Background and Aims: Lysosomal acid lipase (LAL) hydrolyzes lipids in the lysosomal compartment. Patients with genetic LAL deficiency (LAL-D) display liver steatosis and hypercholesterolemia and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) may develop an acquired LAL-D. Aim: to investigate whether low LAL activity could predict MASLD progression.Method: 144 MASLD patients were enrolled, tested for LAL activity (expressed as LAL/platelets) and for the severity of steatosis and fibrosis by Fibroscan (Controlled Attenuation Parameter-CAP; Liver Stiffness Measurement-LSM) and were followed up for a mean of 8.1years. Ninety-four patients underwent liver biopsy which was repeated at the end of follow-up.Results: In biopsied patients 10% developed metabolic dysfunction-associated steatohepatitis (MASH), 10% had worsening of NAFLD activity score (NAS) and 10% had worsening of fibrosis. Overall, 26% of patients had a composite histological endpoint (i.e development of MASH and/or worsening of NAS and/or worsening of fibrosis). Lower baseline LAL/platelet ratio was associated with worsening of NAS, fibrosis and with the composite histological endpoint and remained independently associated with the composite histological endpoint (OR = 0.51, CI 95%0.04-0.60) after adjustment for age, HOMA, gender, CAP and/or LSM. On the other hand, in the whole cohort (n = 144) no statistically significant changes in liver disease assessed non-invasively (median CAP and LSM) was observed.Conclusion: Measurement of LAL activity could help in identifying patients with a higher risk of MASLD progression towards MASH and fibrosis. In particular, lower LAL activity could be associated with the development of inflammation, a feature not detectable by available non-invasive techniques.

Liver inflammation and fibrosis are the key determinants of long-term adverse outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, identifying progressive forms of MASLD is crucial. Lysosomal acid lipase (LAL), a central enzyme in intracellular lipid hydrolysis, has been reported to be reduced in MASLD and linked to liver injury. To evaluate whether baseline LAL activity predicts long-term progression of MASLD. We prospectively followed up 144 adults with biopsy-proven MASLD for a minimum of 5 years (median 8.1). All patients underwent a FibroScan® at baseline and follow-up and 94 of them also had paired liver biopsies. LAL activity (expressed as LAL/platelet-LAL/ptls) was measured on dried blood spots. Liver disease progression was defined by meeting of the histological endpoint at follow-up (i.e., development of MASH and/or NAS worsening ≥ 1 point and/or fibrosis progression ≥ 1 stage) or by liver stiffness measurement (LSM) worsening at Fibroscan. Among the 94 biopsied patients, 26

This study compares anthropometric, metabolic, cardiovascular, and liver parameters in people living with HIV (PLWH) on antiretroviral therapy (ART), and men on pre-exposure prophylaxis (PrEP) in the same age group. This was a single-center, cross-sectional study of males aged 18–50 years, receiving ART for HIV or PrEP for at least 6 months, consecutively enrolled at Policlinico Hospital, Milan. Lifestyle factors were assessed using the International Physical Activity Questionnaire and a food diary. Anthropometric measurements included body mass index (BMI), waist circumference, and bioimpedance analysis. Blood samples were analyzed for glycemic parameters, lipid profile, hepatic enzymes, and adipokines, including leptin. Hepatic steatosis and fibrosis were evaluated using FibroScan®. Group differences were assessed using chi-squared, t tests, and Mann–Whitney tests, while logistic regression determined associations with HIV status. Eighty-two participants were enrolled: 53 PLWH and 29 PrEP users. PLWH had significantly higher BMI, waist circumference, total fat mass, and triglycerides, as well as total and LDL cholesterol. PrEP users engaged in more vigorous-intensity activity, with no differences in dietary habits. Among PLWH, higher physical activity was associated with lower HOMA index. Leptin levels were significantly higher in PLWH compared to PrEP users. Multivariate analysis identified LDL cholesterol as independently associated with HIV status. PLWH exhibited greater adiposity and dyslipidemia than PrEP users, with leptin emerging as a potential marker of metabolic dysfunction. Higher physical activity was linked to improved insulin sensitivity, underscoring the role of exercise in mitigating HIV-related metabolic dysregulation.

ABSTRACT Introduction Type 3 hereditary hemochromatosis (HH) is a rare genetic disease due to mutations in the transferrin receptor 2 ( TFR2 ) gene. Methods and Results Here, we describe the case of an Italian patient presenting with hyperferritinemia and hepatic iron accumulation, not evidenced by magnetic resonance imaging, that was subsequently classified as HH Type 3 by the identification of the novel frameshift mutation c.523_524delC>T (p. Leu175Aspfs*41) in exon 4 of TFR2 gene through the whole exome sequencing (WES) approach. Conclusion WES would allow to diagnose rare HH‐related diseases in patients with unexplained hepatic iron overload and/or aberrant circulating iron parameters. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

IntroductionLiver's susceptibility to sexual hormones leads to gender differences in hepatocellular carcinoma (HCC). Metabolic comorbidities like obesity and diabetes, act as pro-oncogenic factors. Despite higher obesity rates in women, men with obesity face an increased HCC risk. The mechanism of this phenomenon is not fully understood. This study examines gender-based differences in HCC features and staging linked to metabolic comorbidities.MethodsA retrospective evaluation was conducted, evaluating 126 patients (2014-2020) utilizing the Barcelona Clinic Liver Cancer (BCLC) system for staging and treatment decisions. A platelet count <150,000mm³ estimated portal hypertension in 65% of cases. Treatment distribution included 14% undergoing surgery, 74% receiving locoregional therapy, 3% systemic therapy, and 8% best supportive care.ResultsHCC prevalence was higher in men (78% vs. 22%), with men experiencing onset at a significantly younger age (67±11 vs. 74±11, p=0.04). Hepatitis C virus (HCV) was the primary etiology in both genders (41% in men vs. 70% in women, p=0.03). Men also presented with more lesions at onset (52% vs. 80%, p=0.03), were more diabetic (43% vs. 20%, p=0.04) and obese (64% vs. 38%, p=0.09). Metabolic comorbidities correlated with higher percentages of thrombocytopenia (71% vs. 56%, p=0.03) and hyperbilirubinemia (36% vs. 15%, p=0.04), regardless of gender. In multivariate analysis, the coexistence of metabolic risk factors strongly correlated with male gender (OR 10.8, p=0.04), low platelet levels (OR 6.7, p=0.03), and high bilirubin levels (OR 4.95, p=0.04), independently of age. However, multifocality at onset appeared to correlate with male gender (OR 10.5, p=0.04).ConclusionOur study establishes a robust association between metabolic risk factors and male gender, contributing to more severe liver disease and access to less curative treatments. Increased vigilance and early intervention for metabolic comorbidities are crucial for reducing disease progression risk and facilitating more curative HCC treatments.

IntroductionSarcopenia, defined as the loss of muscle mass, is linked to metabolic comorbidities, connecting to steatotic liver disease and cardiovascular damage (CVD). The impact of sarcopenia on liver and CVD progression over time is not well understood.AimTo evaluate the impact of baseline sarcopenia on liver and CVD progression after 5 years in non-cirrhotic metabolic dysfunction-associated liver disease (MASLD) patients.Methods178 patients (62% male, mean age 51±10 years) were enrolled. Sarcopenia was defined as skeletal muscle mass/height2 ≤ 10.7/7.5 kg/m2 in men/women by bioimpedance analysis. CVD was assessed by carotid plaques or increased intima-media thickness (cIMT) > 0.9 mm at ultrasound, liver fibrosis by liver stiffness measurement (LSM) at Fibroscan and severity of steatosis (grade 2 -3) at ultrasound. After 5 years, liver disease and CVD severity were reassessed.ResultsAt baseline 45% were sarcopenic, 35% obese, 39% hypertensive, 25% dyslipidemic, 12% diabetic, sarcopenic patients compared to non-sarcopenic were more prevalently males (p=0.04), had lower BMI (26.5 vs 30.8, p<0.001), lower waist circumference (97 vs 105, p<0.001), greater LSM (5.4 vs 4.9 p=0.01), but similar prevalence of carotid plaques (p=0.88). At 5 yrs of follow-up, despite life-style modification, sarcopenic patients maintained lower BMI (26.5 vs 30.8, p<0.001) with no differences in deltaBMI (p=0.10), showed less improvement in low-density lipoprotein (LDL) (9.7 vs 27.9, p=0.04) despite of lipid-lowering lipid drugs use, a less improvement in LSM (0.1 vs 0.7, p=0.04), with no differences in carotid plaques (p=0.97) and increased cIMT (p=0.88). At multivariate analysis, deltaLSM remained associated with sarcopenia (OR 1.86, p=0.04), irrespective of confounders.ConclusionsBaseline sarcopenia seems to be related to less improvement in liver damage. Despite lower visceral adiposity, sarcopenic patients had greater LSM values, with the same extent of CV damage. SLD patients should be screened for sarcopenia to prevent liver disease progression.

BackgroundIn 2023, the nomenclature of non-alcoholic fatty liver disease (NAFLD) was replaced by the more inclusive terminology of metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic steatosis with at least one cardiometabolic risk factor. MASLD encompasses different disease severities ranging from steatosis, steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. In 2021, the European Society of Cardiology (ESC) redefine CV risk and identified three risk categories (low, high, and very high).AimTo evaluate, in a cohort of MASLD patients without a history of previous CV events, the severity of liver damage and metabolic comorbidities according to the ESC 2021 CV risk.Methods287 MASLD patients, fully characterized for metabolic, liver, and CV features, were divided into 3 groups according to the degree of CV risk. Liver fibrosis was assessed by liver stiffness measurement (LSM) and confirmed by histology in 30. CV damage was defined by the presence of carotid plaques or carotid intima-media thickness (cIMT) ≥ 0.9 mm by ultrasound. Epicardial fat thickness (EFT) was evaluated by echocardiography.Resultswith rising CV risk a significant increase in BMI (29±4.8 vs 31±4.4 kg/m2, p<0.001), obesity (33% vs 58%, p<0.001), liver fibrosis (4.7± 2.0 vs 5.2± 2.2 kPa, p=0.02), EFT (7.3±2.8 vs 8.3±3.0 mm, p=0.04), diabetes (7 vs 23%, p=0.004) and hypertension (39 vs 63%, p=0.003) was observed, as expected, carotid plaques and cIMT progressively increased from low to high-very high CV risk (p<0.001, and p=0.0003, respectively). At multivariate analysis, adjusted for age, sex, and all metabolic parameters, LSM was independently associated with the highest CV risk (OR 1.2, 95% C.I. 1.01-1.31).ConclusionThe association between cardiometabolic factors and liver fibrosis severity exposes patients with MASLD to increased CV risk and should be well evaluated in all patients, thus making integrated management mandatory to reduce CV and liver disease progression.

Aim: People with HIV (PWH) are at high risk of metabolic dysfunction-associated steatotic liver disease (MASLD), defined by the presence of hepatic steatosis plus any among overweight, diabetes, hypertension, or dyslipidemia. There are limited data whether MASLD in PWH differs in clinical presentation from MASLD in the uninfected population. Aim: to compare the severity of metabolic and hepatic dysfunction between MASLD patients with and without HIV. Methods: 212 consecutive HIV mono-infected patients with MASLD at McGill University in Montreal were compared to a sex and age matched MASLD HIV negative control group at Policlinico Hospital in Milan. Fibroscan with controlled attenuation parameter (CAP) was used to define MASLD (CAP≥248 dB/m), severe MASLD (CAP>280 dB/m), and significant liver fibrosis (liver stiffness measurement>7.0 kPa). Results: PWH with MASLD presented lower median BMI (28[25-31] vs 29[27-32] Kg/m2, p=0.002) and lower prevalence of obesity (26% vs 44%, p<0.001) compared to MASLD uninfected patients, along with a lower prevalence of hypertension (21% vs 38%, p<0.001). The prevalence of dyslipidemia (41% vs 26%, p<0.001), hypertriglyceridemia (26% vs 9%, p<0.001) and low HDL cholesterol (34% vs 15%, p<0.001) was higher in MASLD patients with vs without HIV. No difference in cardiovascular events and diabetes prevalence was observed between the two groups. Regarding liver disease, PWH with MASLD had lower prevalence of severe MASLD (54% vs 74% p<0.001) but higher prevalence of significant liver fibrosis (15 vs 7%, p=0.03) compared to MASLD uninfected patients. After adjustment, HIV positivity was an independent factor associated with significant liver fibrosis (figure). Conclusions: Despite having lower BMI, PWH with MASLD have a more severe hepatic presentation and atherogenic lipid profile than MASLD uninfected patients. HIV positivity seems to be independently associated with significant liver fibrosis. Screening and follow-up for MASLD and liver fibrosis is recommended in PWH, even if they are lean.

Background and Aimsearly identification of HCC is crucial for optimal curative treatment. aMAP and Toronto scores, validated for the first occurrence of HCC, lack validation for predicting early HCC recurrence after therapies. The early recurrence of HCC after treatment is a negative prognostic factor and it is related to both treatment and patient features.Aimto assess aMAP and Toronto scores’ accuracy in predicting early HCC recurrence after locoregional treatment.Method126 patients with HCC (mean age 69±11 years, 77% males) from 2014 to 2020 were enrolled. Early recurrence was defined as HCC recurrence within 2 years after the first treatment.Resultscirrhosis etiologies were viral in 55%, alcohol-related in 22%, metabolic in 19%, iron overload-related in 4%. Even in non-metabolic cirrhosis, 59% had diabetes or obesity. At HCC diagnosis, 41% had more than one lesion, 12% underwent surgical resection, 77% locoregional treatment, 3% systemic therapy, and 8% best supportive care. Focusing on 96 locoregionally treated patients, 60% experienced early HCC recurrence. For the prediction of early recurrence, the accuracy of aMAP and Toronto scores were low (AUROC 0.63 for both). To optimize sensibility and sensitivity of the scores an aMAP > 74 and a Toronto score > 250 should be used (sensibility/specificity 54%/75% for aMAP score and 65%/63% for Toronto score). In patients with metabolic comorbidities, the accuracy of both scores for early recurrence decreased (AUROC of aMAP 0.40 vs 0.62 in metabolic and non-metabolic patients, respectively; AUROC of Toronto 0.50 vs 0.76, respectively).ConclusionaMAP and Toronto scores lacked accuracy in predicting early HCC recurrence after locoregional therapies. The presence of diabetes and obesity negatively affected both scores. Given the management implications of early HCC recurrence, there is a need to develop and validate specific scores for the assessment of early recurrence, considering diabetes and obesity presence.