Enhanced liver fibrosis (ELF) score predicts hepatic decompensation and mortality.

Background & Aims: In community pathways for detection of liver disease the most common reason for referral is fibrosis assessment. We investigated the impact of adding the Enhanced Liver Fibrosis (ELF) score as a second-line test (subsequent to an indeterminate or high Fibrosis-4 index [FIB-4] and/or non-alcoholic fatty liver disease fibrosis score) to guide referral and prognostication in our multi-aetiology pathway. Methods: Patients with ELF results from the intelligent Liver Function Testing (iLFT) pathway were recruited. Case note review was undertaken to compare ELF with endpoints of cirrhosis, hepatic decompensation, and mortality (liver-related and all-cause death). Results: In total, 1,327 individuals were included with a median follow-up of 859 days and median ELF score of 10.2. Overall sensitivity for cirrhosis at the 9.8 threshold was 94% (100% for metabolic-associated steatotic liver disease, 89% for alcohol-related liver disease). Determination of the ELF score as a second-line test reduced the referral rate by 34%. ELF scores predicted hepatic outcomes; each unit change was associated with increased decompensation (adjusted Hazard Ratio [aHR] 2.215, 95% CI: 1.934-2.537) and liver-related mortality (aHR 2.024, 95% CI: 1.674-2.446). ELF outperformed FIB-4 for risk of liver-related mortality, particularly in the short-term (area under the curve [AUC] 94.3% vs. 82.8% at six months). Where FIB-4 was indeterminate, ELF had higher AUC for all outcomes within at least 2 years. ELF ≥13 was associated with particularly high rates of decompensation (26% within 90 days) and all-cause mortality (38% at 1 year). Conclusions: The addition of ELF reduced the number of individuals referred for fibrosis assessment following iLFT pathway testing and provided useful prognostic information. Individuals with ELF scores ≥13 were considered at high-risk of negative outcomes warranting urgent clinical assessment. Impact and implications: Primary care pathways for suspected liver disease are increasingly common and often lead to increased specialist hepatology referrals for fibrosis assessment. This study, using clinical follow-up for liver-related outcomes, provides further evidence supporting ELF testing to safely reduce referrals in a two-step approach when combined with other simple fibrosis markers. Additionally, ELF scores predict liver-related morbidity and mortality, with ELF scores ≥13 indicating particularly high-risk patients. This study may help inform the implementation of diagnostic pathways for early detection of liver disease and highlights the need for urgent review of individuals with very high ELF scores.

Intelligent Liver Function Testing (iLFT): An Intelligent Laboratory Approach to Identifying Chronic Liver Disease.

The intelligent Liver Function Testing (iLFT) pathway is a novel, algorithm-based system which provides automated laboratory investigations and clinical feedback on abnormal liver function test (LFT) results from primary care. iLFT was introduced to NHS Tayside, Scotland, in August 2018 in response to vast numbers of abnormal LFTs, many of which were not appropriately investigated, coupled with rising mortality from chronic liver disease. Here, we outline the development and implementation of the iLFT pathway, considering the implications for the diagnostic laboratories, primary care services and specialist hepatology clinics. Additionally, we describe the utility, outcomes and evolution of iLFT, which was used over 11,000 times in its first three years alone. Finally, we will consider the future of iLFT and propose areas where similar 'intelligent' approaches could be used to add value to laboratory investigations.

Implementation of point-of-care HbA1C instruments into community pharmacies: Initial development of a pathway for robust community testing.

BACKGROUND: Point-of-care (POC) analysers in community settings can provide opportunistic and regular HbA1c monitoring. Community pharmacies in NHS Scotland are utilised by populations at greatest risk of type two diabetes (T2D). This study describes initial development of an HbA1c pathway using a POC analyser in community pharmacies. METHODS: The Abbott Afinion analyser was compared in (i) NHS Tayside's Blood Sciences Service and (ii) community pharmacies from four Scottish Health Boards. A side by side comparison with standard operating procedures for HbA1c quantification using 80 T2D patient venous samples. The machine was implemented into 11 community pharmacies and 144 samples obtained from patients for comparison to their recent laboratory HbA1c. Four focus groups examined themes around the intervention and an exit questionnaire was administered. RESULTS: Laboratory assessment verified the efficacy of the POC test machine. The value for level 1 quality control was 44 mmol/mol and the mean during testing 42.7 mmol/mol. The greatest percent coefficient of variation (cv) was within-run for both levels of quality control material, at a value of 1.63% and 1.62%, respectively. The analyser performed robustly within the pharmacy assessment, with a mean difference of 1.68 and a standard deviation of 0.71 (CV 0.423). Patients with T2D reported positive experiences of using a pharmacy. The focus groups identified an appreciation of the convenience of pharmacies and of the longitudinal relationships with pharmacy staff. CONCLUSION: POC HbA1c analysers can be successfully established in community pharmacies. The target patient group responded positively to the opportunity to use a pharmacy service.

Personalising laboratory medicine in the 'real world': Assessing clinical utility, by clinical indication, of serum total B12 and Active-B12® (holotranscobalamin) in the diagnosis of vitamin B12 deficiency.

BACKGROUND: Assessing the pre- and post-test probability of disease in the context of routine health care is challenging. We wished to study how test performance parameters relating to clinical utility vary by clinical indication in a 'real-world' setting. METHODS: The diagnostic accuracy of serum total B12 and Active-B12® (holotranscobalamin) was evaluated in a primary care population, using serum methylmalonic acid as the reference standard. We used electronic requesting to establish the clinical indication for each request. Routine requests from primary care for serum total B12 were included if creatinine was also measured and estimated glomerular filtration rate was at least 60 mL/min/1.73 m2. RESULTS: Clinical indications included peripheral neuropathy (n = 168), anaemia (n = 168), cognitive decline (n = 125), suspected dietary deficiency (n = 76), other (n = 362). For peripheral neuropathy, the area under the receiver operator curve ± 95% confidence interval (AUC ± CI) was 0.63 (0.54-0.71) (P = 0.002) for total B12 and 0.68 (0.60-0.77) (P < 0.0001) for Active-B12®. For anaemia, AUC ± CI was 0.56 (0.47-0.66) (P = 0.10) for total B12 and 0.69 (0.59-0.78) (P < 0.0001) for Active-B12®. For cognitive decline, AUC ± CI was 0.54 (0.43-0.65) (P = 0.26) for total B12 and 0.69 (0.58-0.80) (P = 0.0002) for Active-B12®. The pre-post-test change in probability of disease varied by clinical indication. CONCLUSION: Combining diagnostic accuracy studies and electronic testing in a 'real-world' setting allows clinical utility to be assessed by clinical indication. Wider application of this would permit more personalised laboratory medicine. In this study, diagnostic performance of total B12 and Active-B12® varied across all indications. Active-B12® provided better discrimination, but this may have reflected the cut-offs used.

Intelligent liver function testing (iLFT): A trial of automated diagnosis and staging of liver disease in primary care.

BACKGROUND & AIMS: Liver function tests (LFTs) are frequently requested blood tests which may indicate liver disease. LFTs are commonly abnormal, the causes of which can be complex and are frequently under investigated. This can lead to missed opportunities to diagnose and treat liver disease at an early stage. We developed an automated investigation algorithm, intelligent liver function testing (iLFT), with the aim of increasing the early diagnosis of liver disease in a cost-effective manner. METHODS: We developed an automated system that further investigated abnormal LFTs on initial testing samples to generate a probable diagnosis and management plan. We integrated this automated investigation algorithm into the laboratory management system, based on minimal diagnostic criteria, liver fibrosis estimation, and reflex testing for causes of liver disease. This algorithm then generated a diagnosis and/or management plan. A stepped-wedged trial design was utilised to compare LFT outcomes in general practices in the 6 months before and after introduction of the iLFT system. Diagnostic outcomes were collated and compared. RESULTS: Of eligible patients with abnormal LFTs, 490 were recruited to the control group and 64 were recruited to the intervention group. The primary diagnostic outcome was based on the general practitioner diagnosis, which agreed with the iLFT diagnosis in 67% of cases. In the iLFT group, the diagnosis of liver disease was increased by 43%. Additionally, there were significant increases in the rates of GP visits after diagnosis and the number of referrals to secondary care in the iLFT group. iLFT was cost-effective with a low initial incremental cost-effectiveness ratio of £284 per correct diagnosis, and a saving to the NHS of £3,216 per patient lifetime. CONCLUSIONS: iLFT increases liver disease diagnoses, improves quality of care, and is highly cost-effective. This can be achieved with minor changes to working practices and exploitation of functionality existing within modern laboratory diagnostics systems. LAY SUMMARY: There is a growing epidemic of advanced liver disease, this could be offset by early detection and management. Checking liver blood tests (LFTs) should be an opportunity to diagnose liver problems, but abnormal results are often incompletely investigated. In this study we were able to substantially increase the diagnostic yield of the abnormal LFTs using the automated intelligent LFT system. With the addition of referral recommendations and management plans, this strategy provides optimum investigation and management of LFTs and is cost saving to the NHS.

Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the 'intelligent LFT' pathway for the automated assessment of deranged liver enzymes.

BACKGROUND: Liver function tests (LFTs) are commonly abnormal; most patients with 'incidental' abnormal LFTs are not investigated appropriately and for those who are, current care pathways are geared to find an explanation for the abnormality by a lengthy process of investigation and exclusion, with costs to the patient and to the health service. OBJECTIVE: To validate an intelligent automatable analysis tool (iLFT) for abnormal liver enzymes, which diagnoses common liver conditions, provides fibrosis stage and recommends management. DESIGN: A retrospective case note review from three tertiary referral liver centres, with application of the iLFT algorithm and comparison with the clinician's final opinion as gold standard. RESULTS: The iLFT algorithm in 91.3% of cases would have correctly recommended referral or management in primary care. In the majority of the rest of the cases, iLFT failed safe and recommended referral even when the final clinical diagnosis could have been managed in primary care. Diagnostic accuracy was achieved in 82.4% of cases, consistent with the fail-safe design of the algorithm. Two cases would have remained in primary care as per the algorithm outcome, however on clinical review had features of advanced fibrosis. CONCLUSION: iLFT analysis of abnormal liver enzymes offers a safe and robust method of risk stratifying patients to the most appropriate care pathway as well as providing reliable diagnostic information based on a single blood draw, without repeated contacts with health services. Offers the possibility of high quality investigation and diagnosis to all patients rather than a tiny minority.

L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series.

Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion.

An increased B-type natriuretic peptide in the absence of a cardiac abnormality identifies those whose left ventricular mass will increase over time.

OBJECTIVES: The purpose of this study was to identify the relationship of B-type natriuretic peptide (BNP) with evolution of left ventricular mass (LVM) in optimally treated primary prevention patients. BACKGROUND: Patients who have an elevated BNP no cardiac abnormality on echocardiography are common and at increased risk of adverse events. One hypothesis is that an elevated BNP is an early sensitive indicator of who will develop future structural abnormalities such as left ventricular (LV) hypertrophy. METHODS: We identified optimally treated primary prevention patients with no cardiac abnormality at baseline. In particular, they had no myocardial ischemia, LV hypertrophy, LV dysfunction, or left atrial enlargement. They had a diverse range of plasma BNP levels and underwent cardiac magnetic resonance at baseline and 3 years later on a 3-T scanner. RESULTS: Fifty patients with a diverse range of BNP were studied (with BNP ≤ 10 pg/ml in 25 patients and >10 pg/ml in 25 patients). LVM increased (+4.7 ± 3.5 g) in 24 patients and decreased (-4.9 ± 2.8 g) in 26 patients (p < 0.01). Blood pressure by 24-h monitoring was virtually identical between those whose LVM increased (systolic blood pressure 122 ± 14 mm Hg) and those whose LVM decreased (systolic blood pressure 121 ± 11 mm Hg, p = 0.77). Plasma BNP was nearly 3 times higher in those whose LVM increased versus those in whom LVM decreased (21 ± 9.6 pg/ml vs. 7.9 ± 3.9 pg/ml, p < 0.01). The c-statistic for BNP was 0.88. CONCLUSIONS: In optimally treated primary prevention patients, plasma BNP levels are able to distinguish between those whose LVM will increase during the next 3 years versus those whose LVM will decrease during the next 3 years. This may explain why individuals with high BNP are at increased risk even if no cardiac abnormality can be detected initially.

Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease.

OBJECTIVES: The aim of this study was to examine whether biomarkers can identify silent cardiac target organ damage (cTOD) in a primary prevention population. BACKGROUND: One possible way to improve primary prevention of cardiovascular events is to identify those patients who already harbor silent cTOD (i.e., myocardial ischemia, left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, or left atrial enlargement). This might be possible by screening with a biomarker (e.g. high sensitivity cardiac troponin T [hs-cTnT] or B-type natriuretic peptide [BNP]). METHODS: We prospectively recruited 300 asymptomatic individuals already receiving primary prevention therapy. Transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging were performed to identify silent cTOD. RESULTS: One hundred two (34%) patients had evidence of cTOD. Left ventricular hypertrophy was the most prevalent (29.7%) form of cTOD, followed by diastolic dysfunction (21.3%), left atrial enlargement (15.3%), systolic dysfunction (6.3%), and ischemia (6.3%). The area under the curve (AUC) for BNP to identify any form of silent cTOD was 0.78 overall and 0.82 in men. The equivalent figures for hs-cTnT were 0.70 and 0.75 in women. The AUC for BNP and hs-cTnT together was 0.81 and 0.82 in men. However, the discrimination power of other markers was poor, with AUCs of 0.61 for microalbuminuria, 0.49 for uric acid, and 0.58 for eGFR. CONCLUSIONS: In asymptomatic treated primary prevention patients, BNP screening is able to identify existing silent cTOD. The performance of hs-cTnT was not as good as that of BNP. B-type natriuretic peptide plus hs-cTnT together performed best. Prescreening with BNP ± cTnT followed by targeted phenotyping is worth exploring further as a possible way to improve primary prevention.

The prognostic value of high sensitivity troponin T 7 weeks after an acute coronary syndrome.

OBJECTIVE: The role of high sensitivity troponin T (hs-TnT) in the convalescence phase after an acute coronary syndrome (ACS) is unknown. The authors aim to assess the prognostic utility of a single hs-TnT level at 7-week post-ACS. Second, the authors evaluated whether any serial changes in hs-TnT between the index admission and 7 weeks post-ACS had any link with the prognosis. Third, the authors assessed whether the prognostic utility of hs-TnT is independent of various echocardiographic abnormalities. METHODS: The authors measured hs-TnT levels in 326 consecutive patients at 7 weeks after an ACS event. The composite end point of death from any cause or acute myocardial infarction was evaluated over a median duration of 30 months. RESULTS: A high 7-week hs-TnT (>14 ng/l) predicted adverse clinical outcomes independent of conventional risk factors, left ventricular dysfunction and left ventricular hypertrophy on echocardiography (adjusted RR: 2.69 (95% CI 1.45 to 5.00)). Patients with persistent hs-TnT elevation at 7 weeks were also at an increased risk of cardiovascular events compared with those with an initial high hs-TnT which then normalised (unadjusted RR 3.39 (95% CI 2.02 to 5.68)). CONCLUSION: The authors have demonstrated the prognostic utility of a single 7-week hs-TnT measurement in routine ACS patients and that it could be used to assist medium term risk stratification in this patient cohort. In addition, the authors also showed that hs-TnT predicted long-term adverse prognosis independent of various echo parameters. Future studies should evaluate whether tailoring specific treatment interventions to higher risk individuals as identified by an elevated hs-TnT during the convalescence phase of ACS would improve clinical outcomes.