bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection
Authors: Demetris Jake A. , Belle Steven H. , Hart John , Lewin Klaus , Ludwig Jurgen , Snover Dale C. , Tillery Weldon G. , Detre Katherine
Published: March 2007

A study to determine the reproducibility of histopathological findings and diagnoses of rejection was carried out on a series of 42 liver allograft needle biopsy specimens by five pathologists practicing at four liver transplant centers. Pathologists from each of the four centers read each slide independently on two different occasions and were asked to assess 12 histopathological features and render a diagnosis. For all histological variables, the intrarater agreement was higher than the interrater agreement. Moderate to excellent agreement occurred among the pathologists about all histological variables thought to be important in establishing the diagnosis of acute rejection (i.e., portal tract inflammation, subendothelial inflammation and bile duct damage). Other variables such as lobular disarray, bile duct proliferation and particularly arteritis, however, were only fairly or poorly reproducible. Surprisingly, the diagnosis of acute rejection was more reproducible than the individual histopathological findings that were thought to be the basis for the diagnosis. The agreement for the diagnosis of chronic rejection, however, varied according to observer. We noted that relatively inexperienced observers within this group had some difficulties agreeing with more experienced observers in establishing a diagnosis of chronic rejection. These findings demonstrate that the histopathological diagnosis of acute cellular liver allograft rejection is highly reproducible within a group of experienced pathologists and that this diagnosis can be pooled in a common data base with confidence. (Hepatology 1991;14:751-755).
Overestimation of the prevalence of antibody to hepatitis C virus in retrospective studies on stored sera
Authors: Lok Anna S. F. , Ma Oliver C. K. , Chan Tak-Mao , Lai Ching-Lung , Chung Hau-Tim , Ng Clara P. L. , Lam Jenny S. C.
Published: March 2007

Serum samples (1,428) from 1,149 patients with chronic liver diseases and polytransfused subjects were tested for antibody to hepatitis C virus by first-generation enzyme immunoassays. Antibody to hepatitis C virus was detected in 87% of patients with transfusion-related chronic non-A, non-B hepatitis; 17.6% of patients with nonmalignant, chronic hepatitis B virus infection; 37.3% of patients with hepatocellular carcinoma; 14.3% of patients with alcoholic liver diseases; 22.2% of patients with cryptogenic cirrhosis; 76% of intravenous drug abusers; 16.4% of patients on hemodialysis; 1.8% of patients on peritoneal dialysis; 6.2% of kidney transplant recipients; and 3.1% of normal subjects. A high frequency of weakly positive results was found in “aged” samples: 61.9% of antibody to hepatitis C virus-positive patients whose sera had been stored for more than 2 yr had optical densities less than two times the cut-off values in contrast to 7.9% of those whose sera had been stored for less than 2 yr (p < 0.0001). A significantly lower proportion of patients who had optical densities less than two times the cut-off values were reactive in subsequent samples 27.5% vs. 87.5% (p < 0.0001). On retests, only 70% and 56% of sera that were initially positive for antibody to hepatitis C virus remained antibody to hepatitis C virus positive using second-generation enzyme immunoassays and neutralization enzyme immunoassays, respectively. Our results suggest that retrospective studies on stored sera may have overestimated the prevalence of antibody to hepatitis C virus. We recommend that care be exercised in the interpretation of the results of the first-generation enzyme immunoassays, especially with weakly positive results on “aged” sera. (Hepatology 1991;14:756-762).
Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage
Authors: Day Christopher P. , Bashir Rumaisa , James Oliver F. W. , Bassendine Margaret F. , Crabb David W. , Thomasson Holly R. , Li Ting-Kai , Edenberg Howard J.
Published: March 2007

Little is known about factors determining individual susceptibility to the physical complications of alcohol abuse but genetically determined differences in ethanol metabolism may be important. The oxidative metabolism of alcohol is catalyzed by alcohol and aldehyde dehydrogenase. Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three β subunits) and ADH3 (producing two subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2. We have compared ADH2, ADH3 and ALDH2 allele frequencies in patients with alcohol-related cirrhosis (n = 59) and chronic pancreatitis (n = 13) with 79 local healthy control subjects. The different alleles were detected with allele-specific oligonucleotide probes after amplification of leukocyte DNA by the polymerase chain reaction.

All patients and all but one control subject were homozygous ADH2★1, encoding the β1 subunit. No ADH2★3 alleles were detected. All 34 patients and 39 control subjects tested were homozygous ALDH2★1 encoding the active enzyme. ADH3 allele frequencies were different in patients and control subjects. ADH3★1 frequency: control subjects, 55.1%; cirrhotic patients, 62.7%; chronic pancreatitis patients, 65.4%. The difference between the patient groups combined and the control subjects was significant (p < 0.05; G-test of Sokal and Rohlf) if it was assumed that the allele frequency in our control population was a reasonable estimate of our local population allele frequency.
Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: Univariate and multivariate analyses
Authors: Shirabe Ken , Kanematsu Takashi , Matsumata Takashi , Adachi Eisuke , Akazawa Kohhei , Sugimachi Keizo
Published: March 2007

The purpose of this study was to clarify the factors linked to recurrence of small hepatocellular carcinomas, up to 3cm in diameter, after hepatectomy. Fifty patients with small hepatocellular carcinomas who underwent hepatectomy between 1976 and 1988 were observed for possible recurrence for at least 2 yr. These patients were divided into two groups: 20 patients who had recurrence within 2 yr and 30 patients who had no recurrence within 2 yr. The recurrence pattern was analyzed by hepatic angiography. Statistical analysis by the X2 test and stepwise logistic regression showed that the risk factors linked to recurrence were (a) tumor diameter greater than 2.2 cm, (b) intracapsular infiltration of tumor cells, (c) tumor location deep in the liver, (d) macroscopical and microscopical tumor invasion into the portal vein and (e) tumor invasion into the portal vein or intrahepatic metastasis.

When patients diagnosed with small hepatocellular carcinomas have any of these risk factors, postoperative adjuvant therapy and follow-up should be particularly carefully considered, since these patients are at high risk for early recurrence. (Hepatology 1991;14:802-805).
Hepatocellular peroxisomes in human alcoholic and drug-induced hepatitis: A quantitative study
Authors: de Craemer Dirk , Kerckaert Ingrid , Roels Frank
Published: March 2007

The peroxisomes in the liver of four patients with alcoholic hepatitis and in six patients with druginduced hepatitis are compared to eight control livers by catalase cytochemistry and morphometry. A decrease of catalase activity is observed in alcoholic, amitriptyline, aprindine, clomipramine and methimazole hepatitis. Peroxisomes with a heterogeneous distribution of the catalase reaction product are found in most hepatitis livers. The number of organelles is increased 1.5 to 4.2 times in alcoholic, aprindine, methimazole and phenytoin hepatitis livers. In the last case, peroxisomes are also smaller. Changes in shape are seen in all hepatitis livers; they include invaginations, tails, funnel-like constrictions and gastruloid cisternae. In aprindine, phenytoin, methimazole and two alcoholic hepatitis livers, surface density exceeds the upper control value. These data indicate a loss of catalase activity in most hepatitis livers but also peroxisomal proliferation and shape modifications. It has been proposed that the latter changes are favorable for metabolic activity. (Hepatology 1991;14:811-817).
Regulation of bile acid synthesis in humans: Effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7α-hydroxylation rates in vivo
Authors: Bertolotti Marco , Abate Nicola , Loria Paola , Dilengite Michele , Carubbi Francesca , Pinetti Adriano , Dlgrisolo Antonia , Carulli Nicola
Published: March 2007

The rates of cholesterol 7α-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7α-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7α position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7α-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7α-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoproteincholesterol but exerted no change on 7α-hydroxylation rates. Our results support the existence of a feedback inhibition exerted on cholesterol 7α-hydroxylation (and consequently on bile acid synthesis) by hydrophobic bile acids returning to the liver through the enterohepatic circulation. The finding emphasizes the importance of the physicochemical properties of bile acids in the regulation of hepatic cholesterol balance. Under these experimental conditions, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and presumably reduced availability of newly synthesized cholesterol are not critical for bile acid synthesis. (Hepatology 1991;14:830-837).
Histochemical demonstration of sinusoidal γ-glutamyltransferase activity by substrate protection fixation: Comparative studies in rat and guinea pig liver
Authors: Lanca António José , Israel Yedy
Published: March 2007

Most histochemical methods for the detection of an enzymatic activity are preceded by tissue fixation with chemical agents that partially inactivate the enzymes. It is well known that substrates exert a marked protection against fixative-induced inactivation. The conventional histochemical methods for the demonstration of hepatic γ-glutamyltransferase activity have not been successful in detecting the activity of the enzyme on the sinusoidal side of the hepatocytes despite mounting biochemical evidence for its presence on that pole of the hepatocyte. Under conventional fixation the enzymatic activity in hepatocytes is only seen on the bile canalicular side. This may be the result of a preferential protective effect of γ-glutamyltransferase by its normal substrate, glutathione, present in the bile canaliculus at concentrations 500 times higher than in the sinusoidal lumen (8 mmol/L vs. 10 to 20 mmol/L). To test this hypothesis and to reduce the degree of fixative-induced inhibition of the enzyme activity, glutathione was either incorporated in the fixative solution or the livers were perfused with high concentrations of glutathione (10 mmol/L) before fixation.

Our results histochemically demonstrate, in the normal adult rat liver, the existence of γ-glutamyl-transferase activity not only on the bile canalicular pole but also on the sinusoidal pole of the hepatocytes. Visualization of the enzyme activity on the sinusoidal pole is dependent on glutathione protection. Guinea pig livers, which present a 10-fold higher γ-glutamyltransferase activity than rat livers (similar to that in human beings), showed marked sinusoidal γ-glutamyltransferase activity even in the absence of glutathione protection. Glutathione protection further increased this sinusoidal activity. Histochemical data in the guinea pig paralleled the biochemical findings indicating that in a single pass guinea pig liver can remove considerably higher amounts (more than two thirds) of circulating glutathione than rat liver. The histochemical demonstration of γ-glutamyl-transferase activity in the sinusoidal pole of the hepatocyte in normal adult rat and guinea pig liver adds further evidence to the biochemical data supporting the existence of a sinusoidal γ-glutamyltransferase ectoactivity capable of removing glutathione from the circulation. (Hepatology 1991;14:857-863).
The role of capillarization in hepatic failure: Studies in carbon tetrachloride-induced cirrhosis
Authors: Martinez-Hernandez Antonio , Martinez Jose
Published: March 2007

During the cirrhotic process, the hepatic microvascular phenotype is transformed from sinusoids (discontinuous capillaries) into continuous capillaries. This transformation has been termed capillarization. Many hepatic functions depend on the rapid, bidirectional exchange of macromolecules between plasma and hepatocytes. To determine whether capillarization contributes to hepatic failure in cirrhosis, we decided to study the plasma clearance (125I) and hepatocyte uptake (electron microscopy) of three tracers in normal and cirrhotic rats. The tracers chosen were a hemeundecapeptide with peroxidatic activity (fluidphase pinocytosis), asialofetuin (receptor-mediated endocytosis of a medium size protein) and ferritin (receptor-mediated endocytosis of a large size protein). The results demonstrate a decreased hepatocyte uptake of hemeundecapeptide; a significant delay in plasma clearance of asialofetuin; and a minor delay in plasma clearance of ferritin, but a striking trapping of ferritin in the cirrhotic capillary basement membrane. The delayed plasma clearance in cirrhosis cannot be ascribed to a decreased number of surface receptors because, in isolated hepatocytes, the number of molecules bound per cell was equivalent in normal and cirrhotic livers.

These findings support the concept of capillarization with the formation of continuous diffusion and filtration barriers between plasma and hepatocytes, representing a significant hindrance to the bidirectional macromolecular exchange normally taking place between these two compartments. Furthermore, at least in the case of ferritin, the capiliary basement membrane of cirrhotic livers seems to be the major filtration barrier. This hindrance to hepatocyte uptake, and presumably also to secretion, may be the cause (or at least a major determinant) of the hepatic failure characteristic of cirrhosis. (Hepatology 1991;14: 864-874).
Procoagulant activity and tumor necrosis factor in rat hepatic allograft rejection
Authors: Basista Michael H. , Stieffenhofer Anne , Kim Dong-Goo , Murase Noriko , Todo Saturo , Dindzans Vincents J.
Published: March 2007

We used a model of rat hepatic allograft rejection to evaluate levels of procoagulant activity and tumor necrosis factor during acute cellular rejection. ACI livers were transplanted into Lewis rats, and Lewis-to-Lewis isografts and unoperated animals served as controls. Animals were killed on days 1, 2, 3, 4, 5, 6, 7 and 9. Splenic mononuclear cells were obtained by Ficoll-Hypaque gradients. Collagenase perfusion, metrizamide gradients and centrifugal elutriation were used to isolate Kupffer cells. Procoagulant activity assay of the splenic and Kupffer cells was done using a one-step clotting assay. Tumor necrosis factor was assayed using an L929 cytotoxicity assay. Histological evidence of acute rejection began on the 4th postoperative day, and rats died by the 9th or 10th postoperative day. Splenic procoagulant activity was significantly elevated in rejecting rats on day 4 and remained elevated until death. In contrast, Kupffer-cell procoagulant activity was elevated over controls by day 3 and remained significantly elevated until death. The tumor necrosis factor levels were elevated from day 1 and remained so until death. The data indicate that procoagulant activity is synthesized both by peripheral monocytes and locally by Kupffer cells and that procoagulant activity and tumor necrosis factor levels rise during hepatic allograft rejection. Because procoagulant activity and tumor necrosis factor mediate immune functions that are postulated to be important in acute rejection (immune cell adherence, vascular thrombosis and delayed-type hypersensitivity), these elevations may contribute to the pathogenesis of acute rejection. (Hepatology 1991;14:883-887).
Isolation and characterization of a novel liver-derived immunoinhibitory factor
Authors: Tzung Shie-Pon , Gaines Katherine C. , Henderson Mark , Smith Terry J. , Cohen Stefan A.
Published: March 2007

Cytosolic extracts prepared from perfused whole liver or purified hepatocytes of C57BL/6 mice inhibited interleukin-2- and concanavalin A-induced spleen cell proliferation in vitro. In contrast, cytosolic extracts from purified nonparenchymal liver cells had no effect. Arginase and very-low-density lipoprotein were previously identified as two immunoinhibitory substances present in liver cytosolic extracts. We demonstrated, however, that inhibitory activity remained after removal of very-low-density lipoprotein and arginase from liver cytosolic extract by repeated ultracentrifugation and gel filtration chromatography, respectively, suggesting the presence of another inhibitor. Further purification by anion-exchange chromatography and chromatofocusing led to the isolation of a novel liverderived immunoinhibitory factor. This liver-derived immunoinhibitory factor is sensitive to pronase digestion and heat and acid treatment; it has an estimated isoelectric point of 8.25. The Mr of liver-derived immunoinhibitory factor is 28 kD as estimated from its migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, which is identical under both reducing and nonreducing conditions, indicating a monomeric nature of this protein. Amino acid composition analysis discloses that liver-derived immunoinhibitory factor is relatively rich in glycine and proline residues. Interleukin-2-induced spleen cell proliferation in vitro is inhibited by this liver-derived immunoinhibitory factor, with a 50% inhibitory dose of 1.4 nmol/L. Furthermore, the biological activity of the liver-derived immunoinhibitory factor is not confined to mouse spleen cells, since the growth of B16 mouse melanoma and H35 rat hepatoma cells is also inhibited. A comparison with other liver-derived immunoinhibitors reported previously supports our claim that the liver-derived immunoinhibitory factor is a novel inhibitory protein. (Hepatology 1991;14:888-894).
Stimulation of putrescine production by epidermal growth factor in rat liver after partial hepatectomy
Authors: Nagoshi Sumiko , Tomiya Tomoaki , Sato Yuzuru , Oka Yuji , Ogata Itsuro , Fujiwara Kenji
Published: March 2007

When epidermal growth factor was given to rats after partial hepatectomy, hepatic putrescine content was significantly increased at 4, 6 and 10 hr compared with control rats. Ornithine decarboxylase activity was also increased. Hepatic ornithine decarboxylase messenger RNA content was significantly greater than control levels at 2 hr after epidermal growth factor treatment, but not at 10 hr, when the amount of ornithine decarboxylase messenger RNA in control animals was four times that at 2 hr. When actinomycin D was administered 6 hr after partial hepatectomy, hepatic ornithine decarboxylase activity at 10 hr was reduced to half the control levels. This reduction was attenuated by epidermal growth factor treatment at 6 and 8 hr. Hepatic immunoreactive ornithine decarboxylase protein content showed a highly positive correlation with hepatic ornithine decarboxylase activity at 4, 6 and 10 hr, irrespective of epidermal growth factor treatment. Hepatic spermidine N

1
-acetyltransferase activity was significantly increased at 6 hr compared with control rats. These results suggest that, after partial hepatectomy in rats, exogenous epidermal growth factor may stimulate hepatic putrescine production by increasing ornithine decarboxylase messenger RNA content and altering posttranscriptional ornithine decarboxylase regulation, as well as enhancing spermidine N

1
-acetyltransferase activity. (Hepatology 1991;14:901-905).
Hepatotoxicity in a rat model caused by orally administered methotrexate
Authors: Hall Pauline de la M. , Jenner Mark A. , Ahern Michael J.
Published: March 2007

We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 mg/kg/day doses for variable lengths of time. The 300 mg/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 mg/kg/day, four of the five rats receiving 150 mg/kg/day and five of the five rats on 100 mg/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 mg/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity. (Hepatology 1991;14:906-910).
Transport of free fatty acid and triglyceride in anhepatic rats
Authors: Quarfordt Steven H. , Defaria Eliana , Landis Barry A. , Bollinger Randal R. , Yamaguchi Yasuo
Published: March 2007

Without a liver the fractional plasma removal of free fatty acid is one third and chylomicron triglyceride one half of that in the intact rat. The intestine of the anhepatic rat converted enteral fatty acid to plasma triglyceride but was unable to do the same for plasma free fatty acid. This decrease in plasma free fatty acid removal and the inability to recycle the acid as triglyceride were, in part, responsible for the conversion of large fractions of plasma triglyceride flux to the plasma free acid in hepatectomized rats. Increased intravascular triglyceride lipolysis resulting from high circulating lipoprotein lipase concentrations and reduced plasma triglyceride removal were other factors shifting the partition of anhepatic plasma fatty-acid transport from the ester to the free. After the anhepatic plasma clearance of either free fatty acid or triglyceride, relatively more of both compounds was recovered in the lipid of actively metabolizing (heart and muscle) as opposed to storage (adipose) tissue when compared with controls. Sequential evaluations of the recovery of plasma free fatty acid and triglyceride in tissues of anhepatic rats demonstrated accumulation or storage solely in adipose tissue and only when the plasma fatty acid was in triglyceride. This observation and the large conversion of anhepatic circulating triglyceride to the free acid may, in part, explain the lack of an increase in adipose lipid with reduced hepatic mass. The data help explain the preferential use of a lipid fuel in liver disease and the difficulties in obtaining carbon storage in this condition. (Hepatology 1991;14:911-919).
Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: In vitro studies in rat hepatocytes and human erythrocytes
Authors: Heuman Douglas M. , Pandak Michael W. , Hylemon Philip B. , Vlahcevic Reno Z.
Published: March 2007

Intraduodenal infusion of hydrophobic bile salts to bile-fistula rats leads within hours to severe hepatocellular necrosis and cholestasis; simultaneous administration of conjugates of ursodeoxycholate, either intraduodenally or intravenously, reduces or prevents liver injury. To evaluate the short-term protective effects of ursodeoxycholate at the cellular level, we incubated primary monolayer cultures of adult rat hepatocytes or freshly isolated washed human erythrocytes for 1 to 240 min with varying defined concentrations of different bile salts in the presence or absence of ursodeoxycholate. Cytolysis was quantified by measuring the release into the medium of cytosolic lactate dehydrogenase (hepatocytes) or hemoglobin (erythrocytes). In both systems, cytolysis increased sigmoidally with increasing bile salt concentration, and the relative toxicity of different bile salts proceeded in the following order: tauroursodeoxycholate was less toxic than taurocholate, which was less toxic than taurodeoxycholate. Taurochenodeoxycholate was more toxic to erythrocytes than taurodeoxycholate; the two were equally toxic to rat hepatocytes. Unconjugated bile salts were more toxic than their conjugates. The addition of tauroursodeoxycholate to taurochenodeoxycholate or taurodeoxycholate led to time-dependent and concentration-dependent reduction or elimination of the toxicity of the more hydrophobic component. Protection was evident within minutes. With respect to hemolysis, at pH 8.5 glyco was less protective than tauroursodeoxycholate, and free ursodeoxycholate was only minimally protective. We conclude that the hepatocytotoxicity of hydrophobic bile salts at millimolar concentrations is markedly reduced in the presence of tauroursodeoxycholate. Conjugates of ursodeoxycholate also prevented disruption of erythrocytes by bile salts, suggesting that protection does not depend on liver-specific pathways of bile salt uptake, compartmentation, transport or metabolism. We hypothesize that ursodeoxycholate interferes with solubilization of membranes by bile salts; in vivo, ursodeoxycholate may improve cholestatic liver disease by reducing the toxicity of endogenous bile salts at the luminal surface of the canalicular plasma membrane. (Hepatology 1991;14:920-926).
Loss of HBsAg after interferon-α treatment: Cure of chronic hepatitis B virus?
Authors: Davis Gary L.
Published: March 2007

Sixty-four patients with chronic hepatitis B who were treated with interferon-α (recombinant IFN-α-2a in 9 patients, recombinant IFN-α-2b in 50 patients and lymphoblastoid IFN-α-n1 in 5 patients) in protocols conducted at the Liver Diseases Section of the National Institutes of Health between 1984 and 1986 were observed with sequential determinations of serum ALT levels, HBsAg and serological markers of hepatitis B virus replication (HBeAg, hepatitis B virus DNA polymerase, hepatitis B virus DNA by blot hybridization and hepatitis B virus DNA by polymerase chain reaction). Among the 64 treated patients, 23 responded to interferon treatment with loss of HBeAg and improvement in serum ALT. Three patients (13%) relapsed, all within the first year of follow-up. The remaining 20 patients continued to have no detectable HBeAg or hepatitis B virus DNA (dot blot) in serum during follow-up of 3 to 7 yr (mean = 4.3 yr), although 3 patients had minimal elevations of serum ALT. Thirteen patients (65%) lost HBsAg between 0.2 and 6 yr (mean = 3 yr) after loss of HBeAg. Although none of the 20 patients had detectable serum hepatitis B virus DNA (dot blot), all 7 patients with persistent HBsAg had detectable serum hepatitis B virus DNA by the polymerase chain reaction. Sequential testing in HBsAg-patients indicated the serum hepatitis B virus DNA usually became undetectable by the polymerase chain reaction at about the time of loss of HBsAg. Only 2 of 13 HBsAg- patients had hepatitis B virus DNA detectable in serum by the polymerase chain reaction.
Reperfusion injury: A role for neutrophils
Authors: Lemasters John J. , Thurman Ronald G.
Published: March 2007

To determine the role of neutrophils in the pathogenesis of hepatic ischemia/reperfusion injury, livers from male Fischer rats were subjected to 45 min of no-flow ischemia followed by reperfusion for up to 24 h. Two phases of liver injury were identified, an initial phase during the first hour of reperfusion and a later progression phase with 80 ± 3% hepatocyte necrosis and an 80-fold increase of neutrophil infiltration in the liver after 24 h. Pretreatment with a monoclonal antibody against neutrophils, which caused consistent neutropenia, protected the liver from reperfusion injury as indicated by 28 ± 10% necrosis, and 84% reduction of hepatic neutrophil accumulation and a complete recovery of the hepatic ATP content. Our data suggest that the later progression phase of reperfusion injury after hepatic no-flow ischemia is mediated mainly by neutrophils.
Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: Comparison with uremic encephalopathy
Authors: Steindl Petra , Püspök Andreas , Druml Wilfred , Ferenci Peter
Published: March 2007

Hepatic encephalopathy is ameliorated by drugs acting on the central GABAA-benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15-4513, Ro 15-3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide-induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15-4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15-3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 ± 6.4 [S.E.M.] and 41.3 ± 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15-4513 (by 293%, p < 0.05) and by 10 mg/kg Ro 15-3505 (by 509%, p > 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status. These results indicate that the amelioration of neurobehavioral symptoms both by Ro 15-4513 and Ro 15-3505 seems to be specific for hepatic encephalopathy and is consistent with the hypothesis that hepatic encephalopathy is associated with an increased GABA-ergic tone. (Hepatology 1991;14:963-968.)
Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis
Authors: di Bisceglie Adrian M. , Goodman Zachary D. , Ishak Kamal G. , Hoofnagle Jay H. , Melpolder Jacqueline J. , Alter Harvey J.
Published: March 2007

We have evaluated the clinical and histopathological outcomes of patients who contracted chronic non A, non B hepatitis as a result of transfusions administered during heart surgery at the National Institutes of Health. Posttransfusion hepatitis developed in 65 of 1,070 (6.1%) patients and became chronic in 45 (69%) of those cases. Antibody to hepatitis C virus was detectable in 53 patients (82%) with posttransfusion non A, non B hepatitis. Thirty-three patients with chronic non A, non B hepatitis agreed to liver biopsy (group 1). In addition, six other patients with chronic posttransfusion non A, non B hepatitis were evaluated (group 2). These 39 patients were followed between 1 and 24 yr (mean = 9.7 yr). Cirrhosis developed in 8 patients (20%) between 1.5 and 16 yr after blood transfusion. Of the 33 patients in group 1, 11 (33%) died during follow-up. In two cases (6%), this was related to liver failure. At this writing, two additional patients (6%) have decompensated cirrhosis and one (3%) has debilitating fatigue. Twenty of 33 patients (61%) with histological evidence of chronic active hepatitis or cirrhosis are asymptomatic and have no clinical evidence of liver disease.

Thus chronic non A, non B posttransfusion hepatitis appeared to be due to hepatitis C virus infection in most cases. It was associated with the development of cirrhosis in approximately 20% of cases and end-stage liver disease in 12% of patients followed prospectively. Most patients with histological evidence of cirrhosis or chronic active hepatitis, however, had minimal clinical evidence of liver disease within the time frame of this study. (Hepatology 1991;14:969-974.)
IgA class antibodies to hepatitis delta virus antigen in acute and chronic hepatitis delta virus infections
Authors: McFarlane Ian G. , Chaggar Kanchan , Davies Susan E. , Smith Heather M. , Alexander Graeme J. M. , Williams Roger
Published: March 2007

Sera from 31 patients with chronic hepatitis delta virus infection and 18 patients with acute hepatitis delta virus infection were examined for IgA class antibodies to this virus using a newly developed enzyme immunoassay. IgA antibody to hepatitis D virus was detected in 21 (67.7%) of 31 patients with chronic delta viral hepatitis, but in only 1 (5.6%) of the 18 patients with acute infection (p < 0.0005). Of the 21 patients with chronic delta hepatitis with IgA antibody to hepatitis D virus, 19 (90.5%) had moderate-to-severe activity on liver biopsy: 18 of the 21 had histological features of chronic active hepatitis and three had chronic lobular hepatitis. In all, 23 patients with chronic delta hepatitis had moderate-to-severe activity, and 19 (82.6%) had IgA antibody to hepatitis D virus. No statistically significant correlations were found between IgA antibody to hepatitis D virus and biochemical markers of liver injury (p > 0.4), or the presence of hepatitis delta virus antigen in liver biopsies (p > 0.2), in the patients with chronic delta hepatitis. The finding that IgA antibody to hepatitis D virus was almost exclusively associated with chronic hepatitis delta virus infection and correlated independently with moderate-to-severe histological activity (with a specificity of 90.5% and a sensitivity of 82.6%) suggests that this antibody might be a useful serological marker of underlying liver damage in chronic delta hepatitis. (Hepatology 1991;14:980-984.)
Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease
Authors: Nishiguchi Shuhei , Kuroki Tetsuo , Yabusako Tsuneo , Seki Shuichi , Kobayashi Kenzo , Monna Takeyuki , Otani Shuzo , Sakurai Masami , Shikata Toshio , Yamamoto Sukeo
Published: March 2007

The relationship between alcoholic liver disease and hepatitis C virus was studied in 80 patients by searching for hepatitis C virus RNA with the polymerase chain reaction and by measuring hepatitis C virus antibodies. By C-100 enzyme-linked immunosorbent assay, hepatitis C virus antibodies were found in 2 of 10 patients with fibrosteatosis, 8 of 20 patients with alcoholic hepatitis, 14 of 19 patients with chronic hepatitis and 19 of 31 patients with cirrhosis. Percentages of patients with antibodies found by C-100 radioimmunoassay and by enzyme-linked immunosorbent assay based on sequence peptide 42 were lower; of the 16 patients with a low titer by C-100 enzyme-linked immunosorbent assay, 10 were negative by radioimmunoassay and 6 were negative by sequence peptide 42. By a second-generation recombinant immunoblot assay, hepatitis C virus antibodies were found in 1 of 10 patients with fibrosteatosis, 2 of 20 patients with alcoholic hepatitis, 15 of 19 patients with chronic hepatitis and 18 of 31 patients with cirrhosis. Hepatitis C virus RNA was found in 1 of 10 patients with fibrosteatosis, 3 of 20 patients with alcoholic hepatitis, 13 of 19 patients with chronic hepatitis and 20 of 31 patients with cirrhosis. Of the 37 patients with hepatitis C virus RNA, 31 had antibodies by C-100 enzyme-linked immunosorbent assay (25 patients at a high titer [cut-off index >6]), and 31 had antibodies by second-generation recombinant immunoblot assay. Patients with cirrhosis and hepatitis C virus RNA had higher ALT activity than such patients without hepatitis C virus RNA (p < 0.05). Of the 80 patients, 25 patients stopped drinking, 11 of these patients had hepatitis C virus RNA. The ALT of the 11 patients tended to decrease during hospitalization but increased in 7 of 11 after discharge. Of the 14 patients without hepatitis C virus RNA who stopped drinking, ALT decreased significantly (p < 0.01) during hospitalization and increased only in 3 of the 14 after discharge. The histological activity index of Knodell for patients with fibrosis, chronic hepatitis or cirrhosis with hepatitis C virus RNA was 11.8 ± 4.2, but without hepatitis C virus RNA it was 8.4 ± 4.3 (p < 0.01). Patients with hepatitis C virus RNA had worse periportal and bridging necrosis, intralobular degeneration, focal necrosis and portal inflammation than patients without hepatitis C virus RNA. (Hepatology 1991;14:985-989.)
Long-term follow-up of patients with primary biliary cirrhosis on colchicine therapy†
Authors: Zifroni Abraham , Schaffner Fenton
Published: March 2007

We followed up a group of patients with primary biliary cirrhosis who participated in a 4-yr prospective, double-blind controlled trial of colchicine therapy for 4 additional years. All were placed on open label colchicine (0.6 mg twice daily) after the trial was concluded. Of the original group of 28 patients treated with colchicine, 8 died and 5 recieved transplants (3 of the 5 died). Of the original placebo control group eight patients died and six received transplants (1 of the 6 died). Surviving patients on long-term colchicine therapy (mean period = 8.1 yr, range = 5.3 to 9.1) showed reduction of mean serum alkaline phosphatase from 5.1 times the upper limit of normal values to 1.9 times (p < 0.01). Mean ALT fell from 1.8 to 1.2 times the upper limit of normal (p = 0.05), and mean serum total bilirubin remained stable (1.6 mg/dl vs. 1.5 mg/dl). Major complications of cirrhosis developed in four patients in the colchicine group and five patients in the original control group. The only side effect of colchicine was diarrhea, which was noted in three patients. The diarrhea resolved with reduction in the dose of colchicine. Colchicine is a safe and inexpensive drug for the long-term treatment of primary biliary cirrhosis. The biochemical parameters of disease activity (alkaline phosphatase and ALT) remain improved after long-term follow-up, and bilirubin values remain stable. However, complications of cirrhosis, deaths and transplantations were not prevented. The clinical usefulness of colchicine in the treatment of primary biliary cirrhosis seems to be limited. (Hepatology 1991;14:990-993.)
Colchicine clearance is impaired in alcoholic cirrhosis
Authors: Leighton Jonathan A. , Bay Michael K. , Maldonado Alma L. , Schenker Steven , Speeg Vincent K.
Published: March 2007

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 ± 1.82 ml/mm · kg, whereas cirrhotic patients had a mean clearance of 4.22 ± 0.45 ml/mm · kg (p <0.01). The half-life was 57.4 ± 14.2 min in control subjects vs. 114.4 ± 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 ± 0.1 L/kg in control subjects; 0.716 ± 0.158 L/kg in cirrhotic patients, p > 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination. Hepatology 1991;14:1013-1015.)
Relationships between plasma atrial natriuretic peptide concentrations and hemodynamics and hematocrit in patients with cirrhosis
Authors: Moreau Richard , Hadengue Antoine , Pussard Eric , Soubrane Olivier , Sogni Philippe , Gaudin Christophe , Lebrec Didier
Published: March 2007

We studied the relationships in 29 patients with cirrhosis between pulmonary arterial atrial natriuretic peptide concentrations and the following: systemic and splanchnic hemodynamics, the hematocrit, arterial oxyhemoglobin saturation, oxygen tension and the severity of cirrhosis. Plasma atrial natriuretic peptide concentrations ranged from 21 to 208 pg/ml and averaged 78 ± 8 pg/ml (mean ± S.E.M.). Simple regression analysis showed significant correlations between plasma atrial natriuretic peptide concentration and the following: hematocrit, mean pulmonary arterial pressure, wedged hepatic venous pressure, free hepatic venous pressure, pulmonary wedged pressure and serum bilirubin concentrations. No significant correlations were found between plasma atrial natriuretic peptide concentrations and all other hemodynamic values, arterial oxyhemoglobin saturation and oxygen tension. Multiple stepwise regression analysis showed that the hematocrit, mean pulmonary arterial pressure and wedged hepatic venous pressure were significant and independent predictors of pulmonary artery plasma atrial natriuretic peptide concentrations (R2 = 0.69). Partial regression coefficients were −0.74 (p <0.001), 0.61 (p <0.001) and 0.44 (p < 0.05) for the hematocrit, the mean pulmonary arterial pressure and the wedged hepatic venous pressure, respectively. In conclusion, in patients with cirrhosis, increased plasma atrial natriuretic peptide concentrations were related to the degree of hemodilution, increased pulmonary arterial pressure and the degree of portal hypertension. Plasma atrial natriuretic peptide concentrations were not influenced by the arterial oxygenation levels. (Hepatology 1991;14:1035-1039.)
Serum and bile secretory immunoglobulins and secretory component during the early postoperative course after liver transplantation
Authors: Bresson-Hadni Solange , Rossel Mireille , Seilles Estelle , Vuitton Dominique-Angéle , Guennoune Khadija , Hory Bernard , Miguet Jean-Philippe , Gillet Michel , Vincent Claude , Revillard Jean-Pierre
Published: March 2007

Secretory component was assayed in serum and bile from 34 patients within 40 days after a first or a second (three cases) liver transplantation. Levels of serum secretory IgA and IgM and of a serum component referred to as immunoreactive free secretory component, identified by its reactivity with monoclonal and polyclonal antibodies specific to secretory component, were significantly elevated in all posttransplant patients compared with 45 healthy subjects and 10 kidney transplant patients (p < 0.0001). The highest serum levels of bound secretory component and of immunoreactive free secretory component were observed in patients with acute rejection. The elevation of immunoreactive free secretory component was significantly higher in patients with rejection as compared with patients with a graft ischemia (p = 0.002) or an uncomplicated postoperative evolution (p = 0.01). The highest levels of immunoreactive free secretory component and secretory IgM were observed in a transplant patient with selective IgA deficiency. No significant difference was seen between the levels of serum immunoreactive free secretory component observed in patients with rejection and those of patients with cytomegalovirus hepatitis or sepsis. Immunoreactive free secretory component, secretory IgA and secretory IgM levels measured in the serum of three patients with primary nonfunction were lower than those observed in the other groups. Immunoreactive free secretory component bile/serum ratios calculated from 16 patients were significantly higher in patients with acute rejection than in infected patients. This study provides new insight into the mechanisms of increase of serum immunoreactive free secretory component, secretory IgA and secretory IgM in various types of liver dysfunction. The increase observed in all the transplant patients (except in ischemia and primary nonfunction) could be the result of liver regeneration. However, the major increase observed in rejection could also be explained both by the cholangiocyte cytolysis and by an enhancement of secretory component synthesis by cytokines involved in the mechanisms of this immune reaction. (Hepatology 1991;14:1046-1053.)
Cause and timing of first allograft failure in orthotopic liver transplantation: A study of 177 consecutive patients
Authors: Quiroga Jorge , Colina Inmaculada , Demetris Jake A. , Starzl Thomas E. , van Thiel David H.
Published: March 2007

The cause and timing of first liver allograft failure was evaluated in 177 patients who underwent a second liver transplant between January 1984 and December 1988. The population studied consisted of 94 men and 83 women with a mean age 41.3 ± 1.0 yr (mean ± S.E.M.). Mean first-graft survival was 130.6 ± 22.9 days (range = 0 to 2,073 days). Sixty-eight percent of the grafts failed in the first postoperative month, 26% failed between the second and twelfth month and only 6% failed beyond the twelfth month from the date of the initial transplant. Six principal causes of graft failure were identified. Early allograft losses occurred as a result of four major problems: primary graft nonfunction (30.0% of all grafts; mean graft survival = 3.4 ± 0.3 days); ischemic injury of the graft without overt vascular injury (9.6%; mean graft survival = 17.5 ± 1.9 days); acute rejection (10.7%; mean graft survival = 30.4 ± 6.4 days); and overt vascular complications (26.6%; mean graft survival = 59.6 ± 24.1 days). Late graft failures were the result of either chronic rejection (11.3%; mean graft survival = 496.3 ± 136.0 days) or recurrence of the primary liver disease (6.8%; mean graft survival = 550.5 ± 172.1 days). Graft failure occurred as a result of a variety of miscellaneous causes in 5% of the cases (mean graft survival in this group = 300.0 ± 110.6 days). Overall 6-mo patient survival after a second liver transplant was 46.3%. Patients who had a retransplant because of chronic rejection and ischemic injury had the greatest (65%) and least (23%) 6-mo survival rates respectively after second grafting (p < 0.05). Those who survived the second transplant procedure for 6 mo or more tended be younger (p < 0.01) and had a reduced first transplant requirement for red blood cells (p < 0.05), latelets (p < 0.01) and fresh frozen plasma (p < 0.01) than did those who died during the 6 mo after their second transplant procedure. (Hepatology 1991;14:1054-1062.)