Cancer and hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection.

Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension.

BACKGROUND: The rs738409 C>G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis. AIM: To investigate its impact on hepatic decompensation and (liver-related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter. METHODS: We performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease-induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014-2017; n = 153; cross-sectional study). RESULTS: While survival was similar between PNPLA3-C/C and -C/G patients, we observed substantially increased mortality in PNPLA3-G/G patients. PNPLA3-G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3-G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1-4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22-3.98; P = 0.009; liver-related: aSHR: 2.2, 95% CI: 1.08-4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3-G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27-4.29; P = 0.006). PNPLA3-genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m. CONCLUSION: PNPLA3-G/G-genotype seems to double the risks of hepatic decompensation and (liver-related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis.

Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.

BACKGROUND: Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. AIMS: To assess the rates of HVPG response to different doses of carvedilol. METHODS: Consecutive patients with cirrhosis undergoing HVPG-guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25 mg/d was administered and HVPG response (HVPG-decrease ≥20% or to ≤12 mm Hg) was assessed after 3-4 weeks. In case of nonresponse, carvedilol dose was increased to 12.5 mg/d and a third HVPG-measurement was performed after 3-4 weeks. We also assessed HVPG-response rates according to the Baveno VI consensus (HVPG decrease ≥10% or to ≤12 mm Hg) and changes in systolic arterial pressure (SAP). RESULTS: Seventy-two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG-decrease ≥ 20% with carvedilol 6.25 mg/d and another 10 (14%) with carvedilol 12.5 mg/d. Forty (56%) patients had a HVPG decrease ≥10% with carvedilol 6.25 mg/d and 24 (33%) with carvedilol 12.5 mg/d. Thus, in total, a HVPG-response of ≥20% and ≥10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n = 4 with ascites) did not tolerate an increase to 12.5 mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP < 90 mm Hg at the final HVPG measurement. CONCLUSION: Carvedilol 12.5 mg/d was more effective than 6.25 mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG-response of ≥ 10% to carvedilol 12.5 mg/d, however, arterial hypotension might occur, especially in patients with ascites.

Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.

BACKGROUND: Elevated plasma von Willebrand factor antigen (vWF) has been shown to indicate the presence of clinically significant portal hypertension, and thus, predicts the development of clinical events in patients with cirrhosis. AIM: To investigate the impact of bacterial translocation and inflammation on vWF, as well as the association between vWF and procoagulant imbalance. Moreover, we assessed whether vWF predicts complications of cirrhosis, independent of the severity of portal hypertension. METHODS: Our study population comprised 225 patients with hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg without active bacterial infections or hepatocellular carcinoma. RESULTS: vWF correlated with markers of bacterial translocation (lipopolysaccharide-binding protein [LBP; ρ = 0.201; P = 0.021]), inflammation (interleukin 6 [IL-6; ρ = 0.426; P < 0.001] and C-reactive protein [CRP; ρ = 0.249; P < 0.001]), and procoagulant imbalance (factor VIII/protein C ratio; ρ = 0.507; P < 0.001). Importantly, the associations between vWF and these parameters were independent of HVPG. Moreover, vWF (per 10%) independently predicted variceal bleeding (hazard ratio [HR]: 1.08 [95% confidence interval (95% CI): 1.01-1.16]; P = 0.023), requirement of paracentesis (HR: 1.05 [95% CI: 1.01-1.1]; P = 0.023) and bacterial infections (HR: 1.04 [95% CI: 1-1.09]; P = 0.04) including spontaneous bacterial peritonitis (HR: 1.09 [95% CI: 0.999-1.18]; P = 0.053) on a trend-wise level. After backward elimination, vWF (HR: 1.05 [95% CI: 1.02-1.08]; P = 0.003) and CRP (per 10 mg/L; HR: 1.53 [95% CI: 1.14-2.05]; P = 0.005) remained in the final model for transplant-free mortality. Finally, the independent prognostic value of vWF/CRP groups for mortality was confirmed by competing risk analysis. CONCLUSION: Our results demonstrate that vWF is not only a marker of portal hypertension but also independently linked to bacterial translocation, inflammation and procoagulant imbalance, which might explain its HVPG-independent association with most clinical events. Prognostic groups based on vWF/CRP efficiently discriminate between patients with a poor 5-year survival and patients with a favourable prognosis.

Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension.

BACKGROUND: The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis. AIM: To assess the haemodynamic effects of taurine supplementation in patients with cirrhosis and varices. METHODS: Patients with hepatic venous pressure gradient (HVPG) ≥12 mm Hg were included in this prospective proof of concept study. Concomitant nonselective beta-blockers therapy was not allowed. Patients received either 4 weeks of oral taurine (6 g/day), or placebo, prior to evaluation of HVPG response. RESULTS: Thirty patients were screened and 22 included in the efficacy analysis (12 taurine/10 placebo; 64% male, mean age: 52 ± 11 years, Child A: 9%, B:64%, C:27%, ascites:68%). In the taurine group, mean HVPG dropped from 20 mm Hg (±4) at baseline to 18 mm Hg (±4) on day 28 (mean relative change: -12%, P = .0093). In the placebo group, mean HVPG increased from 20 mm Hg (±5) at baseline to 21 mm Hg (±5) on day 28 (mean relative change:+2%, P = .4945). Taurine had no significant effects on systemic haemodynamics. Seven of 12 patients (58%) on taurine achieved a HVPG response >10%, compared to none in the placebo group (P = .0053). In a multivariate linear model, HVPG reduction was significantly larger in the taurine group compared to placebo group (P = .0091 and P = .0109 for absolute and relative change respectively). Treatment-related adverse events included gastrointestinal discomfort and fatigue, and were usually mild and comparable between treatment groups. CONCLUSION: Taurine is safe and may reduce portal pressure in cirrhotic patients. More studies on the underlying mechanisms of action and long-term effects of taurine supplementation are warranted.