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.

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.

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).

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.

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.

Interleukin-28B and fibrosing cholestatic hepatitis in posttransplant hepatitis C: a case-control study and literature review.

Chronic hepatitis C (CHC)-related cirrhosis is the leading indication for liver transplantation (LT). However, the recurrence of a hepatitis C virus (HCV) infection after transplantation is universal and is associated with worse outcomes. Fibrosing cholestatic hepatitis (FCH) is a particularly severe manifestation of a recurrent HCV infection and frequently results in graft failure and death. The identification of risk factors for FCH is important but has been limited by the low frequency of FCH. The interleukin-28B (IL-28B) genotype is important in an HCV infection: it is related to the clinical severity of an acute infection and may play a role in the development of FCH as well. Two hundred seventy-two consecutive LT cases for CHC were studied at a single institution. Consensus criteria were used to define an FCH cohort. The remainder of the study population served as a control group. The IL-28B genotype (at the rs12979860 locus) from both the donor and the recipient was determined, and other clinically relevant data were tabulated. A nonparametric statistical analysis was performed. Twelve cases of FCH were identified, and they were compared to a control group of 260 LT cases without FCH. A detailed analysis of clinical characteristics, including treatment responses and outcomes, was tabulated. FCH was associated with the earlier recurrence of HCV infections, higher HCV viral loads, and lower levels of immunosuppressive medications. There was a nonsignificant increase in recipient IL-28B non-CC genotypes in cases developing FCH. In conclusion, a high HCV viral load and earlier recurrence were identified as risk factors for FCH. It is still unclear what role immunosuppression plays in the pathogenesis of FCH and whether IL-28B polymorphisms constitute a risk factor. Collaborative studies with larger numbers of study subjects are needed in order to define these issues.

Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis.

Ultrasound-based transient elastography (TE) is a promising noninvasive alternative to liver biopsy for the detection of hepatic fibrosis due to recurrent hepatitis C virus (HCV) after liver transplantation (LT). However, its overall test performance in various settings remains unknown. The aim of this study was to perform a systematic review and diagnostic accuracy meta-analysis of studies comparing ultrasound-based TE to liver biopsy for the detection of hepatic fibrosis due to a recurrent HCV infection after LT. Electronic and manual bibliographic searches (including scientific abstracts) were performed to identify potential studies. A meta-analysis was conducted to generate pooled estimates of the sensitivity values, specificity values, likelihood ratios, and diagnostic odds ratios of individual studies. The extent of the heterogeneity and the reasons for it were assessed. Six fully published studies were identified for analysis. Five studies that evaluated significant fibrosis were identified. Among these studies, the pooled estimates were 83% for sensitivity [95% confidence interval (CI) = 77%-88%], 83% for specificity (95% CI = 77%-88%), 4.95 for the positive likelihood ratio (95% CI = 3.4-7.2), 0.17 for the negative likelihood ratio (95% CI = 0.09-0.35), and 30.5 for the diagnostic odds ratio (95% CI = 12.8-72.4). For the 5 studies that assessed cirrhosis, the pooled estimates were 98% for sensitivity (95% CI = 90%-100%), 84% for specificity (95% CI = 80%-88%), 7 for the positive likelihood ratio (95% CI = 2.8-17.3), 0.06 for the negative likelihood ratio (95% CI = 0.02-0.19), and 130 for the diagnostic odds ratio (95% CI = 36.5-462.1). A diagnostic threshold (or cutoff value) bias was identified as an important cause of heterogeneity for the pooled results of both patient groups. In conclusion, ultrasound-based TE has excellent diagnostic accuracy for identifying cirrhosis due to a recurrent HCV infection after LT. The detection of significant fibrosis is more accurate for these patients versus patients whose native liver is chronically infected with HCV.

Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation.

Drug-induced liver injury (DILI) is increasingly being recognized as a common cause of acute hepatitis. The clinical impact of DILI after liver transplantation (LT) is not known. The aim of this study was to describe the frequency, clinical presentation, and outcomes of DILI in LT recipients. LT recipients with possible DILI were identified with electronic pathology records and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Twenty-nine of 1689 LT recipients (1.7%) were identified with DILI. The mean age was 52 years, and 52% were women. The major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). The severity of DILI was mild or moderate in 92% of the cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at the time of diagnosis. The mean biochemistry values were as follows: alanine aminotransferase, 204 ± 263 U/L; aspartate aminotransferase, 108 ± 237 U/L; alkaline phosphatase, 469 ± 689 U/L; and total bilirubin, 1.9 ± 10.3 mg/dL. The median duration of medication use until the diagnosis of DILI was 57 days, and the major agent classes were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%). Trimethoprim-sulfamethoxazole was the most common implicated agent (n = 11). Serum liver enzymes improved within a median time of 34 days (range = 5-246 days) after drug withdrawal. Hepatic retransplantation or death did not occur. Among the 50 cases with possible DILI explained by other causes, 13 individuals (26%) had no alternative diagnosis despite histological findings compatible with DILI. In conclusion, DILI is a rare yet underrecognized event among LT recipients. The majority of cases are not clinically severe, and they resolve after drug cessation without hepatic retransplantation or death.

Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.

UNLABELLED: Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.

Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: a proteomic signature validated by enzyme-linked immunosorbent assay.

The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme-linked immunosorbent assay (ELISA)-based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high-abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography-tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA-based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed.

Treatment of hepatitis C-mediated glomerular disease.

Chronic kidney disease (CKD) is becoming a major public health issue worldwide, mainly due to the increasing prevalence of hypertension, diabetes and aging population. Chronic hepatitis C virus (HCV) infection commonly involves the kidneys, can be a cause of CKD, and significantly impacts morbidity and mortality in these patients. Prompt recognition and knowledge of how to best manage these patients are essential in order to have a successful renal outcome. Patients with HCV and kidney involvement can often be managed with a specific combination of antiviral drugs, immunosuppressants, plasmapheresis, and newer monoclonal antibodies. However, no large randomized controlled trials have been conducted in this patient population, optimal management of HCV-mediated kidney diseases is not well defined, and treatment itself can be associated with significant toxicity in patients with CKD. This article reviews the recent literature, discusses the limitations of current therapies, as well as toxicity associated with treatment, and suggests future areas for research.

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.

Impact of depressive symptoms and their treatment on completing antiviral treatment in patients with chronic hepatitis C.

BACKGROUND/GOALS: Interferon-induced depression affects 20% to 40% of patients treated for chronic hepatitis C virus (HCV). The aim of our study was to examine the influence of antidepressant treatment and whether this improves the likelihood of completing therapy. METHODS: One hundred randomly selected patients with chronic HCV undergoing antiviral therapy at a single center were identified. Patients were categorized as Group 1 (no depressive symptoms during treatment), Group 2 (depressive symptoms without antidepressant therapy), Group 3 (preexisting or prophylactic antidepressants before therapy), and Group 4 (on-demand antidepressant therapy for depressive symptoms). RESULTS: Mean age was 49 years with 72% men. Genotype 1 infection was noted in 65% of patients, and the mean pretreatment HCV RNA level was 1,419,919 IU. Patients without earlier depression receiving on-demand therapy (Group 4) had a significantly higher rate of antiviral treatment completion compared with Group 3 (92% vs. 52%; P=0.01). Patients in groups 1 and 4 with no baseline history of depression had similar treatment completion rates. No significant relationship between the use of antidepressant therapy, SVR or premature cessation of therapy was observed. CONCLUSIONS: Preexisting depression was associated with lower antiviral treatment completion rates despite the use of prophylactic antidepressant therapy. In patients without preexisting depression, however, on-demand antidepressant therapy for depressive symptoms was strongly associated with the highest treatment completion rates in the cohort. Antidepressant therapy for new or worsening depressive symptoms independent of baseline depression status did not affect the probability of achieving SVR or stopping treatment prematurely.

The prevalence and natural history of untreated isolated central perivenulitis in adult allograft livers.

Central perivenulitis (CP) in the allograft liver can be associated with portal-based acute cellular rejection and autoimmune hepatitis or can occur in isolation (isolated CP). Although several studies have demonstrated the significance of CP, the prevalence and natural history of untreated isolated CP have not been well studied. We examined 100 adult allograft liver recipients who had long-term follow-up, had routine protocol biopsies, and received no treatment for isolated CP. Isolated CP was identified in 28 (28%) patients. It occurred late at a mean of 658 days. Interestingly, patients with late isolated CP (defined as >3 months posttransplant) usually manifested only mildly to modestly elevated liver function tests. However, late isolated CP was associated with prior and subsequent allograft complications. Nearly all (94%) cases of late isolated CP occurred in patients who had early episodes of CP and/or acute cellular rejection. Of 13 patients who developed adverse outcomes in their allografts (zone 3 fibrosis in 10, de novo autoimmune hepatitis in 3, and ductopenia in 3), all experienced episodes of prior CP, and 12 (92%) had late CP; 1 patient required retransplant for chronic rejection, but all were alive within the last year. In summary, "transplant-associated" isolated CP occurs in 28% of adult patients, early CP is predictive of late CP, and late CP (often present as isolated CP) is associated with long-term liver injury in some patients.