>mula>ng Hormone

Thyroid Hormones

Triiodothyronine (T3) Thyroxine (T4)

-‐ve

-‐ve


Hypothyroidism -‐ Epidemiology

•  Most common in FEMALES (6:1)

•  Incidence = 2 in 1000

•  There is often a family history of AUTOIMMUNE conditions


Hypothyroidism -‐ Causes

Thyroid Synthe>c Failure -‐ Iodine Excess (e.g. amiodarone) -‐ Iodine Deficiency -‐ Drugs (e.g. lithium)

Latrogenic -‐ Post Surgery -‐ Post Radio-‐Iodine

Chronic Inflamma>on (à Thyroid Destruc;on) -‐  Hashimoto’s

Autoan;body to thyroglobulin & thyroid peroxidase. Goitre found. -‐  Atrophic

Inhibitory autoan;body to TSH receptor. No goitre.

Hypothalamo-‐Pituitary Disease -‐  Pituitary Disease (2o) -‐  Hypothalamic Disease (3o)

Congenital (agenesis, ectopia, metabolism etc)


Hypothyroidism -‐ Clinical Features

Hypothyroid

Change in Weight Increase

Temperature Cold Intolerance

Change in Voice No

Eye Complaints No

Change in heart rate Bradycardia

Reflexes Decreased

Menstrua>on Heavy / Irregular Fer;lity Problems

Tremor No

Change in Bowel Habit Cons;pa;on

Change in skin/hair Cold Dry & Flaky BriKle Nails


Hypothyroidism -‐ Inves;ga;ons

•  Thyroid Function Tests T4 TSH

•  Thyroid Antibodies

– Peroxidase & Thyroglobulin in Hashimoto’s – Blocking TSH in Atrophic

•  Other – Other Autoimmune conditions (Addison’s/

Pernicious) – ECG (? Bradycardia)


Hypothyroidism -‐ Management

Replace Thyroid Hormones – usually THYROXINE


Hyperthyroidism -‐ Epidemiology

•  Most common in FEMALES (5:1)

•  Prevalence = 2%

•  There is often a family history of AUTOIMMUNE conditions


Hyperthyroidism – Causes

Graves Disease -‐ 75% -‐ Diffusely hot -‐ TSH An;body

Mul>nodular Goitre -‐ 15% -‐ Female -‐ Approx 60

Toxic Adenoma -‐ 5%

Thyroidi>s -‐ 5% -‐ Viral (mumps etc) -‐ Diffusely low

Other (<1%):-‐ •  Amiodarone •  Exogenous T4 administra;on •  TSH Induced (e.g. pituitary tumour)


Hyperthyroidism -‐ Inves;ga;ons

•  Thyroid Function Tests T4 TSH

•  Thyroid Antibodies

– Presence suggests autoimmune aetiology (e.g. Graves)

•  Thyroid Uptake Scan – Can differentiate Grave’s from toxic

adenoma / mutinodular goitre


Hyperthyroidism -‐ Management

Medical CARBIMAZOLE – Dose ;tra;on or “block & replace”

Surgical Thyroidectomy (for Graves relapses/ toxic adenoma / mul;nodular goitre)

Radio-‐Iodine Iodine is taken up preferen;ally by thyroid gland à destruc;on


Hyperthyroidism -‐Clinical Features

Hyperthyroid

Change in Weight Decrease

Temperature Heat Intolerance

Change in Voice Hoarse

Eye Complaints Only in Graves

Change in heart rate Tachycardia/AF/Palpita;ons

Reflexes Increased

Menstrua>on Infrequent menses & fer;lity problems

Tremor Yes

Change in Bowel Habit Increased Frquency

Change in skin/hair Warm Hair Loss Acropachy (clubbing)


Hypo/Hyper-‐Thyroidism -‐ Clinical Features

Hypothyroid Hyperthyroid

Change in Weight Increase Decrease

Temperature Cold Intolerance Heat Intolerance

Change in Voice No Hoarse

Eye Complaints No Only in Graves

Change in heart rate Bradycardia Tachycardia/AF/Palpita;ons

Reflexes Decreased Increased

Menstrua>on Heavy / Irregular Fer;lity Problems

Infrequent menses & fer;lity problems

Tremor No Yes

Change in Bowel Habit Cons;pa;on Increased Frquency

Change in skin/hair Cold Dry & Flaky BriKle Nails

Warm Hair Loss Acropachy (clubbing)

Cushing’s Syndrome


Adrenal Cortex •  Cortex

–  Zona Reticularis - Androgens

–  Zona Fasciculata - Glucocorticoids

–  Zona Glomerulosa – Mineralocorticoids

•  Medulla

–  Catecholamines (adrenaline/noradrenaline)


Cushing’s syndrome •  Chronic glucocorticoid excess

•  loss of normal feedback mechanisms of hypothalamic-pituitary-adrenal axis

•  loss of circadian rhythm of cortisol secretion


Cushing’s syndrome •  ACTH dependent:

•  Pituitary dependent (Cushing’s disease)

•  Ectopic ACTH-producing tumours

•  ACTH administration

•  Non-ACTH dependent:

•  Adrenal adenoma

•  Adrenal carcinoma

•  Glucocorticoid administration


Cushing’s Disease •  ACTH dependent

•  Bilateral adrenal hyperplasia from ACTH secreting pituitary adenoma

•  Peak 30 - 50 years

•  No change : low dose dexamethasone

•  1/2 morning cortisol : 8mg dexamethasone


Cushing’s syndrome •  Symptoms:!

•  Weight gain – central obesity

•  Thin skin

•  Easy bruising

•  Stretch marks

•  Red puffy, round face

•  Tanned skin (Cushing’s disease only)

•  Muscle weakness

•  Depression

•  Tiredness


Cushing’s syndrome •  Signs:!

•  Impaired glucose tolerance

•  Hypertension

•  Pathological fractures – secondary to osteoporosis

•  Hypokalaemia

•  Striae

•  Proximal myopathy


Cushing’s syndrome •  48 hour dexamethasone suppression test

•  Scan adrenals / pituitary

•  Overnight dexamethasone suppression test

•  Transphenoidal surgery to remove pituitary tumour

•  Bilateral adrenalectomy

•  Complication : Nelson’s syndrome (inc skin pigmentation due to inc ACTH)

•  Adrenalectomy

Disorders of growth hormone


Growth Hormone Axis

hKp://www.transd.com/images/charts/hypothalamus.jpg

HYPOTHALAMUS

PITUITARY

LIVER

Somatosta>n (inhibitory) Growth Hormone Releasing Hormone (s>mulatory)

Growth Hormone

IGF-‐1

-‐ve

-‐ve


Acromegaly

ACROMEGALY = Cl inical condit ion resulting from excess GH secretion after epiphyseal fusion (i.e. adults) GIGANTISM = Clinical condition resulting from excess GH secretion before epiphyseal fusion (i.e. children)


Acromegaly -‐ Causes

•  **GH SECRETING PITUITARY ADENOMA**

•  Pituitary carcinoma •  GH-secreting carcinoid tumours (very

rare!)


Acromegaly – Signs & Symptoms

•  Frontal Bossing •  Enlarged tongue, lips & nose •  Prognathism •  Enlarged Hands & Feet •  Hypertension •  Carpal Tunnel Syndrome •  Headaches •  Osteoarthri;s •  Cardiomegaly hKp://openi.nlm.nih.gov/imgs/

512/283/3555549/3555549_ijgm-‐6-‐031f2.png


Acromegaly -‐ Inves;ga;ons

•  Oral Glucose Tolerance Test ( IGF -1 é and GH not suppressed)

•  MRI (Pituitary)


Acromegaly -‐ Management

•  Trans-sphenoidal adenectomy •  Drugs

– Somatostatin Analogues – Dopamine Agonists – GH Receptor Antagonists (Pegvisomant)

Conn’s Syndrome


Primary hyperaldosteronism

•  Hyperaldosteronism

•  Excess mineralocorticoids : aldosterone

•  Usually caused by adrenal adenoma

•  More common in young females

•  Muscle weakness, tiredness, polyuria, nocturia, hypertension, hypokalaemia


Primary hyperaldosteronism

•  Primary Hyperaldosteronism

•  Excess mineralocorticoids : aldosterone

•  Independent of RAAS

•  hypertenion, hypokalaemia, alkalosis


Conn’s Syndrome •  Primary hyperaldosteronism

•  Solitary aldosterone producing adenoma

•  Muscle weakness, tiredness, polyuria, nocturia, hypertension, hypokalaemia

•  Treat : laparoscopic adrenalectomy, spironolactone


Secondary hyperaldosteronism

•  High renin from decreased renal perfusion

•  renal artery stenosis

•  accelerated hypertension, diuretics, CCF, hepatic failure

Addison’s Disease


Addison’s disease •  Primary adrenocortical insufficiency

•  Destruction of adrenal cortex

•  leading to glucocorticoid + mineralocorticoid deficiency

•  Thin, Tanned, Tired, Tearful

•  Pigmented palmar creases, buccal mucosa, postural hypotension, vitiligo, vomiting, depression, psychosis

•  More common in females


Addison’s disease •  Low Na+, High K+ : from dec mineralocorticoid

•  Low glucose : from dec cortisol

•  Short ACTH stimulation test

•  impaired cortisol response

•  Treat

•  mineralocorticoids (fludrocortisone)


Addisonian crisis •  Presents in shock

•  Patient with known Addisons

•  Precipitated by infection, trauma, surgery

•  Treat with hydrocortisone sodium succinate + IV fluids


Secondary adrenal insufficiency

•  Long term steroid therapy

•  suppression of pituitary adrenal axis

•  Only apparent on steroid withdrawal

•  Mineralocorticoid production is intact, no hyper pigmentation as low ACTH

Disorders of an;diure;c hormone


The Thirst Axis

Increased Osmolality Detected by

Hypothalamus

ADH Released

S>mula>on of V2 Receptors

in Renal Collec>ng Ducts

Migra>on of Aquaporin 2 Channels

Reabsorp>on of Water


Diabetes Insipidus

Passage of large volumes (>3L per day) of dilute urine due to impaired water resorption by the kidney as a result of ê ADH secretion from the posterior pituitary (Cranial DI) or due to a ê response of the kidney (Nephrogenic DI)


Diabetes Insipidus -‐ Causes CRANIAL •  Familial •  Idiopathic •  Trauma/ Pituitary surgery •  Infec;on (meningi;s / TB)

NEPHROGENIC •  Familial •  Post Obstruc;ve Uropathy •  Hypokalaemia /Hypercalcaemia •  Amyloid •  Sickle Cell Anaemia


Diabetes Insipidus -‐ Inves;ga;ons

•  Water Deprivation Test

•  Fasting/ Random Glucose (to exclude DM)

[Na+] Osmolality of Plasma

Osmolality of Urine

Urine Osmolality on Water Depriva>on

Response to Synthe>c ADH

Cranial DI é é ê Fails to Concentrate Normal

Nephrogenic DI é é ê Fails to Concentrate Fails to

Concentrate


Diabetes Insipidus -‐ Management

•  CRANIAL Vasopressin (desmopressin) •  NEPHROGENIC Treat cause. Thiazides &

NSAIDs may help reduce polyuria and polydipsia


Syndrome of Inappropriate ADH Secre;on (SIADH) This is a relatively common cause of ê Sodium. Diagnostic Criteria:-

1.  Decreased Serum Osmolality 2.  Inappropriately Concentrated Urine 3.  Euvolaemia 4.  Elevated Urinary Sodium 5.  No adrenal, thyroid, pituitary or renal

insufficiency or diuretic use


SIADH -‐ Causes

Drugs •  Opiates •  SSRIs •  Carbamazepine

CNS

•  Infec;on (e.g. meningi;s) •  Stroke •  Neoplasia •  Trauma

Lung •  Infec;on (e.g. TB) •  Tumour

Oncological •  LUNG CANCER •  Prostate, GI, haematological

Idiopathic -‐-‐-‐


SIADH -‐ Management

•  Treat underlying cause •  Fluid Restriction •  Diuretics •  Demeclocycline (inhibits action of ADH) •  Vasopressin Receptor Antagonists (e.g.

Tolvaptan)

Disorders of calcium metabolism


Calcium Metabolism

Low Concentra;on of Calcium in Blood

Release of Parathyroid Hormone

Efflux of Calcium from Bone

Decreased Loss of Calcium in Urine

Increased Absorp;on of Calcium from Intes;ne

VITAMIN D BONE KIDNEY INTESTINE


Parathyroid Hormone

•  Secreted from the 4 parathyroid glands located on the posterior surface of the thyroid

•  Secreted by CHIEF CELLS •  Acts to increase serum calcium:-‐

Ø é Osteoclas;c resorp;on of bone Ø é Intes;nal reabsorp;on of calcium Ø é Synthesis of 1,25-‐(OH)2D3 Ø é Renal tubular reabsorp;on of calcium Ø é Excre;on of phosphate


Other Hormones

Vitamin D Small amounts are found in oily fish etc. but most is made in the epidermis from UV light. Increases GI absorption of calcium.

Calcitonin Produced by the C-Cells in the thyroid gland and is antagonistic to PTH. It has very little effect naturally in humans.


Hypercalcaemia -‐ Causes

Hypercalcaemia

Increased Osteoclast Ac>vity

-‐ Metasta;c Cancer -‐ Paget’s Disease

Increased PTH -‐ 1o Hyperparathyroidism -‐ 3o Hyperparathyroidism

Increased Vit D -‐ Dietary

-‐ Sarcoidosis

Drugs -‐ Thiazides -‐ Lithium

-‐ Excess Calcium

Endocrine -‐ Hyperthyroidism

-‐ Addisons -‐ Phaechromocytoma

Hypercalcaemia of Malignancy

(PTHrP)


Hypercalcaemia -‐ Symptoms

•  MOANS - General tiredness, malaise, dehydration •  STONES - Renal Colic from stones •  BONES - Bone Pain •  GROANS - Abdominal Pain

+ Features of underlying disease


Hypercalcaemia -‐ Inves;ga;ons

•  Serum PTH •  Fasting calcium & phosphate •  Kidney Function (U&Es) •  Parathyroid Imaging (CT/MRI/Radio-

Isotope)


Hypercalcaemia -‐ Management

•  MEDICAL – High fluid intake – Low calcium / Vit D Diet

•  SURGICAL – Parathyroidectomy


Hypocalcaemia-‐ Causes

Hypercalcaemia

Hypoparathyroid -‐ Post Surgery -‐ Autoimmune

Vitamin D Deficiency -‐ No Sunlight -‐ Liver Failure

-‐ Malabsorp;on -‐ Gene;c Syndromes

Chronic Renal Failure

Pseudohypoparathyroid


Hypocalcaemia – Signs & Symptoms

•  Neuromuscular Irritability (numbness, cramps, paraesthesia etc.)

•  Anxiety •  Psychosis & seizures •  Prolonged QT Interval •  CHVOSTEK’S SIGN •  TROUSSEAU’S SIGN


Hypocalcaemia -‐ Inves;ga;ons

•  Serum PTH •  Kidney Function (U&Es) •  25-hydroxy-vitamin D Level


Hypocalcaemia -‐ Management

Vitamin D & Calcium Supplements (IV calcium gluconate may be used if acute)


Summary of Parathyroid Pathology

Calcium Phosphate PTH

1o Hyperparathyroid é ê é

2o Hyperparathyroid ê ê é

3o Hyperparathyroid é é é

Vitamin D Excess é é ê

Hypoparathyroid ê é ê

Pseudohypoparathyroid ê ê é

Disorders of Potassium


Hyperkalaemia •  plasma potassium > 6.5 mmol / l

•  leads to myocardial hyperexcitability

–  leading to VF + cardiac arrest

•  Fast irregular pulse, Cx pain, weakness, palpitations, lightheadedness


Hyperkalaemia •  ECG : Tall tented T waves, small P waves, wide QRS, VF


Hyperkalaemia •  Causes

–  K+ sparing diuretics

–  Oliguric renal failure

–  Metabolic acidosis

–  Addison’s disease

–  Massive blood transfusion

–  Burns

•  Treat : polystyrene suffocate resin (calcium resonium)

•  binds to K+ in gut, preventing absorption


Hypokalaemia •  Plasma potassium < 2.5 mmol / l

•  Usually asymptomatic

•  Muscle weakness, hypotonia, hyporeflexia, cramps, palpitations, light headedness

•  Causes:

•  IV fluids without K+

•  Diuretics, rectal villous adenoma, Cushings, renal tubular acidosis, insulin treatment, severe diarrhoea, intestinal obstruction

•  Treat : PO K+ or IV K+

Neuroendocrine Tumours


MEN •  Multiple endocrine neoplasia

•  inherited condition > hormone secreting tumours

•  Type 1 & Type 2

•  MEN 1

•  Diagnosis: More than 2 neuroendocrine tumours, plus the genetic mutation

•  Symptoms depend on tumour, gland involved, and hormones secreted

•  95% have parathyroid hyperplasia/adenoma

•  70% have pancreatic endocrine tumours (gastrinoma, insulinoma, somatostatinoma, VIPoma, glucagonoma)


MEN •  MEN 2a / MEN 2b

•  Medullary thyroid carcinoma seen in 100%

•  Phaeochromocytoma seen in 50%

•  Parathyroid hyperplasia in 80%


Carcinoid syndrome •  Symptoms of patients with metastases from carcinoid (neuroendocrine) tumours

•  Implies hepatic involvement

•  Bronchoconstriction

•  Paroxysmal flushing

•  Diarrhoea

•  CCF

•  Measure serotonin metabolite 5-HIAA in a 24 hr urine sample + Imaging

•  Treat : Octreotide + interferon alpha


Carcinoid crisis •  Tumour outgrows blood supply

•  or handled too much during surgery

•  Mediators flow out

•  vasodilatation, hypotension, tachycardia, bronchoconstriction, hyperglycaemia

•  Treat

•  high dose octreotide

The End!!

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