Lisa M. Forman

Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy

Patients with advanced hepatitis C virus (HCV) are at risk of death and are candidates for liver transplantation. After transplantation, HCV recurs and may rapidly progress to cirrhosis and graft loss. Treatment is needed to prevent progression of disease and minimize recurrence after liver transplantation. We evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of antiviral therapy in the treatment of patients with advanced HCV. One hundred twenty‐four patients (male/female ratio 81:43; age range 37‐71 years; 70% genotype 1) were treated with LADR. Sixty‐three percent had clinical complications of cirrhosis (ascites, spontaneous bacterial peritonitis, varices, variceal hemorrhage, encephalopathy). The mean Child‐Turcotte‐Pugh (CTP) score was 7.4 ± 2.3, and the mean MELD score was 11.0 ± 3.7. Fifty‐six patients were CTP class A, 45 were class B, and 23 were class C. Forty‐six percent were HCV RNA–negative at end of treatment, and 24% were HCV RNA–negative at last follow‐up. Sustained virological response (SVR) was 13% in patients infected with genotype 1 HCV and 50% in patients infected with non‐1 genotypes (P < .0001). Non‐1 genotype, CTP class A (genotype 1 only), and ability to tolerate full dose and duration of treatment (P < .0001) were predictors of SVR. Twelve of 15 patients who were HCV RNA–negative before transplantation remained HCV RNA–negative 6 months or more after transplantation. In conclusion, in a sizeable proportion of patients with advanced HCV, LADR may render blood free of HCV RNA, stabilize clinical course, and prevent posttransplantation recurrence. (HEPATOLOGY 2005;42:255–262.)

Survival following liver transplantation from non-heart-beating donors

Objective:To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts. Summary Background Data:With the growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist. Methods:Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database. Results:NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26,856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications. Conclusions:Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.

Hepatic Failure in a Patient Taking Rosiglitazone

Rosiglitazone maleate (Avandia, SmithKline Beecham, Philadelphia, Pennsylvania) is a thiazolidinedione, a relatively new class of oral antidiabetic agents that enhance sensitivity to insulin in skeletal muscle, adipose tissue, and liver (1). Troglitazone, its predecessor, has been associated with idiosyncratic hepatotoxicity (2-6). Cases of liver failure, liver transplantation, and death have been reported, and troglitazone was voluntarily withdrawn from the United Kingdom market in late 1997 (7). In premarketing trials, clinically significant elevations in liver enzyme levels were more frequent with troglitazone than with placebo (8, 9). Whether this hepatotoxicity is a class effect of thiazolidinediones remains to be established. Rosiglitazone is structurally very similar to troglitazone. No severe hepatotoxic adverse effects have been previously noted in patients treated with rosiglitazone (10, 11). We report a case of hepatic failure that may have been associated with rosiglitazone administration. Case Report A 69-year-old man presented with shortness of breath and abdominal pain. His medical history included atrial fibrillation, hypertension, coronary artery disease, and New York Heart Association class II congestive heart failure. A baseline left ventricular ejection fraction was not available, but the patients left ventricular ejection fraction was measured at 35% to 45% on two occasions during his hospitalization. The patient had had coronary artery bypass surgery 10 years before admission. Type 2 diabetes mellitus had been diagnosed approximately 1 month before admission, and the patient was prescribed rosiglitazone, 4 mg/d. The patients hepatic biochemical markers were normal before rosiglitazone therapy began, except for a total bilirubin level of 29 mol/L (1.7 mg/dL). The patients other medications included pravastatin, 20 mg/d; verapamil, 240 mg/d; betaxolol, 5 mg every other day; digoxin, 0.125 mg/d; and warfarin; 3.75 mg/d. He had received each of these medications for more than 1 year. The patient reported no history of exposure to hepatotoxins. He admitted to drinking two cans of beer daily. Within 1 week of starting rosiglitazone therapy, the patient experienced nausea, anorexia, fatigue, and abdominal pain. His symptoms progressed, and 5 days before admission, rosiglitazone therapy was discontinued. Therapy with metformin, 500 mg/d, was substituted, but the patient took only two doses, 5 and 6 days before admission. One day before admission, the patient experienced shortness of breath. At presentation, he was tachypneic, with a blood pressure of 104/48 mm Hg, and his abdomen was diffusely tender. Ascites and hepatomegaly were not present on physical examination. Laboratory values at presentation were as follows: total bilirubin, 65 mol/L (3.8 mg/dL); direct bilirubin, 41 mol/L (2.4 mg/dL); alanine aminotransferase (ALT), 31.57 kat/L; aspartate aminotransferase, 46.68 kat/L; alkaline phosphatase, 3.4 kat/L; prothrombin time, 92.7 seconds (international normalized ratio, 9.59); amylase, 1.82 kat/L; lipase, 3.1 kat/L; albumin, 36 g/L; and creatinine, 300 mol/L (3.4 mg/dL). Arterial blood gas values were as follows: pH, 7.15; Pco 2, 14 mm Hg; bicarbonate, 5 mmol/L; and Po 2, 257 mm Hg. Chest radiography revealed small bibasilar pleural effusions and mild pulmonary edema. Abdominal computed tomography revealed minimal ascites. The patient was admitted and rapidly became comatose. Two hours after admission, he became bradycardic and hypotensive, and he was given atropine, normal saline, epinephrine, and sodium bicarbonate. He had not received sodium bicarbonate therapy up to that point. His systolic blood pressure increased to 117 mm Hg and remained above 90 mm Hg during the remainder of his hospital course. During his hospital course, results of serologic testing were negative for hepatitis A, B, and C; Epstein-Barr virus; and cytomegalovirus. Toxicology screening was negative for acetaminophen, alcohol, and other known hepatotoxins. The patient was negative for antinuclear antibody (titer, 1:80). The patients aspartate aminotransferase level peaked at 184.94 kat/L, and his albumin level decreased to 29 g/L. The patient was not considered a candidate for liver transplantation because of his age and cardiac history. A liver biopsy was not performed. The patient was managed with intensive medical care, including ventilatory assistance, lactulose, vitamin K, and fresh frozen plasma. He received no cardiovascular support during his hospital admission other than renal-dose dopamine. The patient gradually improved over the subsequent 2 weeks, and his mental status and prothrombin time returned to normal. At discharge, his albumin level was 39 g/L, his creatinine concentration was 106 mol/L (1.2 mg/dL), and his ALT level was 3.28 kat/L (Figure). Figure. The patients clinical course. ALT (circles) INR (squares) Discussion Thiazolidinediones, agents that contain a thiazolidine-2-4-dione structure, were first synthesized in 1982. Differences in side chains influence their pharmacologic actions and potential adverse effects (1). They are selective agonists for the peroxisome proliferator-activated receptor-, but their mechanism of action is not well understood (12). Activation of the peroxisome proliferator-activated receptor- regulates the transcription of several genes involved in insulin-mediated glucose uptake in peripheral tissues and in preadipocyte differentiation (13). Rosiglitazone maleate is the second thiazolidinedione to be approved in the United States. Unlike troglitazone, rosiglitazone does not have a lipophilic -tocopherol moiety (1). It has a higher affinity for the peroxisome proliferator-activated receptor- than does troglitazone. Rosiglitazone is 99% bioavailable, reaching peak plasma concentrations 1 hour after administration. It is 99.8% bound to plasma proteins, primarily albumin. Rosiglitazone is extensively metabolized in the liver, mainly by N-demethylation and hydroxylation, followed by conjugation with glucuronic acid and sulfate. In vitro data indicate that rosiglitazone is predominately metabolized by cytochrome P4502C8 and, to a lesser extent, CYP2C9. In contrast to troglitazone, rosiglitazone does not appear to induce CYP3A4 metabolism. It does not inhibit any of the major P450 enzymes at clinically relevant concentrations. Mild to moderate renal failure, age, ethnicity, and tobacco and ethanol intake do not change the pharmacokinetics of rosiglitazone (10, 11). Rosiglitazone has not been previously considered to be hepatotoxic. In particular, premarketing trials found no evidence of rosiglitazone-induced elevation of aminotransferase levels or other signs of hepatotoxicity (14). Of 3455 patients who received rosiglitazone and had frequent liver function tests, the proportion of patients with ALT levels more than three times the upper limit of normal (0.17% [6 of 3455]) was similar to that in patients receiving placebo (0.18% [1 of 561]) or metformin or sulfonylureas (0.48% [4 of 828]). Patients who developed ALT levels more than three times the upper limit of normal during rosiglitazone treatment eventually had normalized, improved, or unchanged ALT levels during continued therapy (14). Moreover, in a study involving rat hepatocytes, rosiglitazone showed no cytotoxicity at concentrations of 100 mol/L or more, unlike troglitazone, which was toxic to these cells at the much lower concentration of 20 mol/L (15). We describe a patient with severe hepatotoxicity that seemed to be associated with rosiglitazone therapy after only 21 days of exposure to the drug. The patient developed nonspecific symptoms during rosiglitazone treatment that in retrospect probably reflected acute liver injury within 1 week of the start of rosiglitazone therapy. Although the patient took metformin, his initial metabolic acidosis is more likely attributable to hepatic failure itself than to metformin therapy; he took only two doses of metformin more than 5 days before presentation. This patient was also taking verapamil and pravastatin, both of which can cause hepatitis, but the patient had been receiving these drugs for more than 1 year. Results of tests for viral or toxic causes of hepatic failure were negative. It is possible that ischemic hepatitis (shock liver) played a superimposed role in this patients hepatic dysfunction, but ischemia alone is unlikely to explain the patients initial clinical picture. He did not have a documented episode of prolonged hypotension or hypoxemia before presentation, and he had only mild congestive heart failure according to physical examination and chest radiography on admission. He did have a bradycardic/hypotensive episode 2 hours after admission, but his liver function test results and prothrombin time were already documented to be markedly abnormal before this event occurred. The profound acidosis that accompanied the patients liver failure may have led to the hypotensive episode, given his history of cardiac disease. Furthermore, the hypotensive episode and potential ischemia cannot explain the weeks of hepatitis-related symptoms that preceded this patients admission. Of note, a decrease in the serum albumin level was associated with this patients illness, a phenomenon not typically associated with shock liver (16, 17). Therefore, this case may represent an idiosyncratic reaction to rosiglitazone, the basis of which is not apparent. The patients liver disease may also represent an adverse reaction to the concomitant administration of rosiglitazone with verapamil, pravastatin, or both. Additional investigations of the metabolism of rosiglitazone are necessary to help elucidate the mechanisms underlying this hepatotoxicity. We suggest that liver enzyme levels be monitored frequently in patients taking rosiglitazone, particularly soon after initiation of therapy. It is important to emphasize the need for patients to report adverse symptoms promptly. I

Impact of Hepatopulmonary Syndrome on Quality of Life and Survival in Liver Transplant Candidates

BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension, but the impact on functional status, quality of life, and survival is poorly defined. We assessed the impact of HPS in patients evaluated for liver transplantation. METHODS We performed a prospective multicenter cohort study of patients being evaluated for liver transplantation in 7 academic centers in the United States. Patients with HPS (defined as an increased alveolar-arterial oxygen gradient with intrapulmonary vasodilation) were compared with those without HPS in terms of demographics and clinical variables. New York Heart Association functional class, quality of life, and survival were assessed. RESULTS Seventy-two patients with HPS and 146 patients without HPS were compared. There were no differences in age, sex, or etiology or severity of liver disease between the groups; however, patients with HPS were less likely to have a history of smoking (P = .03). Patients with HPS had worse New York Heart Association functional class (P = .005) and had significantly worse quality of life in certain domains compared with patients without HPS. In addition, patients with HPS also had a significantly increased risk of death compared with patients without HPS despite adjustment for age, sex, race/ethnicity, Model for End-Stage Liver Disease score, and liver transplantation (adjusted hazard ratio = 2.41; 95% confidence interval, 1.31-4.41; P = .005). CONCLUSIONS HPS was associated with a significant increase in risk of death as well as worse functional status and quality of life in patients evaluated for liver transplantation.

Impact of pretransplant diagnosis of hepatocellular carcinoma on cadveric liver allocation in the era of MELD

The allocation system based on the Model for End‐stage Liver Disease (MELD) has led to more patients diagnosed with hepatocellular carcinoma (HCC) being transplanted. We hypothesized that more patients misdiagnosed with HCC are also being transplanted, leading to inappropriate organ allocation. Therefore, we retrospectively analyzed all liver transplants at our center from July 14, 2000, to October 22, 2002 (N = 172; 129 pre‐MELD, 43 post‐MELD), comparing pretransplant HCC diagnosis to explant histology. Thirty patients met the United Network for Organ Sharing (UNOS) diagnostic criteria for pretransplant HCC diagnosis. There were 25 men (median age, 52.5 yr), and 80% had hepatitis C. The proportion of patients transplanted who had an HCC diagnosis increased from 12% (15/129) pre‐MELD to 35% (15/43) post‐MELD implementation (P < 0.01). Three of 15 (20%) transplanted pre‐MELD and 5 of 15 (33%) transplanted post‐MELD lacked HCC in the explant (P = 0.10). Of the three false‐positives pre‐MELD, one was Status 2B already, and two received living‐donor livers. Of the 5 false‐positives post‐MELD, three had score upgrades that led to early transplantation (13 to 29, 20 to 29, and 9 to 24) while two had MELD scores of 35 and 36 already. The percentage of organs that could have gone to patients with more advanced liver disease without HCC increased from 0% (0/129) pre‐MELD to 7% (3/43) post‐MELD (P < 0.01). Since the implementation of MELD, the proportion of patients transplanted who had an HCC diagnosis nearly tripled, and a small but significant proportion of organs are now going to patients misdiagnosed with HCC. More stringent HCC diagnostic criteria will be required to decrease the effect that misdiagnosis has on organ allocation. (Liver Transpl 2004;10:42–48.)

Hepatic Artery Chemoembolization for Hepatocellular Carcinoma in Patients Listed for Liver Transplantation

We retrospectively analyzed all listed patients having hepatic artery chemoembolization (HACE) for hepatocellular carcinoma (HCC) stage T2 or less. Outcomes were transplantation, waiting list removal, death, and HCC recurrence. Twenty patients (mean age 55.7 years; 15 males) were identified. Twelve (60%) were transplanted, seven (35%) were removed from the list and one (5%) remains listed. Fourteen (70%) are alive. All 12 transplanted patients are alive (mean 2.94 years); one of seven removed from the list is alive (mean 1.45 years). Survival was significantly higher for those transplanted or listed vs. removed from the list (100% vs. 14.3%, p = 0.0002). No HCCs recurred. Three patients (15%) were removed from the list after prolonged waiting times before MELD. Hepatic artery chemoembolization induced deterioration and removal from the list of one (5%) patient. Survival for those transplanted was excellent(100%), but overall survival was significantly lower (61.3%) at a mean 5.48 years. Hepatic artery chemoembolization for listed patients with ≤€ T2 stage HCC is beneficial, but must be weighed against decreased waiting times and risk of HACE‐induced deterioration. This balance is influenced greatly by the MELD systems determination of waiting times for HCC patients.

Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men.

In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether female sex influences outcomes of HCV in the posttransplantation setting is unknown. All patients transplanted for HCV‐related liver disease from 2002‐2007 at five United States transplantation centers were included. The primary outcome was development of advanced disease, defined as biopsy‐proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. A total of 1,264 patients were followed for a median of 3 years (interquartile range, 1.8‐4.7), 304 (24%) of whom were women. The cumulative rate of advanced disease at 3 years was 38% for women and 33% for men (P = 0.31), but after adjustment for recipient age, donor age, donor anti‐HCV positivity, posttransplantation HCV treatment, cytomegalovirus infection and center, female sex was an independent predictor of advanced recurrent disease (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02‐1.70; P = 0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3‐year rates of patient and graft survival were numerically lower in women (75% and 74%, respectively) than men (80% and 78%, respectively), and in multivariable analyses, female sex was an independent predictor for death (HR, 1.30; 95% CI, 1.01‐1.67; P = 0.04) and graft loss (HR, 1.31; 95% CI, 1.02‐1.67; P = 0.03). Conclusion: Female sex represents an underrecognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and posttransplantation therapeutics can equalize HCV‐specific outcomes in women and men. (HEPATOLOGY 2011;)

Outcomes of Donor Evaluations for Adult-to-Adult Right Hepatic Lobe Living Donor Liver Transplantation

The purpose of this study is to determine the role of liver biopsy and outcome of patients undergoing donor evaluation for adult‐to‐adult right hepatic lobe living donor liver transplantation (LDLT). Records of patients presenting for a comprehensive donor evaluation between 1997 and February 2005 were reviewed. Liver biopsy was performed only in patients with risk factors for abnormal histology. Two hundred and sixty patients underwent a comprehensive donor evaluation and 116 of 260 (45%) were suitable for donation, 14 of 260 (5.4%) did not complete evaluation and 130 of 260 (50%) were rejected. Four patients underwent unsuccessful hepatectomy surgery due to discovery of intraoperative abnormalities. Between 1997 and 2001, the acceptance rate of donor candidates (63%) was higher than 2002–2005 (36%), p < 0.0001. Sixty‐six of the 150 eligible patients (44%) fulfilled criteria for liver biopsy and 28 of 66 (42%) had an abnormal finding. Less than half of the patients undergoing donor evaluation were suitable donors and the donor acceptance rate has declined over time. A large proportion of the patients undergoing liver biopsy have abnormal findings. Our evaluation process failed to identify 4 of 103 who had aborted donor surgeries.

Risk of advanced fibrosis with grafts from hepatitis C antibody–positive donors: A multicenter cohort study†

Over the last decade, the use of liver grafts from hepatitis C virus antibody–positive donors [HCV(+)Ds] has tripled in the United States. Although previous studies have demonstrated no association between an HCV(+)D status and graft loss, the effects of an HCV(+)D on histological outcomes are not well known. Hepatitis C virus (HCV)–infected recipients at 5 US centers (2002‐2007) who survived more than 30 days with 1 or more posttransplant biopsy samples were included. Cox regression was used to examine the association between an HCV(+)D status and advanced fibrosis (stage 3/4 or higher). Ninety‐nine of the 1206 patients (8%) received an HCV(+)D graft. Recipients of HCV(+)D grafts were older than recipients of hepatitis C virus antibody–negative donor [HCV(−)D] grafts (P = 0.03), but they were otherwise similar. HCV(+)D grafts were significantly lower in quality according to the donor risk index (P < 0.001). Advanced fibrosis occurred in 32% of HCV(+)D graft recipients and in 28% of HCV(−)D graft recipients (P = 0.39). The unadjusted 1‐ and 3‐year rates of advanced fibrosis were significantly higher for HCV(+)D graft recipients (14% and 48%) versus HCV(−)D graft recipients (7% and 33%, P = 0.01). Transplantation with HCV(+)D grafts was associated with a 58% increased risk of advanced fibrosis [95% confidence interval (CI) = 1.05‐2.36, P = 0.03]. However, in an analysis stratified by the mean donor age of 45 years, an HCV(+)D status was associated with advanced fibrosis only with donors >45 years old [hazard ratio (HR) = 1.76, 95% CI = 1.06‐2.93, P = 0.03] and not with donors ≤45 years old (HR = 0.94, 95% CI = 0.47‐1.87, P = 0.85). In conclusion, a careful consideration of the risks and benefits is needed with HCV(+)D grafts. Recipients of HCV(+)D grafts (especially from older donors) should undergo close monitoring for more rapidly progressive fibrosis. Studies are needed to determine whether early HCV therapy modifies this risk. Liver Transpl, 2012.

Risk of waitlist mortality in patients with primary sclerosing cholangitis and bacterial cholangitis.

Patients with primary sclerosing cholangitis (PSC) are at increased risk for bacterial cholangitis because of biliary strictures and bile stasis. A subset of PSC patients suffer from repeated episodes of bacterial cholangitis, which can lead to frequent hospitalizations and impaired quality of life. Although waitlist candidates with PSC and bacterial cholangitis frequently receive exception points and/or are referred for living donor transplantation, the impact of bacterial cholangitis on waitlist mortality is unknown. We performed a retrospective cohort study of all adult waitlist candidates with PSC who were listed for initial transplantation between February 27, 2002 and June 1, 2012 at the University of Pennsylvania and the University of Colorado–Denver. During this period, 171 PSC patients were waitlisted for initial transplantation. Before waitlisting, 38.6% (66/171) of the patients had a history of bacterial cholangitis, whereas 28.0% (44/157) of the patients with at least 1 Model for End‐Stage Liver Disease update experienced cholangitis on the waitlist. During follow‐up, 30 patients (17.5%) were removed from the waitlist for death or clinical deterioration, with 46.7% (14/30) developing cholangiocarcinoma. Overall, 12 of the 82 waitlist candidates (14.6%) who ever had an episode of cholangitis were removed for death or clinical deterioration, whereas 18 of the 89 candidates (20.2%) without cholangitis were removed (P = 0.34 for a comparison of the 2 groups). No patients were removed because of bacterial cholangitis. In multivariate competing‐risk models, a history of bacterial cholangitis was not associated with an increased risk of waitlist removal for death or clinical deterioration (subhazard ratio = 0.67, 95% confidence interval = 0.65–0.70, P < 0.001). In summary, waitlist transplant candidates with PSC and bacterial cholangitis do not have an increased risk of waitlist mortality. The data call into question the systematic granting of exception points or referral for living donor transplantation due to a perceived risk of increased waitlist mortality. Liver Transpl 19:250–258, 2013.