Non-invasive liver disease assessment to identify portal hypertension: A systematic review supporting the AASLD Practice Guideline.

INTRODUCTION: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. Hepatic venous pressure gradient (HVPG), a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and by its availability, non-invasive liver disease assessments (NILDAs) to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. METHODS: We conducted a systematic review of Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22 nd , 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies which compared non-invasive tests (blood, and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥10 mm Hg) in patients with chronic liver disease (this therefore limited the number of studies that could be included). Outcomes reported included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. RESULTS: Nine studies with 2,492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood based tests, including aspartate to platelet ratio index (APRI) (56% sensitivity and 68% specificity) and fibrosis-4 (FIB-4) (54% sensitivity and 73% specificity) had low accuracy measures. Imaging based tests (transient elastography (TE) and shear wave elastography detection of liver stiffness (LSM)) had better accuracy, but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50% while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging based tests are the best available NILDA to detect CSPH, CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSION: While imaging-based NILDA appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the SR. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Imaging-based non-invasive liver disease assessment for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Transient elastography (TE), shear-wave elastography (SWE), and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). APPROACH AND RESULTS: A comprehensive search for studies assessing LSM by TE, SWE, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), utilizing histopathology as standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV co-infection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. CONCLUSION: LSM from TE, SWE, and MRE show acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Noninvasive assessment of liver fibrosis and portal hypertension.

PURPOSE OF REVIEW: The result of ongoing liver injury - and disease, regardless of cause - is fibrosis, and fibrosis appears to be a critically important result of ongoing injury. Further, in a number of different liver diseases, the presence of fibrosis has prognostic value. Therefore, the assessment of fibrosis is of critical clinical importance. Given the importance of fibrosis, there has been a rapid evolution in the use of noninvasive liver tests. This review highlights a number of the core principles surrounding. RECENT FINDINGS: The use of noninvasive test has progressed rapidly over the last decade and data are rapidly accumulating. New terminology has been adapted by the American Association for the Study of Liver Disease (AASLD) for noninvasive assessment of liver disease and termed 'NILDA' (Non-Invasive Liver Disease Assessment). Blood based such as APRI and or FIB-4 and imaging tests such as liver stiffness measurement (LSM) have moderate to high degrees of accuracy for detection of advanced liver fibrosis (≥ F2) and even higher accuracy for detection of severe fibrosis (F4 or cirrhosis). NILDA are particularly effective at the ends of the liver disease spectrum. For example, a very low LSM (less than 7 kPa) essentially excludes significant fibrosis or portal hypertension, and a very high LSM (> 25 kPa) makes significant fibrosis with portal hypertension (cirrhosis) highly likely. SUMMARY: NILDA are currently front and center in terms of assessment of the severity of liver disease. In all patients with known or suspected liver disease, noninvasive blood tests, including APRI and or FIB-4, should be the initial choice to assess the severity of liver fibrosis and/or portal hypertension. In most patients, these tests should be followed with imaging evaluation. The most commonly available imaging is LSM, which appears to be more accurate in predicting fibrosis severity, and is superior to blood tests in the assessment of portal hypertension. In situations in which there is diagnostic uncertainly, liver biopsy with or without HVPG remains an important consideration.

Improved Mortality But Increased Economic Burden of Disease in Compensated and Decompensated Cirrhosis: A US National Perspective.

INTRODUCTION: Cirrhosis remains a major burden on the health care system despite substantial advances in therapy and care. Studies simultaneously examining mortality, readmission, and cost of care are not available. Here, we hypothesized that improved patient care in the last decade might have led to improved outcomes and reduced costs in patients with cirrhosis. MATERIALS AND METHODS: We identified compensated cirrhosis (CC) and decompensated cirrhosis (DC) patients using carefully chosen ICD-9/ICD-10 codes from the Nationwide Readmission Database (NRD) (years 2010 to 2016). We evaluated trends of 30-day all-cause mortality, 30-day readmission, and inflation-adjusted index hospitalization and readmission costs. Factors associated with mortality and readmission were identified using regression analyses. RESULTS: A total of 3,374,038 patients with cirrhosis were identified, of whom nearly 50% had a decompensating event on initial admission. The 30-day inpatient mortality rate for both CC and DC patients decreased from 2010 to 2016. The 30-day readmission rate remained stable for DC and declined for CC. Over the study period, 30-day readmission costs increased for DC and remained unchanged for CC. The median cost for index hospitalization remained nearly unchanged, but the cost of readmission increased for both CC and DC groups. Gastrointestinal diseases and infections were the leading cause of readmission in CC and DC patient groups. CONCLUSION: Inpatient mortality has decreased for CC and DC patients. Readmission has declined for CC patients and remained stable for DC patients. However, the economic burden of cirrhosis is rising.

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Pearls of wisdom for aspiring physician-scientist residency applicants and program directors.

Postgraduate physician-scientist training programs (PSTPs) enhance the experiences of physician-scientist trainees following medical school graduation. PSTPs usually span residency and fellowship training, but this varies widely by institution. Applicant competitiveness for these programs would be enhanced, and unnecessary trainee anxiety relieved, by a clear understanding of what factors define a successful PSTP matriculant. Such information would also be invaluable to PSTP directors and would allow benchmarking of their admissions processes with peer programs. We conducted a survey of PSTP directors across the US to understand the importance they placed on components of PSTP applications. Of 41 survey respondents, most were from internal medicine and pediatrics residency programs. Of all components in the application, two elements were considered very important by a majority of PSTP directors: (a) having one or more first-author publications and (b) the thesis advisor's letter. Less weight was consistently placed on factors often considered more relevant for non-physician-scientist postgraduate applicants - such as US Medical Licensing Examination scores, awards, and leadership activities. The data presented here highlight important metrics for PSTP applicants and directors and suggest that indicators of scientific productivity and commitment to research outweigh traditional quantitative measures of medical school performance.

A novel phenotype-based drug-induced liver injury causality assessment tool (DILI-CAT) allows for signal confirmation in early drug development.

BACKGROUND: Drug-induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice. AIM: We utilised a novel DILI causality assessment tool (DILI-CAT), which uses drug-specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development. METHODS: We conducted a retrospective analysis of liver injury events from four Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials, in which patients were randomised to receive oral ximelagatran or adjusted-dose warfarin. A stepwise process was used with iterative adjustments. The DILI phenotype was characterised by latency, R-value, and AST/ALT ratio. A scoring algorithm was applied to liver events to assess how closely the liver events matched the Interquatile-Range for the working phenotype for each of the three parameters. FINDINGS: Data from 3115 patients included in the SPORTIF trials as above were available. The initial ximelagatran phenotype was developed based on five liver injury cases from the ximelagatran arm and was then validated against an additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there was a statistically significant difference in the total DILI-CAT scores of the two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten ximelagatran cases generated a second, refined ximelagatran phenotype, which was validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again with statistically significant different DILI-CAT ximelagatran vs. warfarin scores (p < 0.001). CONCLUSION: DILI-CAT, a clinically intuitive, data-driven, computer-assisted scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity in clinical drug development.

Role of Liver Biopsy in Assessment of Radiologically Identified Liver Masses.

BACKGROUND: Despite improvements in imaging techniques that have enhanced the ability to diagnose hepatocellular carcinoma (HCC), histopathological evaluation of many other types of liver masses is critical. AIMS: To evaluate the utility of liver biopsy in patients with radiologically undiagnosed liver masses. METHODS: We retrospectively analyzed 293 consecutive patients who had a liver biopsy for evaluation of an undiagnosed liver mass between January 2014 and January 2018. RESULTS: Out of 293 biopsies, 246 patients were found to have malignancy (84%), including 210 (72%) patients with metastatic malignancy and 36 with primary hepatic malignancies (20 HCC and 16 others). In the 47 patients without malignancy, 17 patients had necrotic abscess/granuloma, 16 patients had normal histology, eight patients had hepatic fibrosis/cirrhosis without malignant foci, and six patients had benign tumors. The most common primary lesion in patients with liver metastasis was breast carcinoma (32/293, 11%), followed by colon and pancreas (31 (each)/293, 11%), and lung (9%) adenocarcinomas. Histopathological analysis confirmed the presence of metastasis in 165/200 (83%) patients with a history of oncological malignancy and in 45/93 (48%) patients who had no malignancy history. CONCLUSIONS: In patients with a radiologically identified liver mass of unclear etiology, liver biopsy/histology made a diagnosis in 95% (277/293) of patients, including 84% (246/293) found to have an oncological malignancy. Liver biopsy/histology also identified malignancy in a high proportion of patients without known underlying cancer. We conclude that liver biopsy is valuable for evaluation of radiologically identified liver masses of unclear etiology.

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.

Tools for causality assessment in drug-induced liver disease.

PURPOSE OF REVIEW: There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tools and discuss how to improve the causality assessment process as a whole. RECENT FINDINGS: Existing DILI-specific causality assessment tools are surprisingly similar and exhibit only minor differences in point allocation. But difference in threshold for likelihood of being DILI. We reviewed the literature on currently used causality assessment tools, identified areas for future improvement, and herein propose approaches for refinement. Opportunities to improve current models, as well as the assessment process, in general, include in particular provision of more precise clinical detail and to perhaps add new components to scoring systems. For example, the incorporation of drug-specific clinical signature patterns, accounting for a drug's inherent hepatotoxicity potential, and/or incorporation of other drug properties to scoring systems may allow enhancement. Further, more systemic exclusion of competing diagnoses is needed. Finally, causality assessment processes will likely benefit from a data-driven and computer-assisted approach. SUMMARY: Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

Trends in Hospitalization, Acute Kidney Injury, and Mortality in Patients With Spontaneous Bacterial Peritonitis.

GOALS: The purpose of our study was to evaluate trends of hospitalization, acute kidney injury (AKI) and mortality in cirrhotic patients with spontaneous bacterial peritonitis (SBP). BACKGROUND: SBP is a frequent bacterial infection in cirrhotic patients leading to increased morbidity and mortality. MATERIALS AND METHODS: A total of 4,840,643 patients hospitalized with cirrhosis from 2005 to 2014 were identified using the Nationwide Inpatient Sample database, of which 115,359 (2.4%) had SBP. We examined annual trends and used multivariable mixed-effects logistic regression analyses to obtain adjusted odds ratios by accounting for hospital level and patient level variables. RESULTS: We identified a striking increase in hospitalizations for SBP in cirrhotic patients (0.45% to 3.12%) and AKI in SBP patients (25.6% to 46.7%) from 2005 to 2014. Inpatient mortality decreased over the study period in patients with SBP (19.1% to 16.1%) and in patients with SBP plus AKI (40.9% to 27.6%). Patients with SBP had a higher inpatient mortality rate than those without SBP [15.5% vs. 6%, adjusted odd ratio (aOR): 2.02, P<0.001]. AKI was 2-fold more prevalent in cirrhotics with SBP than those without SBP (42.8% vs. 17.2%, aOR: 1.91, P<0.001) and concomitant AKI was associated with a 6-fold mortality increase (aOR: 5.84, P<0.001). Cirrhotic patients with SBP had higher hospitalization costs and longer length of stays than patients without SBP. CONCLUSIONS: Despite a higher hospitalization rate and prevalence of concomitant AKI, mortality in patients with SBP decreased during the study period. SBP is associated with high likelihood of development of AKI, which in turn, increases mortality.

Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients.

INTRODUCTION: African Americans (AAs) compared with European Americans (EAs) have poorer stage-specific survival from colorectal cancer (CRC). Recent reports have indicated that the racial difference in survival has worsened over time, especially among younger patients. To better characterize this association, we used population-based Surveillance, Epidemiology, and End Results registry data to evaluate the effect of race on stage IV CRC survival in patients aged < 50 and ≥ 50 years. PATIENTS AND METHODS: The population included 16,782 patients diagnosed with stage IV colon and rectal adenocarcinoma from January 1, 2004 and December 31, 2011. Cox proportional hazards regression was used to evaluate the association between race and other prognostic factors and the risk of death in each age group. RESULTS: Younger AAs compared with EAs had a greater prevalence of proximal CRC at diagnosis, a factor associated with a significantly greater risk of death in both races. Among patients < 50 years old, AAs had a greater risk of death compared with EAs (hazard ratio, 1.35; 95% confidence interval, 1.20-1.51), which was attenuated in patients ≥ 50 years of age (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16); P for interaction = .01. CONCLUSION: The results revealed poor overall survival for AAs compared with EAs, especially for those < 50 years of age. The greater prevalence of proximal CRC at diagnosis among younger AAs (vs. EAs) might contribute to the racial difference in survival. Future studies are needed to understand how the colonic location affects the efficacy of treatment regimens.

Identification of high resource utilizing patients on internal medicine hospital services.

In order to provide high quality, cost-efficient care, it is critical to understand drivers of the cost of care. Therefore, we sought to identify clinical variables associated with high utilization (cost) in patients admitted to medical services and to develop a robust model to identify high utilization patients. In this case-control analysis, cases were identified as the 200 most costly patients admitted to internal medicine/internal medicine subspecialty services using our institution's computerized clinical data warehouse over a 7-month time period (November 1, 2012-May 31, 2013). 400 patients admitted in the same time period were randomly selected to serve as controls. The mean cost for the highest utilization patients was $126,343, while that for randomly matched patients was $15,575. In a multivariable regression model, the following variables were associated with high utilization of resources: African American race, age 35-44, admission through the emergency department, primary service of hematology-oncology, a history of heart failure or paralysis, a diagnosis of HIV, cancer, collagen vascular diseases and/or coagulopathy, a reduced albumin, and/or an elevated creatinine. The in hospital mortality rate for high utilization patients was 19%, compared to 8% for controls (p=0.0002). A predictive model using 14 different readily available clinical variables predicted high utilization with an area under the curve of 0.85. The data suggest that high utilization patients share similar demographic and clinical features. We speculate that a predictive model using commonly known patient characteristics should be able to predict high utilization patients.

Point-of-Care Echocardiography Improves Assessment of Volume Status in Cirrhosis and Hepatorenal Syndrome.

The management of patients with cirrhosis along with acute kidney injury is complex and depends in large part on accurate assessment of intravascular volume status. Assessment of intravascular volume status by point-of-care echocardiography often relies solely on inferior vena cava size and variability evaluation; however, this parameter should be interpretated with an understanding of right ventricular function integrated with stroke volume and flow. Attempts to optimize intra-abdominal hemodynamics favorably are clearly problematic when physical examination findings or rudimentary assessments of central venous pressure or change in central venous pressure are used. Here, we have demonstrated the potential utility of point-of-care echocardiography to optimize the hemodynamic state in patients with decompensated cirrhosis along with acute kidney injury. This case is very unique and describes how this technique may have great promise in optimizing the intra-abdominal hemodynamics and predict the timing of large-volume paracentesis in patients with decompensated cirrhosis, which in turn can aid in promoting favorable renal recovery.

Fasting Blood Ammonia Predicts Risk and Frequency of Hepatic Encephalopathy Episodes in Patients With Cirrhosis.

BACKGROUND & AIMS: There is controversy over the use of measuring blood levels of ammonia (NH3) in the management of patients with overt hepatic encephalopathy (HE). METHODS: We performed a retrospective analysis of data from a randomized, double-blind study of 178 patients with cirrhosis given glycerol phenylbutyrate (an NH3-lowering agent) or placebo for 16 weeks. Blood samples were collected at baseline and on study days 7 and 14 and NH3 levels were measured. The probabilities of having an HE episode, based on ammonia values, were modeled using binary logistic regression. A Cox proportional model was used to determine the risk of HE episodes in patients with baseline fasting NH3 levels ≤1.5-fold the upper limit of normal (ULN) versus patients with fasting NH3 levels >1.5-fold the ULN. RESULTS: The risk and frequency of HE episodes and HE-related hospitalizations correlated with baseline (mean, 51 ± 6 µmol/L; ULN, 35 µmol/L) and on-study fasting levels of NH3, and increased sharply at levels >1.5-fold the ULN. Regardless of baseline level, NH3 exposure and the relative risk of HE episodes were decreased by glycerol phenylbutyrate. CONCLUSIONS: In analysis of data from a phase 2 study of the effects of glycerol phenylbutyrate in patients with cirrhosis, we found that fasting levels of NH3 in blood can identify patients at risk for HE-related morbidity. Patients with HE might benefit from NH3-lowering therapy. ClinicalTrials.gov no: NCT 00999167.