Metabolic dysfunction-associated steatohepatitis exhibits sex differences in people with HIV.

OBJECTIVES: People with HIV are at increased risk for metabolic dysfunction-associated steatohepatitis (MASH). Although sex differences are documented in the general population, their role in the context of HIV is less understood. METHODS: This was a multicentre cohort study including people with HIV without viral hepatitis coinfection. A FibroScan-AST (FAST) score >0.35 was used to diagnose MASH with significant liver fibrosis (stage F2-F4). We investigated sex-based differences in MASH trends as a function of age using a segmented linear mixed-effects model. Random effects accounted for clustering by the four sites. Adjusted models included ethnicity, diabetes, hypertension, and detectable HIV viral load. RESULTS: We included 1472 people with HIV (25% women). At baseline, the prevalence of MASH with fibrosis by FAST score was lower in women than in men (4.8% vs. 9.2%, p = 0.008). Based on the adjusted model, male sex (+0.034; p = 0.04), age per year (+0.003; p = 0.05), detectable HIV viral load (+0.034; p = 0.02), and hypertension (+0.03; p = 0.01) were positively associated with MASH with fibrosis. Although men exhibited generally higher FAST scores, FAST scores increased in women during the critical biological age of presumed perimenopause to menopause (between 40 and 50 years), reaching levels similar to those in men by the age of 55 years. CONCLUSION: Despite women with HIV having a lower prevalence of MASH with fibrosis than men, they exhibit an acceleration in FAST score increase around the perimenopausal age. Future studies should target adequate consideration of sex differences in clinical investigation of metabolic dysfunction-associated steatotic liver disease to fill current gaps and implement precision medicine for people with HIV.

Integrating behavioral interventions into a holistic approach to metabolic dysfunction-associated steatotic liver disease.

INTRODUCTION: The therapeutic landscape of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is rapidly evolving with the FDA approval of resmetirom, the first authorized molecule to treat metabolic dysfunction-associated steatohepatitis. Clinical trials are investigating other promising molecules. However, this focus on pharmacotherapy may overshadow lifestyle interventions, which remain the cornerstone of MASLD management. A significant percentage of patients with MASLD struggle with an underlying eating disorder, often a precursor to obesity. The obesity pandemic, exacerbated by the increasing prevalence of binge eating, underscores the need for a psychological approach to address their common roots. AREAS COVERED: We reviewed the current evidence on behavioral interventions for MASLD. Interventions such as self-monitoring, goal setting, and frequent counseling, have proven effective in achieving at least 5% weight loss. Cognitive behavioral therapy is the first-line treatment for eating disorders and has shown efficacy in treating binge eating and obesity. Further research is needed to establish the optimal behavioral therapy for MASLD, focusing on enhancing compliance and achieving sustained weight loss through diet and physical exercise. EXPERT OPINION: The treatment of MASLD should not rely solely on pharmacotherapy targeting a single-organ manifestation. Instead, we must consider behavioral interventions, emphasizing the pivotal role of a holistic approach to this multifaceted disorder. [Figure: see text].

Material deprivation is associated with liver stiffness and liver-related outcomes in people with HIV.

BACKGROUND: Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH. METHODS: We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis. RESULTS: Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non-white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (ß = 1.86, 95% CI 0.53-3.17) but not with CAP (ß = 6.47, 95% CI -5.55-18.49). Patients were observed for a median follow-up of 3.8 years. Incidence of liver-related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03-8.92), while there was no difference in extrahepatic outcomes or all-cause mortality. Social deprivation showed no association with either LSM or clinical outcomes. CONCLUSIONS: Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver-related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes.

What Not to Overlook in the Management of Patients with Type 2 Diabetes Mellitus: The Nephrological and Hepatological Perspectives.

Diabetes mellitus (DM) significantly impacts renal and hepatic function, necessitating comprehensive understanding and management strategies. Renal involvement, namely diabetic kidney disease (DKD), presents a global challenge, with increasing prevalence paralleling DM rates. Lifestyle modifications and pharmacotherapy targeting hypertension and glycemic control have pivotal roles in DKD management. Concurrently, hepatic involvement in DM, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD), presents a bidirectional relationship. DM exacerbates MASLD progression, while MASLD predisposes to DM development and worsens glycemic control. Screening for MASLD in DM patients is of high importance, utilizing non-invasive methods like ultrasound and fibrosis scores. Lifestyle modifications, such as weight loss and a Mediterranean diet, mitigate MASLD progression. Promising pharmacotherapies, like SGLT2 inhibitors and GLP-1 agonists, demonstrate efficacy in both DM and MASLD management. Special populations, such as diabetic individuals undergoing hemodialysis or kidney transplant recipients, demand special care due to unique clinical features. Similarly, DM exacerbates complications in MASLD patients, elevating the risks of hepatic decompensation and hepatocellular carcinoma. Recognizing the interconnectedness of DM, renal, and hepatic diseases underscores the need for multidisciplinary approaches for optimal patient outcomes. The present review aims to present the main characteristics and crucial points not to be overlooked regarding the renal and hepatic involvement in DM patients focusing on the inter-relationships between the renal and the hepatic involvements.

The effect of weight gain and metabolic dysfunction-associated steatotic liver disease on liver fibrosis progression and regression in people with HIV.

OBJECTIVE: People with HIV (PWH) have high risk of liver fibrosis. We investigated the effect of weight gain and metabolic dysfunction-associated steatotic liver disease (MASLD) on liver fibrosis dynamics. DESIGN: Multicenter cohort study. METHODS: Fibrosis progression was defined as development of significant fibrosis [liver stiffness measurement (LSM) ≥8 kPa], or transition to cirrhosis (LSM ≥13 kPa), for those with significant fibrosis at baseline. Fibrosis regression was defined as transition to LSM less than 8 kPa, or to LSM less than 13 kPa for those with cirrhosis at baseline. MASLD was defined as hepatic steatosis (controlled attenuation parameter >248 dB/m) with at least one metabolic abnormality. A continuous-time multistate Markov model was used to describe transitions across fibrosis states. RESULTS: Among 1183 PWH included from three centers (25.2% with viral hepatitis coinfection), baseline prevalence of significant fibrosis and MASLD was 14.4 and 46.8%, respectively. During a median follow-up of 2.5 years (interquartile range 1.9-3.5), the incidence rate of fibrosis progression and regression was 2.8 [95% confidence interval (CI) 2.3-3.4] and 2.2 (95% CI 1.9-2.6) per 100 person-years, respectively. In Markov model, weight gain increased the odds of fibrosis progression [odds ratio (OR) 3.11, 95% CI 1.59-6.08], whereas weight gain (OR 0.30, 95% CI 0.10-0.84) and male sex (OR 0.32, 95% CI 0.14-0.75) decreased the odds of fibrosis regression. On multivariable Cox regression analysis, predictors of fibrosis progression were weight gain [adjusted hazard ratio (aHR) 3.12, 95% CI 1.41-6.90] and MASLD (aHR 2.72, 95% CI 1.05-7.02). CONCLUSION: Fibrosis transitions are driven by metabolic health variables in PWH, independently of viral hepatitis coinfection and antiretroviral class therapy.

Metabolic dysfunction-associated steatotic liver disease: An opportunity for collaboration between cardiology and hepatology.

Altered metabolic function has many detrimental effects on the body that can manifest as cardiovascular and liver diseases. Traditional approaches to understanding and treating metabolic dysfunction-associated disorders have been organ-centered, leading to silo-type disease care. However, given the broad impact that systemic metabolic dysfunction has on the human body, approaches that simultaneously involve multiple medical specialists need to be developed and encouraged to optimize patient outcomes. In this review, we highlight how several of the treatments developed for cardiac care may have a beneficial effect on the liver and vice versa, suggesting that there is a need to target the disease process, rather than specifically target the cardiovascular or liver specific sequelae of metabolic dysfunction.

Comparison of the severity of metabolic, liver and cardiovascular damage in NAFLD patients attending the hepatology clinic over the last three decades.

BACKGROUND AND AIMS: NAFLD prevalence is increasing worldwide. AIM: to assess whether severity of hepatic, metabolic and cardiovascular (CV) disease changed over time. METHODS: 422 NAFLD patients (388 biopsy proven and 34 clinical cirrhosis) diagnosed between 1990 and 2021 and subdivided according to decade of presentation. Metabolic parameters, early atherosclerosis (carotid plaques at Doppler ultrasound), severity of liver damage (NAS score, NASH, significant fibrosis (≥2) and cirrhosis) and PNPLA3 genotyping were assessed. RESULTS: No difference in age, sex and prevalence of dyslipidemia and hypertension was found across decades (p for trend), whereas a higher prevalence of diabetes (p = 0.02), obesity (p<0.001), histological severe steatosis (p<0.001), NASH (p<0.001), fibrosis ≥2 (p<0.001), cirrhosis (p<0.001) and carotid plaques (p = 0.05) was observed in the last decade compared to the others. A higher prevalence of PNPLA3 GG polymorphism was found over time (p = 0.02). In the whole cohort, age, metabolic alterations and PNPLA3 G homozygosity were independent risk factors for hepatic fibrosis and carotid plaques, independently of the decade considered. CONCLUSION: Over the past 10 years compared to previous decades, NAFLD patients presented to observation with more severe liver disease and subclinical atherosclerosis, paralleling the spread of diabetes and obesity. PNPLA3 unfavorable genotype became more prevalent over time.

Role of fatty liver in the epidemic of advanced chronic liver disease among people with HIV: protocol for the Canadian LIVEHIV multicentre prospective cohort.

INTRODUCTION: Advanced chronic liver disease (ACLD) is a major cause of death for people with HIV (PWH). While viral hepatitis coinfections are largely responsible for this trend, metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging concern for PWH. We aimed to assess the contribution of MASLD to incident ACLD in PWH. METHODS AND ANALYSIS: This multicentre prospective observational cohort study will enrol 968 consecutive HIV monoinfected patients from four Canadian sites, excluding subjects with alcohol abuse, liver disease other than MASLD, or ACLD at baseline. Participants will be followed annually for 4 years by clinical evaluation, questionnaires, laboratory testing and Fibroscan to measure liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). The primary outcome will be incidence of ACLD, defined as LSM>10 kPa, by MASLD status, defined as CAP≥285 dB/m with at least one metabolic abnormality, and to develop a score to classify PWH according to their risk of ACLD. Secondary outcomes will include health-related quality of life (HRQoL) and healthcare resource usage. Kaplan-Meier survival method and Cox proportional hazards regression will calculate the incidence and predictors of ACLD, respectively. Propensity score methods and marginal structural models will account for time-varying exposures. We will split the cohort into a training set (to develop the risk score) and a validation set (for validation of the score). HRQoL scores and healthcare resource usage will be compared by MASLD status using generalised linear mixed effects model. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committees of all participating institutions. Written informed consent will be obtained from all study participants. The results of this study will be shared through scientific publications and public presentations to advocate for the inclusion of PWH in clinical trials of MASLD-targeted therapies and case-finding of ACLD in PWH.

Nutritional and Lifestyle Therapy for NAFLD in People with HIV.

HIV infection and nonalcoholic fatty liver disease (NAFLD) are two major epidemics affecting millions of people worldwide. As people with HIV (PWH) age, there is an increased prevalence of metabolic comorbidities, along with unique HIV factors, such as HIV chronic inflammation and life-long exposure to antiretroviral therapy, which leads to a high prevalence of NAFLD. An unhealthy lifestyle, with a high dietary intake of refined carbohydrates, saturated fatty acids, fructose added beverages, and processed red meat, as well as physical inactivity, are known to trigger and promote the progression of NAFLD to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Furthermore, with no currently approved pharmacotherapy and a lack of clinical trials that are inclusive of HIV, nutritional and lifestyle approaches still represent the most recommended treatments for PWH with NAFLD. While sharing common features with the general population, NAFLD in PWH displays its own peculiarities that may also reflect different impacts of nutrition and exercise on its onset and treatment. Therefore, in this narrative review, we aimed to explore the role of nutrients in the development of NAFLD in PWH. In addition, we discussed the nutritional and lifestyle approaches to managing NAFLD in the setting of HIV, with insights into the role of gut microbiota and lean NAFLD.

An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC.

Remdesivir-induced bradycardia in patients hospitalized with SARS-CoV2 infection: a possible vagally-mediated mechanism.

Recently, case series studies on patients with SARS-CoV-2 infection reported an association between remdesivir (RDV) administration and incidental bradycardia. However, the phenomenon has not yet been described in detail. We conducted a retrospective case-control study to evaluate the occurrence of RDV-related bradycardia in patients hospitalized for SARS-CoV2 pneumoniae. We retrospectively evaluated 71 patients, hospitalized in six internal medicine wards of the Milan area, affected by mild-to-moderate COVID-19 who received RDV (RDV group) and 54 controls, matched for sex, age and disease severity on admission (CTR group). The mean heart rate value recorded during the first two days of hospitalization was considered as baseline heart rate (HRb). Heart rate values relative to the 5-days treatment and the 5-days post-treatment were extracted for RDV group, while heart rate values relative to 10 days of hospitalization were considered for the CTR group. ΔHR values were calculated as maximum HR drop versus HRb. Possible associations between ΔHR and clinical-demographic factors were assessed through regression analysis. The RDV group experienced a significantly higher incidence of bradycardia compared to the CTR group (56% vs 33%, OR 2.6, 95% CI 1.2-5.4, p value = 0.011). Moreover, the RDV group showed higher ΔHR values than the CTR group. The HR progressively decreased with daily administration of RDV, reaching the maximun drop on day six (-8.6±1.9 bpm). In RDV group, patients who experienced bradycardia had higher drop in HR, higher alanine aminotransferase (ALT) values at the baseline (bALT) and during the RDV administration period. ΔHR was positively associated with HRb (ß = 0.772, p < 0.001) and bALT (ß = 0.245, p = 0.005). In conclusion, our results confirmed a significant association between RDV administration and development of bradycardia. This effect was proportional to baseline HR and was associated with higher levels of baseline ALT, suggesting a possible interaction between RDV liver metabolism and a vagally-mediated effect on HR due to increased availability of RDV metabolites.

Interaction between Lifestyle Changes and PNPLA3 Genotype in NAFLD Patients during the COVID-19 Lockdown.

The coronavirus disease 2019 (COVID-19) lockdown dramatically changed people's lifestyles. Diet, physical activity, and the PNPLA3 gene are known risk factors for non-alcoholic fatty liver disease (NAFLD). Aim: To evaluate changes in metabolic and hepatic disease in NAFLD patients after the COVID-19 lockdown. Three hundred and fifty seven NAFLD patients were enrolled, all previously instructed to follow a Mediterranean diet (MD). Anthropometric, metabolic, and laboratory data were collected before the COVID-19 lockdown in Italy and 6 months apart, along with ultrasound (US) steatosis grading and information about adherence to MD and physical activity (PA). In 188 patients, PNPLA3 genotyping was performed. After the lockdown, 48% of patients gained weight, while 16% had a worsened steatosis grade. Weight gain was associated with poor adherence to MD (p = 0.005), reduced PA (p = 0.03), and increased prevalence of PNPLA3 GG (p = 0.04). At multivariate analysis (corrected for age, sex, MD, PA, and PNPLA3 GG), only PNPLA3 remained independently associated with weight gain (p = 0.04), which was also associated with worsened glycemia (p = 0.002) and transaminases (p = 0.02). During lockdown, due to a dramatic change in lifestyles, half of our cohort of NAFLD patients gained weight, with a worsening of metabolic and hepatologic features. Interestingly, the PNPLA3 GG genotype nullified the effect of lifestyle and emerged as an independent risk factor for weight gain, opening new perspectives in NAFLD patient care.