XI International Congress of Clinical Chemistry: Proceedings, Vienna, Austria, August 30–September 5, 1981 [Reprint 2019 ed.] 9783110861051, 9783110084474

Table of contents :
Preface
Contents
I. General Aspects
The Status of Clinical Chemistry
Ethical Aspects of Clinical Chemistry
Future of Clinical Chemistry
Teaching In Clinical Chemistry
Introduction to symposium
Clinical Chemistry in the Medical Curriculum
Teaching in Clinical Chemistry. The Medical Graduate
Technician and Technologist Training in Clinical Chemistry
II. Clinical Aspects
Clinical Chemistry and Hemostasis
Clinical Chemistry In Intensive Care
Interdisciplinary Cooperation between Intensive Medicine and Clinical Chemistry
Biochemistry of the Cardiovascular System in Circulatory Shock
Metabolism in Shock and Therapeutic Consequences
Biochemistry of the Lung in Shock - the role of Clinical Chemistry in the Treatment of Respiratory Failure
Prognostic Value of Enzyme and Acute Phase Protein Determination in Skull Traumatology
Health Screening
Clinical Value of Different Tests in Health Screening
Long-Term Individual Variation in the Concentration of Blood Constituents
Contribution of Health-Testing Centers to Reference Values Determination
Risk Factors in Coronary Heart Disease
Lipoproteins
The Determination of Apoproteins and their Diagnostic Value in Clinical Chemistry
Apolipoprotein Disorders
High Density Lipoproteins: Composition, Analysis, and Significance for Risk Screening and Anti-Risk Factors for Atherosclerosis
Secondary Dyslipoproteinemias
Clinical Chemistry As A Tool In Nutrition Research
Nutrients as Effectors of Enzyme Activity
Erythrocyte Enzymes as an Indicator for the Assessment of Vitamin and Oligoelement Supply
Practical Problems for the Clinical Chemist in the Metabolic Ward
Hospital Malnutrition and the Role of the Clinical Laboratory in the Assessment and Treatment of Nutritional Problems in the Hospital
Environment As A Source Of Metabolic Changes
Environmental Factors in Bladder Cancer in Egypt
Metabolic Bone Disease due to Environment
Findings in Biochemical Adaption to Chronical Malnutrition
Repercussion of Geohelminthiasis in Individual Development and Growth Rate
Recent Advances In The Clinical Biochemistry Of Cancer
A Perspective of Diagnostic Cancer Biochemistry with Special Reference to Enzymes
Timor Antigens and Other Tumor Markers: Their Effectiveness in Cancer Diagnosis
Biochemical Procedures and Cancer Monitoring
Steroid Hormone-Receptor Interactions And Target Cell Response
Sex-Hormone Receptors in Normal and Neoplastic Tissue of the Female Reproductive Tract
Cellular Aspects of Non-Steroidal Antiestrogen Action
Histochemical Identification Of Steroid Hormone Binding In Neoplasia
Quantitation of Fluorescent Steroid Ligand Binding by Photon Counting Techniques
Evaluation of Biochemical and Staining Properties of Direct and Indirect Histochemical Methods for Detection of Steroid Binding Proteins
Histochemistry of Steroid Receptors from a Biochemical Viewpoint
Critical Evaluation of Histochemical "Receptor" Assays
Estrogen Binding Sites in Sections of the Rat Uterus
Evaluating the Performance of Steroid Receptor Cytochemistry
Immunofluorescence Detection of Estrogen Receptors with Monoclonal Antibodies. Clinical Correlations of Steroid Binding by Histochenistry in Breast and Prostate Carcinoma
Comparison of Localisation of Estrogen receptors in Human Mammary Carcinomas using Anti-Receptor Antibodies and FITC-Conjugated BSA-Estradiol
The Use of Peroxidase-labelled Hormones in the Study of Steroid Binding in Breast Carcinomas
Histochemical Detection of Oestrogen Receptors: The Edinburgh Experience
Is Estrogen Receptor-Conjugate Interaction Relevant for the Histochemical Detection of Intracellular Estrogen- Binding?
Inborn Errors Of Metabolism - New Biochemical And Diagnostic Aspects
Introduction
Molecular Heterogeneity in Hyperphenylalaninemia and Phenylketonuria
Gas Chromatography Detection of Organic Acidemias in the General Clinical Chemistry Laboratory
Biochemical Basis of Inborn Errors of Purine Metabolism
Diagnostic Procedures in Lysosomal Enzymopathies
Hyperammonemia in Pediatrics: A Challenge to Clinical Chemists
Prenatal Diagnosis Of Genetic Disorders
Prenatal Diagnosis: Future Trends
Prenatal Diagnosis: Selected Problems and Quality Assurance
Prenatal Screening for Hexosaminidase Deficiencies and for Chromosomal Aberrations in Pregnancies at Risk
Prenatal Diagnosis of Neural Tube Defects
III. Biochemical Aspects
Clinical Biochemistry Of Connective Tissue
Biochemical Changes of Proteoglycans in Joint Disease
Functional Aspects of Proteoglycans in Tissues and Urine
Clinical Biochemistry of Collagen, Structure and Metabolism
Clinical Biochemistry of Inflammation and the Role of Connective Tissue
Connective Tissue Metabolism in Liver Diseases and its Relevance in Clinical-Chemical Diagnosis
Membrane Proteins
Molecular Features of the Cytoskeletal proteins of the Red Cell Membrane
An Oxidase System in the Plasma Membrane of Phagocytic Leucocytes - Function and Dysfunction
Membrane Glycoproteins of Leukaemic Cells
Sialyl transferase Total and Isoenzyme Activity in the Diagnosis of Cancer of the Colon
Novel Concept on Coupling Mechanism between Na,K-ATPase Antiport Activity and Normal as Malignant Cell Multiplication
Enzymes of Brush Border Membranes in Health and Disease
Clinical Chemistry Of Laboratory Animals
Animals and Drug Safety Evaluation: A Summary
Comparative Clinical Chemistry: An Overview in laboratory Animals
Clinical Chemistry in Toxicological Studies
IV. Methodological Aspects
Clinical Chemistry And Evaluation Of Drug Effect
Drug Effect in Clinical Chemistry - Information and Education
Analytical Interferences: Definition of Protocol
Effects of Drugs on Neutrophils
Application of Liver Slices Cultured in Vitro for Hepatotoxicity Studies of Anti-Rheunatic Drugs
Molecular Basis of Drug-Induced Nephropathies
Influence of beta-Blocking Agents on Plasma Lipid Concentrations and Lecithin:Cholesterol Acyltransferase (LCAT) Activity
Laboratory Tests and Drug Effects: Usefulness of a Data Bank
Data Banks on Drug Effects in Clinical Chemistry
Systems for Reporting Drug-Diagnostic Test Interactions to Clinicians
Clinical Toxicology
Drug Monitoring
The Role of the Toxicological Laboratory in Monitoring Drugs and Agricultural Poisons
Monitoring Therapeutic Drugs in Clinical Chemical Laboratories
Applications of Toxicological Analyses in the Diagnosis and Management of Poisoning
Analytical Methodology for Determining Drug Metabolite Profiles
Extraction Procedures in Drug Monitoring
Therapeutic Drug Monitoring
The Importance of Therapeutic Drug Monitoring
The Substrate-Labelled Fluorescent Immunoassay for Therapeutic Drug Monitoring
A New Automated Rate Immunochemistry System For Quantitation Of Specific Proteins, Rheumatoid Factor And Therapeutic Drugs
A New Automated Rate Immunochemistry system for the Quantitation of Specific Proteins, rheumatoid Factor Therapeutic Drugs
Application Of HPLC In Clinical Chemistry
Some Routine Applications of the High Performance Liquid Chromatography in Clinical Chemistry
Application of Derivatization Methods to Fluorimetric Detection
Liquid-Liquid Extraction Systems for the Isolation of Catecholamines from Serum and Urine for HPLC
High-Performance Liquid Chromatography as a Reference Method for the Determination of Uric Acid in Human Serum
Fluorescent High Performance Liquid Chromatography for the Determination of Oxosteroids in Biological Fluids Using Dansylhydrazine
The Separation of Bilirubin Species in Pathological Sera by HPLC
Analysis of Porphyrins from Human Materials by High Performance Liquid Chromatography
Determination of HbA1c by High Performance Liquid Chromatography
Application Of Luminescence In Clinical Chemistry
Fundamental Aspects of Luminescent Systems Used in Clinical Chemistry
Instrumentation for Luminescent Assays and the Standardization of Reagents
The Use of Bacterial Luminescence System for Analytical Applications
Demonstration of the Differential Measurement of Phagocyte Oxygenation Activities in One Half Microliter (0.5 μl). of Whole Blood
Direct Quantification of Phagocyte Activity in Whole Blood: A Chemilumigenic Probe Approach
Bioluminescent Determination of Creatine Kinase Activity in Serum
CK Screening for Duchenne Muscular Dystrophy
A Simplified Method for the Early Detection of Bacterial Growth in Blood Cultures Using Bioluminescent Measurement of ATP
Assay of Picarole Amounts of Pyrurvate Using a Bioluminescence Reagent Specific for NADH
Measurements of Glucose and Uric Acid in Biological Fluids by Chemilurainescence
Trace Elements
Intakes of Trace Elements
Sample preparations for analysis of trace metals in biological materials for electrothermal atomic absorption spectrophotometry and its detection limits
Harmonisation of Trace Metal Analysis in Clinical Biochemistry: A Case Study
Simultaneous Robinson Back Scatter Electron Microscopy and Energy Dispersive X-Ray Analysis for Localized Elemental Determination
Ion-Selective Electrodes
Use of Neutral Carrier Based Electrodes in Biomedical Systems
Ion-Selective Electrodes in Clinical Chemistry. Determination of Sodium and Potassium
Current Methods Urinalysis
Diagnostic Significance of Urinalysis
Standardized Examination of the Urinary Sediment with the MD-KOVA-System
Clinical Chemistry Analysis Using Multilayer Film Technology - Kodak Ektachem Products: Principles; Clinical Evaluation And New Developments
Principles of Multilayer Film Analysis: Colorimetric Analysis Slides
Principles of Multilayer Film Analysis: Potentiometric Analysis Slides
Principles of Kodak Multilayer Film Technology: Results of European Multi.-laboratory Evaluations
Kodak Ektachem 400 Analyzer
Laboratory Evaluation of the Kodak Ektachem 400 System
New Developments
Clinical Evaluation of the Kodak Ektachem 400 Analyzer
Perspectives Of Dry Reagent Chemistry
The Future for Small Solid-Phase Analytical Systems
The SERALYZER Solid-Phase Blood Chemistry System
New Methods And Applications Of Plasma Protein Analysis
Enzyme Immunoassays for Trace Protein Measurements
Methods and Clinical Significance of Prostatic Acid Phosphatase (PAP) Determined by RIA and ELISA
Diagnostic Significance of SP-1-Determinations
Separation Techniques Based On Antigen-Antibody Interaction
Agarose Isoelectric Focusing Followed by Immunoelectrophoresis: A Convenient Technique for the Study of High Molecular Weight Proteins
Affinity Chromatography. An Emerging Technique in the Clinical laboratory
Fluoroimmunoassay
Clinical Applications of Fluoroimmunoassay: An Evaluation in the Diagnosis of Early Prostate Adenocarcinoma
Fluorescence Immunoassay of Cortisol
Immunofluorescence
Introduction To The Topic And Evaluation Of New Reagents
Standardization In Immunofluorescence
Autoantibody Testing By Immunofluorescence: Methods, Indications And Interpretations
Automation Of Immunoassay Techniques
Nephelometry
Macro- And Micro-Spheres As Carriers In Immunoassays
The Adaption Of New Immunoassay Techniques To Automated Systems
Automation Of Immunoassay Techniques: Methods Using Luminescence
A Newly Developed Hormonology Assay: A Fully Enzymatic Cycling Technique, Application For Determination Of Estrogens And Androgens
Enzymatic Assay Of Estrogens: A Further Development In The Enzymatic Determination Of Androgens And A Report On A Two-Year Experiment In Obstetrics And Gynecology
V. Aspects of Laboratory Organization
Laboratory Planning And Organisation
General Aspects
A Clinician's View Of The Laboratory
Laboratory Planning And Organization
Laboratory Planning And Organization
Laboratory Planning And Organization
Integrating A Computerized Clinical Laboratory Information System Into A Global Hospital Information System
Laboratory Organization And Application Of Electronic Data Processing In A Central Laboratory
Work Flow As A Key To Laboratory Organization
A Model For A New Evaluation System In Clinical Laboratories
Clinical Chemistry In A 2000-Bed-Hospital
Establishment Of Department Of Clinical Chemistry, Inselspital, University Of Berne 1969
Planning And Organization Of The Central Laboratory, Department Of Clinical Chemistry And Pathobiodhemistry, Medical Faculty, Rheinisch-Westfälische Technische Hochschule (Kwth), Aachen
Planning Of A Laboratory And Organisation The Laboratories In The "New" MTU Berlin
Laboratory Planning And Organization - History Of The Central Laboratory Of The New University Hospital In Münster
Laboratory Organisation In The Country Hospital Of Salzburg
Planning Of The Laboratories Of The New Vienna University Hospital
Planning of the Clinical Chemistry Routine Laboratory of the Future University Clinic of Vienna
Planning of the Emergency Laboratory of the New University Hospital Vienna
Computers In Clinical Chemistry
Dynamic Communication of laboratory Computers with Clinical Chemical Analyzers
Organization and Installation of the Labor-Computer System MELAS 80 (GFC, Berlin)
EDP in a Hematological Laboratory
Medical Utilization Of Clinical Chemistry Information
Information Theory Applied to the Utilization of Laboratory Data
How Can Appropriate Transfer of laboratory Information be assured?
Concepts for the Standardization of Profile Testing
Quality Control, Experiences And New Aspects
Introductory Remarks
Calibration Materials and Control Materials
The Pole of Reference Methods in Clinical Chemistry
Models for Statistical Quality Control
Industrial Research and Development in the Field of Quality Assurance
Authors' Index
Subject Index

Citation preview

XI International Congress of Clinical Chemistry

XI International Congress of Clinical Chemistry Proceedings Vienna, Austria, August 3 0 - September 5,1981 Editors E. Kaiser • F. Gabi • M. M. Müller • P. M. Bayer

W DE

G Walter de Gruyter • Berlin • New York 1982

Editors Erich Kaiser, Univ.-Prof. Dr. med. Vorstand des Medizinisch-Chemischen Instituts der Universität Wien Währinger Straße 10 A-1090 Wien Franz Gabi, Univ.-Prof. Dr. med. Vorstand des Instituts für Klinische Chemie und Laboratoriumsdiagnostik der Universität Wien Lazarettgasse 14 A-1090 Wien Mathias M. Müller, Univ.-Doz. Dr. med. 2. Chirurgische Universitätsklinik, Klinische Biochemie Spitalgasse 23 A-1090 Wien Peter M. Bayer, Univ.-Doz. Dr. med. Leiter des Zentrallaboratoriums Krankenhaus der Stadt Wien-Wilhelminenspital Montleartstraße 37 A-1171 Wien

CIP-Kurztitelaufnähme der Deutschen Bibliothek International Congress on Clinical Chemistry : Proceedings / XI. [Eleventh] International Congress of Clinical chemistry : Vienna, Austria, August 30 - September 5,1981 / ed. E. Kaiser Berlin ; New York : de Gruyter, 1982. ISBN 3-11-008447-3 NE: Kaiser, Erich [Hrsg.]

Library of Congress Cataloging in Publication Data International Congress of Clinical Chemistry (11th : 1981: Vienna, Austria) Xlth International Congress of Clinical Chemistry, proceedings, Vienna, Austria, August 30-September 5, 1981. Bibliography: p. Includes index. 1. Chemistry, Clinical-Congresses. I. Kaiser, Erich, 1925RB40.16 1981 616.07'56 82-14873 ISBN 3-11-008447-3 Copyright © 1982 by Walter de Gruyter & Co., Berlin 30. Allrights reserved, including those of translation into foreign languages. No part of this book may be reproduced in any form - by photoprint, microfilm or any other means nor transmitted nor translated into a machine language written permission from the publisher. Printing: Karl Gerike, Berlin. - Binding: Dieter Mikolai, Berlin. Printed in Germany.

PREFACE The 11th International and the 4th European Congresses of Clinical Chemistry took place at the Hofburg Congress Centre in Vienna from 30 August to 5 September, 1981. The Organizing Committee had elaborated a joint programme for both Congresses. In setting up the programme, the Organizers intended to define the present status of Clinical Chemistry, to stress the fact that Clinical Chemistry is intimately connected to other fields of medicine and to demonstrate the importance of Clinical Chemistry for public health. The work of the Organizing Committee was supported by a Scientific Advisory Board and the Organizers and Editors take great pleasure in thanking the members of the Advisory Board once more. "Topics in Clinical Chemistry" comprises a complete record of 6 Plenary Lectures, as well as that of the presentations at 23 Symposia and 11 Workshops, thereby demonstrating the progress made in Clinical Chemistry during the last three years, following the International Congress of Clinical Chemistry in Mexico City in 1978. The Editors take great pleasure in thanking all those whose efforts have made possible the publication of the "Topics". The Editors are most grateful to Professor F. Korber (Berlin) who had already contributed so much to the publication of the Abstracts of Papers in the "Journal of Clinical Chemistry and Clinical Biochemistry" (de Gruyter " Berlin • New York).

The

Editors appreciate the most efficient and encouraging attitude of the staff of de Gruyter Publishers, and in particular, Dr. R. Weber, Mrs. J.F. Meier and Mrs. E. Glowka.

Acknowledge-

ment is also due to Mrs. E. Legenstein, from whom the Editors received most valuable help in arranging the manuscripts and preparing the subject index. The Editors of "Topics in Clinical Chemistry" hope that this

VI

publication, which provides an insight into the current state of Clinical Chemistry, will be accepted and appreciated by all those interested in this field. It is also hoped that it will stimulate further research and be of benefit to patients.

Vienna, April 1982

The Editors

C O N T E N T S I.

GENERAL ASPECTS

The Status of Clinical Chemistry M. Rubin Ethical Aspects of Clinical Chemistry E. BenGershom Future of Clinical Chemistry H. Keller TEACHING IN CLINICAL Moderator:

P.

CLINICAL

9 31

CHEMISTRY

Lous

Introduction P. Lous Clinical Chemistry in the Medical Curriculum A. Delbrück Teaching in Clinical Chemistry. The Medical Graduate P. Lous Technician and Technologist Training in Clinical Chemistry W.A. Wahba, F.R.C. Path II.

3

59 61 71 79

ASPECTS

Clinical Chemistry and Hemostasis E. Deutsch

93

CLINICAL CHEMISTRY IN INTENSIVE CARE Moderator:

H.

Benzer

Interdisciplinary Cooperation between Intensive Medicine and Clinical Chemistry H. Benzer, D. Schmid Biochemistry of the Cardiovascular System in Circulatory Shock D. W. Scheuch, H. Orlik Metabolism in Shock and Therapeutic Consequences W. Haider, H. Benzer, F. Coraim, W. I l i a s , T. Riss Biochemistry of the Lung in Shock - the role of Clinical Chemistry in the Treatment of Respiratory Failure P. von Wiehert Prognostic Value of Enzyme and Acute Phase Protein Determination in Skull Traumatology G. Ferard, C. Goester, A. Bourguignat, G. Jung, P. Metais

117 125 141

153 165

Vili HEALTH SCREENING Moderator:

G. Geyer

Clinical Value of Different Tests in Health Screening P. Fernet, M. Carton, P. Valdiguie Long-Term Individual Variation in the Concentration of Blood Constituents D. S. Young Contribution of Health-Testing Centers to Reference Values Determination J. Benny, G. Siest, G. Blin. J. Marty Risk Factors in Coronary Heart Disease G. Klose, W. Därr, H. Greten

173 185 199 211

LIPOPROTEINS Moderator:

G. M.

Kostner

The Determination of Apoproteins and their Diagnostic Value in Clinical Chemistry J. J. Albers Apolipoprotein Disorders G. Assmann, H.-J. Menzel High Density Lipoproteins: Composition, Analysis, and Significance for Risk Screening and Anti-Risk Factors for Atherosclerosis G.M. Kostner Secondary Dyslipoproteinemias D. Seidel

221 229

267 279

CLINICAL CHEMISTRY AS A TOOL IN NUTRITION RESEARCH Moderator:

H. Aebi

Nutrients as Effectors of Enzyme Activity H. Aebi, S.R. Wyss Erythrocyte Enzymes as an Indicator for the Assessment of Vitamin and Oligoelement Supply G. Brubaoher Practical Problems for the Clinical Chemist in the Metabolic Ward H. Berger Hospital Malnutrition and the Role of the Clinical Laboratory in the Assessment and Treatment of Nutritional Problems in the Hospital J.P. Piatt

299 311 3 23

335

IX

ENVIRONMENT AS A SOURCE OF METABOLIC CHANGES Moderator: P. N. Akinyanju Environmental Factors in Bladder Cancer in Egypt

345

Metabolic Bone Disease due to Environment

359

Findings in Biochemical Adaption to Chronical Malnutrition

36 7

Repercussion of Geohelminthiasis in Individual Development and Growth Rate

371

M.A.-M. Abul-Fadl J.L. Meiring

A. Pimentel,J.C. Flores,M.G. Flores, N.M. King

R. Romero-Cabello, J. Tay-Zavala, M. GutierrezQuiroz, A. Gonzales-Paredes, J.T. Sanchez-Vega

RECENT ADVANCES IN THE CLINICAL BIOCHEMISTRY OF CANCER Moderator: D. M. Goldberg A Perspective of Diagnostic Cancer Biochemistry with Special Reference to Enzymes

383

Timor Antigens and Other Tumor Markers: Their Effectiveness in Cancer Diagnosis

395

Biochemical Procedures and Cancer Monitoring

411

D.M. Goldberg

M.K. Schwartz

A.M. Neville, D.J.R. Laurence

STEROID HORMDNE-RECEPTOR INTERACTIONS AND TARGET CELL RESPONSE Moderator: J. L. Wittliff Sex-Hormone Receptors in Normal and Neoplastic Tissue of the Female Reproductive Tract

421

Cellular Aspects of Non-Steroidal Antiestrogen Action

433

O.A. Jänne, A. Kauppila, R. Vihko

R.I. Nicholson, P. Davies, P. Daniel, K. Griffiths

HISTOCHEMICAL IDENTIFICATION OF STEROID HORMONE BINDING IN NEOPLASIA Moderators:

L. P. Pertschuk and M. P. Böhm

Quantitation of Fluorescent Steroid Ligand Binding by Photon Counting Techniques

445

Evaluation of Biochemical and Staining Properties of Direct and Indirect Histochemical Methods for Detection of Steroid Binding Proteins

459

G.H. Barrows, T.C. Allen, J. Drew

M. Böhm, M. Binder, K. Czerwenka, R. Kolb, R. Jakesz, G. Reiner, J. Spona

X Histochemistry of Steroid Receptors from a Biochemical Viewpoint G.C. Chamness, W.L. MoGuire Critical Evaluation of Histochemical "Receptor" Assays G. Daxenbiohler, P. Weiß, E. Piegger Estrogen Binding Sites in Sections of the Rat Uterus S.H. Lee Evaluating the Performance of Steroid Receptor Cytochemistry I. Nenai, E. Marohetti Iimrunofluorescence Detection of Estrogen Receptors with Monoclonal Antibodies. Clinical Correlations of Steroid Binding by Histochenistry in Breast and Prostate Carcinoma L.P. Pertsohuk, K.B. Eisenberg, V.C. Leo, E.A. Rain ford, A.C. Carter, R.J. Maoohia Comparison of Localisation of Estrogen receptors in Human Mammary Carcinomas using Anti-Receptor Antibodies and FITC-Conjugated BSA-Estradiol S. Raam, H. Tamura, E. USemeth, D. O'Briain, J. Cohen The Use of Peroxidase-labelled Hormones in the Study of Steroid Binding in Breast Carcinomas R.A. Walker Histochemical Detection of Oestrogen Receptors: The Edinburgh Experience R.A. Hawkins, G.C. Penney Is Estrogen Receptor-Conjugate Interaction Relevant for the Histochemical Detection of Intracellular EstrogenBinding ? M. Binder, M. Böhm, K. Czerwenka

467 473 481 487

493

499

507 513

519

INBORN ERRRORS OF METABOLISM - NEW BIOCHEMICAL AND DIAGNOSTIC ASPECTS Moderator:

j. p. Colombo

Introduction J. P. Colombo Molecular Heterogeneity in Hyperphenylalaninemia and Phenylketonuria K. Bartholome Gas Chromatography Detection of Organic Acidemias in the General Clinical Chemistry Laboratory S.K. Wadman, M. Duron, J.P. Kamerling Biochemical Basis of Inborn Errors of Purine Metabolism M.M. Miiller Diagnostic Procedures in Lysosomal Enzymopathies U.N. Wiesmann, N. Hersohkowitz Hyperammonemia in Pediatrics: A Challenge to Clinical Chemists C. Baohmann

527 531 541 555 575 585

XI PRENATAL DIAGNOSIS OF GENETIC DISORDERS Moderator:

P. Hösli

Prenatal Diagnosis: Future Trends P. Hösli Prenatal Diagnosis: Selected Problems and Quality Assurance A. Milunski Prenatal Screening for Hexosaminidase Deficiencies and for Chromosomal Aberrations in Pregnancies at Risk B. Goldman, R. Chaki, R. Navon, S. Mashiah Prenatal Diagnosis of Neural Tube Defects D.J.H. Brook

595 605

613 623

III. BIOCHEMICAL ASPECTS CLINICAL BIOCHEMISTRY OF CONNECTIVE TISSUE Moderator:

H. Greiling

Biochemical Changes of Proteoglycans in Joint Disease H. Greiling, K. Kleesiek Functional Aspects of Proteoglycans in Tissues and Urine J.E. Scott Clinical Biochemistry of Collagen, Structure and Metabolism K. Kühn Clinical Biochemistry of Inflammation and the Role of Connective Tissue J. P. Borel Connective Tissue Metabolism in Liver Diseases and its Relevance in Clinical-Chemical Diagnosis A.M. Gressner

635 651 661 673 687

MEMBRANE PROTEINS Moderator:

R. J. Haschen

Molecular Features of the Cytoskeletal proteins of the Red Cell Membrane V.T. Marchesi, J.S. Morrow, D.W. Speicher, W.J. Knowles An Oxidase System in the Plasma Membrane of Phagocytic Leucocytes - Function and Dysfunction A. W. Segal Membrane Glycoproteins of Leukaemic Cells R.A. Newman, R. Sutherland, C. Schneider, M. Greaves

699

713 719

XII Sialyl transferase Total and Isoenzyme Activity in the Diagnosis of Cancer of the Colon J. Griffiths, S. Reynolds Novel Concept on Coupling Mechanism between Na,K-ATPase Antiport Activity and Normal as Malignant Cell Multiplication K.R.H. Repke Enzymes of Brush Border Membranes in Health and Disease R.J. Hasohen

729

737 751

CLINICAL CHEMISTRY OF LABORATORY ANIMALS Moderator:

D. F. Arnold

Animals and Drug Safety Evaluation: A Sunmary D.F. Arnold Comparative Clinical Chemistry: An Overview in laboratory Animals J. J. Kaneko Clinical Chemistry in Tcocicological Studies G. Frank

IV

763 767 775

METHODOLOGICAL ASPECTS CLINICAL CHEMISTRY AND EVALUATION OF DRUG EFFECT Moderator:

G. Siest

Drug Effect in Clinical Chemistry - Information and Education G. Siest Analytical Interferences: Definition of Protocol R. Galimany, A. Galli Effects of Drugs on Neutrophils J.F. Guelfi, J. P. Braun Application of Liver Slices Cultured in Vitro for Hepatotoxicity Studies of Anti-Rheunatic Drugs B. Stawiarska, E. Kuoharz, M. Drozdz Molecular Basis of Drug-Induced Nephropathies J. Rogulski Influence of beta-Blocking Agents on Plasma Lipid Concentrations and Lecithin:Cholesterol Acyltransferase (LCAT) Activity I. Schauer, U. Sahauer, K. Rühling, S. Bummel, K. Thielmann Laboratory Tests and Drug Effects: Usefulness of a Data Bank M.-M. Galteau, D. Hotter, J. Gösset, B. Le Perron, A. Floa'h, R. Gueguem, G. Siest

787 795 803 817 829

841

849

XIII Data Banks on Drug Effects in Clinical Chemistry N. Tvyding Systems for Reporting Drug-Diagnostic Test Interactions to Clinicians J. G. Salway, S. J. Hawkins Clinical Toxicology I. Sunshine

857 865 871

DRUG MONITORING Moderator:

G. Machata

The Role of the Toxicological Laboratory in Monitoring Drugs and Agricultural Poisons R.A.A. Maes, J.G. Leferink, G. de Groot Monitoring Therapeutic Drugs in Clinical Chemical Laboratories M. Oelleriah Applications of Toxicological Analyses in the Diagnosis and Management of Poisoning B. Widdop Analytical Methodoly for Determining Drug Metabolite Profiles R.A. de Zeeuu), B.F.H. Drenth, F. Ovevzet Extraction Procedures in Drug Monitoring W. Vyaudz lik

883 897 911 921 931

THERAPEUTIC DRUG MONITORING Moderator: J. Botero The Importance of Therapeutic Drug Monitoring V. Marks The Substrate-Labelled Fluorescent Iinnunoassay for Therapeutic Drug Monitoring J. Burd

943 945

A NEW AUTOMATED RATE IMMUNOCHEMISTRY SYSTEM FOR QUANTITATION OF SPECIFIC PROTEINS, RHEUMATOID FACTOR AND THERAPEUTIC DRUGS A New Automated Rate Imnunochemistry system for the Quantitation of Specific Proteins, rheumatoid Factor Therapeutic Drugs C. Deaton, C. Emery

947

APPLICATION OF HPLC IN CLINICAL CHEMISTRY Moderator: J.F.K. Huber Some Routine Applications of the High Performance Liquid Chromatography in Clinical Chemistry C.K. Lim

957

XIV Application of Derivatization Methods to Fluorimetric Detection

967

J.-P. Gamier, B. Bousquet, C. Dreux

Liquid-Liquid Extraction Systems for the Isolation of Catecholamines frcm Serum and Urine for HPLC Analysis

977

High-Performance Liquid Chromatography as a Reference Method for the Determination of Uric Acid in Human Serum

983

Fluorescent High Performance Liquid Chromatography for the Determination of Oxosteroids in Biological Fluids Using Dansylhydrazine

989

The Separation of Bilirubin Species in Pathological Sera by HPLC

995

F. Smedes, J.C. Kraak, H. Poppe

0. C. Ingebretsen, J. Borgen, M. Farstad

T, Kawasaki, M. Maeda, A. Tsuji

J.J. Lauf, M.E. Kaspar, R.T. Ambrose

Analysis of Porphyrins frcm Human Materials by High Performance Liquid Chromatography

1001

Determination of HbA1c by High Performance Liquid Chromatography

1007

H.D. Meyer, K. Jakob, W. Vogt

K. Okuda, T. Akai, K. Naka, K. Yamazaki, F. Kamiyama

APPLICATION OF LUMINESCENCE IN CLINICAL CHEMISTRY Moderator:

E. Sahram

Fundamental Aspects of Luminescent Systems Used in Clinical Chemistry

1013

E. Sahram

Instrumentation for Luminescent Assays and the Standardization of Reagents P.E. Stanley

1023

The Use of Bacterial Luminescence System for Analytical Applications S. Ulitzur

Demonstration of the Differential Measurement of Phagocyte Oxygenation Activities in One Half Microliter (0.5 |il). of Whole Blood

1041

R.C. Allen

Direct Quantification of Phagocyte Activity in Whole Blood: A Chemilumigenic Probe Approach

1043

R.C. Allen

Bioluminescent Determination of Creatine Kinase Activity in Serum

1059

CK Screening for Duchenne Muscular Dystrophy

1067

T. Lôvgren, V. Nantô G. Saheuerbrandt

XV A Simplified Method for the Early Detection of Bacterial Grwth in Blood Cultures Using Bioluminescent Measurement of ATP B. Beakers, E.R.M. Lang Assay of Picarole Amounts of Pyrurvate Using a Bioluminescence Reagent Specific for NADH P.E. Stanley Measurements of Glucose and Uric Acid in Biological Fluids by Chemilurainescence W.R. Seitz, T. Cole, J. Mullin

1073 1079 1083

TRACE ELEMENTS Moderator:

M. Rubin

Intakes of Trace Elements B.E. Clayton Sample Preparations for Analysis of Trace Metals in Biological Materials for Electrothermal Atomic Absorption Spectrophotometry and its Detection Limits S. Nomoto Harmonisation of Trace Metal Analysis in Clinical Biochemistry: A Case Study S.S. Brown 'Simultaneous Robinson Back Scatter Electron Microscopy and Energy Dispersive X-Ray Analysis for Localized Elemental Determination M. Rubin, R. Koritzer, C. Milton, E.J. Dwornik

1087

1097 1107

1125

ION-SELECTIVE ELECTRODES Moderator: K. Paschen Use of Neutral Carrier Based Electrodes in Biomedical Systems D. Ammann, P. Anker, H.-B. Jenny, P. Sohulthess, W. Simon Ion-Selective Electrodes in Clinical Chemistry. Determination of Sodiun and Potassium J.D. Kruse-Jarres, F.J. Schott, C. Trene lenburg

1137

1143

CURRENT METHODS URINALYSIS Moderators:

D. Kutter, M.H. Haber, R. Sieck

Diagnostic Significance of Urinalysis W. Graninger, R. Lenzhofer, S. Breyer, G. Stanek Standardized Examination of the Urinary Sediment with the MD-KOVA-System G. Fröhlich, R. Sieck

1149

1157

XVI CLINICAL CHEMISTRY ANALYSIS USING MULTILAYER FIIM TECHNOLOGY - KODAK EKTACHEM PRODUCTS: PRINCIPLES; CLINICAL EVALUATION AND NEW DEVELOPMENTS Moderator:

H. Wisser

Principles of Multilayer Film Analysis: Colorimetric Analysis Slides F.W. Hafner Principles of Multilayer Film Analysis: Potentiometrie Analysis Slides J. Paquet Principles of Kodak Multilayer Film Technology: Results of European Multi.-laboratory Evaluations R.B. Coolen Kodak Ektachem 400 Analyzer B.F. Blake, W.A. Chapman, G.A. Lloyd, G.W. Soherer, G.E. Tersteeg Laboratory Evaluation of the Kodak Ektachem 400 System B.B. Brody, N. Kubasik, H. Sine, M. Riootta New Developments C.F. Holtz Clinical Evaluation of the Kodak Ektachem 400 Analyzer D. Burnett

1161 1167 1173 1179

1185 1191 1197

PERSPECTIVES OF DRY REAGENT CHEMISTRY Moderator:

J. Botero

The Future for Small Solid-Phase Analytical Systems R.D. Falb The SERALYZER Solid-Phase Blood Chemistry System A. Zipp

1201 1203

NEW METHODS AND APPLICATIONS OF PLASMA PROTEIN ANALYSIS Moderator:

H. G. Schuiak

Enzyme Immunoassays for Trace Protein Measurements G. Grenner Methods and Clinical Significance of Prostatic Acid Phosphatase (PAP) Determined by RIA and ELISA W. Prellwitz, W. Ehrenthal, G. Jaaobi, D. Grimm. Diagnostic Significance of SP-1-Determinations G. Tatra

1205 1211 1219

XVII SEPARATION TECHNIQUES BASED ON ANTIGEN-ANTIBODY INTERACTION Moderator:

J. A. Lizana

Agarose Isoelectric Focusing Followed by Immunoelectrophoresis: A Convenient Technique for the Study of High Molecular Weight Proteins

1225

J. A. Lizana, I. Olsson

Affinity Chromatography. An Qnerging Technique in the Clinical laboratory E. Grund

1235

FLUOROIMMUNOASSAY Moderator:

M. Roth

Clinical Applications of Fluoroimmunoassay: An Evaluation in the Diagnosis of Early Prostate Adenocarcinoma J. Griffiths

Fluorescence Iimtunoassay of Cortisol

1241 1251

K. Miyai, F. Watanabe, Y. Kobayashi, N. Tsübota, M. Yahata

IMMUNOFLUORESCENCE Moderator:

W. Knapp

Introduction to the Topic and Evaluation of New Reagents W. Knapp, 0. Ma.jdia

1261

Standardization in Immunofluorescence

1267

Autoantibody Testing by Immunofluorescence: Methods, Indications and Interpretations

1275

E.J. Holborow, G.D. Johnson

H. Carmann

AUTOMATION OF IMMUNOASSAY TECHNIQUES Moderator:

T. P. Whitehead

Nephelometry I. Deverill

Macro- and Micro-Spheres as Carriers in Immunoassays

1283 1297

K.W. Talmadge, E.A. Fischer, H. Gallati, M. McLaren

The Adaption of New Iimtunoassay Techniques to Automated Systems

1307

Automation of Immunoassay Techniques: Methods Using Luminescence

1321

F.H. Fräser, J. A. Buege, S. Ho Chang, C.C. Leflar, W.K. Miller

L.J. Kricka

XVIII A NEWLY DEVELOPED BDRMONOIOGY ASSAY: A FULLY ENZYMATIC CYCLING TECHNIQUE, APPLICATION EOR DETERMINATION OF ESTROGENS AND ANDROGENS Moderator:

A. Crastes de Paulet

Enzymatic Assay of Estrogens: A Further Development in the Enzymatic Determination of Androgens and a Report on TWo-Year Experiment on Obstetrics and Gynecology

J.-C. Nicolas, Y. Chikhaoui, B. Desaomps, A. Crastes de Paulet, B. Uedon, P. Cristol, J. -L. Viala

V.

ASPECTS OF LABORATORY

1329

ORGANIZATION

LABORATORY PLANNING AND ORGANIZATION Moderators:

K. Bauer, W. Biirgi, E. Deutsah, F. Gabi, R. Haeckel, K. Steinbereithner

General Aspects Laboratory Planning and Organization - A Clinicians View of the Laboratory

1337

Laboratory Planning and Organization

1343

laboratory Planning and Organization

1349

A. Blmiberg W. Biirgi

L. Róka

laboratory Planning and Organization

1353

Integrating a Computerized Clinical laboratory Information System into a Global Hospital Information System

1357

D. Neumeier, M. Knedel

A.E. Rappoport

Laboratory Organization and Application of Electronic Data Processing in a Central Laboratory

1363

Work Flow as a Key to Laboratory Organization

1371

A. Roesler-Englhardt D. J. Vonderschmitt

A Model for a New Evaluation System in Clinical laboratories P.M. Bayer, W. Engelhardt, G. Fischer, M. Fischer, P. Nitsch

Clinical Chemistry in a 2000-Bed Hospital

R. Kattermann, H.O. Frey, D. Hannak, P. Haux

1375 1383

XIX Establishment of Department of Clinical Chemistry, Inselspital, University of B e m e 1969 J.P. Colombo Planning and Organization of the Central Laboratory, Department of Clinical Chemistry and Pathobiodhemistry, Medical Faculty, Rheinisch-Westfälische Technische Hochschule (KWTH), Aachen D. Siepen, U. Weiß Planning of a laboratory and Organization - the Laboratories in the "New" MTU Berlin F. Eßer Laboratory Planning and Organization - History of the Central Laboratory of the new University Hospital in Münster H. Sahriewer laboratory Organization in the Country Hospital of Salzburg H.-J. Gibitz

1389

1393 1397

1403 1409

Planning of the laboratories of the New Vienna University Hospital Planning of the Clinical Chemistry Routine Laboratory of the Future University Clinic of Vienna K. Bauer Planning of the Emergency Laboratory of the New University Hospital Vienna M.M. Müller

1415 1423

COMPUTERS IN CLINICAL CHEMISTRY Moderators:

A. E. Rappoport, W. Hohenwallner

Dynamic Corrmunication of laboratory Computers with Clinical Chemical Analyzers E. Jaroseh Organization and Installation of the Labor-Computer System MELAS 80 (GFC, Berlin) W. Hohenwallner, E. Wimmer, R. Sommer EDP in a Hematological Laboratory R. Niederer, R. Flury, H. Keller

1431 1437 1443

MEDICAL UTILIZATION OF CLINICAL CHEMISTRY INFORMATION Moderator:

M. Werner

Information Theory Applied to the Utilization of Laboratory Data J. Büttner How Can Appropriate Transfer of laboratory Information be assured? C.H. Altshuler

1449 1465

XX Concepts

for the Standardization of Profile Testing D.K. Oxley

1479

QUALITY CONTROL, EXPERIENCES AND NEW ASPECTS Moderator:

D, Stamm

Introductory Remarks D. Stamm Calibration Materials and Control Materials M. Hje 1m The Pole of Reference Methods in Clinical Chemistry D.D. Bayse Models for Statistical Quality Control D. Stamm Industrial Research and Development in the Field of Quality Assurance H. U. Bergmeyer

1487 1493 1503 1513 1541

I

General

Aspects

THE STATUS OF CLINICAL CHEMISTRY Martin Rubin, Ph.D. Georgetown University Medical Center, Washington, D.C. I thank you and I treasure this honor you have bestowed upon me. As I stood here a moment ago I thought how strange is the turn of fate which brings me here at this time, in this country and in this city where my wife, her sister and her brother were born, grew up attended its great University and indeed where some of the family still live. Perhaps now at the family gathering they will say Amerikaner ein wenig

"vielleicht ist dieser

österreichisch und ein bisserl Wiener-

isch." For this too I thank you! The Organizing Committee has asked me to discuss the status of clinical chemistry. How does one evaluate the status of such a strange and remarkable profession which functions one way or another in so many different societies and cultures; which demands of its members the consúmate skills and patience of a politician; the capability for organization and management of a captain of industry; the dedication and devotion of a teacher; the vision, persistence and genius of a scientist and in

addition requires that technology be inte-

grated with the biological and physical sciences for the needs of clinical medicine and in the interests of society and the patient? It has been wisely written that the measure of a man as it is for a nation, an organization or a profession is to be found in the answers to three fundamental questions. What home has been built? What family has been raised? What book has been written? What home have we built? In the three decades since the International Federation of Clinical Chemistry was founded we have encouraged the formation of forty-three national societies on all the inhabited continents on the globe and linked them into a

cohesive unit, as stated in the Statutes,

X I International C o n g r e s s of C l i n i c a l C h e m i s t r y © 1982 by W a l t e r d e G r u y t e r &. C o . , Berlin • N e w Y o r k

4

"to advance the science and practice of clinical chemistry and to enhance its services to health and medicine by professional liaison, cooperation, multual confidence and esteem engendered by the tiesof federation." We have confirmed our dedication to medicine in our relation to the World Health Organization and the Pan American Health Organization and our commitment to chemistry in our historic and productive collaboration with the International Union of Pure .and Applied Chemistry. But the ultimate and the most difficult professional issues are those of ethics and morality which are probed and studied by our membership in the Council for International Organizations of Medical Sciences. The structure we have built is solid and functional. Directed by the representatice Council and managed by its Executive Board, it has allowed room for growth and develop-, ent. The work of its standing committees and myriad of expert panels has proceeded well and in an orderly fashion. But a house of many rooms is not a home. That transition requires the communication and the interaction of its inhabitants. The newsletter, whose first edition appeared in 1969 and has been published continuously since provides a lucid account of significant national and international developments. By distribution through the national societies it reaches all their individual members. This Congress, the XI in the series which started in Amsterdam in 1954, offers a major opportunity in this setting of lovely ambience, for the meaningful person-toperson discussion which gives life and an extra dimension to the cold printed page. Yet international congresses such as this one can only be enjoyed by a relatively small proportion of our colleygues at a given time. Thus regional congresses in various parts of the world have added an important avenue of communication. They each have a character and flavor of their own. I well remember my shock at the First Latin American Congress of Clinical Chemistry in Mar del Plata, Argentina in 1968 when I appeared for a lecture at the appointed place and time to find hall completely empty. Only half an hour later

5 did the audience assemble and the proceedings begin. This was the custom, known, of course to all except the innocent Norte Americano! Nor will I forget the sight of well-lubricated clinical chemists, four congresses later in Bogota, Columbia jumping into the ring to match their agility against that of the reigning bull. The bull had no respect for our profession and tossed them about like matchsticks. The European Congresses, the South East Asian and Pacific Congresses, the African and Mediterranean Congresses and the Arab Congresses also now provide the opportunity to consider regional interests and relate them to broad international developments. If one adds to these the national meetings and the specialized symposia such as those on Pediatrics, Clinical Enzymology, Laboratory, Organization and Management, Quality Control, Prospective Biology, Computerization and Automation and many others, it is abundantly clear that we are talking to each other. What family have we raised? The progenitors of our profession were physicans, chemists, pharmacists and biologits. Despite the variety of their backgrounds they had the conviction that the measurement of body constitutents in health and disease could provide new insight to medicine for diagnosis and therapy. That they were correct in their vision and abundantly successful in their efforts is attested by the massive increase in the services provided by the clinical laboratory and the reliance placed upon the results by our colleagues in clinical medicine. In many parts of the world the clinical laboratory has become the single largest, and most expensive part of specialized health care services. In my countrly it has been estimated as more than twenty billion dollars a year. With this growth has come a vast expansion in the need for trained specialists. Depending upon the individual nature of their society they are physicians, chemists, pharmacists and biologists. However, in contrast to the individualists of the past, this generation has formal structured education in our universities and training in our laboratories. They are grounded in clinical medicine.

6

The are ready and able to utilize and advance immunologic and isotopic methods, enzymology and kinetics, complex instruments for optical and physical measurements, automation and computerization, and to translate our growing knowledge of molecular biology into clinically relevant procedures. They have learned the secrets of dealing with staff, the mysteries of finance, and probably most important-the pitfalls in dealing with administration and administrators. Thes are knowledgeable and dedicated. We have defined their requisite qualifications so well that we have begun to talk about transnational personnel interchange, as is

now being

discussed for the European community. But will this generation also feel that passionate need to explore the interfaces of their science where the fundamental truths are concealed? What booi have written? Largely through the vision and persistence of our President ,Dr. Dybkaer, we have achieved the standardizel use of a common language for quantities and units of measurement in a large part of the world. Our committees and expert panels have set basic guidelines for the performance of the instruments we use; for the labelling of diagnostic materials and reagents which cross national borders, for the control

of the precision and accuracy of

the results

from our laboratories, for the best currently available performance of test procedures, for the reference values of the constituents we measure in health and disease, for the analysis of drugs used in therapy, and one by one for the myriad of activities by which we function. These are essential steps assuring our capability to perform the tasks set by society and medicine. With so much achieved and so much undertaken in this relatively short period, what have we overlooked? We have forgotten to remember that what we do now stems from the basic research of the past. We must add in our turn to the fundamental store of knowledge. We must remind industry that the provision of magnificent tools and materials to cope with our ever increasing workload is not enough end indeed may be

7

counterproductive, since its very success sets a hard mold which makes change and improvement increasingly difficult. Having relieved us of much of the tedium of repetitive routine we need their support for unfettered research which ic the path to future progress. Our laboratories must again and for all of medicine become centers of excitement and challenge rather than efficient factories for the production of sterile information. We have forgotten to remember that although we communicate with each other in our many national journals throughout the world, a computer printout or a written report is not a substitute for essential personal dialogue and interaction with our colleagues in medicine. The time has come to again go out cloistered laboratories to join the patient care team. We have forgotten to remember that for the majority of the world's population the immediate overwhelming need is for food, shelter, clothing and the essentials of health care. They need simple, reliable, and inexpensive clinical laboratory supporting services which fit the priorities of their society and their constraints of manpower, money and transportation. And finally we need to remember that the measure of maturity is the capability of self examination, self criticism, and a concern and responsibility for ethics and morals. This Congress marks the first time that these subjects have been accorded a formal place in the total program. My professional generation has been remarkably fortunate. We have grown up in one of those golden transition periods when have known and been inspired by the great pioneers who built the foundation, forged the tools, and made the advances which translated isolated observations into a coherent body of knowledge. While our debt is to many individuals in many countries we cannot fail to mention Van Slyke, King, Stewart, Courtois, Sanz, Richterich, Tiselius, Svedberg, Eldjarn, Laurell, Lous, Astrup, Sigaard-Andersen, Werle and Somogyi. What we may have achieved we could not have done without them. We envy those who follow us their enhanced opportunities to

8

meet the challenges ahead, but we also rejoice in the conviction that they are trauned, educated and dedicated to work together in the service of science and society.

ETHICAL

ASPECTS

OF

CLINICAL

CHEMISTRY

Ezra BenGershdm Sophia Children's Hospital, Academic Hospital, Erasmus University Gordelweg 160, 3038 G E Rotterdam, Holland

Introduction "Computerized medicine" has become a catchword of Utopian hope on the one hand and of deep anxiety on the other. Nowadays various schools of "alternative medicine" as well as scientifically based medicine have to defend themselves in the very countries in which medical science has achieved its greatest triumphs .Has not modern medicine lost sight of humanity and of the human individual it purports to serve? While such issues are being discussed we cannot avoid scrutinizing our own speciality. Clinical chemistry, a fullygrown discipline of its own in health care! We must consider what sort of clinical chemistry we intend in what kind of health care! At a time when medicine is beset with ethical quandaries, and when the very aims and motives of medicine have to be re-examined, what are our ethical responsibilities? I am grateful to the organizing committee of this congress for having invited me to Vienna to talk on this subject in this forum, particularly in view of my former experiences in this city. My first journey to Vienna was made in 1943. I had at that time received an invitation - if you could call it so - to be deported to Auschwitz in order to be deprived there of human face and life, like the rest of my family. That "invitation" I did not accept and so for two months I roamed about in this city as an uninvited guest, disguised as a "Hitlerjunge", hunted by Nazis and other criminals, and always looking for a safe shelter for the next night. And today I may appear before you in Vienna, undisguised and talk about as humane a subject as ethics.

XI international Congress of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

10 The experience of inhumanity has sensitized me to issues of ethics, but this has not rendered me particularly competent on ethics. Nor does my experience in laboratory medicine necessarily guarantee an adequate understanding of interhuman responsibilities. This latter point is illustrated by a notable example. One of the first men who attempted to clarify the interhuman relationship of doctor and patient in terms of sociology, was Lawrence Henderson who is familiar to us from the Henderson-Hasselbalch equation. But in this case no useful equation resulted from the effort of the outstanding scientist. (1) In recent years literature on medical ethics has grown enormously. In addition to the articles scattered in many medical and legal periodicals, new journals devoted entirely to medical ethics have been founded, (2) and each year many pertinent books appear. Three years ago a comprehensive

Encyclopedia of Bioethios was published. (3). Thus there is no lack

of channels in which the ethical dilemmas of modern medicine are described and discussed with their wide ramifications, including the moral involvement of the patients, the public, lawyers, theologians, and of course the health professionals, doctors, nurses, physiotherapists. As for clinical chemists, to the best of my knowledge I have never seen them mentioned in the literature just referred to. A student who would draw his information on health care professions only from these sources, and for that matter from the current textbooks of history of modern medicine,

might doubt whether clinical chemists exist at all. If instead

he would read textbooks and journals of clinical chemistry he might conclude that the clinical chemists do exist but that they are never involved in ethical dilemmas of health care.

11 Medical Decisions and Ethical Dilemmas in Clinical Chemistry I have had many discussions with clinical chemists and with clinicians. All were agreed that the clinical chemist whose work affects the well-being of patients must practise a high standard of professional ethics, but they emphatically exempted him from co-responsibility in medical decisions and decisions pertaining to medical ethics. The underlying distinction can be illustrated by two examples. (1) A high standard of professional ethics is exemplified by a chemist who

is

so

concerned about the possible consequences for the patients

of erroneous lab-results that he or she maintains a very strict quality control, stricter than is required to cover him or her against legal liability. (For the sake of simplicity from now on I shall mention only the "he"-clinical chemist.) (2) The 2nd example: In a small provincial hospital, where a baby developed a severe haemorrhagic diathesis, laboratory tests pointed to disseminated intravascular coagulation. The paediatrician who had less insight in coagulation disorders, consulted the clinical chemist who had acquired considerable knowledge in this special field during his research study, for the treatment to be chosen. However the clinical chemist feels that he could give advice, but he knows from former cases that his advice will have the effect of a clinical decision and that would imply more responsibility than he could accept.

The two situations have different ethical dimensions. Conscientious quality control is part and parcel of practising clinical chemistry well. It is a matter of professional integrity and competence. This type of professional ethics has already been elaborated and emphasized in various codes of national associations of clinical chemists and in the I.F.C.C.recommendations for education and training for clinical chemistry. (4).

12 In contrast the second case represents a situation that demands some heart-searching. A medical decision must be made and the clinical chemist is called upon to share some of the responsibility for it. The medical decision may itself be complicated by a dilemma of medical ethics or the ethical dilemma may arise because the clinical chemist feels that he must fulfil an obligation which is outside his formal competence and legally defined function. It is the involvement of the clinical chemist in this type of decision on which I want to focus during most of my discussion. How many clinical chemists have to cope with such situations and what is the range of dilemmas in which they may find themselves? An opportunity to investigate this arose during the "First International Congress of Pediatric Laboratory Medicine" that was held in Jerusalem last year. Together with Prof. H. Galjaard of Rotterdam and our much respected, late colleague Dr. Noel Raine of Birmingham, we organized a workshop on ethical dilemmas in laboratory medicine. The congress delegates had been invited beforehand to submit cases from their own experience. Although the scope of the session was restricted to paediatric laboratory work, this first attempt at creating a forum for such topics was well appreciated and sufficient problems were presented and discussed to demonstrate their importance. Let us now consider the types and the scope of these dilemmas by looking at some representative examples: (I) The known chemistry of intermediary metabolism has attained such a degree of complexity that it may be difficult for clinicians to keep abreast of the progress in this field. The specialized clinical chemist may be more competent than the clinician in weighing up the risks of a decision e.g. pertaining to a patient with a novel inborn error of metabolism. If the clinician must rely heavily on the advice of the clinical chemist for the treatment of the patient, or for genetic counselling, can one still maintain that the responsibility of the chemist consists only of providing laboratory results and biochemical commentary?

13 In reality clinical chemists who have become consultants in such delicate decisions usually feel only too well the ethical responsibility they must share although the final ethical and, of course, the legal responsibility clearly rests with the clinician in charge of the patient. Knowing that his advice will be accepted increases the share of responsibility of the clinical chemist. The burden of responsibility may become even heavier if a controversy arises and the clinical chemist feels that he must question the diagnosis or treatment chosen by the physician. (II) ai-foetoprotein determination in amniotic fluid has become a routine procedure of prenatal diagnosis for saving mothers from the fate of giving birth to babies with severe neural tube defects. Yet its introduction has aroused considerable controversy. (5). Some feel that the test should be applied to a defined category of mothers at risk who request it and who must also accept the termination of the pregnancy if this is indicated. Others feel that it should be applied as a screening test to -all pregnant women. In the USA a proposal has been submitted to the Food and Drug Administration that test kits for ai-foetoprotein test should be marketed, which would permit commercial laboratories to screen for the disorder. (6). Some specialists would have reservations about performing the test in commercial laboratories devoid of expertise and facilities for supplementary investigations. (7). The question is, is it more appropriate for the clinical chemists to participate actively in such disputes, or should they simply carry out the tests and maintain an attitude of "ours is not to reason why"? Similar questions pertaining to the wide issue of population screening have been a subject of discussion in the Society for the Study of Inborn Errors of Metabolism. Noel Raine who had been very active and competent in this field, has clearly felt deep co-responsibility for the ethical implications of these decisions of public health policy. (8). Many other clinical chemists active in this field feel the same way. (III) Research aspects are inherent in many cases of patient care and

14 therefore within the range of activities of any clinical chemist. The ethical problems pertaining to experiments on human subjects are, however, most pronounced where clinical or basic research is done with the purpose of reaching generally valid diagnostic, therapeutic or other scientific conclusions. The clinical chemist who performs the laboratory tests may accept various degrees of participation: a) he may simply carry out the tests as scheduled in a project, that has been initiated by himself or by the physicians, trusting that the physicians have ascertained the legal and ethical admissibility. b) he may, as a member of the research-team, participate in first examining the scientific soundness of the project, which in itself is an ethical requirement. c) he may participate in examining the merits of the project in terms of risks and benefit from the point of view of social responsibility. d) he may be at odds with the prevailing utilitarian standards of "social responsibility" and examine the project by what he honours as higher ethical standards. Various questions arise: Should it be left to the personal inclination and initiative of the clinical chemist at which level he will take responsibility, or should he derive his special degree of co-responsibility from universally agreed guidelines for human experimentation and medical ethics? At present the Council of International Organizations of Medical Sciences (C.I.O.M.S;) is preparing such an agreement and significantly the I.F.C.C. will participate in the discussion of the proposals. But what should a clinical chemist do who feels co-responsibility on a higher level than the physicians in the research-team consider appropriate?

The Diversity of Clinical Chemists and their Ethical Problems A rather ambiguous picture has emerged from my inquiry. Some clinical chemists I spoke to were at pains to cope with their

15 dilemmas of medical ethics, but the majority said that they were rarely troubled by such dilemmas. This is somewhat less surprising if one considers the multi-disciplinary character of clinical chemistry and the variety of settings in which laboratories function and the different specialists who are in charge of them. They range from independent enterprises that deliver laboratory measurements on a commercial basis, to departments in academic hospitals that serve simultaneously patient care, clinical research and teaching. There are clinical chemists with a degree in

biochemistry, pharmacy or biology. In some countries only

medically trained persons may be appointed as heads of laboratories. In other countries, e.g. the United Kingdom, scientifically qualified biochemists carry out the same function as consultant chemical pathologists. The very diversity of function and qualification which makes it difficult to define the professional identity of the clinical chemist, could be a reason why his involvement in ethical problems may vary so widely - and viae versa. What is the difference between the ethical responsibilities of a laboratory-specialist with a degree in science

and

one with a medical

degree if both produce laboratory results and interpretative advice?

I

think that there is none - except in the case where the medically qualified person has at the same time a clinical relationship with the patient as the-physiaian-in-oharge of him. Otherwise both bear no more and no less than a consultant's responsibility. They are less directly and less frequently confronted with ethical dilemmas than the physicianin-charge of the patient. For our further discourse I prefer to assume that there is no essential difference between them. I shall use the term "clinical chemist" for both. More relevant is the distinction between the clinical chemist who acts as a consultant pathologist and one who runs a mail-order laboratory where only requisition slips and specimens are received and results turned out. Between these two extremes various degrees of health care involvement and co-responsibility occur which could symbolically be represented as in figure 1.

16 Increasing

We have considered so far three representative issues. There are more fields of clinical chemistry in which ethical problems show up. How manysophisticated laboratories are warranted in a developing country where elementary sanitation and health education are still poor? Or consider the following case from a highly industrialized country: A clinical chemist D.D. has doubts whether the lab-test X that is frequently requested by doctors as a part of biochemical profiling is clinically of much value. The low clinical significance of the test appears to escape the attention of the doctors in the flood of figures on the lab-report. Yet D.D. does nothing to discourage the requests for test X for several reasons: There is no better alternative test available as yet. Removal of the well-paid test X from the program would entail financial loss to himself and to the hospital and also reduce his chances of obtaining the funds for adding equipment to the laboratory which might prove useful for another sort of patient.

17

Clinical Chemistry as a Source of Dilemmas of Medical Ethics We cannot consider within one hour the many facets of the involvement of the clinical chemist in the increasing complexity and perplexities of medical ethics. But we can at least obtain a rough notion of the impact of our discipline by looking at it from a chronological point of view. Figure 2 illustrates the surge of discussions on new problems of medical ethics since the mid-fifties.

N u m b e r of p u b l i c a t i o n s related to medical ethics listed in Index M e d i c u s number

(value of 1981 b y extrapolation) Figure 2

From among the many causes that have contributed to this surge of ethical uncertainties two rather disparate causes that combined to perplex the health-professionals, lawyers, patients and public, deserve our special attention. One is the enormous multiplication of possibilities and the increase in power of medicine, engendered by scientific research and sophisticated technology. The other is the diversity of ethical convictions and standards in pluralistic societies, a diversity which manifests itself most in wealthy democratic countries where the rights of

18 the patient have become a topic of public dispute. It was in the decade following World War II that the modern laboratory of clinical chemistry became an integral part of the hospital. It is difficult to believe that the massive entry of clinical chemistry into health care coincided with the surge of ethical problems only by chance. I do not suggest that our profession is the most important contributor to the novel possibilities of medicine, but it is certainly a notable one. The questions of whether to resuscitate a severely handicapped dismature neonate and to prolong his pitiable life, and whether to undertake prenatal detection of hereditary metabolic diseases and pre-planned abortion, would not have become causes of controversy without the scientific achievements and the modern armament of biochemistry and clinical chemistry. As the specialist in a highly sophisticated discipline that plays a distinct role in medicine, the clinical chemist has reason to regard himself as more than an extended arm of the physician. But is the struggle of the laboratory scientist to be put on an equal footing with the medical specialist warranted if he does not partake in the ethical dilemmas and uncertainties of modern health care? To partake in them presupposes that he integrates his work in the clinic. That is in fact what more distinguished colleagues than I have been preaching ever since clinical chemists have become preoccupied with perfecting analytical methods and automating them. Patient-oriented work, ;patient-oriented research has become a leitmotiv of deliberations on the future of our profession. Granting then that the clinical chemist in the full sense of the term is seen working side by side with the physician in a clinical setting, is it feasible that all members of our profession could live up to this ideal? There are clinical chemists who run independent laboratories and provide a supra-regional assay service to physicians and hospitals that cannot do all the tests for themselves. I have not heard anyone questioning their right of existence. It thus appears that we cannot help making

19 distinctions between the degrees of clinical co-responsibility of the various types of clinical chemists as depicted in figure 1.

Vender Veiled in Anonymity In figure 1 there is also symbolized a grading of anonymity of the work. What does anonymity mean? It means first of all that there is no personal relationship between the laboratory-specialist and the patient. In this sense also the work of the consultant clinical chemist is with rare exceptions anonymous. But there is a significant difference: The consultant clinical chemist albeit unknown to the patient can get more involved in delicate decisions concerning that individual patient than the laboratory-specialist who deals only with bloodsamples and results. Does it then follow that the non-consultant laboratory-specialist bears no ethical responsibility except for promptly supplying reliable laboratory-results? Perhaps this would be true if the ethical problems of health care

issued

only

from the condition of the patient. In reality

modern health care is beset with crucial ethical problems that are inherent in its very structure. The fact that the medical establishment has become a target of exaggerated, partly unfair criticism, putting on it the whole blame for the "medicalization of life" (9), should not blind us to the very real trend towards dehumanization in organized health care. In the Encyclopedia of Bioethics Jan Howard described five interdependent processes that contribute to dehumanization in health care: 1. aggregation of services, 2. bureaucratization, 3. secularization of values, 4. professionalization of skills and 5. proliferation of technologies. (10). Who could deny that the clinical chemist has a share in these processes? "Professionalism is a humanizing force when it improves the quality of care, but it also has dehumanizing consequences". Jan Howard continues: "Dehumanization in health care is linked to dehumanization in society at large, because the institutions that deliver care are not closed systems.

20 .... Thus the same social forces that contribute to dehumanization in economic and political milieus lead to dehumanization in health care". The contribution of the laboratory-specialist to processes of dehumanization can easily be discounted as negligible. He only does what all other health-professionals and members of the whole technological society do, or at least acquiesce in. That is a second aspect of the anonymity.

Responsibility Hidden in Anonymity Some critical investigators of our technological age would take a different view. It is precisely because such contributions to dehumanization appear anonymous and negligible that these investigators are disturbed. The ethical issues engendered by the impact of technology on society have been dealt with by a number of noted philosophers, including Karl Marx, Henri Bergson, Karl Jaspers and Herbert Marcuse. The aspect of anonymity and of the loss of responsibility has been investigated in particular depth by Hans Jonas and Gunther Anders. Hans Jonas, professor of philosophy in New York, has become known in the medical world by his classic essays on "Medical Experiments on Human Subjects".(11). In his recent book

Das Prinzip der Verantuortung he

attempted to work out the ethical imperatives of modern technology in general. (12). Gunther Anders completed his major work "Die Antiquiertheit des Mensahen" one year ago. (13). The city of Vienna may pride herself on harbouring this great thinker. It would be futile to attempt to summarize within a few minutes his analysis of societies in East and West that let themselves be dominated by technology. Let me only hint at it. The impetus to Anders' investigation came from two historically crucial

21 events. One is denoted by the name "Auschwitz", the other by "Hiroshima and Nagasaki". Although Anders was well aware of the essential differences between these events they both raised within him the question of how it was possible that the vast numbers of engineers, officials, administrators, soldiers and workers who were involved in preparing and expediting each of these catastrophes, could return to their wives and children undisturbed by any awareness of their complicity and guilt? Anders was singularly well equipped for his investigation. He had acquired a thorough training as a philosopher and had subsequently worked as a simple factory-worker on the production-line. Anders did not limit his inquiry to the two major catastrophes that had manifested themselves with eruptive suddenness. He became no less alarmed by modern technological man who unwittingly and lightheartedly plays his part in eroding his own freedom and in inconspicuously destroying the humane element in the fabric of society. It appears that Anders and Jonas, independently, reached the conclusion that three factors were crucial : 1. Technology enables man to produce effects that transcend his capacity of imagination, by just pressing a push-button. 2. A temptation, fostered by adventurous

and commercial

to realize immediately and exploit every new possibility

interests, that has been

opened by science and technology. 3. A strict division of work according to professional specialities and functional assignments. Everybody is supposed to carry out isolated orders without ascertaining or questioning their ultimate goal.

Proposals for the Ethics of Clinical Chemistry What lesson do we learn from our philosophers? The attack on humanity can be launched without any devilish design by the blind dynamics of scientific research, technology and commerce which are ethically

22 uncontrolled. Our first moral duty is to develop an attitude of informed sensitivity to the humane implications of our decisions. We should always seek an understanding Of the totality of the goal for which our cooperation is requested, and not carry out orders in blind trust and blind compliance. Anders also considered the feasibility of a sort of general hippocratic oath to which, besides physicians, all engineers, specialists and administrators should subscribe whose decisions and activities imperceptibly

affect society and the private life of the

individual. (14). (This idea has not occurred only to the philosopher. Consider for instance the "Ethical Code in Information Processing" of the ACM. (15).) The observations of our philosophers on man in the maze of

technology

certainly deserve our earnest consideration and so do their conclusions. One may, however, doubt whether their rather general advice can be translated into practical ethical guidelines for clinical chemistry (and other professions). Has philosophical analysis ever stopped processes of dehumanization? Have hippocratic oaths and ethical codes any influence on human behaviour unless they are backed by effective legal enforcement? Clinical chemistry is but one, numerically not very impressive section, of the many specialities of health care. Will a revision of our ethical standards have any effect without a simultaneous revision of the total structure of health care? Can the structure of health care be improved without changing the field of social forces in which it functions? Whoever seeks to cure one branch of our highly complex industrial society is likely to encounter such frustrating, seemingly rhetorical questions. One might feel a desperate desire to "redeem" society by violent revolution, or do just nothing. I think that we should yield to neither of these temptations, and rather commit ourselves to piecemeal improvement: It is with such unassuming purposes in mind that I submit the following proposals.

23 A. Ethical Rules for Clinical Chemistry on tuo Levels (i) Practical ethical guidelines should be worked out on a national level to allow for the great variety of specialists and their status and function in different countries. (ii)The fundamental principles, however, on which the guidelines are to be based, should be agreed on in an Ethical Convention of the IFCC similar to the ethical conventions of other health care professions. B. Some theoretical knowledge and practical skill in ethical decisions should be imparted to the student and apprentice of clinical chemistry. C. Sensitivity on issues of medical ethics should be one of the requirements for the appointment of clinical chemists and their co-workers. D. National and international committees of ethics of clinical chemistry should be established to serve as forums for consultation and disciplinary councils. E. At least one of our international periodicals of clinical chemistry should open its pages to reports and discussions of ethical dilemmas in which laboratory-specialists have been involved, and abstracts of dilemmas of medical ethics of particular relevance to our profession, which have been discussed in detail in other publications. Sessions on ethical problems should also be included in congresses of clinical chemistry. Let me only add some brief remarks on the points that require adequate elaboration: An ethical convention of clinical chemistry that comprises both disciplinary and aspirational elements could serve a variety of purposes: a) To further the unification and cooperation of clinical chemists all over the world. b) To make us aware of the scope of our responsibilities.

24 c) To guide us in shaping the future of clinical chemistry. d) In countries where the status and responsibility of clinical chemists are defined by law, the ethical code and guidelines should clarify in which spirit the law ought to be implemented. (Conversely ethical rules should not be derived from law as some erroneously believe). If both law and the ethical rules are in need of revision, revision of the ethical rules should precede and guide the revision of the law. In countries where the clinical chemist has no recognized status, the code could provide a basis for the enactment of legal recognition. An ethical code can become important for court decisions even prior to leg§l recognition of the clinical chemist. e) The ethical code could give authoritative support to a clinical chemist who has moral reservations over certain laboratory-investigations. I have attempted to prepare a draft of an Ethical Convention of the IFCC. To explain it in detail requires more time than we have available at present. You may find it wanting. If it gives a stimulus to someone else to propose a better one I should feel myself rewarded. Ethical problems should be discussed not only in special sessions and special books on ethics but also in the context of practical issues of laboratory-medicine. This is admirably exemplified by Holton in the book "Laboratory Investigation of Fetal Disease". Dr. Holton discusses not only how prenatal diagnosis is done but includes in the same chapter pertinent ethical considerations. (16). Recruitment and promotion policy for clinical chemistry can have decisive influence on the professional morale in our laboratories. However a major problem is the criteria we use to select candidates. We have much to learn from the successes and failures of medical schools that have been grappling with similar problems, as witnessed by unending discussions in journals of medical education.

25 Limitations of Health Care Ethioe During recent years a certain disappointment with medical ethics has been discernable. The disappointment is in a large measure due to misunderstanding about the aims and limitations of ethical rules, committees and deliberations. (17). Ethics of health care is not a programme for the moral improvement of mankind. It cannot serve as an arbiter in ethical perplexities, nor can it relieve us from coping with situations where we plainly see no solution. It does not provide tactical advice for tackling conflicts in situations where ethical controversies intertwine with non-ethical, sometimes personal issues. Health care ethics does not spell out the "one true solution" to a given dilemma because unlike science there may be several equally good solutions. (18). The main role of health care ethics is to help us in clear reasoning about the disputed issues by analyzing the relevant principles and the implications of our decisions. It can sensitize the moral conscience of everyone who wants to be sensitized. It can warn us of ethical agnosticism and nihilism as well as of an arid legalistic view point. Many thousands of hours have been spent the world over discussing problems of medical ethics. I have just added one more discussion and made proposals for discussions of our professional ethics in the future. The world-wide discussions are not in vain. Their visible fruits are codes and practical guidelines of ethics and a certain skill in ethical reasoning that can be gained by study and experience. A rich literature has made the accumulated wisdom of the best ethicists accessible to us. I think that we clinical chemists should fully join the world-wide community of health professionals who take pains with the questions posed by health care ethics.

References

1. Henderson, L.J.: "Physician and Patient as a Social System". New Engl.J.Hed. 212, 819-823 (1935)

26 2. The most widely known are: The Journal of Medical Ethics of the Society for the Study of Ethics> Tavistock House North, Tavistock Square, London, U.K. and The Hastings Center Report, 360, Broadway, Hastings-on-Hudson, New York 10706, USA. 3. Encyclopedia of Bioethics, Warren T. Reich, ed., 4 volumes, The Free Press, New York - Collier Macmillan Publ., London (1978) 4. Rubin, M. and Lous, P.: Education and Training for Clinical Chemistry. IFCC Committee on Education and Training in Clinical Chemistry, MTPPress Ltd., Lancaster, U.K. (1977) 5. "Screening for Spina Bifida", Editorial, J.med.ethics 4, 3-4 (1978) See also: Harris,R. and Read,A.P.,Brit.Med.J. 282, 1416-1418 (1981) 6. Gina Bari Kolata: Hastings Center Report 10, nr. 6, 8-10 (1980) 7. Galjaard, H.: Genetic Metabolic Diseases, p. 535 ff. Elsevier/North-Holland Biomedical Press, Amsterdam, Netherlands (1980) 8. Raine, D.N.: Medico-Social Management of Inherited Metabolic Disease, MTP-Press, Lancaster, U.K. (1977) 9. Illich, I.: Limits to Medicinei Medical Nemesis - The Expropriation of Health. Marion Boyars Publ., London (1976) 10. Encyclopedia of Bioethics, p. 621-622 11. Jonas, H.: Philosophical Essays, From Ancient Creed to Technological Man. Prentice Hall, Inc., Englewood Cliffs, New Jersey (1974) 12. Jonas, H.: Das Prinzip Verantwortung, Versuch einer Ethik für die technologische Zivilisation, Insel-Verlag, Frankfurt/M (1979) 13. Anders, G.: Die Antiquiertheit des Menschen. 2 volumes. Über die Zerstörung des Lebens im Zeitalter der zweiten und dritten industriellen Revolution. Vlg. C.H. Beck, München (1980) 14. Anders, G.: Endzeit und Zeitenende, p. 136-167, C.H. Beck, München (1972) 15. Reprinted &s appendix in Horowitz, E. and Sahni, S.: Fundamentals of Data Structures. Pitman Publ., London (1981) 16. Holton, J.B.: "Prenatal Diagnosis in Metabolie Disease", in Laboratory Investigation of Fetal Disease, Barso, A.J. and Davis, J.A., ed., John Wright & Sons, Bristol, U.K. (1981) 17. Clouser, K.D.: New Engl.J.Med. 293, 384-387 (1975) 18. Perelman, Ch. (1976) "Désaccord et rationalité des décisions" in Droit, Morale et Philosophie", R. Pichon et R. Durand-Auzias, Paris (1976) pages 161-167.

Appendix

Draft of an INTERNATIONAL

ETHICAL

CONVENTION

OF CLINICAL

CHEMISTS

Acknowledgement-: The 2nd paragraph of the preamble in this draft contains a definition of the clinical chemist which has been adapted with the kind permission of the American Association for Clinical Chemistry, from her "Guide to Ethics Governing the Conduct of Clinical Chemists, 1975".

P R E A M B L E The clinical chemist is an ally of the physician and other members of the health care profession in the endeavour to safeguard and restore the health of people. The clinical chemist is a professional who is qualified by academic education and experience to apply chemical concepts, procedures and techniques to investigations that pertain to the understanding, diagnosis and therapy of disease and the assessment of health. The scope of his work is determined by the needs of patient-care and clinical research, by adequate mutual cooperation within the staff of the health care institution of which he is a member and by adequate manpower and technical facilities. The clinical chemist must constantly re-examine the quality of his work, his methods and facilities and keep them up-to-date in order to be of the

28 greatest possible benefit to the patient. Whereas there is an inescapable tendency towards superspecialization in the health-professions, entailing a certain estrangement between the various specialists, the clinical chemist has an important integrative function: He must both attune the laboratory to clinical needs and contribute to the enrichment and refinement of clinical insight by his speciality. As far as feasible the clinical chemist should provide advice to the clinician on the proper choice of laboratory investigations and in the interpretation of laboratory results. The establishment of clinical chemistry as a discipline of its own in health care has materialized in a critical phase of history. Humanity and human dignity are endangered by many forces, a widespread mood of cynicism and also by injudicious initiatives of scientists, technologists and administrators. This gives even greater importance to the duty of all involved in health care to be alert and sensitive to whatever might detract from the dignity of people, both as individuals and as members of the human community. The following declaration contains (i)

a8pirational elements to articulate professional ideals,

(ii) disciplinary elements expressing ethical obligations. The disciplinary means applicable to a member who violates these obligations, may vary from reproach to expulsion from the organization of clinical chemists.

D

E

C

L

A

R

A

T

I

O

N

1. The clinical chemist accepts his share of ethical responsibilities commensurate with the impact of his activities and his advice in the fields of patient-care, clinical research, medical education, planning of health care organizations and institutions and in preventive medicine - including genetic counselling and population surveys.

29

2. The clinical chemist accepts as binding the ethical principles that underly the Geneva-Convention of the World Medical Association (1949) as well as of its sequels adopted in Helsinki (1964) pertaining to clinical research, in Tokyo (1975) pertaining to humane treatment of prisoners and defenseless people, and in Hawaii (1977) pertaining to the practice of psychiatry. 3. The clinical chemist will do everything within his power to create in his laboratory a working climate of devotion to the patient and in keeping with the ideal that health care must be linked up with respect of the dignity of man, whether sick or healthy. His policy of acceptance of students, of appointments, employments and promotions will be directed accordingly and not solely aimed at proficiency and efficiency. 4. In cases of ethical perplexities arising in health care and research the clinical chemist will contribute his appropriate share to ethical deliberations and decisions. He will neither delegate his decisions of conscience, nor will he allow his ethical judgement to be influenced by the opinion of the majority alone. The clinical chemist will refuse to participate in unethical procedures. 5. In keeping with their foremost common goal to help the patient, the clinical chemist will closely cooperate with the physician in a spirit of individual responsibility and respectful fellowship.

FUTURE OF CLINICAL CHEMISTRY H.KELLER Institut fur Klinische Chemie und Hamatologie, St. Gallen, Switzerland Preliminary remarks The future development of Clinical Chemistry has been a permanent theme for many years at out national and international congresses. In Geneva and Copenhagen, in Toronto and Mexico City, trends and aspects of the future were discussed in plenary lectures and symposiums. Frightened by the constantly increasing numbers of tests and fascinated by the possibilities of automation and electronic data processing (EDP) the question has been raised about the further developments in methodology and the future role of Clinical Chemistry in the area of medical disciplines. Many technical problems were solved in the past decades and simultaneously a host of new problems were created requiring new reflections about the future of our own discipline. First, we can assume that clinical chemistry, as a collection of specific methods and as a special type of scientific considerations, will exist as long as a scientific medicine exists. It, is however, a completely different question, whether clinical chemistry will be an autonomous scientific discipline among other medical disciplines in the future, because the independence of our discipline has not yet been achieved, but at best been introduced. Therefore a prognosis is not adequate

if it only analyzes

the isolated subsystem "clinical Chemistry" without taking into account the total system i.e. the health care system. As an introduction to the following paper recent prognoses and trends will be described, which have evolved since our

X I International C o n g r e s s of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

32 congress in Mexico City. The focal point will be an effort to formulate common rules to strengthen the status of clinical chemistry as an independent medical discipline of the health care service. We are fully aware of the fact much of future developments can not be influenced by a single person or a group of individuals. The main component of the future, however. Which we can influence, is the growth of our discipline . Recent prognoses All reviewers agree that the instruments in our laboratories will be smaller and easier to operate due to progress in electronics and control theory. In the future, increasingly more dedicated systems will appear on the market, which makes possible selection of one or several parameters; we can expect also an increasing number of instrument systems for direct monitoring of diseased patients. Another important trend is the simplification of the analytic techniques. The final goal is, that an unquantified drop of blood will be sufficent to measure the most important parameters with acceptable reliability. It seems to me that the approach to this goal has not been very impressive since the Mexico meeting. In any case, many authors, as Mitchell , 2

Galen , Haeckel

3

4 5

and others ' predict an increase in bedside

analyses. Mitchell , especially, has pointed out the trend of devolution of clinical chemical laboratories. This involves not only the hospital laboratories, but also the large independent laboratories. It is believed

that an important

part of laboratory work will be done by non-qualified personal in medical offices and/or on wards. In addition non-destructive methods will become increasingly significant. It is certain that electrochemical g sensors, like ion-sensitive electrodes and enzyme electrodes

9

will be improved markedly in years to come.

33

Raman-spectroscopy^ and NMR measurements^ may also become more important in our laboratories. Fascinating possibilities 12

can be opened by the total internal-reflection technique of biological material, when existent technical difficulties are mastered. Analyses by gas-chromatography1®,HPLC14, flow 15 16 injection techniques and calorimetry , more or less reserved for scientific resarch laboratories today ^ , also can spread to routine laboratories. Concerning methodology in general, we can expect that immuno-assays of different types multiply further. Some working groups are studying methods for a direct measurement 18—22. of immunological reactions by physical/electronic sensors Success in this venture would be a significant technological revolution in our laboratories. It is difficult to assess today whether the development of 23

chromogenic substrates will changes the specific coagulation techniques, currently used, in the routine work of an enzymelaboratory . It is also difficult to forecast the development of the 24

nanoliter techniques . If a need for these methods appears, the existing methods could easily be adapted for routine use. Summarizing, we can cite Mitchell "... Major breakthroughs ... have been a feature of our immediate past, but there is no question that the end of the golden age of innovation is in sight... " This is not likely to be true in the area of electronic data processing. The growing requirements of the technical and commercial sectors will create new products in this field, 25 which will be of interest to clinical chemistry . Without doubt, the significance of computers will increase in our laboratories. This does not only concern the working process and management, but more directly, the instruments and analyzers, which will be equipped with terminals of high intelligence. EDP and telecommunication will prevail also in European

34

laboratories, because we can surmount the current bottleneck of data transfer only in this way. Clinical Chemistry as a scientific discipline and as a profession We can classify Clinical Chemistry in four sectors (Tab.1): 1. Development of instruments and methods, which are specific to the discipline. Multiple influences and stimulation are exerted by the allied aciences: physics, engineering, analytical chemistry, biochemistry etc. 2. Research in the field of theoretical and applied medicine. Besides independent clinical chemical research, cooperation with other medical disciplines is of great importance. Research fertilizes the development, and vice versa, new developments can open new aspects for research activity. 3. Application of clinical chemical methods and instruments. The findings of research and the typical instruments and methods are usedby varied persons: professionals in clinical chemistry, but more often by non-professionals, such as physicians and paramedical personal. 4. Communication is a permanent necessity for clinical chemistry as a participant in the health care system. In the interest of generating a bright future, new findings and new methods must be passed on. We think that an important component of "communication" is education and instruction of different groups of persons. Following this scheme we propose to discuss the different facetes of Clinical Chemistry expected in the next 10 years. The terms "developing and/or inventing" should be understood

35 as the realization of a new idea for a method, an instrument, or for both. In a laboratory of Clinical Chemistry, oriented either to research or for routine study, we can find currently only instruments produced by industry. The inventibn or production of instruments in the workshop of an institute or clinic does not play a significant role. As a result, much of our equipment has a high degree of perfection and sophistication. However we should bear in mind, that the most important and most typical instruments of Clinical Chemistry were developed by scientists outside of industry and who worked in medical or biochemical research or practice. As an example, I would like remind you of microliter-techniques, very typical of clinical chemistry: Maybe the prototype was the Pasteur pipette; Dr. Sahli, a well known physician from Berne has introduced microliter pipets for the determination of hemoglobin; this was followed by pipets of Van Slyke, Lang-Levy, Natelson, Sanz, Mattenheimer-Borner and finally Schnitger. This model, variously modified, and further developed dominates the pipette market today^ Also in the field of mechanisation and automation the outstanding ideas have been created outside industry. Without the work of Skeggs, for instance, we would miss autoanalyzers, and without Anderson rotation analyzers. May I recall to your memory the fact that the first selective multichannel analyzer was constructed according to the ideas of our

29

untimely deceased friend, Roland Richterich, of Berne The most original ideas are created out of the needs of research and practice and not by professional inventors of industry nor technical developing institutions. In contrast to past decades contact between industry and laboratories for research and practice has disappeared increasingly. This decrease has paralleled the growth of the companies, who to the same degree, have lost their ability to develop, acquire or exploit new ideas.

36

In the field of methodology the immense 'availability of readymade reagents and analyzers, operating as "black-boxes", is a dangerous sedative for many laboratories, who restrict themselves to those analytic methods, where a total supply by the industry exists. Indeed the methods newly developed by industry are tested by highly qualified reference laboratories, before they are brought on the market. This evaluation of a new analytic technique or method may be an academic function, but it is not an academic challenge. No fantasy or technical skills are required, but only meticulous observations and interpretation of data. These are not duties which can stimulate the enthusiasm of 30

our younger generation of highly qualified clinical chemists No wonder that technicians seem to be replacing more and more positions formerly held by academicians. The future of a scientific discipline is predetermined by the initiative of its outstanding younger scientists. In order to make Clinical Chemistry more attractive to the junior scientific generation, all laboratories, should, promote the methodological progress of our profession. They may aspire to this goal on their own, or in cooperation with industry, but at the perilof not being very successful, or not creating a new technique used world wilde. Most laboratories are able to work in this field, even though their monetary and personal capacities are limited. Certain improvements, adaptations, miniaturizations etc. can be accomplished without critical prerequisites. These activities represent intellectual and technical training for all coworkers of a laboratory. Their usefulness is not felt primarily in the routine activity; what is more important is the motivation and increased efficiency of the laboratory staff. The distinction between development on the one hand and research on the other is a classification, not a value judgement. Out of a basic research project, a patients oriented problem may result, and induce a search for a new

37 analytical technique. It is an idealistic postulate that in a single laboratory new methods and instruments can be developed, and that basic research can be performed simultaneously. 30 Astrup has said that around the industrialised units" ... other units full of life will appear: for research, for analyses combined with consultative functions, around important new analytical tools..." In the GDR and some other countries this concept is already realised at university

hospitals. In addition to the

chair of Clinical Chemistry, attached to the "Central-laboratory", there has been created a second chair for "PathoBiochemistry". The first is responsible for studies 31 and methodology, the second for research. Dr. Scheuch President of the Clinical Chemical Society of GDR has mentioned: "... research-problems in Clinical Chemistry are not restricted to the refinement of methods, but Clinical Chemistry can, with full right, lay claim to the study of the total area of pathological processes..." It remains undecided wether it will be advisable for the future to split our discipline into a research oriented and into routine work oriented branches. It is a categorical demand of each of us to work on appropriate research projects in addition to our daily duties. In a shortened and simplified form the research areas of Clinical Chemistry can be represented as following (Tab.2): 1. Is there a better application of known parameters (or combinations of these) to well-known clinical problems ? Examples are: multiple sclerosis vs the ratio of proteins in cerebrospinal fluid; myocardial infarction vs the AST/CK ratio. 2. Is there a better application of known parameters (or combinations of these) to newly formulated or newly discovered clinical problems ? Examples are: the determination of uric acid for the

38

diagnosis of ePH gestosis, and the acrodermatitis enterohepatica (a disease occuring as a concequence of artificial nutrition) vs Zn in serum. 3. Should new parameters (or tests) be devoloped for a well known clinical problem? Examples are: the tumor markers, and glycosilated hemaglobin determinations in diabetes. 4. Should new parameters (or tests) be developed for a new clinical problem ? Theoretically a new test for Legionnaire's disease. As you can see, here is an immense field of challenging tasks! Highly qualified research centers will handle basic research 32-34 on pathomechanisms and on etiological connections , but laboratories which limited possibilities in instrumentation personal or space may also investigate in a broad field: The description of the dependence of changes in commonly used parameters on the course of disease is missing in the literature in many instances. A simple example is presented as proof: In order to answer the question about the relationship between the level of the postprandial blood sugar and the probable risk of diabetes mellitus, we must return to 1961, a full 20 years ago, where we find a paper by Remein and Wilkerson which contains useful data. When doing so, however, we must accept that glucose was determined at that time by the Somogyi-Nelson method and that only 70 patients with diabetes included in the group of idseased patients. It can not be estimated how many diabetic patients and healthy persons have been examined for glucose since then by the present reference method (Hexokinase) but data obtained by this method are not available to the medical community. A second example should demonstrate, that basic questions

39

are unanswered although the solution to the problem has been possible for many years: Worldwide, the clinical laboratories use material from reresting patients. There exists only little and hardly 36 accessible literature on the influence of bed rest on clinical chemical parameters. We know from a few investigations that bed rest causes a considerable decrease in blood volume and simultaneously an increase of excretion of calcium-, ammonium-, sodium-, chloride-, and phosphate-ions. Although the underlying few measzrements are not representative, they are sufficient for the assuption that it is nonsense to compare data from immobilised patients with data from healthy and actively working people. It is absolutely necessary to elaborate new reference ranges for all clinical chemical parameters, on immobilised patients, as, for instance, from orthopedic wards i.e. stones of recumbency. Today, not having adequate, it is, in fact, impossible to interprete or to assess the data of many severely diseased patients. It is characteristic of the situation in our discipline that such an ingnorance exists in this field, particularly in a periode when data acquisition, storage and processing can be mastered easily by electronic machines. The exponential growth of our field has prevented such an evaluation of results. Strictly speaking, we have lost in this particular area an important basis of our scientific existence. The section "research" should also include the problems of standardisation. Astrup has pointed out, that "...standardisation ...has not favoured our medical approach...There is no doubt, however, that standardisation of the determination of hemoglobin, many decades ago, for instance, has led to results, which are comparable world-wide. By this means, as a fact of progress, it has fostered medical communication. What about the situation today? The extensive and careful work on standardisation of the IUPAC, IUB, IFCC and other has led to important improvments of our analytical methods. The

40

concept of international standardisation in the form of general instructions and use of reference methods for determination of enzyme activities is necessary, correct and realizable. In contrast to this universal approach, national societies are engaged in modifying the IFCC reference methods in such a way that they can be used more easely in the own national specific methodologies. This attempt costs time and money, and it is difficult to understand the benefit of having a Scandinavian, a French and a German method for determination of ATT, AST, LDH etc. Do not our experts know that the method used, is absolutely immaterial to clinicians ? The only point, important to the clinician, is the claim of accurate and precise values. Uniformity in the literature would facilitate the physicians understanding. A

possible international

comparison would save time and costs in patient-management. The national expert committees harmoniously seem to oppose these goals. The goals of standardisation for the coming years have been formulated nicely by Bergmeyer 37: 1. Satisfy the needs of clinical medicine 2. Obtain measurement of correct values 3. Full comparibility of values 4. Esonomy of time and money 5. Removal of hindrance to scientific progress 6. Absence of hindrance in the market-place. This concept seem to be acceptible without any limitation. Application The application of instruments and methods of clinical chemistry, based.on results of research and development takes plase on three levels: directly at the patient, near the patient, and in centralized laboratories. Monitoring of patients is restricted

today to such physi-

41

cal phenomena as respiration, blood gases, temperature, ECG, EEG, gas-metabolism on the newborn etc. We can expect in the coming years that physical monitoring will be extended to include

chemical monitoring, such as continuous monitoring of

electrolytes and certain substrates, (Glucose). Today this is done only in a few research cliniecs but could become used commonly. Urine volume and many urin-contents could be measured and registered today without new inventions. It is surprising that the industry does not yet offer such a system. Without doubt, the chemical monitoring of patients will produce many technical and scientific problems and the physician, confronted with these and not having special training or experience, will be helpless. The clinical chemists should take advantage of this possibility in hospitals. Thanks to their experience in solving technical problems and to their scientific education, they will be able to occupy a key position in such intensive care units in the future. We can imagine, that these techniques can grow to a special subdiscipline of Clinical Chemistry. Beside monitoring, patient-near-analyses will increase. This means that a slowly increasing number of analyses are performed on the ward or in the doctors office. Various efforts for simplification of analytical techniques will lead to certain success. The most important techniques in this are toose analyses performed on solid phases. The development in the field of electronic sensors also will contribute to this trend. Some parameters of serum and urin already can be determined with sufficiently correct results by this approach while additional parameters will follow, with increased precision and accuracy. When it becomes possible to perform many tests on an unquantified drop of blood (instead on a precisely quantified volume of serum), these techniques then will become enormously popular, even if their results are poor in comparison with "classic" techniques . Their advantages however, such as: no transport of material or data, short delay, individual analyses, and - last but not least - the fact that

42 qualified cing

personal will no longer be necessary, are convin-

arguments for many users. The consequences of this development

are inevitable: The

number of clinical chemistry laboratories, primarily performig routine tests, will decrease, The "survivors" will specialize in rare and difficult tests and techniques. The trend for centralisation will change to decentralisation. Adaption to these new conditions may extend over a period

of 5 to 10

years. Until then,the big central laboratory of the hospital will remain more or less unchanged. The decrease in number of analyses due to minitoring and satellite laboratories will be compensated by introduction of new parameters, especially determinations of drugs and endocrine compounds. 3 Haeckel has pointed out that in the hospital laboratories five system weaknesses should be eliminated as soon as possible: The transport of material and of documents,especially in continental European

laboratories, is frequently achieved by

(human) manpower. This should be

changed. It is a challenge

to industry to offer us flexible and economical mechanical transport systems.A second handicap is the limited availability of the parameters. We should

attempt to offer at least the 20 most

important tests during a 24 hour day. The so-called emergency samples should be analyzed by the same techniques as for routine cases. Batch processing of samples should be replaced by more continuous processing. Introduction of discrete analyzers is a step in the right direction. Short process times are realised for many tests. In contrary to the actual testing, the sample preparation steps, i.e. acceptance, registration, distribution and especially centrifugation, take a disproportionate amount of time. It is disappointing that there is no other method than centrifugation for the separation of cells from plasma. Another challenge to industry!

43

The transfer of data is accomplished in many different ways, i.e. telecommunication on one hand and hand-written messages on the other. We can hope that the progress of EDP will lead to better, faster and safer solutions. Many difficult problems arise from effort to interprete laboratory data. The establishment of reference ranges, corrected for sex and age, is useful but also problematic, because the laboratorian has no knowledge about the clinical problems. The same is true for all kands of validity-indices or interpretative reports. Communication/Teaching Clinical Chemistry subsists - similarly with all other disciplines of laboratory medicine - on the communication with many partners. The most important of whom ts the clinician. Together with him the laboratory forms a communication 39

cycle . This loop means a bidirectional exchange of information; it means permanent and mutual help, advice, and 40

stimulation . The clinical chemist should be able to communicate in a discipline-specific manner. In other words: The clinical chemist discusses different topics with a gynecologist, interested in endocrinology, then with the neurologist, who is a specialist in convulsive diseases. Therefore, the clinical chemist must take into consideration the special interests of his partner. From this it follows that we must study the discipline-specific literature, not only with respect to the analytical techniques, but also with respect to the diagnostic problems and possibilities. A second important group of partners is our colleagues from the other disciplines of laboratory medicine, namely pathology,histology, cytology and medical microbiology with all their different branches, especially immunology. Many institutions of these "classic" theoretical disciplines have realized that they need the methods of analytical biochemistry to further their scientific progress. As a result an

44

increasing number of chemists and biochemists now work in the leading institutes of these disciplines. It would be a catastrophe for the continuing development of Clinical Chemistry, if tis representatives do not search vor contact and cooperation with the classic disciplines, or if they do not find the clear defintions and demarcations of their own fields. Additional, important channels of communications are scientific publications and congresses. Clinical Chemistry is an

interdisciplinary medical

speciality, like radiology, nuclear-medicine, anesthesiology and others. Like, these clinical chemists tend to restrict their scientific contacts to their own peers. We prefer to publish in our own scientific journals, visit our own congresses and meetings, and hear our own colleagues there once again. Only exceptionally do we hear papers by clinicians at a conference of clinical chemists. Through such errors of judgment of our situation, we will become isolated and thus lose our most valuable contacts. In order to eliminate this defect, we should visit the conferences of clinical disciplines more frequently and we should have lectures regularly by clinicians at our congresses. Publications in scientific journals are very important exchanges of experience between experts, but we have to realize that our journals are read only by clinical chemists. They are unfit for communication between laboratory and clinic.This goal can only be served better by well-known general medical journals. We will examine this problem in greater detail below. A rather special kind of communication is involved in education. First of all, think of the young student, interested in clinical chemistry. He should be motivated to strive for an academic career in our discipline. Concerning this Astrup"^ has pointed out: "...a fatal effect of industrialisation has been the lack of interest of medical students and young doctors

45 in making a career in clinical chemistry. They prefer... to do (laboratory) research in association with clinical centers...". Many of our institutions like to outline plans for the education and training of a new generation of clinical 41 chemists , which is may be quite useful. However, what is much more important, are our plans for teaching Clinical Chemistry to medical students and young physicians.This should start in the medical schools where, in many countries, there are no examinations in Clinical Chemistry, where it is not an obligatory discipline, but where it is restricted to one course of only symbolic value. Medical students are trained in many disciplines, as if they were to become specialists in each

of these fields. In fact.

they later possess but minimal further contact with these other disciplines. Applications of laboratory medicine however are vital to nearly all practicing physicians which is exactly what thea have nor learned. It is not necessary that they learn all the technical details of our practise, but they should learn to assess the 42 advantages of Clinical Cehmistry, its goals, and its limits Therefore it should be one of the most important duties of our national and international societies to influence and change the education of medical students in this respect. Clinical Chemistry should be of the same importance in medical study as micro-biology,pharmacology or pathology. Many proposals have been made concerning the education of clinical chemists. It remains undecided whether "...a clinical "43 chemist must be, first of all, a good chemist... It could be argued that a clinical chemist, first of all, has to be a good scientist, a personality, fascinated by biomedical problems, who is willing to work lifelong on these problems. Ultimately, the progress of our discipline depends on outstanding personalities, not on educational programs. It has not been established thus far, that a specific type of education in Clinical Chemistry is also necessary for

46

the nursing staff. Regulations in this field are probably very different in different countries. However, our national and international expert panels also should become active in this field. A qualified nurse must possess specific knowledge about the effect and side-effect of drugs, and she should also be informed about the significance of laboratory data. We do not intend to disturbe the education of nurses, but they should have sufficient information of clinical chemistry, necessary for good patient managment. Future role of clinical chemistry as a medical discipline 44

In a book , well worth-reading "Education and Training for Clinical Chemistry" by Rubin and Lous, it is stated in the introduction, that Clinical Chemistry can be defined in a modern sense since only the past two decades. "Medical Chemistry" was introduced by leading chemists (not physicians) 45 of the last century . Modern Clinical Chemistry was developed out of an IUPAC section, not out of a medical discipline, in contrast to pathology and microbiology whose multiple branches had their roots exclusively in medicine. Their most important representatives have been physicians despite the fact that an increasing number of natural scientists are working in these specialities and share a large degree of the progress of these disciplines. Without doubt Clinical Chemistry is a very important tool for diagnosis, prognosis, and control of patient in many cases and shares equal importance with microbiology and pathology and their subdisciplines. Clinical Chemistry creates information by methods of various analytic disciplines. Clinical Chemistry therefore recruits scientists from different branches of medicine and natural sciences and this multidisciplinary effort is growing. The problems and questions however have come now and in the future from medicine exclusively. Methods of Clinical Chemistry are extremly important tools for research in nearly all medical disciplines, a fact which is

47

evident in any review of literature. As an example, it can be stated that in volume 1980/1 of the "LANCET", 167 clinical, research oriented, articles have been published. In 43 of these papers clinical chemical methods were dominant (Tab.3). In volume 302 (1980) of the "New England Journal of Medicine" 188 clinical research studies were published, of which 50 were based on Clinical Chemistry. These papers originated from nearly all branches of medicine i.e. internal medicine, surgery, pediatrics, gynecology, obstetrics etc. (Tab.4). In other words: All these disciplines are using Clinical Chemistry for research more frequently than any other interdisciplinary speciality, like radiology, pathology, nuclear-medicine or others. This fortunate fact stands in contrast to the following observation: Most papers are written by two or more authors, who may come from different institutions. For instance in the 43 "Lancet" articles 79 adresses are stated (Tab.5): 22 are medical, 7 pediatric, 5 are surgical clinics or departments. The term "Clinical Biochemistry" is used twice,"Chemical Pathology" once, "Medical Biochemistry" once and "Biochemical Medicine" once; Clinical Chemistry never. Fifty papers published in the New England Journal pf Medicine posses 80 adresses. The institutions are approximately of the same variety (Tab.6). A "Department of Biochemistry" is nominated 8 times, "Laboratory Medicine" multiple coded - 7 times, "Clinical Chemistry" only once. Is it ture, that clinical chemist do not publish in the "Lancet" or in the "New England Journal of Medicine" ? Or do some authors prefer to mention their hospital affiliations only, while omitting the exact of their own institute ? It many be that many Clinical Chemistry laboratories are units incorporated in the department of clinical pathology. The answer may be, that many laboratories are not independent from their clinic, but it is difficult to understand why authors quote their place of work as "Division of Allergy", "Cellbiology", "New-born Division", "Pulmonary Branch",

48

"Department of Neurobiology" and other imaginative names of only local significance, whereas the term "Clinical Chemistry" seems to be carefully avoided. Is it not one of the most important duties of our societies to advertise to the medical community the term "Clinical Chemistry" as an independent, interdisciplinary, scientific, profession ? Is it not an imperative obligation to all of our members to propagate the name of their institutions in publications in general medical journals, and not solely in our own journals ? Is it not necessary to find out new and better concepts in order to strengthen clinical chemists self-confidence and 46 self-comprehension

?

Summarizing considerations Certain aspects of modern medicine are causing increasing 47 criticism. It is not necessary to cite Ivan Illich in this connection, also less controversial authors emphasize the fact, that the myth of medicine should be 48 replaced by a more rational view. For instance A.L. Cochrane and recently T.H. 49 McKeown have called for more selfcriticism in medicine: How can we explain that certain surgical operations in the USA have a 10 times higher frequency than in Europe ? Or that in France the prescription of vitamine B12 is 100 times more frequent than in Great Britain ? Or that the chance of survival after a myocardial infarct is better at home, survival after a myocardial infarct is better at home, than in a cardiac intensive care unit ? For the moment, medicine is covered by a mysterious fog, thanks to the activities of the mass-media. This fact causes among a major part of our population expectations of success, which are inappropriately high. This is especially true for hospital medicine. What will happen, if the trend should change,when

49 politicians no longer call for a medicine in which "the biggest is the best", but strive for a simple and "return to nature "-medicine ? Without clairvoyance

it can be

expected, that, the so-

called "technical disciplines" primarily will be incriminated, as the main cause of all inappropriate expansion. And Clinical Chemistry will stand on the frontline of fire. Will we be forearmed ? Can we explain, why in central Europe the determination of blood sugar is performed u5 times more frequently than in England, although the morbidity and mortality of diabetes are not higher there ? Can we explain why the ratio Alcaline phosphatase/GGT in the USA is inverse to Europe ? Or why, in Japan, there are 10 times more electrophoretic studies' of proteins necessary per hospital patient than in Switzerland ? Are we able to explain, which part of our daily work is an absolute medical necessity ? In other words, what is truly useful for prevention, healing or alleviation of disease ? In the event that we do not yet have satisfying response to these questions, we have defined our duties for the next decade: 1.Establishment of the medical effectiveness of our current tests and elimination of all ineffective or questionably valuable procedures. 2.Development of new tests with a high degree of medical usefulness. 3.Promotion of basic research in cooperation with clinical research. 4.Promotion of education in Clinical Chemistry of physicians, medical students, technicians and nurses.

50

5.Strengthening the prestige of Clinical Chemistry as an independent, interdisciplinary, scientific (but not technical) medical discipline.

51

1. Mitchell F L Clinical Chemistry - Per ardua ad... ? Ann.Clin.Biochemistry 16, 289-298 (1979) 2. Galen R S Clinical Chemistry in the year 2000: exquisite technology, quality care. Med.Lab.Obs. 11, 70-83 (1979) 3. Haeckel R Future perspectives of automatization in clinical chemistry J.Clin.Chem.Clin.Biochem. 18, 455 - 459 (1980) 4. Alpert N L Laboratory instruments in the year 2000: stream lined - but much like today's Med.Lab.Obs. 11, 120-127 (1979) 5. Colombo J P Entwicklungstendenzen in der klinischen Chemie Chem.Rundschau, Nr. 22, Mai (1978) 6. Mitchell F L The trend towards devolution in clinical chemistry J.Automatic Chem. 1, 179-181 (1979) 7. Galen R S Laboratory medicine in the year 2000: an overview Med.Lab.Obs.il, 40-50 (1979) 8. Fricke G H Ion-selective electrodes Anal.Chem. 25, 259 R- 275 R (1980) 9. Fishman M M Enzymes in analytical chemistry Anal.Chem. 52, 185R-199R (1980) 10. Gardiner D J Raman spectrometry Anal.Chem.52, 96R-100R (1980) it. Wasson J R & Salinas J E Electron spin resonance Anal.Chem.52, 50R-53R (1980) 12. Watkins R W & Robertson C R A total internal reflection technique for the examination of protein adsorption J.Biomed.Mater.Res. 11, 915-938 (1977)

52

13. Burlingame A L, Baillie T A, Derrick P "J & Chizhor 0 S Mass spectrometry Anal.Chem.52, 214R-258R (1980) 14. Miller J B & Tucker E Use of HPLC for multicomponent serum analysis Internat.Lab. May/June 16-33 (1979) 15. Ranger C B Flow injection analysis Anal.Chem. 53, 83A-94A (1981) 16. Mosbach K & D anielsson B Thermal Bioanalyzers in flow streams Anal.Chem. 53, 83A-94A (1981) 17. Rehak N N & Young D S Perspective applications of calorimetry in the clinical laboratory Clin.Chem.24, 1414-1419 (1978) 18. Janata J An immunoelectrode J.Am.Chem.Soc. 97, 2914-2916 (1975) 19. D'Orazio P & Rechnitz G A Ion electrode measurements of complement and antibody levels using marker-loaded sheep red blood cell ghosts Anal.Chem.49, 2083-2086 (1977) 20. Weber S G & Purdy W C Homogeneous voltametric immunoassay: A preliminary study Analyt.Lett. 12, (Bl), 1-9 (1979) 21. Boitieux J L, Desmet G, & Thomas D An "antibody electrode", preliminary report on a new appraoch in enzyme immunoassay Clin.Chem.25, 318-321 (1979) 22. Rechnitz G A Bio-selective membrane electrodes J.Natl.Bur.Stand (U.S.) Spec.Publ. 519, 525-532 (1979) 23. Scully M F & Kakker V V Ed. Chromogenic peptide substrates Churchill Livingstone Edinburgh (1979) 24. Glick D Microchemical analytical techniques of potential clinical interest Clin.Chem. 23,1465-1471 (1977)

53 25. Kulikowski C A S Weiss S M Laboratory computers in the year 2000: call them intelligence amplifying systems Med.Lab.Obs.11, 150-163 (1979) 26. Natelson S Techniques of clinical chemistry, 3nd Ed. C C Thomas Publ. Springfield.111.1971 27. Mattenheimer H Micromethodes for the clinical and biochemical laboratory Ann Arbor Science Publ. Ann Arbor 1970 28. Trautschold J & Löffler G Mikrotechniken in H.U. Bergmeyer Ed. Methoden der enzymatischen Analyse 3. Aufl. Verlag Chemie Weinheim 1974 29. Richterich R & Colombo J B Klinische Chemie 4. Aufl. S. Karger Verlag Basel 1978 30. Astrup P Current trends in clinical chemistry Ann.Clin.Biochem.16, 338-342 (1979) 31. Scheuch D W Trend und Tendenzen der klinischen Biochemie und laboratoriumsdiagnostik in der DDR Mitt.Dtsche.Ges.f.Klin.Chemie 5, 136-141 (1979) 32. Moss D W Clinical enzymology - a perspective Enzyme 25, 2-12 (1980) 33. Shafrir E Research in the clinical biochemistry department - a reflection of its academic function Clin.Chem. 23, 1961-1963 (1977) 34. Groth T & De Verdier C H The potential use of biochemical physiological simulation models in clinical chemistry Scand.J.Clin.Lab.Invest 39, 103-110 (1979) 35. Remein G R & Wilkerson H L C The efficiency of screening tests for diabetes J.Chronic Dis. 13, 6-21 (1961)

54 36. Pace N, Kodama A M, Price D Grunbaum B W, Rahlman D F & Body composition changes in after 2-3 weeks of bed rest Life Science Space Research

C Newson B D men and women XIV, 269-274 (1976)

37. Bergmeyer H U Persönliche Mitteilung (1981) 38. Hobbie R K & Recce R L A computer reporting and interpretation system: acceptance and accuracy in Benson E S S Rubin M, Eds. Logic and economics of clinical laobratory use Elsevier North-Holland Inc. New York 19 78 39. Mc London W W Communications and data processing in Todd, Sanford, Davidsohn Ed. Clinical diagnosis and management by laboratory methods 16th Edit. W B Saunders Co. Philadelphia 1979 40. Daigneault R & Deschamps Y The biochemical service: the professional function of the clinical chemist in the hospital Clin.Chem. 24, 5-6 (1978) 41. Porter C J & Curnow D H Provisional recommendation (1979) on a scheme for a two year postgraduate course in clinical chemistry J.Clin.Chem.Biochem.18, 439-444 (1980) 42. Astrup P Clinical Chemistry as a medical discipline Scand.J.CIin.Lab.Invest 37, 1-5 (1977) 43. Trawick W G A model program for education and training of clinical chemists Clin.Chem. 25, T685-1690 (1979) 44. Rubin M & Lous P Eds. Education and training for clinical chemistry Publ.for IFCC by MTP Press, Lancaster 1977

45.Büttner H From chemistry of life to chemistry of disease the rise of clinical biochemistry 4th Ann.Meeting, Nat.Acad.Clin.Biochem. Boston, July 19-20, (1980) 46.Vonderschmitt D J Die identitätskrise der klinischen Chemie Swiss Med. 2, 33-39 (1980) 47.Illich J Medical Nemesis Calder & Boyars Ltd London 1975 48.Cochrane A L Effectiveness and efficiency random reflection on health services Nuffield Provincial Hospital Trust London 1972 4 9.McKeown Th. The role of medicine Basil Blackwell, Oxford 1979

56 PHYSICS

CLIN.MEDICINE

ENGINEERING

PATHOLOGY

ANALYT,CHEMIST.

PHYSIOLOGY

BIOCHEMISTRY

EPIDEMIOLOGY

COMPUTER

BIOMETRY

SCI.

DEVELOPMENT

RESEARCH CLINICAL CHEMISTRY

APPLICATION

COMMUNICATION

PROFESSIONALS

STUDENTS

NON-PROFESS.

POSTGRADUATES

Tab. 1

C l a s s i f i c a t i o n of clinical

OLD Parameter

chemistry

NEW Parameter

OLD

MS/§§^ Prot.ratio

D.M./Hb A l c

Problem

M 1 AST

MJ ciT ratio

Canc./TuMarker

NEW

EPH-G/Urac

Leg.Dis./Imm.Test

Problem

Acroder= / y matitis /

Tab. 2

R e s e a r c h areas of clinical

chemistry

Lancet 1980/1 (No 8158-8183) total Original Articles Pre1,Communie.

139

36

28

7

167

Tab. 3

Clin.Chem.essent.

43 = 25.7 %

R e s e a r c h a r t i c l e s of L a n c e t

1980/1

NEW ENGLAND JOURNAL OF MEDICINE 302 Total

Clin.Chem essent.

Original Articles

75

32

Special Articles

17

2

Medical Progress

17

Medical Intellig.

77

10

2

2

Basic Science

188

Tab. 4

50 = 26.6 %

R e s e a r c h a r t i c l e s of E n g l . J . M e d . 203

(1980)

Lancet 1980/1 Departement of Medicine Pediatry Surgery Gynecol. Pathol. other

22 7 5 3

Clin.Biochem. Chem,Pathol, Med.Biochem. Biochem.Med.

2 1 1 1

Clinical Chem.

6

33 5

74 Tab. 5

A d r e s s e s of T a b . 3

New England Journal of Medicine

302

Departement of

Mediciné

29 11

Pediatry Endocrinology 7 other 17

Biochemistry Laborat.Medicine

8 7

Clinical Chemistry

1

64 Tab. 6

A d r e s s e s of T a b . 4

16

TEACHING IN CLINICAL CHEMISTRY Introduction to symposium

Per Lous Dept. of Clinical Chemistry, Bispebjerg hospital, DK-2400 Copenhagen NV, Denmark

In the symposium this morning we shall discuss some of the problems of the large and complex theme: teaching in clinical chemistry. We all know that we are living in a changing world; developments in science, in technology, in economics and in social policy will, in ten years from now, present all of us with a situation, different from today, and with partly new problems. This is the aspect of change with time in our subject. Another important aspect is change with place. We must remember that problems of teaching in clinical chemistry - let us say in Switzerland and in Nepal - have common features, but the differences are very large, when we come to the concrete details of: whom to teach, what to teach and how to teach. Alone from what I have mentioned here you will be aware that today we can only throw light on some of the problems. We shall try to illustrate the theme by giving examples with a few details from our own experience. You will notice that we are coming from the group of senior teachers in our discipline. Ideally we should have had among the speakers today several young persons from different countries telling us, what they expect from the teaching in our discipline and how they want the teaching organised. It was not possible to arrange that type of symposium here at the international congress, but I hope that the discussion after the introductory speeches will bring forward some of the young generation.

XI international Congress of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

60

From the program you will know that we have divided the time allotted to us, according to the recipient groups of the teaching. One group is the non-medical scientists, aiming at a career in clinical chemistry; another group is the medical graduates, specialising in clinical chemistry or chemical pathology; the third group for which we consider the teaching of clinical chemistry is the medical students, that is the persons who in their future professional life will request clinical chemistry investigations and who shall interprete and employ the results. The teaching of technicians and technologists for clinical chemistry is an important problem, and clinical chemists are directly or indirectly involved. We feel it is appropriate to discuss this problem, too. For all these groups we have to consider the aim of the teaching, the content, the frame, the duration, the control of the teaching, licensure and/or certification etc., etc. And in our considerations we shall remember that the typical student receiving the teaching is 20 to 30 years old and he or she will work in clinical chemistry perhaps for the next 40 years. The content of our teaching, the emphasis on knowledge, on skills, on attitude, respectively, shall reflect what we envisage about the future, about the need of the next generation. To establish an adaptive mind and a base for continuing education in our students is very important. I think these few remarks are enough as an introduction for our theme this morning.

CLINICAL CHEMISTRY IN THE MEDICAL CURRICULUM

Axel Delbrück Medizinische Hochschule Hannover, Institut für Klinische Chemie II, Zentrum Laboratoriumsmedizin im Krankenhaus Oststadt D-3000 Hannover 5^/Germany

1.0 The goal of training Clinical chemistry, as a theoretical subject within clinical medicine, has developed over the past 150 years out of the encounter between analytical chemistry and medicine. As an independent discipline, clinical chemistry has been bound up with research, teaching and patient care for roughly 50 years. It makes an immense contribution towards obtaining information on metabolic and functional processes in both healthy and sick individuals, and is an integral component of medical diagnostics and therapy. To a greater or lesser degree, depending on his speciality, the doctor in a position of responsibility will, in his daily work, have to be able to handle the data produced by the methods of clinical chemistry. For this reason, clinical chemistry is a vital part of medical training. As a result of the fragmentation of medicine into a large number of subdisciplines, there are limitations on the extent to which the doctor can acquire the knowledge of clinical chemistry necessary for the exercise of his profession. We are thus confronted with the task of defining study objectives and course content for clinical chemistry which, within the framework of the medical curriculum, will provide the future doctor with the necessary equipment so that "at the time of registration, he has attained a level of knowledge, understanding and self-criticism which will allow him independently to take appropriate medical measures or to

X I International C o n g r e s s of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

62

decide responsibly when, and in what form, he must, in the interests of his patient, enlist the aid of experienced or specialist colleagues"(1). The present situation as regards the training of medical students in clinical chemistry varies greatly from country to country, reflecting not only the development and establishment of the subject in the individual medical faculties, but also differences in national legislation on the practising of the medical profession. A survey conducted by Dr. Lous on behalf of the IUPAC Section on Clinical Chemistry as to the state of teaching in clinical chemistry for medical students in 17 countries showed that teaching in this subject was given sometimes as a part of preclinical, sometimes of clinical studies ; that the subject matter was presented in some cases in the form of separate courses, while, in others, it was integrated into clinical lectures; and that the amount of time set aside for teaching this subject at the universities varied from 0 to 264- hours (2). Although, in West Germany, the guidelines for teaching clinical chemistry as part of the medical curriculum are laid down in state licensing regulations, the instruction actually given has, up until recently, been no less heterogeneous. In order to achieve a more homogeneous medical training in Germany,and at the same time to raise the level of knowledge in this subject,recommendations on the teaching of clinical chemistry were drawn up by a working party of the German Society of Clinical Chemistry,which included representatives of all the faculties (3).It emerged that, at the present stage of development of our subject, it is quite possible to achieve a consensus on study objectives and subject matter. Such a consensus is not only beneficial for the training of individual students,but also strengthens the position of the subject within the faculty,and thus improves the conditions under which teaching is carried out.Since the goal of medical training is to equip doctors to provide qualified treatment for sick people,the above statement can probably be

63

extended in principle to all other countries and faculties. The external constraints will vary in places where the structure of the health service and national differences in the organisation of medical care place different demands on the ability of the doctor to perform practical analytic work. If he is obliged or permitted to maintain his own clinical chemistry laboratory as part of his medical practice,then he must acquire skills in clinical chemistry during his studies.If these activities are the preserve of other professional groups,then his training merely needs to equip him with sufficient knowledge of clinical chemistry so that he can incorporate the subject's methods of investigation into his diagnostic and therapeutic strategies. In the following,"knowledge" of clinical chemistry is conceived as the (cognitive) ability to apply appropriately the investigative techniques of the subject, while "skills" refers to the (psychomotor) ability to perform independently biochemical analyses. 2.0 Study objectives The imparting of knowledge and skills in clinical chemistry takes its orientation from the training goal quoted above and is based on the following study objectives: 2.1 Knowledge of: pathobiochemical and pathophysiological disease mechanisms,relevant application of the investigative techniques of clinical chemistry,selection of parameters, indications for laboratory investigations,selection and collection of test specimens , analytical principles, quality control,analytical evaluation,medical evaluation, indications for further laboratory investigations in diagnosis and treatment monitoring, the use of clinical chemistry in differential diagnosis. 2.2 Skills In the independent execution

of simple analytical techniques

64

for rapid and emergency diagnosis, in the use of standard analytical techniques of clinical chemistry. The acquisition of this knowledge and these skills should enable the qualified doctor to recognise the pathobiochemical and pathophysiological processes determining the selection of biochemical parameters,to relate these mechanisms to medical questions,and from both aspects to arrive at the indications for laboratory investigations.Armed with the above knowledge and skills,the doctor should be able to interpret laboratory findings for typical cases and courses of diseases,to recognise the indications for extending the investigative spectrum, and to determine the criteria for monitoring treatment. The skills acquired in clinical chemistry should enable the medical student,at the end of his training,independently to carry out urgent biochemical investigations and to instruct medical technicians on the principles and execution of basic biochemical tests. 3.0 Prerequisites In general,teaching in clinical chemistry builds on the foundations of preclinical instruction in chemistry,biochemistry and physiology,and may,under favourable conditions, be able to draw on a grounding in the standard procedures of chemical and biochemical analysis. A further prerequisite for a succesful education in clinical chemistry is a familiarity with pathophysiology and basic clinical medicine,these subjects generally being taught in the first year of clinical training. If these prerequisites for the teaching of clinical chemistry are not,or only partly,met,then it will be necessary to include the relevant material in the course of clinical chemistry. 4.0 Subject matter In order that the defined study objectives should be achieved, a syllabus must be assembled which encompasses the required knowledge and skills,and which must take into account the extent to which the above prerequisites are actually met. Each

65

item on the syllabus can be assigned to one of the two categories, knowledge or skills. In view of the varied fields of application for laboratory medicine,the teaching of skills will occupy less space on the curriculum than the imparting of knowledge,and should be limited to basic analytical principles. The training of skills should take up roughly 30 - 40% of the course,while the teaching of theoretical knowledge comprises some 60 - 70% of the total curriculum. 4.1 Knowledge Presentation of biochemical and pathobiochemical/pathophysiological relationships for simple disease entities,as a basis for the selection of biochemical parameters, principles and techniques of patient preparation for laboratory investigat i o n s , ^ particular for function tests, collection,preservation and transport of test specimens, analytical principles of simple biochemical assays, assessment of analytical methods, control of analytical results, factors influencing biochemical parameters, factors interfering with biochemical test procedures, information content of biochemical parameters, reference ranges as aids to the interpretation of analytical results, principles and techniques for the medical evaluation of analytical results, recognition of result patterns, longitudinal testing and following the course of diseases, treatment monitoring, diagnostic value of laboratory tests, application of biochemical screening procedures, illustrative presentation of

pathological mechanisms in disorders of or-

gans, for example kidney,gastrointestinal tract,or of metabolic functions, pathological biochemistry and pathogenesis of special diseases. 4.2 Skills The catalogue of skills to be taught and practised will be based on the level of analytic and technical development,and is bound by the ordinances governing the practice of medicine in the individual countries. In general, this catalogue will

66

include those analytic procedures,chiefly qualitative tests, which can be performed by the doctor himself in his practice, in the hospital admissions ward or the intensive care unit, when information is needed quickly.They include,for example: collection of test samples, inspection of test samples, qualitative tests for substances in urine and stools, microscopic examination of urine sediment, pregnancy testing, quantitative determination of glucose in blood and urine, erythrocyte sedimentation rate»determination of haematocrit and heamoglobin, counting and differentiation of white blood cells, bleeding time, the carrying out of paradigmatic procedures for the following: clotting analysis, chemical assays determination of enzyme activities by the two-point procedure and kinetic measurement of enzyme activities,enzymatic substance determinations. 5.0 Didactic considerations The basic right of freedom of research and doctrine leaves university teachers with a great deal of discretion in choosing the form their instruction is to take. The only limitations on this discretion are set by the prescribed course objectives, the attainment of which should be the guiding principle of every teacher.The teaching of clinical chemistry must be orientated towards the clinical problems with which the future doctor will be confronted as the starting point for the use of skills and knowledge in clinical chemistry. It is for this reason that instruction in clincal chemistry must be given during the clinical phase of training,when the student is becoming, or has become, aquainted with the essential aspects of clinical medicine. Lectures given during preclinical studies must, of necessity, remain restricted to the imparting of analytical techniques and basic biochemical knowledge. The didactic orientation of teaching in clinical chemistry towards solving clinical problems with the aid of the investigative procedures of clinical chemistry will, at the same time, strengthen the .motivation of the student to come to grips with the subject matter,since he will see himself being brought

67

closer to the attainment of his professional goal,namely helping sick people with all the means at his disposal. The paradigmatic presentation of the subject matter,orientated towards clinical questions posed by typical disease entities, suggest a system of dealing with course topics which corresponds,^ outline,to the following: introductory presentation of the case history and symptomatology) evaluation of clinical data, formulation of a working hypothesis (provisional diagnosis), selection of biochemical parameters, indication for laboratory investigations and formulation of the investigation request to the clinical laboratory. This is followed by the practical section with: selection of suitable methods, methodic principles,sources of error,and diagnostic value of the methods employed, carrying out of the analyses, analytical evaluation of the results, quality control in the medical laboratory. The data thus obtained by biochemical analysis are then used to produce a result pattern,with significance being assessed by: plausibility control, medical assessment,including differential diagnosis, indication for further tests, concluding answer to the initial working hypothesis,that is,its acceptance or rejection. The system here presented for imparting knowledge and skills should facilitate the task of the student in making a critical differential diagnosis,in constructing the system of biochemical investigations on the foundations of pathobiochemical principles,and in locating individual results in the result pattern and in the course of the disease. On the one hand,the system of knowledge specific to the subject requires teaching carried out in special clinical chemistry classes.On the other hand,the tight interlocking of biochemical investigative procedures with clinical work makes the

68

offering of clinically-orientated, courses indispensable. It is advisable that basic instruction in clinical chemistry be carried out at the beginning of the clinical part ot training,with teaching being given by a specialist in the subject.This offers the best way of teaching,in a balanced relationship and highlighting clinical applications, matters specific to the subject and the system and methods conditioned by these matters,particulary in the area of biochemical analysis.For teaching the theory of clinical chemistry, lectures,seminars and courses suggest themselves,while the analytical techniques of clinical chemistry can only be learnt through practicals.This means that not only lecture theatres but also well-equipped laboratories must be available.The two forms of teaching cannot be separated,since they are interrelated and complementary.The most useful approach is to offer a course which includes both practicals and seminars dealing with the theory of the subject. Towards the end of clinical studies,the application of laboratory investigations comes to occupy a more prominent place in clinical training and should,at this time,be taught as part of the general clinical curriculum.In particular,the advanced student will have to learn for himself at the bedside to recognise the pathological mechanisms of disease,to use parameters which are disease-specific and important in differential diagnosis for the solving of clinical problems,and to take decisions on the performance of further biochemical investigations for diagnosis and the monitoring of treatment in individual cases.Interdisciplinary seminars,perhaps in the form of a clinical pathology conference,should be used to deepen the knowledge gained by the student in bedside work. 6.0 External constraints The carrying out of these courses and the attainment of the objectives set depend upon certain conditions being fulfilled

69

regarding the number and quality of the lectures,the availability of technical staff for teaching,sufficient and suitable classrooms,and equipment for these rooms which is appropriate to the state of development of the subject. An indispensable requirement is that teaching in clinical chemistry, even for medical students, should be given by qualified clinical chemists,in general by the faculty professor.For the teaching of advanced students,courses run jointly by clinicians, clinical chemists and possibly other clinical specialists, have proved to be very successful. It is the task of clinical chemists in the individual countries and faculties to urge that the prerequisites for qualified teaching in the subject within the framework of the medical curriculum should be created, so that clinical chemistry, with its possibilities for helping the sick, but also with its associated enormous economic burdens, can measure up to the responsibility placed upon it.

Heferences 1.

2.

3.

Empfehlungen zu Aufgaben,Organisation und Ausbau der medizinischen Forschungs- und Ausbildungsstätten (verabschiedet 9.7.1976)»herausgegeben vom Wissenschaftsrat, Marienburgerstr. 8,5000 Köln 51, S.21/22 IUPAC Section on Clinical Chemistry: Teaching of clinical chemistry in the medical curriculum, result of a pilot-questionaire,summer 1978 (summing up 780926) Weitere siehe bei: Das Fach Klinische Chemie in der ärztlichen Ausbildung: Empfehlungen der Deutschen Gesellschaft für Klinische Chemie zur Lehre Deutsche Gesellschaft für Klinische Chemie e.V. Mitteilungen, Heft 6, 254—268 (1980)

TEACHING IN CLINICAL CHEMISTRY The medical graduate

Per Lous Dept. of Clinical Chemistry, Bispebjerg hospital, DK-2400 Copenhagen NV, Denmark

Clinical chemistry is a domain of practical activity, it is a domain of knowledge and teaching, and it is a domain of scientific research. Our subject includes parts of medicine, of biochemistry, of analytical chemistry and of organisation. In discussing programmes and recommendations about education and training for clinical chemistry we shall recognize this position of our subject as an interfacuity discipline. The International Federation of Clinical Chemistry has a Committee on Education and the International Union of Pure and Applied Chemistry has a Commission on Education in Clinical Chemistry. The members of the committee and the members of the commission are the same; for several years I was one of these members. Five years ago we published recommendations for the education and training for the position as head of a clinical chemistry laboratory in a hospital. From these recommendations I shall extract some of the important points. About the necessary medical knowledge of a clinical chemist it was summarised: 1. To have expert knowledge of human biochemistry and appropriate knowledge of other aspects of human biology. 2. To have appropriate knowledge of the medical nomenclature. 3. To have a manifest understanding of the etiology and the pathogenesis of diseases showing chemical disturbances.

XI International Congress of Clinical Chemistry © 1982 by Walter de Gruyter & Co., Berlin • New York

72 4. To be suitably familiar with drug therapy, drug metabolism and with chemical and haematological effects of drugs. 5. To know from practical experience the function of hospital wards and out-patient clinics. To be familiar with laws and rules regarding public health service and hospitals and the medical practice and its ethics. It is seen that more knowledge is needed than is collected in the medical curriculum in most of the medical schools. But for the medical graduate the important problem is the subjects of which he heard very little or nothing during medical school. Recommendations of the IFCC and IUPAC bodies, which I just referred to, are collected in Table 1. Table 1 Supplementary education for the medical graduate Basic sciences

e.g. analytical chemistry statistics

Clinical Chemistry

e.g. quality control instrumentation

Laboratory management

e.g. budgeting data handling

Subjects related to clinical chemistry

e.g. immunochemistry toxicology

The graduate leaving medical school requires additional theoretical and practical training in analytical chemistry, in radiochemistry, in biochemistry, in statistics. He or she should learn how to set up a method in the laboratory and how to evaluate it; the theory and practice of quality control are important subjects as well as instrumentation, including the control of instrument-performance. Laboratory management is a subject containing many important items. The planning of work, laboratory design, purchase of chemicals, setting up of

73 a budget, work simplification, data handling, instruction of staff, techniques of information etc. are learned best by experience gained in a clinical chemistry laboratory under the guidance of an experienced clinical chemist. But courses and workshops can add useful knowledge. The clinical chemist should have a good knowledge of haematology, of endocrinology, of pharmacology and toxicology, and the graduate from many medical schools will have a good background in these subjects. But to master the problems which he or she will meet, additional experience is necessary. Two items have shown a remarkably rapid development and are utilised in many laboratories, these are the use of radioactive isotopes and the use of immunochemistry, and the medical graduate will need extra knowledge and experience in these two items. Whatever the background of the clinical chemists it is very desirable that he or she has experience from research activity. To join a group doing reasearch, utilising laboratory results, can give a unique opportunity of understanding the importance of planning, so essential in all laboratory work. Research activity in most cases will give useful exercise in statistics, too. To this short description of the supplementary knowledge, which the medical graduate should collect in preparation for the job as clinical chemist, must be added details of how to organise this education. Below I shall give some details from Denmark (Table 2): Table 2 Postgraduate education of M.D.'s for license as clinical chemist in Denmark Hospital intern

2 years

Hospital or Institute

1 year

Clinical Chemistry Dept.'s

3 years

10 courses, seven mandatory subjects (total 200 hours' theory).

74 In Scandinavia only medical graduates can obtain the position as head of a hospital department of clinical chemistry. In Denmark six years of postgraduate education and training are required and in three of these years the trainee shall hold a salaried position in departments of clinical chemistry and at least one of the four years in a university department. There are several compulsory courses and workshops. Table 3 gives an idea of the topics. Each of these courses has a duration of two to five days and covers aspects of methodology as well as interpretation, and the whole programme of ten to twelve courses runs over a period of two to three years. A final examination has been discussed for some years, but is not established yet. Table 3 Course topics (Denmark, 1978-80) Organisation and management - Quality control - Plasma proteins - Enzymes Acid base metabolism - Biochemistry of anemia - Coagulation disorders - Clinical toxicology - Chromatography - Immunochemistry - Endocrinology In the introduction to the symposium today I mentioned that we meet different solutions to the same problem in different countries, and over the years we see changes in the educational programmes. We must accept that there is no standardised, correct way of producing clinical chemists. Let me call your attention to some questions often debated. How much analytical chemistry should the medical graduate learn in his postgraduate training? Some will argue that very little is necessary for the clinical chemist cannot change anything in his large multichannel analyzer. Others will emphasize that you cannot choose the best method in a given setting without a good understanding of the chemistry involved, and further stress that you are unable to understand influence

75

of drugs and their metabolites on different analytical methods if you are ignorant of chemistry. My personal view is that analytical chemistry is very important in the daily practice and especially in the development of clinical chemistry. The medical graduate in his postgraduate education and training should give plenty of his time to collect good knowledge in analytical chemistry. Another question: how much knowledge in the field of instrumentation is necessary? Again we will have different answers from different colleagues. I am inclined to think that good knowledge of the principles is necessary, but if you shall have your future in a laboratory with limited staff and away from the capital or large cities, then you must know a lot more than just principles. In the other end of the scale, a large laboratory including staff members with good education in physics and technology and near to other institutes and instrument suppliers, such a laboratory could function although the head of the laboratory mainly knows the principles of instrumentation. Jumping to another question: how important is knowledge in management? and how to organise to have some experience? I have already mentioned that I see the problems of organisation and management as very important. These problems have been neglected in the past in the education of clinical chemists. Courses can be organised to give knowledge and also some training. But it is important that we try directly to teach our younger colleagues working with us, delegate duties especially within this sphere and guide them in a large field which was never covered in their university curriculum. Connected with organisation and management we have the question: how to organise the different laboratory disciplines in the hospital? The answer to this questions has, of course, influence upon the education. As I see it, there are several good arguments for keeping different clinical laboratory disciplines together in a common department of laboratory medicine. But nobody can keep abreast with the fast development in all the disciplines, we must have separate units.

76

The actual need, the size of the hospital and national tradition will influence the decision: how to divide the huge field of laboratory medicine. In a few countries you find departments of nuclear medicine, utilising radioactive isotopes for investigations of circulation, of respiration, of kidney function, of erythrocyte-destruction etc., and further responsible for treatment with radioactive isotopes and doing a lot of clinical chemistry bench analyses as well. But in most countries the isotopes are used in several departments as a good analytical tool, where needed. I find such a system much better. In the sphere of haematology you can find other peculiar separations. Such biochemical determinations as proteins of coagulation, enzymes in erythrocytes and vitamin plasma, could go, not with other biochemical determinations, but with blood-typing and blood-transfusion activity. Again I prefer to have all biochemistry collected in the same department. While advocating separate units I agree that close placing of the laboratory units in the hospital building is a good idea and support efficiency and economy. In the more general discussion after the introductory speeches we could discuss the problems of rules, formalities and legal situation regarding education. Here again we meet many differences from country to country. As decision-makers we could meet ministry of health and ministry of education; in some countries the universities take a large responsibility for the postgraduate education of doctors and other scientists. In other countries we find special institutions for the postgraduate education. The scientific societies and the professional associations play their roles, different from place to place. In IFCC and IUPAC we have discussed part of the relevant terminology. We reached the following results which should give some definitions in English: First about the program of study. Such a program can be officially recognised by accreditation, and this accreditation

77

of the study programme can be given by a non-governmental agency or by a governmental body. Table 4 Accreditation The process by which an agency or organisation or governmental body evaluates the program of study of an institution as meeting certain predetermined specified requirements. An agency of government can give licence to engage in a given occupation and to use a particular title. Table 5 Licensure The process by which an agency of government grants permission to persons meeting predetermined qualifications to engage in a given occupation and/or use of a particular title. Different from the licence we have a certificate given to an individual by a non-governmental agency or association. Table 6 Certification The process by which a non-government agency or association grants recognition to an individual who has met certain predetermined qualifications specified by that agency or association. The important matter is not the exact words, which will change from language to language. The important matter is the notion - to keep these three conceptions apart.

78 These definitions, related to rules and regulations, bring me to the end of this short discourse. I hope that some of the items I have mentioned, will be brought up in the discussion. The postgraduate education is important for clinical chemistry: an education of high quality can recruit good people and it will give both knowledge and skill and attitude. As in many other conditions we should find a balance between regulations and freedom, and we have to be realistic, there will be difference from country to country. One obvious danger is that the rules are too strict and that the candidates shall use all their time to prepare for an examination, then there will be no time for research activity. We need in clinical chemistry individuals of many kinds, also the independent mind, with courage and phantasy. Let me cite Bertrand Russel: "Men are not all equal in congenital capacity and any system of education which assumes that they are involves a possibly disastrous waste of good material".

References 1.

Rubin, M., Lous, P. (eds.): Education and training for clinical chemistry. MTP Press, Lancaster (1977).

TECHNICIAN AND TECHNOLOGIST TRAINING IN CLINICAL CHEMISTRY

W.A. Wahba, M.D., Ph.D., F.R.C.Path,

World Health Organization, Regional Office for Europe, Copenhagen, Denmark

1.

Introduction

Of all the components needed for the establishment, expansion and modernization of laboratory services, personnel occupies a central position.

The reliability and the quality of the work performed depend

largely on the competence and motivation of the manpower involved. subject of training has indeed received and is still receiving

The

serious

consideration, by the national health authorities, the universities and the professional societies.

WHO considered the matter in all technical

papers concerned with laboratory services (1,2,3).

A special WHO Expert

Committee studied the training of Health Laboratory Personnel

(Technical

staff) (4), which resulted in the publication of a technical report, containing useful discussions on the nomenclarure and classification of technicians all around the world.

The committee also attempted to define

the function of the various categories (classes) of technicians. Training programmes for the different categories were suggested, as well as means and ways of career development, condition of service, certification and registration.

While this publication and a follow-up

report (5), has cleared many misunderstandings and provided a basis for the harmonization of training of programmes, there are still various questions arising as laboratory services continue to develop. Some of these questions are formulated hereunder:

What do classifications and stratifications in laboratory really mean?

Were the programmes designed for training

technicians

laboratory

personnel reviewed in the light of modern needs and the ever-changing

X I International C o n g r e s s of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

80 background of those who come to join them? programmes and excluded redundant ones?

Have we included new

Were the differences between

individual tasks and levels of health care, recognized and accommodated? Did we consider the causes of drop-out from the laboratory services and tried to solve this problem, by providing better training facilities and proper socio-economic status in both developed and developing countries? Did we define the education objectives clearly, to make their attainment possible?

Did we study the effects of mechanization and automation on

training and staffing?

These and many other questions are in need of satisfactory answers.

This

paper will attempt to deal with some of these problems, but its main goal is to generate some serious and fuitful thinking and discussion about the training issues.

2.

Laboratory Manpower Prerequisites

Laboratory manpower prerequisites:

an ideal training programme will

highlight the necessity of a perfect man - reagent - equipment relationship.

This can only be achieved through acquiring certain

capacities such as:

Skills: Careful handling and manipulation of materials and equipment and ability to communicate with co-workers.

Knowledge: Basic facts such as terminology, principles and practice, comprehension, creativity and ability to interpret results.

Attitudes: Realism according to real needs and available resources, acceptance of constructive criticism and suggestions and a desire to assist others with less experience.

81 3.

Educational Objectives

Irrespective of the category, the main function of the laboratory worker is to "perform various routine and specialized tests in the clinical laboratory, and thus provide accurate data to health care personnel needed for promotive, preventive, diagnostic, therapeutic and rehabilitative health care activities".

Learning is not undimentional, but is composed of many elements which should be given adequate emphasis in the process of imparting knowledge.

Three educational objectives are suggested:

(a)

The worker should have sufficient knowledge and understanding

of the scientific background in his field.

This is mainly acquired

through theoretical training and to a lesser extent by the practical training offered.

But both types of training should be well

coordinated in a meaningful way.

(b)

The worker should attain certain professional skills by

coordinating manual dexterity and mental capacity.

He should be

able to translate his knowledge and information into activities, through which, skills are gradually developed.

(c)

The third requirement is a moral one by which the worker should

develop certain attitudes and values.

Professional integrity is a

must in a worker who is engaged in developing accurate data to assist in the correct health care action.

In a recent review of

health laboratory services, laboratories were referred to as "the tendon of Achilles" of health services.

This simile stands true if

based on the quality and the integrity of personnel.

A constant

high level performance ensures the credibility of the laboratory results.

82 4.

Categories of laboratory personnel

From the definition and the objectives cited previously, it becomes clear that the stratification of laboratory workers is rather artificial and while it may be avoided as much as possible in the technical sense it may be necessary for administrative purposes.

At present there are at least 6 categories of laboratory workers. pertinent to enquire into their origins and development.

It is

These

categories came in the service late in the 19th century and in the early years of the 20th century.

As hospitals began to incorporate

laboratories, workers were sought and the responsible physician h a d no choice but to take what was available.

These were trained on the spot

for certain jobs and after a long and painstaking apprenticeship period, they produced technicians with skills, but in most cases, with meagre scientific knowledge.

In time, the better qualified person with a good

basic education were taken in and their training went higher and longer resulting in the various categories.

4.1

Technologists

The laboratory technology training is based on four years of university studies and the admission prerequisites are like those set out for admission to pharmacy and sciences (graduation from a secondary school), though the fourth final year may be attached to a hospital.

This system

has been approved in many countries.

The diploma or B.Sc. is a recognized university degree and permits students to continue further post-graduate studies.

After suitable

in-service practice, these technologists become an extremely useful element and can be given supervisory tasks in the various areas of the laboratory.

83 In the clinical chemistry laboratory one may also utilize other science graduates from universities such as in the disciplines of Biochemistry, Physics, Electronics and Data Processing.

4.2

Technicians

After various periods of basic education depending on the countries, national legislation, the urgency of need and the availability of interested and qualified persons, training is conducted in 4 types of establishments:

(a)

Health manpower institutes, where the technicains are trained

with other auxiliaries working in the health care services.

(b)

Specialized institutes for laboratory technicians.

(c)

Hospitals and laboratories either alone or in association with

(b).

(d)

Some universities.

Courses may be full time (a, b, d,) or part-time (c) and vary from 1 to 3 years.

Teaching manpower and facilities can be rationalized and pooled together in order to establish better training programmes.

Whenever possible, a

prerequisite for admission should be the completion of the secondary school education.

5.

Teaching Methods

The teaching methods regarding laboratory technicians utilized until now in most of the developed countries and practically all developing ones are the classical lectures type where a whole group of students join a

84 certain class and, in accordance with the time schedule, are promoted from one year to the other until they graduate.

This classical technique

is useful, but it does not accommodate for differences between individuals and it is a certainty that individuals differ mentally and physically.

Moreover, this method does not stress dicusssions between

student and teacher since most of the time, the lecture is given in a one-way direction.

New training methodologies were introduced, the main

feature being that instruction is personalized and often given part-time.

This allows the students to finish courses at their own pace

and speed.

The instructor will have as his principal responsibilities:

the selection of all study material used in the course, the organization and the mode of presenting this material, the construction of tests and examinations and the final evaluation of each student's progress.

It

will be his duty also to provide lectures, demonstrations and discussion opportunities.

Students in the course are expected to take a final

examination after completing all units.

This system was applied to

clinical chemistry whereby the material of the course (eighteen weeks) was divided into units of study (6) with a guide to the assigned text-book which took the place of lectures.

The study guide pointed out

what material was thought to be of prime importance and directed the students to the different useful literature, for supplementary material. The study guide for each unit also contained questions on the material, providing a basis for the students to evaluate their knowledge and copies of correct answers were provided.

The student passes a unit not only

when he demonstrates mastery of the material but also when he attains achievement of defined levels.

This replaces the focus on fixed-time

constraints and the instructor functions as a manager of learning rather than a watchdog looking out for the completion of certain fixed chapters.

This system is worth considering for training of laboratory technicians since it could be adopted for all laboratory disciplines.

Students could

start with different subjects in accordance with their wishes and could, at the same time, accommodate the practical aspects of the work, e.g. a group of students could start with bacteriology or parasitology and another with haematology,

This has the following advantages:

85 (a)

Instructor-student ratio is high and this allows contact

between teacher and student.

(b)

Whenever a student finishes a subject, he can move to another

subject at his own pace without necessarily losing time by following the pace of the whole class.

(c)

The number of students in one laboratory discipline will be

reduced;

this allows for better attention being given by the

instructors and gives ample space allocation.

However, it is important that each of the students should pass a final examination on completion of each subject unit.

The adequate management of training courses will ensure rational delivery which often provides a m e a n for the expansion of the capacity of the training institution.

These rationalization measures include the

alternation of the theoretical (in institute) and practical (in hospitals) modules, part-time instruction and the personalized system outlined before.

Minimum standards with teaching programme suggestions have been developed both by WHO (4,5) and the Council of Europe (7).

6.

Training of Tutors

Whatever method of training is adopted, be it full-time training in a technical college, laboratory-based training, or a combination of these two methods, all institutions involved in training will be required to appoint teaching personnel - individuals who have qualified as medical laboratory technicians and who at the same time have an inclination to impart their knowledge and skills to others.

More thoughtful and careful

attention should therefore be given to the developing role of the laboratory tutor.

It will be a job that requires special skills and

substantial effort, and that, will need to receive suitable recognition.

86 It is frequently suggested that "good teachers are born, not made", the implication being that time and effort devoted to the training of teachers are unnecessary.

While it is true that some teachers are born

to greatness, most of us do not aspire to greatness, but seek simply to improve what talent we have that in turn we may impart the knowledge and skills we have learnt to others in the hope that they may become more proficient in the practice of laboratory technology.

The training of health laboratory tutors can best be achieved by a combination of a suitable paedagogic course and periods of supervised teaching practice.

A WHO publication (8) has been produced which acts as

a guide to laboratory personnel who, in the absence of suitable courses, seek to improve their teaching and instructional skills.

It is hoped

that as a result, they will be able to implement more effective training and education programmes with the resources they have available and that they will thus be stimulated to think of their teaching function prior to attendance at the courses provided on a rather limited scale.

7.

In-service Training for Technicians

At the present and in particular in many developing countries, training is still of the apprenticeship type.

Experienced technicians with no training in tutoring and paedagogy or newly graduated technicians who had a good score during their training, are used to train the trainees.

These tutor technicinans are also

generally involved in routine laboratory work and thus cannot monitor properly the work of the trainees.

The lectures for the technician

student may be given by university graduates in clinical chemistry, who do not have the appropriate teaching approaches for laboratory technicians, and often overwhelm the trainees with a mass of information that makes it difficult to identify what is essential,

The curricula are

often copies of those used in other countries and not relevant in relation to the local needs and resources.

Training programme documents,

including trainee task description and educational objectives are often lacking.

87 In some developing countries there is still another type of laboratory worker (microscopist) assigned mainly at the peripheral level.

It seems

that there is a growing trend to delete the monovalent microscopist and train a polyvalent laboratory assistant, which would cover all basic microscopic examinations and some basic urine and blood analyses.

This

change is part of the policy of integration, but the scheme may prove to be a failure if the retraining is insufficient, subject an/or time-wise

When newly recruited laboratory assistants are trained and a minimal six months training is provided, a better performance can usually be expected.

8.

Appropriate Technology

While much of the skills are developed through experience, an adequate and appropriate utilization of available modern technology is an essential element in the training.

The various aspects of appropriate

technology include organization, management and resource allocation, reliable methodology including back-up (reagents, supplies, maintenance), and safety.

Already during the basic training, the laboratory worker

should become acquainted with quality assurance and methods for assessing equipment and reagents.

Training programmes have to be adapted according to the real need of the community, the laboratory workers are expected to serve and also according to the technologies available to them.

In-service training has

to be organized periodically in view of the introduction of amended or entirely new technologies.

9.

Legal status and requirements

In some countries there is still a lack of official recognition of the professional status of the laboratory technologist and technician. provisions may also be inadequate.

Some countries have attempted to

improve the situation by creating still more categories such as the

Legal

88 laboratory scientist, scientific officer etc.

It is certainly necessary

in many cases to proceed with the development of certification (formal certificate of training), registration (pass an official national examination and meet requirements for practice) and for licensing (recognition and permission to work).

10.

Promotion of the Laboratory Profession

Promotion of the professional status of technologists and technicians will doubtlessly have to be considered in many instances during any process of evaluation of training programmes as it will greatly help certain situations which may otherwise hamper the development of laboratory activities.

Both the technical and the human approaches may be used and include stimulation of scientific interests, provision or advanced training facilities, visits to similar institutions and attendance of meetings in the country and abroad, improving working conditions, career development, participation in research, special bonuses and allowances and encouragement for the establishment of professional societies and journals.

These various measures will directly or indirectly increase

the efficiency and efficacy of the services.

There is no doubt that even

with the increasing introduction of automation and computerization in the laboratory, results and credibility will still be based on the quality of manpower performing the various types of tests.

11.

Summary

The essential backbone of a laboratory are technologists and technicians.

Facts about job requirements, tasks, minimum standards

determined by scientific bodies and educational objectives are mentioned.

The training programmes have to be amended frequently in view

of the rapidly evolving technologies particular to clinical chemistry and an elaborate in-service training is an important element for the

89 efficient functioning of the laboratory.

Both the technical and the

human approaches must be utilized in promoting the technologist and technician career development.

This would include apart from the

provision of advanced training facilities, attendance at conferences and visits in the home country and abroad, participation in research projects and the creation and actice involvement in professional

societies.

References 1.

WHO/Technical Report Series No 128: Service (1957).

The Public Health Laboratory

2.

WHO/Technical Report Series NO 161: (1959).

Hospital Laboratory

3.

WHO/Technical Report Series No 236: Planning, Organization and Administration of a National Health Laboratory Service (1962).

4.

WHO/Technical Report Series No 345: The Training of Health Laboratory Personnel (Technical Staff) (1966).

5.

WHO/Technical Report Series No 491: The Planning and Organization of a Health Laboratory Service (1972).

6.

Weisman R.A. and Shapiro D.M., Journal of Medical Education, 48, (October 1973).

7.

Council of Europe, on the minimum standards of training and equivalence of qualifications of medical laboratory technicians and teaching technicians, Resolution 70 (8) (1970) and 72 (7) 1972.

8.

M c Minn, A and Russel J.: WHO, Geneva Offset Publication No 21, Training of Medical Laboratory Technicians. A handbook for tutors (1975).

Services

Clinical

Aspects

CLINICAL CHEMISTRY AND HAEMOSTASIS

Erwin Deutsch First Department of Medicine, University of Vienna

Haemostasis is the result of the joint effort of three systems: vessel wall, blood coagulation and platelet function. I shall restrict my discussion to the blood coagulation system. The study of the vessel wall will not be possible in the clinical chemistry laboratory in the near future, and the study of the platelet function will be reserved to special laboratories. My review will be divided in three parts: Biochemistry of blood clotting factors, activation sequence and methodology. I. Biochemistry of Blood Clotting Factors Our knowledge of the biochemistry, structure and activation of the blood clotting factors has made large progress in the last decade. A few general remarks may be presented in the beginning: 1. All blood clotting factors are synthetized in the liver except factor VIII R:Ag, which is produced in the epithelial cells of the vessel wall. 2. The blood clotting factors are either zymogens which are activated into enzymes during the activation sequence (factors II, VII, IX, X, XI, XII, prekallikrein) or cofactors (factors V and VIII, HMW-kininogen). Fibrinogen is the final substrate. 3. A surface, predominantly phospholipids (platelet factor 3 or tissue thromboplastin), is involved as an integral reaction accelerating constituent in at least three steps.

X I International C o n g r e s s of Clinical Chemistry © 1982 by Walter de Gruyter &. Co., Berlin • New York

94

4. The procoagulant enzymes are serin proteases like trypsin, chymotrypsin and plasmin. Only factor XIII has cystin in its active center. 5. There is a far-going homology in large parts of the amino acid sequence in many enzymes probably caused by the genetic origin from a common ancestral gene (26) . 6. The active center of the enzymes is localized in the C-terminal part of the proenzymes with serin, histidin and aspartate as essential constituents and the same tertiary structure. With the N-terminal part they bind to surfaces. 7. The N-terminal and C-terminal regions of the proenzymes remain connected to each other in the active enzyme by a disulfide bridge and remain connected with the surface with the exception of thrombin and BXIIa, which are separated from the C-terminal part of the zymogen and are freely floating in the plasma. 8. The amino acid composition of all procoagulant factors is known. Among them only fibrinogen (24), prothrombin 9,35, 64), bovine factor IX (27) and bovine factor X (15,59) are completely sequenced. 1. Fibrin formation 1.1. Fibrinogen: Its concentration (Table 1) in plasma is 200 - 400 mg/dl, its half life about 3 days, the molecular weight (MW) 340 000. It consists of 2 Aa-(610 amino acid residues, MW 64 000), 2 BB-(461 amino acid residues, MW 56 000) and 2 y-chains (411 amino acid residues, MW 47 000) which are connected with each other by 29 disulfide bridges arranged in 5 knots. The structure of fibrinogen in solution is under discussion. A globular central domain is envisioned which contains the N-DSK to which two terminal globular domains are connected by a-helical-coiled coils. The amino acid sequence of the three chains has been completely analysed by Henschen (24). There is some heterogeneity in fibrinopeptide A and in the y-chains (Y x and y y are shorter, some y-chains are longer) of normal fibrinogen. Fetal fibrinogen differs from adult fifcri-

95

nogen by three peptide spots of the tryptic digest of the Aa-chain (67,68). Genetic variants cause dysfibrinogenemia. So far the amino acid exchange in fibrinogen Detroit (Arg^^-Ser^g), fibrinogen Munic (Arg^g-Asp^g) and Troyes (Arg^g-1/2 Cyst^g) is known. They all are localized in the Aa-chain. Fibrinogen is synthetized in the liver, each chain by an individual mRNA (10) .

Thrombin at first splits fibrinpeptide A from the Aa-chain by splitting an Arg-Gly bond. A conformational change is the consequence by which both are exposed, the N-terminal region of the BB-chain to enable thrombin to split the fibrinpeptide B and the N-terminal domain for polymerisation. Towards the C-terminal region a polymerisation domain is always exposed in intact fibrinogen. By these two domains end-to-end polymerisation of fibrin-monomers is performed. After the splitting of the fibrinopeptide B, the second portion of the amino-terminal domain for polymerisation is uncovered permitting side-to-side polymerisation. Soluble fibrin is formed by it. It is stabilized by the action of factor Xllla at first by forming isopeptide bonds between £-amino groups of lysine residues (position 408) and Y-carboxy groups of glutamine (position 398) between neighbouring y-chains, and later between a-chains (glutamin 328, 366, position of lysin not yet known) (24). 1.2. Factor XIII has a molecular weight of 320 000, its concentration in plasma is 1-2 mg/dl, its half life 100-120 hours. It is not yet sequenced. It is a tetramer formed by two identical a-chains (MW 75 000) which are synthetized in hepatozytes, megakariozytes, spleen and uterus, and two b-chains (MW 80 OOO) which are synthetized only in hepatocytes. Platelet factor XIII consists only of two a-chains. Thrombin or Xa splits an Arg-Gly bond and separates an activation peptide (MW 4 000, 3 7 amino acid residues) from the N-terminal area of both

96

Table 1 Biochemistry of clotting factors C - t o r w . and Ciotti* f

CoMcantrattM

Factor

In Plaaaa

t/2

Ciuiaa Proaklya*

Protkreafelk

S

ag/dl

AMIM-

W

60 k r s

Ola

acids

N-chain

L-ckala

72.000 (k)

N-t*mliul

Cartw-

talk»-

kydratcs

actd sot

10

Ala-il.

(k)

-Kr

(k)

ProtkraAla 1

4»

Protkrafrlo 2

300 ( k )

Ikr-fili»

1S5 (k)

Ala-Arf

(k)

FrapaM

1

17.700

17.920 Ik)

I H

Ik)

F n p M t

2

12.SSO (k)

110

(k.k)

12.774

Ik)

32.000 ( k . k )

3

ag/dl

12-15

kn

Sar-ilu

Sor-Aro

Ik)

T(ira*in *

Factor V

10 t

259 ( k . k ) 4.04S (k)

It

S . 7 I 0 0-90.000 (k) »Ilia

$2.000 (k) 20.000 Ik)

tllla 20.000 ( k ) Factor I I I I

1-2 «9/dl

100-120 kr

120.000 (k)

k-Acotyl l o r 2a(0.000 2i7S.OOO

11.5

I

I

97

Table 1

Ciotti» I Factor

cont'd

Concon tritio* t/i In Flaaa

Prrtalllbrtln «-5 m§/4l Kolllkrvlo mt-Klntiiofon •.0 Frato1n*
i M > i M 0< M i Q. 3 G 1 io e M a o o s M a)

0 rH a e a)

u — u

263 Table 7

APOPROTEIN B-2 HOMOZYGOSITY(Ed/Ed); biochemical and clinical findings - Frequency in population: approx. 1% - VLDL cholesterol concentration elevated - Total serum cholesterol reduced, LDL cholesterol reduced - simultaneous inheritance of additional lipoprotein metabolic defect causes Type III hyperlipoproteinemia - Hypothyroidism, Obesity, estrogen deficiency or glucose intolerance may also result in expression of Type III hyperlipoproteinemia - 1 in 50 people develope a Type III hyperlipoproteinemia - 1 in 5000 people in the general population exhibit clinical signs of Type III hyperlipoproteinemia

264

© ITA- »

E-3— E2—

A-I —

lift-*'

T « I i

jBBpS • |¡Í|í 5

afe' Ï'

'|i|: ®!

OIIIq— Ol M

-

E ° / E n E á /EP Fig. 1

EVt*

En/Ed

E^/E0

En/E*

IllustrâtiDnof Apolipoprotein E-polymorphism using isoèlectric focussing of VLDL

265 A r

B v

D

C

E

G

*

H JI^PP

—

»

©

AI, ~ai 2

—

© Fig. 2

Illustration of Apolipoprotein A-I structural variants (using isoelectric focussing of native serum) Gel A and H: normal serum Gel B : Apolipoprotein A-I-Münster-1 variant Gel C : Apolipoprotein A-I-Münster-2 variant Gel D : Apolipoprotein A-I-Münster-3 variant Gel E : Apolipoprotein A-I-Milano variant Gel F : Tangier disease

HIGH DENSITY LIPOPROTEINS Composition, Analysis and Significance for Screening risk and Anti-Risk Factors for Atherosclerosis

Gerhard M. Kostner Institute of Medical Biochemistry, Univ. of A-8010 GRAZ,Austria

Composition of HDL High density lipoproteins (HDL) comprise the spectrum of serum lipoproteins with hydrated densities ranging from 1.063-1.210. For a long time this density class was considered as a chemically rather homogenous fraction and equaled with «-lipoproteins. On the basis of ultracentrifugal data, HDL were subdivided into two major classes: HDL2 (d 1.063-1.125) and HDL3 ( 1.125-1.210) (1). After the discovery of non-identical polypeptides in HDL (2) it became evident, that HDL in fact represents a mixture of several lipoprotein families or association products thereoff. With that respect, HDL represents the most heterogenous fraction of all lipoprotein classes containing LpA, LpB...LpH. (For a review see Ref.3.) The major family, however, is LpA comprising some 90% of the total HDLmass followed by LpC, LpB and in some individuals also Lp(a). This latter lipoprotein is inherited as a quantitative genetic trait and very similar to LpB the major lipoprotein of LDL. Because of the higher lipid+carbohydrate content, it sediments at d 1.063 and is found in HDL2. Electrophoretically, Lp(a) migrates intermediate between B-and pre-B lipoproteins. Table I lists the major lipoprotein families of HDL and gives some specifications of them. Most of the physicochemical and chemical data were elaborated

XI International Congress of Clinical Chemistry © 1982 by Walter de Gruyter & Co., Berlin • New York

268 TABLE I: Lipoprotein Families in HDL

Density

Family

Apolipoproteins

% Of

HDL-Mass LpA

1.063-1.21

LpB