Clinical Biochemistry Flashcards
(117 cards)
1
Q
Describe briefly the types of LFTs
A
Biilirubin concentration and alkaline phosphatase (ALK) activity indicate cholestasis, a blockage of bile flow. ALT activity is a measure of the integrity of liver cells, or parenchymal liver disease.
2
Q
What are the major functions of the liver
A
-Carbohydrate metabolism
-Fat metabolism
-Protein metabolism
-synthesis of plasma proteins
-hormone metabolism
-Metabolism and excretion of drugs and foreign compounds
-Storage-glycogen, vitamin A and B12, plus iron and copper.
Metabolism and excretion of bilirubin.
3
Q
What are the common disease processes affecting the liver?
A
Hepatitis
Damage to hepatocytes
Cirrhosis Increased fibrosis Liver shrinkage Decreased hepatocellular function Obstruction of bile flow
Tumours
Frequently secondary: colon, stomach, bronchus
4
Q
Outline the biochemical assessment of liver function
A
Biochemical tests (Liver function tests)
Insensitive indicators of liver function,
sensitive indicators of liver damage
Look for pattern of results - a single result rarely provides a diagnosis on its own.
Interpretation must be performed within the context of the patient’s risk factors, symptoms, medications, current condition/illness and physical findings
5
Q
What are LFTs (liver function tests) used for?
A
- Measuring the efficacy of treatments for liver disease
- Assessing prognosis
- Screening for the presence of liver disease
- Differential diagnosis: predominantly hepatic or cholestatic
- Monitoring disease progression
- Assessing severity, especially in patients with cirrhosis
6
Q
What is compensation and it’s associated speeds
A
Compensation
Attempt to return acid / base status to normal
1. Buffering
•Bicarbonate buffer in serum, phosphate in urine (for excretion)
•Skeleton
•Intracellular accumulation/loss of H+ ions in exchange for K+ , proteins and phosphate act as buffers
2. Compensation
•Diametric opposite of original abnormality
•Never overcompensates
•Delayed and limited
3. Treatment
•By reversal of precipitating situation
Compensation Speeds
•Respiratory compensation for a primary metabolic disturbance can occur very rapidly
–Kussmaul breathing (respiratory alkalosis) in response to DKA
•Metabolic compensation for primary respiratory abnormalities take 36-72 hours to occur
–requires enzyme induction from increased genetic transcription and translation etc
–No compensation seen in acute respiratory acidosis such as asthma
–Requires more chronic scenario to include compensation mechanism
7
Q
What are the pitfalls of ABG
A
Expel air •Mix sample •Analyse ASAP •Plastic syringes OK at room temp for ̴ 30mins •Ice not required •Ensure no clot in syringe tip
Errors in blood gas analysis are dependent more on the clinician than on the analyser
8
Q
What are the causes of respiratory acidosis
A
Causes of respiratory acidosis Looking at retention of Carbon dioxide •Airway obstruction •Bronchospasm (Acute) •COPD (Chronic) •Aspiration •Strangulation •Respiratory centre depression •Anaesthetics •Sedatives •Cerebral trauma •Tumours •Neuromuscular disease •Guillain-Barre Syndrome •Motor Neurone Disease •Pulmonary disease •Pulmonary fibrosis •Respiratory Distress Syndrome •Pneumonia •Extrapulmonary thoracic disease •Flail chest
9
Q
Describe respiratory acidosis
A
Respiratory acidosis
•Compensation
–Increased renal acid excretion (metabolic alkalosis, 36-72 hrs delay)
•Correction
–Requires return of normal gas exchange
•Features
–acute: pH ([H+]), pCO2, [HCO3-],– ie. no compensation
–chronic: pH ([H+]), pCO2, [HCO3-],– ie. compensation
10
Q
What are the causes of respiratory alkalosis
A
Causes of respiratory alkalosis Low pCO2 – removing carbon dioxide •Hypoxia •High altitude •Severe anaemia •Pulmonary disease
- Pulmonary disease
- Pulmonary oedema
- Pulmonary embolism
- Mechanical overventilation
- Increased respiratory drive
- Respiratory stimulants eg salicylates
- Cerebral disturbance eg trauma, infection and tumours
- Hepatic failure
- G-ve septicaemia
- Primary hyperventilation syndrome
- Voluntary
11
Q
Respiratory alkalosis
A
Compensation
–Increased renal bicarbonate excretion (metabolic acidosis, 36-72 hrs delay)
•Correction
–Of cause
•Features
–acute: high pH, low [H+], n[HCO3-], low pCO2 – no compensation
–chronic: high pH, low [H+], low [HCO3-], low pCO2
12
Q
What are the causes of metabolic acidosis
A
Causes of metabolic acidosis 1
addition of acid
- Increased H+ formation
- Ketoacidosis
- Lactic acidosis
- Poisoning – methanol, ethanol, ethylene glycol, salicylate
- Inherited organic acidosis
•Acid ingestion
–Acid poisoning
–XS parenteral administration of amino acids eg arginine
Causes of metabolic acidosis 2
H+ excretion
- Renal tubular acidosis
- Renal failure
- Carbonic dehydratase inhibitors
Loss of bicarbonate
- Diarrhoea
- Pancreatic, intestinal or biliary fistulae/drainage
13
Q
Metabolic acidosis
A
Metabolic acidosis •Compensation –hyperventilation, hence low pCO2 •Correction –of cause –increased renal acid excretion •Features –low pH, high [H+], low [HCO3-], low pCO2
14
Q
What are the causes of metabolic alkalosis
A
Causes of a metabolic alkalosis •Increased addition of base •Inappropriate Rx of acidotic states •Chronic alkali ingestion •Decreased elimination of base •Increased loss of acid •GI loss •Gastric aspiration •Vomiting with pyloric stenosis
- Renal
- Diuretic Rx (not-K+sparing)
- Potassium depletion
- Mineralocorticoid excess- Cushing’s, Conn’s
- Drugs with mineralocorticoid activity – carbenoxolone
15
Q
Metabolic alkalosis
A
Compensation
–hypoventilation with CO2 retention (respiratory acidosis)
•Correction
–increased renal bicarbonate excretion
–reduce renal proton loss
•Features
–high pH, low [H+], high [HCO3-], N/highpCO2
16
Q
What are dynamic function tests
A
If deficiency is suspected ->stimulation test done
If excess is suspected -> suppression test done.
Quite straightforward. Measure a hormone, see if it’s too high or low and attempt to correct. You may need to consider range of levels and ask if current level is appropriate.
Finally, there are dynamic function tests, where you stimulate or inhibit an endocrine tissue to see if it is still capable of producing (or supressing) hormone output.
17
Q
Insulin stress test
A
Carried out if hypopituitarism is suspected. It is also known as the insulin tolerance test. Enough insulin is administered to produce hypoglycaemic stress. This tests the ability of the anterior pituitary to produce ACTH and growth hormone in response.
Cortisol is measured, this assumes that the adrenals can respond normally to ACTH.
18
Q
TRH tests
A
Thyrotrophin-releasing hormone (TRH) is given as an intravenous bolus; blood sampling is at 0, 20 and 60 minutes. In normal subjects, TRH elicits a brisk release of TSH and prolactin.
In suspected hypothalamic disease, TSH response to TRH is characteristically delayed (TSH higher at 60 minutes than at 20 minutes).
Can be done in suspected hyperthyroidism, hypothyroidism.
In hyperthyroidism, there will be prolonged negative feedback. The pituitary response to TRH is flat (TSH rises by <2mU/L)
Conversely, an exaggerated TSH response (>25mU/L) s seen in hypothyroidism.
19
Q
Oral glucose tolerance test with GH measurement
A
Just as hypoglycaemia stimulates GH secretion, hyperglycaemia suppresses it. This forms the basis for performing an oral glucose tolerance test with GH measurement. Normal adults suppress GH to less than 1ug/L, but acromegalic patients do not; failure to suppress is therefore highly suggestive of acromegaly. Following trreatment, patients who fail to suppress GH below 2ug/L have a higher prevalence of diabetes, heart disease and hypertension.
20
Q
Synacthen tests
A
Short synacthen tests (SST)
-one of the most commonly performed DFTs.
Long synacthen test (LST)
-where the response to an SST is inadequate or equivocal, it may not be clear whether the adrenal insufficiency is primary, or secondary to pituitary or hypothalamic disease. Secondary adrenal insufficiency is most frequently seen following the use of long term steroid therapy, which causes central suppression of the axis. If the SST is repeated after the administration of a much larger dose of Synacthen (1mg), a normal response may be observed, confirming the diagnosis.
21
Q
Dexamethasone suppression tests
A
Dexamethasone is an exogenous steroid that mimics the negative feedback of endogenous glucocorticoids.
Dexamethasone suppression tests are important in the investigation of suspected overactivity of the hypothalamic-pituitary-adrenal axis.
Low dose DST
-usually performed at an outpatient basis
-involves the patient taking 1mg dexamethasone orally at 23:00 and attending for a cortisol blood test the following morning at 8:00 or 9 am. If the cortisol has suppressed tp less than 50nmol/L, cortisol overproduction is unlikely and no further action is normally required.
High-dose DST
Failure to suppress in response to low dose dexamethasone may occur because of autonomous ACTH production by the pituitary (Cushing’s disease), ectopic ACTH production (usually malignant) or adrenal production of cortisol. The high dose DST (8mg) is used to distinguish the first 2 of these options. ACTH production in Cushing’s disease does usually suppress in response to high dose DST, whereas malignant production of ACTH usually does not.
Dexamethasone: exogenous steroid
Low doses will normally supress ACTH secretion via negative feedback
Low dose fails to supress ACTH secretion with pituitary disease (Cushing’s)
Higher dose will supress ACTH secretion in Cushing’s
No supresssion with low or high dose: suggests ectopic source of ACTH (e.g., tumour elsewhere
22
Q
Thyroid hormone actions
A
THs:
Essential for normal growth and development
Increase basal metabolic rate (BMR) and affect many metabolic processes
Synthesized in thyroid via series of enzyme catalysed reactions, beginning with uptake of iodine into gland
Synthesis and release controlled by TSH
T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4
Effects are mediated via activation of nuclear receptor
TH essential for normal maturation and metabolism of all body tissues. Their effects on tissue maturationare most dramatically seen in congenital hypothyroidism, a condition which, unless treated within 3 months of birth, results in permanent brain damage. Hypothyroid children have delayed skeletal maturation, short stature and delayed puberty.
TH effects on metabolism are diverse. Rates of protein and carbohydrate synthesis and catabolism are influenced. Eg, hypothyroidism is associated with increased cholesterol in blood and cvs disease.
23
Q
Clinical features of hypothyroidism
A
Lethargy and tiredness
Cold intolerance
Weight gain
Dryness and coarsening of skin and hair
Hoarseness
Slow relaxation of muscles and tendon reflexes
Many other associated signs, including anaemia, dementia, constipation, bradycardia, muscle stiffness, carpal tunnel syndrome, subfertility and galatorrhoea.
24
Q
Primary hypothyroidism
A
failure of thyroid gland to produce hormones. Diagnosed by elevated TSH
25
Hypothyroidism
Hypothyroidism is common and is most often due to the destruction of the thyroid gland by autoimmune disease, surgery or radioiodine therapy.
Primary hypothyroidism is confirmed by elevated TSH and low FT4 in a serum specimen.
A TRH test is used to investigate secondary hypothyroidism due to pituitary or hypothalamic causes.
Hypothyroidism is managed by thyroxine replacement, and therapy is monitored by measuring the serum TSH concentration.
26
Clinical features of hyperthyroidism
Weight loss, despite normal or increased appetite.
Sweating and heat intolerance
Fatigue
Palpitations-sinus tachycardia or atrial fibrillation
Agitation and tremor
Generalised muscle weakness
27
What are the causes of hyperthyroidism
Grave's disease (autoimmune)
Solitary toxic ademona
excessive T4 AND T3 ingestion
Toxic multinodular goitre.
28
primary hyperthyroidism
suppressed TSH
| Increased T4 concentration
29
T3 toxicosis
Suppressed TSH
T4 within reference interval (or no increase)
T3 increased
30
Subclinical hyperthyroidism
Low TSH concentration
| T4 and T3 within reference interval.
31
Secondary hyperthyroidism
T4 AND T3 increased
TSH increased (not suppressed)
-pituitary tumour.
32
Hyperthyroidism
Autoimmune disease is the commonest cause of hyperthyroidism.
Diagnosis of hyperthyroidism is confirmed by suppressed TSH and elevated free T4 in a serum specimen, although total or free T3 concentration is needed if T3 toxicosis is suspected.
The management of hyperthyroidism is by antithyroid drugs, radioiodine therapy or thyroidectomy. TSH and free T4 are used to monitor thyroid function after all of these treatments.
33
what do we use the synacthen test for?
The diagnosis of primary adrenocortical failure.
| The long synacthen test may be used to distinguish primary and secondary failure of the adrenal cortex,
34
Describe the hypothalamic-pituitary thyroid axis
Circulating TH levels under negative feedback control at hypothalamic and pituitary levels
Synthesis and release of TH controlled by TSH
T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4
35
What are the disorders of thyroid function
Terminology: euthyroid (normal range), hypothyroid (below), hyperthyroid (above)
Primary hyper/hypothyroidism: dysfunction is in thyroid gland
Secondary: problem is with pituitary or hypothalamus (tertiary)
36
Describe hyperthyroidism
```
Excessive production of thyroid hormones (thyrotoxicosis)
Clinical features
Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)
In extreme: thyroid storm
Causes:
Graves disease (most common)
Due to stimulatory TSH-R antibodies
Toxic multinodular goiter
Toxic adenoma
Secondary: excess TSH production (rare)
```
37
Describe hypothyroidism
Deficient production of thyroid hormones
Clinical features
weight gain, cold intolerance, lack of energy, goitre
congenital - developmental abnormalities
Investigations
Raised TSH, reduced fT4
Reduction in TSH and T4 suggests secondary (hypopituitarism)
```
Causes:
Autoimmune thyroiditis (Hashimoto’s)
Thyroid peroxidase antibodies (anti-TPO)
Iodine defficiency
Toxic adenoma
Secondary – lack of TSH
```
38
Describe the structure of the adrenal cortex
Blood flows from outer cortex to inner medulla
Layer-specific enzymes; steroid synthesis in one layer can inhibit different enzymes in subsequent layers
Results in functional zonation of cortex with different hormones made in each layer
39
What are the actions of adrenal steroids
Mineralocorticoids: salt and water balance in order to maintain plasma volume: maintenance of blood pressure over the long term
Glucocorticoids: metabolism and immune function
Stress increases release, but minimal levels essential for normal function
Androgens: so called ‘weak androgens’
A reminder about aldosterone. It’s function is actually volume regulation. But it accomplishes be regulating the total amount of body sodium – NOT the concentration. If there’s a net loss of salt, then an osmotically equivalent amount of water will be lost with it, resulting in a net loss in volume, and hence plasma volume. The slightly smaller amount of salt in the slightly smaller volume will have the same concentration. However, the reduction in volume will result in a reduction in blood pressure. This will be detected, stimulating aldosterone to retain salt (and water with it) thus restoring blood volume. Now, changes in salt concentration can occur, when salt and water are lost or gained in unequal amounts. However, when this occurs, the hormone to correct it is not aldosterone, but rather …
40
What is the control of the adrenal steroid secretion
Cortisol: synthesis and release regulated by hypothalamic-pituitary-adrenal axis (CRH, ACTH)
Aldosterone: controlled by RAAS
Adrenal androgens: ACTH (not gonadotropins)
41
Random cortisol measurement
Cortisol secretion fluctuates in a circadian rhythm, which means a random plasma cortisol reading cannot exclude abnormality, unless way outside of normal range.
42
Describe the hyperfunction of the adrenal cortex
Aldosterone excess
Conn’s syndrome
Cortisol excess
Cushing’s syndrome
43
Biochemical tests in clinical medicine
```
Screening (subclinical conditions)
Diagnosis (normal vs abnormal values)
Monitoring (course of disease)
Clinical management (treatment/ response)
Prognosis (Risk stratification)
```
44
Describe the Classification of laboratory tests in cardiac disease
Markers of risk factors for development of coronary artery disease
Genetic analysis for candidate genes of risk factors
Markers of cardiac tissue damage
Markers of myocardial function/overload
45
What are cardiac markers
Located in the myocardium
Released in response to cardiac overload
Released in response to cardiac injury
Released in response to cardiac failure
Can be measured in blood samples
46
Describe what biochemical markers of cardiac dysfunction/damage can contribute to
```
Rule in/out an acute MI
Confirm an old MI
Help to define therapy
Monitor success of therapy
Diagnosis of heart failure
Risk stratification of death
```
47
What are the characteristics of the ideal cardiac marker
```
Analytical characteristics
• Measurable by cost-effective method
• Simple to perform
• Rapid turnaround time
• Sufficient precision & accuracy
• Reasonable cost
Clinical characteristics
```
* Early detection of disease
* Sensitivity vs specificity
* Validated decision limits
* Selection of therapy
* Risk stratification
* Prognostic value
* Ability to improve patient outcome
48
Describe the development of atheromatous plaques
Initial lesion, turned into fatty streak, turned into intermediate lesion, turned into atheroma, turned into fibroatheroma, then into a complicated lesion.
49
What are the consequences of coronary thrombosis
Ischaemia -> necrosis -> myocardial infarction.
50
Why is it important to define the type of IHD (ischemic heart disease)
There will be different treatment, prognosis, and management for each, eg Stable Angina, vs Acute myocardial infarction.
51
What are some causes of chest pain
```
Broken rib
Collapsed lung
Nerve infection (shingles)
“Pulled” muscle
Infection
Heart burn (hernia)
Pericarditis
Blood clot in the lungs (PE)
Angina
Myocardial infarction
There are possible areas radiating pain such as neck, jaw, upper abdomen, shoulders and arms.
```
52
What are the different assessments we can do for IHD
```
Medical history
Risk factors
Presenting signs and symptoms
ECG
Biomarkers
Imaging/scans
```
53
Describe myocardial injury
Irreversible injury typically requires 30 minutes of ischaemia
High risk that 80% of cardiac cells die within 3 hours and almost 100% by 6 hours
Cellular content leak out through membrane dependent on size and solubility
Concentration gradient from inside to outside important (high gradient improves detection of early damage)
54
Describe the release kinetics of myocardial cell constituents
-Ions (eg potassium or phosphate), released first (upto 3 hours after)
-Metabolites (lactate or adenosine) released second up to 6 hours.
Macromolecules (eg enzymes or proteins) released last (24hours after MI).
55
Describe the pathophysiology of acute coronary syndromes and biomarker release into the circulation
Coronary artery occlusion-> myocardial ischemia (ATP pump failure
Leakage of ions, e.g. potassium
) ->anoxia->lack collateral blood flow (Accumulation of metabolites
Leakage of metabolites, e.g. lactate
) ->reversible damage -> irreversible damage (Membrane damage
Leakage of myocardial proteins and
cellular enzymes
) -> cell death and tissue necrosis.
56
What are the markers of myocardial damage
7-36 h peak after MI
Heart muscle specific markers troponin-T and troponin-I
Creatine kinase ( 90% MIs, but less specific as also released from skeletal muscle)
Heart specific isoforms of creatine phosphokinase (CPK-MB
Myoglobin raised early but less specific for heart damage
57
Troponins
The troponin complex is a component of the thin filaments in striated muscle complexed to actin
There are three types of troponins:
• Troponin T (tropomyosin binding)
• Troponin I (inhibits actomyosin ATPase)
• Troponin C (calcium binding)
The troponins are three different proteins structurally unrelated with each other
Cardiac troponin T and I differ significantly from troponin T and I found in skeletal muscle.
58
What are the advantages of cardiac troponin
An index of cardiac damage
Blood levels related to severity of cardiac damage
Predicts major adverse cardiac events such as myocardial infarction
59
What test do we do to detect troponin
ELISA test. Enzyme linked immunosorbant assay.
60
What is heart failure
```
“a complex clinical syndrome
that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood”
Some causes:
Coronary Artery Disease
Chronic Hypertension
Cardiomyopathy
Heart Valve Disease
Arrhythmias- AF,VT
Infective endocarditis
Pulmonary Hypertension- PE, COPD
Alcohol and Drugs (eg cocaine)
```
61
What are the signs and symptoms of congestive heart failure
Shortness of breath
Swelling of feet and legs
Chronic lack of energy
Difficulty sleeping at night due to breathing problems
Swollen or tender abdomen with loss of appetite.
Cough with frothy sputum
Increased urination at night
Confusion and/or impaired memory.
Sensitivity and specificity of signs and symptoms of heart failure is relatively poor
62
Describe the clinical utilisation of cardiac biomarker testing in heart failure
```
Initial evaluation of heart failure
Screening for cardiac dysfunction
Guiding management of heart failure
Assessment of prognosis and survival
Natriuretic peptides as markers of cardiac overload.
An A,B,C of natriuretic peptides …….
```
63
Describe measurement of plasma natriuretic peptides & their advantages
Assays available for the active peptides and the N-terminal precursor forms of BNP.
Advantages of N-terminal precursor forms of BNP
Longer half-life
Higher plasma concentrations
Less sensitive to rapid fluctuations
64
Describe some conditions investigated for possible use of plasma BNP
Assessment of severity of congestive heart failure
Screening for mild heart failure
Monitor response to treatment in congestive heart failure
Prognostic outcome/risk stratification
65
Describe calcium homeostasis
99% of body calcium is in bone
Remaining 1% is mainly intracellular
Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance
Extracellular: plasma Ca 2.2-2.6 mmol L-1
About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin)
66
Describe phosphate homeostasis
85% of body phosphorus is in bone
Remainder is mainly intracellular
Extracellular: H2PO4-, HPO42-, 2.5-4.5 mg dL-1 (0.75-1.45 mmol L-1)
May fluctuate more than Ca
67
Describe bone as a metabolic organ
```
Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with
Parathyroid hormone (PTH)
Vitamin D (1,25-dihydroxy D3)
Calcitonin
FGF-23
```
68
Describe the clinical features of hypercalcaemia
Depression, fatigue, anorexia, nausea, vomiting,
Abdominal pain, constipation
Renal calcification (kidney stones)
Bone pain
"painful bones, renal stones, abdominal groans, and psychic moans,"
Severe: cardiac arrhythmias, cardiac arrest
69
what are the causes of hypercalcaemia
```
Most common causes:
In ambulatory patients: primary hyperparathyroidism
In hospitalized patients: malignancy
Less common causes include:
Hyperthyroidism
Excessive intake of vitamin D
```
70
Describe the serum biochemistry of hypercalcaemia
Serum calcium - modest to marked increase
Serum phosphate - low or low normal
Serum alkaline phosphatase raised in ~ 20% of cases
Serum creatinine may be elevated in longstanding disease (kidney damage)
Serum PTH concentration should be interpreted in relation to calcium
71
Describe the hypercalcaemia of malignancy
Most common cause of hypercalcaemia in hospitalized patients
Humoral, e.g., lung carcinoma secreting PTHrP
Metastatic
Haematological
myeloma
72
What are the causes of hypocalcaemia
```
Most common causes:
Vitamin D deficiency
Renal failure
Less common causes include:
Hypoparathyroidism
```
73
What is rickets and osteomalacia
Bone disease associated with vitamin D deficiency
Rickets - in children, failure of bone mineralisation and disordered cartilage formation
Osteomalacia - in adults, impaired bone mineralisation
74
Describe the features of osteomalacia
```
Diffuse bone pain
Waddling gait, muscle weakness
On X-ray, stress fractures
Serum biochemistry:
Low/normal calcium
Hypophosphataemia
Raised alkaline phosphatase
Secondary hyperparathyroidism
```
Vitamin D deficiency: most common cause
Usually due to combination of low dietary intake and lack of exposure to sunlight
Elderly at risk, especially if in nursing home and not taking supplements
Breast-fed babies kept out of sunlight
In the short term, bone remodelling releases minerals, notably calcium, into the circulation, and therefore can be controlled in the short-term in the service of calcium homeostasis.
75
What is osteoporosis
```
Osteoporosis: loss of bone mass
Endocrine
Malignancy
Drug-induced
Renal disease
Nutritional
```
Osteomalacia: loss of bone mineralization
76
Diagnosis of osteoporosis
Measurement of bone mineral density (BMD)
Dual-energy X-ray absorptiometry (DEXA or DXA scan)
T score
Number of SDs below average for young adult at peak bone density. Eg osteopenia is T score lower than -1 or greater than -2.5.
Osteoporosis is T score of -2.5 or lower.
Severe osteoporosis is T score of -2.5 or lower, and presence of at least one fragility fracture.
Z score
Matched to age and/or group
77
What are the endocrine causes of osteoporosis
Hypogonadism – notably any cause of oestrogen deficiency
Excess glucocorticoids – endogenous or exogenous
Hyperparathyroidism
Hyperthyroidism
78
What are the treatments for osteoporosis
Postmenopausal: HRT – effects well established but safety of long term treatment has been questioned
Bisphosphonates – inhibit function of osteoclasts: risedronate, alendronate
PTH analogues
Denosumab – antibody against RANK ligand
Ensure adequate calcium and vit D intake, appropriate exercise
79
Describe the bone remodelling pathway
. Osteocyte regulation of bone remodeling. Osteocytes express RANKL and macrophage-colony stimulating factor (M-CSF) to promote, and OPG and NO to inhibit, osteoclast formation and activity. Osteocytes also regulate bone formation via the secretion of modulators of the Wnt signaling pathway. PGE2, NO, and ATP act to activate Wnt signaling, whereas sclerostin, DKK1, and SFRP1 all inhibit Wnt signaling and subsequent osteoblast activity. Maintenance of this balance between resorption and formation by the osteocyte is essential for bone homeostasis.
80
Describe induction of osteoclast differentiation by RANK ligand
RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation
RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation
OPG (osteoprotogerin): decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK
81
Describe the wnt signalling pathway
Wnt is a family of protein signalling molecules important in development throughout the animal kingdom. The receptor is called frizzled, which requires a co-receptor, Low-density lipoprotein receptor-related protein 5 (LRP5). In adult animals wnt is involved in growth, differentiation and maintenance of many tissues, including bone. Wnt signalling is under negative control by various proteins.
Complex signal pathway, highly conserved, involved in animal development
Drosophila wingless gene (1987)
Required for osteoblast differentiation
Negatively regulated by DKK (dickkopf) and sclerostin (SOST)
82
Vitamin D
Calcitriol (really a steroid hormone, not a vitamin!)
Synthesised in skin in response to exposure to UV (‘sunshine vitamin’)
Activated by 2 metabolic steps
25 hydroxylation in liver to form 25OH D3, major circulating metabolite
1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone.
Nuclear receptor, VDR, typical steroid, DNA binding element, etc. Dimerizes with RX receptor. Effects mainly increasing (sometimes decreasing) transcription of target genes.
83
Describe FGF-23 hormone
FGF-23: a hormone secreted by osteocytes.
Discovered in 2000
Hypophosphatemic rickets: rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
Consortium investigating autosomal-dominant HR (ADHR) traced mutation in gene that turned out to be FGF-23
Central role in phosphate homeostasis
84
Describe renal phosphate reabsorption
Sodium-phosphate co-transporter
| Requires association with Na-H exchanger regulatory factor (NHERF).
85
Describe the distribution of body fluids
Total body fluids is 60% of body weight.
| ECF is then 20% and ICF is 40%
86
What factors are water and sodium balance determined by?
Water:
Intake
-Dietary intake (Thirst)
Output
- Obligatory losses
- Skin
- Lungs
- Controlled losses – these depend on:
- Renal function
- Vasopressin/ADH (anti-diuretic hormone)
- Gut (main role of the colon)
Redistribution
Sodium:
Intake
-Dietary (unless vegan and doesn’t add salt)
-Western diet 100-200 mmol/day
```
Output
-Obligatory loss
-Skin
-Controlled losses / excretion
-Kidneys
-Aldosterone
-GFR
-Gut - most sodium is reabsorbed; loss is pathological
(determined by intravascular volume).
```
87
What are the hormones involved in salt and water balance?
Sodium
-Aldosterone produced in the adrenal cortex: regulates sodium and potassium homeostasis
-Natriuretic hormones (ANP cardiac atria, BNP cardiac ventricles) promote sodium excretion and decrease blood pressure
Water
-ADH/vasopressin: synthesised in hypothalamus and stored in posterior pituitary. Release causes increase in water absorption in collecting ducts
-Aquaporins (AQP1 proximal tubule and not under control of ADP) AQP2 and 3 present in collecting duct and under control of ADH
88
Describe osmotic pressure and water movement
Osmotically active substances in the blood may result in water redistribution to maintain osmotic balance but cause changes in other measured solutes
89
What are the physiological responses to water loss?
gonna do later
| -slide 7 of Salt and warter and acid base balance lecture.
90
What methods can we use to measure the osmotic strength of a solution.
Osmometry
Freezing point depression
Uses colligative properties of a solution
More solute – lower the freezing point
Sodium
Indirect Ion selective electrodes (main lab analysers)
Direct Ion selective electrodes (Blood gas analyser)
91
How to assess a patient with possible fluid/electrolyte disturbance
History
- Fluid intake / output
- Vomiting/diarrhoea
- Past history
- Medication
Examination - Assess volume status
- Lying and standing BP
- Pulse
- Oedema
- Skin turgor/Tongue
- JVP / CVP
Fluid chart
92
Describe the management of fluid/electrolyte problems
Hyponatraemia
Over-rapid correction may lead to central pontine myelinolysis
Hypernatraemia
Over rapid correction may lead to cerebral oedema
It is important to correct sodium at the same speed
no more than 10mmol/L per 24 hours sodium change
93
Describe key laboratory investigations we perform
Urea/creatinine ratio is useful
Urea up a lot = dehydration
Serum osmolality
Indicates if other osmotically active substances are present.
Urinary sodium – ignore the reference interval
<20 mmol/L = conservation
>20 mmol/L = loss
Urinary osmolality - ignore the reference interval
Relate to the serum osmolality
Urine /serum osmolality
>1 = water conservation
< 1 = water loss
Calculated Serum osmolality = 2 x Na + urea + glucose (+/- 10)
290 = (2 x 140 = 280) + 5 + 5
Only useful if you think something else is present
94
Describe the investigation of acid-base balance
Large amounts of protons/hydrogen ions are an inevitable by-product of energy/ATP production
Maintenance of extracellular [H+]/pH is essential to maintain protein/enzyme function
depends on the relative balance between acid production and excretion
carbon dioxide production and excretion (respiration)
hydrogen ion production and excretion (renal) slide 18/
95
Describe blood glucose homeostasis
Glucose is a major energy substrate
How is blood glucose levels are maintained?:
dietary carbohydrate
glycogenolysis
gluconeogenesis
Liver’s role:
after meals - stores glucose as glycogen
during fasting - makes glucose available through glycogenolysis and gluconeogenesis.
During fasting the liver makes glucose available through:
Glycogenolysis: - breakdown of glycogen store to glucose
Gluconeogenesis:- making glucose from non-glucose sources, e.g. lactate, alanine, glycerol
96
Why should glucose level be regulated
Brain and erythrocytes require continuous supply: – therefore avoid deficiency.
High glucose and metabolites cause pathological changes to tissues; e.g. micro/macro vascular diseases, neuropathy: – therefore avoid excess.
97
What are the metabolic effects of insulin
Increases
Lipogenesis
Amino acid uptake, glycogen synthesis, fatty acid synthesis.
Glucose uptake and generalised tissue effects.
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Decreases
Ketogenesis, gluconeogenesis
Glycogenolysis
Lipolysis
Protein breakdown.
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98
Describe diabetes mellitus
…..a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism:
hyperglycaemia result of increased hepatic glucose production and decreased cellular glucose uptake
blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria
Prevalence
Globally 422 million people currently have diabetes; estimated to increase by 2035 (WHO, 2014)
In UK 2018 ~ 3.8 million diagnosed with DM.
99
Describe the diagnosis of diabetes
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ).
OR
Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
OR
Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
In the absence of symptoms:
test blood samples on 2 separate days.
Random is defined as any time of day without regard to time since last meal.
The classic symptoms of hyperglycemia include polyuria, polydipsia, & unexplained weight loss
100
IGT (pre-diabetes) and IFG
Impaired Glucose Tolerance (IGT)
Fasting plasma glucose 6.1-6.9mmol/L**
OGTT value of 7.8 – 11.1 mmol
Impaired Fasting Glycaemia (IFG)
Fasting plasma glucose ‹ 7.0 mmol/L** and
OGTT value of < 7.8
** OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.
101
Describe the oral glucose tolerance test
OGTT should be carried out:
in patients with IFG
in unexplained glycosuria
in clinical features of diabetes with normal plasma glucose values
for the diagnosis of acromegaly
75g oral glucose and test after 2 hour
Blood samples collected at 0 and 120 mins after glucose
Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate
102
What are the different classification of diabetes
Type 1:
Insulin secretion is deficient due to autoimmune destruction of B-cells in pancreas by T-cells.
Type 2:
Insulin secretion is retained but there is target organ resistance to its actions.
Secondary:
chronic pancreatitis, pancreatic surgery, secretion of antagonists
Gestational:
Occurs for first time in pregnancy
103
Type 1 diabetes
More than 90% of newly diagnosed persons with type 1 DM have one or another of these antibodies.
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
Amylin, a glucoregulatory peptide hormone co-secreted with insulin.
lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
104
Describe the metabolic complications of type 1 DM
Insulin deficiency leads to
increased hepatic output and impaired glucose uptake – hyperglycaemia
Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse
Increased lipolysis blood level of ketone bodies formation (DKA) and metabolic acidosis.
You get polyphagia and polydipsia.
105
Type 2 diabetes
Presentation:
Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age. Peak age is 60 years; develops slowly.
Strong familiar incidence
Pathogenesis uncertain – insulin resistance; β-cell dysfunction:
may be due to lifestyle factors - obesity, lack of exercise
106
What are the metabolic complications of type 2 DM
Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemic State (HHS)]
Development of severe hyperglycaemia
Extreme dehydration
Increased plasma osmolality
Impaired consciousness
No ketosis
Death if untreated
107
What is the treatment of type 2 diabetes
Stepwise treatment.
Start with diet and exercise.
Then oral monotherapy such as metformin.
Metformin helps the body to control blood sugar in several ways. Metformin exerts its effect mainly by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose; since it acts only in the presence of endogenous insulin it is effective only if there are some residual functioning pancreatic islet cells. The drug helps type 2 diabetics respond better to their own insulin, lower the amount of sugar created by the liver, and decreasing the amount of sugar absorbed by the intestines.
Then oral combination of pills.
Then insulin and oral agents which may help:
eg sulphonylureas
Sulphonylureas - they work mainly by stimulating the cells in the pancreas to make more insulin.
They also help insulin to work more effectively in the body.
Dipeptidyl peptidase inhibitor (DPP-4; Gliptins): inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed.
Gliptins
GLP-1 analogues
Overall
Metformin: Decreases gluconeogenesis
Sulfonylureas: bind and close KATP channels, depolarize B cell releasing insulin
Thiazolidinediones: activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
SGLT2 inhibitors: promote glucose excretion via kidney
Incretin targeting drugs: potentiate insulin release in response to rising plasma glucose
DPP-4 inhibitors (prevent breakdown of natural incretins)
Synthetic GLP-1 analogues
108
How can we monitor glycaemic control?
Aim: to prevent complications or avoid hypoglycaemia
Self-monitoring to be encouraged:
Capillary blood measurement
urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold
3-4 months: blood HbA1c (glycated Hb; covalent
linkage of glucose to residue in Hb.
Others: urinary albumin (index of risk of progression to nephropathy).
Abnormalities in serum lipids common in T1DM & T2DM increase risk of MI and stroke
HbA1c – aim at <7%
109
Long term complications
Occur in both type 1 and type 2 DM
Micro-vascular disease:
retinopathy, nephropathy, neuropathy
Macro-vascular disease:
related to atherosclerosis heart attack/stroke
Exact mechanisms of complications are unclear
Macrovascular changes - accelerated atherosclerosis: hyperglycaemia and other factors cause endothelial injury, platelet adhesion and plaque formation.
Microvascular changes – structural changes in microvasculature that lead to retinopathy, neuropathy (sequelae .. the diabetic foot), nephropathy: hyperglycaemia causes glycation of proteins and increase in sorbitol. Glycation of proteins causes thickening of basement membrane, loss of pericytes, release of growth factors and prothrombic changes
110
Hypoglycaemia
Defined as plasma glucose < 2.5 mmol/L
Hypoglycaemia in diabetes
Hypoglycaemia in patients with diabetes
111
what are the causes of hypoglycaemia
Drugs are the most common cause,
insulin & insulin secretagogues
Alcohol, beta blockers CAE inhibitors
Endocrines disease; e.g. cortisol disorder
Inherited metabolic disorders, e.g. glycogen storage diseases, galactosaemia, hereditary fructose intolerance.
Insulinoma
Others: severe liver disease,
non-pancreatic tumours (beta cell hyperplasia),
renal disease (metab. acidosis, reduced insulin elimination).
112
What are the inherited metabolic disorders
Glycogen storage disease type l (von Gierke’s disease);
deficiency of G-6-Phosphatase: impaired glucose release from glycogen
Galactosaemia:
deficiency of galactose-1-phosphate uridyl transferase: liver damage
Hereditary fructose intolerance:
deficiency of fructose-1-phosphate adolase B: accumulation of fructose-1-phosphate in liver
113
What is glycogen storage disease type Ia
Autosomal recessive disorder;
Glucose synthesis from glycogen or by gluconeogenesis is blocked.
presents in early infancy; manifested in severe fasting hypoglycaemia as only source of glucose is dietary carbohydrate.
accumulation of glycogen causes hepatomegaly; inability to produce glucose from lactate causes acidosis.
Tx: uncooked cornstarch; a slow releasing glucose prep.
Glycogen storage disease type I (GSD I) is part of a rare group of inherited diseases characterized by enzyme defects that affect the glycogen synthesis and degradation cycle.
There are two subtypes of type I glycogen storage disease, both having autosomal recessive transmission: type Ia is the most common, characterized by a defect in glucose-6-phosphatase (an enzyme found only in the liver, kidney and intestinal mucosa) activity, and type Ib, caused by a defect in microsomal transport of glucose-6-phosphate
deficiency of G-6-Phosphatase
114
Galactosaemia
Defects in 3 enzymes can cause galactosaemia; most common is galactose-1-phosphate uridyl transferase deficiency.
Autosomal recessive disorder.
Deficiency of G-1-PUT impairs conversion of galactose-1-phosphate to glucose-1-P.
Gal-1-phosphate accumulates in liver - toxicity
Hypoglycaemia; and vomiting/diarrhoea after starting milk feeds
Galactose excreted in urine. Tx - exclude galactose from diet.
Later liver damage, poor growth, cataracts
G1PUT – galactose-1-phosphate uridyl transferase
115
Describe hereditary fructose intolerance
Autosomal recessive disorder.
Deficiency of fructose 1-phosphate aldolase B
ingested fructose accumulates – inhibits glycogenolysis at phosphorylase step.
Severe hypoglycaemia and vomiting after ingesting fruit, sweetened foods.
Fructose detected in urine
Benign fructose intolerance: – this due to absence of fructokinase
Blood fructose The metabolism of fructose is initiated by its phosphorylation in liver to D-fructose-1-phosphate, as catalyzed by fructokinase.
Is a recessively inherited condition in which affected homozygotes develop hypoglycaemic and severe abdominal symptoms after taking foods containing fructose and cognate sugars. Continued ingestion of noxious sugars leads to hepatic and renal injury and growth retardation; parenteral administration of fructose or sorbitol may be fatal.
Avoid ingestion of fructose, sucrose.
116
What are the responses to falling glucose levels in fasting
Physiological counter-regulatory response:
Suppression of insulin release, limiting glucose entry into non-cerebral tissues
Secretion of glucagon, adrenaline, noradrenaline, cortisol and growth hormone to raise glucose level.
Glucose Counter-Regulatory Hormones:
Glucagon: Secreted by -cells of pancreas in response to hypoglycaemia
stimulates glycogenolysis and gluconeogenesis
Cortisol: increases Gluconeogenesis
117
What are the signs and symptoms of hypoglycaemia
Neurogenic (autonomic):
triggered by falling glucose levels
activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
Symptoms of hypoglycemia are divided into two categories. Neurogenic (autonomic) symptoms are triggered by a falling glucose level and cause patients to recognize that they are experiencing a hypoglycemic episode.
These symptoms are activated by the ANS and are mediated in part by sympathoadrenal release of catecholamines (norepinephrine
and epinephrine) from the adrenal medullae and acetylcholine from postsynaptic sympathetic nerve endings.
Neurogenic symptoms and signs associated with elevated epinephrine levels include shakiness, anxiety, nervousness, palpitations, sweating, dry mouth, pallor, and pupil dilation
Neuroglycopenic symptoms occur as a result of brain neuronal glucose deprivation. Evidence of neuroglycopenia can be the signal most often recognized by patients’ family and friends. These symptoms include abnormal mentation, irritability, confusion, difficulty speaking, ataxia, paresthesias, headaches, stupor, and eventually (if untreated) seizures, coma, and even death
Neuroglycopaenia:
due to neuronal glucose deprivation.
```
Sign & symptoms include:
confusion,
difficulty speaking,
ataxia,
paresthesia,
seizures,
coma,
death
Neuroglycopenic symptoms occur as a result of brain neuronal glucose deprivation. Evidence of neuroglycopenia can be the signal most often recognized by patients’ family and friends. These symptoms include abnormal mentation, irritability, confusion, difficulty speaking, ataxia, paresthesias, headaches, stupor, and eventually (if untreated) seizures, coma, and even death.
```
Different causes of hypoglycaemia
in infants may result from inherited metabolic disease;
in adults – drugs or may be due to insulinoma.
