Jeffrey S. Crippin

Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation.

Purpose:To evaluate outcomes of downstaging patients with advanced (American liver tumor study group stage III/IV) hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) to allow eligibility for orthotopic liver transplant (OLT). Methods:From 1999 to 2006, 202 patients with HCC were referred for transplant evaluation. Seventy-six (37.6%) patients with stage III/IV HCC were potential transplant candidates if downstaging was achieved by TACE. OLT was considered based on follow-up imaging findings. The number of patients who were successfully downstaged within the Milan criteria, tumor response using Response Evaluation Criteria in Solid Tumors criteria, findings at explant, and outcomes after transplant were tracked. Results:Eighteen of 76 (23.7%) patients had adequate downstaging to qualify for OLT under the Milan criteria. By Response Evaluation Criteria in Solid Tumors, 27/76 (35.5%) patients had a partial response, 22/76 (29%) had stable disease, and 27/76 (35.5%) had progressive disease. Seventeen of 76 (22.4%) patients who met other qualifications underwent OLT after successful downstaging (13/38 stage III;4/38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 90% in 21 (75%). At a median of 19.6 months (range 3.6–104.7), 16/17 (94.1%) patients who underwent OLT are alive. One patient expired 11 months after OLT secondary to medical comorbidities. One of 17 (6%) OLT patients had recurrent HCC. This patient underwent resection of a pulmonary metastasis and is alive, 63.6 months from OLT. Conclusion:Selected patients with stage III/IV HCC can be downstaged to Milan criteria with TACE. Importantly, patients who are successfully downstaged and transplanted have excellent midterm disease-free and overall survival, similar to stage II HCC.

Tenofovir Disoproxil Fumarate Therapy for Chronic Hepatitis B in Human Immunodeficiency Virus/Hepatitis B Virus–Coinfected Individuals for Whom Interferon-α and Lamivudine Therapy Have Failed

A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.

Screening for Wilson Disease in Acute Liver Failure: A Comparison of Currently Available Diagnostic Tests

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

Impact of tacrolimus versus cyclosporine in hepatitis C virus‐infected liver transplant recipients on recurrent hepatitis: A prospective, randomized trial

Hepatitis C virus (HCV)‐induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus‐ and cyclosporine‐treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine‐treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically‐diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV. (Liver Transpl 2004;10:1258–1262.)

Recurrent Primary Sclerosing Cholangitis After Orthotopic Liver Transplantation: Is Chronic Rejection Part of the Disease Process?

BACKGROUND The possibility of primary sclerosing cholangitis (PSC) recurrence after liver transplantation has been debated. The aim of this study is to examine whether recurrent PSC and chronic rejection (CR) are different expressions of the same disease process. METHODS One hundred consecutive patients receiving 118 grafts for the diagnosis of PSC were reviewed and placed into three groups: group A, recurrent disease, as evidenced by cholangiographic and pathologic findings with radiographic arterial flow to the liver (n=18; 15.7%); group B, those who developed CR (n=15; 13.0%); and group C, all others (n=82; 71.3%). Cholangiograms and histopathologic specimens were examined in a blinded fashion. RESULTS Demographic factors were similar, except for age, with a significantly younger age and more episodes of rejection in groups A and B (P<0.03). Group A had a higher incidence of cytomegalovirus hepatitis (P=0.008). Five-year graft survivals for A, B, and C were 64.6%, 33.3%, and 76.1%, respectively (P=0.0001), 5-year patient survivals were 76.2%, 66.7%, and 89.1%, respectively (P=0.0001), and repeat transplantation rates were 27.8%, 46.7%, and 8.5%, respectively (P=0.005). Radiographically, 90% of cholangiograms in patients with recurrent disease showed at least multiple intrahepatic strictures. Histopathologically, patients with recurrent disease and CR shared many features. CONCLUSIONS We have described a high incidence of recurrent PSC and CR in patients who received transplants for PSC. Histopathologic analysis suggests that CR and recurrent PSC could represent a spectrum of indistinguishable disease. However, the distinct difference in clinical outcome, as evidenced by an increased repeat transplantation rate and lower graft and patient survival in the CR group, clearly suggests that they are two distinct entities that require very different treatment strategies.

Troglitazone-induced fulminant hepatic failure

Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey), the first marketed member of a new class of oral agents for type II diabetes mellitus, the thiazolidinediones, has a number of attractive attributes. It reduces insulin resistance and increases insulin-stimulated glucose disposal, resulting in improved glycemic control and decreased insulin requirements in treated patients (1, 2). In addition, it is dosed once a day, is readily absorbed from the gastrointestinal tract, does not induce hypoglycemia, and does not appear to interact with other medications. Because of these attributes, troglitazone has enjoyed widespread use since its introduction in March 1997. In premarketing clinical trials of troglitazone, mild hepatotoxicity identified as reversible elevations of alanine aminotransferase (ALT) greater than three times normal were seen in less than 2% of treated patients (3). However, since the drug was released, several cases of more severe, even fatal, episodes of hepatitis have been reported (4–7). Here we report three cases of apparent troglitazone-induced fulminant liver failure prospectively identified through the Acute Liver Failure Study Group (ALFSG), a consortium of 14 academic medical centers with the purpose of collecting data regarding the etiology, treatment, and outcome of patients with acute liver failure. The cases highlight the potential hepatotoxicity of troglitazone and reinforce the need for close monitoring of all patients taking the drug.The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.

Hepatic arterial chemoembolization for hepatocellular carcinoma: comparison of survival rates with different embolic agents.

PURPOSE The optimal embolic agent for transhepatic arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been identified. This study reports outcomes of TACE for HCC with Gelfoam powder and polyvinyl alcohol (PVA). MATERIALS AND METHODS Eighty-one patients underwent 152 TACE sessions with Gelfoam powder (n = 41) or polyvinyl alcohol (PVA) and Ethiodol (n = 40) as the embolic agent. Chemotherapeutic drugs were the same for all patients (50 mg cisplatin, 20 mg doxorubicin, 10 mg mitomycin-c). The groups were compared based on number of TACE sessions, maximum tumor size, bilirubin level, aspartate and alanine aminotransferase levels, Child-Pugh score, Model for End-stage Liver Disease score, and hepatitis B or C virus positivity. The number of cases of each Child class in each group was also evaluated. Survival starting from the first TACE session was calculated according to Kaplan-Meier analysis. Forty-eight patients died during the study period, 19 received transplants, and 14 were alive at the end of the study period. RESULTS The groups were statistically similar in all categories regarding liver function, Child-Pugh score, tumor size, hepatitis status, and percentage of patients with Child class A, B, and C disease. The number of TACE sessions was significantly greater for the Gelfoam powder group (mean, 2.2) versus the PVA group (mean, 1.6; P = .01). Overall survival was similar between groups whether patients who received transplants were included in the analysis (mean, 659 days +/- 83 with Gelfoam powder vs 565 days +/- 71 with PVA; P = .42) or were excluded (mean, 519 days +/- 80 with Gelfoam powder vs 511 days +/- 75 with PVA; P = .93). CONCLUSION In similar patient groups, survival after treatment of HCC with TACE with Gelfoam powder or PVA and Ethiodol was similar.

Cost-effectiveness of extending medicare coverage of immunosuppressive medications to the life of a kidney transplant

Unless they maintain Medicare status through disability or age, kidney transplant recipients lose their Medicare coverage of immunosuppression 3 years after transplantation. A significant transplant survival advantage has previously been demonstrated by the extension of Medicare immunosuppressive medication coverage from 1 year to 3 years, which occurred between 1993 and 1995.

Celiac sprue: another autoimmune syndrome associated with hepatitis C

OBJECTIVE:Celiac sprue is being diagnosed with increasing frequency by screening individuals with epidemiologically associated autoimmune syndromes. We sought to test our hypothesis that hepatitis C also may predispose to celiac sprue because it can trigger autoimmune reactions.METHODS:Two hundred fifty-nine consecutively evaluated patients with chronic hepatitis C infection, 59 with autoimmune liver disease, 137 with other hepatic diseases, 356 with various GI syndromes, and 221 normal volunteers underwent serologic screening for celiac sprue. Patients with antigliadin, antiendomysial, and antitissue transglutaminase antibodies in serum underwent duodenoscopy and biopsy.RESULTS:There was a statistically significantly higher prevalence of antigliadin antibody in all groups of patients with liver disease compared with GI controls and normal controls. However, only patients with hepatitis C (n = 3; 1.2%) or autoimmune liver disease (n = 2; 3.4%) had antiendomysial/antitissue transglutaminase antibody in serum. One of 221 normal volunteers (0.4%) was antigliadin, antiendomysial, and antitissue transglutaminase positive; this individual also was found to have hepatitis C (previously undiagnosed). Each of these six individuals had mild intestinal symptoms, duodenal histopathology consistent with celiac sprue, and the celiac-associated HLA-DQ2 allele. Five of the six followed a prescribed gluten-free diet and experienced symptomatic improvement.CONCLUSION:Celiac sprue is epidemiologically associated with chronic hepatitis C infection and with autoimmune liver disease. Because hepatitis C is much more frequently encountered than autoimmune liver disease, hepatitis C appears to be the most common hepatic disease associated with the development of celiac sprue.

Retransplantation in hepatitis B--a multicenter experience.

Hepatitis B has become one of the most challenging diseases in liver transplantation. Infection of the allograft with subsequent graft failure is common and may prompt consideration of repeat liver transplantation. The aims of this study were to examine the experience in the United States with retransplantation in hepatitis B patients with recurrent disease as well as for other reasons. Questionnaires were mailed to adult liver transplant centers in the United States, requesting information on retransplantation in HBV patients. Responses were received from 71% of the centers. Thirty-eight patients were retransplanted, 20 for recurrent HBV and 18 for other reasons. The survival rate following retransplantation for HBV was poor. Nine patients (55%) died within 60 days. Eleven patients survived 60 days or longer, though eight died at a mean of 4.1 +/- 2 months, one required a third transplant for recurrent HBV infection at 4 months, and one died at 35 months. Only a single (5%) long-term survivor exists. Recurrent histologic disease occurred earlier in the second transplant at 2.8 +/- 2.9 months versus 6.1 +/- 5.2 months in the first allograft, though this difference did not reach statistical significance (P = .058). Patients transplanted for other reasons (primary non-function [9], hepatic artery thrombosis [6], persistent rejection [2], and a Pseudomonas graft infection [1]) had a better survival rate. Four patients survived less than 60 days. Of the 14 surviving longer than 60 days, 11 patients are alive at a mean of 21.2 +/- 14.8 months. Retransplantation for recurrent HBV appears to be contraindicated due to a high mortality. Retransplantation in HBV patients with graft failure due to other causes, however, should be considered, since over 60% of these patients appear to have good long-term survival. Additional studies examining risk factors for recurrent disease should be considered.