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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)
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Chemical Pathology of Pulmonary Disease
Dr Vivion Crowley
Consultant Chemical PathologistHead of Biochemistry DepartmentSt James’s HospitalDublin
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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
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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
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What factors facilitate Tissue oxygenation?
Alveolar ventilation and function
Pulmonary and systemic blood flows
O2 binding in alveoli and release in tissue (Hb)
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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
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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
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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
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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
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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
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Type 2 Respiratory Failure
Hypoxaemia and Hypercapnia
failure of ventilation to remove CO2
• Reduced total ventilation
• Decreased diffusion
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Arterial Blood Gas (ABG) analysis is an essential investigation for definitive diagnosis of respiratory failure
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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
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Disorders of acid-base balance
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Three mechanisms are involved in regulating changes in ECF acid-base balance
Buffers
Respiratory response
Renal response
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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)
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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
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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)
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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
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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)
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Disorders of acid-base balance
Acidosis/Acidaemia ( pH, [H+] )
-Respiratory PCO2
-Metabolic HCO3
Alkalosis/Alkalaemia ( pH, [H+])
-Respiratory PCO2
-Metabolic HCO3
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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
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Causes of Respiratory Acidosis
-CNS depression e.g. trauma, drug OD
-Neuromuscular disorders
-Chest wall disease e.g. kyphoscoliosis
-Pleural effusions
-COPD
-Pulmonary oedema
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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
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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
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Causes of Respiratory Alkalosis
-Anxiety/hysteria related hyperventilation
-CNS pathology causing hyperventilation
-CCF/pulmonary oedema
-Salicylates
-Sepsis
-Cirrhosis
-Ventilator induced
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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
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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
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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
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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
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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
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A = partially compensated metabolic acidosis
B = Uncompensated metabolic acidosis
C = Uncompensated respiratory acidosis
D = partially compensated respiratory alkalosis
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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
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Examples of mixed acid-base disorders
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Cardiac arrest, pulmonary oedema
pH 7.18
PCO2 6.7
HCO3 18
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Mixed metabolic and respiratory acidosis
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COPD and diuretic therapy
pH 7.42
PCO2 8.9
HCO3 42
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Mixed respiratory acidosis and metabolic alkalosis
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Salicylate poisoning
pH 7.39
PCO2 3.2
HCO3 14
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Mixed respiratory alkalosis and metabolic acidosis
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DKA with vomiting
pH 7.42
PCO2 5.3
HCO3 25
AG 23
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Mixed metabolic acidosis and metabolic alkalosis
(In this case look out for high anion gap)
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Endocrine Manifestations of Bronchial Tumours
• Hypercalcaemia of malignancy
• Syndrome of inappropriate antidiuresis (SIADH) - hyponatraemia
• Cushing’s syndrome
•Carcinoid syndrome - facial flushing, diarrhoea, brochospasm
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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
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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
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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
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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
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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
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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)
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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
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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)