Mastering Core Recommendations during HEPAtology ROUNDS in Patients with Advanced Chronic Liver Disease.

Efficient and thorough care of hospitalized patients with advanced chronic liver disease is of utter importance to improve outcomes and optimize quality of life. This requires understanding current evidence and best practices. To facilitate focus on up-to-date knowledge and a practical approach, we have created the HEPA-ROUNDS mnemonic while outlining a practical review of the literature with critical appraisal for the busy clinician. The HEPA-ROUNDS mnemonic provides a structured approach that incorporates critical concepts in terms of prevention, management, and prognostication of the most common complications frequently encountered in patients with advanced chronic liver disease. In addition, implementing the HEPA-ROUNDS mnemonic can facilitate education for trainees and staff caring for patients with advanced chronic liver disease.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Hemoglobin A1c Has Suboptimal Performance to Diagnose and Monitor Diabetes Mellitus in Patients with Cirrhosis.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) is routinely used to diagnose and monitor type 2 diabetes mellitus (T2DM) in cirrhotic patients. Remarkably, HbA1c may be falsely low in such patients. AIMS: We assessed the diagnostic and monitoring yield of HbA1c in cirrhotic patients with T2DM (DM-Cirr) and without T2DM (NoDM-Cirr). METHODS: We conducted a composite study allocating 21 NoDM-Cirr into a cross-sectional module and 16 DM-Cirr plus 13 controls with T2DM only (DM-NoCirr) into a prospective cohort. Oral glucose tolerance test (OGTT) was performed in NoDM-Cirr. DM-Cirr and DM-NoCirr were matched by sex, age, BMI, and T2DM treatment and studied with continuous glucose monitoring (CGM). Percent deviations from target, low/high blood glucose indexes (LBGI/HBGI) were calculated from CGM, as well as the average daily risk range (ADRR) as a marker of glucose variability. RESULTS: Overall, HbA1c and OGTT diagnostic yield agreed in 12 patients (57%, ρ = 0.45, p < 0.03). CGM captured 3463 glucose determinations in DM-Cirr and 4273 in DM-NoCirr (p = 0.42). Regression analysis showed an inferior association between HbA1c and CGM in DM-Cirr (R2 = 0.52), when compared to DM-NoCirr (R2 = 0.94), and fructosamine did not improve association for DM-Cirr (R2 = 0.31). Interestingly, cirrhosis and Child-Turcotte-Pugh class accounted for HbA1c variance (p < 0.05). Patients in DM-Cirr were less frequently within target glucose (70-180 mg/dL), but at higher risk for hyperglycemia (HBGI > 9) when compared to DM-NoCirr, and they also showed higher glucose variability (ADRR 13.9 ± 2.5 vs. 8.9 ± 1.8, respectively, p = 0.03). CONCLUSION: HbA1c inaccurately represents chronic glycemia in patients with cirrhosis, likely in relation to increased glucose variability.

A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis.

OBJECTIVES: Prednisolone therapy increases the risk of infections in patients with severe alcoholic hepatitis (SAH). We evaluated whether the use of the Lille Model at day 4 (LM4) is useful to predict response to prednisolone compared with the classic day 7 (LM7) in order to limit a futile exposure to corticosteroids. METHODS: We performed a retrospective analysis of a large multinational cohort of patients with SAH with Maddrey's discriminant function (DF) ≥32. Response to corticosteroids was assessed with LM4 and LM7, according to the validated cutoff value (CUV>0.45). Receiver operating characteristics (ROC) curves were constructed to determine the optimal CUV for LM4 and to compare accuracy between LM4, LM7, MELD (Model for End-Stage Liver Disease), and ABIC (age, bilirubin, international normalized ratio, and creatinine). Logistic regression models were constructed to predict 28- and 90-day mortality. Cox regression analysis was performed to assess long-term survival. RESULTS: A total of 163 (62.7%) out of 260 patients received corticosteroids. The median DF for the patients treated with corticosteroids was 64.1 (47.9-81.3). Overall 90-day mortality was 35.9%. The median LM4 and LM7 for the patients who received treatment was 0.39 (0.19-0.83) and 0.36 (0.13-0.77). LM4 was a strong independent predictor of 28-day mortality (OR 25.4, (95% confidence interval (CI) 5.1-126.8), P<0.001). By using LM4 with a CUV>0.45, 28- and 90-day survival was significantly higher for responders (90% and 76%) than non-responders (66% and 40%), P<0.001. Importantly, the area under the ROC curve for predicting mortality for LM4 was similar than the classic LM7 (0.77 vs. 0.75, respectively: P=0.558). CONCLUSIONS: LM4 is as accurate as LM7 in predicting response to corticosteroids, as well as 28- and 90-day mortality. Assessing the efficacy of prednisolone at an earlier time point can avoid a more prolonged futile use of this therapy.

Ipilimumab-Induced Gastrointestinal Toxicities: A Management Algorithm.

Ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4-blocking monoclonal antibody, which has shown a significant survival benefit in metastatic melanoma patients. Despite being a promising therapy for a disease with an otherwise rather dismal prognosis, it is associated with several immune-related adverse effects (IRAE) mainly targeted toward the digestive tract, skin, liver, and hypothalamic-pituitary axis. Ipilimumab-induced gastrointestinal toxicity (IGT) include diarrhea (~44 %), colitis (~18 %), bowel perforation (<1 %), and pancreatitis (<1.5 %). Early recognition of IRAE and treatment initiation are critical to decrease the risk of further complications. Management included steroids as initial therapy, followed by infliximab (anti-tumor necrosis factor alpha antibody) and/or surgical option for complications like bowel perforation. We present a series of three patients with metastatic melanoma, who received treatment with ipilimumab, and presented with varying gastrointestinal clinical manifestations and complications. Through this case series, our attempt is to make practicing gastroenterologists cognizant about the wide spectrum of gastrointestinal toxicity of this rather new clinical entity, as well as to discuss management algorithm for IGT.

Impact of anti-thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation.

BACKGROUND: Induction immunosuppression with anti-thymocyte globulin (ATG) provides potential benefits after liver transplantation (LT). However, its use in patients with LT and hepatitis C (HCV) is controversial. AIM: To evaluate the 1- and 2-year patient survival and HCV recurrence rate in patients receiving ATG during the induction phase of immunosuppression (IPI) after LT. METHODS: A total of 49 patients undergoing their first LT for HCV were randomized to receive ATG during IPI. Patient survival and HCV recurrence were determined at 1 and 2 years. The frequency of acute cellular rejection (ACR), infections, and neoplasms was also evaluated. RESULTS: Twenty-six patients were randomized to receive ATG (Arm-1) and 23 to standard induction therapy (Arm-2). Those given ATG had lower HCV recurrence (26.9 vs 73.9 %, p = 0.001). The 1- and 2-year patient survival rates were similar for both arms (p = 0.33). Infections occurred in 46.1 % subjects in Arm-1 and 34.7 % in Arm-2 (p = 0.562). There was a greater proportion of fungal infections in Arm-1 (19.2 vs 0 %, p = 0.032). CONCLUSIONS: ATG during the IPI was associated with lower frequency of recurrence of HCV in patients undergoing LT. This, however, did not affect the 1- and 2-year survival and the frequency of ACR, infections, or neoplasms.

Recent advances in endoscopic management of gastric neoplasms.

The development and clinical application of new diagnostic endoscopic technologies such as endoscopic ultrasonography with biopsy, magnification endoscopy, and narrow-band imaging, more recently supplemented by artificial intelligence, have enabled wider recognition and detection of various gastric neoplasms including early gastric cancer (EGC) and subepithelial tumors, such as gastrointestinal stromal tumors and neuroendocrine tumors. Over the last decade, the evolution of novel advanced therapeutic endoscopic techniques, such as endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic full-thickness resection, and submucosal tunneling endoscopic resection, along with the advent of a broad array of endoscopic accessories, has provided a promising and yet less invasive strategy for treating gastric neoplasms with the advantage of a reduced need for gastric surgery. Thus, the management algorithms of various gastric tumors in a defined subset of the patient population at low risk of lymph node metastasis and amenable to endoscopic resection, may require revision considering upcoming data given the high success rate of en bloc resection by experienced endoscopists. Moreover, endoscopic surveillance protocols for precancerous gastric lesions will continue to be refined by systematic reviews and meta-analyses of further research. However, the lack of familiarity with subtle endoscopic changes associated with EGC, as well as longer procedural time, evolving resection techniques and tools, a steep learning curve of such high-risk procedures, and lack of coding are issues that do not appeal to many gastroenterologists in the field. This review summarizes recent advances in the endoscopic management of gastric neoplasms, with special emphasis on diagnostic and therapeutic methods and their future prospects.

Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future.

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.

Use of Computed Tomography Coronary Calcium Score for Coronary Artery Disease Risk Stratification During Liver Transplant Evaluation.

Background: End-stage liver disease (ESLD) is not considered a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, lifestyle characteristics commonly associated with increased ASCVD risk are highly prevalent in ESLD. Emerging literature shows a high burden of asymptomatic coronary artery disease (CAD) in patients with ESLD and a high ASCVD risk in liver transplantation (LT) recipients. Coronary artery calcium score (CAC) is a noninvasive test providing reliable CAD risk stratification. We implemented an LT evaluation protocol with CAC playing a central role in triaging and determining the need for further CAD assessment. Here, we inform our results from this early experience. Methods: Patients with ESLD referred for LT evaluation were prospectively studied. We compared accuracy of CAC against that of CAD risk factors/scores, troponin I, dobutamine stress echocardiogram (DSE), and single-photon emission computed tomography (SPECT) to detect coronary stenosis ≥70 (CAD ≥ 70) per left heart catheterization (LHC). Thirty-day post-LT cardiac outcomes were also analyzed. Results: One hundred twenty-four of 148 (84%) patients underwent CAC, 106 (72%) DSE/SPECT, and 50 (34%) LHC. CAC ≥ 400 was found in 35 (28%), 100 to 399 in 17 (14%), and <100 in 72 (58%). LHC identified CAD ≥ 70% in 8 of 29 (28%), 2 of 9 (22%), and 0 of 4, respectively. Two acute coronary syndromes occurred after LT in a patient with CAC 811 (CAD < 70%), and one with CAC 347 (CAD ≥ 70%). No patients with CAC < 100 presented with acute coronary syndrome after LT. When using CAD ≥ 70% as primary endpoint of LT evaluation, CAC ≥ 346 was the only test showing predictive usefulness (negative predictive value 100%). Conclusions: CAC is a promising tool to guide CAD risk stratification and need for LHC during LT evaluation. Patients with a CAC < 100 can safely undergo LT without the need for LHC or cardiac stress testing, whereas a CAC < 346 accurately rules out significant CAD stenosis (≥70%) on LHC, outperforming other CAD risk-stratification strategies.

Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis.

AIM: To evaluate the prevalence of metabolic syndrome (MS), obesity and type 2 diabetes mellitus (T2DM) in a group of Mexican Mestizo patients with cryptogenic cirrhosis (CC) and to compare this group with patients with cirrhosis secondary to other causes (disease controls). METHODS: Patients with CC, diagnosed between January, 1990 and April, 2005, were included in a retrospective study. Patients with cirrhosis caused by chronic hepatitis C, alcohol abuse or autoimmune hepatitis (AIH) served as disease controls. RESULTS: A total of 134 patients with CC were analyzed. Disease controls consisted of 81 patients with chronic hepatitis C, 33 with alcohol abuse and 20 with AIH. The median age of patients with CC was 57 years (range, 16-87); 83 (61.9%) patients were female; 53 (39.6%) were Child A, 65 (48.5%) Child B, and 16 (11.9%) were Child C cirrhosis. The prevalence of MS (29.1% vs 6%; P<0.001), obesity (16.4% vs 8.2%; P=0.04) and T2DM (40% vs 22.4%; P=0.013) was higher in CC patients than in disease controls. There were no differences in sex, age or liver function tests between the two groups. CONCLUSION: The prevalence of MS, obesity and T2DM were higher in patients with CC than in patients with cirrhosis secondary to others causes. Our findings support the hypothesis that non-alcoholic steatohepatitis (NASH) plays an under-recognized role in CC.

Utility of endoscopic ultrasound and endoscopy in diagnosis and management of hepatocellular carcinoma and its complications: What does endoscopic ultrasonography offer above and beyond conventional cross-sectional imaging?

Hepatocellular carcinoma constitutes over 90% of the primary liver tumors, the rest being cholangiocarcinoma. It has an insidious presentation, which is responsible for the delayed presentation. Hence, the management strategy relies on screening to diagnose it an early stage for curative resection and/or treatment with local ablative techniques or chemotherapy. However, even with different screening programs, more than 60% of tumors are still detected at an advanced stage, leading to an unchanged mortality rate, thereby implying a room for improvement in the screening and diagnostic process. In the last few years, there has been evolution of utility of endoscopy, specifically endoscopic ultrasonography along with Fine needle aspiration, for this purpose, which we comprehensively review in this article.

Magnesium Toxicity-Induced Ileus in a Postpartum Patient Treated for Preeclampsia With Magnesium Sulphate.

Hypermagnesemia is a rare and under-recognized cause of paralytic ileus. We report a case of a 21-year-old primigravida who was managed aggressively for preeclampsia and presented with postpartum paralytic ileus. Detailed history was employed to consider hypermagnesemia-induced ileus as the working diagnosis, and the patient improved with correction of the electrolyte imbalance. Hypermagnesemia-induced lethargy, decreased reflexes, muscle weakness, flaccid paralysis, respiratory muscle paralysis, and cardiac arrest are well-described; however, intestinal smooth muscle dysfunction leading to paralytic ileus has never been reported in the setting of magnesium use for peripartum preeclampsia management.

The adverse pharmacology of calcineurin inhibitors and their impact on hepatitis C recurrence after liver transplantation: implications for clinical practice.

Calcineurin inhibitors are widely used as maintenance immunosuppressants in solid-organ transplantation to minimize the risk of allograft rejection. Although the use of these agents has transformed the outcomes for patient and graft survival, this has come at a cost, notably the well-known adverse events of nephrotoxicity and metabolic abnormalities, to name a few. Over the last decade, tremendous interest has also focused on the impact of these medications on the replication of hepatitis C virus (HCV), with cyclosporine in particular having a negative effect on viral replication in vitro. Although small retrospective studies suggested that there may be a beneficial effect with cyclosporine on the progression of recurrent HCV and response to interferon, these findings have not been validated in several well-designed randomized controlled trial studies. The authors will review the pharmacology and pharmacokinetics of these well-known drugs and discuss the impact of these medications on the natural history of HCV recurrence after liver transplantation.

PPIs are not associated with a lower incidence of portal-hypertension-related bleeding in cirrhosis.

AIM: To determine if proton pump inhibitor use in cirrhotic patients with endoscopic findings of portal hypertension is associated with a lower frequency of gastrointestinal bleeding. METHODS: Patients with cirrhosis and endoscopic findings related to portal hypertension, receiving or not receiving proton pump inhibitor (PPI) therapy, were included retrospectively. We assigned patients to two groups: group 1 patients underwent PPI therapy and group 2 patients did not undergo PPI therapy. RESULTS: One hundred and five patients with a median age of 58 (26-87) years were included, 57 (54.3%) of which were women. Esophageal varices were found in 82 (78%) patients, portal hypertensive gastropathy in 72 (68.6%) patients, and gastric varices in 15 (14.3%) patients. PPI therapy was used in 45.5% of patients (n = 48). Seventeen (16.1%) patients presented with upper gastrointestinal bleeding; in 14/17 (82.3%) patients, bleeding was secondary to esophageal varices, and in 3/17 patients bleeding was attributed to portal hypertensive gastropathy. Bleeding related to portal hypertension according to PPI therapy occurred in 18.7% (n = 9) of group 1 and in 14% (n = 8) of group 2 (odds ratio: 0.83, 95% confidence interval: 0.5-1.3, P = 0.51). CONCLUSION: Portal hypertension bleeding is not associated with PPI use. These findings do not support the prescription of PPIs in patients with chronic liver disease with no currently accepted indication.