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)