Endocrinology Flashcards
1
Q
Give an example of a water-soluble hormone
A
Peptides, Monoamines
2
Q
Give an example of a fat-soluble hormone
A
Thyroid hormones, Steroids (e.g. cortisol)
3
Q
What are the different types of hormone?
A
Peptides, Amines, Iodothyronines, Cholesterol derivatives and Steroids
4
Q
How are fat-soluble hormones transported?
A
Bound to proteins
5
Q
How do water-soluble hormones interact with cells?
A
Bind to surface receptors.
6
Q
How do fat- soluble hormones interact with cells?
A
Diffuse into the cell and bind to target receptor
7
Q
Which type of hormone has a longer half life? (water or fat soluble)
A
Fat-soluble
8
Q
Which type of hormones has faster clearance?
A
Water-soluble.
9
Q
How are peptide hormones synthesised?
A
Preprohormones–> Prohormones. Then packaged as prohormones requiring further processing to acitvate
10
Q
How are steroid hormones synthesised?
A
From a series of reactions from cholesterol
11
Q
How are amino acid derivative hormones synthesised?
A
From Tyrosine
12
Q
How are peptides stored and secreted?
A
In vesicles/secretory granules with regulatory secretion (in pulses/bursts)
13
Q
How are steroid hormones stored and secreted?
A
Released immediately
14
Q
How do steroid hormones induce changes?
A
Enter cells directly to nucleus to alter gene expression
15
Q
What is the structure of peptide hormones?
A
Can vary in length and be linear or ring structures.
16
Q
What are some examples of peptide hormones?
A
Insulin, LH, FSH
17
Q
What are the main cholesterol derivative hormones?
A
Vitamin D, Adrenocrotical and gonadal steroids.
18
Q
Are thyroid hormones water soluble?
A
No- 99% is protein bound.
19
Q
Where are peptide hormone receptors?
A
Cell membrane
20
Q
Where are steroid hormone receptors?
A
Cytoplasm
21
Q
Where are thyroid hormone receptors
A
Nucleus
22
Q
Give an example of an amine hormone
A
Dopamine, Noradrenaline and adrenaline
23
Q
what hormones does the hypothalamus release?
A
TRH, CRH, GnRH, Somatostatin, GHRH, Dopamine
24
Q
Does the anterior or posterior pituitary produce hormones?
A
Anterior (posterior just stores and secretes)
25
What hormones does the anterior pituitary gland release? (FLATP(I)G)
TSH, ACTH, FSH, LH, GH, Prolactin
26
What hormones does the posterior pituitary release?
Oxytocin, ADH (both produced in the hypothalamus)
27
What are the main causes of pituitary dysfunction?
Tumour mass defects, hormone excess and hormone deficiency
28
What is the anterior pituitaries blood supply?
Through a portal venous circulation from the hypothalamus.
29
What are the 3 main signs of a pituitary tumour?
1= Pressure on local structures (e.g. optic nerves causing bitemporal hemianopia) 2= Pressure on normal pituitary causing hypopituitarism. 3= Functioning tumour (produces own hormones) causing prolactinoma, acromegaly or Cushing's disease.
30
How would you investigate pituitary function?
Hormonal tests- if target organ working then pituitary is working. If abnormal, perform MRI.
31
What is the function of the thyroid?
Regulate metabolic rate, control heart rate, muscle and digestive function, Brain development and growth rate.
32
Draw out the H-P-Thyroid axis
Hypothalamus--> TRH (Thyrotropin-releasing hormone)--> Anterior pituitary --> TSH (Thyroid stimulating hormone)--> Thyroid --> T3 and T4
33
What is T3's full name and half life?
Tri-iodothronine
| 1 day
34
What is T4's full name and half life?
Thyroxine
| 7 days
35
What is the effect of T3?
Acts on all peripheral tissues to increase metabolic rate.
36
What is the action of thyroid stimulating hormone?
Increases uptake and usage of Iodine, stimulates production of thyroid hormones and stimulates calcitonin production.
37
Outline the synthesis of T3 and T4
Iodide is actively transported into the thyroid from the blood stream. It reacts with a Tyrosine molecule from thyroglobulin to form thyroid hormones.
38
Which is the more active/ main thryoid hormone?
T3. T4 is a store which is converted as required in tissues.
39
What happens to T4 at peripheral tissues?
It is converted to T3
40
What hormones does the adrenal cortex produce?
Mineralocorticoids (ALDOSTERONE), Glucocorticoids (CORTISOL), Androgens (TESTOSTERONE)
41
What hormones does the adrenal medulla produce?
Catecholamines (Adrenaline, noradrenaline, dopamine)
42
Draw out the HPA axis
Hypothalamus --> CRH (Corticotrophin releasing hormone)--> Anterior pituitary--> ACTH (Adrenocorticotrophic hormone)--> Adrenal gland--> Cortisol (+Androgens + Adrenaline)
43
What are the actions of cortisol?
Stress hormone: increases alertness, Inhibits immune system, inhibits bone formation, raises blood glucose, increases metabolism.
44
What is the rhythm of cortisol release?
natural circadian rhythm- rises just before we wake up and falls before we go to sleep
45
Where are the adrenal glands located?
Above the kidneys
46
Draw out the growth hormones axis
Hypothalamus--> GHRH (Growth hormone releasing hormone) (-ve Somatostatin)--> Anterior pituitary--> GH (Growth hormone)--> Liver--> IGF-1.
47
What is IGF-1 and what is its function?
Insulin like growth factor. Stimulates muscle growth, increases bone density and strength, stimulates cell regeneration and reproduction and growth of internal organs.
48
Draw out the male gonadal axis
Hypothalamus--> GnRH--> Pituitary gland--> LH and FSH--> Testicles--> Testosterone, ABG and inhibin
49
What does LH stimulate in males?
Leydig cells to produce testosterone which causes spermatogenesis.
50
What does FSH stimulate in males?
Sertoli cells to produce Androgen binding globulin and inhibin.
51
What is the action of ABG (Androgen binding globulin)?
A protein which binds to testosterone and prevents is from leaving the semineferous tubules.
52
What is the action of Inhibin in males?
Supports spermatogenesis and inhibits the production of FSH, LH and GnRH
53
Draw out the female gonadal axis
Hypothalamus--> GnRH--> anterior pituitary--> LH, FSH--> Ovaries--> Oestrogen, progesterone and Inhibin
54
What is the function of Oestrogen?
Regulates menstrual cycle and many other processes
55
What is the function of inhibin in females?
Causes inhibition of activin which is responsible for GnRH production
56
Under what circumstances is Parathyroid hormone released?
Low serum calcium
Low magnesium
Low serum Phosphate
57
What is the function of the parathyroid glands?
Increase serum calcium concentration
58
What are the 3 main actions of PTH?
1. Increases activity and number of osteoclasts in BONE, causing reabsorption of calcium into blood.
2. Stimulates increase in calcium reabsorption in KIDNEYS so less calcium is excreted.
3. Stimulates kidneys to convert vitamin D3 into calcitriol (active form of vitamin D) which promotes calcium absorption in small INTESTINE.
59
Draw RAAS Sysem
Liver--> Angiotensinogen--> RENIN from kidneys--> Angiotensin I--> ACE from lungs--> Angiotensin II
60
What are the actions of angiotensin II?
Causes vasoconstriction, and stimulates aldosterone release, increasing blood pressure.
61
What are the 4 types of hormone secretion pattern?
Continuous (e.g. prolactin), pulsatile (insulin), Circadian (ACTH, cortisol),.
62
What action does Somatostatin have?
Inhibits growth hormone.
63
Where does the pituitary gland lie?
In the pituitary fossa of the sphenoid bone, just below the hypothalamus
64
What structures are around the pituitary gland?
Optic chiasm, two cavernous sinuses
65
What is the Infundibulum?
Also known as the pituitary stalk- connects hypothalamus and pituitary- contains acons from neurons and small blood vessels.
66
What is the action of Dopamine
Inhibits the release of prolactin, type of neurotransmitter
67
What is the function of LH in females?
Stimulates the release of the egg, which stimulates progesterone release which thickens uterine wall.
68
What is the action of prolactin and where is it released from?
Stimulates the breast to produce milk and helps with breast development. Produced in the anterior pituitary.
69
what are hypophysiotropic hormones?
Hormones produced in the hypothalamus
70
Which hormone has a short loop mechanism and describe it?
Prolactin: Released from the anterior pituitary but this stimulates the secretion of dopamine from the hypothalamus which in turn inhibits the secretion of prolactin.
71
What is the action of Vasopressin?
Acts to retain fluid and maintain blood volume. Causes vasoconstriction and increased water reabsorption. Also stimulates ACTH release to increase aldosterone release to further increase fluid retention.
72
What triggers ADH release?
Decreased blood volume, trauma, stress, Increase blood CO2, Decrease blood O2, increased osmotic pressure.
73
What are the two main functions of Oxytocin?
Ejection of milk during breast feeding, contractions and onset of labour.
74
What are the most common diseases of the pituitary?
Bening pituitary adenoma, craniopharyngioma, trauma, Sheehans, Sarcoid/TB
75
What are the 3 main diseases caused by a functioning pituitary tumour? (Hyperpituitarism)
```
Prolactinoma= Increased prolactin
Acromegaly= Increased GH
Cushings= Increased CTH
```
76
What is the definition of diabetes mellitus?
Disease of chronic hyperglycaemia due to relative insulin deficiency, resistance or both.
77
What are the main micro and macrovascular complications with DM?
Micro: Retinopathy, nephropathy, neuropathy.
Macro: Heart disease, strokes, renovascular disease, limb ischeamia
78
What range should blood glucose levels be between under all conditions?
3.5-8.0 mmol/L
79
What organ is principally in charge of glucose homeostasis?
Liver
80
What does the liver do if blood glucose is high?
Glyogenesis (gluocose-> glycogen)
| Lipogenesis (Makes triglycerides if there are sustained high sugar levels)
81
What does the liver do if blood glucose is low?
Glyogenolysis ( glycogen-> glucose)
| Gluconeogenesis (from amino acids/ fat/ lactate) .
82
How much glucose is produced/used each day and how much of this is from liver glycogen?
200g
90% derived from liver glycogen and hepatic gluconeogenesis
(rest from renal gluconeogenesis)
83
Which organ is the major consumer of glucose and doesn't depend on insulin?
Brain- its function depends on uninterrupted supply.
84
Why can the brain not use ketones as an energy source?
Free fatty acids can't cross the blood brain barrier.
85
What happens to glucose taken up by muscle?
It is stored as glycogen or metabolised to CO2 and H2O or Lactate.
86
What is the action of insulin?
Lowers blood glucose:
- Suppresses hepatic glucose output by decreasing glyocogenolysis and gluconeogenesis.
- Increases glucose uptake into insulin sensitive tissues
- Suppresses lipolysis and breakdown of muscles
87
Which tissues take up glucose under instruction from insulin?
Muscle: Glycogen and protein synthesis
Fat: Fatty acid synthesis
88
What type of hormone is insulin and where is it secreted from?
Peptide hormone secreted from the Beta cells in the Islets of Langerhans in the pancreas
89
What pattern is insulin released and what is the trigger?
Released in response to B-cells sensing rising glucose levels.
Biphasic- Rapid release of stored insulin followed by insulin synthesis and release is glucose levels remain high.
90
Outline insulin synthesis.
Coded for on chromosome 11.
Proinsulin--> insulin
Insulin packaged into secretory granules.
91
What is C- peptide and what does it indicate?
It is what joins the alpha and beta chains together. It is cleaved off when insulin is packaged so with insulin release there are high levels of C peptide in the blood.
Synthetic insulin does not contain C-peptide so blood tests can tell if insulin in natural or synthetic.
92
Where does insulin go after secretion?
Enters the portal circulation and is carried to the liver.
93
What is insulins main action in the fasting state?
Regulate glucose release by the liver
94
What is insulins main actin on the post-prandial state (after eating)?
Promote glucose uptake by fat and muscle.
95
What allows glucose to bypass the cell membrane and enter cells?
GLUT proteins: Specialised glucose- transporter proteins.
96
Function of the GLUT-1 transporter?
Enables basal non-insulin-stimulated glucose uptake into many cells.
97
Function of GLUT-2 transporter?
Found in pancreatic B-cells.
Transports glucose into Beta cell, enabling them to sense glucose levels.
(only allows glucose in when there is a high concentration of glucose.)
98
Function of GLUT-3 transporters?
Enables non-insulin mediated glucose uptake into brain neurones and placenta.
99
Function of GLUT-4 transporters?
Channel through which glucose is taken up into muscle and adipose tissue following stimulation of insulin receptor.
100
What happens when insulin bings to a cell surface receptor?
It triggers a cascade response that results in translocation of the GLUT-4 transporter to the cell surface, increasing transport of glucose into the cell.
101
What is the action of glucagon?
Increases blood glucose levels:
102
By what mechanisms to glucagon increase blood glucose?
Increases hepatic glucose output (glycogenolysis and gluconeogenesis.)
Reduces peripheral glucose uptake.
Stimulates peripheral release of gluconeogenic precursors (e.g. glycerol and amino acids)
Stimulates lipolysis and ketogenesis.
103
Where is glucagon produced?
Alpha cells in the islets of Langerhans of the pancreas.
104
In what conditions is diabetes secondary?
Pancreatic disease (e.g. pancreatectomy, pancreatitis e.t.c.) Endocrine disease (e.g. acromegaly, Cushing's) Drug induced (by thiazide diuretics or corticosteroids) MODY (Maturity onset diabetes of youth- genetic condition)
105
What kind of patient usually presents with Type 1 diabetes?
Young (<30), lean (Northern European more common)
106
What kind of patient usually presents with Type 2 diabetes?
Older (Usually >30), overweight.
107
What is the cause of Type 1 diabetes?
Insulin deficiency caused by autoimmune destruction of pancreatic beta-cells
108
What is LADA?
Latent autoimmune diabetes in adults: Slower progression so insulin deficiency occurs late in life. Can be hard to differentiate from type 2.
109
What is the aetiology of Type 1 diabetes?
Autoimmune, idiopathic, genetic susceptibility.
110
What are the risk factors of type 1 diabetes?
Northern european, Family history (HLA-DR-DQ gene), other autoimmune disease, environmental factors (viruses/diet)
111
What is insulitis?
Inflammation of the islets of Langerhans.
112
What does type 1 diabetes cause?
Insulin deficiency which leads to hyperglycaemia, glycosuria and ketonuria.
113
What are the key presentations of type 1 diabetes?
Polydipsia, polyuria, weight loss and ketosis (more severe).
114
Why do patients get polyuria (and polydipsia) in type 1 diabetes?
The excess glucose draws water into the urine by osmosis.
115
How long is the typical history of symptoms in type 1 diabetes?
2-6 weeks
116
Why is weight loss a main symptom in type 1 diabetes ?
Due to fluid depletion and the accelerated breakdown of fat and muscle.
117
What glucose levels are needed for a diabetes diagnosis?
Random plasma glucose> 11.1mmol/L
| Fasting plasma glucose > 7mmol/L
118
What is the HbA1c test and ideal level?
Measures amount of glucose attached to haemoglobin. HbA1c>6.5% (48mmol/mol)= diabetes
119
What is the main treatment for Type 1 diabetes (especially in those who have been in ketoacidosis or under 40)?
Synthetic (recombinant) human insulin.
120
What are the three main types on insulin treatment?
1. Short acting (soluble) insulins
2. Short-acting insulin analogues
3. Longer-acting insulins
121
When would short acting insulin be used and how long does it last?
Given 15-30 minutes before meals for patients on multiple dose regimens/ during medical emergencies/ in surgery/labour. Lasts for 4-6 hours.
122
What are short-acting insulin analogues and when are they used?
e.g. (Lispro, Aspart, Glulisine) Have fast onset and shorter duration than normal insulin. Used with the evening meal in patients prone to nocturnal hypoglycaemia.
123
How long do long-acting insulins work?
Intermediate: 12-24 hours
| long acting: >24 hours.
124
What is the most common treatment regimen for those with type 1 diabetes?
Basal-bolus: Involves longer acting form of insulin to keep blood glucose levels stable through periods of fasting and separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals.
125
How is insulin usually given?
Subcutaneous injection
126
What are the complications of insulin treatment?
Hypoglycaemia, lipohypertrophy at injection site, insulin resistance, weight gain.
127
What happens if insulin is not given in type 1 diabetes (and severe type 2)?
Diabetic ketoacidosis (DKA)
128
When is diabetic ketoacidosis usually seen?
In undiagnosed diabetes, if insulin therapy is interupted or due to stress from illness (e.g. surgery or infection).
129
Summarise the pathophysiology of ketoacidosis?
In the complete absence of insulin, the body tries to find other sources of energy: ↑gluconeogenesis
↑glycolysis
↑fat and muscle lysis.
Free fatty acids are converted to ketones in the liver and their accumulation causes metabolic acidosis, excarcebated by dehydration from hyperglycaemia.
130
What are the clinical presentations of ketoacidosis?
Pear drop- smelling breath
Dehydration- frequent urination and extreme thirst
Gradual drowsiness and vomiting
Kussmaul's respiration (deep rapid breathing)
131
How is ketoacidosis diagnosed?
Hyperglycaemia (Blood glucose >11mmol/L)
Raised plasma ketones (>3mmol/L)
Metabolic acidosis (plasma bicarbonate<15mmol/L)
132
How is ketoacidosis treated?
```
Immediate ABC
Replacement of fluid loss with saline
Replacement of electrolytes
Acid- base balance restores
Replacement of deficient insulin (usually given with glucose to prevent hypoglycaemia)
```
133
Which of the bodies reactions to ketoacidosis actually make it worse?
Release of stress hormones (adrenaline, noradrenaline, glucagon and cortisol).
Vomiting (leads to futher loss of fluid and electrolytes)
Respiratory compensation (leads to hyperventilation)
134
What are the complications of DKA?
```
Death
cerebral oedema
Adult respiratory distress syndrome
coma
pneumonia
```
135
What are the risk factors for Type 2 Diabetes?
(central) obesity, lack of exercise, age, family history, ethnicity
136
What is the pathophysiology of type 2 diabetes?
Combination of deficient insulin secretion and resistance to action of insulin resulting in hyperglycaemia and high FFA's.
137
At the usual time of type 2 diabetes diagnosis what is the usual reduction in Beta cell mass?
50% reduction
138
What is the Starling curve of the pancreas?
When circulating insulin levels are higher then in non-diabetics following diagnosis and rise further, only to decline again after months/years due to eventual secretory failure.
139
Why is DKA much less likely in type 2 diabetes?
Even a small amount of insulin can halt the breakdown of fat and muscle into ketones.
140
What are IGF and IGT?
pre-diabetes:
IGT= Impaired glucose tolerance
IGF= Impaired fasting glucose.
141
What are the key presentations of Type 2 diabetes?
Asymptomatic: diagnosed incidentally
Obese
Polydipsia + polyuria
142
What are the symptoms of type 2 diabetes?
Polydipsia, polyuria, blurred vision, unexplained weight loss, recurrent infections, tiredness
143
What are signs of type 2 diabetes?
Acanthosis nigricans, retinopathy, tingling/numbness in feet, erectile dysfunction, arterial disease
144
How do you diagnose Type 2 diabetes?
* HbA1c > 48mmol/mol (6.5%)
* Fasting plasma glucose > 7.0 mmol/L
* Random plasma glucose > 11.1 mmol/L in the presence of signs or symptoms.
* If symptomatic: single abnormal HbA1c or fasting plasma glucose level can be used.
* If asymptomatic, repeat testing needed.
145
What is the first line type 2 diabetes treatment?
```
Lifestyle changes:
Dietary changes
Blood pressure and hyperlipidaemia control
Exercise
Reduction of alcohol/ smoking/ drugs
Weight loss
```
146
What is the second line treatment of type 2 diabetes?
Oral metformin
147
What is the action of metformin?
Reduces rate of gluconeogenesis
Increases cells sensitivity to insulin
Weight loss
148
What is the second line treatment of type 2 diabetes?
Dual therapy: Metformin + Sulfonylurea
149
What is the action of Sulfonylureas?
Promote insulin secretion
150
What is the third line treatment of type 2 diabetes?
Triple therapy: metformin + sulfonylurea + insulin/ glitazone e.t.c.
151
What are the main life threatening complication of type 2 diabetes?
Hyperosmolar hyperglycaemic state
152
What is hyperosmolar hyperglycaemia?
A metaboilc emergency where high blood sugar results in high osmolarity without significant ketoacidosis.
153
What are the risk factors for hyperosmolar hyperglycaemia?
Infection: usually pneumonia
Consumption of high glucose fluids
Concurrent medication
154
What are the clinical presentations of hyperosmolar hyperglycaemia?
Severe dehydration
Decreased level of consciousness
Hyperglycaemia
Hyperosmolality
155
What is the treatment of hyperosmolar hyperglycaemia?
Low rate infusion of insulin
Fluid replacement with saline
Low molecular weight heparin to reduce risk of vascular disease
Restore electrolyte loss.
156
What are the main macrovascular complications of diabetes?
Atherosclerosis resulting in stroke, Ischeamic heart disease, MI, peripheral vascular disease, lower limb amputation
157
Why does diabetes cause vascular disease?
High glucose levels damage blood vessels.
158
What are signs of peripheral vascular disease?
Intermittent claudication and rest pain.
| Diminished or absent peal pulses, coolness of feet and toes, poor skin and nails and absence of hair.
159
What are the main microvascular complications of diabetes?
Retinopathy, nephropathy and neuropathy.
160
What are the signs/ symptoms of diabetic retinopathy?
Blindness
Microaneuryssms: tiny red dots
Heamorrhages: blots
Blurred vision, vision loss, impaired colour vision.
161
What are the different types of diabetic retinopathy?
Non-proliferative
Pre-proliferative: micro-infarcts due to occluded vessels.
Proliferative: Retinal ischeamia resylts in release of vascular growth factors.
Maculopathy: Fluid from leaking vessels cleared poorly in the macular area causing oedema.
162
When does clinical nephropathy usually manifest?
15-25 years after diabetes diagnosis
163
Why does nephropathy occur?
Thickening of basement membrane due to poor glyceamic control causes glomerular damage and leads to microalbuminuria.
164
How do you diagnose nephropathy?
Undetectable by dipstick
| Albumin:creatinine ratio>3
165
How do you treat diabetic nephropathy?
Aggressive blood pressure treatment.
166
Why does diabetic neuropathy occur?
Results from occlusion of the vasa nervorum in addition to accumulation of fructose and sorbitol disrupting the structure and functions of nerves.
167
What are the vasa nervorum?
Small arteries that supply peripheral nerves
168
What are the symptoms of diabetic neuropathy?
```
Numbness/ reduced ability to feel pain or temperature
Tingling/ burning sensations
Sharp pain
Hypersensitivity
muscle weakness
loss of balance/ coordination
Ulcers/ infection/ amputation
```
169
What is DFU?
Diabetic foot ulceration: Common consequence of diabetes. Neuropathy results in increased risk of repeated 'silent traume'
170
What is hypoglycaemia?
Plasma glucose< 3 mmol/L.
| Usually due to insulin or sulphonylurea treatment.
171
What are the causes of hypoglycaemia in non-diabetics? EXPLAIN
```
EX: Exogenous drugs
P: Pituitary insufficiency
L: Liver failure
A: Addison's disease
I: Islets cell tumour/ Immune hypoglycaemia
N: Non-pancreatic neoplasm
```
172
What are the presentations of hypoglycaemia?
Autonomic: Sweating, anxiety, hunger, tremor, palpitations, dizziness
Neuroglycopenic (lack of glucose in the brain): confusion, drowsiness, visual problems, seizures, comas.
173
How do you diagnose hypoglycaemia?
Fingerprick
Bloods: glucose, inslin, C-peptide, plasma ketones.
Take drug history and exclude liver failure.
174
How do you treat hypoglycaemia?
Oral sugar and long-acting starch
| If cannot swallow: 50% glucose.
175
What is DAFNE?
Dose adjusted for normal eating: training for insulin administration in those with type 1 diabetes.
176
What is MODY?
MATURITY ONSET DIABETES OF YOUNG: Rare autosomal dominant form of T2DM affecting young people
177
What is gestational diabetes?
Diabetes during pregnancy: usually in the third trimester.
178
What important structures need to be considered when operating on the thyroid gland?
```
Superior and recurrent larygneal nerves
Trachea
Parathyroid glands
Common carotid artery
Internal jugular vein
```
179
What is primary hyperthyroidism?
An over production of thyroid hormone by the thyroid itself.
180
What is secondary hyperthyroidism?
Condition where the thyroid is producing excessive thyroid hormone as a result of overstimulation by TSH (due to hypothalamus or pituitary dysfunction).
181
What is Theyrotoxicosis?
An abnormal and excessive quantity of thyroid hormone in the body.
182
What is Grave's disease?
An autoimmune condition where TSH receptor antibodies (abnormal antibodies produced by the immune system that mimic TSH and stimulate TSH receptors on the thyroid) cause a primary hyperthyroidism.
183
What is the most common cause of hyperthyroidism?
Grave's disease
184
What are the main causes of hyperthyroidism?
Grave's disease, toxic multinodular goitre, solitary toxic thyroid nodule, thyroiditis (e.g. De Quervain's, Hashimoto's e.t.c)
185
What is toxic multinodular goitre (Plummer's disease)?
A condition where nodules develop on the thyroid gland that act independently off the normal system and continuously produce excessive thyroid hormone
186
What is exopthalmos and what causes it?
Bulging of the eyeballs out of their socket (typical of Grave's disease) due to inflammation, swelling and hypertrophy of the tissue behind the eyeball.
187
What is pretibial myxoedema?
A dermatological condition where there are deposits of mucin under the skin on the anterior aspect of the skin., giving is a discoloured waxy appearance.
188
What cause pretibial myxoedema?
A reaction to the TSH receptor antibodies in Grave's disease
189
What are the universal features of hyperthyroidism?
```
Anxiety and irritability
Sweating/ heat intolerance
Tachycardia
Weight loss
Fatigue
Frequent loose stools
Sexual dysfunction
```
190
What are the unique features of Grave's disease?
Diffuse goitre (swelling of neck without nodules)
Graves eye disease
Bilateral exopthalmos
Pretibial Myxoedema
191
What are the unique features of toxic multinodular goitre?
Goitre with firm nodules
| Patients over 50
192
What are solitary toxic thyroid nodules and how are they treated?
A single abnormal thyroid nodule releasing thyroid hormone (usually a benign adenoma)
Treated with surgical removal
193
What is De Quervain's Thyroiditis?
Viral infection that begins with hyperthyroidism.
194
What is thyroid storm/ thyrotoxic crisis?
Rare presentation of hyperthyroidism with pyrexia, tachycardia and delirium.
195
How is hyperthyroidism treated?
```
Carbimazole
Propylthioracil
Radioactive iodine
Beta blockers
Surgery
```
196
What is the first line anti-thyroid drug and how long does it take to work?
CARBIMAZOLE: 4-8 weeks
197
What happens when levels return to normal after treatment with Carbimazole?
1. Maintenance levels continued
2. Titration-block: the dose is carefully titrated to maintain normal levels
3. Block and replace: The dose is sufficient to block all production and the patient takes levothyroxine titrated to effect.
198
How does radioactive iodine work to treat hyperthyroidism?
A single dose of radioactive iodine is drunk. It is taken up by the thyroid gland and the emitted radiation destroys a proportion of the thyroid cells. This results in a reduction of thyroid hormone production.
199
What are the main causes of hypothyroidsm?
```
Hashimoto's thyroiditis
Iodine deficiency
Secondary to treatment of hyperthyroidism
Medications
Secondary hypothyroidism
```
200
What is Hashimoto's thyroitis?
Autoimmune inflamation of the thyroid gland causing hypothyroidism (most common cause in the developed world).
201
Which medications can cause hypothyroidism?
Lithium --> inhibits the production of thyroid hormones in the thyroid gland.
Amiodarone--> interferes with thyroid hormone production and metabolism.
202
What are secondary (central) causes of hypothyroidism?
Where the pituitary gland is failing to produce enough TSH. Can be due to tumours, infection, vascular or radiation.
203
What are the main presentations of hypothyroidism?
Weight gain, fatigue, dry skin, Coarse hair and hair loss, fluid retention, heavy/ irregular periods, constipation.
204
How do you manage hypothyroidism?
Replace thyroid hormone with titrated oral levothyroxine (synthetic T4) .
205
How do you test for thyroid disease? And if positive, how do you get more information?
TSH screening test.
| Then test T3 and T4 levels.
206
What are the TSH and T3/T4 levels like in Hyperthyroidism? What is the exception?
```
TSH= Low
T3/T4= High
```
Pituitary adenoma secretes TSH so levels are high.
207
What are the TSH and T3/T4 levels like in primary hypothyroidism?
```
TSH= High
T3/T4= Low
```
208
What are the TSH and T3/T4 levels like in secondary hypothyroidism?
```
TSH= Low
T3/T4= Low.
```
209
What other tests can be done to test thyroid disease?
Antibodies
Thyroid ultrasound
Radioisotope scan
210
What antibodies can be tested for to confirm thyroid disease?
Anti-TPO antibodies are (antibodies against the thyroid itself.)
Antithyroglobulin antibodies. (antibodies against thyroglobulin)
TSH receptor antibodies (mimic TH)
211
What is the most common clinical presentation of thyroid disease?
Goitre ( swelling of the thyroid gland causing a visible lump in the neck)
212
What does the ZONA GLOMERULOSA of the adrenal cortex produce?
Mineralocorticoids (e.g. Aldosterone)
213
What does the ZONA FASCICULATA produce?
Glucocorticoids e.g. Cortisol
214
What does the ZONE RETICULARIS produce?
Androgens (sex hormones such as testosterone)
215
What does the adrenal medulla secrete?
Catecholamines (adrenaline and noradrenaline)
216
What stimulates cortisol and androgen production by the adrenal cortex?
ACTH secretion from the pituitary.
217
What is Cushing's syndrome?
The signs and symptoms that develop after prolonged abnormal elevation of cortisol.
218
What is Cushing's disease?
Specific form of Cushing's syndrome caused by a pituitary adenoma secreting excessive ACTH.
219
What are the main features of Cushing's syndrome?
Round in the middle with thin limbs (round face, central obesity, abdominal striae e.t.c)
High levels of stress hormone ( Hypertension, cardiac hypertrophy, hyperglyceamia, depression, insomnia)
Osteoperosis, easy bruising.
220
What are the causes of Cushing's syndrome?
Exogenous steroids
Cushing's disease (pituitary adenoma)
Adrenal adenoma
Paraneoplastic Cushing's
221
What is paraneoplastic cushing's?
When excess ACTH is released from a cancer (somewhere other than the pituitary) and stimulates excessive cortisol release.
222
What test is used to diagnose Cushing's disease?
DST test (dexamethasone suppression test)
223
How does the DST test work?
Patient takes a dose of dexamethasone (synthetic glucocorticoid steroid) at night and their cortisol and ACTH are measured in the morning. This is used to see if dexamethasone suppresses their normal morning spike of cortisol . Patient is initially given a low dose test. If this is abnormal, a high dose test is used to differentiate between underlying causes.
224
What is the low dose dexamethasone suppression test and what do the results tell you?
When 1mg dexamethasone is given and ACTH and cortisol levels are checked in the morning. A normal response is for dexamethasone to suppress the release of cortisol by effecting negative feedback on the hypothalamus and pituitary. If the cortisol level is not suppressed this abnormal and a high dose test needs to be used to diagnose Cushing's
225
What is the high dose dexamethasone suppression test and what do the results tell you? (Pituitary adenoma, adrenal adenoma, ectopic ACTH?)
8mg used after an abnormal low dose test.
In Cushing's disease, the pituitary will still show some response and suppress cortisol and ACTH.
With an adrenal adenoma, cortisol production is independent from the pituitary so cortisol is not suppressed but ACTH is due to negative feedback.
With ectopic ACTH, neither cortisol or ACTH will be suppressed.
226
What other investigations can be used to test for Cushing's disease?
```
24 hour urinary free cortisol
FBC + electrolytes
MRI brain (pituitary adenoma)
Chest CT (small cell lung cancer)
Abdominal CT (adrenal tumours)
```
227
What is the main treatment for Cushing's disease?
Remove underlying cause: surgically remove tumour.
228
What is adrenal insufficiency?
Where the adrenal glands don't produce enough steroid hormones (cortisol and aldosterone)
229
What is the action of cortisol?
Main stress hormone. Stimulates gluconeogenesis (breakdown of protein and fat).
Activates antistress and anti-inflammatory pathways
Supresses immune response.
230
What is the action of aldosterone?
Causes an increase in salt and water reabsorption in the kidney- restoring salt levels and blood pressure.
231
What is Addison's disease?
Condition where the adrenal glands have been damaged, causing a reduction in the cortisol and aldosterone secretion. (Primary adrenal insufficiency)
232
What is the most common cause of primary adrenal insufficiency?
Autoimmune
233
What is secondary adrenal insufficiency?
Low cortisol release due to inadequate ACTH levels as a result of pituitary gland damage or loss.
234
What is Sheehan's syndrome?
A condition where massive blood loss during childhood leads to pituitary gland necrosis.
235
What is tertiary adrenal insufficiency?
The result of inadequate CRH release by the hypothalamus.
236
What is the usual cause of tertiary adrenal insufficiency?
When a patient has been on long term oral steroids and then they are suddenly withdrawn, the hypothalamus does not wake up fast enough.
237
What are the main symptoms of adrenal insufficiency?
```
Fatigue
Nausea
Cramps
Abdominal pain
Reduced libido
Bronze hyperpigmentation of skin
hypotension
```
238
What investigations can be done to test for adrenal insufficiency?
```
Short synacthen test
Blood tests: Hyponatraemia*, hypokalamiea, early morning cortisol, ACTH
Adrenal autoantibodies (present in 80%)
CT/ MRI of adrenals
MRI of pituitary
```
239
What is the short synacthen test?
Synacthen (synthetic ACTH) is given in the morning and cortisol levels are tested straight after, 30 and 60 minutes after. A failure of cortisol to rise to at least double the baseline indicates Addison's disease.
240
How do you treat adrenal insufficiency?
Replace steroids titrated.
HYDROCORTISONE: Replaces cortisol
FLUDROCORTISONE: Replaces aldosterone
241
What is an Addisonian crisis?
An acute presentation of severe Addisons where an absence of steroid hormones causes a life threatening presentation.
242
What are the presentation of Addisonian crisis?
Reduced consciousness
Hypotension
Hypoglycaemia, hyponatraemia, hyperkalaemia
243
How is Addisonian Crisis managed?
Intensive monitoring
Steroids
IV fluids
Correct electrolytes.
244
Where is aldosterone released from?
Adrenal glands
245
What stimulated the release of aldosterone?
Angiotensin II from the RAAS system.
246
What type of hormone is aldosterone?
A mineralocorticoid steroid hormone
247
What is the actions of aldosterone?
Electrolyte balance:
- Increases SODUM REABSORPTION from the distal tubule.
- Increase POTASSIUM SECRETION from the distal tubule.
- Increase HYDROGEN SECRETION from the collecting ducts.
248
What is Conn's syndrome?
Primary hyperaldosteronism- when the adrenal glands produce too much aldosterone
249
What happens to serum renin in primary hyperaldosteronism?
It is low as it is suppressed by high blood pressure.
250
What are the main causes of Conn's syndrome?
Adrenal adenoma secreting aldosterone
Bilateral adrenal hyperplasia
Familial hyperaldosteronism
Adrenal carcinoma
251
What is secondary hyperaldosteronism? What is the serum renin like?
When excessive renin stimulates the adrenal glands to produce more aldosterone- high serum high
252
What are the main causes of unnecessarily high renin levels?
When the blood pressure is disproportionately lower than the blood pressure in the rest of the body due to:
- Renal artery stenosis
- Renal artery obstruction
- Heart failure.
253
What causes renal artery stenosis and how can this be diagnosed?
Atherosclerotic plaque causes narrowing of the vessel.
| Can be confirmed with doppler ultrasound, CT angiogram or MRA
254
What is the best screening tool for hyperaldosteronism?
Check renin and aldosterone levels and calculate renin/aldosterone ratio:
High aldosterone/low renin= primary
High aldosterone/ high renin= secondary
255
What other investigations can be used to confirm Hyperaldosteronism?
Blood pressure
Serum electrolytes
Blood gas analysis (check for alkalosis)
CT/ MRI of adrenals
256
How is hyperaldosteronism treated?
- Aldosterone antagonists (Eplerenon, Spironolactine)
| - Treat underlying cause (e.g. surgical removal of adenoma, precutaneous renal artery angioplasty)
257
What is the most common cause of secondary hypertension?
Hyperaldosteronism
258
What is acromegaly?
Clinical manifestation of excessive growth hormone (GH)
259
What is the most common cuase of acromegaly?
Unregulated growth hormone secretion by a pituitary adenoma
260
What are other potential causes of acromegaly?
Secondary to a cancer that secretes ectopic GHRH or GH.
261
What is the main symptom of a substantial pituitary tumour?
Bitemporal hemianopia due to pressure on the optic chiasm.
262
What are the main symptoms of acromegaly?
- Headaches/ visual field defects
- overgrowth of tissues--> Prominent forehead/brow, large nose, tongue, jaw, hands and feet
- arthritis from imbalanced joint growth
- Development of new skin tags
- profuse sweating
263
What other signs can GH cause?
Hypertrophic heart
Hypertension
Type 2 diabetes
Colorectal cancer
264
Why is a random growth hormone test not helpful in investigating acromegaly?
GH fluctuates so may give false positives and negatives
265
What investigation can be done for acromegaly?
IGF-1 levels
Oral glucose tolerance test whilst measuring GH
MRI brain for pituitary tumour
Visual field testing
266
How is acromegaly treated?
Primary: trans-sphenoidal surgical removal of pituitary tumour
Secondary: surgical removal of cancer
Medication to block growth hormone--> Pegvisomant, Somatostatin analogues, Dopamine agonists.
267
Why is a somatostatin analogue given?
Somatostatin is a growth hormone inhibiting hormone secreted by the brain, GI tract and pancreas. It blocks GH release from the pituitary gland. (Dopamine also does this on a smaller scale.)
268
What things have an effect on GH secretion?
GHRH and Ghrelin stimulate secretion
| Somatostatin and high glucose levels inhibit secretion
269
How does GH exert its action?
Indirectly through IGF-1.
| Directly on tissues such as the liver, muscle, bone or fat to induce metabolic changes.
270
What is gigantism?
Excessive GH production in children before fusion of the epiphyses of the long bones.
271
What is a prolactinoma?
Pituitary adenoma secreting excess prolactin
272
What are the symtpoms of prolactinoma?
Irregular/ absent periods,
milk production
sexual dysfunction.
273
Where is ADH produced and secreted from?
Produced in the hypothalamus and secreted from the posterior pituitary
274
What is SIADH?
Syndrome of inappropriate Anti-Diuretic Hormone--> Excessive amounts of ADH
275
What causes SIADH?
Posterior pituitary secreting too much ADH or a cancer (e.g. small cell lung cancer) secreting ectopic ADH.
276
What does the excess ADH result in?
Excessive water reabsorption in the collecting ducts. This dilutes the sodium in the blood, causing hyponatreamia and high urine osmolality.
277
What are the symptoms of SIADH?
```
Non-specific:
Headache
Fatigue
Muscle aches/ cramps
Confusion
Sever hyponatraemia can cause seizures/ loss of consciousness.
```
278
What are some of the causes of SIADH?
```
Post operative
Infection (e.g. pneumonia, lung abscesses)
Head injury
Medications
Malignancy
Meningitis
```
279
How is SIADH diagnosed?
Tests will show:
- Euvolemia (normal volume)
- U+E's show hyponataemia
- High urine sodium + osmolality.
**Diagnosis of exclusion--> exclude other causes of hyponatraemia (e.g. adrenal insufficiency)
280
How is SIADH managed?
```
Establish and treat cause:
e.g. stop causative medication.
Correct sodium slowly.
Fluid restriction
ADH receptor blockers--> Vaptans e.g. Tolvaptan
```
281
What is central pontine mylinolysis?
Osmotic demyelination syndrome--> Complication of long term severe hyponatraemia being treated too quickly.
282
Why should you correct sodium levels slowly after long term hyponatraemia?
As blood sodium levels fall, water moves across the blood-brain barrier, causing the brain to swell. The brain adapts to this by reducing the solutes in the brain cells so the brain does not become oedematous. THis adaptation takes a few days so if hyponatreamia has been present for a long time, the brain cells will have low osmolality. If the blood sodium levels rapidly rise, then water will rapidly shift out of brain cells and into the blood.
283
What happens in the first phase of central pontine mylinolysis?
Patient presents as encephalopathic and confused with headache or nausea/ vomiting caused by electrolyte imbalance
284
What happens in the second phase of central pontine mylinolysis?
Occurs after a few days--> Demyelination of neurones (especially in the pons) causes spastic quadriparesis, pseudobulbar palsy and cognitive/behavioural changed. Significant risk of death.
285
What is the action of ADH on the collecting duct?
Binds to V2R (vasopressin receptor) where kinase actions results in the insertion of aquaporin 2 channels into the apical membrane.
286
What is diabetes insipidus?
A lack of ADH or a lack of response to ADH, preventing the kidneys from being able to concentrate the urine.
287
What are the two types of diabetes insipidus?
Nephrogenic and Cranial
288
What happens in nephrogenic diabetes insipidus?
When the collecting ducts of the kidneys do not respond to ADH.
289
What causes nephrogenic diabetes?
Drugs (lithium)
Genetic mutation
Intrinsic kidney disease
Electrolyte disturbance
290
What happens in cranial diabetes insipidus?
When the hypothalamus does not produce ADH for the pituitary gland to secrete
291
What are the main causes of cranial diabetes insipidus?
- Idiopathic
- Brain tumours
- Head injury
- Brain malformations
- Brain infections
- Brain surgery or radiotherapy
292
What are the key presentations of diabetes insipidus?
```
Polyuria
Polydipsia
Dehydration
Postural hypotension
Hypernatraemia
```
293
How is diabetes insipidus investigated?
Low urine osmolality
High serum osmolality
Water deprivation test
294
What is the water deprivation test?
Patient must avoid fluid for 8 hours. Urine osmolality measured, then Desmopressin (synthetic ADH) given. 8 hours later urine osmolality is measured again.
295
What are the results of the water deprivation test in cranial diabetes insipidus?
After fluid deprivation--> Low urine osmolality
| After desmopressin--> High urine osmolality
296
What are the results of the water deprivation test in nephrogenic diabetes insipidus?
After deprivation--> Low
| After desmopressin--> Low
297
What is primary polydipsia?
When a patient has normally functioning ADH but are drinking excessive quantities of water leading to excessive urine production
298
What are the results of the water deprivation test in primary polydipsia?
After deprivation--> High
| After ADH--> High
299
How is diabetes insipidus treated?
Treat underlying cause.
| Desmopressin (synthetic ADH)
300
What do the parathyroid glands do?
Produce parathyroid hormone in response to hypocalcaemia.
301
Where is parathyroid hormone produced?
In chief cells
302
What are the actions of parathyroid hormones?
Increase osteoclast activity in bones (reabsorb calcium)
Increase calcium absorption from the gut
Increase calcium absorption from kidneys
Increase vitamin D activity by converting it to its active forms.
303
What is the action of Vitamin D?
Increases calcium absorption from the intestines
304
What are symptoms of hypercalcaemia?
Renal stones, painful bones, abdominal groans (constipation/ nausea/ vomiting) and psychiatric moans (fatigue/ depression/ psychosis)
305
What is primary hyperparathyroidism?
When a tumour of the parathyroid glands releases uncontrolled parathyroid hormone, leading hypercalcaemia.
306
How is primary hyperparathyroidism treated?
Surgically removing tumour.
307
What is secondary hyperparathyroidism?
When insufficient vitamin D or chronic renal failure leads to low absorption of calcium from the intestines, kidneys and bones, causing hypocalcaemia.
308
How do the parathyroid glands react to secondary hyperparathyroidism and what does this cause over time?
Excrete more parathyroid hormone. Over time hyperplasia occurs as the number of cells increases to try and meet demand.
309
How is secondary hyperparathyroidism treated?
Correcting vitamin D or treating renal failure (usually with renal transplant)
310
What are the levels of serum calcium and parathyroid hormone like in secondary hyperparathyroidism?
Serum calcium = low or normal
| Parathyroid hormone= High
311
What is tertiary hyperparathyroidism?
Occurs when secondary hyperparathyroidism continues for a long period of time, leading to hyperplasia and the baseline level of PTH to increase dramatically. This means that when secondary hyperparathyroidism is treated, the PTH level remains inappropriately high. , causing hypercalcaemia.
312
How is tertiary hyperparathyroidism treated?
By surgically removing part of the parathyroid tissue to return PTH to normal levels.
313
What is the name of vitamin D's active form in the kidney?
Calcitrol
314
How are serum potassium levels controlled in the body?
- Uptake of K+ into cells
- Renal excretion (mainly controlled by aldosterone)
- Extrarenal losses (e.g GI)
315
What constitutes as hyperkalaemia?
>5.5mmol/mol
| >6.5 mmol/mol =MEDICAL EMERGENCY
316
What are the most common causes of hyperkalaemia?
Renal impairment
| Drug interference with K+ excretion (e.g. ACE inhibitors with potassium sparing diuretics of NSAIDS)
317
What does the level of K+ in the blood determine and what happens when it rises?
Determines the excitability of nerve and muscle cells--> When levels rise, it reduces the electrical potential difference, meaning the threshold for action potential is significantly decreased, causing abnormal action potential and therefore abnormal heart rhythms causing ventricular fibrillation and cardiac arrest.
318
What are the key presentations of hyperkalaemia?
Asymptomatic until K+ is high enough to cause cardiac arrest.
Fast irregular pulse, chest pain, weakness, light headedness
Muscle weakness and fatigue
319
How is hyperkalcaemia treated in non-urgent cases?
Treat underlying cause
| Dietary K+ restriction
320
How is hyperkalcaemia treated in urgent cases?
Stabilise cardica membrane--->calcium Gluconate
| Drive K+ into cells--> Give soluble insulin with glucose and salbutamol.
321
What constitutes as hypokalaemia?
Serum K+ <3.5 mmol/L
| <2.5= MEDICAL EMERGENCY
322
What is the most common cause of chronic hypokalaemia?
Increased renal excretion due to diuretic treatment (e.g. thiazides or loop diuretics)
323
What are the main clinical presentations of hypokalaemia?
Usually asymptomatic
| Muscle weakness, craps, constipation, tetany, e.t.c
324
How is hypokalaemia diagnosed?
Serum K+
| ECG
325
How is hypokalaemia treated?
Treat underlying cause
| Usually resolves on its own but can give K+ supplements.
326
What are neuroendocrine tumours?
Tumours that form from cells that release hormones into the blood in response to a signal from the nervous system.
327
What are the 3 vital presenting signs for diagnosing neuroendocrine tumours?
1. Pressure on local structures (e.g headaches, bitemporal hemianopia)
2. Pressure on normal pituitary
3. Functioning tumour
328
What are the 3 main neuroendocrine tumours?
Prolactinoma--> Adenoma of pituitary gland producing prolactin
Pheochromocytoma--> Adrenaline secreting tumour
Carcinoid--> Seretonin secreting tumour.
329
What are the risk factors for developing a neuroendocrine tumour?
Inherited conditions:
MEN1
Neurofibromatosis type 1
Von-Hippel Linadu syndrome
330
What is a phaeochromocytoma?
A Catacholamine (adrenaline) secreting tumour of the adrenal glands
331
Where is adrenaline produced?
By Chromaffin cells in the adrenal medulla of the adrenal glands.
332
What happens to adrenaline secretion in patients with phaeochromocytoma?
It tends to be secreted in bursts giving periods of worse symptoms followed by settled periods.
333
How is phaeochromocytoma diagnosed?
24 hour urine catecholamines
| Plasma free metanephrines
334
What are the main presentations of phaeochromocytoma's?
Fluctuating symptoms:
| Anxiety, Sweating, headache, hypertension, palpitations, tachycardia, paroxysmal atrial fibirllation
335
How is a phaeochromocytoma treated?
Alpha blockers, Beta blockers, Adrenalectomy.
336
What hormones are involved in appetite regulation and what do they do?
Ghrelin--> Stimulates appetite
Leptin--> Switches off appetite
Cholecystokinin--> Causes satiety via vagus
Peptide YY--> Reduced appetite and inhibits gastric motility
337
What is precocious puberty?
Early on set puberty (before 8 girls, 9 boys)
338
What causes precocious puberty?
Idiopathic, CNS tumours/ disorders, psychosocial
339
How is precocious puberty treated?
WIth GnRH super-agonist to supress pulsality of GnRH
340
What is precocious 'pseudo'puberty?
When a hCG producing tumour tiggers puberty without pituitary of hypothalamus action.
341
How can you test to see if its true or pseudo precocious puberty?
Give GnRH--> If LH/ FSH rise then its true.
342
What is adrenarche?
Peri-pubertal activation of adrenal androgen production/ maturation of adrenal glands
343
What is the sign of puberty onset for girls?
Menarche- first period
344
What is the first sign of puberty for boys?
First ejaculation- often nocturnal
345
What is the scale used to measure pubertal developments?
Tanner stages
346
What is therlarche?
Breast development- first visible change of puberty
347
When is it classed as delayed puberty and what are the consequences?
Absence of secondary sexual characteristics by 14 (girls)/ 16 (boys). Leads to reduced peak bone mass and osteoporosis.
