Moving forward in circles: challenges and opportunities in modelling population cycles

Population cycling is a widespread phenomenon, observed across a multitude of taxa in both laboratory and natural conditions. Historically, the theory associated with population cycles was tightly linked to pairwise consumer–resource interactions and studied via deterministic models, but current empirical and theoretical research reveals a much richer basis for ecological cycles. Stochasticity and seasonality can modulate or create cyclic behaviour in non-intuitive ways, the high-dimensionality in ecological systems can profoundly influence cycling, and so can demographic structure and eco-evolutionary dynamics. An inclusive theory for population cycles, ranging from ecosystem-level to demographic modelling, grounded in observational or experimental data, is therefore necessary to better understand observed cyclical patterns. In turn, by gaining better insight into the drivers of population cycles, we can begin to understand the causes of cycle gain and loss, how biodiversity interacts with population cycling, and how to effectively manage wildly fluctuating populations, all of which are growing domains of ecological research

A low-energy total diet replacement programme demonstrates a favourable safety profile and improves liver disease severity in non-alcoholic steatohepatitis

Objective: Low-energy diets are used to treat obesity and diabetes, but there are fears that they may worsen liver disease in patients with nonalcoholic steatohepatitis (NASH) and significant-to-advanced fibrosis. Methods: In this 24-week single-arm trial, 16 adults with NASH, fibrosis, and obesity received one-to-one remote dietetic support to follow a low-energy (880 kcal/d) total diet replacement program for 12 weeks and stepped food reintroduction for another 12 weeks. Liver disease severity was blindly evaluated (magnetic resonance imaging proton density fat fraction [MRI-PDFF], iron-corrected T1 [cT1], liver stiffness on magnetic resonance elastography [MRE], and liver stiffness on vibration-controlled transient elastography [VCTE]). Safety signals included liver biochemical markers and adverse events. Results: A total of 14 participants (87.5%) completed the intervention. Weight loss was 15% (95% CI: 11.2%–18.6%) at 24 weeks. Compared with baseline, MRI-PDFF reduced by 13.1% (95% CI: 8.9%–16.7%), cT1 by 159 milliseconds (95% CI: 108–216.5), MRE liver stiffness by 0.4 kPa (95% CI: 0.1–0.8), and VCTE liver stiffness by 3.9 kPa (95% CI: 2.6–7.2) at 24 weeks. The proportions with clinically relevant reductions in MRI-PDFF (≥30%), cT1 (≥88 milliseconds), MRE liver stiffness (≥19%), and VCTE liver stiffness (≥19%) were 93%, 77%, 57%, and 93%, respectively. Liver biochemical markers improved. There were no serious intervention-related adverse events. Conclusions: The intervention demonstrates high adherence, favorable safety profile, and promising efficacy as a treatment for NASH

Severe Dietary Energy Restriction for Compensated Cirrhosis Due to Metabolic Dysfunction‐Associated Steatotic Liver Disease: A Randomised Controlled Trial

Background: Compensated cirrhosis due to metabolic dysfunction‐associated steatotic liver disease (CC‐MASLD) increases morbidity and mortality risk but has no aetiology‐specific treatment. We investigated the safety and efficacy signals of severe energy restriction. Methods: In this randomised controlled trial, adults with CC‐MASLD and obesity in a tertiary hepatology centre were randomised 2:1 to receive one‐to‐one remote dietetic support with a low‐energy (880 kcal/day, 80 g protein/day) total diet replacement programme for 12 weeks and stepped food reintroduction for another 12 weeks or standard of care (SoC). Given the exploratory nature of the study, three pre‐defined co‐primary outcomes were used to assess safety and efficacy signals: severe increases in liver biochemistry, changes in iron‐corrected T1, and changes in liver stiffness on magnetic resonance elastography. Changes in liver steatosis on magnetic resonance imaging, physical performance based on the physical performance test and liver frailty index, and changes in fat‐free mass were secondary outcomes. Magnetic resonance outcomes were assessed blind. Results: Between February 2022 and September 2023, 17 participants (36% female, median [IQR] age 58 [7.5] years) were randomised to SoC (n = 6) or intervention (n = 11). The trial stopped earlier than planned due to slow recruitment rate. 91% and 94% of participants completed the intervention and attended the 24‐week follow‐up, respectively. Compared with the SoC, the between‐group weight change in the intervention was −11.9 kg (95% CI: −17.2, −6.6, p < 0.001) at 24 weeks. Liver biochemistry markers (alanine transaminase, aspartate transaminase, and total bilirubin) were stable in everyone throughout the trial. Iron‐corrected T1 and steatosis significantly reduced (−149.9 ms [95% CI −258.1, −41.7, p = 0.01] and −6% [95% CI −11.3, −0.6, p = 0.03], respectively). There were no between‐group differences in changes in liver stiffness (0.2 kPa [95% CI −1.1, 1.6]), the physical performance test (1.5 points [95% CI −1.9 to 4.9], p = 0.70) or the liver frailty index (0 [95% CI −0.6 to 0.6], p = 0.97). Compared with SoC, absolute fat‐free mass reduced (−3.2 kg [95% CI −6 to −0.3], p = 0.04) but relative fat‐free mass as percentage of total body weight increased (5.4% [95% CI 0.5 to 10.3], p = 0.046). No participant met the pre‐defined safety criteria for enhanced observation or intervention discontinuation. There was no between‐group differences in changes in cardiovascular markers and no evidence of hepatic decompensation or serious adverse events. Conclusions: Severe energy restriction appears a safe option to achieve significant weight loss and reduce liver fat without adverse effects in people with CC‐MASLD. A larger study is needed to confirm these findings. Clinical Trial Registration: ISRCTN13053035, prospectively registered, overall study status: closed

Immunotherapy-related hepatitis: real-world experience from a tertiary centre

Objective Immune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids. Design Retrospective review of 453 patients started on immunotherapy over 7 years. Setting Tertiary hepatology and oncology centre. Patients 21 patients identified with immunotherapy-related hepatotoxicity. Results Hepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease. Conclusions Vigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids

Hepatology at home: a novel pathway for the integrated management of patients with liver disease in the home

Objective: Hospital admissions and deaths due to liver disease are increasing worldwide, representing a significant burden on acute services. We describe the first 12 months of Hepatology at home, a novel service that delivers hospital-level care to patients with liver disease in their own home as an alternative to ambulatory or inpatient management. The primary aim was to evaluate the number of at-home days where a patient received assessment and management at home rather than attending hospital. Method: Processes of care and outcomes of patients referred to Hepatology at Home at Oxford University Hospitals NHS Foundation Trust, United Kingdom were collected prospectively for 12 months from 27 April 2024 to 26 April 2025. Results: 40 patients (n=16 female, median age 67) with 67 discrete episodes of care were referred. Most patients (90%) had cirrhosis associated with metabolic and/or alcohol risk factors. The most common reason for referral was the management of ascites/oedema (62.7%). Interventions performed in the home included ascitic tap (n=5), large volume paracentesis (n=5), venesection (n=6) and administration of intravenous iron, diuretics or antibiotics (n=13). Patients had an additional 269 days at home (per-patient median 5, range 1–72), of which 156 replaced inpatient hospital days and 113 replaced hospital-based ambulatory hepatology reviews. Within 30 days of discharge, 58.7% required a further Hepatology at home encounter or inpatient admission. The 30-day mortality rate was 32.5%. There were no unexpected deaths. Conclusion: Hepatology at Home is an alternative to hospital-based ambulatory or inpatient care for patients with liver disease

Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD

Background and Aims Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms maybe important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal. Methods 29 participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA-sequencing, circulating proteome and stool microbiome analysis. Participants were randomized to lifestyle (∼500kcal energy deficit) or GLP1-RA treatment for 12-weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12-weeks after treatment withdrawal. Results Matched weight loss was achieved in both arms. Body composition changes, reductions in ALT, liver steatosis and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12-weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23 and Flt3L were elevated, alongside dysregulated adipose gene expression. Conclusions Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression and the stool microbiome, predisposing to weight regain

Multi-parametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity

BACKGROUND AND AIMS: The diagnosis of non-alcoholic steatohepatitis (NASH) and fibrosis staging are central to non-alcoholic fatty liver disease (NAFLD) assessment. We evaluated multi-parametric magnetic resonance (MR) in the assessment of NASH and fibrosis using histology as standard in NAFLD. METHODS: Seventy one patients with suspected NAFLD were recruited within one month of liver biopsy. MR data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as NASH or simple steatosis, and mild or significant (Activity ≥2 and / or Fibrosis ≥2 as defined by the Fatty Liver Inhibition of Progression consortium) NAFLD. Transient elastography (TE) was also performed. RESULTS: MR success rate was 95% vs 59% for TE (p<0.0001). Fibrosis stage on biopsy correlated with LIF (rs =0.51, p<0.0001). The area under the receiver operating curve (AUROC) using LIF for the diagnosis of cirrhosis was 0.85. LIF score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (p<0.05) with an AUROC of 0.83 for the diagnosis of ballooning. Patients with steatosis had lower LIF (1.3) compared to patients with NASH (3.0) (p<0.0001); AUROC for the diagnosis of NASH was 0.80. LIF scores for patients with mild and significant NAFLD were 1.2 and 2.9 respectively (p<0.0001). The AUROC of LIF for the diagnosis of significant NAFLD was 0.89. CONCLUSIONS: Multi-parametric MR is a promising technique with good diagnostic accuracy for NAFLD histological parameters, and can potentially identify patients with NASH and cirrhosis. This article is protected by copyright. All rights reserved

Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease

Background &amp; Aims: We estimated the accuracy of FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD). Methods: We collected data from 450 consecutive adults who underwent liver biopsy analysis for suspected NAFLD at 7 centers in the United Kingdom from March 2014 through January 2017. FibroScan examinations with M or XL probe were completed within the 2 weeks of the biopsy analysis (404 had a valid examination). The biopsies were scored by 2 blinded expert pathologists according to nonalcoholic steatohepatitis clinical research network criteria. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis and fibrosis. We assessed effects of disease prevalence on positive and negative predictive values. For LSM, the effects of histological parameters and probe type were appraised using multivariable analysis. Results: Using biopsy analysis as the reference standard, we found that CAP identified patients with steatosis with an AUROC of 0.87 (95% confidence interval [CI] 0.82–0.92) for S≥S1, 0.77 (95% CI 0.71–0.82) for S≥S2, and 0.70 (95% CI 0.64–0.75) for S=S3. Youden cutoff values for S≥S1, S≥S2, and S≥S3 were 302 dB/m, 331 dB/m, and 337 dB/m, respectively. LSM identified patients with fibrosis with AUROCs of 0.77 (95% CI 0.72–0.82) for F≥F2, 0.80 (95% CI 0.75–0.84) for F≥F3, and 0.89 (95% CI 0.84–0.93) for F=F4. Youden cutoff values for F≥F2, F≥F3, and F=F4 were 8.2 kPa, 9.7 kPa, and 13.6 kPa, respectively. Applying the optimal cutoff values, determined from this cohort, to populations of lower fibrosis prevalence increased negative predictive values and reduced positive predictive values. Multivariable analysis found that the only parameter that significantly affected LSMs was fibrosis stage (P&lt;10 –16); we found no association with steatosis or probe type. Conclusions: In a prospective analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89. Probe type and steatosis did not affect LSM. Study registration: ClinicalTrials.gov Identifier: NCT01985009. </p

Health-related Quality of Life in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Multi-center UK Study

Background & Aims: It is unclear whether health-related quality of life (HRQoL) is impaired in patients with nonalcoholic fatty liver disease (NAFLD) without advanced fibrosis and how this compares with the general population. We aimed to assess HRQoL in patients with NAFLD in comparison to the general population and any associations of fibrosis severity and metabolic comorbidities with impairments in HRQoL. Methods: We prospectively enrolled 513 consecutive patients with NAFLD who completed the EuroQol 5-dimensional questionnaire (EQ-5D) and Chronic Liver Disease Questionnaires (CLDQ). Demographic and clinical information, liver biopsy results, and/or liver stiffness (LS) by transient elastography were recorded. A general population sub-cohort of the Health Survey for England 2018 was used as a comparator (n = 5483), and a 1:1 propensity-score (PS) matching was performed, according to age, sex, body mass index, and type 2 diabetes mellitus (T2DM). Results: EQ-5D-5L utility was significantly lower in 466 PS-matched patients with NAFLD compared with PS-matched controls (0.77 ± 0.27 vs 0.84 ± 0.19; P < .001), even in those without advanced fibrosis (F ≤2 or LS <8kPa) (0.80 ± 0.24 vs 0.84 ± 0.19; P = .024). HRQoL measures (EQ-5D-5L, EQ-VAS, CLDQ) did not differ between patients with NAFLD with and without advanced fibrosis. LS was independently associated with lower EQ-5D-5L in all patients with NAFLD but not in those without advanced fibrosis. In the latter, lower EQ-5D-5L was associated with female sex, T2DM, and depression. Conclusions: Patients with NAFLD, even those without advanced fibrosis, have worse HRQoL compared with the general population. In patients with NAFLD without advanced fibrosis, HRQoL is independently associated with non-liver comorbidities but not LS. Multi-disciplinary management is therefore required in NAFLD, irrespective of fibrosis severity