Optimal ALT threshold for the automated diagnosis of MASLD: A population-based study using iLFT.

INTRODUCTION AND OBJECTIVES: Early diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD), especially with advanced fibrosis, is crucial due to the increased risk of complications and mortality. Serum alanine aminotransferase (ALT) is commonly used; however, many patients have normal ranges (<55 U/L) who may remain undetected. We investigated the clinical implications of a lower ALT cut-off (>30 U/L) using intelligent liver function testing (iLFT) to identify MASLD patients with and without advanced fibrosis in primary care. MATERIALS AND METHODS: All patients entering the iLFT diagnostic pathway had liver aetiological screening investigations if ALT >30 U/L. In those with MASLD the proportions with and without advanced fibrosis at different ALT thresholds: 31-41 U/L, 42-54 U/L and ≥55 U/L were compared. RESULTS: 16,373 patients underwent iLFT between March 2016 to April 2022. 762 (5 %) patients had MASLD with abnormal fibrosis scores, while 908 (6 %) had MASLD with normal fibrosis scores. 428 (56 %) patients were assessed in liver clinics, where 169 (39 %) had evidence of fibrosis. Of these, 22 (13 %) had ALT 31-41 U/L, 31 (18 %) had ALT 42-54 U/L and 116 (69 %) had ALT ≥55 U/L. 145 (86 %) patients had advanced fibrosis or cirrhosis, where 20 (14 %) had ALT 31-41 U/L, 28 (19 %) had ALT 42-54 U/L and 97 (67 %) had ALT ≥55 U/L. CONCLUSIONS: 33 % of MASLD patients with advanced fibrosis or cirrhosis had ALT 31-54 U/L, who would have been missed using the conventional ALT range. This suggests that lowering the ALT cut-off improves diagnosis of MASLD with advanced fibrosis in primary care.

Thrombocytosis and abnormal liver enzymes: A trigger for investigation of underlying malignancy.

BACKGROUND: Thrombocytosis is often an incidental finding in primary care with a range of causes. Despite evidence of a strong association between thrombocytosis and malignancy, guidelines for investigating thrombocytosis in the absence of red flag symptoms remain unclear. A novel automated system of laboratory analysis, intelligent Liver Function Testing (iLFT), launched in Tayside in 2018 and has identified a patient group with thrombocytosis and abnormal liver test (LFT) results. This study analysed the outcome of these patients and investigated the use of thrombocytosis combined with LFTs in predicting risk of cancer. METHODS AND FINDINGS: Between August 2018 and August 2020, 6792 patients underwent iLFT, with 246 found to have both thrombocytosis and at least one abnormal LFT. A random case-matched control group of 492 iLFT patients with normal platelet count and at least one abnormal LFT was created. 7.7% (95% CI 4.7-11.8%) of patients with thrombocytosis had cancer compared to 2.0% (1.0-3.7%) of controls. Patients <40 years or with pre-existing causes of thrombocytosis were then excluded. Subsequent analysis revealed a 10.8% (6.6-16.3%) incidence of cancer in thrombocytosis patients (n = 176) compared to 2.5% (1.2-4.6%, p = 0.00014) in patients with normal platelet count (PLT) (n = 398). When thrombocytosis is combined with elevated alkaline phosphatase (ALP), there is a positive predictive value (PPV) of 20% for cancer. These rules were subsequently applied to a validation cohort of 71,652 patients, of whom 458 had thrombocytosis and elevated ALP. There was a 30.6% cancer incidence, confirming the strong predictive value of the combined test of PLT and ALP. CONCLUSIONS: These findings suggest a substantial increased risk of cancer in patients with thrombocytosis and raised ALP. This could be developed as an adjunct to current investigation algorithms, highlighting high-risk patients and prompting further investigation (such as computed tomography scans) where indicated.

Intelligent Liver Function Testing: Working Smarter to Improve Patient Outcomes in Liver Disease.

Chronic liver disease (CLD) is a significant health problem affecting millions of people worldwide. In Scotland, CLD is a major cause of premature mortality. Liver function tests (LFTs) are a panel of frequently requested blood tests which may indicate liver disease. However, LFTs commonly contain at least one abnormal result, and abnormalities are rarely investigated to the extent recommended by national guidelines. The intelligent Liver Function Testing (iLFT) pathway is a novel, automated system designed to improve early diagnosis of liver disease. Initial abnormal LFT results trigger a cascade of reflexive testing to help identify the cause of any liver dysfunction. Algorithms combine these results with demographic and clinical data (such as patient age, body mass index, and alcohol intake) and fibrosis estimates to produce an electronic diagnosis and management plan. The pilot trial demonstrated that iLFT increased diagnosis of liver disease whilst remaining cost-effective. As such, iLFT has been fully operational across our region (NHS Tayside, Scotland) since August 2018. In the first year, iLFT generated over 2000 diagnoses from 1824 patient samples with an abnormality in the initial LFTs. The majority of these patients could be safely managed in primary care. iLFT allows maximal value to be obtained from liver blood tests across biochemistry, virology, immunology, and hematology with only minor changes to working practices. 'Intelligent', algorithm-led testing pathways break down the barrier between clinical and laboratory medicine and offer solutions to many of the challenges experienced in modern healthcare systems.

A common missense variant of LILRB5 is associated with statin intolerance and myalgia.

Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54). Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Myocardial ischaemia is associated with an elevated brain natriuretic pepide level even in the presence of left ventricular systolic dysfunction.

AIMS: Plasma BNP and high-sensitivity cardiac troponin-T (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD). As a result, it is unknown whether BNP and/or hs-TnT could be useful biomarkers to identify ischaemia in the presence of LVSD. METHODS AND RESULTS: Three separate patient populations were studied. Study A (n = 500) involved consecutive patients undergoing clinically indicated myocardial perfusion scintigraphy, study B (n = 100) included patients with vascular disease but no known cardiac disease, and study C (n = 300) recruited primary prevention patients with controlled risk factors. Levels of BNP and hs-TnT were measured prior to the stress testing to detect myocardial ischaemia. The prevalence of myocardial ischaemia was 28.2, 28, and 6.3% in study A, B, and C, respectively. For BNP, area under curve (AUC) values to identify ischaemia in the presence and absence of coincidental LVSD were: 0.73 vs. 0.63 (study A), 0.90 vs. 0.81 (study B), and 0.83 vs. 0.80 (study C). Equivalent figures for hs-TnT were: 0.64 vs. 0.60 (study A), 0.75 vs. 0.68 (study B), and 0.53 vs. 0.68 (study C). BNP and hs-cTnT, when combined together, performed better with an AUC of 0.75 vs. 0.65 (study A), 0.91 vs. 0.92 (study B), and 0.84 vs. 0.83 (study C). CONCLUSION: In three separate populations a consistent finding is that BNP is increased further by myocardial ischaemia even in the presence of LVSD. A disproportionately high BNP for the degree of LVSD might be due to (unsuspected) ischaemia, and a disproportionately low BNP could be useful as a 'rule out' test for ischaemia even in the presence of LVSD.

Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio.

The aldosterone-to-renin ratio (ARR) is a marker of aldosterone activity in hypertension. We examined the relationship of the ARR to the distribution of two biallelic polymorphisms at the CYP11B2 gene locus. One polymorphism affects a putative steroidogenic factor-1 binding site (-344 T/C) in the 5'-regulatory region, whereas the other marker reflects replacement of the intron-2 from CYP11B2 with that from the neighboring gene encoding 11beta-hydroxylase (CYP11B1; wild-type/conversion). We studied consecutive referrals to the Tayside hypertension clinic in 1998. Because the specificity of ARR (pmol/liter/ng/ml/h) for hyperaldosteronism increases with its threshold, ARRs of at least 750 and 1000 were used. A total of 375 patients were assessed; 86.9% had complete data. There were significant excesses of steroidogenic factor-1 (T) (ARR >/= 750, 0.62 vs. 0.51, P = 0.014; ARR >/= 1000, 0.63 vs. 0.51, P = 0.039) and intron-2 (conversion) (ARR >/= 750, 0.49 vs. 0.41, P = 0.205; ARR >/= 1000, 0.54 vs. 0.41, P = 0.029) alleles in patients with a raised ARR. The odds ratio for a raised ARR was 2.27 [95% confidence interval, 1.01, 5.09; P < 0.05] comparing patients with a homozygous haplotype for these alleles with those without any such alleles, and this risk increased with age. This study supports the notion that there is a genetic component that regulates aldosterone production and that hyperaldosteronism might develop over time in susceptible individuals.