Clinical Biochemistry Flashcards
Describe briefly the types of LFTs
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.
What are the major functions of the liver
-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.
What are the common disease processes affecting the liver?
Hepatitis
Damage to hepatocytes
Cirrhosis Increased fibrosis Liver shrinkage Decreased hepatocellular function Obstruction of bile flow
Tumours
Frequently secondary: colon, stomach, bronchus
Outline the biochemical assessment of liver function
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
What are LFTs (liver function tests) used for?
- 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
What is compensation and it’s associated speeds
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
What are the pitfalls of ABG
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
What are the causes of respiratory acidosis
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
Describe respiratory acidosis
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
What are the causes of respiratory alkalosis
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
Respiratory alkalosis
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
What are the causes of metabolic acidosis
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
Metabolic acidosis
Metabolic acidosis •Compensation –hyperventilation, hence low pCO2 •Correction –of cause –increased renal acid excretion •Features –low pH, high [H+], low [HCO3-], low pCO2
What are the causes of metabolic alkalosis
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
Metabolic alkalosis
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
What are dynamic function tests
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.
Insulin stress test
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.
TRH tests
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.
Oral glucose tolerance test with GH measurement
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.
Synacthen tests
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.
Dexamethasone suppression tests
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
Thyroid hormone actions
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.
Clinical features of hypothyroidism
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.
Primary hypothyroidism
failure of thyroid gland to produce hormones. Diagnosed by elevated TSH
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.
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
What are the causes of hyperthyroidism
Grave’s disease (autoimmune)
Solitary toxic ademona
excessive T4 AND T3 ingestion
Toxic multinodular goitre.
primary hyperthyroidism
suppressed TSH
Increased T4 concentration
T3 toxicosis
Suppressed TSH
T4 within reference interval (or no increase)
T3 increased
Subclinical hyperthyroidism
Low TSH concentration
T4 and T3 within reference interval.
Secondary hyperthyroidism
T4 AND T3 increased
TSH increased (not suppressed)
-pituitary tumour.
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.
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,
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
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)
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)
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
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
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 …
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)
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.
Describe the hyperfunction of the adrenal cortex
Aldosterone excess
Conn’s syndrome
Cortisol excess
Cushing’s syndrome
Biochemical tests in clinical medicine
Screening (subclinical conditions) Diagnosis (normal vs abnormal values) Monitoring (course of disease) Clinical management (treatment/ response) Prognosis (Risk stratification)
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
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
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
