Endocrinology Flashcards
(189 cards)
1
Q
Outer adrenal cortex
A
Developed from mesoderm
Secretes steroid hormones
Controlled by anterior pituitary
2
Q
Inner adrenal medulla
A
Developed from neuroectoderm
Secretes catecholamines – Adrenaline and noradrenaline.
Under nervous control
3
Q
What are the 3 zones of the adrenal cortex?
What do they produce?
A
- Zona glomerulosa
=> Secretes aldosterone. - Zona fasciculata
=> Secretes cortisol (and also weak androgens) - Zona reticularis
=> Secretes weak androgens (and also cortisol)
4
Q
Cortisol production
A
Mostly produced in zona fasciculata, but also in zona reticularis
HPA axis – CRH => ACTH => stimulates production of cortisol in the adrenal cortex
There are diurnal variations in cortisol production - peak in the early morning and are low in the late evening
Negative feedback loop – cortisol acts at the hypothalamus and pituitary to suppress CRH and ACTH release
5
Q
How does ADH affect cortisol levels?
A
AVP (ADH) acts synergistically with CRH to elevate ACTH levels – e.g. when volume levels are depleted
6
Q
What does cortisol do?
A
Reduce protein and fat stores.
Inhibit glucose uptake by many tissues (but not the brain).
Stimulate hepatic gluconeogenesis.
Permits vasoconstrictive effect of catecholamines.
7
Q
Weak androgen production
A
Zona reticularis (and somewhat fasciculata)
Release is regulated by ACTH (and other unknown factors), but there is no feedback on CRH/ACTH
There is age-related production of androgens, which peaks at age 21 and then gradually declines
8
Q
What do weak androgens do?
A
Constitute about 50% of the androgen activity in women (leading to axillary/pubic hair growth and libido).
There is negligible contribution in men due to their higher levels of testosterone, which is much more potent than weak androgens
9
Q
What is important to note about the rate of production of adrenal steroids?
A
steroids are lipophilic, they diffuse out of cells immediately upon synthesis.
So, rate of synthesis = rate of secretion.
10
Q
Adrenaline
A
Mixed α- and β-agonist
11
Q
Noradrenaline
A
Primarily α-agonist
12
Q
What does stimulation of α-adrenoceptors do?
A
Primarily vasoconstriction
13
Q
What does stimulation of β-adrenoceptors do?
A
tachycardia,
insulin resistance,
vasodilatation in arteries serving skeletal muscle
14
Q
What is Cushing’s syndrome?
A
= an umbrella term for excessive glucocorticoid activity
Most commonly exogenous (after high-dose/long-term steroids).
15
Q
What are primary causes of Cushing’s syndrome?
A
Adrenal carcinoma/adenoma autonomously secreting cortisol
Will be Low ACTH, High cortisol
16
Q
What are Secondary causes of Cushing’s syndrome?
A
excessive production of ACTH
=> Pituitary tumour
=> Ectopic tumour (most commonly lung)
17
Q
What is Cushing’s DISEASE?
A
An ACTH-producing pituitary tumour
18
Q
Signs and Symptoms of Cushing’s Syndrome
A
Due to wide effects of cortisol, there will be varying signs and symptoms
=> Altered fat deposition
=> Excess production of adrenal androgens (if ACTH-dependent)
=> Breakdown of protein, muscle wasting, loss of collagen
=> Mental changes
=> Altered bone metabolism
=> Excess mineralocorticoid activity
=> Hyperglycaemia
19
Q
What can glucocorticoid excess in children lead to?
A
Growth retardation
20
Q
What mental changes are typically seen in Cushing’s syndrome?
A
Cognitive difficulties
Emotional instability
Depression
Sleep disturbances
21
Q
What are signs of excess production of adrenal androgens ?
A
Acne
Female frontal balding
Female hirsutism
Menstrual irregularities
22
Q
Diagnosis of Cushing’s syndrome
A
cortisol measurements
=> identify LOSS OF DIURNAL RYTHYM via a morning and evening cortisol measurement
Constantly high levels of serum cortisol would indicate Cushing’s Syndrome
23
Q
How can you differentiate between primary and secondary Cushing’s syndrome?
A
Decreased ACTH levels would indicate a primary cause.
High ACTH levels would indicate a secondary cause.
24
Q
Dexmethasone suppresion test
A
Dexamethasone = synthetic glucocorticoid
Giving dexamethasone should activate negative feedback loops and cause a decrease in endogenous cortisol
25
lack of suppression with low-dose dexamethasone
indicates hyper-/autonomous secretion of cortisol – confirms Cushing’s syndrome.
26
lack of suppression with high-dose dexamethasone
indicates ectopic ACTH source (not in HPA axis so no negative feedback possible)
High-dose dexamethasone should suppress cortisol release in Cushing's disease
27
when is a CRH Stimulation Test used?
Used to distinguish between pituitary-dependent Cushing’s and an ectopic course of ACTH
Normally - CRH will cause an increase in both ACTH and cortisol
In pituitary-dependent Cushing’s patients, the response is exaggerated.
In ectopic ACTH syndrome, there will be no response to CRH as they do not recognise it
28
What are the long-term risks/complications of Cushing's syndrome?
* Cardiovascular disease
* Diabetes
* Osteoporosis
* Obesity
29
What is Addison's disease?
= Primary Adrenocortical Insufficiency
Failure of adrenal cortex leads to low aldosterone, low cortisol, low androgens
will be elevated ACTH in an attempt to raise hormone secretion due to a lack of negative feedback
30
What tends to cause Addison's disease
Most commonly in UK - autoimmune
Worldwide - TB
Other cause - adrenal metastases
31
Addison's disease - presentation
relatively non-specific symptoms, such as:
LACK OF MINERALOCORTICOID:
Postural hypotension
Muscle weakness, fatigue, lethargy
Hyponatraemia, hyperkalaemia
ELEVATION OF ACTH
Increased pigmentation
LOW GLUCOCORTICOIDS:
Weight loss/anorexia
ALTERED ELECTROLYTES:
Diarrhoea, nausea, vomiting
32
How does elevated levels of ACTH cause hyperpigmentation?
Where is hyper pigmentation often seen?
When ACTH production is increased, so is melanocyte-stimulating hormone (MSH), as they share the same POMC-precursor.
Increased MSH leads to increased melanin content in the skin.
Hyperpigmentation is most often seen in skin creases, old scars, gums and on the inside of the cheek.
33
Tests for Adrenal Failure
Decreased cortisol levels and increased ACTH levels indicates primary disease.
ACTH stimulation test – failure to stimulate confirms a problem with the adrenal gland.
Adrenal autoantibodies – if suspected autoimmune disease
34
Treatment of Addison's disease
Treatment will be with life-long hormone replacement:
Glucocorticoid – hydrocortisone; high dose AM, lower dose PM.
Mineralocorticoid – fludrocortisone.
Higher doses of glucocorticoid are needed during periods of major stress/illness.
35
Secondary adrenal insufficiency
Occurs due to lack of ACTH production
Can be due to a tumour or damage to the pituitary gland/stalk. Can also be caused by exogenous glucocorticoid use.
There will be low cortisol, with around normal aldosterone levels as the RAAS remains intact.
36
Secondary adrenal suppression
long-term, high-dose glucocorticoid use causes suppression of ACTH production and thereby atrophy of the adrenal cortex
Causes reduction in production of endogenous cortisol
37
When should you suspect adrenal suppression in use of exogenous steroids?
cushingoid appearance (truncal obesity, round face, dorsocervical fat pads, striae)
38
What can happen if there is abrupt withdrawal of exogenous steroids?
symptoms of acute adrenal insufficiency (fatigue, N&V, anorexia, weight loss, hypotension, myalgia) due to the patient’s lack of endogenous cortisol.
39
Adrenal Crisis
MEDICAL EMERGENCY
acute adrenal insufficiency and becomes expressed when the patient is under stress (e.g. infection), leading to hypotension, circulatory failure and potentially death
Urgent treatment - IV fluids and hydrocortisone
40
What is Conn's syndrome?
What causes this?
= primary hyperaldosteronism
An abnormally large amount of aldosterone is produced.
Most common cause is a tumour of the adrenal gland
41
What is secondary hyperaldosteronism?
abnormally high aldosterone levels but caused by increased RAAS activity (e.g. Renal artery stenosis or juxtaglomerular cell tumours).
42
Clinical and biochemical presentation of Conn's Syndrome
- retention of Na+ and water => hypertension
- increased K+ elimination => hypokalaemia
- metabolic alkalosis
Muscle weakness and cramps/spasms
Paraesthesia
Polyuria
Headaches
43
Conn's Syndrome - investigations
U&Es (hypernatraemia and hypokalaemia)
| Aldosterone-Renin Ratio (would be raised)
44
Conn's Syndrome - management
If due to a tumour - removed with surgery.
activity of the excess aldosterone will be blocked with aldosterone receptor antagonists (e.g. spironolactone).
45
Phaeochromocytoma
= a rare catecholamine-producing tumour of the chromaffin cells
46
10% rule for Phaeochromocytoma
* 10% malignant
* 10% extra-adrenal
* 10% bilateral
* 10% familial
47
Phaeochromocytoma - clinical features
Classic triad of symptoms:
1. Episodic headache,
2. Diaphoresis (excessive sweating)
3. Tachycardia.
Features by system:
Cardiovascular – angina, palpitations, MI, arrhythmias
CNS – tremor, Horner’s syndrome, haemorrhage
Psychiatric – anxiety, panic, confusion, psychosis, hyperactivity
GI – diarrhoea, vomiting, abdominal pain
Other:
• Hyperglycaemia (stimulation of adrenoceptors leads to glycogenolysis and gluconeogenesis)
• Sweating, flushing, heat intolerance
• Pallor
48
Phaeochromocytoma - management
Surgery needed to remove tumour, using alpha- and beta-blockers during surgery to avoid crisis
49
Where is the body's calcium?
99% is in the bone and combined with phosphate as hydroxyapatite.
Plasma calcium is either bound to albumin or as free ions (Ca2+).
Only free Ca2+ is biologically active.
50
Plasma calcium normal range
2.2 - 2.6 mmol/L
Maintaining calcium at optimum range ensures normal excitability of nerve and muscle.
Calcium is also required for clotting and complement cascades.
Reference ranges are specific to laboratories and reference range can be corrected for low/high serum albumin
51
parathyroid glands
4 pea-sized glands
just posterior to thyroid gland
have calcium and vitamin D receptors
chief cells of the parathyroid glands are responsible for secreting parathyroid hormone (PTH)
52
When is PTH secreted?
when plasma calcium levels are low
also in response to low vitamin D, or high phosphate levels
53
How does PTH work to increase calcium levels?
1. Directly stimulating calcium reabsorption from bone, via increased osteoclast activity.
2. Directly increasing renal tubular calcium reabsorption.
3. Indirectly stimulating increased GI calcium absorption.
=> Via increased vitamin D activation in the kidney
also has a secondary effect of increasing renal phosphate excretion
54
From where is calcitonin secreted?
secreted by the parafollicular/”C” cells of the thyroid gland in response to increased plasma calcium levels.
55
Actions of calcitonin
acts to decrease plasma calcium levels, by antagonism of the effects of PTH on the bone.
=> Reducing osteoclast activity
=> Decreasing renal resorption of calcium and phosphate.
BUT the importance of calcitonin is controversial
56
Actions of Vitamin D
acts to sustain plasma calcium and phosphate levels by increasing their absorption from the GI tract
also required for normal bone formation
57
Sources of vitamin D
Endogenously it is synthesised in the skin, forming D3 (cholecalciferol).
=> Action of UV light on the precursor to vitD (7-dehydrocholesterol)
Exogenously it is ingested as D3/D2
=> D3 – found in fish, liver, dairy products
=> D2 – found in plants/fungi (less potent than D3)
Vitamin D3 is hydroxylated in the liver to form 25-hydroxycholecalciferol. There is a second hydroxylation in the kidney, to produce 1,25-hydroxycholecalciferol.
58
Vitamin D deficiency can occur in those with...
Inadequate sunlight exposure.
Malabsorptive conditions
Liver/kidney disease
59
Symptoms of hypercalcaemia
Mild hypercalcaemia (<3.0 mmol/L) is usually asymptomatic.
Symptoms in hypercalcaemia (>3.0 mmol/L):
- tiredness, dehydration, depression, confusion
- Renal colic, polyuria
- potentially bone pain
- abdominal pain
- ectopic calcification
i.e. “Bones, stones, abdominal moans, psychiatric groans”
60
Signs of hypercalcaemia
Corneal calcifications – subtle yellow area of sclera bilaterally at region of muscle insertion.
Renal calculi
“Brown tumour” – highly vascular lytic lesion of the bone, occurring in hyperparathyroidism.
61
What are the causes of hypercalcaemia?
1. Excessive PTH secretion
2. Malignant disease of bone
3. Excess action of Vit D
4. Excessive calcium intake
5. Drugs
62
What drugs can cause hypercalcaemia?
Thiazide diuretics,
VitD analogues,
lithium administration,
Vitamin A
63
What can cause excessive PTH secretion?
Primary hyperparathyroidism
Tertiary hyperparathyroidism – occurs in renal failure.
Ectopic PTH secretion
64
What malignant diseases can cause hypercalcaemia?
Myeloma – cancer of plasma cells in bone marrow.
Bone metastases
Lytic lesions in bone – due to secretion of osteoclastic factors by tumours
PTH-related protein
65
Clinical features of hypocalcaemia
Most patients with low calcium are asymptomatic.
Abrupt changes in calcium level are more likely to produce symptoms.
CNS - irritation, confusion, cognitive changes, seizures
PNS - muscle cramps, Chvostek's sign, tetany, paraesthesia
Cardiac - bradycardia, arrhythmias, prolonged QT interval, hypotension
66
What is Chvostek's sign?
when tapping over the facial nerve causes facial muscles to twitch
67
What are the causes of hypocalcaemia?
1. Hypoparathyroidism
2. Vitamin D deficiency
3. Increased Phosphate levels
4. Others:
- Drugs – calcium chelators, bisphosphonates, drugs affecting vitamin D.
- Acute pancreatitis
- Acute rhabdomyolysis
- Malignancy – tumour lysis
68
What can cause hypoparathyroidism?
Post thyroidectomy – not enough PT gland.
Destruction of PT gland – e.g. autoimmune or tumour infiltration.
Congenital deficiency
Idiopathic hypoparathyroidism
Severe hypomagnesaemia
69
what can cause VitD deficiency?
Problem with absorption
Problem with conversion – CKD/liver cirrhosis
Osteomalacia/rickets
Vit D resistance
70
Clinical reasoning for hypocalcaemia
Rule out low albumin – make sure the reported calcium level is adjusted for albumin level
Measure Vitamin D level
Measure PTH level
Consider tissue consumption of calcium
71
When can there be increased tissue consumption of calcium?
precipitation of calcium into extra-skeletal tissues occurs in pancreatitis
bone formation in some malignancies
rhabdomyolysis
72
what is diabetes mellitus?
a group of metabolic disorders characterised and identified by the presence of hyperglycaemia in the absence of treatment
73
T1DM - pathophysiology
Autoimmune disease
Antibodies targeted against the insulin-secreting beta cells of the islets of Langerhans in the pancreas.
Leads to cell death and inadequate insulin secretion.
Viral infections may trigger the autoimmune process, or can be idiopathic
74
T1DM - clinical presentation
Presents in childhood/adolescence, with a 2-6 week history of:
- Polyuria – high sugar content in urine leading to osmotic diuresis
- Polydipsia – due to resulting fluid loss.
- Weight loss – fluid depletion and fat/muscle breakdown.
Diabetic Ketoacidosis (DKA) is also a common first presentation
75
T2DM - pathophysiology
“Insulin resistance” – associated with aging, genetic factors, obesity, high fat diets and sedentary lifestyle.
=> Peripheral resistance – tissues become insensitive to insulin.
=> Blood insulin levels are initially normal, or even increased to compensate for insensitivity to insulin.
Eventually pancreatic beta cells decompensate and can no longer produce excess insulin, leading to hyperglycaemia.
76
T2DM - clinical presentation
Onset may be over many months/years.
Classic triad of symptoms (polyuria, polydipsia, weight loss) may be present, but less noticeable than T1DM.
More common presenting features:
Lack of energy
Visual blurring – glucose-induced refractive changes.
Pruritis vulvae/balantis – due to candida infection.
In older patients, it may be the complications of diabetes that are the presenting feature
77
What is metabolic syndrome?
combination of T2DM, central obesity, HTN
78
Maturity Onset Diabetes of the Young
Genetic defect – autosomal dominant inheritance
Defects in beta-cell function.
Usually affects those <25 years of age.
Mimics T1DM
especially consider if drug treatment does not control the hyperglycaemia.
79
What are some secondary causes of diabetes?
Pancreatic disease – CF, chronic pancreatitis, pancreatic carcinoma, pancreatic trauma/surgery.
Endocrine disease – Cushing’s disease, acromegaly, thyrotoxicosis, phaeochromocytoma.
Drug-induced – thiazide diuretics, corticosteroids, antipsychotics, antiretrovirals.
Congenital – insulin-receptor abnormalities, myotonic dystrophy, Friedrich’s ataxia.
Gestational diabetes
Infections – congenital rubella, cytomegalovirus, mumps
80
Release of insulin
Insulin is released by beta cells when glucose levels rise after a meal.
Insulin acts upon glucose transporters (GLUTs).
=> GLUT2 – senses glucose in beta cells.
=> GLUT4 – insulin-mediated glucose uptake in skeletal muscle and adipose tissue.
81
What are the effects of insulin?
anabolic effects - result in glucose being converted to:
- glycogen in muscle,
- glycogen and triglycerides in the liver
- triglycerides in adipose tissue.
82
what occurs to blood glucose during a fasting state?
insulin production is down-regulated and glucose stores are released through glucagon-mediated gluconeogenesis therefore preventing a hypoglycaemic state
83
What occurs in the absence of insulin?
glucose cannot be taken up into the cells effectively, starving the cells of their most effective substrate to make energy
this signals gluconeogenesis, glycogenolysis and lipolysis as the body can no longer make use of the glucose that is available
84
Diabetic Ketoacidosis
= absolute insulin deficiency resulting in hyperglycaemia in the presence of acidosis and ketosis.
medical emergency.
Develops over hours to 1-2 days.
Associated with T1DM, increasingly seen in T2DM
85
what are the common causes of DKA?
1st presentation of diabetes
stress of infection/injury
poor compliance to insulin therapy
MI can also precipitate DKA in diabetic patients.
86
Pathophysiology of DKA
Rapid lipolysis in glucose-starved tissues.
=> will be production of ketone bodies from the conversion of free fatty acids to acetoacetate
Hepatic glucose production via glycogenolysis and gluconeogenesis
=> worsening hyperglycaemia
Hyperglycaemia causes diuresis
=> hypovolaemia and dehydration - can result in AKI and electrolyte disturbances
ABG/VBG will show metabolic acidosis due to bicarbonate consumption by acidic ketone bodies
87
Where can ketones be detected?
In the patients breath or urine
88
What electrolyte disturbances are likely to be seen in DKA?
hyponatraemia
| hypokalaemia
89
How would the body compensate for the metabolic alkalosis
Hyperventilation to blow off CO2 to maintain acid base balance
Initially rapid breathing will give way to Kussmaul’s breathing (deep, laboured breathing) in DKA
90
what are some symptoms of DKA?
```
polyuria, polydipsia
generalised abdominal pain
confusion, drowsiness,
blurred vision (due to the lens being affected)
in severe cases - coma.
```
91
Management of DKA
A-E Assessment (+/- urgent care review)
intravenous insulin
IV fluids with electrolyte replacement
assessment for precipitating factors and treating these
92
Hyperosmolar Hyperglycaemic State (HHS)
severe RELATIVE INSULIN DEFICIENCY resulting in hyperglycaemia leading to diureses (leading to volume depletion, dehydration and haemoconcentration) in the absence of severe ketosis and acidosis
Mortality is 10x more likely in HHS than DKA. HHS requires the same urgent treatment
93
why does ketosis not occur in HHS?
even a small amount of insulin is enough to prevent ketosis
94
What is HHS osmolality compared normal?
```
Normal = 280-295 mmol/kg
HHS = >320 mmol/kg
```
95
What are the criteria for diagnosing HHS?
Hypovolaemia (due to osmotic diuresis)
Marked Hyperglycaemia (serum glucose >30mmol/L)
No significant ketonaemia/ketonuria (serum ketone <3mmol/L)
No significant acidosis (pH >7.3, bicarb >15mmol/L)
Osmolality >320mmol/kg
96
How are the macrovascular complications of diabetes caused?
Hyperglycaemia => formation of advanced glycation end products (AGE) on arterial endothelial cells and activation of inflammatory pathways
this results in formation of foam cells from macrophages in the intimal layer of arteries => exacerbates the process of atheroma formation
97
Microvascular complications of diabetes
Coronary Artery Disease
Cerebrovascular Disease
Peripheral Vascular Disease
98
Microvascular complications of diabetes
Retinopathy
Nephropathy
Sensorimotor peripheral neuropathy
Autonomic neuropathies
99
How are the microvascular complications of diabetes caused?
AGE-activated biochemical pathways resulting in cellular damage caused by abnormal extracellular protein matrix accumulation and reactive oxygen species production.
100
What is vital to prevent complications of diabetes and why?
It is vital to maintain normal and stable glycaemic control in diabetic patients as well as treat hypertension
Avoid chronic hyperglycaemia, wide glycaemic fluctuations and postprandial hyperglycaemia
101
Diabetic foot complications
an interplay between both macro and microvascular pathophysiology
results in an acute localized inflammatory condition that may lead to varying degrees and patterns of bone destruction, subluxation, dislocation, and deformity
102
In which populations is HbA1c inappropriate?
Those <18 years old.
Those acutely unwell (glucose temporarily raised in infection/steroid use)
Pregnancy
HIV, sickle cell disease, recent blood transfusion, liver disease, CKD, iron deficiency anaemia, B12/folate deficiency anaemia
103
What test results are diagnostic of diabetes in a patient WITH symptoms/signs?
Fasting plasma glucose values of ≥ 7.0 mmol/L
Oral Glucose tolerance test (OGTT) – 2-hour plasma glucose ≥ 11.1 mmol/L
HbA1c ≥ 48 mmol/mol
Random blood glucose ≥ 11.1 mmol/L
104
What test results are diagnostic of diabetes in a patient WITHOUT symptoms/signs?
Repeat testing is required as soon as possible for another raised value (ideally same test)
105
Impaired Fasting Glucose (IFG)
Fasting plasma glucose = 6.1 mmol/L to 6.9 mmol/L.
Normal 2-hour plasma glucose (<7.8)
106
Impaired Glucose Tolerance (IGT)
2-hour plasma glucose = 7.8 mmol/L to 11.0 mmol/L.
Normal fasting plasma glucose
107
"Prediabetes"
HbA1c is not at the diabetic level, but not normal either (i.e. 42-47 mmol/mol)
108
Management of T1DM
Basal bolus regime of insulin – long-acting insulin alongside boluses of short-acting insulin with their meals.
Structured education on hyperglycaemic effects of different foods – adjust bolus dose accordingly.
Dose Adjustment for Normal Eating (DAFNE) = a national programme for T1DM education.
Complex carbohydrates encouraged in moderation, with low glycaemic index foods preferred).
Increased fibre intake and 5 F&V are encouraged
109
Lifestyle management of T2DM
Focus on healthy eating and reducing CV risk.
Smoking cessation is vital.
Moderation of alcohol consumption.
Weight loss
Exercise – 20-30 minutes of physical activity per day.
110
Location of pituitary gland
located just below the hypothalamus
sits in the sella turcica, a small bony cavity at the base of the skull
“hangs” from the hypothalamus by a stalk called the infundibulum.
111
What are the two distinct lobes of the pituitary gland?
1. The Posterior Pituitary/“Neurohypophysis”
| 2. The Anterior Pituitary/“Adenohypophysis”
112
Posterior pituitary
The axons of hypothalamic neurons, which pass down the pituitary stalk in the hypothalamic-hypophyseal tract and terminate in the posterior pituitary.
These axon terminals store and release Oxytocin and Vasopressin (ADH)
113
Oxytocin
A neuropeptide produced in the hypothalamus.
Stored and released by the axon terminals in the posterior pituitary.
Involved in lactation, uterine contraction (and cervical dilatation), and bonding
114
Vasopressin/ADH
A hormone produced in the hypothalamus. It is stored and released by the axon terminals in the posterior pituitary.
Released in response to hyperosmolality of extracellular fluid.
Two primary actions:
(i) Increases water reabsorption from the collecting duct of the nephrons
(ii) Causes arteriolar constriction, acting to raise blood pressure.
115
Anterior pituitary
The hypothalamus exerts hormonal control over the anterior pituitary via secretion of various releasing hormones into the small hypophyseal portal vein that directly supplies the adenohypophysis.
The anterior pituitary synthesises and releases:
- Thyroid Stimulating Hormone (TSH)
- Adrenocorticotropic Hormone (ACTH)
- Growth Hormone (GH)
- Follicle-stimulating Hormone (FSH)
- Luteinising Hormone (LH)
- Prolactin (PRL)
116
Thyroid Stimulating Hormone (TSH)
* Release of Thyroid stimulating hormone (TSH) is mediated by the hypothalamus, via release of Thyrotropin Releasing Hormone (TRH).
* The TSH then stimulates the release of T3 (Triiodothyronine) and T4 (Thyroxin) from the thyroid gland.
* The Thyroid hormones (with T3 being the more active form) primarily act to increase the basal metabolic rate. They also affect protein synthesis, neural and long-bone development, and response to catecholamines.
117
Adrenocorticotropic Hormone (ACTH)
* ACTH acts within the Hypothalamic-Pituitary-Adrenal axis.
* It is released in response to stress, under the control of hypothalamic secretion of Corticotropin-Releasing Hormone (CRH).
* The main effect of ACTH is to stimulate production and release of cortisol in the adrenal cortex.
* ACTH is cleaved into α-melanocyte-stimulating hormone after a short period of time.
118
Growth Hormone (GH)
* GH is a peptide hormone that stimulates growth, cell reproduction and cell regeneration.
* It also stimulates IGF-1 production and increases glucose and free fatty acid concentrations.
* Its release is triggered by Growth Hormone Releasing Hormone (GHRH), which is secreted by the hypothalamus.
* Excess Growth Hormone production in adulthood causes Acromegaly
119
Follicle-stimulating Hormone (FSH)
* FSH is a gonadotropic hormone, synthesised and secreted by the anterior pituitary gland.
* Its release is triggered by Gonadotropin-Releasing Hormone (GnRH), which is secreted by the hypothalamus.
* It performs a role in regulating development, growth, puberty, and reproductive processes.
* FSH works with Luteinising Hormone (LH) to regulate the reproductive system.
* In both males and females, FSH stimulates maturation of germ cells.
120
How does FSH influence maturation of germ cells in males?
FSH sustains spermatogenesis
121
How does FSH influence maturation of germ cells in females?
FSH initiates follicular growth, with levels declining in the late follicular phase, which selects only the most advanced follicle to proceed to ovulation.
122
Luteinising Hormone (LH)
* LH is a gonadotropic hormone produced and secreted by the anterior pituitary.
* It acts together with FSH to regulate the reproductive system.
* Its release is triggered by Gonadotropin-Releasing Hormone (GnRH), which is secreted by the hypothalamus.
* In both males and females, LH acts upon gonadal endocrine cells to produce androgens.
123
How does LH cause androgen production in males?
In males, LH acts upon the Leydig cells in the testis, causing them to produce testosterone.
124
How does LH cause androgen production in females?
In females, LH supports ovarian theca cells to provide androgens. The “LH surge” at the end of the follicular phase triggers ovulation.
125
Prolactin (PRL)
* Prolactin is secreted from the anterior pituitary in response to a number of stimuli including eating, mating, ovulation and breastfeeding.
* It helps to regulate metabolism and the immune system.
* Prolactin release is inhibited by secretion of dopamine, making it the only anterior pituitary hormone whose principle control is by inhibition.
* The main effect of Prolactin is to stimulate milk production (lactation) by the mammary glands.
126
Pituitary adenoma
= a benign tumour of the glandular tissue.
Benign but can be life-threatening due to mass effects or secretory actions.
Account for ~10% of intracranial tumours.
Classified by size, function and histology.
127
Pituitary adenoma - size
<10mm = microadenoma
>10mm = macroadenoma
128
Pituitary adenoma - function
Functioning – hypersecretion or one or more pituitary hormones.
Non-functioning.
129
Pituitary adenoma - histology
1. Chromophobe – secrete prolactin/non-functioning.
2. Acidophil – secrete GH or prolactin.
3. Basophil – secrete ACTH
130
Presentation of pituitary adenoma - local effects
```
Headache
Bitemporal Hemianopia
Occular palsies
Hypothalamic disruption
Disconnection prolactinaemia
Hydrocephalus
CSF rhinorrhoea
Pituitary apoplexy
```
131
What is bitemporal hemianopia?
| How can it be caused by a pituitary tumour?
Both temporal visual fields are lost
due to compression of the tumour on the optic chiasm
132
Disconnection prolactinaemia
Compression of pituitary stalk, preventing dopamine (which inhibits prolactin release) from reaching the anterior pituitary.
Disinhibition of prolactin release => hyperprolactinaemia
133
Pituitary apoplexy
= acute haemorrhage/infarction of pituitary gland
Sudden headache, often associated with rapidly worsening visual field defect or diplopia.
Subsequent lack of essential hormones – most notably ACTH resulting in adrenocortical insufficiency
134
How can pituitary tumours cause ocular palsies?
Compression/infiltration of CN III, IV, VI
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How can pituitary tumours cause hydrocephalus?
Compression of ventricles - interruption of CSF flow.
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Presentation of pituitary adenoma - systemic effects
Can result from either:
1. Hormone excess (can be wither micro- or macroadenoma)
2. Hypopituitarism/hormone deficiency (tends to be only macroadenoma)
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Hormone excess - prolactin
= Hyperprolactinaemia
Galactorrhoea/Amenorrhoea/Hypogonadism
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Hormone excess - GH
= Acromegaly
Headache/Sweating/Change in shoe size and/or ring size
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Hormone excess - ACTH
= Cushing’s
Weight gain/Bruising/Myopathy/Hypertension/
Striae/Depression
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Hormone deficiency - GH
Lethargy
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Hormone deficiency - ACTH
Lethargy, Postural Hypotension, Pallor, Hair loss
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Hormone deficiency - TSH
Signs of hypothyroidism
| e.g. Lethargy, constipation, Dry Skin, Weight Gain
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Hormone deficiency - ADH
Diabetes insipidus (thirst, polyuria)
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Hormone deficiency - LH/FSH
Lethargy, Loss of Libido, Hair loss, amenorrhoea, infertility, erectile Dysfunction
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Hypothalamic-Pituitary-Thyroid Axis and its negative feedback loops
TRH secreted by hypothalamus
Stimulated pituitary to produce TSH
TSH is secreted into the systemic circulation
Increased serum T3 and T4
T3 and T4 then enter cells, where they bind to nuclear receptors and promote increased metabolic and cellular activity
Levels of T3 are sensed by receptors in the pituitary and the hypothalamus.
=> If they rise above normal, TRH and TSH production is suppressed, leading to reduced T3 and T4 secretion.
=> Peripheral T3 and T4 levels fall to normal.
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Effects of TSH
1. Stimulates increased thyroidal iodine uptake by the thyroid, and the synthesis and release of thyroxine (T4) and triiodothyronine (T3)
2. stimulation of the conversion of T4 to T3 (the more active hormone) in peripheral tissues
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‘Compensated Euthyroidism’
If the T3 and T4 levels are low (e.g. after thyroidectomy) increased amounts of TRH and TSH are secreted, stimulating the remaining thyroid to produce more T3 and T4.
Blood levels of T3 and T4 may be restored to normal, but there will be high TSH
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What are some other regulatory factors of thyroid hormone secretion?
COLD
=> mainly plays a role in the newborn moving out of the womb during birth
=> cooler temperature stimulates a massive increase in TRH, which then stimulates TSH levels and thereby the release of T3 and T4.
=> The resulting increased metabolism will lead to increased body temperature to cope with the cooler environment.
=> This effect is negligible in adults unless there is chronic exposure (e.g. living in the arctic).
STRESS
=> acute stress (i.e. trauma) has an inhibitory effect on thyroid hormones.
=> directly inhibits release of TRH.
=> also stimulates the release of somatostatin from the anterior pituitary, which inhibits TSH.
=> Inhibition of release of T3/T4 prevents the conversion of stored macromolecules into heat, which is not useful in stressful situations.
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What is hypothyroidism?
= low levels of T3 and T4
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What occurs in primary hypothyroidism?
Will there be a goitre?
= associated directly with the thyroid gland – the gland is not making enough hormones, so there is minimal activation of the negative feedback loop.
This leads to elevated TRH/TSH levels.
TSH is no longer able to stimulate release of T3 and T4, so the levels of the thyroid hormones remain low.
There should be a goitre, due to the elevated levels of TSH enlarging the cells of the thyroid gland.
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Causes of primary hypothyroidism
90% of all hypothyroidism is primary and is due to Hashimoto’s thyroiditis, an autoimmune condition.
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Hashimoto's Thyroiditis
T-cells destroy the gland, alongside B-cell secretion of inhibitory TSH-receptor antibodies.
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What occurs in secondary hypothyroidism?
Will there be a goitre?
Hypothyroidism secondary to hypothalamic anterior pituitary failure causing low levels of TSH.
The lack of TSH means that there is a lack of stimulation for the production of T3 and T4.
There will not be a goitre and there may even be atrophy of the thyroid gland due to the low TSH levels.
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what occurs in hypothyroidism due to lack of dietary iodine?
Will there be a goitre?
= most common global cause of hypothyroidism i
Lack of iodine to synthesise T3 and T4
low levels of T3 and T4 leads to minimal activation of the negative feedback loop and therefore increased TRH and TSH.
Raised TSH causes enlargement of the thyroid gland = "simple, non-toxic goitre"
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How has iodine deficiency been prevented in the UK?
addition of iodine to salt
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Other causes of hypothyroidism
Drug-induced – e.g. anti-thyroid drugs, lithium, amiodarone.
Radioactive iodine therapy, surgery
Thyroid Hormone Resistance – when the body does not recognise thyroid hormones.
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Hypothyroidism - clinical features
Signs and symptoms are generally related to the decrease in BMR and overall metabolic activity
Tiredness
Weight gain
Dry skin, thinning hair
Hoarse voice, slow speech
Menstrual changes – dysmenorrhoea, oligomenorrhoea, menorrhagia, infertility.
Cold intolerance
Loss of appetite
Constipation
Bradycardia
Depression, confusion, poor memory, mental “slowness”
Myxoedema in some patients – a puffy, oedematous appearance of the face and eyelids
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Features of hypothyroidism in children
may not show classic symptoms but can grow poorly, perform poorly at school and may not develop at puberty.
Babies are assessed for congenital hypothyroidism (born with deficiencies in thyroid hormones) by TSH and T4 levels in the heel-prick test.
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Diagnosis of hypothyroidism
thyroid function test to measure T3, T4 and TSH.
- Primary hypothyroidism – low T3 and T4, high TSH
- Secondary hypothyroidism – low T3 and T4, low TSH
Thyroid autoantibodies:
- Thyroid peroxidase antibodies – associated with hypothyroidism
- Thyroglobulin antibodies – associated with Hashimoto’s thyroiditis.
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Which antibodies are associated with hashimoto's thyroiditis?
Thyroglobulin antibodies
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Hypothyroidism - treatment
Hormone replacement therapy with levothyroxine for life.
Starting dose depends on the patient – start low and titrate up to clinical effect.
Reassess every 4-6 weeks to see if TSH goes down (however TSH unreliable if secondary cause)
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What is hyperthyroidism?
= high levels of T3 and T4.
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What are common causes of hyperthyroidism?
most common cause = Graves’ Disease (~70-80%)
Also
- Solitary toxic nodule/adenoma
- Toxic multinodular goitre
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What occurs in Grave's Disease?
Will there be a goitre?
an autoimmune condition with thyroid-STIMULATING immunoglobulins, which bind to TSH-receptors and cause release of thyroid hormones.
There will be elevated T3 and T4, and low TSH (and TRH), as T3/T4 inhibit TSH/TRH release via negative feedback loops.
There will be a goitre due to thyroid-stimulating immunoglobulins stimulating growth of thyroid cells and causing enlargement
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What are uncommon/rare causes of hyperthyroidism?
Secondary hyperthyroidism (excess hypothalamic/anterior pituitary secretion)
De-Quervain’s thyroiditis
HCG-stimulated thyrotoxicosis
Neonatal thyrotoxicosis (due to maternal antibodies)
Iatrogenic causes – e.g. amiodarone, exogenous iodine.
Hypersecreting thyroid tumour
HCG-producing tumour
Hyperfunctioning ovarian teratoma
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What occurs in secondary hyperthyroidism?
Will there be a goitre?
excess hypothalamic/anterior pituitary secretion of TRH/TSH
E.g. a TSH-secreting pituitary tumour.
too much TSH leads to the overstimulation of the thyroid gland to produce T3 and T4.
There will be a goitre due to elevated TSH levels
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De-Quervain’s thyroiditis
= transient hyperthyroidism associated with inflammatory process (viral infection).
Fever, malaise, pain in the neck and tachycardia.
Can cause hypothyroidism after initial over-active phase.
Acute phase treatment is with aspirin and steroids may given in severe cases.
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Hyperthyroidism - clinical features
generally related to the associated increase in cellular/ tissue metabolism and enhancement of beta-adrenoceptor responses
Weight loss
Sweating and heat intolerance
Diarrhoea
Tachycardia (potentially AF in older patients, so TFTs are mandatory in a patient with new AF).
Hypertension
Tremor
Anxiety, emotional, irritability, Restlessness
Goitre
Pre-tibial myxoedema
Exophthalmos in 30% of patients with Graves’ disease
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Grave's ophthalmopathy
1. Lagophthalmos – inability to close eyes properly
2. Exophthalmos – bulging eyes
3. Opthalmoplegia
4. Periorbital oedema
(more common in smokers)
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How can hyperthyroidism present in children?
increase in height and behavioural problems
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thyroid crisis/thyroid “storm"
= a rare presentation of hyperthyroidism
Generally occurs in periods of stress (e.g. infection, surgery, childbirth) in people with untreated/uncontrolled hyperthyroidism.
Hyperpyrexia, severe tachycardia, profuse sweating, confusion/psychosis.
If untreated – coma and death
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Hyperthyroidism - diagnosis
thyroid function test to measure T3, T4 and TSH:
- Primary – increased T3 and T4, decreased TSH.
- Secondary – increased T3 and T4, increased TSH
If Graves’ disease is suspected, you can test for thyroid-stimulating autoantibodies
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Hyperthyroidism - goal of treatment
= to achieve a normal euthyroid state and symptomatic relief from increased sympathetic activity.
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Hyperthyroidism - management
1. Anti-thyroid drugs
2. Radioiodine Therapy
3. Surgery – Thyroidectomy
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Anti-thyroid drugs
Most commonly carbimazole in the UK - inhibits the iodination and coupling processes via TPO
Can use propylthiouracil (PTU) instead of carbimazole – PTU also blocks the deiodination of T4 to T3
It takes several weeks for a clinical response to occur
“Dose titration” or "block and replace" method
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Why does it take several weeks for anti-thyroid drugs to have a clinical response?
due to high colloid stores and long half-lives of hormones
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Side effects of carbimazole
Rashes and pruritus are common (2-25%)
RARE complication (0.1-1.2%) – neutropenia and agranulocytosis (bone marrow suppression).
If there is sensitivity to carbimazole, use propylthiouracil
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Anti-thyroid drugs - "dose titration"
only anti-thyroid drugs are used;
doses are adjusted to achieve normalisation of thyroid hormone production.
This may take several months
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Anti-thyroid drugs - "block and replace"
anti-thyroid drugs at a very high concentration to completely block all thyroid hormone production, and then thyroxine replacement is given
quicker but normally more side effects
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What is given in combination with anti-thyroid drugs for management of hyperthyroidism?
Non-selective beta-blockers
given in combination with anti-thyroid drugs to reduce actions of catecholamines
provide rapid symptomatic relief of tremors, palpitations and anxiety (within 4 days), while waiting for the anti-thyroid drugs to have an effect
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Radioiodine therapy for hyperthyroidism
Suitable for all patients – except during pregnancy and breast feeding.
Iodine is taken up by the thyroid gland and localised radiation destroys the gland.
first-line for older patients with nodular goitres and hyperthyroidism, or when thyrotoxicosis recurs after anti-thyroid drug therapy.
Hypothyroidism may occur if too many cells are destroyed.
There is no increased risk of thyroid malignancy
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When is a thyroidectomy used?
| What are the risks?
not frequently used:
- Used when there is severe thyrotoxicosis associated with a large goitre or concern about tumour development
- Used when there are obstructive symptoms (e.g. effects on swallowing).
Surgical risks – bleeding, infection, risks from general anaesthesia.
Specific risks – tracheal compression, damage to recurrent laryngeal nerve, transient hypocalcaemia.
Hypothyroidism may result if too much of the thyroid gland is removed.
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Goitre
Enlargement of the thyroid gland.
- Usually painless, can be tender if acute cause.
- Large goitres may cause dysphagia or difficulty breathing due to compression.
Can be diffuse, multi nodular, or solitary nodule.
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Diffuse goitre
= smooth, soft enlargement with no apparent cause;
```
Puberty, pregnancy
Grave’s / Hashimoto’s
Iodine deficiency
Sub-acute thyroiditis
Anti-thyroid drugs, Lithium, Iodine excess, Amiodarone
```
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Nodular Goitre
MULTINODULAR
Toxic multinodular goitre
Subacute thyroiditis
```
SOLITARY NODULE
Follicular adenoma
Benign nodule
Thyroid malignancy (most important DDx)
Lymphoma
Metastasis
```
INFILTRATION
TB, Sarcoid
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Examination of neck lump
Observation and palpation to describe:
- Size
- Shape
- Consistency (hard, soft, smooth, firm)
- Mobility (mobile or feels adhered to surrounding tissue)
- Can the lower border be defined on palpation?
=> (If lower border cannot be defined, may indicate retro-sternal extension, which may increase likelihood goitre may affect breathing/swallowing.)
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Thyroid malignancy
uncommon
90% of cases present as thyroid nodules
=> The rest present as cervical lymphadenopathy or metastases (lung, bone, hepatic, cerebral).
Can be: papillary, follicular, medullary cell, anaplastic, lymphoma
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Diagnosis of thyroid malignancy
thyroid ultrasound and biopsy by fine needle aspiration (FNA)
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Presentation of thyroid malignancy
Solitary thyroid lump
Voice changes - due to recurrent laryngeal nerve being affected
Cervical lymphadenopathy (usually deep cervical or supraclavicular)
Difficulty swallowing, breathing or persistent cough (rarely)
General signs: weight loss, shortness of breath.
Symptoms of metastatic disease
