Comparison of 1-Year Morbidity Following Liver Transplant for Acute Alcoholic Hepatitis Versus Alcoholic Cirrhosis.

OBJECTIVES: With limited data on the morbidity profile of liver transplant as therapy for alcoholic hepatitis, we compared 30-day and 1-year morbidity in liver transplant recipients with alcoholic hepatitis versus alcoholic cirrhosis. MATERIALS AND METHODS: We retrospectively reviewed 38 perioperative variables in patients with alcoholic hepatitis (n = 15) and with alcoholic cirrhosis (n = 46). Multivariable analysis was performed to identify factors independently associated with outcomes. RESULTS: Patients with alcoholic hepatitis were younger (43 vs 58 years; P = .001), with higher pretransplant Model for End-Stage Liver Disease scores (36 vs 29; P = .009) and worse Karnofsky scores (20 vs 50; P < .001). All patients with alcoholic hepatitis received standard criteria deceased donor grafts; however, in the alcoholic cirrhosis group, 64% received standard criteria deceased, 11% living, 11% after cardiac death, 9% extended criteria, and 2% split graft donor organ donations (P > .05). The alcoholic hepatitis group had higher degree of steatosis on explant (P < .005), and the alcoholic cirrhosis group had higher 30-day reoperation rate (P = .001); however, 1-year interventions, vascular and biliary complications, graft and patient survival, and all other variables were similar (P > .05). Rates of alcohol relapse, 1-year infection, and 1-year rejection were higher but not significant (P > .05) in the alcoholic hepatitis group. Thirty-day reoperation (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky scores (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significant on multivariate analysis. CONCLUSIONS: Our results showed significant differences between our patient groups, including worse functional status in the alcoholic hepatitis group but significantly higher 30-day reoperation rates and more variable grafts in the alcoholic cirrhosis group, although both groups had similar overall 1-year complication and survival rates. Although not significant, patients with alcoholic hepatitis had higher alcohol relapse and 1-year infection and rejection rates. A larger cohort is necessary to confirm the strength of these findings.

Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

INTRODUCTION: The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies. METHODS: A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs). RESULTS: Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11 days vs 26 days, P = .01). Longer time to DAA initiation resulted in higher peak viral loads (ß = 0.39, R2  = .15, P = .01) and longer time to HCV viral load clearance (ß = 0.41, R2  = .17, P = .01). CONCLUSIONS: D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.

Transplantation of viral-positive hepatitis C-positive kidneys into uninfected recipients offers an opportunity to increase organ access.

The advent of direct-acting antivirals (DAAs) has provided the impetus to transplant kidneys from hepatitis C virus-positive donors into uninfected recipients (D+/R-). Thirty D+/R- patients received DAA treatment. Sustained virologic response (SVR12) was defined as an undetectable viral load in 12 weeks after treatment. An age-matched cohort of uninfected donor and recipient pairs (D-/R-) transplanted during same time period was used for comparison. The median day of viral detection was postoperative day (POD) 2. The detection of viremia in D+/R- patients was 100%. The initial median viral load was 531 copies/µL (range: 10-1 × 108 copies/µL) with a median peak viral load of 3.4 × 105 copies/µL (range: 804-1.0 × 108 copies/µL). DAAs were initiated on median POD 9 (range: 5-41 days). All 30 patients had confirmed SVR12. During a median follow-up of 10 months, patient and graft survival was 100%, and acute rejection was 6.6% with no major adverse events related to DAA treatment. Delayed graft function was significantly decreased in D+/R- patients as compared to the age-matched cohort (27% vs 60%; P = .01). D+/R- transplantation offers patients an alternative strategy to increase access.

Ineffective Absorption? Failure of Direct-Acting Therapy for Chronic Hepatitis C in Cirrhotic Patients With Roux-en-Y Gastric Bypass.

In this era of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection, treated patients have extremely high rates of sustained virologic response to short courses of therapy regardless of stage of fibrosis. Treatment failure is uncommon and often attributed to medication noncompliance or viral resistance to drug. This report describes 2 Child-Pugh-A cirrhotic patients who failed to clear HCV in response to therapy with DAAs. Each patient had Roux-en-Y gastric bypass (RYGB) surgery preceding DAA therapy. RYGB may create multiple barriers to adequate DAA absorption as a result of changes in gastrointestinal physiology. Treatment monitoring and duration should be carefully considered in this unique patient population.

Limited Fibrosis Progression but Significant Mortality in Patients Ineligible for Interferon-Based Hepatitis C Therapy.

BACKGROUND: Individuals ineligible for interferon-based hepatitis C therapy may have a worse prognosis than patients who have failed or not received treatment. AIMS: To provide information about the limitations of medical treatment of hepatitis C in real-world patients. METHODS: We studied 969 treatment-ineligible patients and 403 treated patients enrolled between 1/1/01 and 6/30/06; data were collected until 3/31/13. Treatment barriers were grouped into five categories and classified as health-related or health-unrelated. Fibrosis stage was assessed initially and at the end of follow-up. Mortality was determined by search of the Social Security database. Death certificates of treatment-ineligible patients were reviewed. RESULTS: Initially, 288 individuals had advanced fibrosis and compensated disease; 87 untreated patients developed advanced fibrosis during follow-up. Health-related treatment barriers were more commonly associated with fibrosis progression and worse survival. During follow-up, 247 untreated patients died: 47% of liver-related and 53% of liver-unrelated causes. Patients with significant comorbid illness had the worst five- (70%) and ten-year (50.5%) survival. Despite high mortality (47%) in persons with decompensated liver disease, no treatment barrier was associated with a greater incidence of liver-related death. Only significant comorbid medical illness was an independent predictor of disease progression; however, it was not associated with a greater incidence of liver-related death. Furthermore, treated patients had better 10-year survival than untreated patients on Kaplan-Meier analysis (80.3% vs. 74.5%, P = 0.005). CONCLUSION: Many patients with hepatitis C will die of non-liver-related causes and may not be helped by anti-viral treatment.

Expedited liver allocation in the United States: a critical analysis.

The fate of donor livers allocated via an out-of-sequence expedited placement (EP) pathway has not been previously examined. We determined the originating and receiving United Network for Organ Sharing (UNOS) regions of all donor livers procured between January 1, 2010 and October 31, 2012 and placed out of sequence with UNOS bypass code 863 (EP attempt) or 898 (miscellaneous). We reviewed the early function of these liver grafts and assessed the effect of EP allocation on wait-listed patients at our center. Registrants at our center were eligible to receive 1298 liver offers during the interval studied: 218 (16.8%) of these liver offers bypassed our center and were allocated to other centers and used in patients lower on the match-run list. During the study interval, 560 livers were allocated in the United States by EP. Regions 1, 5, 7, 9, and 10 used the greatest number of EP-placed grafts. Region 1 (New England) used the greatest proportion of all EP livers (33% of all imported EP livers in the United States, P < 0.001 versus all other regions). Graft function data were available for 560 livers placed by EP: 491 (88%) of these grafts were functioning at a mean of 399.5 days after transplantation. In conclusion, the transplantation of livers allocated by means of an expedited refusal code is asymmetric across regions and, in some instances, results in the bypassing of patients with higher wait-list priority but without notification of the bypassed center. Short-term graft function after EP allocation is excellent. Policies governing EP allocation should be created in order to improve access to available organs.

Prevalence and natural history of alcoholic liver disease.

Alcoholic liver disease is a major cause of morbidity and mortality among people who drink excessive amounts of alcohol. There is a spectrum of liver injury that ranges from steatosis to varying stages of hepatic fibrosis and cirrhosis, with subsequent risk for hepatocellular carcinoma. Steatohepatitis can occur at any stage of disease.

Value of noncontrast CT immediately after transarterial chemoembolization of hepatocellular carcinoma with drug-eluting beads.

PURPOSE: To retrospectively evaluate the presence and distribution patterns of contrast agent retention in the liver on noncontrast computed tomography (CT) immediately following chemoembolization with drug-eluting beads (DEBs). MATERIALS AND METHODS: From 2008 to 2010, 95 patients with 224 liver lesions had chemoembolization performed with DEBs and a noncontrast CT examination of the liver performed immediately after embolization. Of these, 85 patients with 193 lesions were included. The postembolization CT scan was reviewed by a diagnostic radiologist, and the presence of contrast agent retention within the lesion was assessed. Varying patterns of contrast agent retention were defined. RESULTS: Of the 193 lesions included, 146 (76%) retained contrast medium. Aside from some contrast medium in vessels, very little if any contrast medium was seen in the surrounding liver. Various patterns of contrast agent retention were noted within lesions. In a single case, repeat imaging was obtained 6 hours later, which demonstrated washout of contrast agent in a lesion that had retained contrast agent on the postprocedure CT scan. Of significance, 13 additional foci of contrast agent retention were identified on postchemoembolization CT scans that, on retrospective review of preprocedure imaging, represented enhancing lesions not previously identified. CONCLUSIONS: Noncontrast CT after chemoembolization with DEBs demonstrates contrast agent retention in 76% of cases, without significant contrast medium seen in the adjacent liver parenchyma. The presence or absence of contrast agent retention may prove to be useful in evaluating accurate targeting of a lesion.

Social barriers to listing for adult liver transplantation: their prevalence and association with program characteristics.

Social barriers to effective medical care are mandated to be routinely assessed as part of an evaluation for liver transplantation. This study explores how frequently liver transplant programs encounter these barriers in patients undergoing an evaluation and whether programs with higher proportions of Medicaid patients, historically disadvantaged minority patients, and rural patients encounter social barriers more frequently. A survey for assessing patient demographics and social barriers was electronically completed by representatives of 61 of 104 eligible US adult liver transplant programs (59%). Fifty-eight of the 61 programs identified themselves, and their characteristics were similar to those of all 104 US programs according to publicly available data from the Organ Procurement and Transplantation Network. Social barriers were reported to be encountered sometimes (10%-30%) or frequently (>30%) by the 61 programs as follows: inadequate or unstable health insurance (68.9% of the programs), a chaotic social environment (63.9%), a lack of a care partner (60.7%), an inability to obtain transportation (49.2%), a low educational level (36.1%), inadequate housing (23.0%), a language barrier (19.7%), no reliable way of contacting the patient (16.4%), difficulty in obtaining child care (11.5%), and food insecurity (8.2%). The frequencies of perceived social barriers did not differ significantly between programs reporting higher or lower proportions of Medicaid, minority, or rural patients. Our analysis suggests that program-level operational planning for addressing social barriers to transplant listing should be considered regardless of the proportions of Medicaid-insured, racial or ethnic minority, and rural patients in the population.

Effectiveness of hepatitis C treatment with pegylated interferon and ribavirin in urban minority patients.

Randomized controlled trials of hepatitis C virus (HCV) therapy with pegylated interferon and ribavirin have demonstrated sustained viral response rates (SVRs) of 54%-63% (efficacy). Treatment results in clinical practice (effectiveness) may not be equivalent. The goal of this study was to assess the effectiveness of HCV treatment with pegylated interferon and ribavirin in a treatment-naïve, human immunodeficiency virus (HIV)-negative, United States urban population with many ethnic minority patients. We evaluated 2,370 outpatients for HCV therapy from 2001 to 2006 in the Faculty Practice of the Albert Einstein College of Medicine or the attending-supervised Montefiore Medical Center Liver Clinic. Care was supervised by one experienced physician under conditions of everyday clinical practice, and appropriate ancillary resources were made available to all patients. Two hundred fifty-five patients were treated with a mean age of 50 years (60% male, 40% female; 58% Hispanic, 20% African American, 9% Caucasian, 13% other; 68% genotype 1, the remainder genotypes 2 or 3). Patients had at least one liver biopsy. Intention-to-treat analysis (ITT) showed SVR in 14% of genotype 1 patients and 37% in genotype 2/3 patients (P < 0.001). SVR was significantly higher in faculty practice (27%) than in clinic patients (15%) by intention-to-treat (P = 0.01) but not per-protocol analysis (46% faculty practice, 34% clinic). 3.3% of 1,656 treatment-naïve, HIV antibody-negative individuals ultimately achieved SVR. Current hepatitis C therapies may sometimes be unavailable to, inappropriate for, and ineffective in United States urban patients. Treatment with pegylated interferon and ribavirin was less effective in this population than is implied by multinational phase III controlled trials. New strategies are needed to care for such patients.

Entry of hepatitis C virus and human immunodeficiency virus is selectively inhibited by carbohydrate-binding agents but not by polyanions.

We studied the antiviral activity of carbohydrate-binding agents (CBAs), including several plant lectins and the non-peptidic small-molecular-weight antibiotic pradimicin A (PRM-A). These agents efficiently prevented hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infection of target cells by inhibiting the viral entry. CBAs were also shown to prevent HIV and HCV capture by DC-SIGN-expressing cells. Surprisingly, infection by other enveloped viruses such as herpes simplex viruses, respiratory syncytial virus and parainfluenza-3 virus was not inhibited by these agents pointing to a high degree of specificity. Mannan reversed the antiviral activity of CBAs, confirming their association with viral envelope-associated glycans. In contrast, polyanions such as dextran sulfate-5000 and sulfated polyvinylalcohol inhibited HIV entry but were devoid of any activity against HCV infection, indicating that they act through a different mechanism. CBAs could be considered as prime drug leads for the treatment of chronic viral infections such as HCV by preventing viral entry into target cells. They may represent an attractive new option for therapy of HCV/HIV coinfections. CBAs may also have the potential to prevent HCV/HIV transmission.

Corticosteroid-responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis.

Cryptogenic chronic hepatitis (CCH) is diagnosed in patients with persistently elevated aminotransferase levels of unknown etiology. The workup of CCH patients must include a liver biopsy in order to exclude the largely unrecognized diagnosis of seronegative autoimmune hepatitis (SAIH). Patients with SAIH have demographic, biochemical, and histologic features of autoimmune hepatitis (AIH) and may be treated effectively with corticosteroids. Recognition and treatment of SAIH are necessary to prevent progression to end-stage liver disease. We performed a retrospective review of a database of 3507 patients seen at our institution over a 5-year period. Thirty patients with conventional AIH and an additional six patients with SAIH were identified. The two groups were similar with respect to mean age, gender, and baseline biochemistry. Of the 20 AIH patients who had pretreatment liver biopsies, 85% had moderate to severe interface hepatitis, compared to 83.3% of patients with SAIH. In the SAIH group, 83.3% had advanced fibrosis (stage 3 or 4), versus 40% in the conventional AIH group (P = 0.16). All patients were treated with corticosteroids followed by azathioprine. The mean time to remission (normal ALT) was similar in both groups, 2.6 vs. 2.7 months. Within 3 months, 88.9% of AIH patients and 66.7% of SAIH patients were in remission. We conclude that a trial of corticosteroids is a reasonable therapeutic measure in patients with chronic hepatitis that has features of AIH despite negative autoantibody markers. In most patients, clinical remission will be seen within 3 months, possibly avoiding progression to end-stage liver disease.

Recombinant human interferon-alpha does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats.

Recombinant human interferon-alpha (IFN-alpha) induces depression, and neuroendocrine and neuroimmune activation, in a significant number of patients undergoing treatment for viral illnesses (e.g., hepatitis C), yet these effects have not been consistently reproduced in rodents. As such, we sought to determine the effects of acute or chronic IFN-alpha treatment on basic reward and immobility in the forced swim test (FST), neuroendocrine and neuroimmune activation, and monoamine turnover in brain. In the first experiment, male Wistar rats (N = 7/group) treated with human recombinant IFN-alpha (100,000 IU/kg, i.p.), as compared to saline, did not exhibit alterations to rate of sucrose pellet self-administration or total reinforcers obtained, corticosterone release, plasma IL-6 release, IL-1beta or IL-6 mRNA expression in hippocampus, or monoamine turnover in prefrontal cortex, striatum, nucleus accumbens, or amygdala. However, acute IFN-alpha decreased body weight and produced a trend toward reduced food consumption in the home cage 2 h after injection. In the second experiment, Wistar rats (N=4/group) were subjected to a chronic treatment regimen of saline or IFN-alpha (100,000 IU/kg, i.p.) once daily for 14 consecutive days. The data reveal that animals exposed to chronic IFN-alpha exhibited similar amounts of time immobile and similar latencies to primary immobility in the FST as compared to saline-treated controls. Chronic IFN-alpha did not induce corticosterone release, plasma TNF-alpha, or IL-6 release. Tissue monoamine analysis revealed that chronic IFN-alpha reduced DA levels in prefrontal cortex, and decreased 5-HT levels and increased 5-HT turnover in amygdala. In the third experiment, Wistar rats (N = 4/group) were exposed to either acute or chronic pegylated IFN-alpha (pegIFN-alpha: 3.25, 10 or 75 mg/kg, i.p.) at one of several time points from 1 h to 23 days. The data reveal that neither acute nor chronic pegIFN-alpha induced corticosterone release. Overall, the current report demonstrates that neither acute nor chronic IFN-alpha induced depressive-like behavior and neither IFN-alpha nor peg-IFN-alpha was capable of inducing neuroendocrine or neuroimmune activation. Despite the neurochemical alterations observed in the chronic treatment regimen, the data indicate that recombinant human IFN-alpha does not produce a robust model of depressive-like behavior in rodents.

Hippocratic Economics (the Physician's Dilemma).

The nature of the medical profession puts physicians in an unusual position. Patients seek out physicians' help because of their expertise in dealing with illnesses, possibly even life-threatening ones. The asymmetry of knowledge in this relationship, the expert physician and the inexpert patient, creates an ethical dilemma for physicians regarding the delivery of care. Physicians determine how much care to offer while receiving remuneration for this care. Here, acting as patients' agents, physicians have immense discretionary power not only with patients' health but also with their pocketbooks. Known as the principal-agency problem, this type of relationship is part and parcel of what business scholars refer to as moral hazard. This article explains the problem of moral hazard and how it affects radiologists and places it in the context of professional and ethical behavior. Its causes and relationship to human nature are explored. The consequences of falling prey to moral hazard in the practice of radiology are discussed.

Factors associated with successful referral for clinical care of drug users with chronic hepatitis C who have or are at risk for HIV infection.

The objective of this study was to determine outcomes of referring drug users (DUs) with chronic hepatitis C for clinical evaluation and care. Two hundred twenty-eight persons with detectable hepatitis C virus RNA were given expedited referrals for evaluation and possible treatment of hepatitis C from a prospective study cohort of current and former opiate-addicted DUs. Four outcomes were analyzed: accepted referral, arrived for clinical evaluation, had liver biopsy, and received treatment. One hundred twenty-seven participants (56%) accepted referral, of whom 54 (43%) arrived for evaluation. Of these participants, 12 (22%) had liver biopsy, and 4 (7%) were treated. Multivariate logistic regression revealed that HIV-infected DUs were significantly less likely to accept referral (adjusted odds ratio [O(Radj)], 0.51; 95% confidence interval [CI], 0.30-0.88), and older participants were more likely to keep an appointment (O(Radj), 1.06/y; 95% CI, 1.00-1.12). Of HIV-seropositive participants, those with a history of injection were more likely to accept referral (O(Radj), 3.60; 95% CI, 1.08-11.96), and those with higher HIV load (O(Radj), 0.50/log10; 95% CI, 0.26-0.94) and Hispanic ethnicity (O(Radj), 0.26; 95% CI, 0.07-0.89) were less likely to keep an appointment. Despite expedited referrals for hepatitis C care, only a few participants received an evaluation, and even far fewer were treated. Because increasingly effective treatment is available, better methods are urgently needed to improve evaluation and treatment of HCV-infected DUs, including those coinfected with HIV.

IFN-induced depression: a role for NSAIDs.

Interferon-alpha (IFN) is widely used for the treatment of viral illnesses and other chronic diseases, though its usefulness is hampered by a problematic side-effect profile. In particular, IFN-alpha induces neuropsychiatric and neurotoxic side effects, including depression, anxiety, insomnia, lethargy, confusion, and psychosis. Of particular interest, a number of patients develop full psychiatric syndromes, particularly depressive disorders. Recent evidence suggests that conventional antidepressants (especially selective serotonin reuptake inhibitors) are effective in preventing or reducing IFN-induced side-effects, but even these compounds are not 100% effective in preventing these symptoms. As such, alternative treatments must be considered. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to counteract a number of IFN-induced side effects, including cytokine activation, stress hormone release, and neurochemical alterations (reduced 5-HT [serotonin]). NSAIDs are widely recommended for various aspects of flu-like symptoms or sickness behaviors in humans, including those induced specifically by IFN. In addition, NSAIDs appear to be effective in treating premenstrual dysphoric disorder. These data indirectly specify a role for NSAIDs in syndromes with a prominent depression component. Drawing from an extensive pre-clinical and clinical research base, we hypothesize that pretreatment with NSAIDs will not only reduce the incidence of flu-like symptoms, but also prove effective for the prevention or reduction of IFN-induced depression.

Sertraline hepatotoxicity: a case report and review of the literature on selective serotonin reuptake inhibitor hepatotoxicity.

The causal role of sertraline in rare cases of liver failure in patients taking the drug has not been proven in a manner consistent with usually accepted standards. We describe an individual who developed clinically significant hepatitis while being treated with sertraline. This case is significant because it is the only one of which we are aware in which the diagnosis of sertraline hepatotoxicity was confirmed when inadvertent rechallenge with the medication resulted in recurrent hepatitis. We review this case and the general role of this widely prescribed class of drugs in causing hepatitis.