Utilization of aquapheresis among hospitalized patients with end-stage liver disease: A case series and literature review.

Third-spacing of fluid is a common complication in hospitalized patients with decompensated cirrhosis. In addition to ascites, patients with advanced cirrhosis may develop significant peripheral edema, which may limit mobility and exacerbate debility and muscle wasting. Concomitant kidney failure and cardiac dysfunction may lead to worsening hypervolemia, which may ultimately result in pulmonary edema and respiratory compromise. Diuretic use in such patients may be limited by kidney dysfunction and electrolyte abnormalities, including hyponatremia and hypokalemia. A slow, continuous form of ultrafiltration known as aquapheresis is a method of extracorporeal fluid removal whereby a pump generates a transmembrane pressure that forces an isotonic ultrafiltrate across a semipermeable membrane. This leads to removal of an ultrafiltrate that is isotonic to blood without the need for dialysate or replacement fluid as is necessary in other forms of continuous kidney replacement therapy. This technique has been utilized in other conditions including acute decompensated heart failure, with trials showing mixed, but generally favorable results. Herein, we present a series of our own experience using aquapheresis among patients with cirrhosis, review the literature regarding its use in other hypervolemic states, and discuss how we may apply lessons learned from use of aquapheresis in heart failure to patients with end-stage liver disease.

Variations in Practice Among Cirrhotic Patients With Portal Vein Thrombosis and Esophageal Varices: A North American Survey Study.

INTRODUCTION: There exists variation regarding the approach to anticoagulation and variceal hemorrhage (VH) prophylaxis among patients with cirrhosis and portal vein thrombosis (PVT). METHODS: A survey was distributed to gastroenterology and hepatology providers to assess the approach to anticoagulation and VH prophylaxis among patients with PVT in cirrhotic patients. RESULTS: Providers were more likely to start anticoagulation if the patient was listed for liver transplantation, was symptomatic, or had superior mesenteric vein thrombosis. For prevention of first VH, many providers opt for combination therapy with both nonselective beta blockers and variceal ligation. DISCUSSION: Although providers agree on the clinical scenarios that merit initiation of anticoagulation, practice variation was identified in the means of preventing first VH.

Early neurologic complications after liver transplant are associated with reduced long-term survival and increased rates of rejection.

Neurologic complications (NCs) are common following liver transplantation (LT) and have been associated with impaired short-term survival. The impact of NC on long-term survival is less defined. We aimed to characterize these outcomes and assess for risk factors for post-LT NC. We performed a single-center, retrospective review of 521 patients with LT from 2016 to 2020. Baseline clinical and laboratory factors, intraoperative events, and outcomes were compared between patients with and without NC. The 5-year overall and rejection-free survival was estimated using the Kaplan-Meier analysis. Multivariable logistic regression assessed for an independent relationship between risk factors and the development of NC. Among 521 LT recipients, 24% experienced post-LT NC. Overall and rejection-free survival at 5 years was, respectively, 69% and 75% among those with NC versus 87% and 88% among those without NC (log-rank < 0.001). Among those who survived the first 3 months after LT, overall survival but not rejection-free survival was reduced among patients with NC. Risk factors for developing NC included peri-LT serum sodium (ΔSNa) ≥ 6 (29.4% vs. 20.5%, p = 0.04), grade 3 or 4 HE pre-LT, SNa < 125 pre-LT, and more intraoperative transfusions. In a multivariable logistic regression model controlling for described variables, SNa < 125 (or 0.21, 95% CI, 0.06-0.74) at LT and pre-LT HE grade 3 or 4 (or 0.45, 95% CI, 0.26-0.76) was independently associated with NC. Long-term survival was reduced among patients who developed NC in the immediate post-transplant period, even when censoring those who died in the first 3 months. Post-LT NC was associated with perioperative ΔSNa ≥ 6. Optimization of SNa pre-LT > 125 and limiting perioperative ΔSNa <6 mEq/L might have a beneficial impact in decreasing NC post-LT, which may improve long-term post-LT survival.

Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis.

BACKGROUND: Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC). AIMS: To identify risk factors for new-onset HCC in patients cured of hepatitis C. METHODS: Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC. RESULTS: Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin<3.5 g/dL (p = 0.02), AST/ALT>1 (p = 0.05), and platelets <100 × 103 cells/µL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p = 0.002) and a higher prevalence of vascular invasion (p = 0.016) than cirrhotic patients. CONCLUSIONS: One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk.

DCD Hepatitis C Virus-positive Donor Livers Can Achieve Favorable Outcomes With Liver Transplantation and Are Underutilized.

BACKGROUND: Hepatitis C virus (HCV)-positive donors (antibody-positive [Ab + ] or nucleic acid test positive [NAT + ] donors) have been underutilized. The aim of this study was to evaluate the utilization of livers from HCV-positive with donation after circulatory death (DCD) and to assess outcomes in recipients of these grafts. METHODS: Data between 2015 and 2019 were obtained from the United Network for Organ Sharing database. The utilization rates and graft survival among 8455 DCD liver and nonliver donors and 2278 adult DCD liver transplantation (LT) recipients were reviewed on the basis of donor HCV Ab/NAT status. RESULTS: The utilization of Ab + /NAT - donors <40 y and Ab + /NAT + donors ≥40 y was low than utilization of HCV-negative donors ( P < 0.001). Multivariate analysis identified HCV status (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.06-2.48 in Ab + /NAT - , and OR, 1.49; 95% CI, 1.09-2.05 in Ab + /NAT + ) as an independent predictor of nonutilization of liver grafts. The rate of significant liver fibrosis was comparable in Ab + /NAT - (3.5%; P = 0.84) but was higher in Ab + /NAT + (8.7%; P = 0.03) than that in Ab - /NAT - donors. Kaplan-Meier survival curves demonstrated comparable 3-y patient survival in recipients of HCV-positive grafts compared with recipients of HCV-negative grafts ( P = 0.63; 85.6% in Ab - /NAT - , 80.4% in Ab + /NAT - , and 88.7% in Ab + /NAT + ). CONCLUSIONS: Patient and graft survival rates are similar between HCV-positive and HCV-negative DCD LT. However, HCV-positive donors are particularly underutilized for DCD LT.

Varying Utilization Rates but Superior Outcomes in Liver Transplantation From Hepatitis C-positive Donors in the United States: An Analysis of the OPTN/UNOS Database.

BACKGROUND: Liver transplantation (LT) from hepatitis C virus (HCV)-positive donors [antibody positive (Ab+) or nucleic acid test-positive (NAT+) donors] has been reported to achieve successful outcomes. However, donor and recipient selection has not been well-characterized. METHODS: Data between 2015 and 2019 were obtained from the United Network for Organ Sharing database. The utilization rates and graft survival among 35 239 potential donors and 23 780 adult LT recipients were reviewed based on donor HCV Ab/NAT status. RESULTS: The utilization of Ab+/NAT+ donors was significantly reduced compared with HCV-negative donors (66.4% versus 80.0%, P < 0.001) among donors aged between 40 and 69 y. Recipients of livers from HCV-positive donors had lower laboratory and allocation Model for End-stage Liver Disease scores (both P < 0.001). HCV-positive donors were younger ( P < 0.001). Kaplan-Meyer survival curves demonstrated significantly superior 1-y graft survival in recipients of HCV-positive grafts compared with those from HCV-negative grafts ( P = 0.004; 97.1% in Ab-/NAT+, 93.9% in Ab+/NAT-, and 93.7% in Ab+/NAT+ versus 91.8% in Ab-/NAT-). Multivariate analysis for 1-y graft survival identified donor age [hazard ratio (HR) = 1.01; 95% confidence interval (CI), 1.00-1.01] and laboratory Model for End-stage Liver Disease score (HR = 1.01; 95% CI, 1.00-1.01) as independent predictors but not donor HCV status: HR 0.77' 95% CI, 0.58-1.02 in Ab+/NAT-; HR 0.82' 95% CI, 0.66-1.03 in Ab+/NAT+; and HR 0.39' 95% CI, 0.10-1.55 in Ab-/NAT+. CONCLUSIONS: More widespread utilization of HCV-positive donors, especially Ab+/NAT+ donors of age 40-69 y, may expand the donor pool without impairing short-term outcomes after LT.

Child-Turcotte-Pugh versus MELD-XI identify distinct high-risk populations for heart transplantation following ventricular assist device placement.

BACKGROUND: Patients with end-stage heart failure frequently have significant congestive hepatopathy requiring hepatology assessment prior to heart transplantation listing. An elevated Model for End-stage Liver Disease score with modification to exclude INR (MELD-XI) has been associated with increased mortality following heart transplantation (HT). This study's primary aim was to examine whether Child-Turcotte-Pugh (CTP) classification is associated with post-transplant mortality in patients bridged to transplant with left ventricular assist devices. METHODS AND RESULTS: We conducted a retrospective analysis of 134 patients from our center. Age, CTP class, and MELD-XI at HT were included in the multivariate model for the primary outcome, which demonstrated a significant association between 1-year mortality and CTP class (CTP-A HR: .08, CI .01-.46, P < .01; CTP-B HR: .25, CI .05-1.2, P = .08; reference group CTP-C), and MELD-XI (HR: 1.15; CI: 1.03-1.28; P = .01), but no significant difference for age (HR: .97; CI: .93-1.01; P = .15). Only 13/33 patients with CTP improvement after assist device also had improvement in MELD-XI. CONCLUSIONS: Patients with relatively low MELD-XI scores with discordantly high CTP classification may be a distinct subset for whom MELD-XI underestimates the risk of mortality after heart transplantation compared to CTP.

Hemophagocytic lymphohistiocytosis occurring after liver transplantation: A case series and review of the literature.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by excessive inflammation and tissue destruction due to a dysregulated immune response. Its secondary form is most commonly triggered by viral infection or malignancy. There have previously been 11 cases of acquired HLH described following liver transplantation in adult transplant recipients, most occurring within the first year following transplantation. Herein, we describe two cases of HLH in liver transplant recipients that both occurred remotely following transplantation. In the first case, HLH was thought to be triggered by the development of a post-transplant lymphoproliferative disorder in a patient who was initially diagnosed with recurrent autoimmune hepatitis. In the second, it was thought to be triggered by a newly acquired human herpesvirus-8 infection. In both cases, the syndrome was not recognized until treatment for the initial putative diagnoses was unsuccessful. Despite treatment, both patients unfortunately died from multiorgan failure. HLH in the post-liver transplant setting is likely under-recognized and has a high mortality; early diagnosis and intervention may lead to improved outcomes.

A protocol for the management of hyponatremia peri-liver transplant reduces post-transplant neurological complications.

Rapid changes in serum sodium (ΔSNa) peri-liver transplant (LT) predispose to post-LT neurological complications (NC). We aimed to assess whether implementation of a protocol directed at limiting peri-LT ΔSNa reduced post-LT NC. A retrospective single-center review of adult LT recipients from 1/2016 to 10/2017 was performed. Patients with hyponatremia (SNa < 135 mEq/L) within 7 days of LT were analyzed in two eras: pre-protocol (1/2016-9/2016) and post-protocol (10/2016-10/2017). The primary outcome was the development of NC within 1 month of LT. Perioperative ΔSNa (ΔSNaPost-LT) was assessed as a secondary outcome. Among 85 and 107 patients who underwent LT pre- and post-protocol, 39 (46%) and 42 (39%) were hyponatremic within 7 days of LT, respectively. Significantly fewer patients in the post-protocol era developed NC vs. pre-protocol (7.1% vs. 25.6%, p = .02). Additionally, fewer LT recipients in the post-protocol era developed ΔSNaPost-LT ≥ 10 mEq/L (9.5% vs. 30.7%, p = .02). Intraoperatively, more patients post-protocol received hypotonic saline (33.3% vs. 2.6%, p < .01). Multivariable logistic regression revealed that transplantation in the post-protocol era was associated with significantly reduced odds (odds ratio 0.11, 95% confidence interval 0.01-0.50) of developing NC. In conclusion, the implementation of a multidisciplinary protocol aimed at reducing ΔSNa peri-LT was independently associated with a reduction in post-LT NC.

The role of endoscopy in the small intestinal transplant recipient: A review.

Intestinal transplantation (ITx) is the treatment of choice for patients with intestinal failure who have developed life-threatening complications related to long-term parenteral nutrition. Patients may also undergo ITx as part of a combined liver-intestine or multivisceral transplant for a variety of indications, most commonly intestinal failure-associated liver disease or porto-mesenteric thrombosis. Endoscopy plays a critical role in the posttransplant management of these patients, most commonly in the diagnosis and management of rejection, which occurs in up to 30-40% of patients within the first-year posttransplant. With a lack of noninvasive biomarkers to identify the presence of rejection, endoscopy and biopsy remain the gold standard for its diagnosis. Endoscopic evaluation of the graft is also important in the identification of other complications post-ITx, including posttransplant lymphoproliferative disorder, graft-versus-host disease, and enteric infections. Each patient's posttransplant anatomy may be slightly different, making endoscopy sometimes technically challenging and necessitating clear and frequent communication with the surgical team in order to help identify the highest yield approach. Herein, we review the most common pathologies found endoscopically in the post-ITx patient and describe some of the unique challenges the endoscopist faces when evaluating these complex patients.

Donor Characteristics and Regional Differences in the Utilization of HCV-Positive Donors in Liver Transplantation.

Importance: Increased utilization of hepatitis C virus (HCV)-positive liver allografts for liver transplant (LT) has been endorsed as one of several ways to combat national organ shortages. However, HCV-positive donors remain poorly characterized, and Organ Procurement and Transplantation Network regional differences in the utilization of HCV-positive liver allografts are unclear. Objective: To characterize HCV-positive donors and the allografts that come from them. Design, Setting, and Participants: In this cross-sectional study, the Scientific Registry of Transplant Recipients database was queried for all donors who underwent HCV testing from June 2015 to December 2018. Clinical and allograft characteristics were evaluated, and utilization across the United States was studied. Patients with positive or negative results for HCV antibody (Ab) and HCV nucleic acid amplification testing (NAT) were included in this study. Donors utilized for living donor transplant and pediatric (age <18 years) recipients were excluded. Main Outcomes and Measures: The primary comparison was between donors who were HCV Ab positive and those who were HCV Ab negative. Regional variations in the utilization of HCV-positive and HCV-negative donors were analyzed. Results: Of 24 500 donors utilized for LT, 1887 (7.7%) were HCV Ab positive; 64.4% of HCV Ab-positive donors were HCV NAT positive. HCV Ab-positive donors were younger (median [interquartile range] age, 35 [29-46] years vs 40 [27-54] years) and had fewer comorbidities, such as diabetes (8.3% vs 12.0%) and hypertension (25.9% vs 35.2%), compared with HCV Ab-negative donors. These findings were even more pronounced in HCV Ab-positive /NAT-positive compared with HCV Ab-positive/NAT-negative donors. Organ Procurement and Transplantation Network regions 2, 3, 10, and 11 had the highest absolute utilization of HCV Ab-positive donors, accounting for 64.4% of all HCV Ab-positive donors used in the United States. Region 1 had the highest relative utilization of HCV Ab-positive donors (18.7%). The use of HCV Ab-positive donors in some regions was associated with the rate of drug overdose, but this was not always the case. Similar utilization results were found with HCV NAT-positive donors. Conclusions and Relevance: In this cross-sectional study, HCV-positive donors were younger and healthier than utilized HCV-negative donors. Significant differences exist in the utilization of HCV-positive donors across the 11 Organ Procurement and Transplantation Network regions, which is not entirely explained by organ demand or by higher availability of HCV-positive livers as per the distribution of the opioid epidemic. Initiatives to increase the use of HCV-positive donors, particularly in regions of high organ demand, should be implemented.

Acute Liver Injury and Decompensated Cirrhosis.

Hospitalists often care for patients with liver disease, including those with acute liver injury and failure and patients with complications of decompensated cirrhosis. Acute liver failure is a true emergency, requiring intensive care and oftentimes transfer of the patient to a liver transplant center. Patients with decompensated cirrhosis have complications of portal hypertension, including variceal hemorrhage, ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. These complications increase the risk of mortality among patients with decompensated cirrhosis. Comanagement by the hospitalist with gastroenterology/hepatology can optimize care, especially for patients being considered for liver transplant evaluation.

Liver, simultaneous liver-kidney, and kidney transplantation from hepatitis C-positive donors in hepatitis C-negative recipients: A single-center study.

Transplantation of organs from hepatitis C virus (HCV)-antibody (Ab) and -nucleic acid test (NAT) positive donors into HCV-negative recipients has been proposed to expand the donor pool and shorten waiting times. Data on early single-center outcomes are lacking. Nineteen liver (LT, including seven simultaneous liver-kidney [SLKT]) and 17 kidney transplant (KT) recipients received organs from HCV (+) donors; of these, 13 were HCV NAT (+) in each group. All patients who received organs from HCV NAT (+) donors developed HCV viremia post-transplant except for 2 KT recipients. Patients were treated with a variety of direct-acting antiviral regimens, with high rates of sustained virologic response among those with at least 12 weeks of follow-up past the end of treatment: 12/13 (92%) and 8/8 (100%) among LT/SLKT, and KT recipients. Median time to treatment start was 42 days (interquartile range [IQR] 35-118 days) and 40 days (IQR 26-73) post-LT/SLKT and KT, respectively. One death occurred in a SLKT recipient unrelated to HCV or its treatment. There was no significant increase in rejection, proteinuria, or changes in immunosuppression in any group. Organs from HCV-viremic donors can be utilized for HCV-uninfected recipients with good short-term outcomes.

Expanding the donor pool: Hepatitis C, hepatitis B and human immunodeficiency virus-positive donors in liver transplantation.

Liver transplantation (LT) remains the best option for patients with end-stage liver disease but the demand for organs from deceased donors continues to outweigh the available supply. The advent of highly effective anti-viral treatments has reduced the number of patients undergoing LT for hepatitis C (HCV) and hepatitis B (HBV) related liver disease and yet the number of patients waiting for LT continues to increase, driven by an increase in the patients listed with a diagnosis of cirrhosis due to non-alcoholic steatohepatitis and alcohol-related liver disease. In addition, human immunodeficiency virus (HIV) infection, which was previously a contra-indication for LT, is no longer a fatal disease due to the effectiveness of HIV therapy and patients with HIV and liver disease are now developing indications for LT. The rising demand for LT is projected to increase further in the future, thus driving the need to investigate potential means of expanding the pool of potential donors. One mechanism for doing so is utilizing organs from donors that previously would have been discarded or used only in exceptional circumstances such as HCV-positive, HBV-positive, and HIV-positive donors. The advent of highly effective anti-viral therapy has meant that these organs can now be used with excellent outcomes in HCV, HBV or HIV infected recipients and in some cases uninfected recipients.

Endoscopic Management of Biliary Issues in the Liver Transplant Patient.

Biliary complications remain a common problem after liver transplantation (LT). The therapeutic endoscopist encounters a variety of situations in LT including strictures at the duct-to-duct biliary anastomosis, strictures elsewhere in the biliary tree caused by an ischemic injury, and bile leaks at the anastomosis or from the cut surface and stone disease. Biliary complications lead to significant morbidity and occasionally reduced graft and patient survival. Several factors increase the risk of strictures and leaks. Endoscopic intervention in experienced hands is successful in the management of biliary complications following LT and percutaneous or surgical correction should seldom be required.

Exploring opportunities to prevent cirrhosis admissions in the emergency department: A multicenter multidisciplinary survey.

Patients with cirrhosis have high admission and readmission rates, and it is estimated that a quarter are potentially preventable. Little data are available regarding nonmedical factors impacting triage decisions in this patient population. This study sought to explore such factors as well as to determine provider perspectives on low-acuity clinical presentations to the emergency department, including ascites and hepatic encephalopathy. A survey was distributed in four liver transplant centers to both emergency medicine and hepatology providers, who included attending physicians, house staff, and advanced practitioners; 196 surveys were returned (estimated response rate 50.6%). Emergency medicine providers identified several influential nonmedical factors impacting inpatient triage decisions, including input from a hepatologist (77.7%), inadequate patient access to outpatient specialty care (68.6%), and patient need for diagnostic testing for a procedure (65.6%). When given patient-based scenarios of low-acuity cases, such as ascites requiring paracentesis, only 7.0% believed patients should be hospitalized while 48.9% said these patients would be hospitalized at their institution (P < 0.0001). For mild hepatic encephalopathy, the comparable numbers were 19.5% and 55.2%, respectively (P < 0.001). Several perceived barriers were cited for this discrepancy, including limited resources both in the outpatient setting and emergency department. Most providers believed that an emergency department observation unit protocol would influence triage toward an emergency department observation unit visit instead of inpatient admission for both ascites requiring large volume paracentesis (83.2%) and mild hepatic encephalopathy (79.4%). Conclusion: Many nonmedical factors that influence inpatient triage for patients with cirrhosis could be targeted for quality improvement initiatives. In some scenarios, providers are limited by resource availability, which results in triage to an inpatient admission even when they believe this is not the most appropriate disposition. (Hepatology Communications 2018;2:237-244).

Direct-acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver-kidney transplant recipients.

Hepatitis C (HCV) remains the single most common etiology of end-stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post-transplant survival compared to non-HCV patients. We aim to assess the effectiveness and tolerance of the all-oral direct-acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post-SLKT. Thirty-four patients were studied retrospectively, composed predominantly of treatment-naïve (73.5%) non-Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post-kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.