Summary Background SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3‐PD (SB3‐PD), presents a substitution in its reactive centre loop, determining the gain of function. Aims To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3‐PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro. Methods We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH‐7 cells transfected to overexpress either wild‐type SB3 (SB3‐WT) or SB3‐PD to assess their endogenous effect, while LX2 and THP‐1 cells were treated with exogenous SB3‐WT or SB3‐PD proteins. Results Patients carrying SB3‐PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3‐WT. In multivariate analysis, SB3‐PD was an independent predictor of cirrhosis complications. Patients with SB3‐PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3‐PD showed higher TGF‐β1 expression than controls. The addition of recombinant SB3‐PD induced an up‐regulation of TGF‐β1 in LX2 cells and a more prominent inflammatory profile in THP‐1 cells, compared to the effect of SB3‐WT protein. Conclusions The polymorphic variant SB3‐PD is highly effective in determining activation of TGF‐β1 and inflammation in vitro. Patients with cirrhosis who carry SB3‐PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.

Proinflammatory cytokine

Decompensation

10.1111/apt.17804

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Citations (4)

Clinical and prognostic characterization of the patterns of decompensation of liver cirrhosis

Journal of Hepatology (2022)

Marta Tonon Simone Incicco Valeria Calvino Alessandra Brocca Antônio Carlos Accetta

Decompensation

Characterization

10.1016/s0168-8278(22)02078-5

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SAT-083-YI Changes in mean arterial pressure are inadequate to guide treatment with terlipressin and albumin in patients with hepatorenal syndrome-acute kidney injury

Journal of Hepatology (2024)

Valeria Calvino Anna Barone Marta Tonon Carmine Gambino Simone Incicco

Terlipressin

10.1016/s0168-8278(24)00928-0

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Citations (0)

Hepatology (2016)

Salvatore Piano Paolo Angeli

Potential conflict of interest: Nothing to report. Reply: We appreciate the interest of de Mattos and de Mattos in our article recently published in hepatology1 comparing the administration of terlipressin in continuous intravenous infusion (TERLI‐INF) versus intravenous boluses (TERLI‐BOL) in the treatment of hepatorenal syndrome (HRS). In our study the primary endpoint was the onset of drug‐related adverse events, and the sample size was calculated accordingly. Regarding the efficacy of treatment, we think 90‐day survival is not the optimal indicator of efficacy in HRS. Indeed, several variables, other than response to treatment, affect survival in patients with HRS, such as age, failure of organs other than the kidney, and degree of liver failure.1 Anyway, when we adjusted our analysis for all these variables, the randomization had no effect on survival. Moving to a more adequate parameter of efficacy, response to treatment, a higher rate of response was observed in the TERLI‐INF group than the TERLI‐BOL group, although the difference was not significant. Concerning the initial dose of terlipressin, we want to highlight that studies on pharmacokinetics and pharmacodynamics of terlipressin are lacking in patients with HRS; thus, the optimal initial dose is still to be determined. de Mattos and de Mattos, while citing our article comparing terlipressin versus midodrine/octreotide in the treatment of HRS,2 forgot to cite our first study on the use of terlipressin in HRS,3 in which we used terlipressin by continuous intravenous infusion starting from 2 mg/24 hours. Therefore, when we planned the study, we selected a 2 mg/24 hours initial dose in the TERLI‐INF group. We accept the speculation that a lower starting dose may justify a lower incidence of side effects in the TERLI‐INF versus the TERLI‐BOL group, but a lower dose could have caused the risk to be less effective. Nevertheless, most of the patients in the TERLI‐INF group responded to 2 mg/24 hours (Fig. 1).Figure 1: Dose of terlipressin needed to achieve response to treatment in patients assigned to TERLI‐BOL (A) and those assigned to TERLI‐INF (B).Finally, concerning economic issues, our study was not planned to identify differences in costs between the two groups. We agree that a comprehensive economic evaluation should take into account the whole treatment administered, invasive procedures, days of hospitalization, and so on. Thus, although in the whole population the mean dose of terlipressin was significantly lower in the TERLI‐INF group than in the TERLI‐BOL group (2.6 ± 1.4 versus 3.5 ± 1.7 mg/day, P < 0.025), no speculation can be made about the global cost of treatment. In conclusion, although there are still open questions, our study provided an answer to what is the most tolerated way of administration of terlipressin in patients with HRS.

Terlipressin

Midodrine

Pharmacodynamics

Clinical endpoint

10.1002/hep.28648

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Immune thrombocytopenic purpura and Kaposi’s sarcoma in a liver transplant recipient

Transplant International (2012)

Salvatore Piano Angelo Gatta Paolo Angeli

Thrombocytopenic purpura

10.1111/j.1432-2277.2011.01424.x

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Citations (4)

PS-083-Serum albumin concentration as guide for long-term albumin treatment in patients with cirrhosis and uncomplicated ascites: Lessons from the ANSWER study

Journal of Hepatology (2019)

Paolo Caraceni Oliviero Riggio Paolo Angeli Carlo Alessandria Sergio Neri

Serum Albumin

Human albumin

10.1016/s0618-8278(19)30095-7

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Morbidity and mortality after transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis

European Journal of Gastroenterology & Hepatology (2018)

D. Dissegna Massimo Sponza Edmondo Falleti Carlo Fabris Alessandro Vit

Objectives Transjugular intrahepatic portosystemic shunt (TIPS) is adopted to treat refractory complications of portal hypertension, such as variceal bleeding and ascites. This study aimed to assess predictors of hepatic encephalopathy (HE) development and cumulative transplant-free survival after TIPS placement in patients with cirrhosis complicated by refractory ascites and major gastroesophageal bleeding. Materials and methods Sixty-three cirrhotic patients who underwent TIPS positioning as a secondary prophylaxis of major upper gastroesophageal bleeding ( N =30) or to control refractory ascites ( N =33) were enrolled. Results After a median follow-up of 26 months following TIPS insertion, only 1/30 (3.3%) patients developed reoccurrence of bleeding. Complete control of refractory ascites was recorded in 19/23 (82.6%) patients. Within the first month after TIPS placement, 34/63 (53.9%) patients developed clinically significant HE, which was associated with the baseline presence of type 2 hepatorenal syndrome ( P =0.022). At the end of 90 months of follow-up, 35 (55.6%) patients were alive, 12 (19.0%) patients underwent liver transplantation, and 16 (25.4%) patients died. Independent predictors of transplant-free survival were a model for end-stage liver disease score up to 15 ( P <0.001), the absence of a history of spontaneous bacterial peritonitis ( P =0.010) pre-TIPS, and no HE within 1 month post-TIPS ( P =0.040). Conclusion TIPS insertion can be considered a safe and effective treatment in patients with cirrhosis and severe complications of portal hypertension that are not manageable with standard treatments. Interestingly, if confirmed in future studies, the history of spontaneous bacterial peritonitis pre-TIPS could be added to the model for end-stage liver disease score as a strong baseline predictor of post-TIPS mortality.

Spontaneous bacterial peritonitis

Hepatic Encephalopathy

Refractory (planetary science)

Liver disease

10.1097/meg.0000000000001342

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Citations (26)

SAT-128-The natural history of acute kidney disease in patients with cirrhosis

Journal of Hepatology (2019)

Marta Tonon Salvatore Piano S. Rosi Carmine Gambino Andréa Martini

10.1016/s0618-8278(19)31367-2

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Assessment of bone mineral density in patients with cirrhosis treated with third-generation nucleos(t)ide analogues: comparison between tenofovir and entecavir

European Journal of Gastroenterology & Hepatology (2018)

Marta Tonon Salvatore Piano A. Romano Silvano Fasolato M. Stanco

Tenofovir and entecavir are nowadays the first-line treatment in hepatitis B virus (HBV)-related cirrhosis. Both drugs were shown to be effective in HBV suppression and well tolerated. The effects of tenofovir on bone mineral density (BMD), however, were shown to worsen the rate of osteoporosis, which is already a common feature in cirrhosis. In contrast, entecavir seems to have no effect on mineral metabolism. The aim of our study was to compare the effects of nucleos(t)ide analogs on bone density in HBV-related cirrhosis.Fourty-eight patients were treated with tenofovir and 22 patients were treated with entecavir, and were followed prospectively from 2008 to 2013. To evaluate BMD, laboratory examinations, dual-X-ray absorptiometry, and Fracture Risk Assessment Tool were assessed.During the study, no difference was found between the two groups in the plasmatic concentration of calcium, phosphate, vitamin D, parathyroid hormone, or creatinine. Dual-X-ray absorptiometry showed no difference in the T-score and Fracture Risk Assessment Tool showed no significant difference in the 10-year risk of osteoporotic fractures in the two groups. On univariate and multivariate analyses, the only predictors of osteoporosis development were the prognostic scores of liver disease and BMI.Both tenofovir and entecavir are effective in treating HBV in cirrhotic patients. The known effects of tenofovir on BMD do not worsen osteoporotic fractures risk compared with entecavir in these patients.

Entecavir

Tenofovir

Hepatitis B

Univariate analysis

10.1097/meg.0000000000001051

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Citations (9)