bluuebunny/crossref_metadata_2025 huggingface dataset:
Lamivudine Treatment Is Beneficial in Patients With Severely Decompensated Cirrhosis and Actively Replicating Hepatitis B Infection Awaiting Liver Transplantation: A Comparative Study Using A Matched, Untreated Cohort
Authors: Yao Francis Y. , Terrault Norah A. , Freise Chris , Maslow Lin , Bass Nathan M.
Published: August 2002

Uncontrolled studies have suggested a beneficial effect of lamivudine in patients with decompensated cirrhosis caused by replicating hepatitis B virus (HBV). We analyzed the outcome of lamivudine treatment in 23 consecutive patients with severely decompensated HBV–cirrhosis defined as a Child–Pugh–Turcotte (CPT) score of ≥10, and compared with a historical untreated control group of 23 patients matched for age, gender, and baseline CPT score. Significant clinical response, defined as a decrease in the CPT score by ≥3 points, was observed in 14 of 23 (60.9%) treated patients versus none of the controls (P < .0001). The median change in CPT scores was -3.0 (range, -6 to +3) in the treated group versus +1.0 in the controls (range, -1 to +2) (P = .016). Orthotopic liver transplantation (OLT) was performed in 34.8% of treated patients (median, 3.5; range, 1–32 months), versus 73.9% of controls (median, 3.0; range, 1–14 months) (P = .04). Excluding transplanted patients, there were no deaths in the treated group versus 6 deaths in the control group (P = .009). Time to death or OLT was significantly longer in treated patients than in controls (P < .001). Two patients developed lamivudine resistance after 9 and 12 months, respectively. Our results suggest that lamivudine significantly improves hepatic function in over half of the patients with decompensated cirrhosis and replicating HBV, and may confer a survival advantage. However, the small sample size and the use of a retrospective control cohort preclude drawing definitive conclusions. Expedited OLT remains the only viable treatment for lamivudine nonresponders.
Hepatocellular carcinomas in native livers from patients treated with orthotopic liver transplantation: Biologic and therapeutic implications
Authors: Kirimlioglu Hale , Dvorchick Igor , Ruppert Kris , Finkelstein Sydney , Marsh Wallis J. , Iwatsuki Shunzaburo , Bonham Andrew , Carr Brian , Nalesnik Michael , Michalopoulos George , Starzl Thomas , Fung John , Demetris Anthony
Published: August 2002

The gross and histopathologic characteristics of 212 nonfibrolamellar hepatocellular carcinomas (HCCs) discovered in native livers removed at the time of liver transplantation were correlated with features of invasive growth and tumor-free survival. The results show that most HCCs begin as small well-differentiated tumors that have an increased proliferation rate and induce neovascularization, compared with the surrounding liver. But at this stage, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear within the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular invasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P < .006), apoptosis/mitosis ratio (P < .03), and number of tumors (P < .04) were independent predictors of tumor-free survival and none of 24 patients with tumors having an apoptosis/mitosis ratio greater than 7.2 had recurrence. A minority of HCCs (<15%) quickly develop aggressive features (moderate or poor differentiation, low apoptosis/mitosis ratio, and vascular invasion) while still small, similar to flat carcinomas of the bladder and colon. In conclusion, hepatic carcinogenesis in humans is a multistep and multifocal process. As in experimental animal studies, aggressive biologic behavior (vascular invasion and recurrence) correlates significantly with profound alterations in the apoptosis/mitosis ratio and with architectural and cytologic alterations that suggest a progressive accumulation of multiple genetic abnormalities. (Hepatology 2001;34:502-510.)
Low-molecular-weight hyaluronic acid induces nuclear factor-κB-dependent resistance against tumor necrosis factor α-mediated liver injury in mice
Authors: Wolf Dominik , Schümann Jens , Koerber Kerstin , Kiemer Alexandra K. , Vollmar Angelika M. , Sass Gabriele , Papadopoulos Thomas , Bang Renate , Klein Sabine D. , Brüne Bernhard , Tiegs Gisa
Published: August 2002

Liver resident NK1.1+ T cells are supposed to play a pivotal role in the onset of inflammatory liver injury in experimental mouse models such as concanavalin A (Con A)-induced hepatitis. These cells, expressing the adhesion receptor, CD44, are largely depleted from the liver by a single intravenous injection of low-molecular-weight fragments of hyaluronic acid (LMW-HA). Here, we report that LMW-HA pretreatment protected mice from liver injury in several models of T-cell- and macrophage-dependent, tumor necrosis factor α (TNF-α)-mediated inflammatory liver injury, i.e., from liver injury induced by either Con A or Pseudomonas exotoxin A (PEA) or PEA/lipopolysaccharide (LPS). Interestingly, apart from inhibition of cellular adhesion, pretreatment of mice with LMW-HA was also capable of preventing hepatocellular apoptosis and activation of caspase-3 induced by direct administration of recombinant murine (rmu) TNF-α to D-galactosamine (GalN)-sensitized mice. LMW-HA-induced hepatoprotection could be neutralized by pretreatment with the nuclear factor-κB (NF-κB) inhibitor, pyrrolidine dithiocarbamate (PDTC), demonstrating the involvement of NF-κB in the observed protective mechanism. Indeed, injection of LMW-HA rapidly induced the production of TNF-α by Kupffer cells and the translocation of NF-κB into hepatocellular nuclei. Both LMW-HA-induced TNF-α production and NF-κB translocation were blocked by pretreatment with PDTC. Our findings provide evidence for an unknown mechanism of LMW-HA-dependent protection from inflammatory liver disease, i.e., induction of TNF-α- and NF-κB-dependent cytoprotective proteins within the target parenchymal liver cells. (Hepatology 2001;34:535-547.)
Discrimination value of the new western prognostic system (CLIP score) for hepatocellular carcinoma in 662 Japanese patients
Authors: Ueno Shinichi , Tanabe Gen , Sako Katsumi , Hiwaki Takuya , Hokotate Hirohumi , Fukukura Yoshihiko , Baba Yoshirou , Imamura Yasushi , Aikou Takashi
Published: August 2002

To reliably estimate the prognoses of patients with hepatocellular carcinoma (HCC), both liver function and tumor-related factors should be accounted for. However, there are few worldwide staging systems that assess prognostic value in the context of selecting individual patients for randomized stratification in therapeutic and clinical trials. We investigated the value of known prognostic systems and verified the usefulness of the new scoring system proposed by the Cancer of the Liver Italian Program (CLIP), as determined from 662 Japanese patients. A retrospective analysis of the HCC diagnoses at 4 Japanese institutions from 1990 and 1998 was performed. Overall survival was the only end point used in the analysis. Discriminatory ability and predictive power of the CLIP score were compared with those of Okuda stage and AJCC TNM stage. Compared with the Okuda and AJCC staging systems, the CLIP score's enhanced discriminatory capacity, which was tested by the linear trend test and Harrels' c-index, revealed a class of patients with an impressively more favorable prognosis and another class with a relatively shorter life expectancy. Moreover, the likelihood ratio test showed that the CLIP score had additional homogeneity of survival within each score above that of the Okuda stage or the AJCC stage. This was true for 3 subgroups of patients who received surgery, transcatheter arterial chemoembolizations, and percutaneous ethanol injections. Collectively, these findings indicate that the CLIP score has the highest stratification ability with regard to prognosis in patients with HCC. The CLIP score could be used internationally to stratify randomization groups in therapeutic and clinical trials. (Hepatology 2001;34:529-534.)
Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles
Authors: Wiencke Kristine , Spurkland Anne , Schrumpf Erik , Boberg Kirsten Muri
Published: August 2002

Susceptibility to primary sclerosing cholangitis (PSC) is associated with HLA-B8, -DR3, -DR2, and -DR6. It is not established whether these HLA genes or closely linked genes confer the primary disease susceptibility. MICA and MICB genes are found in the class I region between HLA-B and DRB. MICA is expressed in gastrointestinal epithelium and activates γδ T cells in the gut. Because PSC is strongly associated with inflammatory bowel disease, we investigated whether MICA and MICB contribute to the HLA-associated genetic susceptibility to develop PSC. The study included 130 PSC patients and 306 healthy controls, previously typed for HLA class I and II genes, typed for 5 MICA and 15 MICB microsatellite alleles. The phenotype frequencies of MICA5.1 and MICB24 were significantly increased among PSC patients compared with controls (90% vs. 74%; odds ratio [OR] = 3.2; P
c = 3 × 10−3 and 58% vs. 29%; OR = 3.3; P
c < 1 × 10−7, respectively). When stratified for B8- or DR3-positive and -negative individuals, the association of these markers to PSC was no longer evident. However, we observed that B8 and DR3 were associated to PSC only in the presence of both MICA5.1 and MICB24 markers. The frequency of individuals carrying all 4 alleles was significantly increased among the PSC patients compared with controls (49% vs. 18%; OR = 4.5; P
c < 1 × 10−7). Our data indicate that PSC is associated to the extended B8-MICA5.1-MICB24-DR3 haplotype.
Autoimmune hepatitis with incidental histologic features of bile duct injury
Authors: Czaja Albert J. , Carpenter Herschel A.
Published: August 2002

Bile duct changes are atypical of autoimmune hepatitis. Our aims were to assess the frequency and significance of these changes in classical disease. Liver biopsy specimens were reviewed under code from 84 patients who satisfied international scoring criteria for autoimmune hepatitis, and the findings were correlated with clinical features and outcome. Twenty patients (24%) had biliary changes, including 6 with destructive cholangitis, 4 with ductopenia, and 10 with nondestructive cholangitis. Patients with and without bile duct changes had similar laboratory findings. Diagnostic scores for autoimmune hepatitis were lower in patients with bile duct changes (16.6 ± 0.6 vs. 19.1 ± 0.2, P < .0001). The frequencies of scores sufficient for a definite (80% vs. 97%, P = .03) or probable diagnosis (20% vs. 3%, P = .03) were also less in this group. Patients with destructive cholangitis and/or ductopenia responded as well to therapy as patients with nondestructive cholangitis, and outcomes in each group were similar to those of patients without biliary changes. We concluded that biliary changes can occur in classic autoimmune hepatitis, and they are not associated with distinctive clinical features or treatment response. They may be coincidental findings associated with classic disease or weak expressions of a variant syndrome. In the absence of a cholestatic clinical syndrome, they do not compel a different management strategy.
Estimating progression to cirrhosis in chronic hepatitis C virus infection
Authors: Freeman Anthony J. , Dore Gregory J. , Law Matthew G. , Thorpe Max , Von Overbeck Jan , Lloyd Andrew R. , Marinos George , Kaldor John M.
Published: August 2002

To gain a clearer understanding of the rate of progression to cirrhosis and its determinants in chronic hepatitis C virus (HCV) infection, a systematic review of published epidemiologic studies that incorporated assessment for cirrhosis has been undertaken. Inclusion criteria were more than 20 cases of chronic HCV infection, and information on either age of subjects or duration of infection. Of 145 studies examined, 57 fulfilled the inclusion criteria. Least-squares linear regression was employed to estimate rates of progression to cirrhosis, and to examine for factors associated with more rapid disease progression in 4 broad study categories: 1) liver clinic series (number of studies = 33); 2) posttransfusion cohorts (n = 5); 3) blood donor series (n = 10); and 4) community-based cohorts (n = 9). Estimates of progression to cirrhosis after 20 years of chronic HCV infection were 22% (95% CI, 18%-26%) for liver clinic series, 24% (11%-37%) for posttransfusion cohorts, 4% (1%-7%) for blood donor series, and 7% (4%-10%) for community-based cohorts. Factors that were associated with more rapid disease progression included older age at HCV infection, male gender, and heavy alcohol intake. Even after accounting for these factors, progression estimates were much higher for cross-sectional liver clinic series. Selection biases probably explain the higher estimates of disease progression in this group of studies. Community-based cohort studies are likely to provide a more representative basis for estimating disease progression at a population level. These suggest that for persons who acquire HCV infection in young adulthood, less than 10% are estimated to develop cirrhosis within 20 years. (Hepatology 2001;34:809-816.)
Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa of portal hypertensive rats: Potential therapeutic implications
Authors: Kawanaka Hirofumi , Tomikawa Morimasa , Jones Michael K. , Szabo Imre L. , Pai Rama , Baatar Dolgor , Tsugawa Kouji , Sugimachi Keizo , Sarfeh James I. , Tarnawski Andrzej S.
Published: August 2002

Portal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as reduced mucosal potential differences, reduced surface oxygenation, and increased susceptibility to injury caused by alcohol, aspirin, and other noxious factors. Because such mucosal injury is initially mediated by oxygen free radicals, and because mitogen-activated protein (MAP) kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from the underlying and continual oxidative state associated with portal hypertension, and is ameliorated by inhibiting MKP-1. Furthermore, we found that supplementing vitamin E, a free radical scavenger, reduces the oxidative state in PHT gastric mucosa, normalizes MKP-1 expression, and thereby reverses impairment of oxidative stress-induced ERK2 activation. Finally, we show that orally administered vitamin E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic basis for PHT gastropathy and provide a new therapeutic modality for protection of PHT gastric mucosa.
Analysis of hepatitis B viral load decline under potent therapy: Complex decay profiles observed
Authors: Lewin Sharon R. , Ribeiro Ruy M. , Walters Tomos , Lau George K. , Bowden Scott , Locarnini Stephen , Perelson Alan S.
Published: August 2002

We used a new real-time polymerase chain reaction (PCR)-based assay that is sensitive, has a wide dynamic linear range, and is highly reproducible to quantify hepatitis B virus (HBV) DNA in the serum of infected individuals undergoing potent antiviral therapy. In addition, we made frequent measurements of viral load after initiation of treatment and maintained follow-up to about 12 weeks. To analyze the data we used a new model of HBV decay, which takes into account that existing drug treatments do not completely block de novo infection and the possibility of noncytolytic loss of infected cells. On initiation of therapy, there was a mean delay of 1.6 days followed by a biphasic or muliphasic decay of plasma HBV DNA. The slope of the first phase varied considerably, with one individual having rapid decay, corresponding to a virion half-life of 1 hour, but others showing half-lives of up to 92 hours. Individuals either had a slow second-phase decline (t
½ = 7.2 ± 1.2 days) or a flat second phase. Some individuals exhibited a complex “staircase pattern” of decay, with further phases of viral DNA decline and phases with little change in viral load.
1α,25-Dihydroxycholecalciferol reduces rejection and improves survival in rat liver allografts
Authors: Redaelli Claudio A. , Wagner Markus , Tien Ying-Hua , Mazzucchelli Luca , Stahel Philip F. , Schilling Martin K. , Dufour Jean-François
Published: August 2002

Vitamin D3 affects the immuno response and improves experimental autoimmune diseases. We investigated the effect of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) Rocaltrol as a single immunosuppresive agent and in combination with low-dose cyclosporin A (CsA) in vascularized liver allografts in rats in a high-responder strain combination (ACI⇒Lewis). Recipients were placed on a low-calcium diet 7 days before transplantation and were treated with 0.1 or 1 μg/kg/d 1,25(OH)2D3 intraperitoneally beginning 3 days before transplantation. Treatment combining 1,25(OH)2D3 with CsA (2 mg/kg/d) was also tested. Graft function and survival, histologic rejection, and concentrations of interleukin (IL)-2, -4, -10, and -12 in serum and in grafts were measured. 1,25(OH)2D3 increased allograft survival in a dose-dependent manner when compared with controls (P < .05 for both groups). Serum bilirubin, aspartate transaminase (AST), and lactate dehydrogenase (LDH) activities were significantly lower in 1,25(OH)2D3-treated animals. Vitamin D reduced the concentration of IL-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity index 10 days after transplantation was significantly lower in low- and high-dose 1,25(OH)2D3-treated rats compared with vehicle-treated controls (P < .0001 for both groups). The combination of either low-dose or high-dose vitamin D3 and CsA prolonged graft survival when compared with low-dose CsA only (P < .05 for both groups). After 3 weeks, hypercalcemia developed in high-dose 1,25(OH)2D3-treated rats. It is concluded that 1,25(OH)2D3 prolongs survival of liver allografts in rats by decreasing the severity of acute rejection. Analogues of vitamin D with fewer hypercalcemic effects may have potential as immunosuppressive drugs in liver transplantation.
Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes
Authors: Alpini Gianfranco , Ueno Yoshiyuki , Glaser Shannon S. , Marzioni Marco , Phinizy Jo Lynne , Francis Heather , LeSage Gene
Published: August 2002

Bile acids (BA) enter cholangiocytes by the Na+-dependent apical BA transporter (ABAT). By this mechanism, taurocholate (TC) and taurolithocholate (TLC) increase cholangiocyte proliferation. No in vivo studies exist regarding the anatomical sites involved in BA-regulation of cholangiocyte growth. Specific cholangiocyte subpopulations participate in BA-regulated proliferation. Proliferation was assessed in liver sections by determining the number of proliferating cellular nuclear antigen (PCNA)-positive cholangiocytes and cytokeratin-19 (CK-19)-positive ducts. We isolated small and large cholangiocytes from rats fed for 1 week TC, TLC, or BA control diet and determined PCNA and ABAT expression and BA transport activity. We evaluated if TC and TLC induction of ABAT expression was dependent on activation of PKC alpha. DNA replication was active only in large normal cholangiocytes. TC and TLC feeding increased proliferation of large cholangiocytes, induced the de novo activation of proliferation of small cholangiocytes, overexpression of ABAT and BA transport activity in large cholangiocytes, and de novo expression of ABAT and BA transport activity in small cholangiocytes. BA-stimulated ABAT expression was dependent on PKC activation in cholangiocytes. TC and TLC stimulate proliferation of small and large cholangiocytes associated with PKC-dependent up-regulation of ABAT.
Alcohol-induced free radicals in mice: Direct toxicants or signaling molecules?
Authors: Yin Ming , Gäbele Erwin , Wheeler Michael D. , Connor Henry , Bradford Blair U. , Dikalova Anna , Rusyn Ivan , Mason Ronald , Thurman Ronald G.
Published: August 2002

Tumor necrosis factor α (TNF-α) and free radicals are produced in early alcohol-induced liver injury. Recently, pathology caused by alcohol was blocked nearly completely in tumor necrosis factor α receptor 1 (TNF-R1) knockout mice. With this model, it is now possible to evaluate whether free radicals are directly toxic or act as redox regulators of TNF-α production. Specifically, if free radicals were directly toxic, a parallel decrease in free radicals and pathology in TNF-R1 knockout mice would be predicted. If they only affect TNF-α production, radicals would be expected to remain high while pathology is diminished. Accordingly, free radical production in TNF-R1 knockout mice was studied here. The enteral alcohol delivery model used mice lacking TNF-R1 (p55) and wild-type control C57Bl/6J mice. Animals received a liquid diet continuously with either ethanol or isocaloric maltose-dextrin as control for 4 weeks. Urine ethanol levels fluctuated from 10 to 500 mg/dL in a cyclic pattern in mice receiving ethanol. Ethanol elevated liver:body weight ratios, serum alanine transaminase (ALT) levels, and pathology scores in wild-type mice. These parameters were blunted nearly completely in TNF-R1 knockout mice. Ethanol treatment increased free radical production in wild-type mice compared with animals fed a high-fat control diet. There were no differences in intensity of free radical signals regardless of the presence or absence of TNF-R1; however, pathology differed markedly between these groups. These findings are consistent with the hypothesis that free radicals act as redox signals for TNF-α production and do not directly damage cells in early alcohol-induced hepatic injury.
Effective treatment of small murine hepatocellular carcinoma by dendritic cells
Authors: Lee Wei-Chen , Wang Hui-Chuan , Jeng Long-Bin , Chiang Yang-Jen , Lia Chen-Rong , Huang Pei-Fang , Chen Miin-Fu , Qian Shiguang , Lu Lina
Published: August 2002

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. This investigation examined whether dendritic cell-based immunotherapy can treat murine HCC effectively. Bone marrow-derived dendritic cells were propagated from C57BL/10J mice in GM-CSF (4 ng/mL) and interleukin (IL)-4 (1,000 μ/mL). The dendritic cells were pulsed with a Hepa1-6 lysate overnight and employed to treat murine HCC. For in vivo study, HCC was created by inoculation of hepa1-6, 5 × 105 cells, in the flank of C57BL/10J mice. HCC were categorized into small (3 × 3-mm) and large (5 × 5-mm) tumors. These HCC were treated by dendritic cells intravenously, twice at weekly intervals. The results revealed that lymphocytes could be gathered around small HCC after administration of Hepa1-6 lysate-pulsed dendritic cells. Seven of 12 (58.3%) small HCC could be eradicated completely by dendritic cell-based immunotherapy, and 33.3% of the small tumors responded to immunotherapy partially which were held in a stable condition for 34.0 ± 7.4 days before the tumors regrew. For large HCC, lymphocytes did not gather around the tumors, and the tumors cannot be eradicated effectively by dendritic cells. However, dendritic cell-based immunotherapy could slow down the growth rate of large tumors (116.2 ± 91.4 mm3 vs. 234.0 ± 149.1 mm3 of the control on day 7, P = .043; and 280.3 ± 224.7 mm3 vs. 870.0 ± 418.9 mm3 of the control on day 17, P < .001). Conclusively, dendritic cells pulsed with a Hepa1-6 lysate can be employed to treat small HCC in vivo effectively. However, the efficacy of dendritic cell-based immunotherapy decreases while tumors grow.
Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat
Authors: Peralta Carmen , Bartrons Ramón , Serafin Anna , Blázquez Cristina , Guzmán Manuel , Prats Neus , Xaus Carme , Cutillas Blanca , Gelpí Emilio , Roselló-Catafau Joan
Published: August 2002

Hepatic ischemia-reperfusion (I/R) injury associated with liver transplantation and hepatic resections are an unresolved problem in the clinical practice. Preconditioning is known to preserve energy metabolism in liver during sustained ischemia, but the molecular mechanisms underlying this effect are still unclear. Different metabolic signals, including adenosine monophosphate (AMP) and nitric oxide (NO), have been implicated in preconditioning. AMP-activated protein kinase (AMPK) protects cells by acting as a low-fuel warning system, becoming switched on by adenosine triphosphate (ATP) depletion. NO synthesis is induced by AMPK in the heart during ischemia. The aim of this study was to investigate: 1) whether preconditioning induces AMPK activation; and 2) if AMPK activation leads to ATP preservation and reduced lactate accumulation during prolonged ischemia and its relationship with NO. Preconditioning activated AMPK and concomitantly reduced ATP degradation, lactate accumulation, and hepatic injury. The administration of an AMPK activator, AICAR, before ischemia simulated the benefits of preconditioning on energy metabolism and hepatic injury. The inhibition of AMPK abolished the protective effects of preconditioning. The effect of AMPK on energy metabolism was independent of NO because the inhibition of NO synthesis in the preconditioned group and the administration of the NO donor before ischemia, or to the preconditioned group with previous inhibition of AMPK, had no effect on energy metabolism. Both preconditioning and AICAR pretreatment, through AMPK activation, may be useful surgical and pharmacologic strategies aimed at reducing hepatic I/R injury.
New challenge of hepatorenal syndrome: Prevention and treatment
Authors: Wong Florence , Blendis Laurence
Published: August 2002

Hepatorenal syndrome (HRS) remains one of the major therapeutic challenges in hepatology today. The pathogenesis is complex, but the final common pathway seems to be that sinusoidal portal hypertension, in the presence of severe hepatic decompensation, leads to splanchnic and systemic vasodilatation and decreased effective arterial blood volume. Renal vasoconstriction increases concomitantly, renal hemodynamics worsens, and renal failure occurs. Renal failure was shown 15 years ago to be potentially reversible after liver transplantation. This potential reversibility together with increased understanding of the pathogenesis has led to successful preliminary attempts to reverse HRS nonsurgically with combinations of splanchnic vasoconstrictors and colloid volume expansion, insertion of transjugular intrahepatic portovenous shunt radiologically, and improved forms of dialysis. Recent classification of HRS into the acute onset or severe type 1 with virtually 100% mortality and the more insiduous less severe type II promises to shed more light on the pathogenesis of HRS, especially on the currently unrecognized precipitating factors. It is hoped that this classification will be included in the necessary and carefully performed clinical trials, which should lead to clearer indications for the available therapies. The challenge now is to use all this information to improve our management of cirrhotic patients to prevent occurrence of HRS in the future.
Contrast-enhanced doppler ultrasonography in the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis
Authors: Fracanzani Anna Ludovica , Burdick Larry , Borzio Mauro , Roncalli Massimo , Bonelli Nicola , Borzio Franco , Maraschi Alessandra , Fiorelli Gemino , Fargion Silvia
Published: August 2002

Hepatocellular carcinogenesis in cirrhosis is a multistage process that includes large regenerative nodules, dysplastic nodules, and hepatocarcinoma. The aim of this study was to establish whether contrast-enhanced Doppler ultrasonography (US) is able to distinguish between early hepatocellular carcinoma (HCC) and small nonmalignant nodules in cirrhosis. Between January 1998 and December 1999, 500 cirrhotic patients with no previous history of HCC or evidence of hepatic focal lesions were enrolled and prospectively followed-up with US every 6 months until December 2000. Sixty-one patients developed focal lesions, 12 multifocal, and 49 monofocal. Biopsy of focal lesions, contrast-enhanced Doppler US, and spiral computed tomography (CT) were performed in 41 consecutive patients with small (<3 cm) monofocal lesions. Twenty nodules were diagnosed as HCC and 21 as nonmalignant (14 large regenerative nodules, 3 low-grade, and 4 high-grade dysplastic nodules) by liver biopsy. Intratumoral arterial blood flow was detected in 19 of 20 (95%) HCC and 6 of 21 (28%) nonmalignant nodules by contrast-enhanced Doppler US (P<.0001). The mean peak resistance and pulsatility indices were 0.82 ± 0.09 and 1.56 ± 0.2 in HCC and 0.62 ± 0.08 and 0.82 ± 0.08 in dysplastic lesions (P = .002 and .0001), respectively. Spiral CT revealed arterial perfusion in 19 of 20 HCC and in 4 of 21 nonmalignant nodules (high-grade dysplastic nodules). Four of the apparently false-positive nodules at enhanced Doppler US were high-grade dysplastic nodules and 2 evolved to HCC during follow-up. In conclusion, contrast-enhanced Doppler US is a noninvasive, very sensitive technique in differentiating malignant and premalignant lesions from nonmalignant focal lesions in the liver.
Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients
Authors: Crespo Javier , Cayón Amalía , Fernández-Gil Pedro , Hernández-Guerra Manuel , Mayorga Marta , Domínguez-Díez Agustín , Fernández-Escalante José Carlos , Pons-Romero Fernando
Published: August 2002

The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor α (TNF-α) system in the development of nonalcoholic steatohepatitis (NASH). Fifty-two obese patients were studied. We investigated: (1) the expression of mRNA of TNF-α and their p55 and p75-receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and (2) the relationship between TNF-α, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF-α was found in patients with NASH in hepatic tissue (0.65 ± 0.54) and in peripheral fat (0.43 ± 0.45); in the control samples, the mRNA expression was 0.28 ± 0.32, P < .007, and 0.26 ± 0.22, P < .018, respectively. Furthermore, we found a significant increase in the mRNA levels of p55 receptor (2.42 ± 1.81 vs. 1.56 ± 1.17; P < .05); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF-α in comparison with those with a slight or nonexistent fibrosis. An overexpression of TNF-α mRNA is found in the liver and in the adipose tissue of NASH patients. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This overexpression is more elevated in patients with more advanced NASH. These findings suggest that the TNF-α system may be involved in the pathogenesis of NASH.
Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States
Authors: Nair Satheesh , Verma Sumita , Thuluvath Paul J.
Published: August 2002

Studies assessing morbidity and mortality in obese patients undergoing orthotopic liver transplantation (OLT) have produced conflicting results, mainly because of the small sample size. The objective of our study was to determine graft and patient survival in obese adults receiving OLT in the U.S. between 1988 through 1996 using the United Network for Organ Sharing (UNOS) database. Among the 23,675 transplantations performed during the 9-year study period, 18,172 (75%) patients fulfilled the inclusion criteria. Of these, 8,382 (46%) were nonobese (body mass index [BMI] < 25 kg/m2), 5,913 (33%) were overweight (BMI, 25.1-30 kg/m2), 2,611 (14%) were obese (BMI, 30.1-35 kg/m2), 911 (5%) were severely obese (BMI, 35.1-40 kg/m2), and 355 (2%) were morbidly obese (BMI, 40.1-50 kg/m2). The outcome measures assessed were immediate (30-day), 1-, 2-, and 5-year patient survival. Obese groups had a higher proportion of women, a greater prevalence of cryptogenic cirrhosis (P < .05) and diabetes (P < .05), and a higher serum creatinine. Primary graft nonfunction, and immediate, 1-year, and 2-year mortality were significantly higher in the morbidly obese group (P < .05). Five-year mortality was significantly higher both in the severely and morbidly obese subjects (P < .05), mostly as a result of adverse cardiovascular events. Kaplan-Meier survival was significantly lower in morbidly obese patients, and morbid obesity was an independent predictor of mortality. Obesity is associated with a significant increase in long-term mortality, mostly as a result of cardiovascular events. Weight loss should be recommended for all patients awaiting a liver transplantation, especially if their BMI is more than 35 kg/m2.
Regulation of the α-fetoprotein gene by the isoforms of ATBF1 transcription factor in human hepatoma
Authors: Ninomiya Toshiaki , Mihara Koichiro , Fushimi Kazuo , Hayashi Yoshitake , Hashimoto-Tamaoki Tomoko , Tamaoki Taiki
Published: August 2002

We investigated mechanisms regulating expression of α-fetoprotein (AFP) in 3 human hepatoma cell lines, HuH-7, HepG2, and huH-1, producing high, medium, and low levels of AFP, respectively. The silencer, a negative cis-acting element of the AFP gene, was highly activated in huH-1 and HepG2 to repress AFP enhancer activity by 91%, whereas only 26% repression was observed in HuH-7. To account for the difference in AFP production between HepG2 and huH-1, we investigated the roles of two isoforms of the AT motif-binding factor 1 (ATBF1) transcription factor, ATBF1-A and -B. Cotransfection assays showed that the ATBF1 isoforms regulated the AFP gene differently in HepG2 and huH-1. In huH-1 and HuH-7, both ATBF1 isoforms suppressed strongly enhancer activity and slightly promoter activity. In HepG2, on the other hand, ATBF1-A suppressed the enhancer and promoter activities, but surprisingly, ATBF1-B was found to stimulate enhancer activity while showing no effect on the promoter. Levels of ATBF1-A mRNA were similar in all 3 cell lines, whereas the expression ATBF1-B mRNA varied greatly, with the highest level seen in HepG2 followed by huH-1 and HuH-7. These results suggest that, in HepG2, ATBF1-B may have a dominant negative effect to relieve the transcriptional repression caused by its isoform. In support of this view, we found that the N-terminal region specific to the ATBF1-A molecule possessed transcriptional repressor activity. Thus, the use of the ATBF1 variants as well as the silencer may provide a unique mechanism that contributes to the determination of AFP levels in human hepatoma cell lines.
Correction of CFTR malfunction and stimulation of Ca2+-activated Cl− channels restore HCO3 − secretion in cystic fibrosis bile ductular cells
Authors: Zsembery Ákos , Jessner Wolfgang , Sitter Gerlinde , Spirlí Carlo , Strazzabosco Mario , Graf Jürg
Published: August 2002

In view of the occurrence of hepatobiliary disorders in cystic fibrosis (CF) this study addresses the role of the cystic fibrosis transmembrane conductance regulator (CFTR) and of Ca2+-activated Cl− channels in promoting HCO3
− secretion in bile ductular cells. Human cholangiocytes were isolated from control livers and from 1 patient with CF (ΔF508/G542X mutations). Single channel and whole cell currents were analyzed by patch clamp techniques, and HCO3
− secretion was determined by fluorometric analysis of the rate of recovery of intracellular pH following alkaline loading. In control cholangiocytes, both cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) catalytic subunit, activated CFTR Cl− channels that exhibited a nonrectifying conductance of 8 pS and appeared in clusters. Activation of Cl− current by cAMP was associated with an increase in the rate of HCO3
− secretion. The basal rate of HCO3
− secretion was lower in CF than in control cholangiocytes. In both control and CF cholangiocytes, raising intracellular Ca2+ concentrations with ionomycin led to a parallel activation of Cl− current and HCO3
− secretion. Consistent with reports that premature stop codon mutations (class I; e.g., G542X) can be read over by treatment with aminoglycoside antibiotics, exposure of CF cholangiocytes to gentamicin restored activation by cAMP of Cl− current and HCO3
− secretion. The observation that activation of Ca2+-dependent Cl− channels can substitute for cystic fibrosis transmembrane conductance regulator (CFTR) in supporting HCO3
− secretion and the efficacy of gentamicin in restoring CFTR function and HCO3
− secretion in class I mutations are of potential clinical interest.
Current and novel immunosuppressive therapy for autoimmune hepatitis
Authors: Heneghan Michael A. , McFarlane Ian G.
Published: August 2002

Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with autoimmune hepatitis (AIH) and results in remission induction in over 80% of patients. Sustained response to therapy may result in substantial regression of fibrosis even in advanced cases. The outcome of rapid withdrawal of immunosuppression is disease relapse in many patients. Consequently, the use of 2 mg/kg/d of azathioprine as a sole agent to maintain remission has been widely accepted in clinical practice. Persistent severe laboratory abnormalities or histologic abnormalities such as bridging necrosis or multilobular necrosis are absolute indications for treatment based on controlled clinical trials, but debate exists as to whether all patients with AIH need treatment. Examination of liver tissue remains the best method of evaluating both treatment response and need for treatment in patients who have little biochemical activity. Alternative strategies in patients who have failed to achieve remission on “standard therapy” of corticosteroids with or without azathioprine or patients with drug toxicity include the use of cyclosporine, tacrolimus, or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease. In this review we examine current management strategies of AIH, and evaluate available data pertaining to the use of novel immunosuppressive agents in this condition.
Response to steroids in de novo autoimmune hepatitis after liver transplantation
Authors: Salcedo Magdalena , Vaquero Javier , Bañares Rafael , Rodríguez-Mahou Margarita , Alvarez Emilio , Vicario Jose Luis , Hernández-Albújar Alicia , Tíscar José Luis R. , Rincón Diego , Alonso Sonia , De Diego Alejandro , Clemente Gerardo
Published: August 2002

Graft dysfunction associated with autoimmune phenomena has been recently described in liver transplant recipients without previous autoimmune disease. However, the natural history, diagnostic criteria, and definitive therapeutic approach of de novo autoimmune hepatitis (de novo AIH) are poorly understood. We report 12 cases of de novo AIH 27.9 ± 24.5 months after liver transplantation: the outcome of 7 patients treated with steroids is compared with a group of 5 nontreated patients. Nontreated patients lost the graft after 5.8 ± 2.6 months from de novo AIH onset. All treated patients were alive after 48.4 ± 14 (29-65) months from de novo AIH onset, and none of them lost the graft. However, 5 patients relapsed in relation to steroid tapering. All patients presented an atypical antiliver/kidney cytosolic autoantibody, associated to classical autoantibodies in 10 cases. Histological study showed several degrees of lobular necrosis and inflammatory infiltrate. HLA antigen frequencies and matching were compared with 2 control groups (16 orthotopic liver transplantation [LTX] patients without de novo AIH and 929 healthy blood donors); de novo AIH patients showed a higher prevalence of HLA-DR3 (54.5% vs. 25.9%, P = .04) than healthy controls, which was not observed in LTX patients without de novo AIH. In conclusion, this new disease should be included in the differential diagnosis of unexplained graft dysfunction. In addition, treatment with steroids results in a dramatically improved outcome. However, maintenance therapy is usually required.
Hepatic arterial buffer response in patients with advanced cirrhosis
Authors: Gülberg Veit , Haag Klaus , Rössle Martin , Gerbes Alexander L.
Published: August 2002

Hepatic arterial buffer response (HABR) is considered an important compensatory mechanism to maintain perfusion of the liver by hepatic arterial vasodilation on reduction of portal venous perfusion. HABR has been suggested to be impaired in patients with advanced cirrhosis. In patients with hepatopetal portal flow, placement of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal venous liver perfusion. Accordingly, patients with severe cirrhosis should have impaired HABR after TIPS implantation. Therefore, the aim of this study was to investigate the effect of TIPS on HABR as reflected by changes in resistance index (RI) of the hepatic artery. A total of 366 patients with cirrhosis (Child-Pugh class A, 106; class B, 168; class C, 92) underwent duplex Doppler ultrasonographic examination with determination of RI and maximal flow velocity in the portal vein before and 1 month after TIPS placement. Portosystemic pressure gradient was determined before and after TIPS placement. In 29 patients with hepatofugal portal blood flow, RI was significantly lower than in 337 patients with hepatopetal flow (0.63 ± 0.02 vs. 0.69 ± 0.01; P < .001). TIPS induced a significant decrease of the RI in patients with hepatopetal flow (RI, 0.69 ± 0.01 before vs. 0.64 ± 0.01 after TIPS; P = .001) but not in patients with hepatofugal flow (RI, 0.63 ± 0.02 before vs. 0.63 ± 0.02 after TIPS; NS). This response was not dependent on the Child-Pugh class. In conclusion, our results suggest that some degree of HABR is preserved even in patients with advanced cirrhosis with significant portal hypertension.
Histologic and biochemical changes during the evolution of chronic rejection of liver allografts
Authors: Neil Desley A. H. , Hubscher Stefan G.
Published: August 2002

Criteria for histologic diagnosis of chronic rejection (CR) are based on changes seen late in the disease process that are likely to be irreversible and unresponsive to treatment. Changes occurring during the evolution of CR are less clearly defined. The serial biopsy specimens, failed allografts, and biochemical profiles of 28 patients who underwent retransplantation for CR were examined with the aim of identifying histologic and biochemical features that were present during the early stages of CR. For each case, a point of acute deterioration in liver function tests (LFTs) was identified (“start time” [ST]) that subsequently progressed to graft failure. Biopsy specimens before, at the time of (“start biopsy” [SB]), and after the ST were assessed histologically, and findings were correlated with the biochemical changes. CR resulted from acute rejection (AR) that did not resolve. Centrilobular necroinflammation (CLNI) associated with an elevated aspartate transaminase (AST) level and portal tract features of AR were present at the start. Portal AR features resolved, CLNI persisted, AST level remained elevated, and bilirubin and alkaline phosphatase levels progressively increased throughout the evolution of CR. Portal tracts also showed a loss of small arterial and bile duct branches, with arterial loss occurring early and bile duct loss as a later progressive lesion. Foam cell arteriopathy was rarely seen in needle biopsy specimens. In conclusion, findings from this study may help identify patients at risk of progressing to graft loss from CR at a stage when the disease process is potentially reversible and amenable to treatment.
Risk factors of fibrosis in alcohol-induced liver disease
Authors: Raynard Bruno , Balian Axel , Fallik David , Capron Frédérique , Bedossa Pierre , Chaput Jean-Claude , Naveau Sylvie
Published: August 2002

In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P = .001), BMI (P = .002), female sex (P < .05), Perls grade (P < .05), and blood glucose level (P < .05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.
Dissolution of cholesterol gallstones in mice by the oral administration of a fatty acid bile acid conjugate
Authors: Gilat Tuvia , Leikin-Frenkel Alicia , Goldiner Ilana , Halpern Zamir , Konikoff Fred M.
Published: August 2002

Gallstones, mostly cholesterol stones, affect some 15% of the population. Oral bile salts dissolve human cholesterol gallstones, but with low efficacy, and surgery remains the main therapeutic option. Fatty acid bile acid conjugates (FABACs) were shown to prevent formation of cholesterol gallstones in experimental animals. The aim of this study was to test whether these compounds could dissolve preexisting cholesterol gallstones via oral administration. Inbred, gallstone-susceptible C57J/L mice were given a lithogenic diet for 2 months, and the presence of gallstones was ascertained. The mice were then switched to a regular diet while part of them were given in addition C20-FABAC, by gavage, at a dose of 0.5 or 3 mg per animal per day. All mice tested had cholesterol gallstones after 2 months on the lithogenic diet. In study I, after 2 months on the regular diet, 3 of 4 (75%) of the controls had gallstones, whereas none of the 6 FABAC-fed animals (3 mg/d) had stones (P = .033). In study II, evaluating 2 FABAC doses, after 2 months on the regular diet, 8 of 8 (100%) of the controls had gallstones, which were found in 2 of 7 (28%) and 1 of 8 (12%) of the mice supplemented with 0.5 mg/d (P = .007) or 3 mg/d (P = .001) FABAC, respectively. On a molar basis, the dose of 0.5 mg FABAC is equivalent to 14 mg/kg/d of a bile acid. In conclusion, FABACs given orally can dissolve preexisting cholesterol gallstones in mice. This was accomplished with a dose of FABAC equivalent to the dose of bile acids used in human gallstone dissolution.