recommended reading lecture notes in clinical biochmesitry 7 th edition g beckett, s walker, p rae,...
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Recommended Reading
Lecture Notes in Clinical Biochmesitry 7th EditionG Beckett, S Walker, P Rae, P Ashby (Blackwell publishing)
Clinical Chemistry 5th EditionW J Marshall, S K Bangert (Pubslished by Mosby)
An illustrated Colour text - Clinical Biochmeistry 3rd editionAlan Gaw et al (Churchill Livingston)
Handbook of Clinical biochmeistry 1st EditionR Swaminathan (Oxford University Press)
Clinical Chemistry in diagnosis and treatmentPhilip Mayne (Edward Arnold)
A Guide to Diagnostic Clinical Chemistry 3rd EditionWalmsely & White (Blackwell)
Chemical Pathology of Pulmonary Disease
Dr Vivion Crowley
Consultant Chemical PathologistHead of Biochemistry DepartmentSt James’s HospitalDublin
The critical function of the pulmonary system is to facilitate respiration
Respiration comprises
Lung uptake and delivery of O2 to tissues
Lung removal of CO2 from tissues
Why Tissue Oxygenation?
O2 is required for the production of energy (as ATP) duringoxidative metabolism in the mitochondria
CO2 is a toxic by-product of the of the metabolism of CHO and fats
What factors facilitate Tissue oxygenation?
Alveolar ventilation and function
Pulmonary and systemic blood flows
O2 binding in alveoli and release in tissue (Hb)
How can we assess tissue oxygenation / tissue hypoxia?
ClinicallyCentral cyanosis >5g/L deoxygenated Hb (SaO2 < 67%)HypotensionOrgan dysfunction e.g. ARDS, ARFMental obtundation
Plasma/Blood lactate
Arterial O2 Saturation (SaO2) -limitations-pulse oximeter
PaO2 (arterial partial pressure of O2)- Still an essential index of tissue O2 supply
Limitations of SaO2
O2 dissociation curve
No information about respiratory ventilation – require ABG
Large fall in PO2 might cause only a small fall in SaO2 e.g. SaO2 90% could still reflect a large fall in PO2
PaCo2 is a useful means of assessing ventilation
Clinically:
•Rate and depth of respiration – limited accuracy
PaCO2 (arterial partial pressure of CO2):
•Key assessment of alveolar ventilation•Increase ventilation lowers PCO2
•Decreased ventilation increases PCO2
Respiratory failure is a severe clinical endpoint of pulmonary disease
Respiratory failure can be caused by
Acute pulmonary disease-Pneumonia-Pulmonary oedema-ARDS-Acute asthma-Pulmonary embolism-Atelectasis (collapse)
Chronic pulmonary disease-COPD (Chronic Bronchitis/Emphysema)-Pulmonary fibrosis
How is respiratory failure classified?
Type 1 Respiratory Failure
Hypoxaemia (normo or hypocapnia)
failure of O2 transfer
• Ventilation-perfusion (V/Q) defects
• Right-to-Left shunts e.g. pulmonary oedema
Type 2 Respiratory Failure
Hypoxaemia and Hypercapnia
failure of ventilation to remove CO2
• Reduced total ventilation
• Decreased diffusion
Arterial Blood Gas (ABG) analysis is an essential investigation for definitive diagnosis of respiratory failure
How is Respiratory failure defined using ABG?
Type 1 Respiratory Failure (low PO2, normal/low PCO2)
-PO2 < 8.0 kPa
-PCO2 < 6.7 kPa
Type 2 Respiratory Failure (low PO2, high PCO2)
-PO2 < 8.0 kPa
-PCO2 > 6.7 kPa
Disorders of acid-base balance
Three mechanisms are involved in regulating changes in ECF acid-base balance
Buffers
Respiratory response
Renal response
Buffers act to limit change in acid-base status
Intracellular buffers
- Proteins e.g Hb in red cells- Bone
Extracellular buffers
- Phosphate (HPO4)
- Bicarbonate buffer (HCO3)
The Bicarbonate buffer system is uniquely tailored to regulating acid-base balance
Most extracellular buffers have a limited capacity i.e. become saturated
However in the case of the HCO3 Buffer system
H + HCO3 H2CO3 CO2 + H2O
The end product CO2 can be dissipated via lungs
Thus the HCO3 buffer system is less likely to become saturated
The relationship between the HCO3 buffer and pH can be predicted by the Henderson-Hasselbach equation
pH = 6.1 + log HCO3/H2CO3
pH = 6.1 + log HCO3/0.03PCO2
depends upon
HCO3PCO2
[H+] (nmol/l) = 180 X PCO2/[HCO3] N.B. PCO2 (kPa)
pH (Renal)(Lung)
Regulation of acid-base balance is primarily dependent on two main organ systems
Respiratory (lungs) – regulates PCO2•Increased or decreased ventilation
Renal – regulates HCO3•Reabsorption of HCO3 (proximal tubule)•Generation of HCO3 (distal tubule – urine pH < 5.5)•Titratable acidity (HPO4 buffers throughout tubule)
The respiratory response occurs more quickly thanthe renal response
The relationship between the HCO3 buffer and pH can be predicted by the Henderson-Hasselbach equation
pH = 6.1 + log HCO3/H2CO3
pH = 6.1 + log HCO3/0.03PCO2
depends upon
HCO3PCO2
[H+] (nmol/l) = 180 X PCO2/[HCO3] N.B. PCO2 (kPa)
pH (Renal)(Lung)
Disorders of acid-base balance
Acidosis/Acidaemia ( pH, [H+] )
-Respiratory PCO2
-Metabolic HCO3
Alkalosis/Alkalaemia ( pH, [H+])
-Respiratory PCO2
-Metabolic HCO3
Compensatory mechanisms exist to limit the extent of acid-base disturbance and restore pH towards normal
Metabolic acidosis Respiratory alkalosis ( PCO2)
Respiratory acidosis Metabolic alkalosis ( HCO3)
Metabolic alkalosis Respiratory acidosis ( PCO2)
Respiratory alkalosis Metabolic acidosis ( HCO3)
The respiratory response can occur within minutes but the renal response can take 2-4 days to develop
Full compensation does not occur except in the case of chronicrespiratory alkalosis
Causes of Respiratory Acidosis
-CNS depression e.g. trauma, drug OD
-Neuromuscular disorders
-Chest wall disease e.g. kyphoscoliosis
-Pleural effusions
-COPD
-Pulmonary oedema
High anion gap •Ketoacidosis•Lactic acidosis•Toxins e.g. methanol, ethanol,salicylate OD•Renal failure
Normal anion gap (hyperchloraemic)•Renal tubular acidosis (Type I, II and IV)•Early stages of CRF•Diarrhoea, ureteric diversion (HCO3 loss)•Ingestions/infusions e.g. HCl
Causes of Metabolic Acidosis
The Anion Gap may be useful in determining the cause of acidaemia
AG = (Na + K) – (HCO3 + Cl)
Ref range: 7- 17 mmol/l
Increased AG suggests the presence of circulating anione.g ketones, lactate, salicylate
Causes of Respiratory Alkalosis
-Anxiety/hysteria related hyperventilation
-CNS pathology causing hyperventilation
-CCF/pulmonary oedema
-Salicylates
-Sepsis
-Cirrhosis
-Ventilator induced
Chloride/Saline ResponsiveGI losses e.g. vomiting, gastric suction, Cl diarrhoea
Chloride/Saline UnrepsonsiveDiuretic therapyMineralocorticoid excess e.g. Conn,s syndrome, exogenousCushing’s syndromeBartter/Gitelman syndrome
Hypokalaemia is very often associated with the pathogenesis of metabolic alkalosis
Causes of Metabolic Alkalosis
Evaluation of patient with suspected acid-base disturbance (1)
What is the clinical picture?-Hx DM, CRF, -Vomiting, diarrhoea-COPD, -Hyperventilating
What are the plasma electrolytes?-hypo/hyperkalaemia-Renal failure-Glucose-AG
Evaluation of patient with suspected acid-base disturbance (2)
Arterial Blood Gases (ABG)-usually done by trained staff as a point of care test (POCT)
3 basic values provided
• pH or [H+]
• PCO2 (also PO2)
• [HCO3] (derived from H-H equation)
Other valuesBase excess – measure of metabolic componentStandard HCO3 – measure of metabolic component
What are the measured components of an ABG?
Component Ref. Range
PO2 (kPa) 11.1-14.1
PCO2 (kPa) 4.4-6.4
pH 7.35-7.45
[H+] (nmol/L) 36-45
HCO3 (mmol/L) 21-31
Standard HCO3 and Base Excess (BE) are measures of “metaboliccomponent” but give similar information to actual HCO3
pH 7.27 (7.35 – 7.45)PCO2 2.66 (4.6 – 6.4)HCO3 9 (22-31)
pH 7.05PCO2 5.5HCO3 8
pH 7.58PCO2 1.6HCO3 19
pH 7.25PCO2 7.2HCO3 22
A
B
C
D
A = partially compensated metabolic acidosis
B = Uncompensated metabolic acidosis
C = Uncompensated respiratory acidosis
D = partially compensated respiratory alkalosis
Mixed Acid-Base disturbances
•Implies that there is more than one disorder of acid-base balance ocurring simultaneously
•Usually there is a primary (dominant) disorder
•pH may be normal or near normal
•But the pH is usually outside compensatory limits of primary disorder
Examples of mixed acid-base disorders
Cardiac arrest, pulmonary oedema
pH 7.18
PCO2 6.7
HCO3 18
Mixed metabolic and respiratory acidosis
COPD and diuretic therapy
pH 7.42
PCO2 8.9
HCO3 42
Mixed respiratory acidosis and metabolic alkalosis
Salicylate poisoning
pH 7.39
PCO2 3.2
HCO3 14
Mixed respiratory alkalosis and metabolic acidosis
DKA with vomiting
pH 7.42
PCO2 5.3
HCO3 25
AG 23
Mixed metabolic acidosis and metabolic alkalosis
(In this case look out for high anion gap)
Endocrine Manifestations of Bronchial Tumours
• Hypercalcaemia of malignancy
• Syndrome of inappropriate antidiuresis (SIADH) - hyponatraemia
• Cushing’s syndrome
•Carcinoid syndrome - facial flushing, diarrhoea, brochospasm
Hypercalcaemia in Lung cancer
Usually associated with squamous cell lesions
Mechanisms:1. Metastasis to bone - osetolytic lesions
2. Humoral Hypercalcaemia of malignacy HHM)- Tumoral production of PTH related peptide (PTHrP)- PTHrP acts on same receptors as PTH
Dx•Plasma Ca usually > 3.0 mmol/L•Reduced levels of plasma PTH
NB. Tumours rarely demonstrate ectopic production of PTH
SIADH in Lung Cancer
In lung tumours SIADH results from ectopic secretion of ADH (AVP)
Can produce severe Hyponatraemia (plasma Na <120)
Hyponatraemia/SIADH may be a feature of different pulmonary pathologies•Reset osmostat•Increased sensitivity to ADH
Cushing’s Syndrome
Associated with Small Cell Carcinoma
Ectopic production of Adrenocroticotrophic hormone (ACTH)
Rarely, ectopic Corticotrophin releasing hormone (CRH)
Clinically presents with•Weight loss•Hypokalaemia•Metabolic alkalosis•Pigmentation•Extremely poor prognosis
Carcinoid Syndrome
2% of Bronchial tumours are Carcinoid
Overproduce serotonin and related amines
Diagnosis -urinary 5 hydroxyindole actetic acid (5HIAA)
Clinically they can present with Carcinoid syndrome because amines enter the systemic circulation•Facial flushing•Right heart valvular disease•Brochospasm
Use of Biochemistry Tests in Pleural Fluid analysis
Main purpose is to differentiate Transudative and Exudative effusions
Transudates •CCF•Cirrhosis•Nephrotic syndrome
Exudates•Malignancy•Infection e.g. bacterial pnemonia, TB•PE•GI disease e.g pancreatitis•Chylothorax•Connective tissue disorders
Traditionally pleural fluid protein level • < 30g/L in Transudate• >30g/L in Exudate • Misclassification in 10%
Light’s Criteria for Exudative Pleural effusion
Any one of the following
•Pleural fluid :Plasma Protein ratio >0.5•Pleural fluid:Plasma LDH >0.6•Pleural fluid > 2/3 upper limit of normal plasma LDH
Use of Biochemistry Tests in Pleural Fluid analysis (2)
Other Biochemical Tests used in Pleural Fluid Analysis
Amylase e.g. pancreatic disease, malignancy
Glucose <3.4 mmol/L-Malignancy-TB-Empyema-Rhematoid arthritis
Chylothorax
The following criteria apply•Pleural fluid triglyceride >1.25 mmol/L•Pleural fluid:Plasma Triglyceride >1.0•Pleural fluid:plasma cholesterol <1.0
Miscellaneous Biochemistry Tests in Pulmonary Disease
Serum Angiotensin Converting enzyme (ACE)-Increased in 75% patinet with sarcoidosis-Reflects activity of disease -?Use in monitoring response to treatment
α1-antitrypsin deficiency-Multiple phenotypes (genotypes)-Associated with susceptibility to emphysema
Cystic Fibrosis-Genotyping e.g. Δ508-Diagnosis Sweat Test -Screening using immunoreactive trypsin (IRT)