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Laboratory diagnosis of thyroid disease: a clinician’s perspective
PATHOLOGY UPDATE 2009 ABSTRACT PUBLICATION
immunoassays, while mass spectrometry is being introduced to evaluate proteins and peptides. The protein in urine is more or less unstable and heterogeneous due to degradation or modification by urine proteases, resulting in altered immunochemical reactions. A quality assurance system for each analyte by each is a key, by setting proper pre-analytical conditions and establishing reference measurement systems, especially by qualified reference material. Indication for urine protein measurement is to seek pathogenesis, localisation of the affected organ or tissue, evaluation of prognosis or response to therapy in systemic, renal and genitourinary diseases. Albumin, a marker for glomerular dysfunction, is essential not only for diabetic nephropathy, but a reliable risk and prognostic marker for cardiovascular diseases. Measurement of very low levels is underway for early detection and prevention of related diseases. a1-microglobulin is a wellestablished reliable tubular marker. Among post-renal markers IL-8 is a good inflammatory marker especially for urinary tract infection (UTI). The pre-renal marker may specifically detect systemic diseases; a specific antibody against microorganisms is in use by point of care testing (POCT). Clinical usefulness is being expanded by discovery of new proteins and peptides that may be incorporated in the expert system.
SERUM FREE LIGHT CHAINS Jill Tate Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia Background: Serum free light chains (FLC) assay measures the concentration of free kappa and lambda immunoglobulin light chains. Clinical uses: FLC assay is clinically indicated for screening and prognosis of multiple myeloma and related plasma cell disorders including oligosecretory disease, AL amyloidosis and monoclonal gammopathy of undetermined significance. There are no data to support its use in myeloma with measurable disease by other methods. In assessment of disease response to treatment, FLC measurement is recommended in documenting stringent complete response in multiple myeloma, and in oligosecretory diseases but is unvalidated in light chain myeloma and intact immunoglobulin disease. Analytical issues: Use of polyclonal FLC antibodies raises the question of adequate specificity and binding affinity to measure monoclonal FLC. Problematic samples can give FLC under- or over-estimation due to sample dilution anomalies, giving rise to difficulties in result interpretation, particularly when monitoring patients with clonal plasma cell diseases. Laboratory staff and clinicians should be aware of the potential for non-reactivity of individual monoclonal FLC, the effect that dilution has on FLC measurement, and the impact of assay imprecision on result interpretation. These issues, if not adequately appreciated, have the potential to mislead clinical diagnosis and assessment of response to therapy.
RCPA QAP
CHEMICAL PATHOLOGY UPDATE
Graham Jones The RCPA Chemical Pathology Program is now 26 years old and provides over testing for over 220 analyte-matrix combinations in over 20 different programs to over 1300 participants in over 40 countries. New programs were commenced in 2008 for BNP and NT-proBNP, Thyroglobulin, Angiotensin Converting Enzyme and Clozapine as well as pilot programs for Plasma Metanephrines
17
and Vitamins B1 and B6. The session will briefly overview current activities, summarise the findings from the new programs and outline some plans for the future.
LABORATORY SUPPORT FOR THE DIAGNOSIS AND MONITORING OF THYROID DISEASE Carole Spencer Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States Over the last 40 years, thyroid testing has evolved from manual isotopic tests performed in specialised laboratories to automated non-isotopic measurements made in routine clinical chemistry laboratories. Despite improvements in methodological sensitivity and specificity, a number of technical issues still negatively impact the accuracy and interpretation of thyroid testing in clinical practice. The diagnostic sensitivity of TSH measurement has been maximised by sensitivity improvements (third generation functional sensitivity 0.01 mlU/L). However, controversy remains regarding the setting of the TSH reference range and the clinical significance of mild subclinical hypothyroidism. Heterophilic antibodies (HAMA) can still interfere with a number of the tests, especially when patients have received monoclonal antibody therapies. Free hormones measured by equilibrium dialysis/tandem mass spectrometry or the older two-test index approach (FT4I and FT3I) appear to be more reliable than the newer free hormone immunoassays (FT4 and FT3) when binding proteins are grossly abnormal such as during pregnancy or non-thyroidal illness. Expanded clinical utility and new physiological insights have resulted from technical improvements in the thyroid autoantibody tests (TPOAb, TgAb and TRAb). This presentation will discuss the strengths and weaknesses of current thyroid tests relative to their use and interpretation in clinical practice.
LABORATORY DIAGNOSIS OF THYROID DISEASE: A CLINICIAN’S PERSPECTIVE John P Walsh Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands; School of Medicine and Pharmacology, University of Western Australia, Crawley; and PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia Thyroid disease is common and readily treatable, but key aspects of diagnosis and management remain controversial. For example, serum thyrotropin measurement is central to the diagnosis of thyroid dysfunction, but the laboratory reference range remains contentious, despite a wealth of population-based normative data. The health impact of mild thyroid dysfunction (particularly in elderly people) is unclear, making it difficult to establish reference ranges for thyroid function tests based on clinical outcomes, as is done for other analytes such as cholesterol. Pregnant women are increasingly screened for thyroid disease, but many laboratories do not apply pregnancy-specific reference ranges, leading to misclassification, with the potential for mismanagement. Difficulties in management can be compounded by poor communication between clinical pathology staff and clinicians, and vice versa. This presentation will review controversial aspects of the diagnosis and management of thyroid disease, with an emphasis on the often inadequate evidence base which guides clinical decision-making, and the shaky foundations which underlie the ever more numerous guidelines and position statements on thyroid disease.
immunoassays, while mass spectrometry is being introduced to evaluate proteins and peptides. The protein in urine is more or less unstable and heterogeneous due to degradation or modification by urine proteases, resulting in altered immunochemical reactions. A quality assurance system for each analyte by each is a key, by setting proper pre-analytical conditions and establishing reference measurement systems, especially by qualified reference material. Indication for urine protein measurement is to seek pathogenesis, localisation of the affected organ or tissue, evaluation of prognosis or response to therapy in systemic, renal and genitourinary diseases. Albumin, a marker for glomerular dysfunction, is essential not only for diabetic nephropathy, but a reliable risk and prognostic marker for cardiovascular diseases. Measurement of very low levels is underway for early detection and prevention of related diseases. a1-microglobulin is a wellestablished reliable tubular marker. Among post-renal markers IL-8 is a good inflammatory marker especially for urinary tract infection (UTI). The pre-renal marker may specifically detect systemic diseases; a specific antibody against microorganisms is in use by point of care testing (POCT). Clinical usefulness is being expanded by discovery of new proteins and peptides that may be incorporated in the expert system.
SERUM FREE LIGHT CHAINS Jill Tate Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia Background: Serum free light chains (FLC) assay measures the concentration of free kappa and lambda immunoglobulin light chains. Clinical uses: FLC assay is clinically indicated for screening and prognosis of multiple myeloma and related plasma cell disorders including oligosecretory disease, AL amyloidosis and monoclonal gammopathy of undetermined significance. There are no data to support its use in myeloma with measurable disease by other methods. In assessment of disease response to treatment, FLC measurement is recommended in documenting stringent complete response in multiple myeloma, and in oligosecretory diseases but is unvalidated in light chain myeloma and intact immunoglobulin disease. Analytical issues: Use of polyclonal FLC antibodies raises the question of adequate specificity and binding affinity to measure monoclonal FLC. Problematic samples can give FLC under- or over-estimation due to sample dilution anomalies, giving rise to difficulties in result interpretation, particularly when monitoring patients with clonal plasma cell diseases. Laboratory staff and clinicians should be aware of the potential for non-reactivity of individual monoclonal FLC, the effect that dilution has on FLC measurement, and the impact of assay imprecision on result interpretation. These issues, if not adequately appreciated, have the potential to mislead clinical diagnosis and assessment of response to therapy.
RCPA QAP
CHEMICAL PATHOLOGY UPDATE
Graham Jones The RCPA Chemical Pathology Program is now 26 years old and provides over testing for over 220 analyte-matrix combinations in over 20 different programs to over 1300 participants in over 40 countries. New programs were commenced in 2008 for BNP and NT-proBNP, Thyroglobulin, Angiotensin Converting Enzyme and Clozapine as well as pilot programs for Plasma Metanephrines
17
and Vitamins B1 and B6. The session will briefly overview current activities, summarise the findings from the new programs and outline some plans for the future.
LABORATORY SUPPORT FOR THE DIAGNOSIS AND MONITORING OF THYROID DISEASE Carole Spencer Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States Over the last 40 years, thyroid testing has evolved from manual isotopic tests performed in specialised laboratories to automated non-isotopic measurements made in routine clinical chemistry laboratories. Despite improvements in methodological sensitivity and specificity, a number of technical issues still negatively impact the accuracy and interpretation of thyroid testing in clinical practice. The diagnostic sensitivity of TSH measurement has been maximised by sensitivity improvements (third generation functional sensitivity 0.01 mlU/L). However, controversy remains regarding the setting of the TSH reference range and the clinical significance of mild subclinical hypothyroidism. Heterophilic antibodies (HAMA) can still interfere with a number of the tests, especially when patients have received monoclonal antibody therapies. Free hormones measured by equilibrium dialysis/tandem mass spectrometry or the older two-test index approach (FT4I and FT3I) appear to be more reliable than the newer free hormone immunoassays (FT4 and FT3) when binding proteins are grossly abnormal such as during pregnancy or non-thyroidal illness. Expanded clinical utility and new physiological insights have resulted from technical improvements in the thyroid autoantibody tests (TPOAb, TgAb and TRAb). This presentation will discuss the strengths and weaknesses of current thyroid tests relative to their use and interpretation in clinical practice.
LABORATORY DIAGNOSIS OF THYROID DISEASE: A CLINICIAN’S PERSPECTIVE John P Walsh Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands; School of Medicine and Pharmacology, University of Western Australia, Crawley; and PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia Thyroid disease is common and readily treatable, but key aspects of diagnosis and management remain controversial. For example, serum thyrotropin measurement is central to the diagnosis of thyroid dysfunction, but the laboratory reference range remains contentious, despite a wealth of population-based normative data. The health impact of mild thyroid dysfunction (particularly in elderly people) is unclear, making it difficult to establish reference ranges for thyroid function tests based on clinical outcomes, as is done for other analytes such as cholesterol. Pregnant women are increasingly screened for thyroid disease, but many laboratories do not apply pregnancy-specific reference ranges, leading to misclassification, with the potential for mismanagement. Difficulties in management can be compounded by poor communication between clinical pathology staff and clinicians, and vice versa. This presentation will review controversial aspects of the diagnosis and management of thyroid disease, with an emphasis on the often inadequate evidence base which guides clinical decision-making, and the shaky foundations which underlie the ever more numerous guidelines and position statements on thyroid disease.