Acceptability of an integrated care program to identify patients at risk of advanced chronic liver disease in Australian primary care settings.

Objective: To investigate the prevalence and independent risk factors of non-alcoholic fatty liver disease (NAFLD) and advanced chronic liver disease among the type 2 diabetes mellitus (T2DM) population in the Shenyang community, so as to provide evidence for the prevention and control of T2DM combined with NAFLD. Methods: This cross-sectional study was conducted in July 2021. 644 T2DM cases from 13 communities in Heping District, Shenyang City were selected. All the surveyed subjects underwent physical examination (measurements of height, body mass index, neck circumference, waist circumference, abdominal circumference, hip circumference, and blood pressure), infection screening (excluding hepatitis B and C, AIDS, and syphilis), random fingertip blood glucose, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). The study subjects were divided into the non-advanced chronic liver disease group and the advanced chronic liver disease group according to whether the LSM value was greater than 10 kPa. Cirrhotic portal hypertension development was indicated in patients with LSM ≥ 15 kPa. The comparison of multiple mean values among the sample groups was performed by analysis of variance when the normal distribution was met. Results: In the T2DM community population, there were 401 cases (62.27%) combined with NAFLD, 63 cases (9.78%) combined with advanced chronic liver disease, and 14 cases (2.17%) combined with portal hypertension. There were 581 cases in the non-advanced chronic liver disease group and 63 cases (9.78%) in the advanced chronic liver disease group (LSM ≥10 kPa), including 49 cases (7.61%) with 10 kPa≤LSM<15 kPa, 11 cases (1.71%) with 15 kPa ≤LSM<25 kPa, and 3 cases (0.47%) with LSM ≥ 25 kPa. Age, body mass, body mass index, neck circumference, waist circumference, hip circumference, waist-to-height ratio, systolic blood pressure, and CAP were all statistically different between the non-advanced chronic liver disease group and the advanced chronic liver disease group (F=-1.983,-2.598,-4.091,-2.062,-3.909, -4.581,-4.295,-2.474, and -5.191, respectively; P<0.05). There was a statistically significant difference in terms of whether or not there was combined cerebrovascular disease (2=4.632, P=0.031); however, there were no statistically significant differences in terms of lifestyle, diabetes complications, and other complications (P>0.05). Conclusion: Patients with T2DM have a higher prevalence of NAFLD (62.27%) than those with advanced chronic liver disease (9.78%). 2.17% of T2DM cases in the community may not have had early diagnosis and early intervention, and they might have been combined with cirrhotic portal hypertension. So, the management of these patients should be strengthened.

Background & AimsAlpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi∗Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi∗Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion.MethodsA total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi∗Z/Pi∗S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks.ResultsViral hepatitis was the most common etiology (44%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi∗Z and Pi∗S variants, respectively. Pi∗Z carriers had more severe portal hypertension (HVPG: 19±6 vs.15±7 mmHg; p <0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1±1.9 vs. 6.5±1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi∗S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi∗Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi∗MZ genotype (adjusted subdistribution hazard ratio: ≈1.56 vs. Pi∗MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi∗S carriers had no increased risk of events.ConclusionGenotyping for the Pi∗Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease-modifying treatments in Pi∗Z allele carriers with ACLD.Lay summaryAlpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect.

Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have much better outcomes than those with decompensated disease and may be eligible for interventions to prevent disease progression. A cloud-based software solution ("the Liver Toolkit") was developed to access primary care practice software to identify patients at risk of ACLD. Clinical history and laboratory results were extracted to calculate aspartate aminotransferase-to-platelet ratio index and fibrosis 4 scores. Patients identified were recalled for assessment, including Liver Stiffness Measurement (LSM) via transient elastography. Those with an existing diagnosis of cirrhosis were excluded. Existing laboratory results of more than 32,000 adults across nine general practices were assessed to identify 703 patients at increased risk of ACLD (2.2% of the cohort). One hundred seventy-nine patients (26%) were successfully recalled, and 23/179 (13%) were identified to have ACLD (LSM ≥10.0kPa) (10% found at indeterminate risk [LSM 8.0-9.9kPa] and 77% low risk of fibrosis [LSM <8.0kPa]). In most cases, the diagnosis of liver disease was new, with the most common etiology being metabolic dysfunction-associated steatotic liver disease (n=20, 83%). Aspartate aminotransferase-to-platelet ratio index ≥1.0 and fibrosis 4 ≥3.25 had a positive predictive value for detecting ACLD of 19% and 24%, respectively. Patients who did not attend recall had markers of more severe disease with a higher median aspartate aminotransferase-to-platelet ratio index score (0.57 vs. 0.46, p=0.041). This novel information technology system successfully screened a large primary care cohort using existing laboratory results to identify patients at increased risk ACLD. More than 1 in 5 patients recalled were found to have liver disease requiring specialist follow-up.

We thank Tahir et al. [1] for their interest in our manuscript on insulin-like growth factor-1 (IGF-1) levels in patients with advanced chronic liver disease (ACLD) and their prognostic impact [2]. The authors raise a number of interesting issues that we are happy to comment. Firstly, Tahir et al. [1] mention the included sample size of 269 patients with ACLD as a potential limitation of our study. This critique is well received; however, we are not aware of a larger sized cohort of patients with verified advanced chronic liver disease (ACLD) or liver cirrhosis that is characterised to a similar degree for the severity of liver disease, portal hypertension, fibrogenesis, systemic inflammation and liver-related outcomes. Regarding generalizability, we want to emphasise that the main liver disease aetiology in our study was steatotic liver disease (SLD) with 57.8%, while only 14.0% of patients had ACLD due to viral hepatitis. In our opinion, this composition is reflective of a typical contemporary Western cohort of patients with ACLD [3-5], which increases generalizability. Moreover, our sample size is comparable to other studies examining endocrine dysfunctions in ACLD [6-8]. Thus, we are confident that the results presented in our study are representative and applicable to contemporary ACLD patients. Next, the authors mention metabolic cofactors such as obesity as a very relevant parameter in studies focusing on IGF-1 signalling. Instead of obesity, which is a dichotomous variable, we decided to include body mass index (BMI) as a metric variable in our multivariate competing risk regression model, as we felt that in this way, we could better account for a potential gradual impact of increasing body weight spanning overweight and obesity. Indeed, as presented in more detail in our manuscript [2], IGF-1 was an independent predictor of clinical outcomes independently of BMI, suggesting that the dysregulations in IGF-1 levels with increasing ACLD severity were not merely a by-product of (over-)weight. Regarding diabetes, there was no difference between median IGF-1 levels of patients with (n = 71; 66.0 [IQR 49.0–94.0] ng/mL) and without diabetes (n = 198; 67.0 [45.0–91.0] ng/mL; p = 0.732). While the follow-up of our cohort will continue to also assess the long-term prognostic value of IGF-1 levels in ACLD, we actually think that a blood-based, that is, easily repeatable biomarker should be updated on a regular basis anyways, as the dynamics related to liver disease progression/regression can be covered. Thus, we do think that for a blood-based biomarker, the follow-up period in our study of about 2 years is sufficient to reflect its prognostic value. We thank the authors for discussing these important issues on the prognostic value of IGF-1 levels in liver disease, particularly in ACLD, liver cancer development and the impact of obesity and diabetes. We agree that further research is necessary to better understand the mechanistic effect of the growth hormone/IGF1 axis in ACLD across different etiologies and particularly for metabolic dysfunction-associated steatohepatitis where effective treatments are urgently needed. Lukas Hartl: investigation, conceptualization, funding acquisition, writing – original draft, formal analysis, data curation. Michael Schwarz: investigation, writing – review and editing, validation, data curation. Thomas Reiberger: conceptualization, funding acquisition, writing – review and editing, methodology, data curation, supervision, resources. L.H. and M.S. have nothing to disclose. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W. L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead and Roche. This article is linked to Hartl et al papers. To view these articles, visit https://doi.org/10.1111/apt.18289 and https://doi.org/10.1111/apt.18366. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Increased gallbladder wall thickness (GBWT) is a common finding. Reported causes include advanced chronic liver disease (ACLD), ascites and hypalbuminemia. GBWT is a marker for the prediction of esophageal varices. It remains unclear which of these factors is the decisive driver of GBWT. We aim to investigate whether there is a predominant factor associated with the GBWT. We enrolled 258 patients with ascites, hypalbuminemia and/or ACLD and 98 healthy volunteers that underwent abdominal ultrasound. Differences of mean GBWT in subgroups of patients with ACLD, ascites, and/or hypalbuminemia were analyzed. Correlation between various parameters and GBWT were calculated using multiple regression analysis. GBWT in patients with ACLD + ascites + hypalbuminemia (n=59; 5.70 ± 2.05 mm) was pathologically increased compared to patients with hypalbuminemia + ascites without ACLD (n=36; 2.14 ± 0.66 mm; p < .001) and to patients with only hypalbuminemia (n=76; 2.02 ± 0.80 mm; p < .001). GBWT of patients with ACLD + hypalbuminemia (n=30; 3.42 ± 1.52 mm) and with ACLD and normal albumin level were not different (n=46; 3.10 ± 1.62 mm; p > .999). Significant correlation was seen between GBWT and ACLD (r=.53; p < .001) and ascites (r=.51; p < .001) but not albumin level (r=.04; p=.510). We demonstrate that ACLD is predominantly associated with GBWT. In contrast to the current literature, serum albumin level appears not to be associated with pathological GBWT.

BackgroundLiver disease in the UK is the third commonest cause of premature death. Patients with advanced chronic liver disease (ACLD) have reduced life-expectancy and many are not candidates for curative...

Direct-acting antivirals (DAA) achieve high virological response rates with minimal side effects for many patients. Despite their significant impact on the progression and epidemiology of hepatitis C virus (HCV) associated liver disease, the global annual incidence of chronic infections is expected to remain relatively constant, averaging 1.42 million new cases each year until 2030. Furthermore, by 2030, there will be a 14-17% increase in end-stage liver disease outcomes such as liver-related deaths, hepatocellular carcinoma (HCC), and decompensated cirrhosis in adults aged 18 years and over. Although reductions in liver decompensation, HCC occurrence, and mortality have been shown in patients with advanced liver disease who achieved sustained virological response (SVR) with DAA, these benefits may be less significant in those with decompensated liver cirrhosis. This review aims to summarise the impact of the virological response to DAA on liver disease progression and outcomes in patients with advanced chronic liver disease, which appears to be crucial for defining patient-specific follow-up.

In the past, advanced chronic liver disease was considered irreversible, but with better understanding and improved treatments, it is now recognized that fibrosis is a dynamic process that can regress even when it has reached the stage of cirrhosis. We present the case of a 60-year-old male patient with advanced chronic liver disease due to chronic hepatitis B, whose follow-up liver biopsy revealed significant fibrosis regression after successful antiviral therapy. We confirmed the predominantly regressive pattern using the P-I-R classification, a new histological classification that defines the tissue features as predominantly "Progressive, Intermediate or Regressive" by comparing stroma to parenchymal ratios. Furthermore, we also point out the prognostic value of P-I-R classification, as the patient has remained free of decompensation over time. In this clinical case, we highlight important aspects of the pathophysiology and histopathology of cirrhosis regression, emphasizing its critical prognostic significance. Finally, familiarizing clinicians and pathologists with the application of the P-I-R classification may improve prognostication based on histology in patients with advanced liver disease.

The Baveno VI criteria have set the stage for noninvasive assessment of compensated advanced chronic liver disease (ACLD). The algorithm combining liver stiffness measurement (LSM, <20 kPa) and platelet count (>150,000/μL) safely avoids screening endoscopy for varices needing treatment (VNT) but identifies only a relatively low number of patients. We aimed to evaluate the value of spleen stiffness measurement (SSM) using spleen-dedicated elastography in ruling out VNT. In this real-life multicenter retrospective derivation-validation cohort, all consecutive patients with ACLD (defined by LSM ≥10 kPa) with available upper endoscopy, laboratory results, spleen diameter, LSM, and SSM measured with spleen-dedicated transient elastography were included. VNT were defined as medium-to-large varices or small varices with red spots. In the derivation cohort (n = 201, 11.9% VNT), SSM demonstrated excellent capability at identifying VNT (area under the receiver operating characteristic curve [AUROC] 0.88), outperforming LSM (AUROC 0.77, P = 0.03) and platelets (AUROC 0.73, P = 0.002). In comparison with Baveno VI criteria (33.8% spared endoscopies), the sequential Baveno VI plus SSM and a novel spleen size and stiffness model were able to increase the number of patients avoiding endoscopy (66.2% and 71.1%, respectively) without missing more than 5% of VNT. These findings were confirmed in an external validation cohort of patients with more advanced liver disease (n = 176, 34.7% VNT) in which the number of spared endoscopies tripled (27.3% and 31.3% for SSM-based algorithms) compared with Baveno VI criteria (8.5%). Spleen stiffness-based algorithms are superior to Baveno VI criteria in ruling out VNT in patients with ACLD and double the number of patients avoiding screening endoscopy.

Background & AimsWhile direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.MethodsLiver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low‐molecular‐weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti‐Xa peak levels and thrombomodulin‐modified thrombin generation assays (TM‐TGAs) were measured in a subgroup of 35/28 DOAC patients.ResultsAmong patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child‐Pugh‐stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure‐related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow‐up of 10.5 (IQR: 4.0‐27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS‐B/C (at 12 months: 36.9% vs CPS‐A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59‐6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00‐16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82‐9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti‐Xa peak levels were higher in patients with CPS‐B/C (345 [95% CI: 169‐395] vs CPS‐A: 137 [95% CI: 96‐248] ng/mL, P = .048) and were associated with lower TM‐TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients.ConclusionsAnticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Early diagnosis and management can mitigate the long-term morbidity and mortality of chronic obstructive pulmonary disease (COPD). To gain insights into the initial diagnostic process and early management of COPD by Australian general practitioners (GP). A random sample of Australian GP was invited to complete a postal survey, which assessed familiarity with and use of contemporary practice guidelines, diagnostic criteria and management preferences for COPD. A total of 233 GP completed the survey. While most GP based a COPD diagnosis on smoking history (94.4%), symptoms (91.0%) and spirometry (88.8%), only 39.9% of respondents recorded a formal diagnosis of COPD after the patient's first symptomatic presentation. Tiotropium was the preferred treatment in 77.3% of GP for the initial management of COPD, while only 27.5% routinely recommended pulmonary rehabilitation. GP routinely recorded patients' smoking status and offered smoking cessation advice, but the timing of this advice varied. Less than half of the respondents routinely used COPD management guidelines or tools and resources provided by the Australian Lung Foundation. There is scope for major improvement in GP familiarity with and use of COPD management guidelines and readily available tools and resources. Some systematic issues were highlighted in the Australian primary care setting, such as a reactive and relatively passive and delayed approach to diagnosis, potentially delayed smoking cessation advice and underutilisation of pulmonary rehabilitation. There is an urgent need to devise strategies for improving patient outcomes in COPD using resources that are readily available.

Advanced chronic liver disease (ACLD) is the strongest risk factor for the development of HCC, the third leading cause of cancer-death worldwide [1]. Studies show that within the population of ACLD, there is wide heterogeneity in the individual risk for HCC development and more study into individual risk factors is needed [2]. Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene and is a rare cause of both advanced liver and lung disease. Patients with two copies of a diseased allele (Pi*ZZ) are likely to have clinically significant disease, while carriers with one diseased allele (Pi*MS or MZ) are at higher risk for ACLD but generally require another co-factor to progress to ACLD [3]. The role of the heterozygous diseased genotypes in the development of HCC is yet to be determined. In this study, Balcar et al. [4] examined the role of the heterozygous Pi*MZ genotype in the development of HCC in patients with ACLD. They retrospectively studied a cohort of 815 patients with ACLD caused by viral disease or steatotic liver diseases (alcohol, MASLD) from a single center; they included patients who had HVPG measurements and genetic data available. Patients were followed to time of death, liver transplant, HCC development or date of last follow-up; the median time of follow-up was 47.3 months. 68 (8%) patients developed HCC during the study period, including 8 (27%) with the Pi*MZ genotype. Using univariable and multivariable competing risk regression analysis, the authors showed that the Pi*MZ genotype was independently associated with increased risk for HCC including when adjusted for other variables including aMAP score and in a smaller cohort which included AFP data. Previous epidemiological data is limited but has not suggested a relationship between the heterozygous diseased genotypes and HCC development in the ACLD population [5, 6]. This work [4] marks the first epidemiologic study where the Pi*MZ allele has been implicated in the development of HCC, although limited autopsy and animal data have also supported this conclusion. In interpreting these findings, it is vital to consider the study cohort carefully. The group defined ACLD based on HVPG, a robust way to ensure that patients had ACLD. However, it only included patients with viral or steatotic etiologies of liver disease, leaving out at least one major group (autoimmune) as well as those with cryptogenic disease. This limits the generalizability of these findings largely to the steatotic and viral liver diseases. In comparison, other tests that evaluate risk for HCC in ACLD are validated across etiologies, including FIB-4 and liver stiffness [7, 8]. In addition, this was a single-center study in Europe and included patients who received HVPG measurements; the results may not be generalizable to other demographic groups. This study constitutes a step forward in understanding the role that the Pi*MZ genotype plays in the development of HCC in patients with ACLD; in the future it may be possible to target therapeutics using this information. More data, including validation studies, will be needed to understand the generalizability of these results across all demographics and etiologies of ACLD. Kaitlyn Carlson: writing – original draft, conceptualization, writing – review and editing. Abbey Barnard Giustini: conceptualization, writing – review and editing. The authors have nothing to report. This article is linked to Balcar et al. papers. To view this article, visit https://doi.org/10.1111/apt.70530. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Enhanced primary care after hospitalization: General practitioner, pharmacist and patient feedback from the REMAIN HOME trial.

Sarcopenia, first introduced as a concept by I. Rosenberg in 1989, has since been extensively studied, particularly in its correlation with chronic diseases. In recent years, sarcopenia has been increasingly associated with advanced chronic liver disease, leading to a lower quality of life and poor outcomes for these patients. Studies have shown that sarcopenia has a prevalence of 33% in individuals with advanced chronic liver disease, impacting not only the patient’s health but also contributing to increased healthcare costs. The prevalence of frailty in patients with advanced chronic liver disease is 27%. Given the high prevalence of sarcopenia and frailty in this population, early diagnosis and treatment are crucial to improving patient quality of life outcomes and reducing the strain on healthcare systems globally.

A Prospective Study of Prevalence and Impact of Sarcopenia on Short-term Mortality in Hospitalized Patients with Liver Cirrhosis