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Pasireotide does not improve efficacy of aspiration sclerotherapy in patients with large hepatic cysts, a randomized controlled trial.
Wijnands, TFM, Gevers, TJG, Lantinga, MA, Te Morsche, RH, Schultze Kool, LJ, Drenth, JPH
European radiology. 2018;(6):2682-2689
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Abstract
OBJECTIVES We tested whether complementary use of the somatostatin analogue pasireotide would augment efficacy of aspiration sclerotherapy of hepatic cysts. METHODS We conducted a double-blind, placebo-controlled trial in patients who underwent aspiration sclerotherapy of a large (>5 cm) symptomatic hepatic cyst. Patients were randomized to either intramuscular injections of pasireotide 60 mg long-acting release (n = 17) or placebo (sodium chloride 0.9 %, n = 17). Injections were administered 2 weeks before and 2 weeks after aspiration sclerotherapy. The primary endpoint was proportional cyst diameter reduction (%) from baseline to 6 weeks. Secondary outcomes included long-term cyst reduction at 26 weeks, patient-reported outcomes including the polycystic liver disease-questionnaire (PLD-Q) and safety. RESULTS Thirty-four patients (32 females; 53.6 ± 7.8 years) were randomized between pasireotide or placebo. Pasireotide did not improve efficacy of aspiration sclerotherapy at 6 weeks compared to controls (23.6 % [IQR 12.6-30.0] vs. 21.8 % [9.6-31.8]; p = 0.96). Long-term cyst diameter reduction was similar in both groups (49.1 % [27.0-73.6] and 45.6 % [29.6-59.6]; p = 0.90). Mean PLD-Q scores improved significantly in both groups (p < 0.01) without differences between arms (p = 0.92). CONCLUSIONS In patients with large symptomatic hepatic cysts, complementary pasireotide to aspiration sclerotherapy did not improve cyst reduction or clinical response. KEY POINTS • Complementary pasireotide treatment does not improve efficacy of aspiration sclerotherapy. • Cyst fluid reaccumulation after aspiration sclerotherapy is a transient phenomenon. • Aspiration sclerotherapy strongly reduces symptoms and normalizes quality of life.
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Efficacy and safety of linagliptin in type 2 diabetes patients with self-reported hepatic disorders: A retrospective pooled analysis of 17 randomized, double-blind, placebo-controlled clinical trials.
Inagaki, N, Sheu, WH, Owens, DR, Crowe, S, Bhandari, A, Gong, Y, Patel, S
Journal of diabetes and its complications. 2016;(8):1622-1630
Abstract
AIMS: Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. METHODS Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS Of the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean±standard error (SE) change in HbA1c from baseline in those with hepatic disorders was -0.75%±0.05 with linagliptin and -0.20%±0.08 with placebo [treatment difference: -0.54% (95% confidence interval-0.72 to -0.36); P<.0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders (P=.4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders. CONCLUSIONS This large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease.
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Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.
Sterneck, M, Kaiser, GM, Heyne, N, Richter, N, Rauchfuss, F, Pascher, A, Schemmer, P, Fischer, L, Klein, CG, Nadalin, S, et al
Clinical transplantation. 2016;(6):741-8
Abstract
BACKGROUND The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. METHODS PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. RESULTS A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease (MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. CONCLUSION Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up.
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Higher Glucose and Insulin Levels Are Associated with Risk of Liver Cancer and Chronic Liver Disease Mortality among Men without a History of Diabetes.
Loftfield, E, Freedman, ND, Lai, GY, Weinstein, SJ, McGlynn, KA, Taylor, PR, Männistö, S, Albanes, D, Stolzenberg-Solomon, RZ
Cancer prevention research (Philadelphia, Pa.). 2016;(11):866-874
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Abstract
Insulin resistance likely increases the risk of chronic liver disease (CLD) and liver cancer, but long-term prospective studies with measured fasting glucose and insulin are lacking. We evaluated the associations of prediagnostic fasting glucose, insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) with liver cancer and CLD mortality in a prospective study of Finnish male smokers with extended follow-up time (≤22 years) and information on known risk factors using data from 138 incident primary liver cancer cases, 216 CLD deaths, and 681 matched controls. Fasting glucose and insulin were measured in baseline serum. We used unconditional logistic regression to estimate ORs and 95% confidence intervals adjusted for age, alcohol, education, smoking, body mass index, and hepatitis B and C viral status. Among those without self-reported diabetes, glucose was positively associated with liver cancer [quartile 3 vs. quartile 1 (Q3/Q1): OR = 1.88; 1.03-3.49; Q4/Q1: OR = 2.40; 1.33-4.35; Ptrend = 0.002], and undiagnosed, biochemically defined, diabetes was associated with higher risk of liver cancer (OR = 2.95; 1.46-5.96) and CLD mortality (OR = 1.88; 1.00-3.56). Serum insulin and HOMA-IR were also positively associated with liver cancer (Q4/Q1: OR = 3.41; 1.74-6.66; Ptrend < 0.0001; OR = 3.72; 1.89-7.32, Ptrend < 0.0001, respectively) and CLD (OR = 2.51; 1.44-4.37; Ptrend = 0.0002; OR = 2.31; 1.34-3.97; Ptrend = 0.001, respectively), with stronger associations observed for liver cancer diagnosed >10 years after baseline. In conclusion, elevated fasting glucose and insulin and insulin resistance were independently associated with risk of liver cancer and CLD mortality, suggesting a potentially important etiologic role for insulin and glucose dysregulation even in the absence of diagnosed diabetes. Cancer Prev Res; 9(11); 866-74. ©2016 AACR.
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Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil.
Lopez-Solis, R, DeVera, M, Steel, J, Fedorek, S, Sturdevant, M, Hughes, C, Humar, A
Clinical transplantation. 2014;(7):783-8
Abstract
In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I-randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.
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Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER).
Everett, BM, Mora, S, Glynn, RJ, MacFadyen, J, Ridker, PM
The American journal of cardiology. 2014;(11):1682-9
Abstract
Recent US guidelines expand the indications for high-intensity statin therapy, yet data on the safety of attaining very low-density lipoprotein cholesterol (LDL-C) levels are scarce. Among 16,304 participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) with on-treatment LDL-C levels, we identified 767 who did and 7,387 who did not achieve LDL-C <30 mg/dl on rosuvastatin 20 mg daily and 718 participants who did and 7,436 who did not achieve LDL-C reductions of ≥70% on rosuvastatin, and 8,150 allocated to placebo. In participants with an LDL-C <30 mg/dl, we observed an increase in the risk of physician-reported type 2 diabetes with an adjusted hazard ratio (95% confidence interval) of 1.56 (1.09 to 2.23, p = 0.01) and physician-reported hematuria (hazard ratio 2.10 [1.39 to 3.19], p <0.001) compared with rosuvastatin-treated participants with LDL-C ≥30 mg/dl. There was also an increased risk of certain musculoskeletal, hepatobiliary, and psychiatric disorders. No difference in renal failure, cancer, memory impairment, or hemorrhagic stroke was observed, although there were few events in these categories. In rosuvastatin-treated participants, achieving LDL-C reduction ≥70% versus <70% did not appear to be associated with increased risk of hepatobiliary, renal, or urinary disorders. In conclusion, in this post hoc analysis in the JUPITER, achieving LDL-C levels <30 mg/dl with high-intensity statin therapy appeared to be generally well tolerated but associated with certain adverse events, including more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia. These data may guide the monitoring of patients on intensive statin therapy and adverse events in trials of therapies that lead to very low LDL-C levels.
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Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.
Sterneck, M, Kaiser, GM, Heyne, N, Richter, N, Rauchfuss, F, Pascher, A, Schemmer, P, Fischer, L, Klein, CG, Nadalin, S, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014;(3):701-10
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Abstract
The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
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Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial.
Zelber-Sagi, S, Buch, A, Yeshua, H, Vaisman, N, Webb, M, Harari, G, Kis, O, Fliss-Isakov, N, Izkhakov, E, Halpern, Z, et al
World journal of gastroenterology. 2014;(15):4382-92
Abstract
AIM: To evaluate the effect of resistance training (RT) on non alcoholic liver disease (NAFLD) patients. METHODS A randomized clinical trial enrolling NAFLD patients without secondary liver disease (e.g., without hepatitis B virus, hepatitis C virus or excessive alcohol consumption). Patients were randomly allocated either to RT, three times weekly, for 3 mo or a control arm consisting of home stretching. The RT included leg press, chest press, seated rowing, latissimus pull down etc. with 8-12 repetitions, 3 sets for each exercise, for a total duration of 40 min. Hepatic ultrasound, fasting blood tests, anthropometrics and body composition by dual energy X-ray absorptiometry were assessed. At baseline and follow-up, patients filled out a detailed semi-quantitative food frequency questionnaire reporting their habitual nutritional intake. Steatosis was quantified by the hepatorenal-ultrasound index (HRI) representing the ratio between the brightness level of the liver and the right kidney. The HRI has been previously demonstrated to be highly reproducible and was validated against liver biopsy and proton magnetic resonance spectroscopy. RESULTS Eighty two patients with primary NAFLD were randomized to receive 3 mo of either RT or stretching. After dropout or exclusion from analysis because of protocol violation (weight change > 3 kg), thirty three patients in the RT arm and 31 in the stretching arm completed the study per protocol. All baseline characteristics were similar for the two treatment groups with respect to demographics, anthropometrics and body composition, blood tests and liver steatosis on imaging. HRI score was reduced significantly in the RT arm as compared to the stretching arm (-0.25 ± 0.37 vs -0.05 ± 0.28, P = 0.017). The RT arm had a significantly higher reduction in total, trunk and android fat with increase in lean body mass. There was no correlation between the reduction in HRI in the RT arm and weight change during the study, but it was positively correlated with the change in trunk fat (r = 0.37, P = 0.048). The RT arm had a significant reduction in serum ferritin and total cholesterol. There was no significant difference between arms in dietary changes and these did not correlate with HRI change. CONCLUSION Three months RT improves hepatic fat content accompanied by favorable changes in body composition and ferritin. RT may serve as a complement to treatment of NAFLD.
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Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study.
Lai, GY, Weinstein, SJ, Taylor, PR, McGlynn, KA, Virtamo, J, Gail, MH, Albanes, D, Freedman, ND
British journal of cancer. 2014;(12):2220-3
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BACKGROUND Recent data suggest the possible benefits of α-tocopherol and β-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited. METHODS We evaluated the efficacy of supplemental 50 mg day(-1) α-tocopherol and 20 mg day(-1) β-carotene on incident liver cancer and CLD mortality in a randomised trial of 29,105 Finnish male smokers, who received supplementation for 5-8 years and were followed for 16 additional years for outcomes. RESULTS Supplemental α-tocopherol, β-carotene, or both, relative to placebo, did not reduce the risk of liver cancer or CLD, either overall, during the intervention or during the post-intervention period. CONCLUSIONS Long-term supplemental α-tocopherol or β-carotene had no effect on liver cancer or CLD mortality over 24 years of follow-up.
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Prevalence of risk factors for liver disease in a random population sample in southern Germany.
Huetter, ML, Fuchs, M, Hänle, MM, Mason, RA, Akinli, AS, Imhof, A, Kratzer, W, Lorenz, R, ,
Zeitschrift fur Gastroenterologie. 2014;(6):558-63
Abstract
BACKGROUND Chronic liver disease leads to fibrosis and cirrhosis of the liver. This may, in turn, result in chronic liver failure or the development of hepatocellular carcinoma (HCC). Main risk factors for chronic liver disease are viral hepatitis and alcoholism. The present study assessed a randomly selected population in southern Germany for risk factors for chronic liver disease such as fatty liver disease, viral hepatis infection and life-style factors. In addition, the potential association with elevated liver enzymes was investigated. METHODS A total of 2256 subjects (1182 females, 1074 males), aged 18 - 65 years, participated in the study. Each subject underwent a standardized ultrasound examination, and anthropometric and biochemical assessments. Test subjects were randomly selected from the general population of a town in southwestern Germany. Data were acquired from November to December 2002 without further follow-up. RESULTS Several factors were found to be associated with chronic liver disease in the study population. Alcohol consumption >20 g/d was seen in 18.1% (n=409). Metabolic syndrome was diagnosed in 5.9% (n=132). The number of people with a BMI greater than 25 kg/m(2) was 45.1% (n=1017). The prevalence of subjects with chronic hepatitis B was 0.7% (n=15), that of anti-HCV positive patients, 0.6%(n=15). Elevated gGT was seen in 10.4% (n=14) of the patients. Prevalence of hepatic steatosis was 25.0% (n=564). CONCLUSIONS Many cases of chronic liver disease could be prevented by healthy nutrition, optimized medical treatment of associated disorders, and prevention strategies such as routine vaccination, in particular, against hepatitis B virus (HBV).