Ahmet Gurakar

Cadmium Exposure and Liver Disease among US Adults

BackgroundEffects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population.MethodsWe analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988–1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study.ResultsThe cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83xa0μg/g for men and women, respectively (Pu2009<u20090.001). After multivariate adjustment for other factors including smoking, the odds ratios [95xa0% confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95xa0% CI, 1.64–3.00), 1.30 (95xa0% CI, 1.01–1.68) and 1.95 (95xa0% CI, 1.11–3.41) for men and 1.26 (95xa0% CI, 1.01–1.57), 1.11 (95xa0% CI, 0.88–1.41) and 1.34 (95xa0% CI, 0.72–2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95xa0% CI, 1.12–10.47) and 1.25 (95xa0% CI, 0.37–4.27).ConclusionsEnvironmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality.

Delayed and Unsuccessful Endoscopic Retrograde Cholangiopancreatography Are Associated With Worse Outcomes in Patients With Acute Cholangitis

BACKGROUND & AIMSnAcute ascending cholangitis usually is treated with antibiotics, and biliary drainage is treated by endoscopic retrograde cholangiopancreatography (ERCP). We investigated the effects of the timing of ERCP on outcomes of patients with acute cholangitis factors that predict prolonged hospital stays, increased costs of hospitalization, and composite clinical outcomes (death, persistent organ failure, and admission to the intensive care unit).nnnMETHODSnWe performed a retrospective analysis of data from 90 patients (mean age, 60 y; 48% female) admitted to Johns Hopkins Hospital from January 1994 to June 2010 who were diagnosed with acute cholangitis and underwent ERCP. A delayed ERCP was defined as one performed more than 72 hours after admission. Electronic and paper medical records were reviewed, and relevant data were abstracted.nnnRESULTSnERCP was performed successfully in 92% of the patients, at a mean time period of 38 hours after admission (14% of ERCPs were delayed). Factors that were associated independently with prolonged length of hospital stay (top 10%) included unsuccessful ERCP (odds ratio [OR], 52.5; P = .002) and delayed ERCP (OR, 19.8; P = .008). Factors associated with increased hospitalization cost (top 10%) included unsuccessful ERCP (OR, 33.8; P = .004) and delayed ERCP (OR, 11.3; P = .03). Factors associated with composite clinical outcome included age (OR, 1.1; P = .01), total level of bilirubin (OR, 1.36; P = .002), and delayed ERCP (OR, 7.8; P = .04).nnnCONCLUSIONSnDelayed and failed ERCP are associated with prolonged hospital stays and increased costs of hospitalization. Delayed ERCP is associated with composite clinical outcome (death, persistent organ failure, and/or intensive care unit stay). Older age and higher levels of bilirubin also are associated with patients composite end point.

Diffuse infiltrative hepatocellular carcinoma: assessment of presentation, treatment, and outcomes.

BackgroundData on infiltrating hepatocellular carcinoma (HCC) are limited. We sought to define treatment and outcome of patients treated with infiltrating HCC compared with patients who had advanced multifocal HCC.MethodsBetween January 2000 and July 2011, a total of 147 patients with advanced HCC were identified from the Johns Hopkins Hospital database (infiltrative, nxa0=xa075; multifocal, nxa0=xa072). Clinicopathologic data were compared by HCC subtype.ResultsPatients with infiltrating HCC had higher alfa-fetoprotein levels (median infiltrative, 326.5xa0ng/mL vs. multifocal, 27.0xa0ng/mL) and larger tumors (median size, infiltrating, 9.2xa0cm vs. multifocal, 5.5xa0cm) (Pxa0<xa00.05). Imaging failed to reveal a discrete lesion in 42.7xa0% of patients with infiltrating HCC. Most infiltrating HCC lesions presented as hypointense on T1-weighted images (55.7xa0%) and hyperintense on T2-weighted images (80.3xa0%). Among patients with infiltrating HCC, most (64.0xa0%) were treated with intra-arterial therapy (IAT), and periprocedural morality was 2.7xa0%. Patients treated with IAT had longer survival versus patients receiving best support care (median survival, IAT, 12xa0months vs. best supportive care, 3xa0months; Pxa0=xa00.001). Survival after IAT was similar among patients treated with infiltrating HCC versus multifocal HCC (hazard ratio 1.29, 95xa0% confidence interval 0.82–2.03; Pxa0=xa00.27). Among infiltrating HCC patients, pretreatment bilirubin >2xa0mg/dL and alfa-fetoprotein >400xa0ng/mL were associated with worse survival after IAT (Pxa0<xa00.05). Patients with progressive disease after IAT had higher risk of death versus patients who had stable/responsive disease (hazard ratio 3.53, 95xa0% confidence interval 1.49–8.37; Pxa0=xa00.004).ConclusionsPatients with infiltrative HCC often present without a discrete lesion on imaging. IAT for infiltrative HCC was safe and was associated with survival comparable to IAT outcomes for patients with multifocal HCC. Infiltrative HCC morphology is not a contraindication to IAT therapy in select patients.

Three-year Results of a Pilot Program in Early Liver Transplantation for Severe Alcoholic Hepatitis.

Objective: To examine our pilot to transplant selected patients with acute alcoholic hepatitis, initiated in October 2012. Background: Six months of alcohol abstinence is typically required before liver transplant. A Franco-Belgian protocol showed that early transplant in severe alcoholic hepatitis could improve survival with low incidence of alcohol relapse. Application of this controversial indication is growing despite unclear generalizability. Methods: Data was collected on all patients with alcohol-related liver disease since initiation of the pilot through June 2015. Patients were stratified into two groups: severe alcoholic hepatitis as first liver decompensation (Group 1), alcoholic cirrhosis with ≥6 months abstinence (Group 2). Alcohol relapse was defined as any evidence of alcohol consumption after transplant, which was assessed for harmful patterns of binge or frequent drinking. Results: Forty-three patients underwent liver transplant, including 17 patients in Group 1. Six-month survival was 100% versus 89% for Groups 1 and 2, respectively (P = 0.27). Alcohol relapse was similar in Group 1 versus Group 2: 23.5% versus 29.2% (P > 0.99). Harmful drinking was higher in Group 1 versus Group 2, despite lack of statistical significance: 23.5% versus 11.5% (P = 0.42). Conclusions: In this pilot with carefully selected patients, early liver transplant provided excellent short-term survival, and similar rates of alcohol relapse compared with patients with 6 months of abstinence. Harmful patterns of relapse remain challenging in this population, highlighting the need for validated models to predict alcohol relapse, and need for extreme caution in selecting patients for this exceptional indication. Larger prospective studies and longer follow up are necessary.

Changes in Utilization and Discard of Hepatitis C–Infected Donor Livers in the Recent Era

The impact of interferon (IFN)‐free direct‐acting antiviral (DAA) hepatitis C virus (HCV) treatments on utilization and outcomes associated with HCV‐positive deceased donor liver transplantation (DDLT) is largely unknown. Using the Scientific Registry of Transplant Recipients, we identified 25 566 HCV‐positive DDLT recipients from 2005 to 2015 and compared practices according to the introduction of DAA therapies using modified Poisson regression. The proportion of HCV‐positive recipients who received HCV‐positive livers increased from 6.9% in 2010 to 16.9% in 2015. HCV‐positive recipients were 61% more likely to receive an HCV‐positive liver after 2010 (early DAA/IFN era) (aRR:1.451.611.79, p < 0.001) and almost three times more likely to receive one after 2013 (IFN‐free DAA era) (aRR:2.582.853.16, p < 0.001). Compared to HCV‐negative livers, HCV‐positive livers were 3 times more likely to be discarded from 2005 to 2010 (aRR:2.692.993.34, p < 0.001), 2.2 times more likely after 2010 (aRR:1.802.162.58, p < 0.001) and 1.7 times more likely after 2013 (aRR:1.371.682.04, p < 0.001). Donor HCV status was not associated with increased risk of all‐cause graft loss (p = 0.1), and this did not change over time (p = 0.8). Use of HCV‐positive livers has increased dramatically, coinciding with the advent of DAAs. However, the discard rate remains nearly double that of HCV‐negative livers. Further optimization of HCV‐positive liver utilization is necessary to improve access for all candidates.

Continuous Cerebral Blood Flow Autoregulation Monitoring in Patients Undergoing Liver Transplantation

BackgroundClinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively.MethodsWe performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and NIRS. A continuous Pearson’s correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity and between MAP and NIRS data, rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30xa0min of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mxxa0≥xa00.4.ResultsAutoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD scorexa0>15 (pxa0=xa00.015) and postoperative seizures or stroke (pxa0<xa00.0001). Analysis of Mx categorized in 5xa0mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased toxa0≥xa00.4) ranged between 40 and 85xa0mmHg. Average Mx and average COx were significantly correlated (pxa0=xa00.0029). The relationship between COx and Mx remained when only patients with bilirubinxa0>1.2xa0mg/dL were evaluated (pxa0=xa00.0419). There was no correlation between COx and baseline bilirubin (pxa0=xa00.2562) but MELD score and COx were correlated (pxa0=xa00.0458). Average COx was higher for patients with a MELD scorexa0>15 (pxa0=xa00.073) and for patients with a neurologic complication than for patients without neurologic complications (pxa0=xa00.0245).ConclusionsThese results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.

Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review

Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.

Impact of a single-day multidisciplinary clinic on the management of patients with liver tumours.

PURPOSEnMultidisciplinary cancer clinics may improve patient care. We examined how a single-day multidisciplinary liver clinic (mdlc) affected care recommendations for patients compared with the recommendations provided before presentation to the mdlc.nnnMETHODSnWe analyzed the demographic and clinicopathologic data of 343 patients assessed in the Johns Hopkins Liver Tumor Center from 2009 to 2012, comparing imaging and pathology interpretation, diagnosis, and management plan between the outside provider (osp) and the mdlc.nnnRESULTSnMost patients were white (n = 259, 76%); median age was 60 years; and 146 were women (43%). Outside providers referred 182 patients (53%); the rest were self-referred. Patients travelled median of 83.4 miles (interquartile range: 42.7-247 miles). Most had already undergone imaging (n = 338, 99%) and biopsy (n = 194, 57%) at the osp, and a formal management plan had been formulated for about half (n = 168, 49%). Alterations in the interpretation of imaging occurred for 49 patients (18%) and of biopsy for 14 patients (10%). Referral to the mdlc resulted in a change of diagnosis in 26 patients (8%), of management plan in 70 patients (42%), and of tumour resectability in 7 patients (5%). Roughly half the patients (n = 174, 51%) returned for a follow-up, and 154 of the returnees (89%) received treatment, primarily intraarterial therapy (n = 88, 57%), systemic chemotherapy (n = 60, 39%), or liver resection (n = 32, 21%). Enrollment in a clinical trial was proposed to 34 patients (10%), and 21 of the 34 (62%) were accrued.nnnCONCLUSIONSnPatient assessment by our multidisciplinary liver clinic had a significant impact on management, resulting in alterations to imaging and pathology interpretation, diagnosis, and management plan. The mdlc is an effective and convenient means of delivering expert opinion about the diagnosis and management of liver tumours.

Liver transplant patients have a risk of progression similar to that of sporadic patients with branch duct intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can progress from low‐ to high‐grade dysplasia to invasive adenocarcinoma. The management of patients with IPMNs is dependent on their risk of malignant progression, with surgical resection recommended for patients with branch‐duct IPMN (BD‐IPMN) who develop high‐risk features. There is increasing evidence that liver transplant (LT) patients are at increased risk of extrahepatic malignancy. However, there are few data regarding the risk of progression of BD‐IPMNs in LT recipients. The aim of this study was to determine whether LT recipients with BD‐IPMNs are at higher risk of developing high‐risk features than patients with BD‐IPMNs who did not receive a transplant. Consecutive patients who underwent an LT with BD‐IPMNs were included. Patients with BD‐IPMNs with no history of immunosuppression were used as controls. Progression of the BD‐IPMNs was defined as development of a high‐risk feature (jaundice, dilated main pancreatic duct, mural nodule, cytology suspicious or diagnostic for malignancy, cyst diameter ≥3 cm). Twenty‐three LT patients with BD‐IPMN were compared with 274 control patients. The median length of follow‐up was 53.7 and 24.0 months in LT and control groups, respectively. Four (17.4%) LT patients and 45 (16.4%) controls developed high‐risk features (Pu2009=u20090.99). In multivariate analysis, progression of BD‐IPMNs was associated with age at diagnosis but not with LT. There was no statistically significant difference in the risk of developing high‐risk features between the LT and the control groups. Liver Transpl 20:1462‐1467, 2014.

Management of Large Hepatocellular Carcinoma in Adult Patients with Alagille Syndrome: A Case Report and Review of Literature

BackgroundAlagille syndrome is a multi-system developmental disorder associated with paucity of interlobular bile ducts and cholestasis, rarely associated with hepatocellular carcinoma. Associated syndromic co-morbidities may complicate surgical management. As such, we herein review the modern management of a large hepatocellular carcinoma in an adult patient with Alagille syndrome and review the literature of adult Alagille patients with hepatocellular carcinoma.Case PresentationA 29-year-old woman with a history of Alagille syndrome was referred with biopsy-proven 12xa0×xa08xa0cm hepatocellular carcinoma replacing her right liver. Biopsy of the contralateral liver demonstrated findings consistent with Alagille syndrome, but no underlying cirrhosis. CT volumetrics demonstrated a future liver remnant of 40%. Extensive hematologic and cardiac work-up was performed pre-operatively, given the syndrome’s associated bleeding dyscrasias and cardiac abnormalities. The patient underwent a margin-negative right hepatectomy using the “hanging” technique through a thoracoabdominal approach. The patient developed a transient hyperbilirubinemia but no hepatic insufficiency and did well post-operatively.ConclusionSince Alagille syndrome affects multiple organ systems, preoperative evaluation of cardiac, hematologic, and hepatic function should be considered. This case illustrates the peri-operative management of an Alagille patient, and highlights several key technical points that contributed to a successful resection.