Prevention of the Osmotic Demyelination Syndrome After Liver Transplantation: A Multidisciplinary Perspective.

The osmotic demyelination syndrome (ODS) is a serious neurologic condition that occurs in the setting of rapid correction of hyponatremia. It presents with protean manifestations, from encephalopathy to the "locked-in" syndrome. ODS can complicate liver transplantation (LT), and its incidence may increase with the inclusion of serum sodium as a factor in the Mayo End-Stage Liver Disease score. A comprehensive understanding of risk factors for the development of ODS in the setting of LT, along with recommendations to mitigate the risk of ODS, are necessary. The literature to date on ODS in the setting of LT was reviewed. Major risk factors for the development of ODS include severe pretransplant hyponatremia (serum sodium [SNa] < 125 mEq/L), the magnitude of change in SNa pre- versus posttransplant, higher positive intraoperative fluid balance, and the presence of postoperative hemorrhagic complications. Strategies to reduce the risk of ODS include correcting hyponatremia pretransplant via fluid restriction and/or ensuring an appropriate rate of increase from the preoperative SNa via close attention to fluid and electrolyte management both during and after surgery. Multidisciplinary management involving transplant hepatology, nephrology, neurology, surgery, and anesthesiology/critical care is key to performing LT safely in patients with hyponatremia.

Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL-HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct-acting antiviral (DAA) to prevent HCV recurrence post-transplant in an open-label exploratory efficacy trial. Eight subjects received MBL-HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post-transplantation. Following FDA approval of sofosbuvir, two subjects received MBL-HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8-12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post-treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2-12 weeks post-treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof-of-concept study demonstrates that peri-transplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.

Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in HCV-infected patients treated with sofosbuvir-containing regimens.

To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real-world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013-June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case-control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment-related (scale = 0-4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment-related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, 'likely treatment-related'), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end-stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin (OR = 0.12/g/dL, P = 0.01) and higher total bilirubin (OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events.

Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States--A Single-Center Experience.

Early liver transplantation (LT) in European centers reportedly improved survival in patients with severe alcoholic hepatitis (AH) not responding to medical therapy. Our aim was to determine if a strategy of early LT for severe AH could be applied successfully in the United States. We reviewed 111 patients with severe AH at our center from January 2012 to January 2015. The primary end point was mortality at 6 months or early LT, with a secondary end point of alcohol relapse after LT. Survival was compared between those receiving early LT and matched patients who did not. Using a process similar to the European trial, 94 patients with severe AH not responding to medical therapy were evaluated for early LT. Overall, 9 (9.6%) candidates with favorable psychosocial profiles underwent early LT, comprising 3% of all adult LT during the study period. The 6-month survival rate was higher among those receiving early LT compared with matched controls (89% vs 11%, p<0.001). Eight recipients are alive at a median of 735 days with 1 alcohol relapse. Early LT for severe AH can achieve excellent clinical outcomes with low impact on the donor pool and low rates of alcohol relapse in highly selected patients in the United States.

Clinical characteristics of human immunodeficiency virus patients being referred for liver transplant evaluation: a descriptive cohort study.

BACKGROUND: Liver transplantation (LT) is a treatment option for select human immunodeficiency virus (HIV)-infected patients with advanced liver disease. The aim of this study was to describe LT evaluation outcomes in HIV-infected patients. METHODS: All HIV-infected patients referred for their first LT evaluation at the Mount Sinai Medical Center were included in this retrospective, descriptive cohort study. Multivariable logistic regression was used to identify factors independently associated with listing. RESULTS: Between February 2000 and April 2012, 366 patients were evaluated for LT, with 66 (18.0%) listed for LT and 300 (82.0%) not listed. Fifty-one patients (13.9%) died before completing evaluation and 85 (23.2%) were too early for listing. Reasons patients were declined for listing were psychosocial (15.8%), HIV-related (10.4%), loss to follow-up (9.6%), surgical/medical (6.0%), liver-related (4.4%), patient choice (3.4%), and financial (1.6%). Listed patients were more likely to have hepatocellular carcinoma (HCC) (43.1% vs. 17.1%; P < 0.0001) and less likely to have hepatitis B (6.2% vs. 15.7%; P = 0.04) or a psychiatric history (19.7% vs. 35.2%; P = 0.02) than those not listed. In multivariable analysis, HCC (odds ratio [OR] 5.79; 95% confidence interval [95% CI]: 2.97-11.28), model for end-stage liver disease (MELD) score at referral (OR 1.06; 95% CI 1.01-1.11), and hepatitis B (OR 0.26; 95% CI 0.08-0.79) were associated with listing. CONCLUSION: MELD score and HCC were positive predictors of listing in HIV-infected patients referred for LT evaluation and, therefore, timely referrals are vital in these patients. As MELD is a predictor for death while undergoing evaluation, rapid evaluation should be performed in HIV-infected patients with a higher MELD score.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir.

BACKGROUND: Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients. AIM: To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting. METHODS: Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event. RESULTS: Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03). CONCLUSIONS: Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Liver transplantation is possible in some patients with liver metastasis of colon cancer.

Liver metastases from colorectal cancer are an absolute contraindication for liver transplantation. Aggressive therapy with liver resection and local chemotherapy in selected patients may be able to provide long-term cure. Given the risks of tumor recurrence, whether patients with post chemotherapy complications leading to liver failure should be offered transplantation is a challenging question in an era of limited organ availability. Herein we have presented 2 cases of liver transplantation performed in patients with colorectal cancer metastases treated with liver resection followed by hepatic artery infusion chemotherapy leading to development of sclerosing cholangitis and eventual liver failure. This report demonstrates that liver transplantation may be an option in selected patients with colorectal cancer liver metastases that have been well treated.

Pneumatosis intestinalis and mesenteric venous gas - a manifestation of bacterascites in a patient with cirrhosis.

We herein report a patient with decompensated cirrhosis secondary to autoimmune hepatitis, who presented with pneumatosis intestinalis (PI) and portal venous gas. Mesenteric ischemia has been recognized as a common and life-threatening cause of PI which portends a grave prognosis. The patient was found to have bacterascites and recovered after appropriate antibiotic therapy. Spontaneous bacterial peritonitis/bacterascites with gas-forming organisms manifesting as PI has not been previously reported.

Factors associated with persistent thrombocytopenia after liver transplantation.

BACKGROUND: Thrombocytopenia typically resolves with resolution of portal hypertension after liver transplantation (LT) but persists in some patients. Identifying risk factors associated with persistent post- LT thrombocytopenia may provide important information about its pathogenesis. METHODS: Cirrhotic adults with platelet levels of <150,000 mu/L at the time of LT and followed at least 1 year were studied. A retrospective analysis of lab values, radiologic spleen index (SI), and donor data using nonparametric methods was performed to characterize patients having persistent thrombocytopenia, defined as persistently low platelet levels at 3 and 12 months after LT. RESULTS: One hundred patients were studied: mean age 55 y (range 23-75 y); platelet count at LT 62,000/microL (range 14,000- 148,000/microL; mean total bilirubin 2.6 mg/dL; mean Mayo end-stage liver disease score 29; SI 1,476 (range 347-4,843 mL; normal 120-480 mL). Platelet count at 3 and 12 months after LT correlated with SI (r = -0.41 and -0.54; P < .001). Fifty-seven patients had persistent thrombocytopenia. Compared with patients whose platelet levels normalized by month 3 or 12, they had higher SI and lower platelet count before LT (P < .001). The SI and platelet levels at the time of LT were independent predictive factors for platelet levels at 3 and 12 months after LT (P < .001). CONCLUSIONS: High SI and low platelet count at the time of LT are associated with persistent thrombocytopenia after LT. They are also independent predictive factors of platelet levels at 3 and 12 months after LT. This suggests that patients may have persistent thrombocytopenia after LT owing to persistence of some degree of hypersplenism and incomplete resolution of splenomegaly.

Image segmentation of liver fibrosis.

Quantitation of connective tissue versus parenchymal tissue compartments is important in assessment of fibrosis (scarring) and its progression in liver disease. This paper presents a two-step algorithm for quantifying fibrosis in liver biopsies stained with Sirius red. With this staining technique, collagen and cell nuclei appear similarly stained, whereas cytoplasm appears pale. The first step of the algorithm is to separate similarly stained areas occupied by collagen and hepatocyte nuclei. Since the total area of the combined collagen and cell nuclei is usually much smaller than the remaining liver parenchyma, a non-linear intensity mapping is applied to enhance the smaller cluster in order to match the larger one in both intensity and size. The second step is to differentiate the fibrotic areas usually having irregular shapes from hepatocyte nuclei that have relatively uniform size and have circular shape. The proposed algorithm has been applied to quantify the development of progressive fibrosis and its possible regression in liver biopsy specimens from patients with parenteral-induced liver injury undergoing intestinal transplantation.

The burden of chronic kidney disease in long-term liver transplant recipients.

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for morbidity and mortality post-liver transplantation (OLT). This study focused on investigating the incidence and risk factors associated with the development CKD after OLT. METHODS: We performed a retrospective cohort study of recipients followed at least 5 years at our institution. CKD was diagnosed and classified according to National Kidney Foundation and the Kidney Disease Outcomes Quality Initiative guidelines. RESULTS: There were 231 patients, 64% men, 67% Caucasian, 16% African-American, and 17% others, with a mean age of 56 +/- 13 years. The mean glomerular filtration rate (GFR) of the population was 56 +/- 28 mL/min/1.73 m2. CKD was defined as GFR less than 60 mL/min; 144 patients (61%) were identified as having CKD. When these patients were compared to the non-CKD group, the former were significantly older (62 +/- 9 vs 52 +/- 12 years, P = .03), more likely to be hypertensive (59% vs 38%, P = .003), and required more antihypertensive medications (0.83 +/- 0.81 vs 0.52 +/- 0.77, P = .02); 26% of all patients had diabetes. However, the incidence of diabetes (43.3% vs 19.3%, P = .02) as well as the incidence of insulin dependency (21.6% vs 12.5%, P = .001) was significantly higher in the CKD population. Mean uric acid levels were higher in CKD patients compared to non-CKD patients (8.00 +/- 2.00 mg/dL vs 6.70 +/- 1.99 mg/dL respectively, P = .001); patients with uric acid more than 6.0 had a 1.7 risk of having CKD. CONCLUSIONS: CKD defined as GFR < 60 mL/min is highly prevalent in long-term OLT survivors. Older age, elevated systolic blood pressure, insulin-dependent diabetes mellitus, and elevated uric acid levels are independently associated with CKD.

Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus recurrence after liver transplantation.

BACKGROUND: Because of a critical shortage of deceased donor (DD) livers, more extended criteria allografts are being utilized; these allografts are at increased risk for ischemia-reperfusion injury (IRI). We assessed whether, in a large cohort of patients transplanted for hepatitis C virus (HCV) either via a DD or live donor (LD), there was a relationship between the degree of IRI and the frequency and timing of acute cellular rejection (ACR) and histologic HCV recurrence. METHODS: During an 8-year study, patients were separated into four groups based on peak alanine aminotransferase (ALT) levels and three groups based on severity of IRI on postreperfusion liver biopsy. RESULTS: The mean follow-up time of 433 DD and 44 LD recipients was 1212 days. We noted a strong correlation in DD between peak ALT and the histologic degree of IRI (P = .01). There was no difference in the incidence or grade of ACR among the four groups. There was no correlation between the severity of IRI and the incidence or time to histologic recurrence of HCV. CONCLUSIONS: The magnitude of peak ALT correlated with the severity of IRI on postreperfusion liver biopsy. Among this large HCV cohort, there was no correlation between the severity of IRI and the incidence or timing of histologic HCV recurrence or incidence of ACR.

Development of hepatic granulomas in patients receiving pegylated interferon therapy for recurrent hepatitis C virus post liver transplantation.

UNLABELLED: Infrequently, hepatitis C (HCV) appears to be the cause of hepatic granulomas. Interferon therapy for HCV has been increasingly associated with the development of sarcoidosis. AIMS: We sought to determine the incidence of hepatic granulomas in patients with recurrent HCV post liver transplantation (LT). METHODS: Between 1994 and 2005, 820 patients were transplanted for HCV at our institution. The pathology database was searched for patients having recurrent HCV and granulomas. At Mount Sinai Medical Center, protocol biopsies have been performed for the last 2 years in patients receiving pegylated interferon-alpha2b and ribavirin (PEG) for recurrent HCV. Review of slides from explanted livers, pre- and post-perfusion biopsies, and all allograft biopsies were evaluated. Lipogranulomas were excluded because of their frequent association with steatosis. RESULTS: A total of 10,225 liver biopsies were performed on HCV patients, and 25 (0.24%) showed non-caseating epithelioid granulomas. Hepatic granulomas were detected in 14 post-LT HCV patients; 9 patients received PEG. Typically, only 1 lobular granuloma was found. None of these patients had granulomas in the native liver or in any biopsy before interferon therapy; 6/9 patients had undetectable HCV-RNA levels, and 4 had sustained viral response. No other cause for granuloma formation was identified in the 6 patients. CONCLUSIONS: Hepatic granulomas are infrequently found in HCV liver biopsies and rarely found in post-LT biopsies with recurrent HCV. When present, they occur more commonly in patients receiving and virologically responding to PEG therapy. The presence of granulomas in patients with HCV being treated with PEG may not warrant an extensive etiologic work-up for granulomatous hepatitis unless otherwise clinically indicated.

Comparison of hepatitis C histological recurrence rates and patient survival between split and deceased donor liver transplantation.

INTRODUCTION: Controversy exists as to whether there is an increased severity or frequency of recurrent hepatitis C viral (HCV) infection in recipients of adult living donor liver transplantation (LDLT) grafts. We sought to examine the time to histological recurrence and survival in HCV (+) patients who underwent split liver transplantation (SLT), which is technically similar to what occurs in the LDLT procedure. METHODS: Twenty four HCV (+) adult recipients were identified through the UNOS database as having had SLT procedures at three centers: Mount Sinai Medical Center, University of Chicago, and University of California at Los Angeles. Of these, 17 patients with comprehensive data were matched to 32 HCV (+) patients who underwent whole deceased donor liver transplantation (DDLT) during the same time period. Outcome and time to initial HCV recurrence as documented by liver biopsy were assessed. Liver biopsy was performed when clinically indicated. RESULTS: Patients who had SLT were significantly older (P=.01). There was no difference in number of rejection episodes (P=.40). Fifteen of 17 SLT (88%) versus 24/32 DDLT (75%) patients had documented HCV recurrence by biopsy (P=.46). The time to median cumulative incidence of recurrence of HCV post-liver transplantation was 12.6 months (SLT) versus 39.8 months (DDLT) patients. There was no difference in survival between SLT and DDLT patients (47 vs 70 months, P=.62) nor in cumulative incidence of histological HCV recurrence at 1, 2, and 3 years (P=.198, .919, and .806, respectively). CONCLUSION: There is no difference in the cumulative incidence of histological recurrence of HCV post-liver transplant or in survival between recipients of deceased donor and split liver transplants.

Review article: drug hepatotoxicity.

BACKGROUND: Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. AIMS: (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre-existing liver disease and in the post-liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. METHODS: A Medline search was performed to identify relevant literature using search terms including 'drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics'. RESULTS: Amoxicillin-clavulanic acid is one of the most frequently implicated causes of drug-induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co-infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. CONCLUSIONS: Drug-induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.

Identification of ultrastructural changes in liver allografts of patients experiencing primary nonfunction.

BACKGROUND: Primary nonfunction (PNF) after liver transplantation is fatal without timely retransplantation. PNF has been associated with many risk factors, but the etiology remains unknown in most cases. Using electron microscopy, we examined the hepatic ultrastructure of donor allografts in patients experiencing PNF and compared the findings with a well-matched group of other donor allografts. MATERIALS AND METHODS: Archival paraffin-embedded pre- and post-reperfusion donor liver biopsies were examined by electron microscopy in 10 patients with PNF and in 10 controls, matched by donor age +/- 5 years, gender, cold ischemic time +/- 1 hour, and donor cause of death. Mitochondria, endoplasmic reticulum, sinusoidal endothelial cells, and the glycogen content of the cells were assessed. The donors' serum peak transaminases, bilirubin and sodium levels, as well as the recipient age and serum creatinine were compared. RESULTS: There were no significant differences in recipient age at the time of transplantation, peak recipient serum creatinine, donor peak serum transaminase, sodium or bilirubin levels. In all cases, the endoplasmic reticulum and sinusoidal endothelial cells were ultrastructurally normal. Hepatocytes had variable degrees of glycogen pooling. Hepatic steatosis and intramitochondrial inclusions cells were present in 5/10 PNF compared to 0/10 controls patients on preperfusion liver biopsy (P = .17). CONCLUSION: Liver allografts from patients suffering from PNF can have mitochondrial ultrastructural changes on preperfusion biopsies.

Results of steroid-based therapy for the hepatitis C-autoimmune hepatitis overlap syndrome.

OBJECTIVE: Overlap syndromes in which persons manifest clinical, histological, or immunological features of both hepatitis C infection and autoimmune hepatitis are well described. The discordant forms of treatment for hepatitis C and autoimmune hepatitis have made medical management of these patients difficult. We report our experience in using corticosteroids as first line therapy for the hepatitis C-autoimmune hepatitis overlap syndrome. METHODS: Seven patients with this overlap syndrome (diagnosis based on the presence of serum hepatitis C antibody by RIBA and serum hepatitis C RNA by polymerase chain reaction, and serum hypergammaglobulinemia, elevated ANA or ASMA titers, or histological findings consistent with autoimmune hepatitis) were treated with prednisone with or without azathioprine or cyclosporine, and followed for a median duration of 44.5 months. RESULTS: Five patients (71%) showed improvement of median serum ALT level from 162 U/L to 38 U/L (p = 0.04) and median serum gamma-globulin from 2.1 g/dl to 1.4 g/dl (p = 0.04) by 6 months of therapy. The mean modified histological activity index score also decreased from 11.4 +/- 2.5 to 6.6 +/- 2.6 (p = 0.04) by at least 1 yr of therapy. One patient discontinued prednisone while taking azathioprine and experienced a rebound elevation of serum ALT that did not respond to retreatment with prednisone. Antiviral therapy was subsequently administered and resulted in biochemical and virologic response. Hepatitis C virus RNA remained detectable in all other patients. CONCLUSION: Corticosteroids are beneficial as a first line therapy for some patients with the hepatitis C-autoimmune overlap syndrome, resulting in appreciable biochemical and histological response but without viral eradication.