Key Insights and Clinical Pearls in the Identification and Management of Cirrhosis and Its Complications.

Cirrhosis is a prevalent, chronic condition with an asymptomatic compensated phase, in which patients may feel well, and a decompensated phase that begins with onset of complications (eg, hepatic encephalopathy, ascites, and/or variceal bleeding). Because patients with cirrhosis may appear healthy with normal liver enzymes, alkaline phosphatase, and serum bilirubin levels, awareness of clinical signals is important. For example, patients with thrombocytopenia should be evaluated for chronic liver disease and cirrhosis. Early recognition and management of cirrhosis-related complications (eg, hepatic encephalopathy, ascites, and/or variceal bleeding) is important, given their association with hospitalization and poor prognosis (eg, increased odds of short-term mortality). Hepatic encephalopathy can be the most subtle cirrhosis-related complication, and associated cognitive impairment may be misdiagnosed. Because hepatic encephalopathy can be associated with hospital readmissions, reducing readmission rates after hepatic encephalopathy-related hospitalizations is critical. This includes incorporating ongoing therapy (eg, rifaximin plus lactulose) in postdischarge management plans to reduce the risk of hepatic encephalopathy recurrence. Strategies that mitigate cirrhosis progression and prevent development of cirrhosis-related complications are key to improving patient outcomes.

Adherence in Hepatitis C Virus Treatment: What We Know.

Although therapy with direct-acting antiviral (DAA) agents achieves high hepatitis C virus (HCV) cure rates and is forgiving of missed doses, certain patient populations, such as people who inject drugs (PWID), are often denied therapy because of a perceived high risk of nonadherence. However, a relationship between adherence to DAAs for various patient populations and efficacy has not been well defined. The lack of a standardized method for evaluating adherence complicates making comparisons between studies, making it difficult to develop and implement novel measures that may improve adherent behavior. Traditional methods for assessing adherence may overestimate medication adherence, while newer, technology-based methods may assist with accurately assessing and maintaining patient adherence to therapy. Data demonstrate that special populations of patients with HCV, such as PWID, can be successfully treated, with relatively high rates of sustained virologic response (SVR) despite less-than-optimal adherence. While rates of adherence, and subsequently SVR, can be improved, antiviral therapy should not be withheld because of fear of nonadherence. This article addresses medication adherence and forgiveness of DAA regimens, such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, in different patient populations with HCV. Considerations in evaluating adherence in HCV therapy and available methods for assessing adherence are detailed.

Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis.

INTRODUCTION: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration-approved therapies. METHODS: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study. RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study. DISCUSSION: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

Clinical Consult in NASH: Are Your Patients at Risk? Based on a Medscape Education Online Activity.

Nonalcoholic steatohepatitis, or NASH, is the most severe form of nonalcoholic fatty liver disease (NAFLD). If left untreated, NASH can develop into advanced liver disease, such as cirrhosis. Moreover, patients with NASH and cirrhosis are also at increased risk of developing hepatocellular carcinoma. Therefore, early detection and intervention are key components to prevent disease progression, particularly in the primary care setting where many patients with NASH are typically encountered.

Alcohol-Related Liver Disease Including New Developments.

The prevalence of alcohol consumption, alcohol use disorder (AUD), and alcohol-related liver disease (ALD) has exponentially increased over the last several years and rates continue to increase. Significant alcohol use can cause progression from steatosis in the liver to inflammation, fibrosis, and eventually cirrhosis. Additional risk factors for the progression of ALD disease include gender, race, and genetic predisposition. As such, it is essential for clinicians to understand and implement screening tools for early diagnosis of both AUD and ALD and be aware of emerging novel treatment options.

Screening, Diagnosis, and Treatment of Alcohol-Related Liver Disease and Alcohol-Associated Hepatitis.

Alcohol-related liver disease is a spectrum of disease in which continued, significant alcohol use can cause progression from fatty changes in the liver to inflammation, fibrosis, and eventually cirrhosis. The rates of alcohol consumption, alcohol use disorder, and alcoholrelated liver disease have increased substantially during the past several years. However, the amount of alcohol consumption may not be the only risk factor for such progression of disease. Studies have found several other risk factors, including sex, race, and genetic predisposition, as possible culprits of worsening disease. As a result, clinicians must understand and implement screening tools for early diagnosis and remain up-to-date with the evolving nature of treatment options. This article reviews the diagnosis and treatment of alcohol use disorder as well as the pathophysiology, clinical presentation, and treatment of alcohol-related liver disease, including alcohol-associated hepatitis.

AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with suspected acute kidney injury in patients with cirrhosis. METHODS: This article provides practical advice for the management of patients with cirrhosis and acute kidney injury based on the best available published evidence. This best practice document is not based on a formal systematic review. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Clinical Gastroenterology & Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Acute kidney injury (AKI) should be diagnosed when the serum creatinine increases by ≥0.3 mg/dL within 48 hours or is ≥50% from baseline or when the urine output is reduced below 0.5 mL/kg/h for >6 hours. BEST PRACTICE ADVICE 2: Preventive measures against the development of AKI in cirrhosis include (1) avoidance of potentially nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs), (2) avoidance of excessive or unmonitored diuretics or nonselective beta-blockade, (3) avoidance of large-volume paracentesis without albumin replacement, and (4) counseling patients to avoid alcohol use. BEST PRACTICE ADVICE 3: (A) Investigation is directed to determining the cause of AKI, which can be due to hypovolemic causes (volume responsive, and the most common cause of AKI in patients with cirrhosis); acute tubular necrosis; hepatorenal syndrome with AKI (HRS-AKI) (a functional renal failure that persists despite volume repletion); HRS with acute kidney disease, a type of functional renal failure of <3 months- duration in which criteria for HRS-AKI are not met; or postrenal, which occurs only rarely. (B) The specific type of AKI should be identified through a careful history, physical examination, blood biochemistry, urine microscopic examination, urine chemistry (Na+ and urea) and selected urinary biomarkers, and renal ultrasound. BEST PRACTICE ADVICE 4: A rigorous search for infection is required in all patients with AKI. A diagnostic paracentesis should be carried out to evaluate for spontaneous bacterial peritonitis; blood and urine cultures and chest radiograph are also required. There is no role for routine prophylactic antibiotics in patients with AKI, but broad-spectrum antibiotics should be started whenever infection is strongly suspected. BEST PRACTICE ADVICE 5: When AKI is diagnosed, diuretics and nonselective beta-blockers should be held, NSAIDs discontinued, the precipitating cause of AKI treated, and fluid losses replaced, administering albumin 1 g/kg/d for 2 days if the serum creatinine shows doubling from baseline. Urine output, vital signs, and when indicated, echocardiography or CVP (if there is a pre-existing central line) should be used to monitor fluid status. BEST PRACTICE ADVICE 6: When the serum creatinine remains higher than twice the baseline value despite these measures, treatment of HRS-AKI should be initiated with albumin at a dose of 1 g/kg intravenously on day 1 followed by 20-40 g daily along with vasoactive agents (terlipressin; if terlipressin is not available, either a combination of octreotide and midodrine; or norepinephrine, depending on institutional preferences) and continued either until 24 hours following the return of the serum creatinine level to within ≤0.3 mg/dL of baseline for 2 consecutive days or for a total of 14 days of therapy. BEST PRACTICE ADVICE 7: Terlipressin should be initiated as a bolus dose of 1 mg every 4-6 hours (total 4-6 mg/d). The dose should be increased to a maximum of 2 mg every 4-6 hours (total 8-12 mg/d) if there is no reduction in serum creatinine at day 3 of therapy by at least 25% compared to the baseline value. Alternatively, clinicians can administer terlipressin by continuous intravenous infusion at a lower starting dose of 2 mg/d, which may reduce ischemic side effects and increase the dose gradually every 24-48 hours up to a maximum dose of 12 mg/d, or reversal of HRS. As per Food and Drug Administration restrictions, terlipressin should not be used in patients with a serum creatinine ≥5 mg/dL, or oxygen saturation of <90%. BEST PRACTICE ADVICE 8: Oral midodrine when used should be initiated at doses of 7.5 mg and titrated upward to 12.5 mg 3 times daily with octreotide (starting with 100 µg and titrating upward to 200 µg subcutaneously 3 times daily). BEST PRACTICE ADVICE 9: Norepinephrine should be used as a continuous intravenous infusion at a starting dose of 0.5 mg/h and the dose increased every 4 hours by 0.5 mg/h to a maximum of 3 mg/h with the goal of increasing the mean arterial pressure by ≥10 mm Hg and/or the urine output to >50 mL/h for at least 4 hours. BEST PRACTICE ADVICE 10: The risks of ischemic side effects of terlipressin and norepinephrine include angina and ischemia of fingers, skin, and intestine. These side effects may be lowered by starting at the lowest dose and gradually titrating upward. BEST PRACTICE ADVICE 11: Fluid status should be closely monitored because of the risk of pulmonary edema with excessive use of albumin. BEST PRACTICE ADVICE 12: Renal replacement therapy (RRT) may be used in the management of (A) AKI secondary to acute tubular necrosis; (B) HRS-AKI in potential candidates for liver transplantation (that is, RRT should not be used in patients with HRS-AKI who are not candidates for liver transplantation); and (C) AKI of uncertain etiology in which the need for RRT may be considered on an individual basis. BEST PRACTICE ADVICE 13: Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI. BEST PRACTICE ADVICE 14: Liver transplantation is the most effective treatment for HRS-AKI. Pharmacotherapy for HRS-AKI before proceeding with liver transplantation may be associated with better post-liver transplantation outcomes. Selected patients with HRS-AKI may require simultaneous liver kidney transplantation based on updated Organ Procurement and Transplantation Network listing criteria.

Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child-Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance.

INTRODUCTION: Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known. The present analysis was performed to determine the pharmacokinetics, efficacy, and safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease. METHODS: Data for patients with Child-Pugh class C chronic liver disease were collected from three data sets: a phase 1/2 Child-Pugh class C study (n = 5) (JapicCTI-163289 [Japan Pharmaceutical Information Center]), a phase 3 pivotal study (L-PLUS 2, n = 3) (NCT02389621 [Clinicaltrials.gov]), and ongoing post-marketing surveillance (n = 27) (JapicCTI-163432 [Japan Pharmaceutical Information Center]). Patients received lusutrombopag at 3 mg for up to 7 days. Safety and efficacy assessments were collected from two clinical studies and the post-marketing surveillance; pharmacokinetic data were collected from the phase 1/2 study. RESULTS: Mean Cmax and AUC0-τ were lower in Child-Pugh class C patients than Child-Pugh class A and B; individual patients' Cmax and AUC0-τ values overlapped among Child-Pugh classes. In lusutrombopag patients who did not receive platelet transfusion (n = 4 in phase 1/2, n = 1 in phase 3, n = 24 in post-marketing surveillance), the median (range) maximum platelet count was 88.5 × 109/L (54-105 × 109/L), 80 × 109/L, and 91 × 109/L (41-186 × 109/L; n = 23), respectively. There were no treatment-related adverse events or treatment-related serious adverse events. One patient from the phase 1/2 study had a non-serious portal vein thrombosis, which was not considered treatment-related. CONCLUSIONS: The analysis presented in this study suggests that lusutrombopag increases platelet counts in Child-Pugh class C patients and is safe and well tolerated in this patient population. TRIAL REGISTRATION: L-PLUS 2: NCT02389621 (Clinicaltrials.gov). Phase 1/2: JapicCTI-163289 (Japan Pharmaceutical Information Center [JAPIC]). Post-marketing surveillance: JapicCTI-163432 (JAPIC).

Overt Hepatic Encephalopathy: Current Pharmacologic Treatments and Improving Clinical Outcomes.

Overt hepatic encephalopathy is a generally reversible neurologic complication of cirrhosis. Overt hepatic encephalopathy has been associated with poor hospitalization- and mortality-related outcomes, which is important given increasing hepatic encephalopathy-related hospitalizations over time. The aim of this narrative review is to provide an overview of hospital- and mortality-related outcomes in patients with overt hepatic encephalopathy and the pharmacologic therapies that may improve these outcomes. Guideline-recommended prophylaxis with lactulose (first-line therapy) or secondary prophylaxis with rifaximin plus lactulose decreases hospital admissions and mortality rates. Rifaximin or lactulose treatment was beneficial for reducing the hospitalization rate in patients with hepatic encephalopathy compared with no treatment. Further, retrospective studies have shown that rifaximin with or without lactulose was effective for decreasing the number of hepatic encephalopathy episodes, hepatic encephalopathy-related hospitalizations, and duration of hospitalization. Ornithine phenylacetate, an ammonia-reducing agent currently in development, is also being investigated in hospitalized patients with hepatic encephalopathy. Overall, data support that prophylaxis for the prevention of hepatic encephalopathy recurrence improves outcomes in patients with cirrhosis and a history of hepatic encephalopathy.

Prevalence of drug-drug interactions with pangenotypic direct-acting antivirals for hepatitis C and real-world care management in the United States: a retrospective observational study.

BACKGROUND: Direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) have varying potentials for drug-drug interactions (DDIs). OBJECTIVES: To (1) identify prevalence of potential DDI with glecaprevir-pibrentasvir (GLE-PIB) and sofosbuvir-velpatasvir (SOF-VEL) and (2) describe health care provider actions in response to pharmacist recommendations based on potential interactions with GLE-PIB or SOF-VEL, using 2 complementary data sources. METHODS: Possible interacting drugs were identified among adult patients in a United States electronic medical record database covering 21 health care organizations and 26 million patients in 2018. DDIs were categorized as potential weak interaction (Level 1), potential interaction (Level 2), or contraindicated (Level 3). Real-world recommendations and resultant actions regarding DDIs with GLE-PIB and SOF-VEL were obtained from a specialty pharmacy database. Categorical variable comparisons were done via chi-square analysis with subsequent z-tests of column proportions. RESULTS: DDI prevalence was higher for patients prescribed GLE-PIB (317/769 [41%]) compared with those prescribed SOF-VEL (170/633 [27%]), and the prevalence of a Level 3 (contraindicated) interaction was higher with GLE-PIB than SOF-VEL (61/769 [8%] vs 2/633 [< 1%]). Across all DDI levels, analgesics (139/317 [44%]), proton-pump inhibitors (129/317 [41%]), and lipid-lowering agents (59/317 [19%]) were the top drug classes for the GLE-PIB group with potential for DDI. For SOF-VEL prescribed patients, the top drug classes were proton-pump inhibitors (83/170 [49%]), histamine-2 blockers (42/170[25%]), and lipid-lowering agents (42/170 [25%]). In real-world care management, the overall prevalence of pharmacist recommendations regarding DDIs was significantly lower for SOF-VEL (28/419 [7%]) relative to GLE-PIB (151/1,216 [12%]). Recommended guidance from pharmacists was not followed for 39% (69/179) of patients, 36% (54/151) for GLE-PIB, and 54% (15/28) for SOF-VEL. CONCLUSIONS: The potential for DDIs with pangenotypic HCV DAAs is frequent and may be more frequent with GLE-PIB than SOF-VEL. Physician responses to pharmacist alerts regarding potential interaction can be highly variable, even in cases of contraindication. DISCLOSURES: Funding for this study was provided by Gilead Sciences, Inc. Trio Health Analytics received funding from Gilead Sciences, Inc., to conduct research for this study. Tsai consults for and has received grants and honoraria from Gilead, AbbVie, Merck, and Bristol Myers Squibb; he has also received lecture fees from Gilead and AbbVie. Curry consults for Trio Health Analytics and Gilead and has also consulted for and received grants from Mallinckrodt. Flamm consults for and has received lecture fees from Gilead and AbbVie; he has also received grants from Gilead and AbbVie. Milligan and Wick are employed by Trio Health Analytics and have received research support from Gilead, Merck, and AbbVie. Younossi has received grants from Gilead, Intercept, Bristol Myers Squibb, GlaxoSmithKline, and Novo Nordisk. Afdhal is a paid consultant/advisory board member for Gilead, Echosens, Ligand, Shionogi, and Trio Health; owns stock in Spring-Bank and Allurion and has stock options in SpringBank; receives royalty income from UpToDate; and is on the board of directors for the nonprofit Liver Institute for Education and Research. Data from this study were presented at the American Association for the Study of Liver Disease (AASLD) Liver Meeting 2019; November 8-12, 2019; Boston, MA, and the European Association for Study of the Liver (EASL) International Liver Congress 2020; August 27-29, 2020; virtual.

The Current Management of Hepatorenal Syndrome-Acute Kidney Injury in the United States and the Potential of Terlipressin.

Acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) is a severe and often fatal complication of end-stage liver disease. The goals of treatment are to reverse renal failure and prolong survival in patients who are critically ill. However, interventions have limited efficacy, and mortality rates remain high. In the United States, the mainstay of pharmacologic therapy consists of the off-label use of vasoconstrictive agents in combination with plasma expanders, a strategy that produces modest effects. Liver transplantation is the ultimate solution but is only an option in a minority of patients because contraindications to transplantation are common and organ availability is limited. Renal replacement therapy is a temporary option but is known to confer an extremely poor short-term prognosis in patients with HRS-AKI and at best serves as a bridge to liver transplantation for the minority of patients who are transplantation candidates. The high mortality rate associated with HRS-AKI in the United States is a reflection of the suboptimal standard of care. Improved therapeutic options to treat HRS-AKI are sought. Terlipressin is a drug approved in Europe for treatment of HRS-AKI and supported by recommendations for first-line therapy by some liver societies and experts around the world. This review article will discuss the substantial unmet medical need associated with HRS-AKI and the potential benefits if terlipressin was approved in the United States.

Safety and Efficacy of Segmental Yttrium-90 Radioembolization for Hepatocellular Carcinoma after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To evaluate safety and efficacy of segmental yttrium-90 (Y90) radioembolization for hepatocellular carcinoma (HCC) after transjugular intrahepatic portosystemic shunt (TIPS) placement. The hypothesis was liver sparing segmental Y90 for HCC after TIPS would provide high antitumor response with a tolerable safety profile. MATERIALS AND METHODS: This single-arm retrospective study included 39 patients (16 women, 23 men) with ages 49-81 years old who were treated with Y90. Child-Pugh A/B liver dysfunction was present in 72% (28/39) with a median Model for End-stage Liver Disease score of 18 (95% confidence interval, 16.4-19.4). Primary outcomes were clinical and biochemical toxicities and antitumor imaging response by World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria. Secondary outcomes were orthotopic liver transplantation (OLT), time to progression (TTP), and overall survival (OS) estimates by the Kaplan-Meier method. RESULTS: The 30-day mortality was 0%. Grade 3+ clinical adverse events and grade 3+ hyperbilirubinemia occurred in 5% (2/39) and 0% (0/39), respectively. Imaging response was achieved in 58% (22/38, WHO criteria) and 74% (28/38, EASL criteria), respectively. Median TTP was 16.1 months for any cause and 27.5 months for primary index lesions. OLT was completed in 88% (21/24) of listed patients at a median time of 6.1 months (range, 0.9-11.7 months). Median OS was 31.6 months and 62.9 months censored and uncensored to OLT, respectively. CONCLUSIONS: Segmental Y90 for HCC appears safe and efficacious in patients after TIPS. Preserved transplant eligibility suggests that Y90 is a useful tool for bridging these patients to liver transplantation.

Transjugular Intrahepatic Portosystemic Shunts: Advances and New Uses in Patients with Chronic Liver Disease.

Transjugular intrahepatic portosystemic shunts is an established treatment for portal hypertensive complications. Advancements in technology and technique have led to novel indications, including treatment of chronic portal vein thrombosis and use before abdominal surgery to alleviate portal hypertensive complications. Use of TIPS can facilitate the embolization of large portal-systemic shunts to alleviate refractory hepatic encephalopathy owing to excessive portal shunting. Despite these advances, transjugular intrahepatic portosystemic shunts is an invasive procedure with risk for complications and should be performed at a center with expertise to ensure a successful patient outcome.

Thrombocytopenia in Chronic Liver Disease: New Management Strategies.

Thrombocytopenia is common in advanced liver disease, and such patients frequently need invasive procedures. Numerous mechanisms for thrombocytopenia exist, including splenic sequestration and reduction of levels of the platelet growth factor thrombopoietin. Traditionally, platelet transfusions have been used to increase platelet counts before elective procedures, usually to a threshold of greater than or equal to 50,000/µL, but levels vary by provider, procedure, and specific patient. Recently, the thrombopoietin receptor agonists avatrombopag and lusutrombopag were studied and found efficacious for increasing platelet count in the outpatient setting for select patients with advanced liver disease who need a procedure.