Thoetchai Peeraphatdit

Aspirin use and the risk of cholangiocarcinoma.

Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital‐based case‐control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n = 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29‐0.42), 0.34 (95% CI 0.27‐0.42), and 0.29 (95% CI 0.19‐0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR = 453, 95% CI 104‐999) than intrahepatic (AOR = 93.4, 95% CI 27.1‐322) or distal (AOR = 34.0, 95% CI 3.6‐323) CCA, whereas diabetes was more associated with distal (AOR = 4.2, 95% CI 2.5‐7.0) than perihilar (AOR = 2.9, 95% CI 2.2‐3.8) or intrahepatic (AOR = 2.5, 95% CI 2.0‐3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. Conclusions: Aspirin use was significantly associated with a 2.7‐fold to 3.6‐fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents. (Hepatology 2016;64:785‐796)

Clinical impact of delirium and antipsychotic therapy: 10-Year experience from a referral coronary care unit

Background: Little is known about safety of antipsychotic therapy for delirium in the coronary care unit (CCU). Our aim was to examine the effect of delirium and antipsychotic therapy among CCU patients. Methods and results: Pre-study Confusion Assessment Method-Intensive Care Unit (CAM–ICU) criteria were implemented in screening consecutive patients admitted to a referral CCU from 2004–2013. Death status was prospectively ascertained. Of 11,079 study patients, the incidence of delirium was 8.3% (n=925). Delirium was associated with an increased risk of in-hospital mortality (adjusted odds ratio (OR) 1.49; 95% confidence interval (CI), 1.08–2.08; p=0.02) and one-year mortality among patients who survived from CCU admission (adjusted hazard ratio (HR) 1.46; 95% CI, 1.12–1.87; p=0.005). A total of 792 doses of haloperidol (5 mg/day; interquartile range (IQR) 3–10) or quetiapine (25 mg/day; IQR 13–50) were given to 244 patients with delirium. The clinical characteristics of patients with delirium who did and did not receive antipsychotic therapy were not different (baseline corrected QT (QTc) interval 457±58 ms vs 459±60 ms, respectively; p=0.65). In comparison to baseline, mean QTc intervals after the first and third doses of the antipsychotics were not significantly prolonged in haloperidol (448±56, 458±57 and 450±50 ms, respectively) or quetiapine groups (470±66, 467±68 and 462±46 ms, respectively) (p>0.05 for all). Additionally, in-hospital mortality (adjusted OR 0.67; 95% CI, 0.42–1.04; p=0.07), ventricular arrhythmia (adjusted OR 0.87; 95% CI, 0.17–3.62; p=0.85) and one-year mortality among the hospital survivors (adjusted HR 0.86; 95% CI 0.62–1.17; p=0.34) were not different in patients with delirium irrespective of whether or not they received antipsychotics. Conclusion: In patients admitted to the CCU, delirium was associated with an increase in both in-hospital and one-year mortality. Low doses of haloperidol and quetiapine appeared to be safe, without an increase in risk of sudden cardiac death, in-hospital mortality, or one-year mortality in carefully monitored patients.

Association of Serum Magnesium on Mortality in Patients Admitted to the Intensive Cardiac Care Unit

BACKGROUND Although electrolyte disturbances may affect cardiac action potential, little is known about the association between serum magnesium and corrected QT (QTc) interval as well as clinical outcomes. METHODS A consecutive 8498 patients admitted to the Mayo Clinic Hospital-Rochester cardiac care unit (CCU) from January 1, 2004 through December 31, 2013 with 2 or more documented serum magnesium levels, were studied to test the hypothesis that serum magnesium levels are associated with in-hospital mortality, sudden cardiac death, and QTc interval. RESULTS Patients were 67 ± 15 years; 62.2% were male. The primary diagnoses for CCU admissions were acute myocardial infarction (50.7%) and acute decompensated heart failure (42.5%), respectively. Patients with higher magnesium levels were older, more likely male, and had lower glomerular filtration rates. After multivariate analyses adjusted for clinical characteristics including kidney disease and serum potassium, admission serum magnesium levels were not associated with QTc interval or sudden cardiac death. However, the admission magnesium levels ≥2.4 mg/dL were independently associated with an increase in mortality when compared with the reference level (2.0 to <2.2 mg/dL), having an adjusted odds ratio of 1.80 and a 95% confidence interval of 1.25-2.59. The sensitivity analysis examining the association between postadmission magnesium and analysis that excluded patients with kidney failure and those with abnormal serum potassium yielded similar results. CONCLUSION This retrospective study unexpectedly observed no association between serum magnesium levels and QTc interval or sudden cardiac death. However, serum magnesium ≥2.4 mg/dL was an independent predictor of increased hospital morality among CCU patients.

The incidence rates and survival of gallbladder cancer in the USA

Gallbladder cancer is a rare malignancy in most countries. The racial and sociodemographic factors associated with its incidence and survival are poorly defined. We aimed to investigate population-based gallbladder cancer incidence and survival trends on the basis of clinical characteristics and sociodemographic factors in the USA. Gallbladder cancer incidence and survival data from 2001 to 2012 were obtained from 18 registries of the Surveillance, Epidemiology, and End Results database. Incidence rates and Joinpoint trends were calculated by demographic subgroup. Survival trends were assessed using Cox proportional hazard models. A total of 7769 patients were identified. The overall gallbladder cancer incidence rates did not significantly change during the 2001–2012 period. Incidence rates were three times higher in Hispanics and 1.6 times higher in Blacks compared with Whites. Over the time period, incidence rates significantly increased among Blacks and decreased among Hispanics. Male sex [hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.03–1.17], older age (HR: 1.73, 95% CI: 1.53–1.96), and single and divorced statuses (HR: 1.19, 95% CI: 1.09–1.30 and 1.12, 95% CI: 1.01–1.24) were independently associated with shorter overall survival, whereas higher education (HR: 0.89, 95% CI: 0.82–0.97) and higher income (HR: 0.89, 95% CI: 0.82–0.96) were associated with longer survival. Furthermore, overall survival has improved in all races/ethnicities except for Hispanics and Blacks. The overall incidence rates for gallbladder cancer were stable during 2001–2012. Hispanics have the highest incidence rates, but the incidence rates in Blacks are on the rise.

Adherence to diagnostic guidelines of hepatocellular carcinoma: 12-year experience in a veterans affairs medical center.

Background Noninvasive diagnostic criteria for cirrhotic hepatocellular carcinoma (HCC) were first established in 2001 by the European Association for the Study of the Liver. Objectives The aim of this study was to evaluate adherence to the HCC diagnostic algorithm over time and identify factors associated with nonadherence. Methods Between 2001 and 2013, 224 consecutive cirrhotic HCC cases were retrospectively reviewed. Nonadherent biopsy (NAB) was defined as cases diagnosed either by biopsy despite meeting noninvasive criteria for HCC or by biopsy in place of an optional second imaging modality. Nonadherent nonbiopsy (NANB) was defined as cases diagnosed without performing biopsy when noninvasive criteria were not met. Factors associated with nonadherence were identified using multivariate analysis. Results Nonadherence rate decreased from 52 to 30% over the study period (P=0.003). Among all patients, there were 34% NAB and 13% NANB cases. Compared with the adherence group, both NAB and NANB groups were likely to undergo only computed tomography scanning [odds ratio (OR) 3.08, 95% confidence interval (CI) 1.71–5.66 and OR 3.18, 95% CI 1.28–8.27, respectively] and were less likely to undergo MRI (OR 0.29, 95% CI 0.16–0.53 and OR 0.26, 95% CI 0.10–0.66, respectively). In addition, the NAB group was less likely to be presented in a multidisciplinary tumor conference (OR 0.12, 95% CI 0.02–0.61). Conclusion This is the first study to report adherence to HCC diagnostic guidelines over time in a veteran hospital. Despite overall improvement, nonadherence at the present time is still high (∼30%). Underutilization of MRI and the multidisciplinary tumor conference is associated with nonadherence, representing a potential area for improvement.

Latest Concepts in Inpatient Hepatic Encephalopathy Management

Hepatic encephalopathy (HE), a common complication in patients with decompensated cirrhosis, significantly impacts quality of life and also survival. Current nomenclature recognizes type A HE (acute liver failure), type B (portosystemic shunts absent liver disease), and type C (liver disease). Recently, it has been observed that HE is an additional risk factor for death in patients with acute-on-chronic liver failure (ACLF). Thus, it has been proposed that HE in the setting of ACLF be considered a separate entity and that there may be important subtypes, namely isolated HE (without extrahepatic organ failure) and HE-associated ACLF (with extrahepatic organ failure), that carry different prognoses. The mechanism of the latter is not well known but thought to be from the combination of hyperammonemia and systemic inflammation. The confirmation of HE diagnosis requires exclusion of other possible causes. Precipitating factors of HE must be treated if they are identified. Early detection of extrahepatic organ failure is vital for risk stratification purposes and to determine the need for organ support. Specific HE treatment should be initiated with a nonabsorbable disaccharide (i.e., lactulose) in most cases. Rifaximin can be added in patients not responding to lactulose. Other treatments including zinc, l-ornithine l-aspartate, branched-chain amino acids, and molecular adsorbent recirculating system (MARS) can be considered in refractory HE. If technically feasible, large portosystemic shunts may be embolized. Ultimately, liver transplant is the most definitive treatment option for HE, especially in the setting of ACLF. However, current organ allocation system does not take HE into account and active infection in ACLF can be a contraindication for liver transplant.

Beta‐blockers in patients with advanced cirrhosis: Red light, green light, yellow light…

Since the landmark study by Lebrec et al. in 1980, multiple randomized controlled trials have confirmed the benefit of nonselective beta-adrenergic blocking agents (NSBB) as primary and secondary prophylaxis for variceal bleeding. However, concerns about their detrimental effects in advanced cirrhosis have more recently been voiced. Serst e et al. noted increased mortality in patients with cirrhosis with refractory ascites treated with NSBB. Mandorfer et al. implicated NSBB in the development of hepatorenal syndrome in patients with cirrhosis with spontaneous bacterial peritonitis. The detrimental effect of NSBB use is thought to be from a decrease in cardiac output and mean arterial pressure in patients with cirrhosis. Diminished cardiac output leads to renal hypoperfusion, increasing the risk for acute kidney injury (AKI) and death. Ge et al. have proposed the “window” hypothesis which postulated that NSBB are of benefit in less decompensated patients with cirrhosis but NSBB can have a detrimental effect in the later stages dominated by severe fluid and renal derangements. It appears there is a critical range of mean arterial pressure where NSBB are safe and effective in prevention of variceal hemorrhage, but below this range, there is an increased risk of AKI. However, after the initial report by Serst e et al., subsequent studies could not confirm a detrimental effect of NSBB. For example, Leithead et al. suggested that NSBB were actually associated with reduced shortterm mortality in patients with cirrhosis with ascites listed for liver transplantation (LT). Another large post hoc analysis evaluating 1198 patients found comparable mortality between patients with cirrhosis with ascites who were or were not on NSBB. In this issue of Liver Transplantation, Kim et al. also examined whether longterm use of NSBB is associated with the development of AKI in patients with cirrhosis wait-listed for LT. Using a nested case control study design, the authors retrospectively reviewed 205 patients with cirrhosis who had developed stage 2 AKI (or 2 times the baseline creatinine) after a median follow-up of 18.2 months following LT listing. Controls were matched 1:1 using age, serum creatinine, Model for End-Stage Liver Disease–Sodium score at baseline, and the follow-up duration. Although there was no statistical difference in NSBB use between cases (46%) and controls (37%), a key finding was that the effect of NSBB on AKI was bidirectional depending on the presence or absence of ascites. More specifically, NSBB were associated with a 3-fold increased risk of AKI in patients with ascites but were associated with a 5-fold decrease in risk of AKI in patients without ascites. A strength of this study is the nested case-control design. Controls were from the same population and were well matched by the severity of cirrhosis. A limitation of the study is its retrospective design in which important data including the severity of ascites, hemodynamic status, and concomitant medications were unavailable. Thus, it remains unclear whether (1) the risk of AKI is present in all patients with cirrhosis with ascites or only those with refractory ascites; or (2) the effect on AKI is primarily due to NSBB or due to other factors associated with advancing liver disease that lead to hemodynamic instability. Thus, the effects of NSBB in those with and without ascites are intriguing although the underlying mechanisms of the divergent effects cannot be definitively evaluated from this study. So, what should we recommend for these sick patients? A recent meta-analysis concluded that NSBB Abbreviations: AASLD, American Association for the Study of Liver Diseases; AKI, acute kidney injury; EVL, endoscopic variceal ligation; LT, liver transplantation; NSBB, nonselective beta-adrenergic blocking agents.

Beta-Blockers in Advanced Cirrhotics: Red Light, Green Light, Yellow Light…

Since the landmark study by Lebrec et al. in 1980, multiple randomized controlled trials have confirmed the benefit of nonselective beta-adrenergic blocking agents (NSBB) as primary and secondary prophylaxis for variceal bleeding. However, concerns about their detrimental effects in advanced cirrhosis have more recently been voiced. Serst e et al. noted increased mortality in patients with cirrhosis with refractory ascites treated with NSBB. Mandorfer et al. implicated NSBB in the development of hepatorenal syndrome in patients with cirrhosis with spontaneous bacterial peritonitis. The detrimental effect of NSBB use is thought to be from a decrease in cardiac output and mean arterial pressure in patients with cirrhosis. Diminished cardiac output leads to renal hypoperfusion, increasing the risk for acute kidney injury (AKI) and death. Ge et al. have proposed the “window” hypothesis which postulated that NSBB are of benefit in less decompensated patients with cirrhosis but NSBB can have a detrimental effect in the later stages dominated by severe fluid and renal derangements. It appears there is a critical range of mean arterial pressure where NSBB are safe and effective in prevention of variceal hemorrhage, but below this range, there is an increased risk of AKI. However, after the initial report by Serst e et al., subsequent studies could not confirm a detrimental effect of NSBB. For example, Leithead et al. suggested that NSBB were actually associated with reduced shortterm mortality in patients with cirrhosis with ascites listed for liver transplantation (LT). Another large post hoc analysis evaluating 1198 patients found comparable mortality between patients with cirrhosis with ascites who were or were not on NSBB. In this issue of Liver Transplantation, Kim et al. also examined whether longterm use of NSBB is associated with the development of AKI in patients with cirrhosis wait-listed for LT. Using a nested case control study design, the authors retrospectively reviewed 205 patients with cirrhosis who had developed stage 2 AKI (or 2 times the baseline creatinine) after a median follow-up of 18.2 months following LT listing. Controls were matched 1:1 using age, serum creatinine, Model for End-Stage Liver Disease–Sodium score at baseline, and the follow-up duration. Although there was no statistical difference in NSBB use between cases (46%) and controls (37%), a key finding was that the effect of NSBB on AKI was bidirectional depending on the presence or absence of ascites. More specifically, NSBB were associated with a 3-fold increased risk of AKI in patients with ascites but were associated with a 5-fold decrease in risk of AKI in patients without ascites. A strength of this study is the nested case-control design. Controls were from the same population and were well matched by the severity of cirrhosis. A limitation of the study is its retrospective design in which important data including the severity of ascites, hemodynamic status, and concomitant medications were unavailable. Thus, it remains unclear whether (1) the risk of AKI is present in all patients with cirrhosis with ascites or only those with refractory ascites; or (2) the effect on AKI is primarily due to NSBB or due to other factors associated with advancing liver disease that lead to hemodynamic instability. Thus, the effects of NSBB in those with and without ascites are intriguing although the underlying mechanisms of the divergent effects cannot be definitively evaluated from this study. So, what should we recommend for these sick patients? A recent meta-analysis concluded that NSBB Abbreviations: AASLD, American Association for the Study of Liver Diseases; AKI, acute kidney injury; EVL, endoscopic variceal ligation; LT, liver transplantation; NSBB, nonselective beta-adrenergic blocking agents.

PATTERNS OF LEFT VENTRICULAR HYPERTROPHY AND ADVERSE OUTCOMES IN LIVER TRANSPLANT RECIPIENTS WITHOUT HISTORY OF HYPERTENSION

Little is known about the prevalence and prognosis of left ventricular hypertrophy (LVH) in patients with liver failure. We included 589 consecutive patients without known hypertension (HTN) who had liver transplant at a tertiary medical center between 1994 and 2014. Based on pre-transplant

Prognostic Value of Model for End-Stage Liver Disease Score Measurements on a Daily Basis in Critically Ill Patients With Cirrhosis.

OBJECTIVE To determine whether daily measurement of Model for End-Stage Liver Disease (MELD) score adds prognostic value to the initial MELD score in predicting mortality among patients with cirrhosis admitted to the intensive care unit (ICU). METHODS We included 830 consecutive patients with cirrhosis admitted to a tertiary care ICU from January 1, 2003, through December 31, 2013, who had MELD scores on admission day 1 (MELD-D1). Daily MELD score during the first 7 days of ICU admission were retrospectively abstracted. The performances of MELD-D1 to MELD-D7 and changes in MELD score on consecutive days (Δ-MELD) in predicting 90-day mortality were determined using logistic regression. RESULTS MELD-D1 was an independent predictor of mortality (adjusted odds ratio, 1.07; 95% CI, 1.05-1.10; P<.001), with an area under the receiver operating characteristic curve (AUC) of 0.72. MELD-D2 to MELD-D7 yielded comparable performance to MELD-D1 with an approximately 10% increase in risk of death per each incremental unit of MELD score (odds ratios, 1.09-1.11; P<.001; AUCs, 0.68-0.72). Δ-MELD-D2 to Δ-MELD-D7 were not independently associated with mortality (P=.69, P=.42, P=.81, P=.94, P=.83 and P=.28, respectively) and did not increase the predictive performance (AUCs) when combined with MELD-D2 to MELD-D7. CONCLUSION Repeating MELD score assessment during the first 7 days after ICU admission does not improve the ability of the initial MELD score for predicting 90-day mortality among patients with cirrhosis. Our finding does not support the practice of routine daily measurement of the MELD score.