Introduction

Primary Biliary Cholangitis (PBC) represents a chronic inflammatory cholestatic autoimmune disease and a prominent cause of liver cirrhosis, whose pathogenesis remains still partially obscure. In this scenario, the local and systemic impact of oxidative stress on biliary epithelial cells (BECs), contributing to apoptosis, premature senescence, destruction, and loss of ductal cells, configure a promising new “tail” of the pathogenetic mosaic. Moreover, it could represent the fil rouge linking the liver disease progression and extrahepatic complications onset.
Biological antioxidant potential (BAP) and Reactive Oxygen Metabolites (dROMs) evaluations are two complementary routinely-used validated tests largely adopted to assess the systemic oxidative stress balance, never applied before in the clinical PBC context.

Aims & Methods

We aimed to evaluate the systemic oxidative balance of PBC patients and explore its correlation with different stages of liver disease progression. In this observational study, from January 2020 to January 2023, we consecutively enrolled 21 patients receiving a first serological diagnosis of PBC and 10 healthy subjects. All the PBC patients started ursodeoxycholic acid (UDCA) treatment after the enrolment and none underwent to a previous UDCA-based and/or systemic antioxidants therapeutic regimen. For each patient, clinical, biochemical, and anthropometric parameters as well as a 5 ml venous blood sample were collected. A transient-elastometry-based non-invasive assessment of liver disease progression defined the hepatic fibrosis degree [Liver Stiffness Measurement (LSM) (kPa)] and steatosis severity [Controlled Attenuation Parameter (CAP) (db/m)]. The systemic oxidative balance was evaluated by using colorimetric determination of d-ROMs and BAP test. According to manufacturer instructions, we considered d-ROMs > 340 CARR-U and/or BAPs < 2000 µmol iron/L as related to oxidative stress imbalance.

Results

d-ROMs levels appeared higher in PBC patients in comparison to healthy subjects (p <0.0001); contrariwise, lower BAP levels were observed in PBC than in healthy individuals (p <0.0001). Consistently, dROMs and BAP levels showed respectively a direct and inverse correlation with both liver fibrosis (dROMs, R:0.96; BAP, R: -0.84) and steatosis (dROM, R:0.80; BAP, R: -0.68) severity (p<0.0001 all). A progressively increasing trend of d-ROMs values (F0-F2 vs F3: p<0.0001; F3 vs F4: p=0.002) and reduction of BAP levels (F0-F2 vs F3: p<0.0001; F3 vs F4 p=0.04) according to the worsening of liver fibrosis was also highlighted. Finally, the prevalence of oxidative stress imbalance was significantly different between mild fibrosis (F0-F2) and advanced-fibrosis (F3-F4)-affected patients.

Conclusion

PBC patients are characterized by a disequilibrium of the oxidative balance whose correlation with liver disease progression remarks its importance as relevant pathogenetic mechanisms which cannot be underestimated.

References

-Lleo A, Leung PSC, Hirschfield GM, Gershwin EM. The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review. Semin Liver Dis. 2020 Feb;40(1):34-48. Doi: 10.1055/s-0039-1697617. Epub 2019 Sep 19. PMID: 31537031.
-Motoko Sasaki; Hiroko Ikeda; Hironori Haga; Toshiaki Manabe; Yasuni Nakanuma (2005). Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. 205(4), 451–459. Doi:10.1002/path.1729
-Sorrentino P, Terracciano L, D’Angelo S, Ferbo U, Bracigliano A, Tarantino L, Perrella A, Perrella O, De Chiara G, Panico L, De Stefano N, Lepore M, Mariolina, Vecchione R. Oxidative stress and steatosis are cofactors of liver injury in primary biliary cirrhosis. J Gastroenterol. 2010 Oct;45(10):1053-62. Doi: 10.1007/s00535-010-0249-x. PMID: 20393861.
-Sasaki M, Ikeda H, Nakanuma Y. Activation of ATM signaling pathway is involved in the oxidative stress-induced expression of mito-inhibitory p21WAF1/Cip1 in chronic non-suppurative destructive cholangitis in primary biliary cirrhosis: an immunohistochemical study. J Autoimmun. 2008 Aug;31(1):73-8. Doi: 10.1016/j.jaut.2008.03.005. Epub 2008 May 5. PMID: 18456456.

Introduction

Two years after the Delphi consensus-proposed revolution in the nomenclature and diagnosis of Steatotic Liver Disease (SLD), the potential benefits of adopting Metabolic dysfunction-associated steatotic liver disease (MASLD) rather than Metabolic dysfunction-associated fatty liver disease (MAFLD) diagnostic criteria in defining the disease progression risk of SLD patients have never been systematically and longitudinally evaluated in real-life.

Aims & Methods

The present study aimed to compare MASLD and MAFLD criteria in estimating the 3-year risk of advanced fibrosis (AF) progression and Acute Cardiovascular Event (ACE) occurrence in not-lean (NL) and lean (L) SLD patients.
For this purpose, we retrospectively analyzed the anthropometrical, biochemical, clinical, and Liver Stiffness Measurement (LSM - FibroScan) data stored in the University Hospital (UH)-official Health Documents Digitization Archive of 931 SLD patients admitted to UH “Luigi Vanvitelli” (between January 2016 and May 2021), and followed up for 3 years. Based on baseline Body Mass Index (BMI), patients were subdivided into “L” (BMI <25 kg/m2) (n:134) and “NL” (n:797) and, subsequently, by applying MAFLD and MASLD criteria, in NL-MASLD (n:206), NL-MASLD/MAFLD (n:481), NL-MAFLD (n:110), and L-MASLD (n:39), L-MASLD/MAFLD (n:68), L-MAFLD (n:27). The following validated LSM cut-offs were used to identify the different liver fibrosis stages according to the Metavir score: (a) F0-F2 ≤ 9.6 kPa; (b) F3: 9.7 - 13.5 kPa; (c) F4 ≥ 13.6 kPa. AF (F3-F4) was defined by LSM values > 9.7 kPa. The transition from F0-F2 to F3-F4 defined AF progression. Retrospectively collected and documented ACEs were: (1) Acute Myocardial Infarction (IMA), (2) Acute Coronary Syndrome (ACS), (3) Ictus cerebri (IC), and (4) Transient Ischemic Attack (TIA).

Results

MASLD and MAFLD criteria similarly estimated [MASLD: OR: 2.334, C.I.95%: 1.878 - 3.028, MAFLD: OR: 2.469, C.I.95%: 1.892 - 3.668, p < 0.0001; positive predictive value (PPV), MASLD: 0.800, C.I. 95%: 0.641-0.89 vs MAFLD: 0.785, C.I. 95%: 0.604-0.897, p: 0.076)] the overall 3-year risk of AF progression in NL-SLD, whereas in L-SLD, MAFLD criteria better estimated the overall 3-year risk of AF progression [PPV, MASLD: 0.571, C.I. 95%: 0.405-0.841 vs MAFLD: 0.714, C.I. 95%: 0.558-0.794, p: 0.006].
Compared to MASLD, MAFLD diagnostic criteria better estimated the 3-year risk of ACEs occurrence in NL [HR: 1.104, C.I..95%: 0.024-1.293, p:0.025], and not in L [HR: 1.260, C.I..95%: 0.665-2.101, p:0.071] patients. Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed diabetes (aHR: 2.113, C.I. 95%: 1.981-2.434, p:0.001), high-sensitivity-C-reactive protein (aHR: 1.441; C.I. 95%: 1.232-1.775; p:0.02) and Homeostatic-model-assessment-for-insulin-resistance (aHR: 1.228; C.I. 95%: 1.152-1.893; p:0.03) as associated with ACE occurrence in NL-MAFLD patients.

Conclusion

MAFLD criteria better estimate the 3-year AF progression and the ACE occurrence risk in L-SLD and NL-SLD patients, respectively.

References

1. Rinella ME, and NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023 Dec;79(6):1542-1556. doi: 10.1016/j.jhep.2023.06.003. Epub 2023 Jun 24. PMID: 37364790.
2. Ramírez-Mejía MM, Jiménez-Gutiérrez C, Eslam M, George J, Méndez-Sánchez N. Breaking new ground: MASLD vs. MAFLD-which holds the key for risk stratification? Hepatol Int. 2024 Feb;18(1):168-178. doi: 10.1007/s12072-023-10620-y. Epub 2023 Dec 21. PMID: 38127259.
3. Alboraie M, Butt AS, Piscoya A, Dao Viet H, Hotayt B, Al Awadhi S, Bahcecioglu IH, Alkhalidi N, Al Mahtab M, Méndez-Sánchez N. Why MASLD Lags Behind MAFLD: A Critical Analysis of Diagnostic Criteria Evolution in Metabolic Dysfunction-Associated Liver Diseases. Med Sci Monit. 2024 Jul 30;30:e945198. doi: 10.12659/MSM.945198. PMID: 39075772; PMCID: PMC11299466.
4. De A, Bhagat N, Mehta M, Taneja S, Duseja A. Metabolic dysfunction-associated steatotic liver disease (MASLD) definition is better than MAFLD criteria for lean patients with NAFLD. J Hepatol. 2024 Feb;80(2):e61-e62. doi: 10.1016/j.jhep.2023.07.031. Epub 2023 Aug 7. PMID: 37558135.

Clinical Case Summary

In advanced chronic liver disease (ACLD) patients, the endoscopic evidence of esophageal and/or gastric varices denotes the presence of clinically significant portal hypertension (CPSH), representing the main clinical consequence of portal hypertension (PH).
In this setting, although infrequently, besides typical sites (i.e., esophagus and stomach), PH-related varices can manifest even in other atypical portosystemic-shunt districts, including the vagina. CSPH-related vaginal varices bleeding can occur as a rare complication documented by limited case reports.
A 62-year-old female patient with viral (eradicated Hepatitis C Virus infection)-related- decompensated (grade 2 ascites)-ACLD, complicated by CSPH (grade F2 esophageal varices), was admitted to our Department in February 2025 for microcitic anemia. Anamnesis revealed a previous gastric cancer managed with total gastrectomy resection in 2021.
On admission, abdominal imaging showed radiological signs of ACLD/PH (coarse pattern, splenomegaly, dilated splenic-portal axis). Esophagogastroduodenoscopy ruled out active sources of bleeding, whereas colonoscopy revealed anal congestive not-bleeding varices. During the hospitalization, an episode of metrorrhagia imposed gynecologic evaluation with vaginal speculum examination. This assessment documented vaginal varices with the relative rupture as the current cause of the bleeding, suggesting this site is the further district for (CS)PH manifestation consequently to potentially occurred total gastrectomy-determined changes in abdominal vascular anatomy.
In ACLD patients receiving surgery altering abdominal vascularization, variceal bleeding represents a possible CSPH-related complication occurring even in atypical sites, such as the vagina. This scenario imposes an adequate tailored management, monitoring unusual bleeding signs, and adopting appropriate preventive strategies by including gynecologic evaluation in follow-up.

References

1. McHugh PP, Jeon H, Gedaly R, Johnston TD, Depriest PD, Ranjan D. Vaginal varices with massive hemorrhage in a patient with nonalcoholic steatohepatitis and portal hypertension: Successful treatment with liver transplantation. Liver Transpl. 2008 Oct;14(10):1538-40. doi: 10.1002/lt.21506. PMID: 18825698.
2. Kreek MJ, Raziano JV, Hardy RE, Jeffries GH. Portal hypertension with bleeding vaginal varices. Ann Intern Med. 1967 Apr;66(4):756-9. doi: 10.7326/0003-4819-66-4-756. PMID: 6067181.
3. Chan G, Taqi A, Drage M, Quan D. A case report of massive vaginal variceal hemorrhage in a patient with cirrhosis secondary to nonalcoholic steatohepatitis unresolved even after successful liver transplantation. Transplant Proc. 2013 Mar;45(2):835-7. doi: 10.1016/j.transproceed.2012.04.033. Epub 2012 Sep 19. PMID: 23267803.
4. Lebrec D, Benhamou JP. Ectopic varices in portal hypertension. Clin Gastroenterol. 1985 Jan;14(1):105-21. PMID: 3872747.
5. Nagata J, et al. Vaginal bleeding in a patient with type C liver cirrhosis without a past history of laparotomy: successful treatment with partial splenic artery embolization. Clin J Gastroenterol. 2012 Aug;5(4):275-81. doi: 10.1007/s12328-012-0316-3. Epub 2012 Jun 30. PMID: 26182393.

Introduction

Phase Angle (PA) represents a useful bioimpedance analysis-assessable marker of sarcopenia, accurately predicting liver-related hospitalizations in advanced chronic liver disease (ACLD), correlating with C-reactive protein levels. Clinically significant portal hypertension (CSPH) and systemic inflammation constitute the main hepatic decompensation drivers. A relevant proportion of Metabolic dysfunction-associated steatotic liver disease (MASLD) patients present sarcopenia (configuring the paradox of “sarcopenic obesity”), as well as compensated ACLD (cACLD)-MASLD individuals more rapidly progress to decompensation (dACLD) rather than other etiologies. However, the clinical applications of PA have never been specifically investigated in the setting of MASLD.

Aims & Methods

Considering the background, in MASLD, we primarily aimed to evaluate the trend of PA values across the different liver disease progression stages, investigating the relationship with the hepatic decompensation drivers; in dACLD-MASLD, we aimed to estimate the accuracy of the novel PA/C-reactive protein (CRP) index (PAC-I) in predicting 3-month further liver-related events (LREs)-determining hospitalizations.
In this observational study, between December 2023 and January 2025, MASLD patients were consecutively enrolled and stratified according to current LSM and eventual previous LREs in < F3 fibrosis (AF) (n.50), cACLD (n.50), and dACLD (n.50) patients. At baseline, anthropometrical, biochemical, nutritional, and clinical data [including the endoscopic assessment of CSPH and the relative severity (F1, F2, F3) of esophageal varices (OEVs)] were collected. Bioimpedance analysis was adopted to assess body composition parameters. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia (EGWSOP2) criteria. MASLD-dACLD patients were followed up, and further acute decompensation (AD)-LREs-determining hospitalizations [severe ascites, severe hepatic encephalopathy (HE), OEV bleeding, and any acute bacterial infections] in the subsequent 3 months were recorded.

Results

In MASLD patients, PA (°) values inversely correlated with LSM [R: -0.711; p<0.0001], progressively decreasing according to the worsening of liver disease stages, emerging as statistically significantly lower in dACLD compared with cACLD individuals (p<0.0001). In dACLD patients, PA inversely correlated with CRP levels [R: -0.945; p:0.001]. Focusing on CSPH, PA values were significantly lower in > F2-OEV-affected individuals (p<0.0001). Multivariate analysis revealed CSPH (aHR 1.221, p<0.0001), CRP (aHR: 1.112, p:0.002), and PA (aHR: 1.178, p:0.003) as the variables significantly associated with 3-month further LREs’ occurrence in dACLD patients.
ROCy analysis revealed an elevated accuracy and superiority compared to PA alone (AUC PA:0.717; AUC PAC-I: 0.893; p:0.003) of PAC-I in predicting 3-month further LREs’ occurrence, identifying PAC-I < 2.35 as the best cut-off. Consistently, dACLD patients showing baseline PAC-I < 2.35 presented a higher risk [HR: 2.287, p: 0.032] of further LREs.

Conclusion

In MASLD, PA correlates with the main driver of progression, and the PAC-I represents a useful noninvasive tool in predicting short-term liver-related hospitalizations in dACLD patients.

References

1. Espirito Santo Silva DD, Waitzberg DL, Passos de Jesus R, Oliveira LPM, Torrinhas RS, Belarmino G. Phase angle as a marker for sarcopenia in cirrhosis. Clin Nutr ESPEN. 2019 Aug;32:56-60. doi: 10.1016/j.clnesp.2019.05.003. Epub 2019 May 31. PMID: 31221291.
2. Saueressig C, Glasenapp JH, Luft VC, Alves FD, Ferreira PK, Hammes TO, Dall'Alba V. Phase Angle Is an Independent Predictor of 6-Month Mortality in Patients With Decompensated Cirrhosis: A Prospective Cohort Study. Nutr Clin Pract. 2020 Dec;35(6):1061-1069. doi: 10.1002/ncp.10584. Epub 2020 Oct 15. PMID: 33058222.

Introduction

Malnutrition, sarcopenia, and frailty constitute the three vertices of a nutrition-status-determined physio-pathological triangle constantly featuring and dramatically burdening the prognosis of advanced chronic liver disease (ACLD) patients.
Dysgeusia is defined by a distortion of the sense of taste whose prevalence, relationship with the progression of the disease, and the direct contribution to malnutrition (and consequently, sarcopenia-frailty) in ACLD have never been systematically explored.

Aims & Methods

This observational study aimed to explore the prevalence of dysgeusia in a cohort of ACLD patients and evaluate the impact of this disorder on appetite levels and nutritional status (malnutrition, sarcopenia, and frailty), as well as to prospectively estimate the repercussions of dysgeusia-induced impaired nutritional status on liver-related events (LREs) occurrence. For this purpose, 40 controls, 50 chronic-liver disease-affected individuals staging initial-mild fibrosis (<F3), and 150 ACLD patients of various etiologies were enrolled. Anthropometrical, biochemical, clinical, and nutritional [European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire] data were collected. The opportunely modified Chemotherapy-induced Taste Alteration Scale (CITAS) questionnaire was used to assess the dysgeusia. Child-Pugh (CP) and Liver Frailty Index (LFI) calculations, Liver Stiffness Measurement (LSM), and Bioelectrical Impedance Analysis (BIA) were performed. Skeletal Muscle Mass (SMM) index (SMMI) (SMM/height²) < 7 kg/m² (male) and < 5.7 kg/m² (female) defined sarcopenia. ACLD patients were 3 years followed up semiannually and LREs (including ascites, hepatic encephalopathy, and bleeding) were collected.

Results

The prevalence of dysgeusia was significantly higher in ACLD (68%) in comparison to <F3 (8%) individuals and controls (5%) and in decompensated ACLD (dACLD) than compensated (cACLD) (54% vs 6%) patients (all p<0.0001). In line, CITAS-dysgeusia severity positively correlated with CP (R:0.81), as well as with the levels of appetite impairment (R:0.93) (both p<0.0001). Logistic regression analysis, appropriately weighted for factors notoriously impacting food intake in ACLD patients (low-sodic diet, drugs/supplements taken, physical activity frequency, occurrence of encephalopathy and ascites episodes in the previous 2 weeks), revealed the level of impairment of the appetite as a factor significantly associated with dysgeusia [HR: 2.12; p:0.02]. Compared to no-dysgeusia-affected dACLD (p:0.03), dysgeusia-affected dACLD patients (dys-dACLD) showed a decreased daily protein intake, reduced Free Fat Mass % (p<0.0001), and SMMI (p<0.0001: p:0.04), in contrast with increased LFI (p<0.0001). Consistently, dys-dACLD patients showed a higher prevalence (59% vs 39%) of sarcopenia (p:0.0002). The Kaplan-Meier Log-Rank Test analysis on LREs occurrence showed HR:3.53 [95% C.I: 1.58-4.92] for dys-dACLD individuals.

Conclusion

The prevalence of dysgeusia, increasing in parallel to the worsening of liver disease, promoted sarcopenia-frailty pictures, negatively influencing ACLD patients' outcomes.

References

1. Jafari A, Alaee A, Ghods K. The etiologies and considerations of dysgeusia: A review of literature. Journal of oral biosciences. 2021;63(4):319-26.
2. Sieber CC. Malnutrition and sarcopenia. Aging clinical and experimental research. 2019;31(6):793-8.
3. Tandon P, Montano-Loza AJ, Lai JC, Dasarathy S, Merli M. Sarcopenia and frailty in decompensated cirrhosis. Journal of hepatology. 2021;75 Suppl 1(Suppl 1):S147-s62.