Insulin-like growth factor-1 in cirrhosis is linked to hepatic dysfunction and fibrogenesis and predicts liver-related mortality.

BACKGROUND AND AIMS: We aimed to characterise insulin-like growth factor-1 (IGF-1) signalling in patients with advanced chronic liver disease (ACLD). METHODS: Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6-9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non-bleeding hepatic decompensation and S5: further decompensation. RESULTS: In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF-1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF-1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF-1 showed an independent negative association with body mass index (BMI; aB: -1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: -8.43; p < 0.001), MELD (aB: -1.13; p = 0.042) and age (per 10 years; aB: -6.87; p < 0.001). IGF-1 exhibited an excellent AUROC (0.856) for the prediction of liver-related death at 6 months of follow-up. Lower IGF-1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83-0.98; p = 0.016), acute-on-chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68-0.93; p = 0.004) and liver-related death (asHR: 0.76; 95% CI: 0.63-0.91; p = 0.004). CONCLUSION: Decreased levels of IGF-1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF-1 was independently linked to high BMI. Lower IGF-1 in cirrhosis predicts decompensation, ACLF and liver-related death.

Prevalence and prognostic value of zinc and selenium deficiency in advanced chronic liver disease.

BACKGROUND AND AIMS: Zinc and selenium are essential trace elements involved in important (patho)physiological processes. The prevalence and prognostic implications of zinc and selenium deficiency in patients with advanced chronic liver disease (ACLD) remain unknown. METHODS: We determined serum zinc and selenium concentrations in 309 patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement between 2019 and 2022. We evaluated the prevalence of zinc/selenium deficiency and assessed its association with severity of ACLD and liver-related events (LRE, i.e. first/further hepatic decompensation/liver-related death). RESULTS: Among 309 ACLD patients (median: age: 57 [IQR: 50-64], MELD: 11 [IQR: 9-16], HVPG: 17 [IQR: 11-20]), 73% (227) and 63% (195) were deficient in zinc and selenium, respectively. Decompensated (dACLD) patients showed significantly lower serum zinc (median: 48 [IQR: 38-59] vs. compensated, cACLD: 65 [IQR: 54-78], p < 0.001) and selenium levels (median: 4.9 [IQR 4.0-6.2] vs. cACLD: 6.1 [IQR 5.1-7.3], p < 0.001). Significant correlations of zinc/selenium levels were found with MELD (zinc: ρ = -0.498, p < 0.001; selenium: ρ = -0.295, p < 0.001), HVPG (zinc: ρ = -0.400, p < 0.001; selenium: ρ = -0.157, p = 0.006) and liver disease-driving mechanisms (IL6, bile-acid homeostasis). On multivariable analysis, low zinc/selenium levels, age and MELD remained independently associated with LRE. CONCLUSION: Zinc and selenium deficiencies are common in ACLD patients especially with higher MELD and HVPG. Low zinc and selenium levels independently predicted hepatic decompensation and liver-related death. The effect of zinc/selenium supplementation in ACLD should be investigated in future trials.

Rapid improvement of hepatic steatosis and liver stiffness after metabolic/bariatric surgery: a prospective study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and related steatohepatitis (MASH) are common among obese patients and may improve after metabolic/bariatric surgery (MBS). 93 Patients undergoing MBS in 2021-2022 were prospectively enrolled. Liver stiffness measurement (LSM; via vibration-controlled transient elastography [VCTE], point [pSWE] and 2D [2DSWE] shear wave elastography) and non-invasive steatosis assessment (via controlled attenuation parameter [CAP]) were performed before (baseline [BL]) and three months (M3) after surgery. 93 patients (median age 40.9 years, 68.8% female, median BL-BMI: 46.0 kg/m2) were included. BL-liver biopsy showed MASLD in 82.8% and MASH in 34.4% of patients. At M3 the median relative total weight loss (%TWL) was 20.1% and the median BMI was 36.1 kg/m2. LSM assessed by VCTE and 2DSWE, as well as median CAP all decreased significantly from BL to M3 both in the overall cohort and among patients with MASH. There was a decrease from BL to M3 in median levels of ALT (34.0 U/L to 31 U/L; p = 0.025), gamma glutamyl transferase (BL: 30.0 to 21.0 U/L; p < 0.001) and MASLD fibrosis score (BL: - 0.97 to - 1.74; p < 0.001). Decreasing LSM and CAP, as well as liver injury markers suggest an improvement of MASLD/MASH as early as 3 months after MBS.

The deep abdominal ultrasound transducer (DAX) increases the success rate and diagnostic accuracy of shear wave elastography for liver fibrosis assessment in patients with obesity-A prospective biopsy-controlled study.

BACKGROUND: Obesity impacts the diagnostic accuracy of shear wave elastography (SWE). A deep abdominal ultrasound transducer (DAX) capable of point (pSWE) and two-dimensional (2D)-SWE has recently been introduced to address this issue. METHODS: We performed a prospective study in a cohort of mostly patients with obesity undergoing liver biopsy with a high prevalence of metabolic dysfunction-associate steatotic liver disease (MASLD). Liver stiffness measurement (LSM) was measured using vibration-controlled transient elastography (VCTE), as well as pSWE and 2D SWE on the standard (5C1) and the DAX transducers. RESULTS: We included 129 patients with paired LSM and liver biopsy: median age 44.0 years, 82 (63.6%) women, median BMI: 43.2 kg/m2. Histologic fibrosis stages: F0: N = 55 (42.6%), F1: N = 14 (10.9%), F2: N = 50 (38.8%), F3: N = 2 (1.6%), F4: N = 8 (6.2%). VCTE-LSM failed (N = 13) or were unreliable (IQR/median ≤30% in ≥7.1 kPa, N = 14) in 20.9% of patients. The Pearson correlation of reliable VCTE-LSM with both pSWE and 2D SWE was strong (all >0.78). The diagnostic accuracy for all LSM techniques was poor for significant fibrosis (≥F2, AUC: 0.54-0.63); however, it was good to excellent for advanced fibrosis (≥F3, AUC: 0.87-0.99) and cirrhosis (F4, AUC: 0.86-1.00). In intention-to-diagnose analysis, pSWE on DAX was significantly superior to VCTE-LSM. CONCLUSIONS: pSWE- and 2D-SWE enable the non-invasive identification of advanced fibrosis and cirrhosis in patients with obese MASLD. The use of the DAX transducer for acoustic radiation force imaging (ARFI)-LSM avoids technical failures in an obese population and subsequently offers advantages over VCTE-LSM for the evaluation of fibrosis in an obese MASLD population at risk for fibrosis.

Von Willebrand factor for outcome prediction within different clinical stages of advanced chronic liver disease.

BACKGROUND AND AIMS: The prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage-specific prognostic utility. METHODS: We retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C-reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua. RESULTS: We observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver-related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver-related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver-related death in cACLD. Notably, the performance of the non-invasive CRP/VWF-based model was comparable to invasive HVPG-based models (C-index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF-based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values. CONCLUSION: VWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF-based model is equivalent to an invasive HVPG-based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease-driving mechanism.