Time to focus on chronic liver diseases in the community: A review of primary care hepatology tools, pathways of care and reimbursement mechanisms.

Addressing primary care's low confidence in detecting and managing chronic liver disease is becoming increasingly important owing to the escalating prevalence of its common lifestyle-related metabolic risk factors - obesity, physical inactivity, smoking and alcohol consumption. Whilst liver blood testing is frequently carried out in the management of long-term conditions, its interpretation is not typically focused on specific liver disease risk. Educational steps for primary care should outline how liver fibrosis is the flag of pathological concern, encourage use of pragmatic algorithms such as fibrosis-4 index to differentiate between those requiring referral for further fibrosis risk assessment and those who can be managed in the community, and emphasise that isolated minor liver function test abnormalities are unreliable for estimating the risk of fibrosis progression. Measures to increase primary care's interest and engagement should make use of existing frameworks for the management of long-term conditions, so that liver disease is considered alongside other metabolic disorders, including type 2 diabetes, cardiovascular disease, chronic kidney disease etc. Selling points when considering the required investment in developing local fibrosis assessment pathways include reduced repeat testing of minor abnormalities and improved secondary care referrals, plus improvements in the patient's journey through long-term multimorbidity care. A focus on improving chronic liver disease is likely to have wide-ranging benefits across co-existing metabolic disorders, particularly when pathways are aligned with community lifestyle support services. The important message for primary care is to increase the value of existing monitoring rather than to generate more work.

The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig.

Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized (n=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5-1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, P<0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, P<0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, P=0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, P=0.046 and PCS = 8.3 ± 1.2 mmHg, P=0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, P<0.0001 and PCS = 488.4 ± 106.4 ml/min, P=0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, P=0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.

Using MRI to study the alterations in liver blood flow, perfusion, and oxygenation in response to physiological stress challenges: Meal, hyperoxia, and hypercapnia.

BACKGROUND: Noninvasive assessment of dynamic changes in liver blood flow, perfusion, and oxygenation using MRI may allow detection of subtle hemodynamic alterations in cirrhosis. PURPOSE: To assess the feasibility of measuring dynamic liver blood flow, perfusion, and T2 * alterations in response to meal, hypercapnia, and hyperoxia challenges. STUDY TYPE: Prospective. SUBJECTS: Ten healthy volunteers (HV) and 10 patients with compensated cirrhosis (CC). FIELD STRENGTH/SEQUENCE: 3T; phase contrast, arterial spin labeling, and T2* mapping. ASSESSMENT: Dynamic changes in portal vein and hepatic artery blood flow (using phase contrast MRI), liver perfusion (using arterial spin labeling), and blood oxygenation ( T2* mapping) following a meal challenge (660 kcal), hyperoxia (target PET O2 of 500 mmHg), and hypercapnia (target increase PET CO2 of ∼6 mmHg). STATISTICAL TESTS: Tests between baseline and each challenge were performed using a paired two-tailed t-test (parametric) or Wilcoxon-signed-ranks test (nonparametric). Repeatability and reproducibility were determined by the coefficient of variation (CoV). RESULTS: Portal vein velocity increased following the meal (70 ± 9%, P < 0.001) and hypercapnic (7 (5-11)%, P = 0.029) challenge, while hepatic artery flow decreased (-30 ± 18%, P = 0.005) following the meal challenge in HV. In CC patients, portal vein velocity increased (37 ± 13%, P = 0.012) without the decrease in hepatic artery flow following the meal. In both groups, the meal increased liver perfusion (HV: 82 ± 50%, P < 0.0001; CC: 27 (16-42)%, P = 0.011) with faster arrival time of blood (HV: -54 (-56-30)%, P = 0.074; CC: -42 ± 32%, P = 0.005). In HVs, T2* increased after the meal and in response to hyperoxia, with a decrease in hypercapnia (6 ± 8% P = 0.052; 3 ± 5%, P = 0.075; -5 ± 6%, P = 0.073, respectively), but no change in CC patients. Baseline between-session CoV <15% for blood flow and <10% for T2* measures. DATA CONCLUSION: Dynamic changes in liver perfusion, blood flow, and oxygenation following a meal, hyperoxic, and hypercapnic challenges can be measured using noninvasive MRI and potentially be used to stratify patients with cirrhosis. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1577-1586.

The XL probe: A luxury or a necessity? Risk stratification in an obese community cohort using transient elastography.

BACKGROUND: Transient elastography is a non-invasive tool which can stratify patients at risk of chronic liver disease. However, a raised body mass index has been independently associated with a failed or unreliable examination. OBJECTIVE: The purpose of this study was to analyse the performance of two probes (M/XL) on a portable transient elastography device within an obese community population. METHOD: The method involved a prospective study with recruitment from a primary care practice. Patients identified with a risk factor for chronic liver disease were invited to a community-based risk stratification pathway for transient elastography readings with both probes. A threshold of ≥8.0 kPa defined elevated liver stiffness. RESULTS: A total of 477 patients attended the pathway. Of the patients, 21% had no valid measurements with the M probe. There was a significant difference between the probes in the proportion achieving ≥10 valid readings (M versus XL probe: 66.2% versus 90.2%; p ≤ 0.001) and in their reliability (M versus XL probe: 77.4% versus 98.5%; p = 0.028). Unreliable readings with the M probe increased as the body mass index increased. The XL probe re-stratified 5.2% of patients to have a normal reading. CONCLUSION: The XL probe on a portable device significantly improves the applicability of transient elastography within a community-based risk stratification pathway.

Analysis of genotyping for predicting liver injury marker, procollagen III in persons at risk of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. RESULTS: The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). CONCLUSIONS: Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting.

Screening for liver fibrosis in the general population: a call for action.

Liver cirrhosis is one of the main causes of death and disability-adjusted life-years worldwide. Generally, cirrhosis develops after a long period of liver-cell injury that leads to the deposition of collagen, leading to progressive fibrosis and nodule formation in the liver tissue. Most patients are diagnosed in late stages when liver decompensation or liver cancer develops. The diagnosis is rarely made in early stages-when liver fibrosis is mild to moderate but cirrhosis is not yet established-because the disease is asymptomatic. No strategies for detection of liver fibrosis at these early stages have been developed, but therapies are more effective in early stages than late stages of chronic liver diseases, so enabling early detection is an important research topic. Non-invasive methods for assessing liver fibrosis have been developed, of which the most commonly used are transient elastography-which estimates liver fibrosis by measuring liver stiffness-and serum biomarkers of fibrosis. Studies have shown that 6-7% of the adult population without known liver disease have liver fibrosis, mostly associated with non-alcoholic fatty liver disease. These data suggest that programmes of screening for liver fibrosis in the general population should be assessed.

Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus.

UNLABELLED: Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long-term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2-4.4). CONCLUSION: KIR and HLA-C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families.