Exogenous copper exposure causing clinical wilson disease in a patient with copper deficiency.

BACKGROUND: Human Swayback is a disease characterized by acquired copper deficiency which primarily manifests as myeloneuropathy. Common causes include malabsorptive disorders, gastric surgery, total parenteral nutrition and excessive zinc intake. In contrast, copper supplementation should be closely monitored as excessive doses can lead to acute intoxication and in chronic cases, cirrhosis. Copper derangements are rare, however it is important to consider them due to potential severe complications. CASE PRESENTATION: We present a middle-aged man who had been previously diagnosed with Human Swayback after presenting with various neurological symptoms. The patient was subsequently placed on copper supplementation. A decade later, he was referred to our hospital for liver transplant evaluation due to new diagnosis of decompensated end-stage liver disease after an abdominal surgery. His initial workup was suggestive of Wilson disease-subsequent ATP7B gene was negative. Ultimately, the patient underwent liver transplantation; liver explant was significant for a copper dry weight concentration of 5436 mcg/g. CONCLUSIONS: Human Swayback is a very rare copper-related disease which deserves awareness due to its potential irreversible health effects in the human body. Additionally, in patients who require copper supplementation, serial levels should be monitored to ensure adequate copper levels.

Direct-Acting Antiviral Therapy in Liver Transplant Patients With Hepatocellular Carcinoma and Hepatitis C.

Direct-acting antivirals (DAA) are highly effective for the treatment of hepatitis C (HCV), although there are limited data on the safety and efficacy of DAA therapy in hepatitis C-positive individuals awaiting liver transplantation for hepatocellular carcinoma (HCC). METHODS: We conducted a retrospective cohort study of HCV-positive patients who underwent liver transplantation for HCC at 3 liver transplant centers across the United States from 2014 to 2017 with follow-up to July 2018. Transplant recipients who received DAA before transplant were compared with those who did not (DAA naive) for posttransplant HCC recurrence rate, sustained virological response (SVR), allograft failure, and death using Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: A total of 171 HCV-HCC transplant recipients (99 pretransplant DAA; 72 DAA naive controls) were included, with a median follow-up of 24 months. The overall posttransplant HCC recurrence rate was 9% (15/171). Pretransplant DAA was not associated with HCC recurrence (5% versus 14%; P = 0.07), graft failure (7% versus 3%; P = 0.21), or death (12% versus 19%; P = 0.19) as compared with DAA naive patients. SVR rates were significantly lower (P < 0.01) with pretransplant DAA (75%, 39/52) than posttransplant DAA (97%, 59/61) therapies. Those who received pretransplant DAA and those who did not were not statistically different in age, gender, alpha fetal protein levels, model for end-stage liver disease scores, or transplant wait time. CONCLUSIONS: Pretransplant DAA for HCV was not associated with an increased risk of posttransplant HCC recurrence, though pretransplant DAA had lower efficacy than posttransplant DAA in HCV-HCC transplant recipients.

Outcomes following liver transplantation from HCV-seropositive donors to HCV-seronegative recipients.

BACKGROUND & AIMS: Grafts from HCV-seropositive donors can now be considered for liver transplantation (LT) owing to the advent of direct-acting antivirals (DAAs). We report on our multicenter experience of transplanting liver grafts from HCV-seropositive donors into HCV-seronegative recipients. METHODS: This is a prospective multicenter observational study evaluating outcomes in adult HCV-seronegative LT recipients who received grafts from HCV-seropositive donors in 3 US centers. RESULTS: From 01/18 to 09/19, 34 HCV-seronegative LT recipients received grafts from HCV-seropositive donors (20 HCV-viremic and 14 non-viremic). Seven grafts were from cardiac-dead donors. The median MELD-Na score at allocation was 20. Six recipients underwent simultaneous liver-kidney transplant and 4 repeat LT. No recipient of an HCV-non-viremic graft developed HCV viremia. All 20 patients who received HCV-viremic grafts had HCV viremia confirmed within 3 days after LT. DAA treatment was started at a median of 27.5 days after LT. Median pre-treatment viral load was 723,000 IU/ml. All (20/20) patients completed treatment and achieved SVR12. Treatment was well tolerated with minimal adverse events. One patient developed HCV-related acute membranous nephropathy that resulted in end-stage kidney disease, despite achieving viral clearance. This patient died due to presumed infectious complications. A recipient of an HCV-non-viremic graft died with acute myocardial infarction 610 days post LT. CONCLUSIONS: Transplantation of liver grafts from HCV-seropositive donors into HCV-seronegative recipients resulted in excellent short-term outcomes. Antiviral therapy was effective and well tolerated. Careful ongoing assessment and prompt initiation of antiviral therapy are recommended. Longer term follow-up in carefully conducted clinical trials is still required to confirm these results. LAY SUMMARY: This study shows that livers from donors exposed to HCV expand the donor pool and can be used safely in patients who are seronegative for hepatitis C infection. Treatment, initiated early post transplantation, is effective and resulted in cure in all patients.

Hepatitis C Testing and Liver Fibrosis Predictors in the Birth Cohort of a Primary Care Practice.

OBJECTIVE: To determine the prevalence of and risk factors for advanced fibrosis in patients born from 1945 through 1965 (birth cohort) who underwent testing for hepatitis C virus (HCV). PATIENTS AND METHODS: Data were extracted from the electronic health record of all patients receiving primary care at a single academic institution who underwent HCV testing between September 8, 2010, and March 5, 2018. The birth cohort patients were the primary focus of the study. Fibrosis 4 (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI) scores were calculated to screen for fibrosis. RESULTS: During the study period, 7097 birth cohort patients had HCV antibody testing, 3462 (48.8%) of whom were men, 6435 (91.0%) were white, 1028 (14.5%) had diabetes mellitus, 2,034 (36.5%) had an alanine aminotransferase (ALT) level greater than 30 U/L, and 2,396 (34.2%) had body mass index of 30 kg/m2 or greater. Hepatitis C virus antibody was present in 124 (1.7%), 33 (26.6%) of whom had HCV viremia. Estimated prevalence of METAVIR [Meta-analysis of Histological Data in Viral Hepatitis] stage 4 fibrosis was 4.1% (180 of 4433) by a FIB-4 score of 3.25 or greater and 4.3% (204 of 4763) by an APRI score greater than 1.0. The odds ratio (OR) for fibrosis, determined by APRI, was significant for HCV RNA positivity (OR, 15.98; 95% CI, 7.23-35.32; P<.001), diabetes mellitus (OR, 1.98; 95% CI, 1.40-2.79; P<.001), and ALT value greater than 30 U/L (OR, 15.07 U/L; 95% CI, 9.27-24.52 U/L; P<.001) but not for body mass index of 30 kg/m2 or greater (OR, 0.77; 95% CI, 0.56-1.06; P=.11). CONCLUSION: Hepatitis C virus viremia, diabetes mellitus, and elevated ALT levels were associated with increased odds for development of fibrosis. In addition to HCV testing, diabetes mellitus and elevated ALT level are potential parameters to use for recommending noninvasive testing for fibrosis.

Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

BACKGROUND: Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. AIM: To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. METHODS: This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. RESULTS: Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. CONCLUSION: Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. CONCLUSION: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV.

Explanted liver inflammatory grade predicts fibrosis progression in hepatitis C recurrence.

UNLABELLED: Factors present prior to liver transplantation (LT) that predict fibrosis progression in recurrent hepatitis C infection (HCV) after LT would be important to identify. This study sought to determine if histologic grade of HCV in the explant predicts fibrosis progression in recurrent HCV. The clinical and histologic data of all 159 patients undergoing their first LT for HCV at our center from 1998 to 2001 were retrospectively reviewed with follow-up through June 2008. Twenty-five cases were excluded for: non-HCV-related graft loss <90 days (19), recidivism (4), or unavailable explant or follow-up biopsies (2). A single pathologist scored (Ishak) explants in a blinded fashion. Patients were grouped by explant inflammatory grade ≤ 4 (group1) and >4 (group 2). Prospectively scored liver biopsies (protocol months 1 and 4, annually, and as indicated clinically) were reviewed for development of advanced fibrosis (bridging or cirrhosis). Cox proportional hazard regression was used to analyze the association of explant grade, donor, viral and LT factors with progression to advanced fibrosis. The groups were well-matched for patient, viral, donor, and transplant factors. Five-year advanced fibrosis-free survival in group 1 versus group 2 was 63% versus 28%, P < 0.001. Explant grade >4 was associated with increased HCV-related graft loss at 1 (6% versus 3%) and 5 (36% versus 14%) years post-LT (P = 0.003). On univariate and multivariate Cox regression analysis, predictors of advanced fibrosis were explant grade >4 (hazard ratio [HR] = 3.3, 95% confidence interval [CI] = 1.9-5.6, P < 0.001) donor age >50 (HR = 3.3, 95% CI = 1.9-5.7, P < 0.001) and viral load at LT of >158,730 IU/mL (HR = 1.8, 95% CI = 1.05-3.1, P = 0.03). CONCLUSION: Explant histologic grade can identify patients requiring more aggressive monitoring and intervention for HCV recurrence post-LT.

Improving graft survival for patients undergoing liver transplantation.

Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998-2002) and Era 2 (2003-2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3-65.9) vs. 75.4 (68.9-81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non-HCV patients up to three yr. The change in management of donor organs into HCV and non-HCV patients likely contributed to this outcome.

Long term survival and complications after liver transplantation in patients with chronic hepatitis B.

BACKGROUND: Following introduction of effective antiviral prophylaxis, recurrent hepatitis B after liver transplantation (LT) has become a rare event. MATERIAL/METHODS: From 1998 to 2001, 402 patients underwent 467 LTs at our center including 24 individuals (28 LTs) with chronic hepatitis B. All patients received HBIg prophylaxis; 23 in combination with lamivudine and one (YMDD mutant) received adefovir. RESULTS: Eleven patients (46%) had HCC (five outside the Milan criteria); only one died from tumor recurrence four years post LT. The one-year graft and patient survival were 87% and 92%, respectively. Currently 19 patients (79%) are alive with well functioning grafts (minimum follow up of >7 years). No patient developed recurrent hepatitis B; 12 currently receive lamivudine/HBIg, 3 lamivudine monotherapy, 3 discontinued antivirals. Follow up liver biopsies showed minimally active or no active hepatitis and negative HBV immunostains in all patients. Long term comorbid conditions included hypertension (77%), chronic renal failure (50%), diabetes mellitus (77%), hyperlipidemia (36%), obesity (55%), malignancies (37%) and neuropsychiatric disorders (55%). During the study period, 24 individuals (6%) were transplanted for chronic hepatitis B as opposed to only 38 individuals (3.3%) from 2002 to 6/2008 (1298 LTs in 1162 patients). CONCLUSIONS: LT for chronic HBV produced excellent long term results despite inclusion of patients with HCC outside the Milan criteria. Long term medical complications must be considered. Indication for LT for chronic HBV is declining but long term development of resistance remains a matter of concern.

HCV recurrence in HIV-infected patients after liver transplant.

Patients coinfected with hepatitis C virus (HCV) and HIV undergoing liver transplantation (LT) are at risk of early, aggressive HCV recurrence. This study investigates the use of frequent protocol-driven biopsies to identify HCV recurrence post LT in coinfected patients. Five consecutive HIV/HCV-coinfected patients underwent LT. Liver biopsies were obtained post LT at 1 hour; days 7, 120, and 365; then annually; and as clinically indicated. Stage 2 (Ishak) or higher fibrosis occurred in 4 of the 5 patients by 60, 120, 270, and 365 days. Two patients died of HCV recurrence and liver failure at 6 and 35 months post LT. Three patients survived more than 4 years after LT, 2 having sustained virologic responses to anti-HCV treatment. Another has histologic recurrence not responding to treatment. Hepatitis C virus recurrence can be rapid and aggressive after LT in HIV-coinfected patients. Serial biopsies identify recurrence early, allowing for prompt initiation of treatment.

Outcomes after liver transplant in patients aged 70 years or older compared with those younger than 60 years.

OBJECTIVE: To compare mortality, graft loss, and postoperative complications after liver transplant in older patients (> or =70 years) with those in younger patients (<60 years). PATIENTS AND METHODS: Outcomes for 42 patients aged 70 years or older who underwent liver transplant were compared with those of 42 matched controls younger than 60 years. All patients underwent transplants between March 19, 1998, and May 7, 2004. Information was collected on patient characteristics, comorbid conditions, laboratory results, donor and operative variables, medical and surgical complications, and mortality and graft loss. RESULTS: Preoperative characteristics were similar across age groups, except for creatinine (P=.01) and serum albumin (P=.03) values, which were higher in older patients, and an earlier year of transplant in younger patients (P<.001). Intraoperatively, older patients required more erythrocyte transfusions (P=.04) and more intraoperative fluids (P=.001) than did younger patients. Postoperatively, bilirubin level (P=.007) and international normalized ratios (P=.01) were lower in older patients, whereas albumin level was higher (P<.001). The median follow-up was 5.1 years (range, 0.1-8.5 years). Compared with younger patients, older patients were not at an increased risk of death (relative risk, 1.00; 95% confidence interval, 0.43-2.31; P>.99) or graft loss (relative risk, 1.17; 95% confidence interval, 0.54-2.52; P=.70). The frequency of other complications did not differ significantly between age groups, although older patients had more cardiovascular complications. CONCLUSION: Five-year mortality and graft loss in older recipients were comparable with those in younger recipients, suggesting that age alone should not exclude older patients from liver transplant.

Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.

Liver transplantation may occasionally be indicated in patients with unique clinical scenarios. Little is known regarding the outcomes of patients who have had a pancreatic resection prior to, in combination with, or after liver transplantation. A retrospective review of all patients undergoing liver transplantation from March 1998 to March 2008 identified 17 patients who also underwent pancreatic resection. An additional literature review was performed. Five underwent pancreatic resection prior to liver transplantation (1.7, 3.6, 3.8, 6.8, and 8.1 years), another 9 underwent pancreatic resection together with liver transplantation, and 3 underwent pancreatic resection after liver transplantation (2.2, 2.6, and 3.8 years). Indications for pancreatic resection included cholangiocarcinoma (n = 6), neuroendocrine tumor (n = 5), pancreatic cancer (n = 2), gastrointestinal stromal tumor (n = 1), periampullary adenocarcinoma (n = 1), duodenal adenomas (n = 1), and benign pancreatic mass (n = 1). Indications for liver transplantation were metastatic neuroendocrine tumor disease (n = 5), primary sclerosing cholangitis (n = 5), hepatitis C virus (n = 2), metastatic gastrointestinal stromal tumor (n = 1), Klatskin tumor (n = 1), alcohol cirrhosis (n = 1), alpha-1 antitrypsin deficiency (n = 1), and chemotherapy-induced cirrhosis (n = 1). One patient died intraoperatively, 7 patients died of tumor recurrence, 2 patients died from transplant complications, and 7 patients are still alive. Pancreatic resection-related complications included 4 pancreatic fistulas. A literature review confirmed liver transplantation/pancreatic resection-related complications. In conclusion, liver transplantation and pancreatic resection remain uncommon, and a good outcome can be achieved. Recurrence of malignant disease is the main factor limiting survival, and specific morbidity may be related to pancreatic resection and liver transplantation.

Treatment modalities for hypersplenism in liver transplant recipients with recurrent hepatitis C.

Hepatitis C is the most common indication for orthotopic liver transplantation in the United States. Unfortunately, hepatitis C recurs universally in the transplanted liver and is the major cause of decreased graft and patient survival. The combination therapy of interferon and ribavirin has been shown to be the most effective therapy for recurrent hepatitis C. However, pre- and post-transplant hypersplenism often precludes patients from receiving the antiviral therapy. Splenectomy and partial splenic embolization are the two invasive modalities that can correct the cytopenia associated with hypersplenism. In this report we review the two treatment options, their associated outcomes and complications.

Liver transplantation using controlled donation after cardiac death donors: an analysis of a large single-center experience.

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow-up was 48 months. The 1-, 3-, and 5-year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1-, 3-, and 5-year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long-term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts.

Liver transplantation using young pediatric donor grafts in adults with hepatitis C infection.

BACKGROUND: The impact of using grafts from donor's age less than or equal to 13 years on adult hepatitis C virus (HCV) recipients in terms of survival and HCV recurrence is undefined. To determine if adults undergoing liver transplantation for HCV who receive a graft from a donor age less than or equal to 13 years have similar outcomes to recipients of organs from 18- to 35-year-old donors. METHODS: Records from adult HCV patients undergoing liver transplantation between April 1998 and April 2004 who received whole grafts from non-HCV donors less than 35 years old after brain death were reviewed. Patients with donor age less than or equal to 13 years (group 1) and 18 to 35 years (group 2) were compared for patient and graft survival, allograft rejection, biliary complications, and HCV recurrence. RESULTS: Fifty-one HCV patients were analyzed. The two groups were similar except that group 1 donors and recipients were smaller in size. One year patient and graft survival for groups 1 vs. 2 were 93% vs. 94% and 93% vs. 83%, respectively (P=NS). Biliary complications, HCV recurrence, and advanced fibrosis free survival were not significantly different. CONCLUSION: Whole liver grafts from donors age less than or equal to 13 years can potentially be used in selected size-matched adult HCV patients in the absence of an acceptable pediatric recipient.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non-heart-beating or donation after cardiac death (DCD) are encouraging. However, long-term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow-up >4.5 years. During 1998-2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart-beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non-function and biliary complications as compared with SCD and ECD. The overall one-, two-, and five-yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long-term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.