Harmonisation ofLaboratory Profiles

Tony Badrick

(AACB Harmonisation Committee)

The (Almost)Final Frontier –Profiles!

MBA

Why Profiles

• Screening?

• Diagnostic?

• Monitoring?

Core Tests in a Profile

• Is test specific to the organ or system?

• If not specific why include it?

• Does an abnormal result add additional diagnostic orprognostic information to the other tests?

• Does the added information justify the cost?

• Is there a clinical intervention available?

GROUP P2 - CHEMICAL

66500

Quantitation in serum, plasma, urine or other body fluid(except amniotic fluid), by any method except reagent tabletor reagent strip (with or without reflectance meter) of: acidphosphatase, alanine aminotransferase, albumin, alkalinephosphatase, ammonia, amylase, aspartate aminotransferase,bicarbonate, bilirubin (total), bilirubin (any fractions), C-reactive protein, calcium (total or corrected for albumin),chloride, creatine kinase, creatinine, gamma glutamyltransferase, globulin, glucose, lactate dehydrogenase, lipase,magnesium, phosphate, potassium, sodium, total protein,total cholesterol, triglycerides, urate or urea - 1 testFee: $9.70 Benefit: 75% = $7.30 85% = $8.25

665032 tests described in item 66500Fee: $11.65 Benefit: 75% = $8.75 85% = $9.95

66506

3 tests described in item 66500Fee: $13.65 Benefit: 75% = $10.25 85% =$11.65

66509

4 tests described in item 66500Fee: $15.65 Benefit: 75% = $11.75 85% =$13.35

66512

5 or more tests described in item 66500Fee: $17.70 Benefit: 75% = $13.30 85% =$15.05

Financial Incentives

• Cost of average profile test - <0.20c

• Incentive to do 5.

Renal

Electrolytes

Urea and Electrolyte Profile

• Chloride –comes with Na/K but still a cost

• Bicarbonate – useful in acute illness

• Urea- adds little

• False positives• cost

Bone

Bone and Calcium

• ?Phosphate

• Albumin

LFT

Opportunistic Screening

• AST, GGT – Alcohol abuse

• Total Protein - paraproteinaemia

Total Protein in LFTIncluded as a screen for monoclonal gammopathy.

Can opportunistic case-finding of paraproteins be clinically justified?Ann Clin Biochem. 2005 Jul;42(Pt 4):245-53. Beetham R, Howie N, Soutar R.

1% of all malignancies.

Definition of hyperproteinaemia – hypergammaglobulinaemia

Cost effective?

Intervention?

Bhoji Watts, Leslie Burnett, and Doug Chesher Measurement of Total Protein Is Not aUseful Inclusion in Liver Function Test Profiles Clinical Chemistry 2000; v. 46, p.1022-1023. $1.2 million unnecessary expenditure

Standard Profile: Alt, Ast, GGT, Bili, AlP, Protein,Alb, GlobAge/Sex Reference intervalAny abnormality in any test followed up

• Patient and clinical characteristics, including age, sex, ethnic group, countryof birth, reason for blood testing, medication and history of illness,substance abuse, travel, immunisation and transfusion history;

• Alcohol use, via a standardised questionnaire;• Weight, height, waist and hip circumference measurements;• Repeat of the eight-analyte LFT panel;• Blood for specific (auto-immune, genetic and viral) diseases in the ‘liver

work up’ ;• Ultrasound scan (USS) of the upper abdomen. Any tumours of the

hepatobiliary system were noted and the liver was classified as normal,echobright (in three levels of intensity) or cirrhotic. A sample of ultrasoundfilms were reviewed by the study radiologist.

• 2 year followup

Results

• 1290 patients

• 32 cases with hepatcellular (2.5%)• 12 with biliary (0.9%)• Cancer 9 cases

• Most efficient panel for significant liver disease is Alt + ALP• TP to FP 1:48

Results

• <5% of people with an abnormal LFT panelhad liver disease

• 1.7% needed treatment (antiviral/venesection)

A recent large general practice study based in Birmingham, 1118 patientswith raised liver enzymes were thoroughly investigated, and a liver relatedcause could only be identified in 55% of patients.

Continued reliance on alanine transaminase (ALT) elevation hascontributed to both over-referral;

in one study, 33% of secondary care referrals from general practitioners oninvestigation had simple steatosis only, as well as under-referral;

nearly 50% of those who required investigations in primary care wereneither referred nor adequately investigated in another study from thesame region.

Evidence for the use of liver enzymes as a screening test

Presence and severity of non-alcoholic fatty liver disease in a largeprospective primary care cohort. Matthew J. Armstrong, Diarmaid D. Houlihan, et alJournal of Hepatology, Volume 56, Issue 1 , Pages 234-240, 2012.

All Causes of Abnormal LFT

Cause Percentage (n)

NAFLD 26.4 (295)At-risk alcohol intake

Non-Fatty liverFatty liver

14.0 (156)11.3 (126)

PBC 0.81 (9)HBV 0.72 (8)Haemochromatosis

Homozygote [C282Yor H63D] Comp.heterozygote[C282Y + H63D]

Other (inc. cancer,drug, abscess)

0.54 (6)

0.36 (4)

0.36 (4)

HCV* 0.17 (2)PSC* 0.17 (2)A1AD* 0.17 (2)Unexplained group 45.1 (504)

Frequency of Abnormal LFT Tests inNAFLD

AST/ALT is validated as a marker of severity in chronic liver diseasessecondary to alcohol, NAFLD , and primary sclerosing cholangitis.

AST/ALT reflects the structural changes (the degree of liver fibrosis) within theliver which precede any deterioration in liver function.

Cut-off value of 0.8 for the AST/ ALT ratio, and in combination withestablished risk factors for chronic liver disease such as presence of diabetesand obesity (the BARD score), a negative predictive value of greater than95%, to rule out significant liver scarring in NAFLD can be achieved.

Routine reporting of AST/ALT ratio would improve the clinical utility of the liverprofile without added cost.

Value as a Diagnostic test – perhaps we should be adding more?

Response to Stuart Smellie Article: David J Harman, Guruprasad Padur Aithal

Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease:a record-linkage population cohort study and decision analysis (ALFIE). Authors: Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, Rosenberg W

Journal: Health Technology Assessment Volume: 13 Issue: 25 Publication date: May 2009

The most striking observations of this study are that:(1) liver disease is not common in those with ALFTs over a

median follow-up time of 3.7 years;

(2) GGT shows highest sensitivity for liver disease above otherLFTs and is a good predictor of liver disease and liver mortalityafter adjustment for the bias of selective testing;

(3) ALFTs are predictive of death from non-hepatic causes(particularly albumin); and

(4) the rise in the number of LFTs requested does not alter theprevalence of abnormal tests.

ACB Suggestion

Harmonisation• Time to ask what should we be doing?

• Reduce cost and confusion

• Important as we have more electronic requesting and e-records

• Is test for screening or monitoring

• Reflex testing?

• We need to know more about the utility of these basic tests!

The Ultimate Harmonisation!

Routine Chemistry Profile

Harmonisation to Disinvestment

Positive diagnoses from different index panels.

Lilford R J et al. BMJ Open 2013;3:e003099

©2013 by British Medical Journal Publishing Group

The effect of increasing the threshold of abnormality for four analytes.

Lilford R J et al. BMJ Open 2013;3:e003099

©2013 by British Medical Journal Publishing Group

Liver enzymes don’t assess the degree of liverinjury nor do they predict clinical outcomes.

Lack of correlation of elevated liver enzymeswith the degree of liver injury or loss of function

None of the validated prognostic models used inclinical decision making such as Child-Pughscore, King’s College Criteria, Model for End-stage Liver Disease (MELD) or UK End Stage LiverDisease (UKELD) include liver enzymes as theircomponents.