Symptomatic Val122del mutated hereditary transthyretin amyloidosis: Need for early diagnosis and prioritization for heart and liver transplantation.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and misfolding they reassemble as insoluble fibrils (i.e. amyloid). Apart from the common Val30Met mutation there is a very heterogeneous group of non-Val30Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy. METHODS: A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed. RESULTS: Three patients needed a staged (1 patient) or simultaneous (2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac (allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months. CONCLUSIONS: This is the first report in (liver) transplant literature about the rare Val122del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.

Evaluation of Charcot Triad, Reynolds Pentad, and Tokyo Guidelines for Diagnosis of Cholangitis Secondary to Choledocholithiasis Across Patient Age Groups.

OBJECTIVE: To determine the prevalence of Charcot triad, Reynolds pentad, and Tokyo Guidelines criteria and clinical outcomes among patients with cholangitis across different age groups. PATIENTS AND METHODS: We conducted a retrospective analysis of 257 consecutive hospitalized adult patients with acute cholangitis due to endoscopic retrograde cholangiopancreatography-confirmed choledocholithiasis between January 1, 2015, and December 31, 2019. Patients were divided into 3 age groups: less than 65 years, 65 to 79 years, and 80 years or older. Symptoms, vital signs, and laboratory data on admission were collected. Outcomes included length of hospitalization, intensive care unit stay, and 3-month mortality. Nominal variables were tested with the Pearson χ2 test, and continuous variables were tested with the Wilcoxon rank sum test. RESULTS: Charcot triad decreased with older ages. In the group that was age 80 years or older, malaise was the most common symptom; 33.6% (37 of 110) presented with altered sensorium, 9.1% (10 of 110) had no pain, fever, or jaundice, and positive blood culture results were more frequent. Tokyo cholestasis criterion was present in 96.0% (247 of 257), while inflammation (considered essential for diagnosis) was present in 75.9% (195 of 257). Patients 80 years or older had significantly higher mean length of hospital stay (P<.001) and mean length of intensive care unit stay (P=.021). CONCLUSION: Compared with patients in younger age groups, patients with cholangitis who are 80 years or older are less likely to have Charcot triad, are more likely to have features of Reynolds pentad, or present with unexplained malaise. Within the Tokyo Guidelines, cholestasis should replace inflammation as an essential diagnostic criterion.

Development of Quality Measures in Cirrhosis by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

Health care delivery is increasingly evaluated according to quality measures, yet such measures are underdeveloped for cirrhosis. The Practice Metrics Committee of the American Association for the Study of Liver Diseases was charged with developing explicit process-based and outcome-based measures for adults with cirrhosis. We identified candidate measures from comprehensive reviews of the literature and input from expert clinicians and patient focus groups. We conducted an 11-member expert clinician panel and used a modified Delphi method to systematically identify a set of quality measures in cirrhosis. Among 119 candidate measures, 46 were identified as important measures to define the quality of cirrhosis care, including 26 process measures, 7 clinical outcome measures, and 13 patient-reported outcome measures. The final process measures captured care processes for ascites (n = 5), varices/bleeding (n = 7), hepatic encephalopathy (n = 4), hepatocellular cancer (HCC) screening (n = 1), liver transplantation evaluation (n = 2), and other care (n = 7). Clinical outcome measures included survival, variceal bleeding and rebleeding, early-stage HCC, liver-related hospitalization, and rehospitalization within 7 and 30 days. Patient-reported outcome measures covered physical symptoms, physical function, mental health, general function, cognition, social life, and satisfaction with care. The final list of patient-reported outcomes was validated in 79 patients with cirrhosis from nine institutions in the United States. Conclusion: We developed an explicit set of evidence-based quality measures for adult patients with cirrhosis. These measures are a tool for providers and institutions to evaluate their care quality, drive quality improvement, and deliver high-value cirrhosis care. The quality measures are intended to be applicable in any clinical care setting in which care for patients with cirrhosis is provided.

Natural History of Established and De Novo Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis.

Background: The course of inflammatory bowel disease (IBD) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is poorly understood. We describe the natural history of established IBD after LT (including risk of disease progression, colectomy, and neoplasia) and de novo IBD. Methods: In a retrospective cohort, we identified all patients with PSC who underwent LT for advanced PSC at Mayo Clinic, Rochester, Minnesota. Risk factors were identified using multivariate Cox proportional hazard analysis. Results: Three hundred seventy-three patients were identified (mean age, 47.5 ± 11.7 years; 64.9% male). Over a median (range) of 10 (5.5-17.1) years, 151 patients with PSC-IBD with an intact colon at the time of LT were studied. Post-LT, despite transplant-related immunosuppression, 56/151 (37.1%) required escalation of therapy, whereas 87 had a stable course (57.6%) and 8 patients (5.3%) improved. The 1-, 5-, and 10-year risks of progression of IBD were 4.0%, 18.5%, and 25.5%, respectively. On multivariate analysis, tacrolimus-based immunosuppression post-LT were associated with unfavorable course, and azathioprine use after LT was associated with improved course post-LT. Of 84 patients with no evidence of IBD at the time of LT, 22 (26.2%) developed de novo IBD post-LT. The 1-, 5-, and 10-year cumulative incidences of de novo IBD were 5.5%, 20.0%, and 25.4%, respectively. On univariate analysis, mycophenolate mofetil use after LT was associated with increased risk of de novo IBD, but azathioprine use after LT seemed to be protective. Conclusions: The 10-year cumulative probability of IBD flare requiring escalation of therapy after LT for PSC was 25.5%, despite immunosuppression for LT. The 10-year cumulative risk of de novo IBD after LT for PSC was 25.4%. Transplant-related immunosuppression may modify the risk of de novo IBD, with an increased risk with mycophenolate and a decreased risk with azathioprine. 10.1093/ibd/izx096_video1izx096.video15746673864001.

Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long-term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long-term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow-up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre-LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow-up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow-up. CONCLUSION: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow-up. (Hepatology 2018).

Patient-reported outcomes in cirrhosis: A scoping review of the literature.

Patients with cirrhosis seek improvement in their symptoms, functioning, quality of life, and satisfaction with the care they receive. However, these patient-reported outcomes (PROs) are not routinely measured for clinical care, research, or quality improvement. The members of the American Association for the Study of Liver Diseases Practice Metrics Committee, charged with developing quality indicators for clinical practice, performed a scoping review of PROs in cirrhosis. The aim is to synthesize a comprehensive set of PROs for inclusion into a standard patient-centered outcome set. We searched Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and the Cochrane Trial Library since inception, with final searches run between April 20 and June 1, 2017. Studies were included if they reported the construction and/or validation of a PRO instrument for patients with cirrhosis or if they assessed the clinical (case-mix) variables determining responses to established PRO scales. Eleven studies were selected that yielded 259 items specific to patients with cirrhosis. After removing duplicates, 152 unique items were isolated. These items were consolidated into seven domains: physical symptoms, physical function, mental health, general function, cognition, social life, and satisfaction with care. The seven domains included 52 subdomains (e.g., physical domain, abdominal pain subdomain). Twelve variables were identified that independently modified established PRO scales. These included clinical factors (severity of liver disease and its complications, medication burden, and comorbidities), specific PROs (cramps, pruritis), and surrogate outcome measures (falls, hospitalization). CONCLUSION: This scoping review identified and categorized a large existing set of PRO concepts that matter to patients with cirrhosis; these outcomes may now be translated into usable measures both for the assessment of the quality of cirrhosis care in clinical practice and to perform research from the patient's perspective. (Hepatology 2018;67:2375-2383).

Fontan-Associated Liver Disease: Proceedings from the American College of Cardiology Stakeholders Meeting, October 1 to 2, 2015, Washington DC.

Over the past decade, as the majority of patients with single ventricle anatomy who have undergone the Fontan operation reach adulthood, a newly recognized disease process, Fontan-associated liver disease (FALD), has emerged. FALD is an extracardiac complication that may lead to substantial comorbid disease and premature mortality. The risk factors, pathophysiology, longitudinal consequences, and therapeutic options related to FALD remain poorly defined. Although we recognize that Fontan circulatory properties are associated with extracardiac organ dysfunction, numerous gaps in our understanding of the nature of this relationship exist. Such extracardiac manifestations, in addition to other late complications of the circulation, can significantly affect quality of life and healthcare use. Therefore, to initiate a formal evaluation of FALD, the American College of Cardiology (ACC) sponsored a stakeholders meeting on October 1 to 2, 2015, in Washington, DC. The goal of the meeting was to bring together subspecialty experts in the fields of adult and pediatric hepatology, congenital cardiology (adult congenital and pediatric cardiology), heart failure/transplant, epidemiology, and cardiothoracic surgery, as well as patient advocates, patients, parents of children and young adults who have had the Fontan procedure, and research organizations and societies to discuss the current state of FALD. Topics included gaps in knowledge, optimal care, research opportunities and barriers, and sound practices to guide providers, patients, and families. This report summarizes findings from the stakeholders meeting and seeks to establish a platform for understanding and addressing FALD.

Outcomes of Patients With Familial Transthyretin Amyloidosis After Liver Transplantation.

BACKGROUND: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. RESEARCH QUESTION: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. DESIGN: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. RESULTS: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. DISCUSSION: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Risk Factors and Outcomes of De Novo Cancers (Excluding Nonmelanoma Skin Cancer) After Liver Transplantation for Primary Sclerosing Cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) may be at higher risk of malignancy after liver transplantation (LT) compared to other LT recipients. We aimed to determine the cumulative incidence of/risk factors for long-term cancer-related mortality in patients with PSC after LT. METHODS: All adult patients underwent LT for PSC without cholangiocarcinoma from 1984 to 2012, with follow-up through June 2015. We estimated cumulative incidence, risk factors, and mortality from de novo malignancies after LT. RESULTS: Two hundred ninety-three patients were identified (mean [SD] age, 47 [12] years; 63.3% males; 2.4% smoking at LT). Over a median of 11.5 years (range, 6.4-18.6 years), 64 patients (21.8%) developed 73 nonskin cancers, including 46 solid-organ cancers (renal, 11; colorectal, 11; prostate, 7; breast, 5; pancreas, 5; ovarian/endometrial/vulvar cancers, 3; and de novo cholangiocarcinoma, 4). Twenty-two patients developed hematologic malignancies (posttransplant lymphoproliferative diseases, 18; Hodgkin disease, 2; and myelodysplastic syndrome, 2). Five patients developed melanoma. The 1-, 5-, 10-, and 20-year cumulative incidences of cancer were 2.1%, 8.6%, 18.7%, and 27%, respectively. Mortality of patients with PSC who developed cancer was higher than that of patients with PSC without cancer (hazard ratio, 2.2; P < 0.01). On multivariate analysis, recipient's age and elevated pre-LT international normalized ratio were associated with increased risk of de novo (nonskin) malignancy. CONCLUSION: The 10-year cumulative risk of cancer after LT for advanced-stage PSC was 18.7%, with posttransplant lymphoproliferative diseases, colorectal cancer, and renal cell cancer being the most common. Post-LT de novo nonskin cancer decreased overall posttransplant survival. Only recipient's age and elevated international normalized ratio at LT were associated with increased nonskin cancer risk.

Surveillance for liver complications after the Fontan procedure.

The physiological consequences of the Fontan circulation impose risk for hepatic dysfunction and may culminate in hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Consensus regarding appropriate surveillance modalities to diagnose liver disease in Fontan patients is lacking, in part due to the relative lack of strong evidence and prospective studies in this patient population. The goal of this paper is to critically review the current evidence and provide recommendations for the surveillance of hepatic complications in the post-Fontan patient population.

Longterm clinical and radiological follow-up of living liver donors.

Although short-term risks of living donor hepatectomy have been well defined, little is known about the longterm impact. We aimed to perform a systematic follow-up to screen for unanticipated health consequences of liver donation. All donors who were more than 1 year from donation were invited for a systematic evaluation including physical and laboratory assessment, quality of life questionnaire, and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP). Those unable to return were offered the questionnaire and laboratory assessment at home. Out of our total of 97 donors, 45 returned for a full assessment and 23 completed labs and survey locally (total n = 68; 70%) after a median of 5.5 years (1.5-10.9 years) after donation. The only laboratory abnormality was a significant decrease in platelet count (median 198 ×10(9) /L versus 224 ×10(9) /L before donation; P < 0.001), whereas 93% of patients were still above normal limits. No late biliary strictures or other structural abnormalities were found on MRI/MRCP. Liver regeneration was complete. Spleen volume did significantly increase (median 278 cm(3) versus 230 cm(3) before donation; P < 0.001) without resulting in lowered platelets (P = 0.73). The most common complaints were persistent incisional numbness and changed bowel habits. Seven donors (11%) reported problems obtaining insurance. The vast majority (97%) would have donated again. In conclusion, longterm outcome following liver donation appears satisfactory. None of our donors have developed occult biliary strictures, failure of regeneration, abnormal liver function, or other important health consequences after a median of 5.5 years from surgery. These findings can be used when counseling potential donors in the future. Liver Transplantation 22 934-942 2016 AASLD.

Incidence and Risk Factors for Adverse Events Related to Image-Guided Liver Biopsy.

OBJECTIVE: To determine the incidence of major adverse events related to a large volume of image-guided liver biopsies performed at our institution over a 12-year period and to identify risk factors for major bleeding events. PATIENTS AND METHODS: A retrospective analysis of an internally maintained biopsy registry was performed. The analysis revealed that 6613 image-guided liver biopsies were performed in 5987 adult patients between December 7, 2001, and December 31, 2013. Liver biopsies were performed using real-time ultrasound guidance and a spring-loaded biopsy device, with rare exceptions. Adverse events considered major and included in this study were hematoma, infection, pneumothorax, hemothorax, and death. Using data from the biopsy registry, we evaluated statistically significant risk factors (P<.05) for hematoma related to image-guided liver biopsy, including coagulation status, biopsy technique, and medications. RESULTS: A total of 49 acute and delayed major adverse events (0.7%) occurred after 6613 liver biopsy events. The incidence of hematoma requiring transfusion and/or angiographic intervention was 0.5% (34 of 6613). The incidence of infection was 0.1% (8 of 6613), and that of hemothorax was 0.06% (4 of 6613). No patient (0%) incurred a pneumothorax after biopsy. Three patients (0.05%) died within 30 days of liver biopsy, 1 being directly related to biopsy. Thirty-eight of 46 major adverse events (83%) presented acutely (within 24 hours). More than 2 biopsy passes, platelets 50,000/µL or less, and female sex were statistically significant risk factors for postbiopsy hemorrhage. CONCLUSION: Image-guided liver biopsy performed by subspecialized interventionalists at a tertiary medical center is safe when the platelet count is greater than 50,000/µL. With appreciation of specific risk factors, safety outcomes of this procedure can be optimized in both general and specialized centers.

Potential Efficacy of Pegylated Interferon-α and a Nucleos(t)ide Analogue as Combination Therapy for HBeAg-Positive Chronic Hepatitis B.

BACKGROUND/AIMS: Despite the potent suppression of the hepatitis B virus with modern antiviral agents, only a minority of HBeAg-positive patients achieve hepatitis B e antigen seroconversion. We aimed to explore the potential efficacy of combination therapy consisting of pegylated interferon (p-IFN) and an oral antiviral agent in patients with HBeAgpositive chronic hepatitis B. METHODS: The treatment protocol consisted of p-IFN-α-2a at 180 µg/wk for 48 weeks, with either entecavir or tenofovir added 8 weeks after the initiation of p-IFN and continued for at least 6 months after HBe seroconversion was achieved. RESULTS: To date, 10 patients have been treated under the protocol (eight adults, mean age 36±8 years; two adolescents, aged 12 and 16 years). All eight adult patients experienced loss of HBeAg at a mean of 72.3±66.9 weeks, including six patients who also developed anti-HBe and one patient who had HBs seroconversion. Although both adolescents remain on therapy, one adolescent had HBs seroconversion without HBe seroconversion. A total of nine of our 10 patients experienced a favorable serological transition. CONCLUSIONS: The combination of p-IFN and a modern oral antiviral agent may be more effective than monotherapy with either class of agent in the treatment of HBeAg-positive chronic hepatitis B patients.

Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?

BACKGROUND: Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. METHODS: Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. RESULTS: From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease. CONCLUSIONS: Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.