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‘Appropriate Diagnostics’ Launch Event(N.B. includes important changes to pathology services)

Dear colleagues,

We would like to warmly invite you to the TST Appropriate Diagnostics launch event to be held on Wednesday 28th September at 6:30 – 8.30pm at Stratford Circus, E15 1BX.

Over the next five years, we believe that – by working together - we could save £20m of waste on unnecessary testing and, most importantly, do the right thing for our patients by reducing the negative impact of over-diagnosis. We will be positively seeking your feedback on our plans.

The evening will include a lecture outlining the evidence base and harms of over treatment, previous success stories and patient vignettes as shared by Dr Julian Treadwell, Co-Chair, National RCGP Over-diagnosis Group.

The programme of changes to diagnostic testing (pathology and radiology) being implemented in the next few months will also be outlined. Our first batch of changes include: ESR, Urea and Electrolytes, GGT and ALT testing, as well as links to iRefer (for radiology referral best practice).

CPD certificates will be awarded to attendees – please reserve your place as soon as possible here: https://tstappropriatediagnosticslaunchevent.eventbrite.co.uk. We believe that this will prove to be a thought provoking agenda and really look forward to your input and discussion.

This is the first of our regular bulletins to inform you of the improvements that are underway to develop clinical guidelines and update requesting and reporting of results.

Please see the attachment for more information – if you have any questions or comments about the programme, please contact us or Babar Shafiq, our TST Programme Manager ([email protected]).

Very best wishes,

Dr Stuart SuttonProf Finbarr CotterDr Matthew Matson

[email protected]@[email protected]

GP Board MemberClinical Director, PathologyClinical Director, Imaging

Newham CCGBarts HealthBarts Health

Co-Chairs, TST Diagnostics Working Group

The TST Diagnostics Working Group is clinically led and co-chaired by Professor Finbarr Cotter, (Barts Health Clinical Director for Pathology), Dr Matthew Matson (Barts Health Clinical Director for Imaging) and Dr Stuart Sutton (Newham CCG GP Board Member). Dr Dinesh Kapoor (Waltham Forest CCG GP Clinical Director) and Dr Shah Ali (Tower Hamlets CCG GP Board Member) are providing strategic Primary Care input to the group to ensure each TST borough is represented. Dr Ruth Ayling (Consultant Chemical Pathologist) is providing the group’s expert biochemistry advice.

Changes to Diagnostics & Associated Guidelines

ESR testing

· ESR testing is one of the most frequently over used tests in clinical practice and has extremely poor sensitivity for ruling out serious disease

· Measurement of more than one marker of inflammation is generally not indicated and CRP would, in most cases, be the appropriate first line test

· Please find attached the Barts Health Guidelines for ESR testing as well as a BMJ article outlining the evidence base (or lack of!) for ESR in clinical practice

· With the exception of a normal result being useful in ruling out myeloma and Giant Cell Arteritis, ESR is not recommended

· We have included population standardised ESR and CRP request graphs for each of the three boroughs to help you identify whether your practice could look at reducing the number of inappropriate ESR tests requested and/or the number of inflammatory markers requested overall

Changes to the LFT panel – removal of GGT

· Gamma Glutamyl Transferase (GGT) has been removed from the standard panel of Liver Function Tests

· GGT has limited clinical value other than for potentially identifying whether an isolated rise in ALP is related to liver disease

· GGT has a high false-positive rate and the degree of abnormality is not indicative of severity of any hepatic disease

· Please see the attached BALLETS (Birmingham and Lambeth Liver Evaluation Testing Strategies) paper for more information

Use of ALT for statin monitoring

· Current guidance (http://cks.nice.org.uk/lipid-modification-cvd-prevention#!prescribinginfosub) advises the testing of ALT only (not full LFTs) for statin monitoring – before, at 3 months and at 12 months after starting treatment

· ALT is now available as a separate test and should be used alone for monitoring patients who are taking a statin

Removal of Urea from U&Es panel

· Creatinine is the key marker for identifying and monitoring chronic renal disease in primary care

· Newham practices have not received Urea as part of their ‘U&Es’ panel for many years, whilst in Waltham Forest and Tower Hamlets this is still automatically added to every request

· Urea is of little clinical value in addition to creatinine in the vast majority of primary care monitoring situations and therefore we plan to remove urea from the standard U&E panel

· Please note that Urea will still be available as a separate test outside the U&E panel where it is clinically indicated

· Please see the ‘Best Tests’ paper below which outlines the limited role for Urea testing in primary care

iRefer Radiology Software

· iRefer has been developed by the Royal College of Radiologists to help primary and secondary care clinicians choose the most appropriate investigation for a given clinical problem

· The guidelines are free and can be accessed from any NHS network. There is also an app (small charge) available for iOS devices.

· Click here: http://nww.irefer.nhs.uk/ to access the guidelines free from any NHS network

Use of Ultrasound in place of MRI as first line imaging in painful shoulder

· iRefer (as well as consensus from Barts MSK imaging clinical lead) clearly reports that ‘US is the investigation of choice in the assessment of rotator cuff and surrounding soft tissues’

· As well as being a less time consuming or distressing investigation for patients (especially for those with claustrophobia) ultrasound is £120 cheaper than an MRI

· We would like to suggest that, whenever considering investigating a painful shoulder, colleagues should consider an US (+/- Xray if indicated) as the most appropriate first line investigation

Use of TQuest for pathology requesting

· As the work of the Appropriate Diagnostics group continues, there will be significant changes to TQuest to support clinicians to easily identify the most appropriate first line tests – with plans for additional links to evidence based resources and prompts

· The uptake of TQuest across Tower Hamlets is high but usage across Waltham Forest and Newham is more variable – as a result your local clinical leads will be working closely with practices to support you to implement TQuest requesting within your practice

· Use of TQuest hugely reduces the administrative workload in the pathology laboratories and improves the accuracy of transfer of results to the correct clinician and is therefore a win-win for both primary care and Barts Health!

Barts Health ESR

policy.docx

MEASUREMENT OF INFLAMMATORY MARKERS

The laboratory receives frequent requests for measurement of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).

One indication for such measurements is to detect acute inflammation that might indicate specific disease. There are very few situations in which testing of inflammatory markers is the optimum “rule in” or “rule out” test – although it is likely to be useful in certain conditions e.g. suspected polymyalgia rheumatic, giant cell arteritis or myeloma. (ESR).

It has been reported previously that over a quarter of laboratory requests for inflammatory markers are for non-specific diagnostic purposes. When used as a general marker to differentiate between the presence and absence of disease the tests are generally unhelpful. The presence of an inflammatory marker concentration within the reference range does not necessarily indicate the absence of disease and an incidental minor elevation may be difficult to interpret and can lead to unnecessary further investigation. Moreover, ESR is notoriously non-specific and can be spuriously elevated e.g. by renal failure, hypercholesterolaemia, extreme obesity, pregnancy and advanced age and lowered e.g. by polycythaemia, heart failure and cachexia.

Inflammatory markers are also used to monitor response to treatment response.

Summary

· Inflammatory markers are too non-specific to be a useful tool for diagnosing serious underlying disease

· The finding of a normal inflammatory marker concentration may be helpful in ruling out a few very specific conditions e.g. polymyalgia rheumatic/giant cell arteritis, myeloma

· Measurement of more than one inflammatory marker simultaneously is not generally required

The laboratory proposes that CRP should be the first line test for assessment of inflammation, with ESR reserved for patients suspected of having possible polymyalgia rheumatic, giant cell arteritis or myeloma.

RM Ayling 6.15

BMJ Inflammatory

Markers Article.pdf

RATIONAL TESTING

Raised inflammatory markersWhat is the evidence for using C reactive protein, erythrocyte sedimentation rate, and plasmaviscosity in diagnosis?

JessicaWatson academic clinical fellow, specialist trainee year 1 in general practice1, Alison Roundgeneral practitioner2, William Hamilton general practitioner and professor of primary care diagnostics3

1School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK; 2Castle Place Practice, Tiverton EX16 6NP, UK; 3PeninsulaCollege of Medicine and Dentistry, Exeter EX2 4SG, UK

This series of occasional articles provides an update on the best useof key diagnostic tests in the initial investigation of common or importantclinical presentations. The series advisers are Steve Atkin, professor,head of department of academic endocrinology, diabetes, andmetabolism, Hull York Medical School; and Eric Kilpatrick, honoraryprofessor, department of clinical biochemistry, Hull Royal Infirmary, HullYork Medical School. To suggest a topic for this series, please emailus at [email protected].

A 72 year old man consulted a general practitioner colleagueof ours last week complaining of a non-specific feeling ofmalaise for about three weeks, with mild headache and pain inhis left knee. He has generalised moderate osteoarthritis, mainlyaffecting his back and both knees. Our colleague had foundnothing relevant on examination and had ordered several bloodtests. A full blood count and liver and renal function werenormal, but the erythrocyte sedimentation rate was moderatelyraised at 35 mm/h.

What is the role of inflammatorymarkers?Measurement of inflammatory markers has twomain functions:to detect acute inflammation that might indicate specificdiseases, or to give a marker of treatment response (we will notconsider this second indication here). Measurement ofinflammatory markers can also be used as a general, butnon-specific, test for serious underlying disease. Inflammatorymarkers are measured in about 4% of general practitionerconsultations, for a range of indications, with 44-47% requestedfor specific diagnostic purposes, 27-33% for monitoring ofdisease, and 14-28% for non-specific diagnostic purposes.1 2There is considerable inter-practice variation in themeasurementof inflammatory markers and in general practitioners’ responsesto abnormalities.1 3 4 We found no health-economic analyses ofthese tests, but the total costs of testing must be considerable.For example, 63 000 primary care requests for inflammatorymarkers are tested annually at the University Hospitals BristolNHS Foundation Trust, which serves a population of about 300

000 in 40 general practices (personal communication, WWoltersdorf, 2011).Diseases with prominent activation of the inflammatory responsefall into three main groups: infections, autoimmune diseases,and some haematological malignancies. Inflammatory markersinclude C reactive protein (CRP), erythrocyte sedimentationrate, plasma viscosity, fibrinogen, ferritin, and several otheracute phase proteins, though only the first three are commonlyreferred to as inflammatory markers. CRP is considered to beparticularly useful in detecting bacterial infection.4 Plasmaviscosity is now generally preferred to the erythrocytesedimentation rate (ESR), as it is unaffected by anaemia orpolycythaemia, or by delays between sampling andmeasurement, and has results independent of age or sex.5 Allthese factors potentially affect the ESR. The change to use ofviscosity is relatively recent, so most reports have studied theESR or CRP. This article considers the evidence for and therational use of CRP, ESR, and viscosity in diagnosis, both forspecific diseases and non-specifically.

Diagnostic testing for specific diseasesThe classic conditions for which testing may be useful arepolymyalgia rheumatica or giant cell arteritis, recently reviewedin the BMJ.6 Systemic features may predominate, with myalgiaor headache minor or absent. A normal viscosity or ESR andnormal CRP virtually rules out the condition. False negativeresults are rare—probably below 3%—though studies examiningthis required a positive result from a temporal artery biopsy, sothe patients evaluated would have had more severe disease.6Another condition with characteristic raised inflammatorymarkers is myeloma.7 If polymyalgia rheumatica, giant cellarteritis, or myeloma are suspected, measurement ofinflammatory markers is a simple “rule out” test: normalinflammatory markers make the chance of any of these diseasesbeing present so low as to allow the clinician to omit specific

Correspondence to: W Hamilton [email protected]

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2012;344:e454 doi: 10.1136/bmj.e454 (Published 3 February 2012) Page 1 of 5

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Learning points

Normal levels of inflammatory markers are valuable in ruling out a few specific conditions, notably polymyalgia rheumatica, giant cellarteritis, myeloma, and infection of hip revisionsRaised levels of inflammatory markers may be found in many other conditions, particularly infections, autoimmune conditions, andcertain cancers. In these cases, they increase the probability of the condition being present, but additional information would be neededto be confident the disease is present or absentInflammatory markers are too non-specific to be a useful tool for diagnosing serious underlying disease and should rarely be used inthis situationIn an incidental finding of raised levels of inflammatory markers, if history and examination yield no clues as to cause, it is reasonableto wait and see if symptoms develop. If levels are markedly raised (such as ESR >100 mm/h), the likelihood of disease is much higher,but history, examination, and focused investigations are usually sufficient to establish a diagnosis

testing with protein electrophoresis and urinary Bence Jonesprotein.7

CRP and ESR have been studied as an aid to differentiatingbetween minor illness and more serious disease, either inprimary care or emergency departments. Some subjects havebeen systematically reviewed (table 1⇓). Most of these reviewsshow amoderate relation between raised inflammatory markersand the target condition, but almost always the authorsconcluded that the sensitivities and specificities, on their own,were insufficient to rule in or rule out the condition safely. Thiswas particularly so for primary care, where the prevalence ofthe target condition is usually lower. However, inflammatorymarkers may have some value as part of a clinical predictionrule incorporating other relevant clinical features, such as fever,although none seems to have entered mainstream clinicalpractice. One reason for this may be the inevitable delay inobtaining a result if the specimen requires analysis off site.Recent studies have examined whether CRP testing influencesthe decision to prescribe antibiotics for respiratory infectionsin primary care. One study in Norway, Sweden, and Walesfound that the CRP result was the strongest influence on thedecision to prescribe antibiotics, outweighing physical signssuch as crackles on auscultation.18A cluster randomised trial inthe Netherlands examined the effect of two interventions: CRPtesting or training in enhanced communication skills. Antibioticprescribing was significantly reduced in both interventiongroups—from 57% in control patients to 43% for those whosedoctors were in an intervention group.19 General practitionersresponded positively to having point of care access to CRP, asit enhanced patients’ and general practitioners’ confidence inprescribing decisions and empowered the doctors to prescribeantibiotics less often.20 In all these studies, negative tests seemedto give the doctors additional confidence in avoiding prescriptionof antibiotics: this is clinically supported by the negativelikelihood ratio of 0.33,11 meaning that bacterial infection isabout a third less likely once a negative test has been reported.The health economic aspects of point of care access to CRPtesting would need to be examined before its use was to berecommended.Observational studies have shown that inflammatory markersmay be raised in ovarian, renal, and colorectal cancers,especially in advanced disease.21-23 However, has been shownto have no discriminatory value in diagnosing these conditions,even in secondary care, where there is a higher prevalence thanin primary care.24

In summary, there are a few clinical situations in which testingof inflammatory markers is the optimum test, as either a “rulein” or a “rule out” test. These include suspected polymyalgiarheumatica or giant cell arteritis, myeloma (ESR or viscosity),and infection of hip revisions (ESR or CRP). In most conditions,however, there is only a moderate association between raisedinflammatory markers and the disease of interest, so they can

refine the probability of disease, particularly if the test result isused in conjunction with other factors, such as symptoms.

Non-specific testing for systemic diseaseThe previous paragraphs focus on the value of inflammatorymarkers when a specific disease is being considered. However,another use is as a general marker to differentiate between thepresence and absence of disease. Several old, mostly small,studies have examined this use (table 2⇓).25 Generally, whengeneral practitioners test inflammatory markers for non-specificpurposes the results are afterwards seen as being of little or noclinical value.2 “Incidental” abnormalities in inflammatorymarkers are difficult to interpret and can lead to expensive andpotentially harmful investigations. Although doctors may bereassured by negative testing when no disease is suspected,26diagnostic tests yielding normal results make hardly anydifference to the level of reassurance of patients.25

What is the interpretation of an abnormalresult?Interpreting an abnormal result is relatively straightforward ifthere is a clear pretest hypothesis against which the test resultcan be evaluated—for example, if assessing the likelihood ofserious infection in a child with a fever and abdominal pain.This was best shown in a Dutch study of patients in whom theraised ESR seemed to confirm an initial diagnosis as opposedto showing unexpected disease.29 The difficulty lies in theinterpretation of an “incidental” abnormality, when no specificdisease is suspected, as in our hypothetical case. A systemsinquiry, focusing on infection, autoimmune conditions, andmalignancy, plus examination of the patient should generallypoint towards specific investigations. If history and examinationyield no clues, it is reasonable to wait and see if symptomsdevelop rather than conduct an extensive search for occultdisease. This investigation plan is supported by studies that havefollowed up patients with unexplained increases in levels ofinflammatory markers. In one large (n=1462) study ofasymptomatic Swedish women, 60% of these increases weretransitory; none of the women with a raised ESR developedcancer; and in 46% of the women the cause of the increaseremained undiagnosed over six years of observation.30

In cases with markedly raised levels of inflammatory markers(such as ESR >100 mm/h) the likelihood of disease is muchhigher. The diagnoses found in these conditions depend on studysetting, but include infection (33-60%), inflammatory disease(14-30%), and malignancy (5-28%).7 24 31-33 No diagnosis isfound in fewer than 3% of patients with an ESR of >100 mm/h.In most patients, the diagnosis is likely to be clinically apparent;once again, history, examination, focused investigations, andcareful follow-up should be sufficient to establish a cleardiagnosis.



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OutcomeThe patient was asked to reattend surgery. His headache hadsettled, though he still felt non-specifically unwell. Nothinguntoward was found on history or examination. He graduallyimproved over the next two weeks without treatment or furtherinvestigation. Measurement of ESR was not repeated.

Contributors: JW and WH did the searches and drafted the article. Allauthors made revisions. WH is the guarantor.Competing interests: All authors have completed the ICMJE uniformdisclosure form at www.icmje.org/coi_disclosure.pdf (available onrequest from the corresponding author) and declare: no support fromany organisation for the submitted work; no financial relationships withany organisations that might have an interest in the submitted work inthe previous three years; no other relationships or activities that couldappear to have influenced the submitted work.Provenance and peer review: Commissioned; externally peer reviewed.Patient consent not required (patient anonymised, dead, or hypothetical).

1 Dahler-Eriksen BS, Lassen JF, Lund ED, Lauritzen T, Brandslund I. C-reactive protein ingeneral practice—how commonly is it used and why? Scand J Prim Health Care1997;15:35-8.

2 Gronlie M, Hjortdahl P. The erythrocyte sedimentation rate; its use and usefulness inprimary health care. Scand J Prim Health Care 1991;9:97-102.

3 Thue G, Sandberg S, Fugelli P. The erythrocyte sedimentation rate in general practice:clinical assessment based on case histories. Scand J Clin Lab Invest 1994;54:291-300.

4 Johnson HL, Chiou CC, Cho CT. Applications of acute phase reactants in infectiousdiseases. J Microbiol Immunol Infect 1999;32:73-82.

5 Kesmarky G, Kenyeres P, Rabai M, Toth K. Plasma viscosity: a forgotten variable. ClinHemorheol Microcirc 2008;39:243-6.

6 Hassan N, Dasgupta B, Barraclough K. Giant cell arteritis. BMJ 2011;342:d3019.7 Ford MJ, Innes JA, Parrish FM, Allan NC, Horn DB, Munro JF. The significance of gross

elevations of the erythrocyte sedimentation rate in a general medical unit. Eur J Clin Invest1979;9:191-4.

8 Wiwanitkit V. Maternal C-reactive protein for detection of chorioamnionitis: an appraisal.Infect Dis Obstet Gynecol 2005;13:179-81.

9 Sanders S, Barnett A, Correa-Velez I, Coulthard M, Doust J. Systematic review of thediagnostic accuracy of C-reactive protein to detect bacterial infection in nonhospitalizedinfants and children with fever. J Pediatr 2008;153:570-4.

10 Van den Bruel A, Thompson MJ, Haj-Hassan T, Stevens R, Moll H, Lakhanpaul M, et al.Diagnostic value of laboratory tests in identifying serious infections in febrile children:systematic review. BMJ 2011;342:d3082.

11 Flood RG, Badik J, Aronoff SC. The utility of serum C-reactive protein in differentiatingbacterial from nonbacterial pneumonia in children: a meta-analysis of 1230 children.Pediatr Infect Dis J 2008;27:95-9.

12 Falk G, Fahey T. C-reactive protein and community-acquired pneumonia in ambulatorycare: systematic review of diagnostic accuracy studies. Fam Pract 2009;26:10-21.

13 Van der Meer V, Neven AK, van den Broek PJ, Assendelft WJJ. Diagnostic value of Creactive protein in infections of the lower respiratory tract: systematic review. BMJ2005;331:26.

14 Holm A, Pedersen SS, Nexoe J, Obel N, Nielsen LP, Koldkjaer O, et al. Procalcitoninversus C-reactive protein for predicting pneumonia in adults with lower respiratory tractinfection in primary care. Br J Gen Pract 2007;57:555-60.

15 Bundy DG, Byerley JS, Liles EA, Perrin EM, Katznelson J, Rice HE. Does this child haveappendicitis? JAMA 2007;298:438-51.

16 Butalia S, Palda VA, Sargeant RJ, Detsky AS, Mourad O. Does this patient with diabeteshave osteomyelitis of the lower extremity? JAMA 2008;299:806-13.

17 Spangehl MJ, Masri BA, O’Connell JX, Duncan CP. Prospective analysis of preoperativeand intraoperative investigations for the diagnosis of infection at the sites of two hundredand two revision total hip arthroplasties. J Bone Joint Surg Am 1999;81:672-83.

18 Jakobsen KA, Melbye H, Kelly MJ, Ceynowa C, Molstad S, Hood K, et al. Influence ofCRP testing and clinical findings on antibiotic prescribing in adults presenting with acutecough in primary care. Scand J Prim Health Care 2010;28:229-36.

19 Cals JWL, Butler CC, Hopstaken RM, Hood K, Dinant G-J. Effect of point of care testingfor C reactive protein and training in communication skills on antibiotic use in lowerrespiratory tract infections: cluster randomised trial. BMJ 2009;338:b1374.

20 Cals JW, Chappin FH, Hopstaken RM, van Leeuwen ME, Hood K, Butler CC, et al.C-reactive protein point-of-care testing for lower respiratory tract infections: a qualitativeevaluation of experiences by GPs. Fam Pract 2010;27:212-8.

21 Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incidentcolorectal cancer. JAMA 2004;291:585-90.

22 Iversen OH, Roger M, Solberg HE, Wetteland P. Rising erythrocyte sedimentation rateduring several years before diagnosis can be a predictive factor in 70% of renal cellcarcinoma patients. The benefit of knowing subject-based reference values. J Intern Med1996;240:133-41.

23 Toriola AT, Grankvist K, Agborsangaya CB, Lukanova A, LehtinenM, Surcel HM. Changesin pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: alongitudinal study. Ann Oncol 2011.

24 Monig H, Marquardt D, Arendt T, Kloehn S. Limited value of elevated erythrocytesedimentation rate as an indicator of malignancy. Fam Pract 2002;19:436-8.

25 Van Ravesteijn H, van Dijk I, Darmon D, van de Laar F, Lucassen P, Hartman TO, et al.The reassuring value of diagnostic tests: a systematic review. Patient Educ Couns2012;86:3-8.

26 Dinant GJ, Knottnerus JA, van Wersch JW. Diagnostic impact of the erythrocytesedimentation rate in general practice: a before-after analysis. Fam Pract 1992;9:28-31.

27 Froom P, Margaliot S, Caine Y, Benbassat J. Significance of erythrocyte sedimentationrate in young adults. Am J Clin Pathol 1984;82:198-200.

28 Thomas PD, Goodwin JS. Diagnostic importance of an elevated erythrocyte sedimentationrate in the elderly. Clin Rheumatol 1987;6:177-80.

29 Dinant GJ, Knottnerus JA, van Wersch JW. Discriminating ability of the erythrocytesedimentation rate: a prospective study in general practice.Br J Gen Pract 1991;41:365-70.

30 Rafnsson V, Bengtsson C, Lennartsson J, Lindquist O, Noppa H, Tibblin E. Erythrocytesedimentation rate in a population sample of women with special reference to its clinicaland prognostic significance. Acta Med Scand 1979;206:207-14.

31 Fincher RM, Page MI. Clinical significance of extreme elevation of the erythrocytesedimentation rate. Arch Intern Med 1986;146:1581-3.

32 Lluberas-Acosta G, Schumacher HR, Jr. Markedly elevated erythrocyte sedimentationrates: consideration of clinical implications in a hospital population. Br J Clin Pract1996;50:138-42.

33 Wyler DJ. Diagnostic implications of markedly elevated erythrocyte sedimentation rate:a reevaluation. South Med J 1977;70:1428-30.

Cite this as: BMJ 2012;344:e454© BMJ Publishing Group Ltd 2012



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Tables

Table 1| Reviews of inflammatory markers for diagnosis of specific conditions

OutcomeStudy typeSettingTarget condition (test)

Summary sensitivity 73%, specificity 76%Systematic review (6 reports; 466patients)8

Secondary careChorioamnionitis in prematuredelivery (CRP)

Likelihood ratio of raised CRP 3.2 (95% CI 2.7 to 3.7);negative likelihood ratio 0.33 (0.23 to 0.49).10 Similarresults in second review9

Systematic reviews (5/6 reports onCRP/ESR; 1379 patients having CRP)910

Secondary careSerious infections in febrile children(CRP, ESR)

Pooled odds ratio for raised CRP and bacterialinfection 2.6 (1.2 to 5.6)

Systematic review (8 reports; 1230patients)11

Secondary careBacterial chest infection in children(CRP)

Likelihood ratio of raised CRP 2.1 (95% CI 1.8 to 2.4);negative likelihood ratio 0.33 (0.25 to 0.43). Similarresults in an earlier review13 and a subsequent studyin primary care14

Systematic review (8 reports, with 2194patients)12

Primary care; accident andemergency departments

Bacterial chest infection in adults(CRP)

Likelihood ratio of raised CRP increases as CRPincreases: 5.2 (1.7 to 16) for CRP >25 mg/L. Fornormal CRP, 0.44 to 0.47. For ESR >20 mm/h, 3.8(1.8 to 8.1)

Systematic review of all features ofappendicitis, including 5 studies of CRP,1 of ESR; 730 and 162 childrenrepsectivley15

Secondary care (mainlyemergency departments)

Appendicitis in children withabdominal pain (CRP, ESR)

Summary likelihood ratio of ESR >70 mm/h 11 (1.6 to79).

Systematic review of all features ofosteomyelitis, including 3 studies of ESR;92 patients16

Secondary care (inpatientsand outpatients)

Osteomyelitis of the leg in diabetes(ESR)

ESR >30 mm/h: sensitivity 0.82 (0.65 to 0.93),specificity 0.85 (0.78 to 0.91); CRP >100 mg/L 0.96(0.78 to 1.0), 0.92 (0.85 to 0.96). No patient with aninfected arthroplasty had negative result on both tests

Cohort study of 178 patients; 202arthroplasties 17

Secondary careInfection in revision hiparthroplasties (CRP, ESR)

CRP=C reactive protein; ESR= erythrocyte sedimentation rate. 95% CI= 95% confidence interval.



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Table 2| Community and primary care studies investigating the diagnostic role of inflammatory markers as diagnostic or screening toolsfor non-specific disease

OutcomeParticipantsStudy typeSetting (test)

44 had persistently raised ESR; of these, 10 subsequentlydeveloped disease (4 myocardial infarctions, 3 ankylosingspondylitis, and one each of inflammatory bowel disease,psoriasis, benign monoclonal gammopathy)

1000 healthy men aged 18-33 years:yearly ESR measurement

Prospective study, 15 yearfollow-up27

Israeli airmen (ESR)

9 subjects had an ESR >30 mm/h for ≥6 months; a previouslyundiagnosed illness was identified in 4 of these (2 polymyalgia,1 pancytopaenia, 1 anaemia)

100 healthymen and women aged over70 years

Prospective study, 12 monthfollow-up28

Community study of ageingin the US (ESR)

ESR values were on average higher in those with malignancyor inflammatory diseases. Almost all diagnoses“revealed” by the raised ESR had been suspected at the initialconsultation before the ESR result was known

362 patients presenting with a newcomplaint for which the generalpractitioner considered ESR to beindicated

Prospective study, 3 monthfollow-up29

Primary care in theNetherlands (ESR)

ESR=erythrocyte sedimentation rate.



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Standardised ESR

+CRP Requests Tower Hamlets.docx

Standardised ESR + CRP Requests (May 2016) Tower Hamlets

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ESR Requests CRP Requests – standardised for practice size

Standardised ESR

and CRP Requests Newham.docx

Standardised ESR + CRP Requests (May 2016) Newham

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Standardised

ESR+CRP requests Waltham Forest.docx

Standardised ESR + CRP Requests (May 2016) Waltham Forest

CRP ReqsDr Mohammed Dr Bailey Phillips & Patel Churchill MCRidgewaySinnott Road MicrofacultyOrient PracticeFrancis Road MCChingford MPHandsworth MPAllum MCClaremont MCThe FirsLime Tree Old ChurchHigh RoadLeyton Green Vicarage Rd MCThatched House Langthorne HCSMA MPLangthorne St James MPAddison Rd MPDr Dhital Queens Rd MCPenrhyn EcclesbourneDr Shantir Hampton MCHarrow RdLyndhurst Leyton Waltham Fst C/FCrawley Rd MCManor Kings Head MPHigham Hill Larkshall MCKiyani MPHayat MC161107949999268363828173779272745769465910384677434843493648395215413232138241015177ESR reqsDr Mohammed Dr Bailey Phillips & Patel Churchill MCRidgewaySinnott Road MicrofacultyOrient PracticeFrancis Road MCChingford MPHandsworth MPAllum MCClaremont MCThe FirsLime Tree Old ChurchHigh RoadLeyton Green Vicarage Rd MCThatched House Langthorne HCSMA MPLangthorne St James MPAddison Rd MPDr Dhital Queens Rd MCPenrhyn EcclesbourneDr Shantir Hampton MCHarrow RdLyndhurst Leyton Waltham Fst C/FCrawley Rd MCManor Kings Head MPHigham Hill Larkshall MCKiyani MPHayat MC1081481211011011629411089829078597874846989711157062306452565062484528542634334940213326217


BALLET LFT

study.pdf

Scientific summaryBirmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS)Health Technology Assessment 2013; Vol. 17: No. 28 DOI: 10.3310/hta17280

NIHR Journals Library www.journalslibrary.nihr.ac.uk

Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study

RJ Lilford,1* L Bentham,1 A Girling,1 I Litchfield,1 R Lancashire,1 D Armstrong,2 R Jones,2 T Marteau,3 J Neuberger,1 P Gill,1 R Cramb,4 S Olliff,4 D Arnold,5 K Khan,4 MJ Armstrong,6 DD Houlihan,6 PN Newsome,6 PJ Chilton,1 K Moons7 and D Altman8

1School of Health and Population Sciences, University of Birmingham, Edgbaston, UK

2Department of Primary Care and Public Health Sciences, Kings College London, London, UK

3Health Psychology Section, Kings College London, London, UK4Queen Elizabeth Hospital Birmingham, Birmingham, UK5School of Medicine, Cardiff University, Cardiff, UK6National Institute for Health Research Biomedical Research Unit, Birmingham, UK7Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands8Centre for Statistics in Medicine, University of Oxford, Oxford, UK

*Corresponding author


SCIENTIFIC SUMMARY: BIRMINGHAM AND LAMBETH LIVER EVALUATION TESTING STRATEGIES (BALLETS)

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Scientific summary

Background

Many millions of liver function tests (LFTs) are performed in England each year. Yet it is not known whether or not it is appropriate to order so many LFTs, what should be done when the LFT result is abnormal, and which of the analytes that might be included in the LFT ‘panel’ are most useful. These uncertainties all stem from ignorance about what LFT results mean in terms of the probabilities of the various diseases they may portend. This state of affairs has come about because almost all of the 14,000 studies reviewed in the literature describe laboratory findings given a disease. The Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study set out to describe the probability of the various diseases given the pattern of abnormal LFTs. BALLETS achieved this objective by generating a large cohort of people with abnormal LFT results in primary care, fully characterising these people on the basis of clinical features and special investigations and then following them up after 2 years.

Objectives

The primary objective was to measure the probabilities of various diseases (or classes of diseases) when LFT results are abnormal and to determine how these probabilities vary according to the type of LFT abnormality and the clinical features of each patient. The secondary objectives were to evaluate the extent to which abnormal LFT results progressed or remitted over a 2-year period; to find out which combinations of clinical features and laboratory tests best predict ‘fatty liver’; to determine proportions of ‘fatty livers’ that progressed, improved or stayed the same; to investigate the effect of ultrasound findings on health behaviour; and to investigate redundancy among LFT analytes. We also set out to:

z measure the psychological effects of positive LFT and ultrasound tests z explore the effect of these tests on attitudes towards unhealthy behaviours z document general practitioners motivations for ordering LFTs z model the efficiency of various options when LFT test results are abnormal z obtain preliminary information on use of a liver fibrosis scale in primary care.

Methods

We created a cohort of 1290 patients with abnormal LFT results in primary care and characterised them fully by means of their clinical details, an extensive battery of blood tests and ultrasound examination of the upper abdomen. We also followed up the patients after 2 years. Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFTs and the following categories:

1. specific viral, genetic and autoimmune diseases of the liver, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis

2. a range of other serious diseases affecting the liver, such as metastatic cancer and hypothyroidism3. ‘fatty liver’ not associated with the above4. no disease detected.

These interactions were explored by means of univariate analyses and multivariate analyses carried out with and without imputations for missing data. We also examined the influence of lifestyle and of weight loss on ‘fatty liver’, and then looked for evidence that the finding of a ‘fatty liver’ would motivate people to lose weight.

© Queen’s Printer and Controller of HMSO 2013. This work was produced by Lilford et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 28 (SCIENTIFIC SUMMARY)

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In addition, we studied the psychological effects of receiving an abnormal test result. Patients were sent a validated psychological questionnaire to measure anxiety and self-reported health on entry to the study and again at the 2-year follow-up point. A qualitative study was conducted after 2 years to explore perceptions of the effects of participating in the BALLETS study, and of abnormal test results, on behaviours and attitudes toward health. Clinicians’ motivations for ordering LFTs were explored by means of a semistructured interview. We created a decision-analytic model to evaluate strategies that might be pursued in the face of an abnormal LFT result and to identify the most efficient option. Lastly, we conducted a preliminary study of a liver fibrosis score that might identify cases of ‘fatty liver’ at greatest risk of progression.

Results

1. Fewer than 5% of people with abnormal LFT results had a specific disease affecting the liver and there was a serious liver disease requiring immediate therapy in 1.3% of cases (all 13 cases of viral hepatitis and four cases of homozygous haemochromatosis).

2. The majority of serious or potentially serious diseases can be detected by just two analytes alanine aminotransferase (ALT) and alkaline phosphatase (ALP) from the LFT panel of eight analytes. The ALT enzyme is sensitive for hepatocellular disease, whereas ALP is sensitive for both hepatobiliary diseases and systemic diseases (such as metastatic cancer) affecting the liver.

3. Aspartate aminotransferase (AST) adds little to ALT and is considerably less sensitive (although it is slightly more specific).

4. The gamma-glutamyltransferase (GGT) enzyme was the most frequently abnormal analyte with a very high false-positive rate, but offered only a marginal increase in sensitivity in return. Unlike other analytes, the degree of abnormality is not indicative of the probability of disease. This is consistent with the poor discriminatory characteristics of this test in determining the presence, or absence, of pathology. GGT levels were sensitive, however, to alcohol intake.

5. Protein levels (albumin, globulin and total protein) are the least frequently abnormal analytes and they are typically only very ‘mildly’ abnormal. Albumin increases with age and comorbidity, but was not strongly related to any disease involving the liver.

6. Viral hepatitis was found in 1% of patients. Nine of the 13 patients with chronic viral hepatitis had more than one abnormal analyte and ALT was the most commonly abnormal analyte, followed closely by AST. The degree of ALT and AST abnormalities was, on average, considerably higher in patients with viral hepatitis than in the remaining patients. Country of origin (not ethnic group) was, by a considerable margin, the strongest predictor of viral hepatitis.

7. Guidelines recommend repeating LFTs in the event of an abnormal result, but 84% of tests remained abnormal on retesting after an average of 1 month, and even at 2 years 75% remained abnormal. Modelling confirmed the intuition that it is frequently more efficient, when confronted by an abnormal LFT, to proceed directly to a specific test rather than repeat the LFT with a view to specific testing only if it remains abnormal.

8. Nearly 4 in 10 patients had a ‘fatty liver’ on ultrasound, and an abnormal ALT level was the strongest laboratory predictor of this finding. Obesity was more strongly associated with ‘fatty liver’ than with alcohol use, but one-quarter of patients with ‘fatty liver’ were neither overweight nor excessive alcohol drinkers.

9. A small amount of weight loss over 2 years (1.3% reduction in body mass index) was associated with a reduced incidence of ‘fatty liver’. There was a J-shaped relationship between alcohol intake and ‘fatty liver’ in men.

10. An abnormal LFT result generated anxiety and this anxiety was non-significantly greater if the liver was ‘fatty.’ However, anxiety dissipated over 2 years. Recall of an abnormal test result was hazy after 2 years and a tendency towards greater weight loss in patients with ‘fatty liver’ was not statistically significant.


SCIENTIFIC SUMMARY: BIRMINGHAM AND LAMBETH LIVER EVALUATION TESTING STRATEGIES (BALLETS)

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11. Doctors’ motivations for performing LFTs are mixed, and the tests are often carried out to meet perceived patient need for a ‘blood test’ or as a defensive practice. There was evidence that they were often undertaken as a semiautomatic or ‘tick-box’ response.

12. Eight per cent of patients with non-alcoholic ‘fatty liver’ had a fibrosis score that has been shown to be associated with a progressive disease in hospital-based studies.

Conclusions

1. It is unusual for an abnormal LFT result to signify a serious treatable disease of which the doctor was previously unaware.

2. Liver function tests are often carried out for social and psychological, rather than clinical, reasons. Given the high false-positive rate of LFTs and the fact that an abnormal result does not signal any particular disease, we recommend a more selective approach to this particular ‘blood test’.

3. Aspartate aminotransferase is less sensitive than ALT for hepatocellular diseases, and GGT is very non-specific. There is a case for omitting these tests from the standard LFT panel and holding them in reserve for patients in whom alcohol abuse is suspected.

4. The standard advice to repeat an abnormal LFT does not gain support from the decision model and was one of the least efficient strategies with respect to diagnosis of viral hepatitis.

5. Country of origin is the strongest predictor of viral hepatitis among people with abnormal LFTs.6. An abnormal ALT is strongly predictive of a ‘fatty liver’, as is obesity. If a person is obese and has a

high ALT then an ultrasound diagnosis of ‘fatty liver’ is very probable.7. There is no good evidence that single abnormal LFTs or ultrasound findings promote

healthy behaviour.

Implications for practice

1. Liver function tests should be used sparingly in primary care.2. The default LFT panel of five to eight analytes is obsolete.3. When a chronic disease affecting the liver is suspected, a panel of two analytes (ALT and ALP) should

be used, supplemented by bilirubin if an acute disease or poisoning is suspected.4. When the clinician wishes to exclude a non-liver disease or simply reassure the patient, a selection

should be made from a ‘dropdown’ menu of tests, and tests that provide a clear pointer to the next appropriate step should be favoured.

5. All patients who drink too much alcohol or who are obese should be given appropriate advice, irrespective of their LFT result. A single abnormal LFT does not promote healthy behaviour and use of serial LFTs to promote behaviour change is an unproven therapy that might do more harm than good.

Implications for research

1. A pilot study of a ‘customised’ approach to test ordering should be considered. The clinical value of different tests when patients have vague symptoms, such as tiredness or upper abdominal pain, should be evaluated. Likewise, the need to carry out more blood tests when patients are on treatment for chronic disease, such as hypertension, is unclear. There is a mismatch between the frequency with which blood tests are used to monitor chronic diseases and investigate symptoms, on the one hand, and scientific exploration of this subject, on the other.

2. The BALLETS cohort should be followed up over time to find out whether it is possible to identify the minority of patients with ‘fatty liver’ who are likely to progress to cirrhosis and to evaluate the fibrosis score in a primary-care setting.


HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 28 (SCIENTIFIC SUMMARY)

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3. A controlled study of the net effects of using serial LFTs (including liver ultrasound) as part of a package to reduce unhealthy behaviours should be seriously considered, especially in light of the rising incidence of obesity.

Funding

Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Publication

Lilford RJ, Bentham L, Girling A, Litchfield I, Lancashire R, Armstrong D, et al. Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study. Health Technol Assess 2013;17(28).


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Best Tests Urea

article.pdf

8 | December 2009 | best tests

Should we still be measuring urea?

www.bpac.org.nz keyword: urea

best tests | December 2009 | 9

Key point:In most situations choose eGFR or serum creatinine for assessing renal function

Over recent years the role of urea as a renal function test, has been mostly superseded by creatinine and more recently by the estimated glomerular filtration rate (eGFR). Despite urea being well recognised as less useful for routine investigation of renal function, there continues to be significant variation in the patterns of testing of urea throughout New Zealand.

Urea is a less reliable test of renal function

In the past “U&Es” (urea and electrolytes) was frequently requested for assessing renal function. Creatinine is now used in preference to urea as it has become recognised as a more constant measure of renal function (because it is an end-product of creatine metabolism in muscles). In constrast, urea is an end product of protein metabolism, therefore levels can vary for a number of reasons, see sidebar. For example, a high protein diet, tissue breakdown, major GI haemorrhage and corticosteroid therapy can lead to an increase in urea whereas a low protein diet and liver disease can lead to a reduction. Also, because 40–50% of urea filtered by the glomerulus may be reabsorbed by the tubules,1 urea is a less useful indicator of either glomerular or tubular function

Urea is not longer indicated in most situations. Although there are some limitations with creatinine, it is considered a better measure of renal function. Furthermore, the eGFR (calculated by the laboratory) reflects renal function more accurately even when the creatinine levels are normal.

In most situations choose eGFR or serum creatinine for assessing renal function

Although creatinine is widely used as a test of renal function and is raised in chronic renal failure, it is an insensitive marker of early renal loss. In many patients with early renal dysfunction, serum levels do not increase until at least 50% of the filtration capacity is lost.

Causes of a raised urea

Pre-renal:• increased hepatic production of urea:

– high protein diet

– gastrointestinal haemorrhage

– increased protein catabolism – trauma, major surgery, extreme starvation with muscle breakdown

• increased renal reabsorption of urea – any cause of reduced renal perfusion, for example, congestive cardiac failure, shock, severe diarrhoea

• iatrogenic e.g. drug therapy leading to an increased production of urea – corticosteroids

Renal:• any cause of acute or chronic renal failure

Post-renal:• any cause of urinary outflow obstruction

10 | December 2009 | best tests

eGFR has superseded creatinine measurement alone as the preferred measure of chronic renal disease because it reflects renal function more accurately even when the creatinine levels are normal. Creatinine and eGFR are recommended for screening and monitoring of patients with early loss of glomerular function.

The eGFR formula assumes a number of factors including normal diet, average weight and stable renal function, therefore it does not work in a number of situations, including:

• childrenunderage18

• patientswithacutechangesinrenalfunction,including dialysis

• vegetariansorpatientstakingsupplementssuchascreatine

• thosewithunusualmusclebulk,eitherverylow(wasting diseases, amputees) or high (very obese patients or body builders)

The formula was derived in Caucasians and, while it is used for other ethnic groups, it may underestimate renal function in Māori and Pacific Island patients who have relatively higher weight and muscle bulk.

For patients on diuretics or ACE-inhibitors monitor changes in renal function with with eGFR

Any changes in renal function associated with diuretics2 or ACE-inhibitors3 are best monitored with eGFR (as well as electrolytes).

Confirm acute renal failure with falling eGFR or rising creatinine

If the eGFR is found to be unexpectedly low, best practice is to exclude acute renal failure by a repeat eGFR and serum creatinine. Discuss urgently with the nephrology team if acute renal failure is confirmed and there is evidence of rising blood pressure, oedema, proteinuria or haematuria.

Both urea and creatinine are increased in acute renal failure. Previously the urea:creatinine ratio was used to distinguish between pre-renal and renal causes, but this is now considered unreliable. Instead, a serum creatinine greater than 250 μmol/L is suggestive of a renal cause with 90% probability.4

References:1. Traynor J, Mactier R, Geddes C, Fox J. How to measure renal

function in clinical practice. British Medical Journal. 2006; 333:733.

2. Drug monitoring – Monitoring diuretics in primary care. BT 2009;2:2-7

3. Making a difference in chronic kidney disease. Part 2: Management. BPJ 2009;22:30-7

4. Kyle C (Ed), A Handbook for the Interpreation of Laboratory tests. 4th Edition, 2008, Diagnostic Medlab.

5. Meyer TW, Hostetter TH. Medical Progress: Uremia. The New England Journal of Medicine 2007;357(13):1316

6. Vivanti A, Harvey K, Ash S, Battistutta D. Clinical assessment of dehydration in older people admitted to hospital What are the strongest indicators? Archives of Gerontology and Geriatrics. 2008; 47:340-55.

Does urea testing have a role in Primary Care

The role of urea is limited to the following:

Urea is used for managing dialysis in end stage renal failure

Both serum urea and creatinine may be required by nephrologists for dialysis patients.

In end stage renal failure (equivalent to CKD 5), urea levels are used as a proxy measure for all the metabolites that accumulate with poor renal excretion causing the symptoms of ‘uraemia’. When the decision to use peritoneal or haemo-dialysis, the prescription is adjusted on the urea levels in order to remove about two thirds of the total-body urea content during each treatment.5

Urea is rarely used for the assessment of hydration status

Initial assessment of dehydration is best made with clinical, rather than biochemical parameters.6 Occasionally urea may be helpful for the assessment of dehydration in the frail elderly, when clinical indicators are less reliable.

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