bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between imatinib resistance conferring mutations and Philadelphia positive clonal cytogenetic evolution in CML
Authors: Schnittger Susanne , Bacher Ulrike , Dicker Frank , Kern Wolfgang , Alpermann Tamara , Haferlach Torsten , Haferlach Claudia
Published: July 2010

In patients with chronic myeloid leukemia (CML), resistance against imatinib is associated with mutations in the kinase domain (KD) of the BCR‐ABL1 fusion gene and/or with additional chromosomal abnormalities (ACAs) secondary to the Philadelphia chromosome. To evaluate associations between these molecular and cytogenetic events, we correlated cytogenetic data with results of KD mutation analysis in 205 CML patients with acquired resistance to imatinib (100 females, 105 males, 17.9‐90.3 years). In 79/205 patients (38.5%), at least one KD mutation was detected; in 13/79 (16.5%) even two different mutations were observed. A second KD mutation was frequent in cases with G250E (4/9), E255V (1/3), T315I (5/18), F317L (2/7), F359C/V (4/7), or H396R (2/3), but was never detected in cases with V299L (n = 3) or Y253H (n = 4). With respect to cytogenetics, ACAs were identified in 76/205 patients (37.1%), in 29 (36.7%) together with KD mutations. ACAs were frequent in cases with E255V (2/3), T315I (8/18), F317L (4/7), F359C/V (4/7), or H396R (2/3), but rare in those with M351T (1/9). Therefore, some KD mutations (e.g., T315I) might be associated with higher genetic instability paving the way to additional cytogenetic and molecular genetic events. © 2010 Wiley‐Liss, Inc.
Endocytic Capacities of Kupffer Cells Isolated From the Human Adult Liver
Authors: Kirn André , Bingen Annick , Steffan Anne-Marie , Wild Marie-Thérèse , Keller Francoise , Cinqualbre Jacques
Published: July 2010

Kupffer cells isolated from human adult livers and maintained in culture display the main structural features of macrophages. They are able to phagocytose latex particles and opsonized sheep erythrocytes in vitro. Vaccinia virus as well as Frog Virus 3 are taken up and uncoated in cultured Kupffer cells. Such a model may be used advantageously for studying different problems in liver physiopathology.
Chronic Persistent Hepatitis: Serological Classification and Meaning of the Hepatitis B E System
Authors: Aldershvile Jan , Dietrichson Odd , SkinhøJ Peter , Kryger Peter , Mathiesen Lars R. , Christoffersen Per , Nielsen Jens O.
Published: July 2010

In order to evaluate the prognostic implications of the hepatitis B e system in patients with chronic persistent hepatitis (CPH), 53 consecutive patients were studied. Fourteen of 16 patients with HBsAg and HBeAg were followed from 12 to 120 months (mean, 38 months). Eleven of the 14 patients were persistently HBeAg positive and five of these developed chronic active hepatitis (CAH) or cirrhosis. A further nine patients were HBsAg positive but HBeAg negative at time of CPH diagnosis (mean follow–up, 47 months). One of these nine patients developed CAH during follow–up. The remaining 28 patients were all HBsAg negative, and only 2 of the 28 patients progressed to CAH or cirrhosis during the time of follow–up (mean, 43 months). It is concluded that the persistence of HBeAg in patients with CPH indicates a serious prognosis with a frequent transition to CAH or cirrhosis.
The Aminopyrine Breath Test and Serum Bile Acids Reflect Histologic Severity in Chronic Hepatitis
Authors: Monroe Paul S. , Baker Alfred L. , Schneider John F. , Krager Patricia S. , Klein Peter D. , Schoeller Dale
Published: July 2010

To determine whether the aminopyrine breath test (ABT) and serum bile acid concentrations reflect histologic severity of chronic hepatitis, 56 patients were prospectively evaluated with liver biopsies and ABTs, and the results were compared to results of standard liver chemistry tests; 44 of these patients also had fasting and 2–hr postprandial serum bile acid measurements. Mean values for the ABT were significantly lower, and serum bile acids were significantly higher in patients with chronic active hepatitis with bridging or cirrhosis than in patients with mild chronic active hepatitis or chronic persistent hepatitis. Thirty of 35 patients with bridging or cirrhosis had ABTs <5.7% (mean of controls -2 S.D.) and 21 of 25 with mild chronic active hepatitis or chronic persistent hepatitis had values >5.7% (sensitivity 0.86, specificity 0.84). Fasting and 2-hr postprandial bile acids were also more sensitive than standard chemistries in identifying patients with bridging or cirrhosis. Thus, the ABT and serum bile acids reflect histologic severity in chronic hepatitis patients and may be helpful in selecting patients for liver biopsy.
Effect of Dihydrotestosterone on Rat Liver Alcohol Dehydrogenase Activity
Authors: Mezey Esteban , Potter James J.
Published: July 2010

Castration was previously demonstrated to result in an increase in liver alcohol dehydrogenase and in rates of ethanol elimination in male rats. In this study, the effect of dihydrotestosterone, which is a more potent androgen than testosterone in the rat, was determined on liver alcohol dehydrogenase and ethanol elimination in the castrated rat. Dihydrotestosterone was found to be a substrate of liver alcohol dehydrogenase in the reductive direction and a competitive inhibitor of ethanol oxidation by the enzyme. Also, the administration of a single dose of dihydrotestosterone inhibited liver alcohol dehydrogenase 4 hr after the injection, but this effect was not persistent at later intervals following injection. This transientin vivoinhibition of liver alcohol dehydrogenase was associated with a delay in ethanol elimination. The microsomal ethanol–oxidizing enzyme system was found to play no role in the changes in ethanol elimination observed after castration and dihydrotestosterone administration since its activity remained unchanged. These studies provide further evidence of an effect of androgenic steroids on liver alcohol dehydrogenase activity and ethanol metabolism.
Bile Acid–Dependent Secretion of Alkaline Phosphatase in Rat Bile
Authors: Hatoff David E. , Hardison William G.M.
Published: July 2010

The role of bile acids in the biliary secretion of alkaline phosphatase was studied. Rats with external bile fistulae were drained for 4 hr. After 2 hr, bile acid secretion fell progressively. Alkaline phosphatase secretion also decreased progressively during the period of drainage, suggesting that secretion of the two components was related. Each rat was then given an i.v. infusion of the taurine conjugate of either cholate, chenodeoxycholate, or ursodeoxycholate. Alkaline phosphatase secretion increased in a dose–dependent manner as bile acid secretion was varied over and beyond the physiologic range. Each bile acid affected alkaline phosphatase secretion differently: given at 0.5 /imoles per min per 100 gm, tauroursodeoxycholate caused a 3–fold, taurocholate a 14–fold, and taurochenodeoxycholate a 75–fold increase in enzyme secretion. To determine if these findings might represent elution of canalicular enzyme by bile acids, isolated liver surface membranes were incubated with the bile acids. Like the findings in vivo, taurochenodeoxycholate was strongest and tauroursodeoxycholate weakest in removing alkaline phosphatase from the membrane. Differential centrifugation of liver surface membranes after exposure to bile acids and ultracentrifugation of bile showed that more than half of the enzyme released by the action of bile acids did not sediment at 100,000 g and, thus, could be considered soluble. These results document bile acid–dependent secretion of alkaline phosphatase in rat bile and suggest that the process involves solubilization of both membrane fragments and free enzyme from membranes lining the biliary space.
Hepatitis A and Non–A, Non–B Viral Hepatitis in São Paulo, Brazil: Epidemiological, Clinical, and Laboratory Comparisons in Hospitalized Patients
Authors: Koff Raymond S. , Pannuti Claudio S. , Pereira Marcelo L.G. , Hansson Bengt G. , Dienstag Jules L. , NETO Amato V. , Wong Doris C. , Purcell Robert H.
Published: July 2010

During a 33–month period, 295 patients with acute viral hepatitis were admitted to a state hospital for civil servants and their dependents in Sao Paulo, Brazil. Seventy–nine per cent (232) were HBsAg negative. To define the contribution of non–A, non–B viral hepatitis to hepatitis morbidity in this population, further serological studies were performed in 147 confirmed HBsAg–negative patients. One hundred and twelve (76%) were serologically classified as hepatitis A based on identification of IgM antibody to hepatitis A virus. Thirty patints (20%) without IgM antibody to hepatitis A virus, HBsAg, or anti–HBc were categorized as the non–A, non–B hepatitis group. The remaining five patients had probable hepatitis B (IgM antibody to hepatitis A virus negative, HBsAg negative, anti–HBs negative but anti–HBc positive). These data suggest that all three etiological forms of viral hepatitis are endemic in Sao Paulo.

Epidemiological, clinical, and laboratory features were compared in the hepatitis A and non–A, non–B hepatitis groups. Patients with non–A, non–B hepatitis were significantly older than patients with hepatitis A (mean age ± S.D.: 30 ± 22 years vs. 9 ± 9 years, p < 0.001). Contact with hepatitis or jaundice was recognized in 26 (23%) of 112 hepatitis A patients and 3 (10%) of 30 non–A, non–B patients, a difference which was not statistically significant. Parenteral exposures were identified in 13 (43%) of 30 patients with non–A, non–B hepatitis and 23 (21%) of the 112 hepatitis A patients. Blood transfusion in the 2 months preceding onset of illness was reported in 5 (17%) of the 30 non–A, non–B patients and in none of the hepatitis A group (p < 0.001). Although prodromal symptoms and fever were more common in patients with hepatitis A, neither these nor other clinical features appeared to be distinguishing characteristics. Similarly, mean peak SGPT levels, peak SGPT levels of > 1,000 HJ/per liter, and the mean duration of SGPT elevations for each group were not significantly different. Mean peak serum bilirubin levels were slightly higher in the non–A, non–B group than in the hepatitis A group (7.6 ± 8.0 mg per dl vs. 5.1 ± 2.7, p < 0.01) and peak bilirubin levels > 10 mg per dl were found in 27% of the non–A, non–B group and 5% of the hepatitis A group (p < 0.001). Whether the higher bilirubin levels reflect an agent–related phenomenon or an older population of affected patients is uncertain.
Comparison of Different Methods of Expressing Results of the Aminopyrine Breath Test
Authors: Schoeller Dale A. , Baker Alfred L. , Monroe Paul S. , Krager Patricia S. , Schneider John F.
Published: July 2010

Different methods of expressing the results of the aminopyrine C02breath test (ABT) were compared to determine the method that would be most sensitive for evaluating liver function. The patient population included healthy controls (n = 22); patients with mild (4), moderate (9), and severe (7) alcoholic liver disease; and patients with chronic persistent hepatitis (7), chronic active hepatitis (18), chronic active hepatitis with bridging (18), and chronic active hepatitis with cirrhosis (17). The ABT was performed with 2 μCi [14C]aminopyrine or 2 mg per kg [13C]aminopyrine, and the results were expressed as the instantaneous labeled CO2excretion rates at 30, 60, 90, and 120 min after the dose, the maximum excretion rate, and the 120–min cumulative excretion. The 30–min parameter had the highest sensitivity toward moderate alcoholic hepatitis, severe alcoholic hepatitis, chronic active hepatitis with bridging, and chronic active hepatitis with cirrhosis (96%); however, when the ABT was repeated in six normal controls with 225 ml of orange juice, the 30–min rate was significantly reduced (7.8 ± 1.3 vs. 5.6 ± 1.2% dose per hr), and the rate of false–positive test results was increased (0 of 6 vs. 2 of 6) indicating that gastric delay influenced the 30–min parameter. The 60–min excretion rate, maximum rate, and 120–min cumulative excretion were the next most sensitive expressions of the ABT, and were not altered by the small gastric load. Of these three expressions, the 60–min parameter was the most convenient because it required fewer samples and a shorter test period.
Polycystic Liver Disease: A Study of Cyst Fluid Constituents
Authors: Patterson Marcel , Gonzalez-Vitale Juan C. , Fagan Charles J.
Published: July 2010

Cyst fluid from a patient with polycystic liver disease was obtained by needle aspiration using ultrasound guidance. The constituents of the fluid resembled the “bile salt–independent” fraction of human bile and supports the hypothesis that such cysts are lined by a functioning, secretory bile duct epithelium.
Valproate–Induced Hepatic Injury: Analyses of 23 Fatal Cases
Authors: Zimmerman Hyman J. , Ishak Kamal G.
Published: July 2010

Analyses of 23 fatal instances of hepatic injury in patients taking valproic acid reveals that all but three were less than 20 years old, and all but four had been taking the drugs for more than 1 month. Convulsions, facial edema, lassitude, and vomiting were prominent clinical features. Hypoglycemia was recorded in six patients. Rash and eosinophilia were not seen. Values for transaminases were modestly elevated in most patients. Most levels of SGOT were below 500 IU, and SGPT levels were below 200 IU. Livers showed microvesicular steatosis in most patients, usually accompanies by necrosis. Four patients had cirrhosis. Overt valproic acid–induced hepatic injury appears to be rare and hence, by definition, idiosyncratic. That it may be an idiosyncratic exaggeration of a much more frequent phenomenon is suggested by the higher incidence of seemingly trivial injury. The idiosyncrasy appears to be metabolic rather than immunologic, and the available information leads to the plausible hypothesis that a metabolite is responsible for the microvesicular steatosis seen in most fatal cases. The steatosis resembles that of Reye's syndrome and Jamaican vomiting sickness, and there is reason to believe that the metabolite responsible for the steatosis resembles the agent responsible for Jamaican vomiting sickness. A different metabolite is presumably responsible for the necrosis seen in many of the cases.
Hypothesis: Metabolic Activity of the Colonic Bacteria Influences Organ Injury From Ethanol
Authors: Levitt Michael D. , Doizaki William , Levine Allen S.
Published: July 2010

Incubation of human fecal homogenates with ethanol (0.078 gm per dl) resulted in accumulation of increased quantities of higher alcohols and other unidentified metabolites when compared with homogenates incubated without ethanol. Studies in rats demonstrated nearly perfect equilibration between blood and colonic luminal ethanol suggesting that the colonic flora in alcoholics is chronically exposed to ethanol concentrations in the range used in the homogenate experiments. The higher alcohols produced by the homogenates were rapidly absorbed from the colon. We hypothesize that, when exposed to ethanol, the colonic flora produced toxic compounds which are absorbed and influence the body's response to ingested ethanol. Individual differences in this bacterial metabolism may account for the wide individual differences in susceptibility to ethanol–related organ injury.
Effect of Inhibitors of Prostaglandin Synthesis on Induced Diuresis in Cirrhosis
Authors: Mirouze Daniel , Zipser Robert D. , Reynolds Telfer B.
Published: July 2010

The effect of inhibitors of prostaglandin synthesis on diuretic action was examined in patients with ascites due to chronic liver disease and in normal subjects. In patients with ascites, natriuresis after 80 mg i.v. furosemide was reduced 82% by pretreatment with indomethacin. Creatinine clearance was reduced only 16%. These effects were likely due to inhibition of renal prostaglandin synthesis, since urinary prostaglandin E2 fell and there was also reduction in natriuresis with naproxen (52%). The effects were not specific for furosemide since spironolactone–induced natriuresis was also reduced by indomethacin (82%), naproxen (52%), and aspirin (33%). In normal subjects, indomethacin reduced furosemide natriuresis by only 14% while creatinine clearance was not affected. The mechanisms of these, drug interactions are uncertain but probably involve renal hemodynamics which appear to be supported importantly by renal prostaglandins in patients with ascites due to liver disease.
A Controlled Clinical Trial of Cimetidine in the Recurrence of Variceal Hemorrhage: Implications About the Pathogenesis of Hemorrhage
Authors: Macdougall Brian R.D. , Williams Roger
Published: July 2010

In a prospective randomized double–blind controlled trial, 51 patients, 16 with cirrhosis and 35 with extrahepatic portal hypertension all of whom presented with variceal bleeding, were given either long–term cimetidine in a dosage of 1.6 gm daily (24 patients) or placebo tablets (27 patients). Thirty–eight patients completed 2 years of treatment. For 16 patients with cirrhosis, there was no significant difference in the frequency of rebleeding between the cimetidine (62.5%) and placebo (75.0%) groups. Similarly, in 35 patients with extrahepatic portal hypertension, the frequency with which bleeding recurred in the cimetidine (37.5%) and placebo groups (36.8%) was not significantly different. Gastric acid and esophageal function studies, including basal acid output, lower esophageal sphincter pressure, esophageal acid reflux, and clearance measurements, showed no significant differences between patients with cirrhosis or extrahepatic portal hypertension both before and after variceal bleeding and in healthy control subjects. These results suggest that it is unlikely that gastric acid reflux is a significant factor in the pathogenesis of variceal hemorrhage, and cimetidine does not prevent recurrent episodes of bleeding.
Arteriohepatic Dysplasia. I. Pitfalls in Diagnosis and Management
Authors: Markowitz James , Daum Fredric , Kahn Ellen I. , Schneider Keith M. , So Henry B. , Altman Peter R. , Aiges Harvey W. , Alperstein Garth , Silverberg Mervin
Published: July 2010

Differentiating intrahepatic cholestasis from extrahepatic biliary tract obstruction may be difficult. Four patients with intraoperative cholangiographic evidence of extrahepatic ductal atresia who underwent hepatoportoenterostomy are described. All were ultimately shown to have arteriohepatic dysplasia with hypoplastic but patent extrahepatic ductal systems. The difficulty in establishing an accurate diagnosis, hazards associated with hepatoportoenterostomy, and suggestions for evaluation and management are discussed.
Dieldrin–Induced Mallory Bodies in Hepatic Tumors of Mice of Different Strains
Authors: Meierhenry Earl F. , Ruebner Boris H. , Gershwin Eric M. , Hsieh Lucy S. , French Samuel W.
Published: July 2010

Mallory bodies (MBs) were induced in hepatic tumors by administration for up to 85 weeks of a diet containing 10 ppm dieldrin to 50 C3H/He and 62 C57BL/6J X C3H/He B6C3F1 male mice. MBs were seen in 15 of 28 (54%) mice which developed benign hepatic tumors and 33 of 45 (73%) mice with hepatocellular carcinoma, but in only 3 of 39 (8%) mice without hepatic tumors. In mice with tumors, the MBs were predominantly confined to tumor tissue and persisted in a carcinoma transplanted into a nude mouse. MBs were not observed, however, in hepatic tumors of 67 C57BL/ 6J, 49 C3H/He, or 81B6C3F1 mice given 12 jug diethylnitrosamine i.p. on Days 0, 3,9, and 15. Thirty–one of 195 control mice of all three strains had hepatic tumors. Only one of the controls had a tumor with an MB, and no MBs were seen in nontumor–bearing livers of control animals. These observations, coupled with the results of a previous study in which MBs were observed in hepatocytes of dieldrin–treated C57BL/6J mice, indicate that mice treated with dieldrin are a reliable animal model for the study of MBs.
Radioimmunoassay of Human Ligandin
Authors: Sherman Morris , Bass Nathan M. , Campbell John A.H. , Kirsch Ralph E.
Published: July 2010

A sensitive and specific radioimmunoassay for human ligandin has been developed and used to study ligandin release into the serum in acute and chronic hepatitis. Serum ligandin concentrations were elevated in 67 of 68 cases of acute viral hepatitis. Ligandin levels frequently returned to normal within the first 2 weeks of illness. The rapid disappearance of ligandin preceded the return to normal of serum SGOT. In chronic active hepatitis, serum ligandin levels correlated significantly (p < 0.01) with histologic severity of disease. This correlation was not seen with SGOT. Serum ligandin may be useful in monitoring progress and the need for therapy in chronic active hepatitis.
Splanchnic and Hepatic Metabolism of Somatostatin: A Study in Cirrhotic Patients With A Portacaval Shunt
Authors: Webb Susan , Kravetz David , Bosch Jaume , Wass John A.H. , Evans Joan , Gomis Ramon , Rees Lesley H. , Rodes Joan
Published: July 2010

Experimental data suggest that somatostatin is metabolized by both liver and kidneys. Results in humans are conflicting. By studying a group of cirrhotic patients with surgically induced end–to–side portacaval shunts, basally and during a somatostatin infusion, we have been able to analyze separately the hepatic and splanchnic metabolism of this peptide. After catheterization, samples were obtained from the pulmonary artery, portal and hepatic veins. Basal pulmonary artery immunoreactive somatostatin (IRS) was significantly higher (p < 0.001) in the cirrhotic patients (96 ± 11 pg per ml) than in a sex– and age–matched control group (31.4 ± 5.8 pg per ml). During the infusion of exogenous somatostatin, HiS values were higher in arterial (12,269 ± 1, 198 pg per ml) than in hepatic venous blood (7,648 ± 1,234 pg per ml), indicating hepatic extraction of the peptide; but there was also a substantial splanchnic extraction demonstrated by higher arterial (12,269 ± 1,532 pg per ml) than portal values (6,754 ± 1,040 pg per ml) of IRS.

During the somatostatin infusion, at very high circulation IRS levels, the liver was able to extract 38% of the peptide. This suggests that the high basal IRS levels found in liver cirrhosis are not likely to be due to hepatic failure. Possible mechanisms may involve increased somatostatin secretion, predominance of high molecular weight moieties of IRS which may not be as effectively removed by the liver, and/or portal–systemic shunting.
An Analysis of the Composition of the Inflammatory Infiltrate in Autoimmune and Hepatitis B Virus-Induced Chronic Liver Disease
Authors: Montano Luis , Aranguibel Fernando , Boffill Margarita , Goodall Alison H. , Janossy George , Thomas Howard C.
Published: July 2010

The composition of the mononuclear cell infiltrate in the liver was studied in patients with autoimmune and hepatitis B virus (HBV)-induced liver disease. The ratio of inducer to cytotoxic/ suppressor cells was greater in patients with lupoid chronic active liver disease, primary biliary cirrhosis, and HBeAb positive HBV-induced chronic active liver disease than in patients with HBeAg positive HBV-induced chronic hepatitis. In patients with chronic HBV-induced (HBeAb positive) liver disease, this ratio was greater in the periportal/portal area than in the lobule. These data are consistent with a relative deficiency of the cytotoxic/suppressor population of T cells in autoimmune liver diseases and possibly in HBeAb positive HBV-induced chronic active liver disease. In the latter patients, different ratios in the periportal and centrilobular zones suggest different mechanisms for periportal and lobular hepatitis.
Abnormal Matrix Recognition By Morris Hepatomas Correlates with Low Glucagon Binding Capacity†
Authors: Mourelle Marisabel , Cordero-Hernández Javier , Ponce-Noyola Patricia , Rojkind Marcos
Published: July 2010

Liver biomatrix contains a group of connective tissue components needed for attachment, survival, and maintenance of liver-specific functions of adult rat hepatocytes in culture. An acidic extract of liver biomatrix that contains a group of glycoproteins can replace intact biomatrix in promoting attachment and survival of hepatocytes. However, except for albumin synthesis, liver-specific functions have not been tested. Acidic extracts of biomatrices prepared from heart, kidney, lung, and spleen (heterologous) contain a similar group of glycoproteins, but differ with respect to liver glycoproteins in their capacity to sustain hepatocyte binding. Normal hepatocytes attach poorly to heterologous glycoprotein extracts, although regenerating and tumoral hepatocytes attach to liver glycoproteins and adhere equally well or with greater efficiency to heterologous glycoprotein extracts. The increased efficiency of hepatocytes to attach to kidney biomatrix-derived glycoproteins showed a linear correlation with the decreased glucagon binding capacity of their isolated plasma membranes. An epithelioid cell-line derived from kidney (MDCK) attached with higher efficiency to kidney than to liver glycoproteins. These results suggest that biomatrices may contain specific glycoproteins needed for attachment and survival of their epithelial cells. This specificity is lost during the proliferative state of regenerating and tumoral hepatocytes and could be important in the general mechanism of tumor dissemination and metastases.
Plasma Lipid and Lipoprotein Response to Fat Feeding in Alcoholic Liver Disease
Authors: Avgerinos Alec , Chu Peter , Greenfield Charles , Harry David S. , Mcintyre Neil
Published: July 2010

Serum lipids and lipoproteins were analyzed after an overnight fast, and following a fatty meal in 10 patients with cirrhosis, 5 with fatty liver, and 5 normal subjects. Cirrhotic patients were divided into two groups of five on the basis of serum lecithin-cholesterol acyltransferase activity. Fasting triglyceride levels were similar in all four groups. In all but cirrhotic patients with low lecithin-cholesterol acyltransferase activity, most fasting triglyceride was found in very low density lipoproteins; in the latter group, most of it was found in low density lipoproteins.

We confirmed that patients with fatty liver have a higher serum triglyceride response to fat feeding than normal subjects, but we did not find higher levels in cirrhotic patients. Cirrhotic patients with “normal” lecithin-cholesterol acyltransferase activity had a normal triglyceride response to dietary fat. In patients with cirrhosis and low lecithin-cholesterol acyltransferase activity, the increase in triglyceride was less than in normal subjects. In this group, most of the extra triglyceride was carried in low density lipoprotein, and not in chylomicrons and very low density lipoprotein, as in the other groups.
Mucin Glycoprotein Content of Human Pigment Gallstones
Authors: Lamont Thomas J. , Ventola Allen S. , Trotman Bruce W. , Soloway Roger D.
Published: July 2010

Mucin glycoproteins, a secretory product of the gallbladder, are thought to contribute to the matrix or nucleus of gallstones. Human black pigment stones originate in the gallbladder and have as their major constituent calcium bilirubinate, as well as inorganic salts and small amounts of cholesterol. The object of this study was to estimate the amount of glycoprotein in black pigment stones and to isolate gallbladder mucin from dissolved stones. Black pigment stones containing 18 to 65% calcium bilirubinate were first dissolved in 12.5 mMEDTA/0.1 iVNaOH and decolorized, then subjected to glycoprotein assay. The mean glycoprotein content of eight stones was 12.4%. In separate experiments, pigment stones were partially dissolved by brief exposure to EDTA/NaOH to minimize glycoprotein breakdown, and the glycoproteins isolated by gel filtration and ultracen-trifugation. Pigment stones contained two glycoprotein fractions on Sepharose 4B; a high molecular weight mucin glycoprotein in the void volume and a lower molecular fraction in the included volume. Mucin was further purified by density gradient ultracentrifugation in cesium chloride. Three separate mucin fractions had an average buoyant density of 1.48 gm per ml which is typical for these glycoproteins. Bile pigment was associated with high molecular weight mucin even after extensive dialysis, gel filtration, and density gradient ultracentrifugation. The identity of mucin was further established by β-elimination of glycoproteins in alkaline borohydride which yielded galactosaminitol from cleavage of O-glycosidic bonds.

Our results indicate that mucin glycoproteins are present in significant concentrations in human black pigment stones and can be purified from stones solubilized in EDTA/NaOH. The association of bile pigment with gallbladder mucin, even after extensive purification, is consistent with the hypothesis that mucin contributes to the matrix of pigment gallstones.
Similarities and Differences Between Models of Extrahepatic Biliary Obstruction and Complete Biliary Retention without Obstruction in the Rat
Authors: Hardison William G. M. , Weiner Robin G. , Hatoff David E. , Miyai Katsumi
Published: July 2010

Biliary obstruction in the rat causes known biochemical and morphological abnormalities. These abnormalities might be caused simply by retention of biliary constituents or might require other factors such as high biliary pressure, interruption of the normal flux of fluid, ions, and other biliary constituents through the hepatocyte and/or changes in intracellular concentrations, binding, and distribution of biliary constituents. We studied a choledochocaval (CC) fistula rat model characterized by complete biliary retention without bile stasis. CC fistula animals were compared with biliary obstructed rats over a 46-hr period. Bile flow and bile acid excretion rate reached high levels by hour 5 and remained high in CC fistula rats. Urinary bile acid excretion, shrinkage of the rapidly exchangeable bile acid pool, and serum bile acid and bilirubin concentrations were equivalent in the two models. Serum cholesterol concentration was higher and serum alkaline phosphatase and 5′-nucleotidase activities lower in obstructed rats. The percentage of β-muricho-late rose and the percentage of cholate decreased in bile acid from obstructed rats. This was associated with increased microsomal 6 β-hydroxylase activity. Bile acid composition and microsomal 6 β-hydroxylase activity changed little in CC fistula rats. Morphological examination revealed greater damage in obstructed rat livers. These data indicate that factors other than simple retention of biliary constituents contribute to the abnormalities observed in extrahepatic biliary obstruction.
Quantitation of Hepatic Granulomas and Epithelioid Cells in Primary Biliary Cirrhosis
Authors: Nakanuma Yasuni , Ohta Goroku
Published: July 2010

The number of granulomas and loosely arranged epithelioid cell foci in wedge liver biopsy specimens of 39 patients with primary biliary cirrhosis were counted and correlated with other hepatic lesions. Granulomas and cell foci were present in 76.9 and 87.2% of the patients, respectively; their numbers varied greatly from case to case (mean ± S.D.: 2.4 ± 3.4 per cm2 and 4.7 ± 5.5 per cm2 of liver section; range: 0 to 18.5 per cm2 and 0 to 23.3 per cm2, respectively) and decreased as bile duct loss progressed. There was positive correlation between the number of cell foci with the extent of florid duct lesions, and negative correlation with hepatic fibrosis and deposition of copper granules.
Is Intravenous Administration of Branched Chain Amino Acids Effective in the Treatment of Hepatic Encephalopathy? A Multicenter Study
Authors: Wahren John , Denis Jacques , Desurmont Philippe , Eriksson Ljusk S. , Escoffier Jean-Marc , Gauthier André P. , Hagenfeldt Lars , Michel Henri , Opolon Pierre , Paris Jean-Claude , Veyrac Michel
Published: July 2010

The influence of intravenous infusion of branched-chain amino acids (BCAAs) on brain function in patients with liver cirrhosis and acute hepatic encephalopathy was examined using a double-blind, randomized study design. Five medical centers in France and Sweden participated, and 50 patients were studied. The patients received either BCAAs (40 gm per day) in 5% glucose or 5% glucose alone (placebo) for 5 days or until “wake up”. Nutritional support was provided with equal proportions of carbohydrate and fat. During BCAA adminstration, plasma concentrations of aromatic amino acids and methionine fell (20 to 40%, p < 0.05 to 0.01), and the ratio of BCAAs to aromatic amino acid concentrations increased significantly. Clinical improvement was seen in 14 of 25 BCAA-treated patients and in 12 of 25 patients receiving placebo (N.S.). EEG responses were similar in the two groups during treatment. In the BCAA group, 10 of 25 patients died in the course of the study, compared to 5 of 25 in the placebo group (N.S.); six patients died from encephalopathy in the BCAA group as compared to three among placebo-treated patients. It is concluded that BCAA adminstration, in the dose and composition employed in the present study, reduces the concentrations of aromatic amino acids but neither improves cerebral function nor decreases mortality in patients with hepatic encephalopathy.
Diethylstilbestrol-Induced Jaundice in the Chinese and Armenian Hamster
Authors: Coe John E. , Ishak Kamal G. , Ross Mary J.
Published: July 2010

An unusual and impressive hyperbilirubinemia was induced in Chinese hamsters by administration of diethylstilbestrol (DES). This icterus was dose-dependent and affected females more severely than males. However, a similar mortality was detected in both sexes. Another hamster, the Armenian hamster, was even more susceptible to the icteric and lethal effects of DES. The hamster model of DES-induced icterus showed many clinical dissimilarities when compared to the human estrogen-induced jaundice, simple cholestatic jaundice. Furthermore, hepatic pathology was distinctly different as canalicular cholestasis was absent although other degenerative and regenerative hepatocellular changes were present. Livers of Armenian hamsters were more severely affected than were livers from Chinese hamsters and contained Mallory bodies even within 1 week after DES treatment. A modest, nonlethal jaundice also was detected in European hamsters after DES injection, whereas Syrian hamsters were not affected even after larger doses. This unique sensitivity to DES, and the spectrum of sensitivity within these related hamsters (Armenian ± Chinese ± European vs. resistant Syrian) provide an interesting model for study of DES effect on hepatic function.
Value of Screening for Markers of Hepatitis in Dialysis Units
Authors: Ware Athol J. , Gorder Nancy L. , Gurian Lawrence E. , Douglas Clark , Shorey James W. , Parker Thomas
Published: July 2010

The value of monitoring the serum activity of SGOT, as well as markers of hepatitis B virus and hepatitis A virus infections, in the patients and staff of two dialysis units has been assessed retrospectively. Sera were checked each month for SGOT and HBsAg on 406 patients and 170 staff members over a 4-year period. Anti-HBc, anti-HBs, and anti-hepatitis A antibodies were assayed on the stored sera. Only 30% of the patients had normal SGOT values (<65 units per ml) on all occasions. Most of the abnormal values were <100 units per ml and could not be explained. Viral hepatitis was a reasonable explanation for only half of those instances where the SGOT value was greater than 100 units per ml. Hepatitis A virus contributed nothing to the problem of dialysis-associated liver disease. Testing for HBsAg alone missed approximately 40% of the hepatitis B events acquired in the unit. Only two of these episodes were of epidemiologic importance, however, because the rest were recognized only after there was serologic resolution of the infection. There was a high frequency of potentially “false positive” reactions with all the antibodies tested. It is not cost-effective to monitor dialysis patients and staff regularly with anti-HBc, anti-HBs, or antibodies against hepatitis A. Initial screening with anti-HBc and anti-HBs on entry to the unit is of value but weak positive results must be interpreted with caution since approximately half of such results will prove to be nonspecific.
Ground Squirrel Hepatitis Virus Infection
Authors: Marion Patricia L. , Knight Susan S. , Salazar Felix H. , Popper Hans , Robinson William S.
Published: July 2010

Twenty-four adult Beechey ground squirrels persistently infected with the hepatitis B virus-related ground squirrel hepatitis virus (GSHV) remained infected with high levels of viral surface antigen (GSHsAg) and virion-associated DNA polymerase activity in the blood for over 2 years in captivity. Unlike humans infected with hepatitis B virus, no GSHsAg-bearing ground squirrels had surface antigen in the blood without DNA polymerase-containing virions, and the levels of these did not change. Only a very mild hepatitis was observed histologically in some of the virus-infected animals, with faint Shikata-staining detectable in some. Other animals exhibited no histologic evidence of hepatitis. While the closely related woodchuck hepatitis virus has been associated with more severe chronic hepatitis and a high incidence of liver cancer in woodchucks, these were not found in GSHV-infected ground squirrels when a similar number of animals were followed for a similar time of observation. Experimental infection of ground squirrels with no evidence of current or past GSHV infection resulted in three types of response: (i) self-limited or transient GSHV-positive infection; (ii) GSHV-positive infection which became persistent, and (iii) primary anti-GSHs and anti-GSHc (antibody to the viral core antigen) responses without detectable GSHsAg or virion DNA polymerase activity in the blood. These responses are similar to those observed following experimental infection of man with HBV. GSHV produced none of the three responses when injected into a variety of laboratory animal species and a chimpanzee, causing only an antibody response to GSHsAg. No evidence of current or past infection was detected in a number of animal species from an area endemic for GSHV. The virus has only been found in one area of northern California, with a carrier rate in that location reaching 52%.
The Role of Fat-Storing Cells in Disse Space Fibrogenesis in Alcoholic Liver Disease
Authors: Minato Yukihito , Hasumura Yasushi , Takeuchi Jugoro
Published: July 2010

Liver biopsy samples from 40 chronic alcoholic patients, including 9 with minimal changes of the liver, 6 with mild hepatic fibrosis, 14 with moderate fibrosis, and 11 with severe fibrosis (cirrhosis) were studied by electron microscopy to assess fibrogenesis in the Disse space and the role of fat-storing cells in this process. In the Disse space of normal liver, collagen fibers are few, and while lipid droplets containing fat-storing cells exist, their rough endoplasmic reticulum (RER) is inconspicuous. In the course of progressive hepatic fibrosis, collagen in the Disse space increased. This was significantly associated with gradual development of RER in fat-storing cells, confirmed by morphometric analysis. It is likely, therefore, that the development of RER in the fat-storing cells is a morphological correlative of their activated fibrogenesis and transformation into fibroblasts. To further clarify this, the rate of collagen synthesis was measured by the method of in vitro incorporation of [3H]proline into collagen in 17 liver biopsy samples from alcoholic patients and compared with the degree of morphological changes of RER in fat-storing cells. In liver samples with well-developed RER in fat-storing cells, a significantly higher rate of collagen synthesis was observed. These results suggest that in alcoholic liver injury, fat-storing cells may play an important role in Disse space fibrogenesis.
Immunosuppressive Serum Factors in Viral Hepatitis. I. Characterization of Serum Inhibition Factor(s) as Lymphocyte Antiactivator(s)
Authors: Brattig Norbert W. , Berg Peter A.
Published: July 2010

Sera from patients with acute viral hepatitis B were found to inhibit the in vitro proliferation of normal lymphocytes induced by different mitogens and antigens. In addition, an effect on concanavalin A-induced T suppressor cell activity and pokeweed mitogen-stimulated IgG and IgM synthesis was demonstrated.

Studies concerning the kinetics of serum immunosuppressive effects indicated that serum immunosuppressive factor (SIF) interfered with the intermediate phase of mitogen-induced lymphocyte activation which was defined by protein and RNA synthesis. Thus, when SIF-positive sera were added to lymphocytes, which were already activated by phytohemagglutinin, for 8, 12, or 18 hr, the inhibitory effect decreased in relation to the duration of lymphocyte activation. No inhibition could be demonstrated when SIF-positive sera were added 24 hr after initiation of mitogen stimulation. Furthermore, similar inhibitory effects were found measuring either uptake of [3H]uridine (RNA synthesis) or [3H]leucine (protein synthesis) in a 24 hr culture of phytohe-magglutinin-stimulated lymphocytes or [3H]thymidine uptake (DNA synthesis) after 48 hr.

These results indicate that SIF act(s) like an antiactivator and may belong to immunoregulatory physiologic serum factors.
Analysis of Liver Disease, Nuclear HBcAg, Viral Replication, and Hepatitis B Virus DNA in Liver and Serum of HBcAg Vs. Anti-HBe Positive Carriers of Hepatitis B Virus
Authors: Hadziyannis Stephanos J. , Lieberman Harvey M. , Karvountzis Gerassimos G. , Shafritz David A.
Published: July 2010

Nine HBeAg+and 24 anti-HBe+subjects with chronic hepatitis B virus (HBV) infection were studied for HBV DNA in the serum by molecular hybridization, for HBeAg in the liver by immunofluorescence, and for histologic evidence of liver disease. All HBeAg+patients had underlying chronic liver disease (chronic persistent hepatitis, chronic active hepatitis, or cirrhosis with or without hepatocellular carcinoma), and all were found positive for both HBV DNA in the serum and HBeAg in the nucleus of hepatocytes. Of the 24 anti-HBe+individuals, 18 had various forms of chronic liver disease. Six HBsAg+/anti-HBe+patients had normal liver histology except for numerous “ground-glass” hepatocytes with abundant cytoplasmic HBsAg. All six were negative for nuclear HBeAg and serum HBV DNA, but three showed HBV DNA which appeared to be integrated into unique sites in host liver DNA by hybridization analysis. In contrast, 14/18 (78%) of HBsAg+/anti-HBe+patients with chronic liver disease were positive for nuclear HBeAg, serum HBV DNA, or both of these markers of HBV replication. It is suggested that in long-term HBsAg carriers with serum anti-HBe and normal liver histology, viral replication is suppressed or inactive and HBV potential infectivity is presumably very low or absent. However, when viral replication is present in HBsAg+/anti-HBe+carriers (as demonstrated by serum HBV DNA and/or nuclear HBeAg), active liver disease is often found. In these individuals, active chronic liver disease appears to be related to continued replication and secretion of HBV and may occur in a much higher proportion of HBsAg+/anti-HBe+carriers than was previously suspected.
Idiopathic Hemochromotosis and Alpha-1-Antitrypsin Deficiency: Coexistence in a Family with Progressive Liver Disease in the Proband
Authors: Anand Suri , Schade Robert R. , Bendetti Carlos , Kelly Robert , Rabin Bruce S. , Krause John , Starzl Thomas E. , Iwatsuki Shunzaburo , Van Thiel David H.
Published: July 2010

A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed.
Determinants of Drug Disposition in Patients with Cirrhosis†
Authors: Huet Pierre-Michel , Villeneuve Jean-Pierre
Published: July 2010

The effects of alterations of the hepatic blood flow, the intrinsic clearance, and the anatomy of the portal circulation on drug disposition were investigated in 53 cirrhotic patients with portal hypertension using indocyanine green (ICG) and lidocaine as model drugs. ICG disposition was studied by sampling from an artery and one hepatic vein following i.v. injection, with determination of systemic and intrinsic clearances and hepatic blood flow. Lidocaine disposition was studied following i.v. and oral administration from peripheral vein disappearance curves, with determination of systemic and intrinsic clearances and systemic availability. The shunted fraction of intestinal blood flow (f) was measured from the combined ICG and lidocaine disposition studies. In the 53 patients, systemic clearances of ICG and lidocaine varied widely and were significantly correlated with each other (r = 0.725, p < 0.001). The systemic clearances of both ICG and lidocaine were not related to hepatic blood flow but were significantly correlated to their respective intrinsic clearances (for ICG: r = 0.948, p < 0.001; for lidocaine: r = 0.873, p < 0.001). Lidocaine systemic availability was also found to vary widely from 0.2 to 1.0. In 28 patients, f was <0.1 indicating minimal extrahepatic shunting and in these patients, lidocaine systemic availability was related to its intrinsic clearance (r = -0.717, p < 0.001); in the 25 other patients with significant extrahepatic shunting (f > 0.1), the extent of lidocaine systemic availability was related to both intrinsic clearance (r = −0.819, p < 0.001) and extrahepatic shunting (r = 0.913, p < 0.001). It is concluded that, in patients with cirrhosis: (i) the disposition of drugs with intermediate-high hepatic extraction ratios is no longer influenced by hepatic blood flow but becomes limited by intrinsic clearance; and (ii) the decrease of intrinsic clearance plus extrahepatic shunting, when present, are responsible for the increased systemic availability of this type of drug.
Cimetidine Kinetics and Dynamics in Patients with Severe Liver Disease
Authors: Villeneuve Jean-Pierre , Fortunet-Fouin Hélène , Arsène Dominique
Published: July 2010

Following cimetidine administration, 60% of the dose is excreted as unchanged drug in the urine, and 40% is eliminated by metabolism. We evaluated the effect of liver disease on cimetidine disposition by comparing its kinetics in 7 healthy subjects and 8 patients with alcoholic cirrhosis. Cirrhotic patients had severe liver disease as evidenced by the presence of ascites, hepatic encephalopathy, jaundice, muscle wasting, and low serum albumin, but serum creatinine and creatinine clearance did not differ significantly between controls and cirrhotics. Following intravenous administration, cimetidine systemic clearance was decreased by 56% in cirrhotics. This reduction was due in major part to an impairment of the renal clearance of unchanged drug. The ratio of cimetidine to creatinine clearance was 3.71 ± 0.63 in controls, indicating active tubular secretion, and was decreased in cirrhotics (1.22 ± 0.09, p < 0.05). The volume of distribution of cimetidine was also decreased by 39% in cirrhotics. To verify whether these findings observed after a single dose could be extended to patients receiving chronic cimetidine treatment, cimetidine trough (predose) plasma levels were measured in an additional group of 56 subjects receiving continuous cimetidine therapy (15 controls and 41 cirrhotics). Trough plasma levels did not differ significantly in controls and patients with compensated liver disease, but were elevated in patients with moderate and severe hepatic dysfunction. It is concluded that cimetidine clearance is decreased in patients with severe liver disease, mostly due to an impairment of the tubular secretion of unchanged drug, and that a reduction of cimetidine dosage is warranted in these patients, even in the presence of a normal creatinine clearance.