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Hiperprolactinemia , Humanos , Femenino , Hiperprolactinemia/diagnóstico , Prolactina , ReproducciónRESUMEN
Phaeochromocytomas and paragangliomas are rare catecholamine-producing neuroendocrine tumours which can potentially cause catastrophic crises with high morbidity and mortality. This best practice article considers the causes and presentation of such tumours, screening and diagnostic tests, management of these patients and consideration of family members at risk.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/terapia , Paraganglioma/diagnóstico , Paraganglioma/patología , Catecolaminas/metabolismoAsunto(s)
Adenoma , Hiperandrogenismo , Humanos , Receptores de HL , Posmenopausia , Hormona Luteinizante , Andrógenos , Gonadotropina Coriónica , TestosteronaRESUMEN
Diabetes insipidus (DI) is a group of disorders that lead to inappropriate production of large volumes of dilute urine. The three main forms are central DI (CDI), nephrogenic DI (NDI) and primary polydipsia (PP). Differentiating CDI/NDI from PP is important as patients with true DI are at risk of severe dehydration without treatment. Biochemical testing is key in the diagnosis of DI. The indirect water deprivation test (WDT) is commonly used in the investigation of DI but has drawbacks including being cumbersome and sometimes producing equivocal results. Direct measurement of AVP has theoretical advantages but has generally only been used in specialist centres. Disadvantages include the requirement to measure AVP under hypertonic stimulation and pre-analytical/analytical challenges. Copeptin (CT-proAVP) is a proxy marker for AVP that is more stable, easier to measure and has been studied more widely in recent years. Historically, the evidence supporting the diagnostic performance of these tests has been relatively poor, being based on a few small, usually single-centre studies. However more recent, well-designed prospective studies are improving the evidence base for investigation of DI. These studies have focused on the utility of copeptin measurements during stimulation tests. There is evidence that measurement of copeptin under stimulation offers improved diagnostic performance compared to the WDT. There is currently a lack of systematic, evidence-based guidelines on the diagnosis of DI, but as the quality of the evidence defining the diagnostic performance of tests for DI continues to improve, a clearer consensus on the optimal approach should become achievable.
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Diabetes Insípida Neurogénica , Diabetes Insípida , Diabetes Mellitus , Humanos , Estudios Prospectivos , Poliuria/diagnóstico , Glicopéptidos , Diagnóstico Diferencial , Diabetes Insípida/diagnóstico , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Mellitus/diagnósticoRESUMEN
Phaeochromocytomas (PC) and sympathetic paragangliomas (PGL) are potentially malignant tumours arising from the adrenal medulla (PC) or elsewhere in the sympathetic nervous system (PGL). These tumours usually secrete catecholamines and are associated with significant morbidity and mortality, so accurate and timely diagnosis is essential. The initial diagnosis of phaeochromocytoma/paraganglioma (PPGL) is often dependent on biochemical testing. There is a range of pre-analytical, analytical and post-analytical factors influencing the analytical and diagnostic performance of biochemical tests for PPGL. Pre-analytical factors include patient preparation, sample handling and choice of test. Analytical factors include choice of methodology and the potential for analytical interference from medications and other compounds. Important factors in the post-analytical phase include provision of appropriate reference ranges, an understanding of the potential effects of various medications on metanephrine concentrations in urine and plasma and a consideration of PPGL prevalence in the patient population being tested. This article reviews these pre-analytical, analytical and post-analytical factors that must be understood in order to provide effective laboratory services for biochemical testing in the diagnosis of PPGL.
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Background: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilis eassay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain.Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. Results: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.
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Hipogonadismo , Humanos , Masculino , Adulto , Hipogonadismo/diagnóstico , Laboratorios , Testosterona , Inmunoensayo , Espectrometría de MasasRESUMEN
BACKGROUND: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. DESIGN: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. RESULTS: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. CONCLUSIONS: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.
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Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.
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Apolipoproteínas E , Hiperlipoproteinemia Tipo III , Apolipoproteínas E/genética , Genotipo , Humanos , Hiperlipoproteinemia Tipo III/diagnóstico , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , FenotipoRESUMEN
INTRODUCTION: Copeptin concentrations are a useful component of the diagnostic workup of paediatric patients with polyuria and polydipsia, but the value of measuring copeptin in patients with hyponatraemia is less clear. CASE REPORTS: We report 5 children with hyponatraemia in the context of different underlying pathologies. Copeptin concentrations were elevated in 4 cases (13.7, 14.4, 26.1, and 233 pmol/L; reference range 2.4-8.6 pmol/L), suggesting that non-osmoregulated vasopressin release (syndrome of inappropriate antidiuretic hormone) was the underlying mechanism for low sodium levels. In one of the patients, there was an underlying diagnosis of Schaaf-Yang syndrome (MAGEL2 gene mutation) with a clinical picture suggestive of dysregulated vasopressin production with inappropriately high and then low copeptin release. In one hyponatraemic patient, low copeptin concentrations indicated that non-osmoregulated arginine vasopressin release was not the cause of hyponatraemia and oliguria. DISCUSSION: Copeptin measurement did not influence management acutely but helped to clarify the mechanism leading to hyponatraemia when the result was available. Relatively high and low copeptin concentrations in association with hypo- and hypernatraemia indicate dysregulated vasopressin production in Schaaf-Yang syndrome.
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Hiponatremia , Artrogriposis , Niño , Anomalías Craneofaciales , Femenino , Glicopéptidos , Humanos , Hiponatremia/diagnóstico , Hipopituitarismo , Discapacidad Intelectual , Masculino , Polidipsia/diagnóstico , Proteínas , VasopresinasRESUMEN
BACKGROUND: Phaeochromocytomas and paragangliomas (PPGL) are catecholamine secreting tumours associated with significant morbidity and mortality. Timely diagnosis and management are essential. A range of laboratory tests can be utilised in the investigation of PPGL. There is scope for significant variation in practice between centres. We aimed to investigate how the laboratory investigation of PPGL is performed in laboratories across the United Kingdom. METHODS: A questionnaire consisting of 21 questions was circulated to Clinical Biochemistry laboratories in the United Kingdom via the Association for Clinical Biochemistry and Laboratory Medicine office. The survey was designed to allow audit against Endocrine Society Guidelines on the Investigation and Management of PPGL and to obtain information on other important aspects not included in these guidelines. RESULTS: Responses were received from 58 laboratories and the data were compiled. The majority of laboratories use either urine or plasma metanephrines in first-line testing for PPGL, although a number of different combinations of biochemistry tests are utilised in different centres. All laboratories measuring metanephrines or catecholamines in-house use LC or LC-MS/MS methods. There are some marked differences between laboratories in urine metanephrines reference ranges used and sample requirements. CONCLUSIONS: There is evidence of good practice in UK laboratories (as assessed against Endocrine Society Guidelines) such as widespread use of urine/plasma metanephrines and appropriate analytical methodologies used. However, there is also evidence of variations in practice in some areas that should be addressed.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Cromatografía Liquida , Humanos , Laboratorios , Metanefrina , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. METHODS: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. RESULTS: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. CONCLUSIONS: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.
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Neoplasias de las Glándulas Suprarrenales , Metanefrina , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Cromatografía Liquida , Dopamina/análogos & derivados , Humanos , Normetanefrina , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Many young adults with Duchenne Muscular Dystrophy (DMD) receive long-term glucocorticoids (GC). GC can cause hypogonadotrophic hypogonadism and adolescents may therefore be candidates for pubertal induction. It is unclear whether men with DMD on or off GC have age-appropriate endogenous testosterone production. METHODS: We undertook a quality improvement project to assess the feasibility of measuring salivary testosterone (SalT) levels in men with DMD at home. A Sal-T sampling kit was sent by post to all patients with DMD, aged 17 and older, registered at the John Walton Muscular Centre in Newcastle (n = 75). Submitted Sal-T samples were collected and submitted for analysis. RESULTS: Twenty-eight out of seventy-five patients returned samples (age range: 17-34 years). 6/28 samples were unsuitable for analysis. Overall Sal-T levels (n = 22) were significantly lower than in the healthy population (178 ± 107 v 287 ± 109 pmol/l, p = 0.0001). Sal-T was lower in those on GC compared to those off GC (144 ± 81 versus 218 ± 125 pmol/l, p = 0.05). Three patients were unable to collect a sample due to ventilator dependence. CONCLUSION: Sal T can provide information about androgen status in DMD patients at home, overcoming barriers such as mobility difficulties and challenging venepuncture. However we only obtained samples in a minority of patients suggesting that Sal-T measurement may not be appropriate or acceptable to everyone. There needs to be a more detailed exploration of the barriers to sample submission.
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Distrofia Muscular de Duchenne/metabolismo , Juego de Reactivos para Diagnóstico/normas , Saliva/metabolismo , Testosterona/metabolismo , Adolescente , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Saliva/química , Testosterona/análisis , Adulto JovenAsunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Vitamina D , Betacoronavirus , COVID-19 , Humanos , SARS-CoV-2 , Vitamina D/análogos & derivadosRESUMEN
Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a potentially underdiagnosed inherited dyslipidemia associated with greatly increased risk of coronary and peripheral vascular disease. The mixed hyperlipidemia observed in this disorder usually responds well to appropriate medical therapy and lifestyle modification. Although there are characteristic clinical features such as palmar and tuberous xanthomata, associated with dysbetalipoproteinemia, they are not always present, and their absence cannot be used to exclude the disorder. The routine lipid profile cannot distinguish dysbetalipoproteinemia from other causes of mixed hyperlipidemia and so additional investigations are required for confident diagnosis or exclusion. A range of investigations that have been proposed as potential diagnostic tests are discussed in this review, but the definitive biochemical test for dysbetalipoproteinemia is widely considered to be beta quantification. Beta quantification can determine the presence of "ß-VLDL" in the supernatant following ultracentrifugation and whether the VLDL cholesterol to triglyceride ratio is elevated. Both features are considered hallmarks of the disease. However, beta quantification and other specialist tests are not widely available and are not high-throughput tests that can practically be applied to all patients with mixed hyperlipidemia. Using apolipoprotein B (as a ratio either to total or non-HDL cholesterol or as part of a multi-step algorithm) as an initial test to select patients for further investigation is a promising approach. Several studies have demonstrated a high degree of diagnostic sensitivity and specificity using these approaches and apolipoprotein B is a relatively low-cost test that is widely available on high-throughput platforms. Genetic testing is also important in the diagnosis, but it should be noted that most individuals with an E2/2 genotype do not suffer from remnant hyperlipidemia and around 10% of familial dysbetalipoproteinemia cases are caused by rarer, autosomal dominant mutations in APOE that will only be detected if the gene is fully sequenced. Wider implementation of diagnostic pathways utilizing apo B could lead to more rational use of specialist investigations and more consistent detection of patients with dysbetalipoproteinemia. Without the application of a consistent evidence-based approach to identifying dysbetalipoproteinemia, many cases are likely to remain undiagnosed.
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Hiperlipoproteinemia Tipo III/diagnóstico , Hiperlipoproteinemia Tipo III/metabolismo , Hiperlipoproteinemia Tipo III/fisiopatología , Colesterol/análisis , Humanos , Laboratorios , Lipoproteínas/análisis , Lipoproteínas VLDL/análisis , Triglicéridos/análisisRESUMEN
BACKGROUND: Familial dysbetalipoproteinemia is associated with the accumulation of remnant lipoproteins and premature cardiovascular disease. Identification of dysbetalipoproteinemia is important because family members may be affected. Diagnostic testing involves demonstration of ß-lipoprotein in the VLDL fraction or characterization of apo E3. These investigations are complex and relatively expensive. The ratios of apo B to total cholesterol and triglycerides have been proposed as screening tests. However, the ratio of non-HDL cholesterol to apo B (NHDLC/apoB) could offer improved performance as the confounding effect of variations in HDL cholesterol is removed. METHODS: We evaluated NHDLC/apoB as a screening test for dysbetalipoproteinemia, using ß-quantification analysis as a reference standard. Data from 1637 patients referred over a 16-year period for ß quantification were reviewed retrospectively. In 63 patients, diagnostic criteria for dysbetalipoproteinemia (VLDL cholesterol/triglyceride ratio ≥0.69 and presence of ß-VLDL) were fulfilled, and 1574 patients had dysbetalipoproteinemia excluded. RESULTS: Mean NHDLC/apoB in patients with dysbetalipoproteinemia was 7.3 mmol/g (SD, 1.5 mmol/g) and with dysbetalipoproteinemia excluded was 4.0 mmol/g (SD, 0.5 mmol/g). The optimum cutoff of >4.91 mmol/g achieved a diagnostic sensitivity of 96.8% (95% CI, 89.0-99.6) and specificity of 95.0% (95% CI, 93.8-96.0). NHDLC/apoB offered improved performance compared to total cholesterol/apoB [diagnostic sensitivity 92.1% (95% CI, 82.4-97.4) and specificity 94.5% (95% CI, 93.2-95.6) with a cutoff of >6.55 mmol/g]. NHDL/apoB reference ranges were not sex-dependent, although there was a significant difference between men and women for total cholesterol/apoB. CONCLUSIONS: NHDLC/apoB offers a simple first-line test for dysbetalipoproteinemia in selecting patients with mixed hyperlipidemia for more complex investigations.
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Apolipoproteínas B/sangre , Colesterol/sangre , Hiperlipoproteinemia Tipo III/diagnóstico , Lipoproteínas VLDL/sangre , Triglicéridos/sangre , Área Bajo la Curva , Femenino , Humanos , Masculino , Nefelometría y Turbidimetría , Curva ROC , Estudios Retrospectivos , Factores Sexuales , UltracentrifugaciónRESUMEN
Background Measurement of plasma metanephrines is regarded as one of the best screening tests for phaeochromocytoma/paraganglioma. Current guidelines recommend that samples are ideally collected in the supine position after 30 min rest and interpreted using supine reference ranges, in order to optimize the diagnostic performance of the test. Current practice in our centre is to collect samples for plasma metanephrines from seated patients. The aim of the study was to determine, if seated sampling for plasma metanephrines provides acceptable diagnostic performance in our centre. Methods Clinical and laboratory data of 113 patients, gathered over a four-year period 2010-2014, were reviewed. All had undergone preoperative plasma metanephrines measurement and had postoperative histopathology confirmation or exclusion of phaeochromocytoma/paraganglioma. Results Of 113 patients included in the study, 40 had a histological diagnosis of phaeochromocytoma/paraganglioma. The remaining 73 patients had an alternative adrenal pathology. The diagnostic sensitivity of normetanephrine or metanephrine above the upper limit of our in-house seated reference range was 93%. However, excluding three cases of paraganglioma determined clinically and biochemically to be non-functional raised the sensitivity to 100%. Diagnostic specificity was 90%. Applying published supine reference ranges made no difference to diagnostic sensitivity in this group of patients but decreased diagnostic specificity to 75%. Conclusions While these data are derived from a relatively small study population, they demonstrate acceptable diagnostic performance for seated plasma metanephrines as a screening test for phaeochromocytoma/paraganglioma. These data highlight a high diagnostic sensitivity for plasma metanephrines with seated sampling in our centre.
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Neoplasias de las Glándulas Suprarrenales/diagnóstico , Biomarcadores de Tumor/sangre , Metanefrina/sangre , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Postura , Adolescente , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paraganglioma/sangre , Paraganglioma/patología , Posicionamiento del Paciente/métodos , Feocromocitoma/sangre , Feocromocitoma/patología , Guías de Práctica Clínica como Asunto , Valores de Referencia , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
CONTEXT: Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 µg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. METHODS: We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. RESULTS: In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348ânmol/l provided 100% specificity for passing the SST; a cortisol value <34ânmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. CONCLUSION: Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.
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Insuficiencia Suprarrenal/inducido químicamente , Insuficiencia Suprarrenal/diagnóstico , Cosintropina , Glucocorticoides/efectos adversos , Hidrocortisona/sangre , Administración por Inhalación , Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/epidemiología , Adulto , Glucocorticoides/administración & dosificación , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Prevalencia , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
Diagnosis and management of pancreatic cyst lesions is challenging as there is currently no investigation that offers both high diagnostic sensitivity and high specificity for the identification of potentially malignant lesions. Accurate classification of these lesions is vital in order to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of lesions that are malignant/pre-malignant. Pancreatic cyst fluid analysis has an important role in diagnosis, although all currently available investigations based on fluid analysis have significant limitations. Cytological analysis can reveal features that are specific for a certain class of cyst, but offers limited sensitivity in detecting malignant/pre-malignant cysts. Measurement of tumour markers, particularly carcinoembryonic antigen can also be informative. Concentrations of cyst fluid carcinoembryonic antigen tend to be higher in malignant/pre-malignant cysts, although there is a wide overlap between the various classes of cyst. A number of studies have suggested that diagnostic carcinoembryonic antigen cut-offs can be chosen that provide a high degree of specificity but limited sensitivity. Studies of the analytical validity of tumour marker assays in pancreatic cyst fluid analysis have highlighted discrepancies in some fluid specimens, which require further investigation. DNA analysis also has a role. In particular, K-Ras-2 mutational analysis appears to provide high specificity for detection of malignant/pre-malignant lesions. A number of diagnostic algorithms have been published, integrating use of available investigations in order to achieve the optimum discrimination of benign and potentially malignant cysts. Research into new biochemical markers and optimal use of available pancreatic cyst fluid analyses is ongoing.