Core clinical biochemistry Flashcards
What do endocrine glands do
Secrete hormones directly in to the blood stream and act systemically
What does the paracrine system do
Secrete hormones that act locally
What do the autocrine secretions do
Affect the cell secreting the protein
What is the pituitary gland
Situated in the sella turica
Weighs ~ 1g
Consists of two parts: Anterior and posterior
75% anterior lobe adenohypophysis formed by outpouching of the oral cavity (Rathke’s pouch)
25% posterior lobe neurohypophysis- down growth of the hypothalamus
What does the Aden-hypophysis produce
Prolactin Adenocorticotropic growth hormone Thyroid stimulating hormone Follicle stimulating hormone Luteinsing
What does the neurohypophysis produce
Oxytocin
Antidiuretic peptide
What are the causes of hypo function in the anterior pituitary
Vascular - infarction Inflammation - granulomatous Trauma Autoimmune - Pituitary autoimmune disease Metabolic Infection Neoplasia - non-secretory adenoma, metastatic carcinoma D3 - doctors
What are the types of anterior pituitary adenomas and how do they present
Prolactinoma (galactorrhoea, menstrual disturbance)
Growth hormone secreting (gigantism in children, acromegaly in adults)
ACTH secreting (Cushing’s syndrome)
What is the anatomy of the thyroid gland
Bilobed organ joined by an isthmus encased in thin fibrous capsule
~18g in male, ~15g in female
Located at the level of 5th - 7th vertebra
Leans on the thyroid cartilage
Recurrent laryngeal nerve located in the tracheo-oesophageal groove
How does Hashimoto’s present
Autoimmune chronic inflammatory disorder Chronic lymphocytic thyroiditis F>M Peak age is 59 years Hypothyroid Diffusely enlarged non-tender gland
What is Grave’s disease
An autoimmune process Diffuse hyperplasia of the follicular epithelium Causes 80% of hyperthyroidism F>M Peak in third and fourth decades Symptoms: Pretibial myxoedema, hair loss, wide-eyed stare or proptosis, tachycardia, hyperactive reflexes Enlarged thyroid T3 and T4 elevated, TSH suppressed
What are hormones
Messenger molecules secreted by endocrine glands
They circulate and influence other tissues
Produce long and short term changes in various cells
Can only influence cells that have specific target receptors for that particular hormone
What are three types of hormone and some examples of each type
Peptide hormones (PTH, ACTH, TSH) Steroid hormones (testosterone, oestradiol, cortisol) Tyrosine-based hormones (thyroxine T4, Triiodothyronine T3)
What are the three ways that a steroid hormone can interact with a cell
The classical model
Receptor-mediated endocytosis
Signalling through cell-surface receptors
What is the classical model of steroid hormone interaction
The steroid hormone dissociates from its plasma carrier protein and diffuses across the cell membrane
After gaining entry to the cell, the free hormone binds to an intracellular receptor and alters gene transcription
What is receptor mediated endocytosis type of steroid hormone interaction
The steroid hormone, bound to its plasma carrier protein, is Brough into the cell via a cell surface receptor. The complex is broken down inside lysosome and free steroid hormone diffuses into the cell where it subsequently exerts its action at the genomic level or undergoes metabolism
What is signalling through cell-surface receptors type of steroid hormone interaction
The free steroid hormone alters intracellular signalling by binding to cell-surface receptors. The steroid hormone could exert these effects directly or could alter signalling by blocking the actions of peptide hormones
What effect does thyroxine-binding globulin have on thyroid function test interpretation
Only the free inbound forms are physiologically active. If the level of TBG changes this results in a change in the level of the free hormones. Therefore, measurement of total hormone levels can be misleading
What are causes of abnormal TBG conc
Increased:
- Genetic causes
- Pregnancy
- Oestrogens
Decreased:
- Genetic causes
- Protein losing states
- Malnutrition
- Malabsorption
- Acromegaly
- Cushing’s disease
- High dose corticosteroids
- Sever illness
- Androgens
How often should TFTs be repeated
Healthy: 3 years
Hyperthyroid:
- 1-2 months after radioactive iodine, if patient remains thyrotoxic then biochemical monitoring to continue at 4-6 week intervals
- Following thyroidectomy for Graves’ disease and commencement of levothroxine, serum TSH to be measured 6-8 weeks post-op
Hypothyroidism -monitoring treatment
- The minimum period to achieve stable conc after a change of dose of thyroxine is 2 months and TFTs should not normally be assessed before this period has elapsed
- Patients stabilised on longterm thyroxine therapy should have serum TSH checked annually
- An annual fT4 should be performed in all patients with secondary hypothyroidism
What are the two main types of immunoassay used in clinical chemistry
Immunometric assays
Competitive immunoassays
What are the 2 types of adrenal medullary tumours
Phaeochromocytoma (adults)
Neuroblastoma (children)
What is a phaeochromocytoma
Tumour of neuroendocrine chromaffin cells, the majority in the adrenal medulla
What are the clinical features of phaeochromocytoma
Excessive and often episodic release of catecholamines may result in paroxysmal features:
- Hypertension
- sweating
- panic attacks
- headaches
- abdominal pain
- Sometimes nothing!
What follow up tests are done on those with suspected phaeochromocytoma
Clonidine suppression test Plasma chromogranin A MRI or CT of adrenals MIBG scan, especially to detect extra-adrenal phaeochromocytomas or metastases Genetic counselling or screening
What are the clinical features of Cushing’s
Obesity: moon face, central deposits, lump between shoulder blades Skin: thin, purple striae, easy bruising Hypertension Glucose intolerance Menstrual disturbances Thin limbs/muscle weakness Back pain due to osteoporosis Psychiatric disturbances (depression, psychosis)
What is ectopic ACTH secretion most commonly associated with
Benign carcinoid tumours of the lungs Small cell tumours of the lungs Islet cell tumours of the pancreas Medullary carcinoma of the thyroid Tumours of the thymus gland
What is diabetes
Group of disorder characterised by hyperglycaemia (high blood glucose)
Caused by lack of insulin or reduced action of insulin
Which islet cells produce which substance
Alpha cells: glucagon
Beta cells: insulin
Delta cells: somatostatin
F cell: pancreatic polypeptide
What is insulin
Soluble protein made of an alpha chain and a beta chain
What are the diagnostic readings for diabetes
Fasting glucose: >7mmol/l
Random glucose: >11.1mmol/l
Two hours reading post OGTT> 11.1mmol/l
HbA1c >48mmol/mol
What is HbA1c
Reflects average plasma glucose over the previous 8-12 weeks
Diabetes: >48mmol/mol
Pre-diabetes:>41 and <48 mol/mol
What are the types of diabetes
Type 1 Type 2 Gestational Specific types due to: -Genetics -Endocrinopathies -Disease of the exocrine pancreas
What is type 1 diabetes
Autoimmune destruction of insulin producing beta cells in the islet of langerhans
Can occur at any age but peaks around puberty
What are the risk factors for type 1 diabetes
Family history
Perinatal factors - low birth weight
Viral infections
Diet - cows milk
How does type 1 diabetes present
Rapid onset (often few weeks) Weight loss and osmotic symptoms and low energy Abdominal pain Often slim Presents as diabetic ketoacidosis
How is type 1 diabetes managed
Insulin injections
How does type 2 diabetes present
Often overweight Symptoms present over a few months Minimal weight loss Complications: -vision loss -foot ulcers -fungal infection In state of hyperosmolar hyperglycaemia state
How is type 2 diabetes managed
Lifestyle:
- exercise
- diet and weight loss
Oral therapy:
- metformin (first line)
- DDp4 inhibitor, SGLT-2 inhibitor, GLP-1 agonist, sulphonylureas
- Up to three agents
Insulin:
- Once daily
- multiple injections
What is gestational diabetes
Diabetes in pregnancy
New and not present prior to pregnancy
Hyperglycaemia first detected in pregnancy
Fasting glucose>5.6mmol/l or 2 hours plasma glucose level of 7.8mmol/l
How is gestational diabetes diagnosed
Oral glucose tolerance test
When is gestational diabetes checked in pregnancy
12 weeks
If normal repeat at 24 to 28 weeks
What are the risk factors for gestational diabetes
BMI>30 Previous macrosomic baby Previous gestational diabetes FH of diabetes Ethnic minority
Why is gestational diabetes important
Short term: Macrosomia Pre-eclampsia Stillbirth Neonatal morbidity
Long term:
Obesity (child)
Development of Type 2 diabetes (mother)
How is gestational diabetes managed
Diet (if mild)
Limited oral option (metformin or glibenclamide)
Majority require insulin (only during pregnancy)
What is MODY
Maturity onset diabetes of the young
Clinically heterogenous disorder characterised by noninsulin-dependent diabetes diagnosed <25 years with autosomal dominant transmission and lack of autoantibodies
What are the causes of secondary diabetes
Essentially any condition that damages pancreatic organ:
- Pancreatitis (gallstones, alcohol)
- Pancreatectomy (for cancer, trauma
- Cystic fibrosis
- Haemochromotosis
What causes drug induced diabetes
High dose and prolonged steroid use
Atypical anti-psychotics
Immunotherapy (nivolumab used in melanoma treatment)
Protease inhibitor (used in HIV treatment)
Which endocrinopathies can cause diabetes
Cushings syndromes
Acromegaly
Somatostatin secreting tumours (somatostatinoma)
Glucagon secreting tumours (glucagonoma)
What are counter regulatory hormones
Hormones which usually oppose action of insulin Secreted as a result of stress response -Glucagon -Epinephrine/norepinephrine -Glucocorticoid -Growth hormone
What stimulates insulin release
Glucose Fatty acid and ketones Vagal nerve stimulation Gut hormones Drugs (diabetes medication Prostaglandins
What stimulates inhibition of insulin release
Sympathetic stimulation Alpha adrenergic agents (adrenaline) Beta blockers Dopamine Serotonin Somatostatin
What is glucagon
Polypeptide of 29 amino acids that is rapidly degraded in the tissues (especially in the liver and kidney)
What stimulates glucagon release
Amino acids Beta adrenergic stimulation Fasting, hypoglycaemia Exercise Cortisol
What stimulates inhibition of glucagon release
Glucose Somatostatin Free fatty acids Ketones Insulin
What are the actions of glucagon
- Increase secretion of insulin and growth hormone
- Reduces intestinal motility and gastric acid secretion
- Increase glucose levels through:
- -glycogenolysis
- -gluconeogenesis
- -lipolysis
What is a multinodular goitre
Enlargement of thyroid ± modularity
Most are euthyroid
Large dominant nodules may be mistaken clinically for thyroid carcinoma
Compressive symptoms
What is a follicular adenoma
Benign encapsulated tumour with evidence of follicular cell differentiation
Females>males
Wide age range, usually fifth to sixth decade
Pailess, chronic
Solitary
Cold nodule on radioactive iodine imaging
What is the commonest type of thyroid carcinoma
Papillary carcinoma
What is papillary carcinoma
Familial autosomal dominant non-medullary thyroid carcinoma FAP Cowden's syndrome Therapeutic irradiation Radiation exposure
How does papillary carcinoma appear macroscopically
Ill defined, infiltrative
Some encapsulated
May be cystic
Granular
What are types of follicular neoplasms
Follicular adenoma
Follicular carcinoma
Hurthle cell neoplasms
Ras mutations
What are the clinical behaviours of Hurthle cell carcinoma
Significant incidence of cervical lymph node metastases Common haematogenous sites: -bone -liver -lung
What is primary hyperparathyroidism
Excessive secretion of parathyroid hormone form one of more glands
What is secondary hyperparathyroidism
Hyperplasia of glads with elevated PTH in response to hypocalcaemia:
-renal insufficiency, malabsorption, vitamin D deficiency
What is tertiary hyperparathyroidism
In association with longstanding secondary hyperparathyroidism
What are the hyperparathyroidism signs
Painful bones (classically osteitis fibres cystica) Renal stones (kidney stones -> renal failure) Abdominal groans (GI symptoms of nausea, vomiting, constipation, indigestion Psychiatric moans (lethargy, fatigue, memory loss, psychosis, depression)
What is parathyroid adenoma
An encapsulated benign neoplasm of parathyroid cells
Symptoms of hypercalcaemia
Association with MEN1 and MEN2 syndrome and hyperparathyroidism and jaw tumour syndrome
Single enlarged parathyroid gland with remaining glans suppressed and small
What are the features of secondary and tertiary hyperparathyroidism
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 and may be associated with massive gland enlargement
What is parathyroid carcinoma and how is it treated and what is the prognosis
Malignant tumour derived from parathyroid parenchymal cells
Treated with surgery
50% 10 year survival
What are the causes of Cushing’s syndrome
Exogenous: excessive glucocorticoid medication
Endogenous causes: adrenal cortical tumours, adrenal cortical hyperplasia and ACTH secreting pituitary adenoma
What are the signs and symptoms of Cushing’s syndorme
Hypertension Moon face Central obesity Buffalo hump Weak muscles Osteoporosis Insomnia Excess sweating Mood swings Headaches Chronic fatigue Women may have increase hard growth (hirsutism) and irregular menstruation
What is Conn’s syndrome
Hyperaldosteronism
Excess production of the hormone aldosterone leading to low renin levels
Primary: adrenal cortical hyperplasia, adenoma and familial hyperaldosteronism
Secondary: low circulating volume or poor renal circulation
What are the symptoms of Conn’s syndrome
High BP Headache Muscular weakness Muscle spasms Cardiac arrhythmia Excessive urination
What is Addison’s disease
Adrenal cortical insufficiency
Primary: adrenal dysgenesis, adrenal destruction, autoimmune adrenalitis, TB
Secondary: failure ACTH secretion
High mortality if not diagnosed
What makes up the Addison’s disease triad
Hyperpigmentation
Postural hypotension
Hyponatraemia
How is Addison’s disease treated
Long term steroid replacement
What is adrenal cortical nodule and who is at greatest risk
Benign non-functional nodules of adrenal cortex
Elderly, hypotensive and diabetic patients
What are the symptoms of adrenal cortical adenoma
Benign neoplastic proliferation of adrenal cortical tissue
Symptoms related to endocrine hyperfucntion:
-Aldosterone-producing tumours cause Conn’s syndrome
-Cortisol producing tumours cause Cushing’s syndrome
-Rare tumours cause virilisation
What is adrenal cortical carcinoma
Malignant counterpart adrenal cortical adenoma Symptoms related to hormone excess Abdominal mass 5 year survival about 70% -prognosis is age and stage dependent
What is phaeochromocytoma
Catecholamine-secreting tumour arising from adrenal medulla
What is the phaeochromocytoma rule of 10s
10% bilateral 10% extra-adrenal 10% malignant 10% familial 10% in children
What are the symptoms of phaeochromocytoma
Symptoms of hypertension, palpitations, headaches, anxiety
Elevated urine catecholamines, adrenaline, noradrenaline
What are the two layers of bone
Cortical bone: hard outer layer
Trabecular bone: spongy inner layer
How is bone composed
Cells:
- bone forming cells
- bone resorbing cells
- bone co-ordinating cells
Extracellular:
- Organic matrix (30%)
- mainly collagen (osteoid)
- ground substance
- Inorganic components (70%)
- hydroxyapatite (calcium and phosphate)
- Minerals (magnesium, sodium, potassium)
What is the role of osteoblasts
Creates and repairs new bone
What is the role of osteoclasts
Breakdown old bone
What is remodelling of normal bone
In a constant state of turnover caused by resorption by osteoclasts and formation osteoblasts
Adult skeleton is replaced every 10 years
How is bone disease investigated
Gross structure: Xray, MRI, CT Bone mass (calcium): DEXA Cellular function/turnover: biochemistry Microstructure/ cellular function: biopsy, qCT
What is bone alkaline phosphatase
Phosphatase involved in mineralisation Released by osteoblasts Release is stimulated by increased bone remodelling: -Childhood/ pubertal growth spurt -Fractures -Hyperparathyroidism --primary --secondary -Pagets disease of the bone
What is P1NP
Procollagen type 1N propeptied
- Synthesised by osteoblasts
- precursor molecule of type 1 collagen
- Has low diurnal and intra-individual variation
- Serum conc not affects by food intake
- Increased with increased osteoblast activity
- Decreased by reduced osteoblast activity
What are collagen cross-links
NTX, CTX Cross-linking molecules which are released with bone resorption, correlate highly with bone resorption Increased in periods of high bone turnover: -hyperthyroidism -adolescents -menopause Have diurnal variation Do not predict bone mineral density Decrease with anti-resorptive therapy
What are bone markers
Collagen-related markers are based primarily on type 1 collagen, which is widely distributed in several tissues
Changed in bone markers are not disease specific but reflect alterations in skeletal metabolism
Some markers are characterised by significant intra-individual variability
What are the uses of new bone markers
Evaluation of bone turnover and bone loss
Evaluation of treatment effect (CTX used to monitor response to anti-resorptive therapy)
Evaluation of adherence with medication (P1NP used to monitor compliance with teriparatide; CTX used to monitor compliance/ response to anti-resorptive therapy)
What do the T-scores mean
-1 and above: normal bone density
Between -1 and -2.5: osteopenia (low bone mass)
-2.5 and below: osteoporosis
What are the bone disorders
Metastatic disease Hyperparathyroidism Osteomalacia/ Rickets Osteoporosis Paget's disease
What is osteoporosis
Decreased bone mass and deranged bone micro architecture resulting in failure of structural integrity
A systemic skeletal disease characterised by low bone mass and micro architectural deterioration of bone tissue, with consequence increase in bone fragility and susceptibility to fracture
What are the common risk factors for osteoporosis
- ageing
- gluccorticoids
How is osteoporosis detected and managed
No abnormalities seen in routine biochemical tests
Diagnosis relies on DEXA/ Xray
Increasing use of bone markers in management
What is a fragility fracture
A fracture caused by injury that would insufficient to fracture a normal bone
A fracture that occurs as a result of minimal trauma such as a fall from a standing height or less, or no identifiable trauma
What are common sites of fragility fracture
Spine
Neck of femur
Wrist
What are the risk factors for fracture
Age Sex Recent fragility fracture Vertebral fractures (number and severity) Smoking Alcohol Falls Drugs Inflammatory conditions Malabsorption T1 DM Family history BMI
What is the mechanism of action of bisphosphonates
Mimic pyrophosphate structure
Taken up by skeleton
Ingested by osteoclasts
Inhibit osteoclast formation, migration and osteolytic activity, promote apoptosis
What are bone metastases and the types
Common in several malignancies
Lytic:
- destruction of normal bone (osteoclasts)
- breast/ lung
- kidney/ thyroid
Sclerotic/ osteoblastic
- deposition of new bone
- prostate
- lymphoma
- breast/ lung
Usual sites of spread:
- Spine, pelvis femur
- Humerus, skull
What are the presenting symptoms of bone metastases
Pain:
- often worse at night and gets better with movement initially
- usually becomes constant
Broken bones:
- pathological fractures
- 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:
-disruption of bone marrow
What are the symptoms of hypercalcaemia
Mild:
- polyuria, polydipsia
- Mood disturbance
- Anorexia
- Nausea
- Fatigue
- Constipation
Sever:
- abdominal pain
- vomiting
- coma
- pancreatitis
- dehydration
- cardiac arrhythmias
What are the causes of hypercalacaemia
Malignancy Primary hyperparathyroidism Medications Vit D excess Hyperthyroidism Bone disease/ immobilisation
What is PTH
Parathyroid hormone
Secreted by chief cells of parathyroid gland
Polypeptide containing 84 amino acids
How do the types of hyperparathyroidism present
Primary:
- Calcium usually high
- PTH inappropriately high
- Low phosphate and high alk phos common
- Causes are sporadic or familial
Secondary:
- Calcium normal or low
- PTH appropriately high
- Phosphate high if due to chronic kidney disease
- Causes are mainly CKD or vit D deficiency
Tertiary:
- Calcium usually high
- PTH inappropriately high
- Phosphate can be high or low
- Causes: after prolonged secondary HPT, usually in CKD
What is Paget’s disease of bone
Rapid bone turnover and formation Leading to abnormal bone remodelling Mainly over 50yo >male Genetic and environmental triggers FH in 10-15% of cases Polyostotic or monostotic Elevated alkaline phosphatase reflecting increased bone turnover
What are the clinical features of Paget’s disease
Bone pain
Bone deformity
Fractures
Arthritis
Cranial nerve defects if skull affected (hearing and vision loss)
Risk of osteosarcoma
Most commonly affects pelvis, femur and lower lumbar vertebrae
What is osetomalacia
Lack of mineralisation of bone
Adult form: widened osteoid seams with lack of mineralisation
Classic childhood rickets: widened epiphyses and poor skeletal growth
What are the causes of osteomalacia
Insufficient calcium absorption from intestine:
-due to lack of dietary calcium or vitamin D deficiency/ resistance
Excessive renal phosphate excretion:
-Rare genetic forms (hereditary hypophosphataemic rickets)
What are the clinical features of osteomalacia
Diffuse bone pains (usually symmetrical)
Muscle weakness
Bone weakness
High alk phos, low vit D, possibly low calcium and high PTH (secondary hyperparathyroidism)
Who’s is at greatest risk of osteomalacia
Adult population at risk:
- nursing home residents/ elderly
- asian population (hijab/ burka wearing)
- malabsorption
Why is calcium physiologically important and structurally important
Physiologically: Blood clotting Muscle contraction Neuronal excitation Enzyme activity (Na/K ATPase, hexokinase etc)
Structurally: Hydroxyapatite Ca10(PO4)6(OH)2 is the predominant mineral in bone
How is adjusted Ca calculated
Adjusted Ca = Total Ca + [(40 - Alb) x 0.025]
Reference range for adjusted calcium 2.2-2.6 mmol/L
Equation is not valid if albumin <20g/L
Why is phosphate physiologically important
The P in ATP - our fuel!
Intracellular signalling
Cellular metabolic processes eg glycolysis
Why is phosphate structurally important
Backbone of DNA
Component of hydroxyapatite (Ca10(PO4)6(OH)2)
Membrane phospholipids
What results from deficiency of phosphate
Sever deficiency can be fatal
How is homeostasis of calcium regulated
Two key controlling factors:
- Parathyroid hormone (PTH)
- Vit D and matabolites
Balance of:
- GI uptake
- Bone storage
- Renal clearance
What factors affect vit D level
Season Latitude Climate Clothing Use of sunscreen Time spent indoors and outdoors Skin tone Age Diet Body fat and BMI Malabsorption
what are the regulators of calcium and phosphate homeostasis
PTH Vit D FGF23 Calcitonin Oestrogen
What are the signs and symptoms of hypocalcaemia
Tetany Paraesthesia in the extremities Cramps Convulsions Psychosis
Why is magnesium physiologically and structurally important
Physiological:
- Cofactor for ATP
- Neuromuscular excitability
- Enzymatic function
- Regulates ion channels
Structural:
-comprises 0.5-1% of bone matrix
How is the homeostasis of magnesium controlled
Predominantly by the kidneys
What are the causes of magnesium depletion
Inadequate intake
Renal loss
GI loss
Redistribution into cells
What are the signs and symptoms of magnesium depletion
Neuromuscular hyperexcitability (tremor, tetany, convulsions), muscle weakness
CNS- depression, psychosis
Cardio- ECG changes, reduced contractility, arrhythmia
GI- nausea and anorexia
Biochemical consequences: hypokalaemia, hypocalcaemia, with associated signs and symptoms
