Core Clinical Biochemistry Flashcards
1
Q
What is the difference between endocrine, paracrine and autocrine secretion?
A
- ENDOCRINE gland hormone secretion directly into blood- act systemically
- PARACRINE system secretes hormones- act locally (on tissues in same organ)
- AUTOCRINE secretion affects the cell secreting the protein
2
Q
Where is the Pituitary Gland located?
A
- In the Sella Turcica beneath hypothalamus
* Weighs 500-1000mg
3
Q
What are the different parts of the Pituitary Gland?
A
• Anterior & posterior parts
o 75% ant lobe (also called adenohypophysis)- outpouching of oral cavity (Rathke’s pouch)
o 25% post lobe- downgrowth of hypothalamus
4
Q
What are the Causes of Anterior Pituitary Hypofunction?
A
- Tumours (non-secretory adenoma, metastatic carcinoma)- e.g. destroys pituitary gland, or is benign non-secretory
- Trauma
- Infarction
- Inflammation (granulomatous, autoimm, other infecs)
- Iatrogenic
5
Q
What are Primary Pituitary Tumours? What can they cause? What are common types?
A
- Can cause hypOfunction
- Majority are ADENOMAS & BENIGN;
- Can be from any hormone producing cell
- If functional clinical effect 2ndry to hormone being produced e.g. ACTH will cause cushings
- Local effects due to pressure on optic chiasma/ adjacent pituitary
o Prolactinoma- COMMONEST, galactorrhoea & menstrual disturbance
o Growth hormone secreting- gigantism in children, acromegaly in adults
o ACTH secreting (stim adrenal cortex)- Cushings syndrome
6
Q
What is Prolactinoma?
A
COMMONEST anterior pituitary adenoma;
Symptoms include: galactorrhoea & menstrual disturbance
7
Q
Where is the Thyroid Gland?
A
- Bilobed, joined by isthmus encased in thin fibrous capsule
- Located level of 5th, 6th & 7th vertebrae in anterior neck (close to trachea- 2nd & 3rd tracheal rings)
- Weight 18g (adult males), 15g (adult females)
8
Q
What does the Thyroid Gland touch and have a common boundary with?
A
o Larynx thyroid cartilage
o Recurrent laryngeal nerve (in trachea-oesophageal groove near posterior aspects of lateral lobes)
9
Q
What is the development and migration of the Thyroid Gland ?
A
- Main part migrates from foregut to ant neck (remnant is foramen caecum at junction ant 2/3 & post 1/3 of tongue)- forms follicular cells
- Ultimobrachial body forms in brachial arches & fuses with main bit laterally- gives rise to C cells (can form medullary carcinomas)
10
Q
What is Lingual thyroid?
A
- Lingual thyroid (type of ectopic thyroid)- small nodule of ectopic thyroid tissue on dorsal tongue (posterior to circumvallate papillae) – failure to migrate from foramen caecum to neck
- > 75% of patients with lingual thyroid have no other thyroid tissue. 70% hypothyroid; 10% with cretinism (stunted physical & mental growth from congenital thyroid hormone deficiency)
11
Q
What is Ectopia & Heterotropia of the Thyroid Gland ?
A
- Foramen cecum to suprasternal notch.
- Lingual thyroid: Most common, usually at base of tongue.
- Lingual thyroid (type of ectopic thyroid)- small nodule of ectopic thyroid tissue on dorsal tongue (posterior to circumvallate papillae) – failure to migrate from foramen caecum to neck
- > 75% of patients with lingual thyroid have no other thyroid tissue. 70% hypothyroid; 10% with cretinism (stunted physical & mental growth from congenital thyroid hormone deficiency)
- Other sites: Sella turcica, larynx, trachea, aortic arch, esophagus, heart, pericardium, liver, GB, pancreas, vagina.
12
Q
What is Chronic Lymphocytic Thyroiditis?
A
HASHIMOTOS - HYPOTHYROIDISM
• Autoimmune chronic inflammatory disorder associated with diffuse enlargement & thyroid autoantibodies.
13
Q
What is the epidemiology of Chronic Lymphocytic Thyroiditis?
A
- Much more common in females than males.
* Peak age 59 years.
14
Q
What are the clinical features of Chronic Lymphocytic Thyroiditis?
A
- Diffusely enlarged non-tender gland.
- Serum thyroid antibodies elevated.
- Lymphocytic infiltration of thyroid parenchyma, often with germinal centre formation.
- Many patients become hypothyroid.
15
Q
What can Chronic Lymphocytic Thyroiditis also cause?
A
- 80-fold increased risk of thyroid lymphoma.
- Increased risk of papillary carcinoma of the thyroid.
- Common cause of hypothyroidism
16
Q
What is Graves Disease?
A
- Autoimmune process results in clinical hypothyroidism (after Grave’s treatment) & diffuse hyperplasia of follicular epithelium.
- One of common cause of hypErthyroidism
17
Q
What is the epidemiology of Graves Disease?
A
- Incidence 1% world wide.
- Responsible for 80% of cases of hyperthyroidism.
- Much more common in females than men.
- Peak in third and fourth decades.
18
Q
What are the clinical features of Graves Disease?
A
- Symptoms of hyperthyroidism.
- Physical findings – Pretibial myxoedema (fluid collection in deeper layers of skin), hair loss, wide-eyed stare or proptosis, tachycardia, hyperactive reflexes.
- Thyroid diffusely enlarged.
- T3 and T4 elevated. TSH markedly suppressed.
- Thyroid autoantibodies, especially thyroid stimulating immunoglobulin (bind to TSH recep & cause T3 & T4 release)
19
Q
What can Graves Disease also cause?
A
One of common cause of hypErthyroidism
• May develop permanent hypothyroidism?
20
Q
What is a Multinodular Goitre?
A
- Enlargement of thyroid with varying degrees of nodularity.
- 1 or more thyroid nodules discovered by patient or health care provider.
- Most patients are euthyroid (normally functioning thyroid gland- hormone levels normal).
- Dominant nodule may be mistaken clinically for thyroid carcinoma.
- Tracheal compression or dysphagia may develop with large nodules.
21
Q
What is a Follicular Adenoma?
A
- Benign encapsulated tumour with evidence of follicular cell differentiation.
- Females more than males.
- Wide age range, usually fifth to sixth decade.
- Painless neck mass, often present for years.
- Solitary nodule involving only one lobe (unlike multinodular goitre).
- Usually cold nodule on radioactive iodine imaging
22
Q
What are examples of Malignant Tumours of the Thyroid?
A
- 1.1% of new cancers
- 0.32% of cancer deaths
- 85% are differentiated thyroid carcinoma
- 5-9% are medullary carcinoma (from C cells- associated with MAN)
- 1-2% are anaplastic carcinoma (most aggressive- only live 6-9 mnths from time of diagnosis, if poorly differentiated then live slightly longer)
- 1-3% are malignant lymphoma
23
Q
What is a Papillary Carcinoma?
A
- Commonest type of thyroid carcinoma >70%
* Familial, autosomal dominant non-medullary thyroid carcinoma
24
Q
What is the epidemiology of Papillary Carcinoma?
A
- Female predominance 2.5:1
* Wide age range mean 43 years
25
What is the aetiology of Papillary Carcinoma?
* FAP (familial adenomas polyposis)
* Cowden’s syndrome
* Therapeutic irradiation
* Radiation exposure
* Activation of RET or NTRK1
* Variety of chromosomal translocations or inversions
26
What are the genetics of Papillary Carcinoma?
* Variety of chromosomal translocations or inversions
* Fusion of RET tyrosine kinase regions with constitutively expressed thyroid proteins eg PTC1 in inv(10)(q11;q21). PTC2 t(10;17(q11.2;q21)
* BRAF V600E mutation
* RAS mutations
27
What is the Macroscopic appearance of Papillary Carcinoma?
```
• Macroscopic appearance;
o Ill defined, infiltrative
o Some encapsulated (better prognosis)
o May be cystic
o Granular
```
28
What condition are Psammoma bodies seen in? What are they?
Papillary Carcinoma
| calcified rings usually seen in papillary carcinoma can (seen in USS)
29
What are Follicular Neoplasms? What mutation is present? What are the types?
All show RAS mutations
1. Follicular adenoma
2. Minimally invasive follicular carcinoma
3. Widely invasive follicular carcinoma
4. Hurthle cell neoplasms
30
What is a Follicular Carcinoma?
* 10-20% of all thyroid cancers
* 90% present with solitary nodule in thyroid (helps with diagnosis)
* 10% present with distant metastasis
31
What are the different types of Follicular Carcinoma?
* Minimally invasive < 5% metastasis
| * Widely invasive >60% metastasis
32
What is Minimally invasive Follicular Carcinoma?
• Minimally invasive < 5% metastasis
• Minimally invasive ;
o Completely encapsulated.
o Invasion only detectable histologically
33
What is a Widely invasive Follicular Carcinoma?
```
• Widely invasive >60% metastasis
• Widely invasive;
o Macroscopic evidence of invasion.
o Widespread invasion histologically.
o Minimally invasive but tumour invades > 4 capsular blood vessels
```
34
What is Hurthle Cell (Oncotic) Carcinoma?
* Recognised large acidophilic cells in canine thyroid
* Cells with oncoyctic cytoplasm
* These were parafollicular or C cells
* 3% of all differentiated thyroid carcinomas
* Median age 53 ( range 24-85 years)
* Sex ratio of F:M; 7:3
35
What are the clinical features of Hurthle Cell (Oncotic) Carcinoma?
• Clinical behaviour;
o Unlike Follicular Carcinoma there is a significant incidence of cervical lymph node metastases
o Can be multifocal
o Common haematogenous sites – Bone, Liver and Lung
36
What is Primary hyperparathyroidism?
excessive section of parathyroid hormone from one or more glands (PHPT)
37
What is the incidence of Primary Hyperparathyroidism ?
* 25-28 cases per 100,000 population
| * White women over 60 – 190/100,000
38
What is pathogenesis Primary Hyperparathyroidism ?
1. Aging, tumorigenesis in general
2. Association with ionizing irradiation
3. MEN 2a syndrome- multiple endocrine neoplasia
39
What are the different symptoms of Primary Hyperparathyroidism ?
1. ASYMPTOMATIC OR OLIGOSYMPTOMATIC\: 50+%
2. ARTERIAL HYPERTENSION : 5-48%
3. PSYCHIATRIC PROBLEMS: 14-20%
4. HYPERCALCEMIA SYMPTOMS: 20%
5. DECREASED RENAL FUNCTION :4-14%
6. OSTEOPOROSIS :12%
7. HYPERPARATHYROID BONE DISEASE: 8%
8. HYPERCALCEMIA SYMPTOMS: 8%
9. UROLITHIASIS: 4-7%
40
What are the different types of Primary Hyperparathyroidism ?
1. SINGLE ADENOMA (most common) 85 - 90%
2. DIFFUSE CHIEF OR CLEAR CELL HYPERPLASIA 10 – 15%
3. CARCINOMA 1%
41
What is Parathyroid Adenoma?
* An encapsulated benign neoplasm of parathyroid cells.
* 1 per thousand people.
* Symptoms of hypercalcaemia.
* Association with MEN1 and MEN2 syndrome and hyperparathyroidism and jaw tumour syndrome.
* Single enlarged parathyroid gland; remaining glands suppressed and small.
* HRPT2 gene mutation- parathyroid carcinoma
42
What is Secondary Hyperparathyroidism ?
hyperplasia of glands with elevated PTH in response to hypocalcemia
o Seen in patients with renal insufficiency, malabsorption, vitamin D deficiency
• Non-neoplastic increase in parathyroid parenchymal cell mass within all parathyroid tissue with a known stimulus.
• Common in patients with renal failure and on dialysis.
• Identical pathologic features to primary hyperplasia. May be associated with massive gland enlargement
• PTH levels fall when affected gland removed
above same as tertiary
43
What is Tertiary Hyperparathyroidism ?
adenoma in association with longstanding secondary hyperparathyroidism
44
What is Parathyroid Carcinoma ?
* Malignant tumour from parathyroid parenchymal cells.
* Only 1% of primary hyper-parathyroidism.
* Symptoms referable to excess calcium
* Indolent with recurrences common (about 50%).
* 50% 10-year survival.
* Treated with surgery.
45
What are the layers of the Adrenal glands?
Adrenal glands on top of kidneys
Diff layers;
• Central part- medulla
• Outer part- cortex (has 3 layers- glonerulosa(aldosterone), fasciculata(cortisol), reticularis (catecholamines))
Diff hormones from diff layers- so depending on where affected affects type of tumour
e.g. Zona fasiculata- Cushing’s syndrome
46
What is Cushing’s Syndrome?
• Collection of signs and symptoms due to prolonged exposure to cortisol.
47
What are the causes of Cushing’s Syndrome?
* Exogenous causes - excessive glucocorticoid medication
| * Endogenous causes - adrenal cortical tumours, adrenal cortical hyperplasia and ACTH secreting pituitary adenoma
48
What are the signs and symptoms of Cushing’s Syndrome
* Signs and symptoms - high BP, moon face (oedema of face), central obesity, buffalo hump, weak muscles, weak bone, excess sweating, mood swings, headaches, excess sweating, osteoporosis, chronic fatigue. Women may have increased hair growth (hirsuitism) and irregular menstruation.
* Insomnia
49
What is Paraneoplastic Cushing’s ?
• Paraneoplastic Cushing’s seen in small cell lung carcinoma- tumour not affecting renal/ pituitary
50
What is Conn’s Syndrome ?
* Hyperaldosteronism, primary 7 secondary, W>M, 30-50yrs
* Excess aldosterone production by adrenal cortex leading to low renin levels (controlled by renin-angiotensin system)
* Aetiology include adrenal cortical hyperplasia, adenoma and familial hyperaldosteronism
51
What are the signs and symptoms of Conn’s Syndrome?
high BP, headache, muscular weakness, muscle spasms, excessive urination.
52
What is Addison’s Disease ?
* Primary adrenal cortical insufficiency caused by adrenal dysgenesis (lack of formation of adrenal gland), adrenal destruction, autoimmune adrenalitis, TB
* Secondary to failure of ACTH secretion
* 5.3 per million population.
* High mortality if not diagnosed.
* Autoimmune form is most common.
* Treatment with long term steroid replacement
* If undiagnosed can prove fatal
53
What are the signs and symptoms of Addison’s Disease?
• Triad of hyperpigmentation, postural hypotension and hyponatraemia.
54
What is a Adrenal Cortical Nodule?
* Benign non-functional nodules of adrenal cortex.
* Between 1.5 and 3% of population. Higher in elderly, hypotensive and diabetic patients.
* No clinical symptoms (as non functional). Incidental discovery on radiographic studies.
* No treatment required.
55
What is a Adrenal Cortical Adenoma?
* Benign neoplastic proliferation of adrenal cortical tissue.
* Incidence from 1-5% of population.
* Symptoms related to endocrine hyperfunction (hypertension, Cushing’s symptoms and virilisation)- depending on which layer of adrenal cortex affected depends on which hormone affected
* Aldosterone-producing tumours cause Conn’s syndrome. Cortisol-producing tumours cause Cushing’s syndrome. Rare tumours cause virilisation.
56
What is a Adrenal Cortical Carcinoma?
* Malignant counterpart of adrenal cortical adenoma.
* 3% of endocrine neoplasms. About 1 per million of population.
* Symptoms related to hormone excess.
* Abdominal mass.
* Prognosis, age and stage dependent (e.g. if has metastasised or not).
* 5 year survival about 70%.
57
What is a Phaeochromocytoma?
* Catecholamine-secreting tumour arising from adrenal medulla.
* Extra renal- paragandioma
* 8 per million of population.
* 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial and 10% in children.
* Most are sporadic but familial syndromes MEN2a and 2b, von Recklinghausen's disease and von Hippel-Lindau disease
* symptoms of hypertension, palpitations, headaches, anxiety.
* Elevated urine catecholamines, adrenaline, noradrenaline.
* Excellent prognosis when benign and properly managed surgically.
* Malignant tumour may pursue an aggressive course
58
What are the three different Types of Hormones?
* Peptide hormones (e.g. PTH, ACTH, TSH)
* Steroid hormones (e.g. Testosterone, Oestradiol, Cortisol)
* Tyrosine-based hormones e.g. Thyroxine (T4) and Triiodothyronine (T3)
59
What inhibits GnRH?
inhibited by estradiol/inhibin/progesterone and stimulated by environment an higher brain centres
Inhibin inhibits FSH production via negative signalling
60
What inhibits GHRH?
inhibited by somatostatin
61
What inhibits PRH?
inhibited by dopamine
62
What are the tree models of steroid hormone response?
1. Classical model= steroid hormone dissociates from plasma carrier protein & diffuses across cell memb. Enters cell & binds to intracell recep & alters gene transcription
2. Receptor-mediated endocytosis= steroid hormone bound to plasma protein carrier brought into cell via cell-surface recep. Complex broken inside lysosome & free steroid hormone diffuses into cell & acts on genomic level/ undergoes metabolism
3. Signalling through cell surface receps= free steroid hormone alters intracell signalling by binding to cell-surface receps. Steroid hormone could directly exert these effects or alter signalling by blocking actions of peptide hormones , alteration of intracellular signalling including ion channels and PLs
• Steroid hormones- circulate bound to serum proteins
• Steroid hormones made when there is a stimulus to make them & they act rapidly
63
What is the Classical model of steroid hormone function?
steroid hormone dissociates from plasma carrier protein & diffuses across cell memb. Enters cell & binds to intracell recep & alters gene transcription
64
What is the Receptor-mediated endocytosis model of steroid hormone function?
steroid hormone bound to plasma protein carrier brought into cell via cell-surface recep. Complex broken inside lysosome & free steroid hormone diffuses into cell & acts on genomic level/ undergoes metabolism
65
What is the Signalling through cell surface receptors model of steroid hormone function?
free steroid hormone alters intracell signalling by binding to cell-surface receps. Steroid hormone could directly exert these effects or alter signalling by blocking actions of peptide hormones , alteration of intracellular signalling including ion channels and PLs
• Steroid hormones- circulate bound to serum proteins
• Steroid hormones made when there is a stimulus to make them & they act rapidly
66
What is GPR146?
Peptide Hormone Signalling Cascades
• Cascade amplifies signal e.g. insulin action depends on calcium entering cell
• C-peptide-initiated signaling cascades; regulating diff signaling cascades e.g. phospholipase C (PLC) & NF-κB pathway.
• These intracellular signaling events are likely mediated by a G protein-coupled recep e.g. GPR146
• GPR146 interacts with G protein (Gαi or Gαo)
• GPR146 may interact physically with additional proteins on the cell memb e.g. an integrin
• C-peptide and insulin appear to functionally interact, particularly at the level of Akt.
67
What is the role of Thymosin?
stimulates T cell production
68
What is the role of C-peptide?
activates GLUT-1 transporter
69
When do you use stimulation? When do you use suppression tests?
o Stimulation for hypO-function
o Suppression for hypErfunction
* When to take blood samples- physiological & pathological factors
* When to use integrated urine sampling
* Free, bound & total hormone concs
70
What is the difference between Primary & Secondary Disorders?
1. Normal pituitary & thyroid
2. Primary thyroid disease (in primary synthetic hromone for that hormone( - not enough thyroid hormones produced
3. Secondary thyroid disease – i.e pituitary tumour
71
What is the The Hypothalamic-Pituitary-Adrenal Axis ?
* Stress stimulation from amygdala to paraventicular nucleus which releases CTRH (corticotropin releasing hormone) this causes ACTH release which acts on adrenal cortex to cause cortisol release. CRF also controls the stress response- brain and peripheral function
* Cortisol causes stress response
* Glucocorticoids then causes –ve feedback to ensure stress response doesn’t carry on by sending -ve signals to all areas of the brain.
72
What is primary cortisol excess?
| What is secondary cortisol excess?
* Which is primary cortisol excess?- Disease in Adrenal
| * Which is secondary cortisol excess?- Due to excess ACTH
73
What are three causes of Excess Cortisol Production?
* in pituitary disease, May get adrenal gland hypertrophy
* Adrenal makes lots of cortisol-ve feedback on pituitary
* Ectopic- something outside of normal tissue secreting hormone when it shouldn’t , Get effects of cortisol excess
74
What can cause Ectopic ACTH Secretion?
```
o Benign carcinoid tumors of the lung
o Small cell tumours of the lung
o Islet cell tumours of the pancreas
o Medullary carcinoma of the thyroid
o Tumours of the thymus gland
```
75
What are the three causes of Adrenal Insufficiency?
* Primary adrenal insufficiency- disease in adrenal gland so doesn’t make cortisol- so can’t respond to stresses (EMERGENCY SITUATION), lots of ACTH secreted to try to get cortisol produc, no –ve feedback so excess ACTH
* Secondary adrenal insufficiency due to pituitary prob (not enough ACTH secreted)
* Exogenous cortisol- ACTH not secreted because of exogenous cortisol
* Measure cortisol after cortisol being given e.g. dexamethasone, may detect cortisol in their circ but person won’t be able to mount a stress response (EMERGENCY)
76
What is the Diurnal Rhythm in Serum Cortisol?
* Diurnal rhythm in cortisol secretion
* E.g. won’t be secreting cortisol at night
* Peak produc at 9am when wake up (above 150nmols/L)
* Peaks after eating & exercise
* So taking cortisol values during the day not informative for diagnosis of insufficiency or excess also random day test isn’t useful
77
What is cushions disease? What is cushings syndrome? What test is used?
* Cushing’s DISEASE- tumour producing ACTH
* Cushings SYNDROME- anything producing secondary excess
• Conduct dexamethasone suppression test
78
What are Features of Cushing’s?
```
o Obesity; moon face, central, shoulders
o Skin; thin, purple striae, bruising
o Hypertension
o Glucose intolerance
o Menstrual disturbances/ impotance
o Thin limbs/ muscle weakness
o Back pain due to osteoporosis
o Psychiatric disturbances; depression psychosis
```
79
What is adrenal failure? What test is used?
• In ability to make enough cortisol in response to stress
• Due to adrenal atrophy/ destruction
• Serum cortisol after 250 mmol Synacthen 350 nmol/L (no increase in cortisol- shows adrenal insufficiecncy)
Syncathen test; syncathen given IM, measure serum cortisol at 9am (baseline), if unsufficeincy this is low but could be higher, syncathin (ACTH stim)- meaure later & expect to see an increment & if no incrememnt then insufficiency
80
What are features of Adrenal Failure?
```
o Tiredness
o Weight loss
o Pigmentation
o Hypoglycaemia
o Abdominal pain
o Hypovolaemic collapse
```
81
What are some Thyroid Abnormalities?
* TSH ↑ & thyroxine ↓ -unresponsive thyroid
* TSH ↑ & thyroxine ↑ -npituitary gland overproduction or feedback failure
* TSH ↓ & thyroxine ↓- pituitary failure
* TSH ↓ & thyroxine ↑- thyroid gland overproduction
82
What is the The Hypothalamic-Pituitary-Thyroid Axis ?
TRH from hypothalamus stimulates pituitary to release TSH which stimulates the thyroid to release T3 and T4.
T3 and T$ inhibit the pituitary and the hypothalamus and the pituitary also releases TSH which inhibits the hypothalamus.
83
What is sick euthyroid disease?
Thyroid hormones in critically unwell patients (‘sick euthyroid disease’)
• Euthyroid (normally functioning thyroid)- no thyroid disease
• If very unwell (shock, MI etc)- cytokines mount inflammatory response, then act centrally on thalamus & systemically
• Cytokines inhibit iodide uptake in thyroid & thyroid peroxidase activity & deiodinase= decrease T4 and T3synthesis and secretion and also decreased TRH secretion from the hypothalamus due to the central effects of cytokines
84
What is the Menstrual Cycle ?
• FSH & LH values change through the cycle
• Ovaries failing (may be menopausal)- no eistrodial –ve feedback occurring
But if still menstruating may have just taken sample mid cycle where there is a peak of FSh & LH- so taking blood sample to measure hormones not always accurate (need to also look at the clinical pic- also help you to decide WHEN to take the sample to help interpret results)
85
What is the pattern of Testosterone Throughout Life in Males?
* Peak in foetus & infancy (spotty at around 2 months- as surge in testosterone)
* Low conc in childhood until puberty
* In adulthood- peaks & trophs throughout the day
* Andropause- degree of testicular failure & testosterone decreases
86
When Might You Want to Measure Hormones in Urine?
* Integration of fluctuating single serum hormone e.g. pulsatile secretion e.g. 24hr urine sample & measure cortisol from this
* Integration of multiple hormones
* Analysis of unstable serum hormones but more stable in urine
* Collection at time of symptoms (when symptomatic can take a spot urine)
* Avoid venepuncture
* e.g. Phaeochromocytoma (tumour of adrenal medulla NOT cortex), chromaffin cells release excess catcholamines e.g. adrenaline (get palpitations, hypertenion, flushing-red flag for phaeochromocytoma)- mesure catecholamine metabolites (as catcholamines themselves unsatble so measure products they are metabolised to in urine- DO 24hr URINE is suspect phaeochromocytoma)
* e.g. metanephrine & normetanephrine in a 24hr urine collection
87
What is a Insulinoma?
* Insulinomas- rare pancreatic endocrine tumors
* Most insulinomas are solitary & benign, but when in patients with MEN1 multiple tumors are usually present
* Nonspecific symptoms (e.g. hypoglycaemic symptoms- e.g. shivering, feeling nervous/ faint) & small size of these tumors- difficulties of diagnosis & localization
* Hypoglycemia & endogenous hyperinsulinemia are diagnostic
* Can remove insulinoma by enucleation
* Before operation- transabdominal USS (localise tumour) or CT (identify potentially malig or metastatic tumours)
* Intraoperative ultrasound- so far best localization of insulinoma, improving success rate and possibly decreasing the already low postoperative complication rate for resection of these tumors.
* Excision of benign insulinomas- long-term cure.
88
How do you measure T4 and T3?
• Hormones in equilibrium: Free + protein-bound = total hormone (equilibrium)
• fT4 and fT3 are the biologically active forms of thyroid hormones (pmol/L)
• fT4 and fT3 in the circulation are bound to proteins (TBG, albumin)- NOT biologically active when bound to protein
• Immunoassays – use labelled Ab to recognise and bind fT3 / fT4;
o Take sample & add fluorescent antibodies to it
o The antibodies will capture the free hormones (then you can wash sample out & measure the fluorescent antibodies bound to homones to see how much free hormones are in sample)
o BUT results may be affected as need to add excess antibodies to sample so when you leave the reaction to happen the antibodies may take hormones that are bound to the proteons in the sample- so not just measuring the free but also some of the bound hormone- so may look like you have raised level of free hormones when don’t
o Immunoassays specific to hormones- antibodies labelled, capture & measure labelled to give idea of how much free sample in hormone
o BUT hormones in equalib- e.g. if capture hormone might cause mass effect causing bound hormone to be released
o So need to be careful when assay so don’t affect the equalib
89
What are common endocrine rhythms?
* Annual cycles- hair growth
* Monthly cycles- menses
* Diurnal (daily)- cortisol
* Rapid amplitude cycles- insulin
* Stress related- ant. pituitary hormones
* Stimulus related- insulin
90
What are the sources of glucose?
• People use glucose for fuel
• 3 sources of glucose in the body;
o Dietary carbs
o Glycogenolysis
o Gluconeogenesis (glucose produc from other precursor molecules)
• Glucose is stored as glycogen in liver & muscle
• In fasting- glycogen broken down= glucose
91
What is the normal glucose level? What is Hypoglycaemia? What is Hyperglycaemia ?
• Maintained at about 5mmol/l
• Achieved by balancing liver glucose release, dietary intake & use of glucose by the body to keep glucose at a stable level e.g. use more in exercise
• Insulin (made by pancreas)- controls glucose release from liver & promotes glucose UPTAKE in tissues
Hypoglycaemia <4mmol/L
Hyperglycaemia >11mmol/L
92
What is insulin? What is its effects?
• Made by beta cells in Islets of Langerhans in pancreas
• Secreted in response to raised blood glucose conc
• Reduces blood glucose through diff mechanisms
Effects of insulin;
• Glucose- lowering effects;
o Increases cellular glucose UPTAKE
o Increases SYNTHESIS of GLYCOGEN
o Inhibits gluconeogenesis
o Inhibits glycogenolysis
• Other metabolic effects;
o Increases fatty acid, triglyceride & protein synthesis
o Inhibits ketogenesis, lipolysis & proteolysis (so if not enough insulin- build up of ketones)
93
What hormoneS increase blood glucose?
```
Hormones that INCREASE blood glucose;
• Glucagon
• Adrenaline (made by adrenal gland) & growth hormone (made by ant pituitary);
o Stimulate glycogenolysis
o Stimulate lipolysis
• Cortisol (made by adrenal gland)
o Stimulates gluconeogenesis
o Increases glycogen synthesis
o Stimulates proteolysis
o Reduces tissue glucose use
```
94
What is Glucagon?
• Made by alpha cells of pancreatic islets
• Rise in blood glucose decreases it’s secretion
• Increases blood glucose by;
o Stimulating glycogenolysis
o Stimulating gluconeogenesis
• Also increases ketogenesis & lipolysis
95
What is Diabetes?
Diabetes- medical condition with high blood glucose levels
• Blood glucose level drifts up- chronic hyperglycaemia
• Is a syndrome of raised blood glucose (hyperglycaemia) due to diff causes
• Has acute & chronic complications
• Patients often have high BP & high lipid levels
• How common;
o Leeds: 30,000 in 730,000 pop (4%)
o Prevalence rising fast
o Associated with rise in obesity & reduction in physical activity
o High prevalence in Asians & Afro-Caribbeans
96
Diabetes signs and syndromes?
* Syndrome- collection of symptoms & signs that may be due to more than 1 cause (more than 1 cause of high blood glucose in diabetes)
* Symptoms: thirst, polyuria, weight loss, tiredness
* Signs: dry mouth, weight loss, glycosuria, hyperglycaemia
* Diabetes may be due to several causes
97
What is the pathophysiology Diabetes?
* Insulin deficiency (body doesn’t make enough) or resistance to it’s action or both
* Causes increased gluconeogenesis & glycogenolysis (so more glucose from liver to blood) & impaired glucose uptake by cells (so blood glucose keeps rising)
* Leads to chronic hyperglycaemia
98
How do you diagnose diabetes?
Diabetes Diagnosis (excluding gestational diabetes)
• Typical symptoms and 1 of;
o Random plasma glucose (taken at any time of day) ≥11.1 mmol/L or
o Fasting plasma glucose (e.g. overnight fast) ≥7.0 mmol/L or
o 2 hr post-load plasma glucose ≥11.1 mmol/L during 75g oral glucose tolerance test (OGTT) (measure before & after 2hrs) or
o HbA1c ≥48 mmol/mol (6.5%) (long term marker)
• If no typical diabetes symptoms, repeat testing on a diff day to confirm diagnosis (so have 2 values above cut off)
99
What is the Glucose Tolerance Test?
• Can be oral (OGTT) or IV (IVGTT)
• OGTT;
o Fasting plasma glucose
o Then 75g oral glucose load (e.g. sugary drink)
o Plasma glucose at intervals & as 2hrs post-glucose load
o Interpretation;
Fasting: normal <6.1mmol/l, diabetic ≥ 7mmol/l
2-hr post-glucose load: normal <7.8mmol/L, diabetic ≥ 11.1 mmol/l
100
What is ‘Borderline Diabetes’?
* In between normal & diabetic range
* Impaired fasting glucose: plasma glucose ≥ 6.1 mmol//L and <7mmol/l
* Impaired glucose tolerance: 2 hour post-glucose load plasma glucose ≥7.8 and <11.1 mmol/l, on the 75g OGTT
* HbA1c 42-47 mmol/mol (high risk of going onto type 2 diabetes)
101
What is the investigations of diabetes?
• HbA1c;
o Glycated Hb- depends on blood glucose level
o As RBCs live for 120 days, this values shows you blood glucose for a couple of months (rather than just 1 moment in time)
o Not reliable in patient’s with anaemia
o A test for diabetes diagnosis & assessing degree of glycaemic control
• Renal function
• Liver function (might have fatty liver causing affected LFTs)
• Lipids
• Thyroid function (as thyroid disease also autoimm)
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How do you diagnose Gestational Diabetes?
• Diagnosed using 75g 2-hour OGTT
• Gestational Diabetes diagnosed if:
o Fasting plasma glucose ≥ 5.6 mmol/L
o 2-hour post-glucose load plasma glucose ≥ 7.8 mmol/L
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What are Types of Diabetes?
* Type 1: insulin dependent
* LADA (Latent Autoimmune Diabetes in Adults)
* Type 2
* Gestational Diabetes
* Pancreatic disorders
* Drug induced
* Endocrine disorders
* Ethnic variants of diabetes
* Genetic syndromes
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What is Type 1 Diabetes?
* Autoimmune destruction of the insulin producing islet beta cells so can’t make insulin
* Insulin deficient: insulin dependent (exogenous insulin injections otherwise can get diabetic ketoacidosis)
* Usually young, but can be ANY age
* Symptoms; thirst, passing lots of urine etc over a couple of months (other types of diabetes develop more slowly)
* Autoantibody tests: ICA, IA2, GAD
* Often other endocrine disorders in patient or family
105
What is Latent Autoimmune Diabetes in Adults?
* Subtype of type 1 diabetes
* Older patients, often female
* Medical or family history of related autoimmune conditions: type 1 diabetes, thyroid, PA, Addison’s (autoimm- don’t make enough steroids), coeliac, vitiligo
* Presents often as ‘type 2’ diabetes- present slowly
* Progressive deterioration in control, increasing therapy (need insulin treatment)
* Autoantibodies: GAD, ICA, tTG, TPO
106
What is Type 2 Diabetes?
* Insulin resistant/deficient (don’t respond to insulin the way normal people do)- overtime less made by pancreas
* Not absolutely insulin dependent
* Strong family history
* Often obese or overweight (metabolic syndrome associated with this)
* Usually hypertensive and hyperlipidaemic
* Initailly lifestyle changes e.g. control blood glucose
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What is Ketosis-prone Type 2?
* Often obese, ethnic minority
* Ketosis when physically stressed with intercurrent illness e.g. infecs (may need insulin treatment for these periods of time when unwell)
* Temporarily requires insulin
* Not insulin dependent
108
Are All People with Diabetes Overweight?
* Diabetes & obesity are closely interlinked
* Not every diabetic person is overweight
* Not every overweight person is diabetic or will become diabetic
* Population association between overweight and diabetes
109
What is Gestational Diabetes?
* Diabetes arising/ diagnosed in pregnancy
* In late 2nd or early 3rd trimester
* Diabetes appears during pregnancy & resolves after pregnancy (associated with insulin resistance)
* At risk of diabetes in later pregnancy
* At risk of diabetes in future- as have underlying insulin resistance that preg brings to the surface
110
What is Diabetes Secondary To Pancreatic Disorders ?
* (Secondary diabetes- diabetes caused by anything that’s not type 1 or 3 diabetes)
* Chronic or acute pancreatitis
* Need insulin treatment
* Calcific, tropical pancreatitis- calcium deposits damage insulin producing cells
* Pancreatectomy (e.g. if had pancreatic cancer)
* Pancreatic cancer- as damage beta cells
* Cystic fibrosis- blocked ducts in pancreas causing inflamm & destroying beta cells (acute illness can also cause resistance)
* Haemochromatosis- hereditary iron overload storage disorder (iron deposits in tissues e.g. pancreas- damages cells)
111
What is Drug-Induced Diabetes?
Thiazide) diuretics
• Steroids e.g. for rheumatoid arthritis or asthma
• Antipsychotics e.g. Olansazpine
• Psychiatric drugs: weight gain
112
What is Phaeochromocytoma?
(adrenal gland tumour- causes adrenal medulla to make too much adrenaline & noradrenaline)- adrenaline is a counter- regulatory hormone so too much adrenaline=too much glucose in blood
113
What is J type diabetes?
‘Jamaican’ diabetes, Afro-Caribbeans;
o Mimics type 2 diabetes
o Ketosis prone
o Not particularly obese
o On and off insulin therapy for episodes of high glucose (associated with acute illness)
o Variable insulin requirements as when recover from illness sometimes don’t need inulin anymore just manage with e.g. diet
o But always at risk of having episodes in the future if they become unwell
o Also called Flatbush diabetes
114
What is Flatbush diabetes?
US Afro-Americans
115
What is malnutrition-related diabetes?
tropical diabetes
116
What is Chronic calcific pancreatitis?
secondary diabetes
117
What is Z type diabetes?
(associated with pancreatitis)
118
What are Genetic diabetes Syndromes?
* Most people are diabetic on Pacific Island of Nauru- highest prevalence of diabetes in the world (genetic predisposition & lifestyle factors)
* Pima native Americans of Arizona- Pima tribe: obesity & diabetes (highest prevalence of diabetes in the world)
* Friedreich’s ataxia (neurodegen condition)
* Dystrophia myotonica
* Maturity Onset Diabetes of the Young (MODY)
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What is Maturity Onset Diabetes of the Young (MODY)-
‘Mason-type’ diabetes;
o Subtype of type 2 diabetes- clinical features of type 2 but present under age 25
o Autosomal dominant pattern
o 1-2% of diabetic cases
o Onset under 25
o Insulin not required initially
o 6 diff types- have mutations in genes; Glucokinase, HNF 1A, HNF 4A
120
What is Biochemistry of Calcium?
• Divalent cation – Ca2+ (beware EDTA!!)
• EDTA binds divalent cations (e.g. calcium) so stops clotting process
• Physiologically important
o Muscle contraction
o Neuronal excitation
o Enzyme activity (Na/K ATPase, hexokinase etc.)
o Blood clotting
• Structurally important- key component of hydroxyapatite Ca₁₀(PO₄)₆(OH)₂ (predominant mineral in bone)
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What is Biochemistry of Phosphate?
• Monovalent anion (-vly chrged so will bind +vly chrged entities)– PO4
• Physiological importance
o The P in ATP – our fuel!
o Intracellular signalling
o Cellular metabolic processes e.g. glycolysis
• Structural importance
o Backbone of DNA
o Component of hydroxyapatite Ca₁₀(PO₄)₆(OH)₂
o Membrane phospholipids
• PREDOMINANTLY INTRACELLULAR
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What is Biochemistry of Magnesium?
```
• Divalent cation – Mg2+
• Physiological importance
o Cofactor for ATP– our fuel!
o Neuromuscular excitability (memb potentials)
o Enzymatic function
o Regulates ion channels
• Structural importance- comprises 0.5 – 1% of bone matrix
• PREDOMINANTLY INTRACELLULAR
```
123
What is high K+ on normal renal function?
* If have normal renal function- not physically possible to have a extremely high K+
* EDTA is a K+ salt
124
What are the normal levels of calcium? what factors maintain this?
• Calcium normally tightly regulated 2.20 -2.60 mmol/L
• Two key controlling factors:
o PTH (parathyroid hormone)
o Vitamin D and metabolites
• Vit D helps with Ca intake, PTH helps balance
• Complex (but well-characterised) relations between
o GI uptake (where get calcium from)
o Renal Clearance
o Bone
125
What are the three forms of Plasma Calcium?
Total Ca = Ionised Ca + Bound Ca + Complexed Ca
• Ionised Calcium
o Physiologically active fraction- biologically active
o Calcium sensing receptor- controls regulations that control ca homeostasis
o Cellular Effects
o Regulation of PTH
• Bound Calcium
o Physiologically inactive
o Albumin main binding protein (~50%) (can also bind to immunoglobulins so if have myeloma will affect calcium)
• Complexed Calcium
o Salts – calcium phosphate & calcium citrate (if too much will create salts in high concs)
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What is Adjusted Calcium?
```
• Calcium values can be corrected for changes in albumin
• Adjusted Ca = Total Ca + (40 - Alb) x 0.025
• Reference range is unchanged but patient samples are adjusted for better diagnostic performance
o Total Ca (not all biologically active) 2.20 - 2.60 mmol/L
o Ca(adj) 2.20 - 2.60 mmol/L
```
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What are the effects of pH Changes on Ca?
* H+ & Ca2+ compete for binding to –ve albumin
* Too many hydroxyl & less H+ so more Ca binds to albumin 1.25, less ionized 1.0
* e.g. normal adj Ca but if acidotic than that is not normal calcium- look at everything together .
* Acidosis reduces Ca-albumin, Alkalosis increases Ca-albumin
* Acidosis ionized Ca is increased 1.5 and less bound calcium 0.75
* Direct measurement with ion specific electrodes confirms the relationship
* Alkalosis (e.g. hyperventilation) can precipitate tetany
* Hypocalcaemic patients with acidosis don’t develop symptoms
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What are Lab Measurements of Ca?
• Routine measurement is total Calcium; cost & convenience
• Doesn’t necessarily reflect ionised calcium;
o Total Ca affected by [albumin]
o pH influences ionised Ca
• Ionised more expensive so only use in ITU
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What can cause high albumin?
• Not many conditions cause high albumin- mainly just dehydration, or put tornequey on too tight
130
What are bound calcium levels like in Nephrotic patients?
can’t hold onto albumin so less bound calcium
131
What is Vitamin D? What affects the levels?
Physiology
• Need sunlight for vit D
• Can give active vit D but very potent so don’t really want to give
• Renal patients have low calcium & vit D
• Enzyme converting inactive vit D- kidney cells regulate this so if kidneys affected low vit D low Ca
Env Factors
• Endogenous; Skin colour (lower vit D), Aging- elderly (e.g. may not get out as much)
• Exogenous; Ozone, Sunscreens & clothing, Latitude and season, Time of day (circadian rhythm), Diet & supplements
Vit D falls with AGE, BMI & BODY FAT (as vit D hydrophobic- so if lots of fatty tissue- vit D re-distributes into fatty tissue so not biologically available)
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What is the Calcium- Parathyroid Hormone Loop?
* Sense how much Ca or phosphate
* Low Ca= PTH secreted= act on kidneys (so more Ca reabsorption), stim enzyme so more vit D converted to active vit D, Ca from bones
* PTH in zymogens- zymogens need to combine with extracell surface to release contents (need Mg to do this)- so if patient has low Ca & low Mg replace Mg first and this may sort out the low Ca
* Negative feedback from Ca on parathyroid glands, positive feedback
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What are the Causes of Hypocalcaemia?
• Hypoproteinaemia
• Vitamin D deficiency; Dietary / Malabsorption, Hepatic disease, Renal Disease (can’t hold onto Ca), End organ Vitamin D resistance
• Hypoparathyroidism;Primary, Secondary to Mg depletion
• Inadequate intake of calcium
• Pseudohypoparathyroidism (low Ca as recep is ignoring PTH); End organ PTH resistance
• Artefactual cause?
o EDTA contamination
o Venestasis will cause low adjusted calcium (total calcium is unaffected)
• Can have low Ca as post op recent blood transfusion which contains citrate (bins Ca)
• Low Ca & high PTH- Vit D deficiency
• Low Ca, high phosphate & low PTH- hypoparathyroidism
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What are the Causes of Hypercalacaemia?
• Hyperparathyroidism
• Malignancy; Lytic lesions, Humoral eg PTHrp
• Drugs e.g. lithium affect Ca
• Vitamin D excess; 1a cholecalciferol, Sarcoidosis
• Bone disease + immobilisation
“Bones, stones, moans and groans”- bone pain, stones, abdo pain & mood dampening
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What are the Differential diagnosis of Hypercalcaemi?
• Consider Adjusted Ca - look at the albumin
• Check drug history
• Exclude excess vitamin D intake
• Check for renal failure
• Simultaneous measurement of Ca & PTH
• Consider rarer causes & more complex investigations
High calcium, PTH & low phosphate- primary hyperparathyroidism
High Ca & low PTH- malignancy
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What are the Differential Diagnosis of Calcium Disorders?
low serum ionised Ca and low plasma PTH: primary hypo PTH
increased plasma PTH and low serum ionised Ca: secondary hyper PTH (renal/nutritional)
increased plasma PTH and increased serum ionised Ca: primary hyper PTH
low plasma PTH and increased serum ionised Ca: PTH independent hypercalcemia (e.g malignancy and fit D toxicity)
137
What is mild hypercalcaemia?
* Untreated mild hypercalcaemia has serious consequences
* < 1.6 mmol/L is a medical emergency requiring immediate treatment
Hypercalcaemia calcium > 3.5 mmol/L is alos a medical emergency.
138
What is phosphate?
* Major intracellular ion - small proportion in plasma – similar to Potassium
* Involved in high energy reactions - e.g. those involving ATP - Na/K pumps, Hexokinase
* Deficiency can cause weakness (as importnce with ATP- muscles need this) and dysfunction
* Severe depletion can be fatal
* Low phosphate (if undetectable)= can die of resp failure (as diaphragm is a muscle)
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What are the causes of Phosphate Deficiency?
• Hyperparathyroidism (High PTH= causes kidneys to give out more phosphate)
• Excess losses
o renal tubular damage
o Gastro intestinal
o diabetes (diuresis)
• Poor intake; malnutrition, inadequate IVN
• ECF/ ICF redistribution - like potassium
140
What are the symptoms of Phosphate Deficiency?
• Often overlooked or disregarded
• Symptoms of phosphate deficiency include:
o Haemolysis, thrombocytopenia and poor granulocyte function e.g. low platelets
o Severe muscle weakness, respiratory muscle failure and rhabdomyolysis
o Confusion, irritability and coma may be due to a metabolic encephalopathy due to phosphate deficiency
o Renal dysfunction
• If confirmed treatment is essential: often necessitates changes to IV fluid regimens including TPN formulations
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What are Magnesium and phosphate disorders?
* Commoner than generally appreciated- ‘Mg - The forgotten cation’
* Up to 10% of hospital admissions
* Close relationship with Ca and K disorders
* Similar problem with disorders of phosphate metabolism
* In Kidneys; cations move across memb, calcium & Mg closely linked
142
What effects Magnesium Homeostasis?
• COPD = acidotic=affects cations
143
What is Hypomagnesaemia?
```
Causes of Magnesium
• Prevalence in hospitalised patients: alone on routine estimation 6 - 11%
• Associated with :-
o Hypokalaemia 40%
o Hyponatraemia 23%
o Hypophosataemia 29%
o Hypocalcaemia 25%
```
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What are the Causes of Magnesium depletion?
```
Renal
• Diuretic phase of Acute Tubular Necrosis
• Hypercalcaemic states
• Drugs
o Antibiotics - gentamicin / carbenicillin
o Chemotherapy - cisplatin
o Diuretics
o FK506 (immunosuppressant?)
GI Tract
• Malnutrition
• Intravenous nutrition
• Diarrhoea
• Malabsorption
```
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What are the effects of Magnesium depletion?
25% of energy maintains Na & K+ gradient across cells
• Cellular
o Reduced mitochondrial respiration (involved in ATP) & impaired phosphorylation
o Defective Na-K ATPase activity
o Impaired DNA synthesis
• Biochemical
o Hypocalcaemia
o Hypophosphataemia
o Hypokalaemia
• Endocrine; Impaired PTH release, PTH resistance in bone
• CVS; Cardiac irritability, Reduced contractility (as affects ATP)
• CNS; Hyper-reflexia,Tetany, Ataxia / Vertigo, Psychosis / Depression
• Muscle; Weakness, Muscle fibrillation, Myopathic EMG
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How do you assess Tissue Magnesium Status?
```
• Serum Mg
o Poor correlation with actual Mg status
o Of value acutely
• Erythrocyte (RBC) Mg
o Poor correlation
o Affected by high reticulocyte count
o Not done very often
• Leucocyte Mg
o Good correlation & predictive value
• Muscle Mg
o 20% body Mg
o Important physiologically
o Requires biopsy
```
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How do you Screen for Mg Deficiency?
Advocated because of high prevalence but :
• Most patients asymptomatic in hypoMg
• Many patients recover spontaneously
• Hypomagnesaemia usually manifests itself alongside obvious causative disease, eg chemotherapic side-effects.
Should always be considered with combined hypokalaemia & hypocalcaemia
148
What is the Purpose of Bone?
* Structural support
* Protects vital organs (e.g. heart)
* Blood cell produc (via marrow)
* Storage bank for minerals (esp calcium)
149
What is the Composition of bone?
• Cortical (compact) bone= hard, outer (cortex) layer (most of strength & mass);
o Multiple microscopic columns each called an osteon
o Each column- multiple layers of osteoblasts & osteocytes
o Cortical bone covered by a periosteum on outer surface & andosteum on inner surface
• Trabecular (cancellous) bone=spongy, inner layer, high surface area (metabolically active, where bone marrow & cell produc)
o Open cell porous network
o In spaces; bone marrow & haemopioetic stem cells
• Cortical majority bones- femur, trabecular majority bones- vertebrae
• Bone made of cells= bone forming & reabsorbing cells
• Extracellular= organic matrix (mainly collagen), inorganic components (hydroxyapatite- harden bone, minerals- Ca, phosphate)
150
What are Osteoblasts?
* Terminally differentiated products of mesenchymal stem cells.
* Make osteoid (non-mineralised organic matrix (gets mineralised to make hardened bones), consists of mainly Type 1 collagen)- helps form bone
* Communicate with other bone cells
* Need osteoid to mineralise bone
* Make hormones (e.g. osteocalcin), matrix proteins and alkaline phosphatase
* Prerequisite for mineralisation
* Osteoblasts that are trapped within the matrix are called osteocytes
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What are Osteoclasts?
* Large & multi nucleated
* Ruffled-resorption border- high surface area
* Break down bone – critical for repair and maintenance of bone (this is always done)
* Found in bone pits (resorption bays)
* Produce enzymes such as tartrate resistant acid phosphatase (TRAP) and Cathepsin K - secreted to breakdown extracellular matrix
* Help enhance blood calcium levels (can be used to maintain blood Ca levels)
* PTH increases osteoclastic activity
* Regulated by hormones including PTH, calcitonin and IL-6
* RANK ligand (monoclonal antibody- treatment for osteoporosis) and osteoprotegrin help with osteoclastic maturation and activity
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What are Osteocytes?
* Star shaped
* Trapped/buried osteoblasts in matrix
* Communicate with each other via long cytoplasmic extensions
* Mechanosensory properties- helps bone sense what’s going on
* Involved with regulating bone matrix turnover
153
Why is bone a dynamic tissue?
* Extracell matrix
* Protein & mineral
* Mainly collagen- tensile strength
* BEFORE mineralisation- called osteoid
* Matrix then MINERALISED by HYDROXYAPETITE (calcium-phosphate-hydroxide salt)
* Constant re-modelling
* Highly vascular tissue & metabolically active
* Osteoblasts constantly producing and secreting matrix and helping with mineralisation
* Osteoclasts causing bone resorption
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What is the bone cycle?
* Osteoclasts- munch at them (little bone reabsorption)
* Then osteoblasts= mineralisation= resting
* Resting (mineralised bone) then resorption (osteoclast, ruffled border and resorption pit) the osteoid formation (osteoblasts) then mineralisation
155
What is the relationship between Aging & Bone?
* Balance between bone formation & reabsorption changes
* Peak bone mass in mid 20s
* After 40- middle age- start loosing bone mass
* Women- loss of oestrogen (menopause)- loose bones more
* Osteoporpsosis determined by peak bone mass & rate of decline
* With increasing age; decrease in bone formation & increase in bone reabsorption in bothe males and females
156
How do you investigate for bone disease?
* Gross struc- xray
* Bone mass (calcium)- DEXA scan (look at bone mass/ density)- radiation shone through bone
* Cellular function turnover- biochemistry
* Microstruc/ cellular function- biopsy, qCT (microstruc & bone quality)
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What are the Biochemical Markers of Bone Formation?
Products of active OB (products of osteoblast formation):
• Alkaline phosphatase (TAP, BAP)
• Osteocalcin (OC)
• Procollagen type I propeptides (P1NP)- marker of how much osteoblastic activity happening
158
What are the Biochemical Markers of Bone Reabsorption?
Degradation products of bone collagen:
• Hydroxyproline
• Pyridinium crosslinks
• Crosslinked telopeptides of type I collagen (NTX, CTX,)- can meaure in blood
Osteoclast enzymes:
• Tartrate-resistant acid phosphatase (TRACP 5b)- released from osteoclasts
• Cathepsin K
159
What is Alkaline Phosphatase?
• Measured by the laboratory in LFTs and Bone profiles
• In health approximately comes form (so if elevated look at these two);
o 50% liver
o 50% bone
• Specific isoenzymes can be measured where there is diagnostic doubt
160
What is Bone Alkaline Phosphatase?
• Phosphatase involved in mineralisation
• Released by osteoblasts
• Release stimulated by increase bone remodelling (causes of increased alkaine phosphatase);
o Childhood/ pubertal growth spurt
o Fractures
o Hyperparathyroidism (primary, secondary)
o Pagets disease of the bone
161
What is P1PN (Procollagen type 1 V propeptide)?
* Synthesized by OSTEOBALSTS- precursor molecule of type 1 collagen
* Low diurnal & intraindividual variation (doesn’t change that much during the day, can measure on diff days & get similar result)- stable marker
* Serum concs NOT affected by food intake (don’t need to be fasting)
* Increased with increased osteoblast activity
* Decreased by reduced osteoblast activity
162
What is Collagen Cross-links (NTX, CTX)?
* Cross-linking molecules released with bone RESOPTION
* Increased in periods of high bone turnover (when bone breaking down get cross linking molecules); hyperthyroidism, adolescents, menopause
* Have diurnal variation
* DO NOT predict bone mineral density
* Decrease with anti-reabsorptive therapy
* Prob of CTX- varies from morning to evening (take evening), need to be fasting & certain medication affect it
163
What are Bone Markers ?
• Collagen-related markers mainly based on type I collagen which is widely distributed in several tissues
• Changes in bone markers NOT disease specific, just reflect alterations in skeletal bone metabolism
• Reflects how much bone turnover but doesn’t tell you what disease so NOT diagnostic
• Some markers- signif intraindividual variability
• Uses of new bone markers;
o Evaluate bone turnover & loss
o Used for eval of treatment effect- CTX monitors response to anti-reapsorptive therapy
• Evaluation of medication compliance;
o P1NP monitors teriparatide compliance
o CTX monitors compliance/ response to anti-reabsorptive therapy
164
What is DEXA Image & Report?
```
• Measure spine & hip
• Measures bone density
• Help used to determine if have osteoporosis
• T-scores;
o -1 & above: bone density NORMAL
o Between -1 & -2.5: OSTEOPENIA
o -2.5 & below: OSTEOPOROSIS
• Gives you a T score; normal distrib 0 (mean- compared to young healthy person of same sex), if -/+1 is 1 standard deviation away from that mean
```
165
What is osteoporosis?
• Systemic skeletal disease characterised by low bone mass & microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture
• E.g. in spine with osteoporosis;
o Increase in biconcavity of lower thoracic bodies
o In anterior compression of mid thoracic vertebral bodes
o Wedge fracture in 2nd vertebrae
• Generalised loss of bone with propensity to fractures - spine, hip
• Several common risk factors for bone loss
• No abnormalities are seen in routine biochemical tests (may see Ca & vit D deficiency- but rare) perhaps because they are too insensitive
• Diagnosis relies on DEXA/XRay
• Increasing use of bone markers in management
• Decreased bone mass (quanity DEXA)+ deranged bone microarchitecture (quality)= failure of stuructural integrity
166
What is Fragility Fracture?
* Fracture that occurs that shouldn’t
* WHO: ‘a fracture caused by injury that would be insufficient to fracture a normal bone.’
* NOS: ‘a fracture that occurs as a result of a minimal trauma, such as a fall from a standing height or less, or no identifiable trauma’
* Neck of femur, hip, spine, humerus & wrist- common sites of fragility fracture
167
What is the Assessment of Fracture Risk?
• Suspect low bone mass in any person with history of fragility fracture!
• Unexplained loss of height, kyphosis (spine curvature) or severe back pain should prompt investigation for vertebral fractures.
• FRAX calculation tool;
o Can access over the internet- for patients that you may think at risk of osteoporosis to help decide if need treatment (mainly for use by GPs)- includes risk factors & gives you a number
o E.g. 75 year old, female, 70 kgs, 160cm, previous fragility fracture, nil else = 10 year probability of major OP fracture 21% and hip fracture 6.1%.
168
What are the Secondary Causes of Osteoporosis?
• Any inflamm disease- risk factors for osteoporosis
• Investigations for secondary causes of osteoporosis;
o Calcium and bone profile
o U&Es (estimated GFR)- kidney function
o TFTs (thyroid function)
o FBC
o Vitamin D
o PTH
o Plasma viscosity (+/- myeloma screen)
o Coeliac screen
o In men: 9am testosterone, SHBG, LH, FSH and LFTs.
o In young amenorrhoeic women: LH, FSH, estradiol, prolactin
o Loss of height, back pain or kyphosis consider Lateral X-ray T5-L5 spine.
169
What are Treatment Options for Prevention of Osteoporotic Vertebral Fractures?
• Selective oestrogen recep modulator (SEMA)
• All drugs stop drug breakdown
• Only teriparatide- builds more bone
Anti resorptive treatments: SERMS (raloxifene)/Biphosphonates (oral therapy- alendronate, risedronate, ibandronate/IV therapy- zoledronate, ibandronate)/RANK-L inhibitor (Denosumab)
Anabolic treatments – parathyroid hormone analogue (teriparatide)
170
What are Bisphosphonates?
• E.g. Alendronate, Risedronate, Ibandronate, IV Zoledronic acid
• Mechanism of action: stops bone break down but prob as this will eventually stop bone formation, modulate signalling from osteoblasts to osteoclasts, inhibit osteioclast formation migration and osteolytic activity and promote apoptosis
• Mimic pyrophosphate structure
• Taken up by skeleton
• Ingested by osteoclasts concentrated in newly mineralising bone and under osteoclasts
• Then bisphosphate disrupts osteoclasts- apoptosis
• DIsadvs;
o Poor absorption
o Difficult to take
o Can cause oesophageal/ upper GI problems
o Flu-like side effects
o Osteonecrosis of the jaw (non-healing of jaw)
o Atypical femur fractures;
E.g. 69-year-old woman- history of cervical & lumbar spondylosis, had bilateral thigh pain for two months before fracture. She had been on alendronate for 5 yrs. She heard a snapping sound in a) her right thigh while shopping. b) The left lateral subtrochanteric region- evidence of a stress injury
171
What are the two types of bone metastasis?
Common in several malignancies
Diff types of cancers- diff types of bone mets- 2 key types;
• Lytic
o Destruction of normal bone (osteoclast mediated)
o Breast / Lung
o Kidney/ Thyroid
• Sclerotic/osteoblastic
o Deposition of new bone
o Prostate
o Lymphoma
o Breast/lung (15-25%)
• Usual sites of spread: spine, pelvis, femur, humerus, skull
• If have high Ca= LYTIC (as as bone breaks down releases Ca into blood)
Nuclear medicine bone scan- inject radioisotope & use gamma radiation to see where it’s gone
172
What are the Presenting symptoms of bone metastasis?
* Pain; often worse at night and gets better with movement initially, usually becomes constant
* Broken bones; pathological fractures (that happen without trauma)- investigate further (commonly femur, humerus, vertebral)
* Numbness, paralysis, trouble urinating; spinal cord compression from bone metastases
* Loss of appetite, nausea, thirst, confusion, fatigue; symptoms of hypercalcaemia
* Anaemia; as bone mets disruption of bone marrow
173
What are the symptoms of Hypercalacaemia?
Mild: Polyuria, polydipsia, Mood disturbance, Anorexia, Nausea, Fatigue, Constipation
Severe: Abdo pain, Vomiting, Coma, Pancreatitis, Dehydration, Cardiac arrhythmias
174
What are the causes of Hypercalacaemia?
Non-PTH Mediated
• Malignancy (high Ca low PTH)
• Vitamin D intoxication
• Chronic granulomatous disorders e.g. sarcoidosis
• Medications; thiazide diuretics, Lithium, Teriparatide, Theophylline toxicity
• Immobilisation
• Other endocrine conditions; hyperthyroidism, acromegaly, phaeochromocytoma, adrenal insufficiency
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PTH Mediated
• Sporadic primary hyperparathyroidism (prob in PTH gland so will have high Ca and high PTH)
• Familial:
o MEN1 and 2A
o Familial hypocalciuric hypercalcaemia
o Familial isolated hyperparathyroidism
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• HyperCA 95% of the time caused by malignancy & sporadic primary hyperparathyroidism
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What is Parathyroid Hormone?
* Secreted by chieft cells of parathyroid gland
* Polypeptide contating 84 amino acids
* Lots of adipose cells in parathyroid gland
* Parathyroid gland has two cell types, chief cells (make PTH) and oxyphil cells (unknown function)
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What is the Regulation of Parathyroid Hormone (PTH) Levels?
* PTH- maintains blood Ca
* As Ca levels increase, parathyroid senses this via CaSR (trasmemb GTP binding protein)- switches off/↓ PTH secretion.
* In cases where this doesn’t happen hyper secretion of PTH and nonsuppressibility of PTH result.
* Serum levels of parathyroid hormone & magnesium depend on each other.
* Parathyroid hormone secretion physiologically controlled by serum Ca level, but Mg can exert similar effects.
* Low levels of Mg stim parathyroid hormone secretion, but very low serum concentrations induce a paradoxical block (hypocalcemia in severely hypomagnesaemia patients).
* The mechanism of this effect linked to activation of the alpha-subunits of heterotrimeric G-proteins- mimicks calcium sensing receptor activation so inhibits parathyroid hormone secretion.
* Parathyroid hormone also in turn regulates magnesium homeostasis- modulates renal magnesium reabsorption (distal convoluted tubule- parathyroid hormone-regulated magnesium homeostasis), incraeses decomposition of bone realising Ca, and increases CA absorption from food by intestine and increases reabsorption of Ca from urine by kidneys
* As previously described increased calcitriol may directly inhibit PTH secretion. Vit D =inhibition of PTH sectetion
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What is primary Hyperparathyroidism?
high alk phos as getting more bone turn over . Ca high, PTH inappropriatly high, Low phosphate and High ALk phos. Causes: sporadic/familial
* Previously used to present with severe hypercalcaemia, and/or symptomatic renal and skeletal disease
* Now presentation is much earlier in disease course and is usually asymptomatic
* Majority of cases present at >45 years of age
* Women twice as likely to be affected compared to men
* Inappropriately elevated PTH in the presence of high calcium suggests PHPT
* Usually caused by single adenoma
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What is secondary Hyperparathyroidism?
what you’d expect but if does this excessivly over long time PTH glands loose ability to switch off & develops into tertiatey . Ca normal/low, PTH appropriatly high, phosphate high if due to CKD. Causes: CKD/VVit K deficiency
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What is tertiary Hyperparathyroidism?
Ca high, PTH inappropriatly high, Phosphate can be high or low Most common cause of tertiary- after prolonged secondary HPT usually in CKD
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What are PHPT: Adenomas?
primary Hyperparathyroidism
• Adenomas (benign)- single adenoma account for 85% of cases of primary HPT
• Glandular hyperplasia
o Approx. 6-10% of cases of primary HPT
o All 4 glands enlarged
o Can occur sporadically or part of genetic syndromes
o Medical or surgical therapy
• Ectopic adenomas
o Rarely ectopic adenomas in mediastinum
o Some parathyroid adenomas found in thymus gland
o Parathyroid cells which migrated during embryogenesis
• Parathyroid carcinoma (malignant)
o 1-2% of all cases of hyperparathyroidism
o Features of invasion on histology
o Usually aggressive disease, with significant hypercalcaemia and possibility of distant metastases
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What are Clinical Manifestations of primary Hyperparathyroidism?
* Symptoms related to hypercalcaemia(as described)
* Renal disease (nephrolithiasis, chronic kidney disease)
* Bone disease (osteoporosis, osteitis fibrosa cystica- round tumours in hands)
* Proximal muscle wasting
* Bone pain
* Subperiosteal bone resorption typically middle phalanges, clavicles, skull, long bones
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What is imaging of primary Hyperparathyroidism?
Primary HPT: Imaging. Tc 99 Sestamibi
• Right parathyroid adenoma
• Look for swollen parathyroid glands
CT SPECT (Tc-99m MIBI)
• Ectopic parathyroid tissue in mediastinum
• (1st line investigation)
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What are treatments for primary Hyperparathyroidism?
SURGERY
• Symptomatic hypercalcaemia
• In asymptomatic patients with primary HPT if have one of the below criteria:
o Calcium >0.25mmol/L above normal
o Renal stone disease
o Calculated creatinine clearance <60ml/min
o Age <50 yrs
o Osteoporosis at any site or history of fragility fracture
MEDICAL
• Calcimimetics (Cinacalcet)- lower Ca levels (makes PT gland think there’s more Ca then there is)
• Activates CaSR in the parathyroid gland (so leads to reduced PTH secretion)
• Use to normalise calcium in symptomatic patients, or those who are not fit for or unwilling to have surgery
• Does not seem to alter bone disease
• No data on renal outcomes or quality of life
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What is Paget’s Disease?
* Rapid bone turnover and formation (in a chaotic manner)
* Leading to abnormal bone remodelling
* Mainly over 50 years old
* Higher prevalence in men
* Don’t know why it happens- probable genetic and environmental triggers
* Fam HX in 10-15% of cases
* Polyostotic or monostotic
* Elevated alkaline phosphatase reflecting increased bone turnover
* Bone thickening, & moisac apperance of bone
* cotton wool apperance of skull
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What are clinical features of Paget’s Disease?
* Bone pain & deformity
* Fractures
* Arthritis- abnormal loads on knee & hp (2ndry osteoarthritis)
* Cranial nerve defects if skull affected (skull getting larger)
* Hearing and vision loss
* Risk of osteosarcoma (ongoing pain)
* Most commonly affects pelvis, femur and lower lumbar vertebrae
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What is the management of Paget’s Disease?
• Investigations:
o Lab assessment
o Plain X-rays
o Nuclear medicine bone scan (locaisation- tells you which bones affected)
• What would be the best treatment?- Bisphosphonates (reduce osteoclastic activity- but as they talk to osteoblasts, also end up reducing osteoblastic activity)
• How could you monitor disease activity? – alkaline phospahtase
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What is osteomalacia?
• Lack of mineralisation of bone e.f. vit D deficiency/ resistance e.g. riskets
• Adult form - widened osteoid seams with lack of mineralisation
• Classic childhood rickets - widened epiphyses & poor skeletal growth
• Causes of osteomalacia:
o Insufficient calcium absorption from intestine (lack of dietary calcium or Vit D deficiency/resistance)
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What are clinical features of osteomalacia?
• Diffuse bone pains (usually symmetrical)
• Muscle weakness
• Bone weakness (propensity to fracture increased)
• High alk phos, low Vit D (causes 2ndry hyperparathyroidism= increases PTH t get Ca), possibly low Calcium and high PTH (secondary hyperparathyroidism)
• Prolonged vit D= high alk phos (?)
• Adult population at risk
o Nursing home residents/ elderly
o Asian population (Hijab/ Burka wearing)
o Malabsorption
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What is the Biochemistry of hyperparathyroidism?
High PTH is primary prob- low phosphate as excreting more, high pth drives osteoclastic activity= high Ca , alk phos and PTH, low phosphate
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What is the Biochemistry of osteomalacia?
Vit d deficinceny= low Ca which causes 2ndry hyperparathyroidism= high alk phos. Low phosphate and high PTH
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What is the Biochemistry of osteoporosis?
can only diagnosie via dexa scan & history. Normal Ca, phosphate, alk phos and PTH
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What is the Biochemistry of Paget’s Disease?
High alk phos , Normal Ca, phosphate and PTH
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What is the Biochemistry of bone metastasis?
Might get high Ca if lytic bone mets, high alk phos , low PTH, normal phoshate
