bluuebunny/crossref_metadata_2025 huggingface dataset:
Sn-protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase activity in normal human subjects
Authors: Berglund Lars , Angelin Bo , Blomstrand Rolf , Drummond George , Kappas Attallah
Published: March 2007

Sn-protoporphyrin, a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in the degradation of heme to bile pigment, was administered to 10 normal volunteers: 8 males and 2 females. A significant decrease in the levels of serum (mean decrease; 38%) and biliary bilirubin (mean decrease: 47%) was demonstrated in all 10 subjects. The decrease in these parameters lasted for a minimum of 4 days after administration of the metalloporphyrin. Sn-protoporphyrin also facilitated the excretion of endogenous heme in bile during the 24- to 48-hr period following administration of the compound. The metalloporphyrin was rapidly cleared from plasma with a half-life of 3.4 hr. A small amount (3 to 6%) of Sn-protoporphyrin was excreted in both urine and bile. The activity of microsomal heme oxygenase was measured in five human liver samples freshly obtained at the time of cholecystectomy and varied from ˜2 to 4 nmoles bilirubin formed per mg protein per hour. The addition of Sn-protoporphyrin to microsomal heme oxygenase isolated from these liver samples resulted in a dose-dependent decrease in the activity of this enzyme at concentrations of the metalloporphyrin in the range of 10−7 to 10−9
M. The findings reported here provide strong evidence that the suppression of biliary and serum bilirubin levels and the enhancement of heme excretion in the bile of the normal volunteers examined in this study were due to inhibition of physiological rates of heme oxidation activity by the synthetic heme analog, Sn-protoporphyrin.
Assessment of the effect of respiration on the esophageal variceal blood flow using transesophageal real-time two-dimensional doppler echography
Authors: Sukigara Minoru , Ohata Masahiko , Komazaki Toshiro , Omoto Ryozo
Published: March 2007

The effect of spontaneous respiration on esophageal variceal flow was evaluated using 5 MHz color flow Doppler echography. Twenty-one patients with esophageal varices, of whom 19 had liver cirrhosis (95%), were examined with a convex array transesophageal transducer. The direction and velocity of the variceal flow during inhalation and exhalation could be inferred from the color, its brightness or the Doppler time-velocity spectrum. The mean intravariceal flow velocity was significantly higher during inhalation (20. 6 cm per sec) than in exhalation (11.5 cm per sec; p < 0.01). The direction of intravariceal flow at any given point did not change throughout the respiratory cycle. However, a combination of real-time color flow imaging and the doppler time-velocity spectrum revealed that, when the sampling point was near the peak of the curve of the varix, the spectrum falsely indicated reversal of direction between inhalation and exhalation. This semiinvasive method, which yields anatomical and physiological information simultaneously, appears to be very useful for the study of variceal flow.
Clinical and statistical analyses of new and evolving therapies for primary biliary cirrhosis
Authors: Wiesner Russell H. , Grambsch Patricia M. , Lindor Keith D. , Ludwig Jurgen , Dickson Rolland E.
Published: March 2007

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease thought to be related to abnormalities in immune regulation. The disease is associated with granulomatous bile duct destruction, cholestasis, hepatic copper overloading and the development of hepatic fibrosis or cirrhosis or both. There have been numerous therapeutic trials evaluating immunosuppres-sive, antifibrotic and cupruretic agents. Prednisolone, D-penicillamine, azathioprine, colchicine and chloram-bucil have been evaluated in controlled clinical trials, and biochemical improvement of liver function has been noted with all of the agents, except D-penicillamine. Improved survival has also been reported in patients treated long-term with azathioprine and colchicine. However, none of the therapeutic agents has been demonstrated to halt histologic progression of the disease or to induce a complete clinical, biochemical and histologic remission as has been reported in patients with autoimmune chronic active hepatitis treated with corticoste-roids. Many of the trials did not use a double-blind design, failed to use the “intent to treat” rule or failed to define an objective time to analyze results. Many of the studies involved small numbers of patients with short-term follow-up and thus potentially were inadequate to appreciate drug effects that might be of clinical benefit. Currently, there is no totally effective therapy for primary biliary cirrhosis. We believe that well-designed clinical trials can provide important information to better understand this disease until a totally effective therapy is available. New clinical trials should use well-established methodologic guidelines in study design and well-accepted statistical standards in the analysis and interpretation of results.
Estrogens keep alive the hepatocyte memory
Authors: Tiribelli Claudio , Bellentani Stefano
Published: March 2007

Transient stimulation of target tissues by sex steriods can cause long-lasting changes that may facilitate or alter responses to subsequent hormonal treatment. How these altered characteristics are propagated during cell division in the absence of the stimulating hormone is unknown. The human hepatocarcinoma cell line HepG2 was used as a model to examine the effects of estrogen on the synthesis of serum apolipoproteins in vitro. Treatment with low concentrations of estrogen for 24 to 48 hours resulted in long-lasting alterations in the kinetics with which the cells respondent to subsequent stimulation with estrogen. Manifestation of this memory effect was correlated quantitatively with the induction and propagation of a moderate-affinity, nuclear, estrogen-binding protein with the characteristics of a type II estrogen receptor. The data indicate that transient exposure of these cells to estrogen can induce changes in their response, characteristics and composition of nuclear proteins that are inherited by daughter cells grown in the absence of hormone for more than ten generations.
Lymphoblastoid interferon in controlled trials of chronic hepatitis B virus infection
Authors: Hadziyannis Stephanos J.
Published: March 2007

A controlled trial of lymphoblastoid interferon versus no therapy in patients positive for HBsAg, HBeAg and DNA polymerase activity with separate randomisation for sexual preference and histology is underway. Thirty-two patients have been followed for a minimum period of 6 months of whom 15 have been randomised to receive interferon thrice weekly for 6 months after a 5-day induction phase.

Five treated patients developed an hepatitis-like illness during the 3rd month of therapy concurrent with an abrupt and complete loss of DNA polymerase activity from serum. In 3 this was permanent and anti-HBe subsequently developed; 2 of these have also lost HBsAg. In the other 2 patients inhibition of viral replication was transient. In 5 further treated patients DNA polymerase activity was completely inhibited throughout treatment only to return as soon as interferon was withdrawn. In this group serum aminotransferase became normal during treatment. In the remaining 5 treated patients, inhibition of DNA polymerase activity was never complete and serum amino-transferases were unaffected. All the control patients remain seropositive for HBsAg, HBeAg and DNA polymerase activity. The low seroconversion rate in treated patients and the absence of seroconversion in the control group are probably a reflection of the exclusion of patients with marked elevation of serum aminotransferases.

The occurrence of an hepatitis-like illness in the 3rd month of therapy in a third of the patients and the loss of HBsAg in 2 of 3 who eventually sero-converted are likely to be a consequence of therapy rather than spontaneous events. If these data prove representative of the completed trial, the results will indicate a small but real benefit from interferon therapy in patients with stable disease.

Thirty male patients (27 homosexual) with biopsy proven chronic active hepatitis B were randomised to receive lymphoblastoid interferon (Wellferon) or no treatment. All patients were HBeAg positive and had continuing viral replication. Patients receiving treatment were given a single daily intramuscular injection of interferon for 28 days at a starting dose of 2.5 MU/m2 increasing to a maximum of 7.5 MU/m2/day. Transient side effects of malaise and influenza like symptoms occurred in all patients and resolved rapidly after treatment. Hepatitis B viral replication was suppressed during interferon treatment in all patients but the effect was limited to the period of therapy. After one year there was not appreciable difference in viral markers between the two groups of patients and this treatment schedule appears less effective than the thrice weekly, three month regimes recently reported from other centres.
Multiple gastric red spots, capillary ectasia, hypergastrinemia and hypopepsinogenemia i in cirrhosis: A new syndrome?
Authors: Samloff Michael I.
Published: March 2007

To characterize bleeding from gastric red spots in patients with cirrhosis, three groups of patients were studied: (a) 11 cirrhotic patients bleeding from gastric red spots, (b) 18 nonbleeding cirrhotic patients without gastric red spots, and (c) 13 non-cirrhotic patients with endoscopic normal mucosa (controls). Histologic examination of antral biopsy specimens revealed a diffuse capillary ectasia without inflammation in 8 of the 11 cirrhotic patients with gastric lesions. Morphometric analysis disclosed a significantly greater mean mucosal capillary cross-sectional area in cirrhotic patients with gastric lesions (mean ± SE, 1371 ± 320 μm2) than in those without gastric lesions (541 ± 61 μm2) (p < 0.005) or controls (353 ± 20 μm2) (p < 0.001). Hypergastrinemia was detected in 8 of the 11 cirrhotic patients with lesions, in 2 of the 18 cirrhotic patients without gastric lesions, and in none of the controls (p < 0.001). Gastrin serum levels correlated significantly (r = 0.80) with mean mucosal capillary cross-sectional area in patients with cirrhosis. Pepsinogen I serum levels below 20 ng/ml were observed in 7 of the 11 cirrhotic patients with lesions, in 1 of the 18 cirrhotic patients without lesions, and in none of the controls. These data indicate that bleeding from gastric red spots in patients with cirrhosis is a distinct entity characterized by vascular ectasia of the gastric mucosa. This condition seems to be associated with hypergastrinemia and low serum levels of pepsinogen I.
Effects of vitamin A and ethanol on liver plasma membrane fluidity
Authors: Kim Cho-Il , Leo Maria Anna , Lowe Nancy , Lieber Charles S.
Published: March 2007

To study possible mechanisms whereby vitamin A and ethanol may affect liver plasma membranes, rats were fed liquid diets containing either 6 international units of vitamin A per kcal or 5 times more, with or without ethanol (36% of total energy as isocaloric substitution for carbohydrate). Vitamin A supplementation resulted in 2- to 3-fold increases of liver plasma membrane free retinol (p < 0.005) and retinyl esters (p < 0.001), particularly esters of palmitate and oleate, whereas cholesterol ester did not change. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene revealed decreased fluidity as measured by an increase in fluorescence polarization which correlated significantly with retinyl palmitate plus oleate content in membranes. In rats fed ethanol chronically, we first verified our previous observation of a decrease in liver plasma membrane fluorescence polarization. We now find this effect to be associated with (and possibly due to) an increase of cholesterol ester content. In linear regression analysis, the change in fluorescence polarization correlated positively with vitamin A (p < 0.02) and negatively with cholesterol ester contents (p < 0.001). Ethanol feeding partially offset the effect of vitamin A supplementation on fluorescence polarization. We conclude from these observations that liver plasma membranes contain a significant amount of vitamin A, that vitamin A supplementation increases membrane fluorescence polarization and that chronic ethanol administration can interfere with this effect.
Influence of male hormones on rates of ethanol elimination in man
Authors: Mezey Esteban , Oesterling Joseph E. , Potter James J.
Published: March 2007

The effect of a reduction in androgens on ethanol elimination was determined in man. Bilateral therapeutic orchiectomy in nine patients for prostatic carcinoma decreased mean plasma testosterone levels from 489.8 ± 31.2 (S.E.) ng per dl to 55.3 ± 3.8 ng per dl and resulted in an increase in the rate of ethanol elimination in seven patients, no change in one, and a decrease in one. The mean rate of ethanol elimination for all nine patients increased from 83.6 ± 4.0 to 100.4 ± 4.2 mg per kg body weight per hr (p < 0.02). The most likely mechanism for an increase in ethanol elimination after orchiectomy is an increase in liver alcohol dehydrogenase content, which remains to be demonstrated in man.
In Vitro transmission of duck hepatitis B virus to primary duck hepatocyte cultures
Authors: Uchida Toshikazu , Suzuki Koyu , Okuda Yasunori , Shikata Toshio
Published: March 2007

An attempt was made to infect primary duck hepatocyte cultures with duck hepatitis B virus in vitro in order to clarify the biology of hepatitis B virus. Livers of ducklings, 0 to 17 days posthatch, without viremia were digested ex situ by perfusion of collagenase solution through the portal or hepatic vein. Homogeneous hepatocyte suspensions were seeded into plastic dishes in L-15 medium containing 10−8
M insulin, 2 × 10−8
M glucagon and 10−8
M dexamethasone and were subsequently inoculated with sufficient numbers of duck hepatitis B virus. As a result, duck hepatitis B virus multiplication started weakly on Day 2, gradually increased and reached the maximum level approximately on Day 10 postinoculation. Viral replication was revealed by duck hepatitis B virus DNA in the cell pellet and in the culture medium and duck hepatitis B virus DNA-specific transcripts in the cell pellet. Immunostaining demonstrated duck hepatitis B virus core antigen in approximately 10% of cultured hepatocytes, and an increase in numbers of positive cells was not observed with time for up to 18 days of culture. Viral particles were found within the endoplasmic reticulum, and the inoculation of culture medium provoked viremia in the ducklings. The age of ducklings did not influence the numbers of cells infected. The in vitro infection system was similar to the in vivo one; however, the former seemed to be age-independent and to allow replication of duck hepatitis B virus in the limited number of hepatocytes.
Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal
Authors: Stellon Anthony J. , Keating John J. , Johnson Philip J. , McFarlane Ian G. , Williams Roger
Published: March 2007

Forty-seven patients with autoimmune chronic active hepatitis in remission on azathioprine and/or prednisolone were entered into a randomized controlled trial to assess the value of azathioprine alone in maintenance of remission. The trial design involved administering azathioprine at a dose of 2 mg per kg to one-half of the patients, in whom prednisolone was then gradually withdrawn, whereas the remaining patients, the “control” group, were maintained on the conventional combination regimen of azathioprine (1 mg per kg) with prednisolone. At 1 year there was no significant difference in respect of standard liver function tests or histological appearances between the two groups. Two patients in the azathioprine group required dosage reduction because of myelosuppression and both subsequently relapsed. Following withdrawal of corticosteroids Cushingoid features were lost with a return of weight and blood pressure to normality. In 75% of the patients, corticosteroid withdrawal was marked by arthralgias and myalgias which lasted for up to 12 months: no other major side effects of corticosteroid withdrawal were noted. Thus in the majority of cases, remissions in autoimmune chronic active hepatitis which are induced by corticosteroids can be maintained with azathioprine alone.
Alterations of hepatic enzyme levels and of the acinar distribution of glutamine synthetase in response to experimental liver injury in the rat
Authors: Gebhardt Rolf , Burger Hans-Jörg , Heini Hans , Schreiber Karl-Ludwig , Mecke Dieter
Published: March 2007

Glutamine synthetase shows a striking heterogeneous distribution in normal rat liver as consistently revealed by immunohistochemistry using a specific antiserum against the rat liver enzyme or a cross-reacting antiserum. The effects of zonal liver injury induced by allylformate or CC14 on this distribution and on the activity of glutamine synthetase as well as of enzymes with different acinar distribution were investigated. Treatment with allylformate or CC14 at appropriate concentrations led to severe hepatocyte necrosis in the periportal and perivenous zone, respectively, as revealed by histological examination and by the levels of serum marker enzymes. Exposure to allylformate (50 to 100 μl per kg) for less than 1 day did not change the distribution and activity of glutamine synthetase but reduced the specific activities of the urea cycle enzymes. In contrast, treatment with CC14 (1,000 μl per kg) strongly reduced the activity and the acinar region covered by glutamine synthetase but not, for instance, the activities of the urea cycle enzymes. These results in conjunction with the data obtained for other enzymes indicate that a short exposure to these hepatotoxins affects different enzyme activities in close accord with their preferential acinar localization. During prolonged exposure this initial response was often modified due to adaptation. In the case of glutamine synthetase, however, no adaptive appearance of glutamine synthetase in other parts of the acinus could be detected even if the cell population originally expressing this phenotype was destroyed. This extremely inflexible distribution suggests that glutamine synthetase expression is a matter of cell differentiation rather than of modulation by nutritional and hormonal factors (or their acinar gradients) as found for many other hepatic enzymes.
Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension
Authors: Navasa Miquel , Bosch Jaime , Reichen Jürg , Bru Conxita , Mastai Ricardo , Zysset Thomas , Silva Guillermo , Chesta Jaime , Rodés Joan
Published: March 2007

The effects of verapamil on hepatic and systemic hemodynamics and on liver function were investigated in 10 patients with portal hypertension due to advanced micronodular cirrhosis to verify whether, as it has been suggested, this calcium channel blocker may improve liver function and reduce portal pressure in these patients. The oral administration of 100 mg of verapamil caused systemic vasodilation, evidenced by a significant reduction in mean arterial pressure (−8.1 ± 7.6%, p < 0.025) and systemic vascular resistance (−12.5 ± 9.5%, p < 0.001), and increased heart rate (+13.9 ± 10.4%, p < 0.01). However, no beneficial effect was noted on portal pressure evaluated by hepatic vein catheterization (baseline 19.8 ± 4.0, verapamil 20.2 ± 3.6 mmHg, NS), hepatic blood flow (1.45 ± 0.64 vs. 1.47 ± 0.62 liters per min, NS) and hepatic vascular resistance (1.314 ± 611 vs. 1,266 ± 513 dyn per sec per cm−5, NS). Similarly, no change was observed in portal blood flow, measured in six patients by pulsed Doppler flowmeter (0.94 ± 0.30 vs. 0.89 ± 0.35 liter per min, NS). In addition, verapamil did not increase the hepatic intrinsic clearance of these patients (0.20 ± 0.07 vs. 0.19 ± 0.06 liter per min, NS). This study suggests that verapamil is of no beneficial effect in patients with advanced cirrhosis of the liver.
Feedback regulation of bile acid synthesis in the rat by dietary vs. Intravenous cholate or taurocholate
Authors: Stange Eduard F. , Scheibner Jürgen , Lutz Christine , Ditschuneit Hans
Published: March 2007

The regulation of bile acid synthesis was studied (i) in intact or colectomized rats receiving cholate or taurocholate as a dietary supplement and (ii) in experiments using chow-fed animals with a graded intravenous or intraduodenal taurocholate infusion. After the 2-week diet period a bile fistula was established and rates of taurocholate, tauromuricholate and taurochenodeoxy-cholate secretion were quantitated by high-performance liquid chromatography. During the infusion experiments taurocholate production was calculated from the difference in specific activity of [14C]taurocholate between infusate and bile, whereas tauromuricholate and taurochenodeoxycholate synthesis was derived directly from their secretion rates after pool depletion. Both the 0.5% cholate and taurocholate diet suppressed tauromuricholate and taurochenodeoxycholate secretion nearly totally, but only cholate led to a prolonged inhibition taurocholate synthesis. The diets stimulated total bile acid secretion and expanded the total bile acid pool size 2- to 3-fold, but they also prompted a dramatic increase in the biliary secretion of taurodeoxycholate. In contrast, colectomized animals did not secrete taurodeoxycholate following the cholate diet and, despite a comparable increase in bile acid pool size, tauromuricholate and taurochenodeoxycholate secretion was inhibited to a lesser extent. In addition, the rate of bile acid secretion and synthesis was significantly enhanced when compared to that of intact rats. To determine whether taurocholate affected bile acid synthesis directly, the bile acid was infused intravenously or intraduodenally at varying rates up to 300 μmoles per kg per hr for 54 hr, i.e. a rate exceeding normal total bile acid secretion in these acute bile fistula animals nearly 3-fold. However, there was no decrease in both tauromuricholate, and taurocholate synthesis and taurochenodeoxycholate was lowered only by the highest dose of taurocholate and only during the derepressed phase. When a taurocholate infusion was given to rats prefed 0.5% cholate there was no evidence for an enhanced feedback regulation by a preceding pool expansion. It is suggested that the suppressive effect of dietary cholate or taurocholate or bile acid formation may not be mediated by the primary bile acid directly, but rather by secondary bile acids formed in the colon.
Phospholipids and bile acids as diffusional carriers of Na+ across nonpolar media
Authors: Accatino Luigi , Gavilan Patricia
Published: March 2007

Phospholipids and bile acids, by virtue of their amphiphilic properties, can interact in nonpolar media forming “inverted” structures (micelles) which presumably have an hydrophilic core and might act as diffusional carriers (ionophores) of electrolytes across low dielectric constant media or lipid membranes.

The Na+ ionophoretic capability of various purified phospholipids and the modulating effects of bile acids and phospatidylcholine was examined by: (a) measurement of 22Na+ partition into the organic phase (chloroform) of a two-phase system and (b) direct measurement of the translocation of 22Na+ across a bulk chloroform phase separating two aqueous phases in a Pressman cell. All phospholipids tested, except for phosphatidylcholine, showed ionophoretic capability for Na+ at micromolar concentrations. Cardiolipin and phosphatidylserine were the most efficient Na+ carriers, comparable with monensin, an established Na+ ionophore. In contrast, cholic acid as well as other bile acids demonstrated only marginal or no Na+ ionophoretic capability. However, hydroxylated bile acids (particularly cholic acid), sodium dodecyl sulfate and Triton X-100, which can induce and stabilize inverted structures in lipid membranes, were able to increase 5- to 8-fold the phospholipid-mediated Na+ transport. Interaction of cardiolipin with Na+ in the chloroform phase followed a rectangular hyperbolic function with an apparent Kd within the physiological Na+ concentration range (16.9 ± 5.1 mM). Addition of cholic acid to the cardiolipin-containing organic phase resulted in a 10-fold increase of maximal Na+ uptake and no change in apparent Kd. The effect of cholic acid on both cardiolipin-mediated Na+ partition and Na+ translocation across the chloroform phase showed a marked dependence on pH, being greater at pH 7.4. On the other hand, phosphatidylcholine, which is reported to stabilize phospholipid bilayers and to inhibit formation of inverted structures, inhibited Na+ cardiolipin interactions. Cholic acid addition completely prevented the inhibitory effect of phosphatidylcholine.

This study permits us to establish that the acidic phospholipids cardiolipin and phosphatidylserine can act as efficient Na+ ionophores in this in vitro system, at physiological Na+ concentrations and with kinetics comparable to those of systems involved in Na+ transport (e.g. Na+/H+ antiports) in liver surface membrane and other biomembranes. Modulation by bile acids (stimulation) and phosphatidylcholine (inhibition) of cardiolipin-mediated Na+ transport suggests that the underlying mechanism probably involves inverted-mixed micelle formation in the organic phase. The possibility exists that the Na+ ionophoretic properties of acidic phospholipids are relevant to the bile secretory process.
Fragmentation of gallstones using extracorporeal shock waves: An in Vitro study
Authors: Schachler Roland , Sauerbruch Tilman , Wosiewitz Ulrich , Holl Joseph , Hahn Dietbert , Denk Roland , Neubrand Michael , Paumgartner Gustav
Published: March 2007

Eighty in vitro experiments were performed with single (n = 51) or multiple (n = 29) gallstones in order to find out which parameters are of prime importance for their disintegration by extracorporeal shock waves. A Dornier lithotripter and an upper limit of 1,500 discharges were employed.

Although computed tomography density was significantly lower in cholesterol stones than in the noncholesterol stones (p < 0.0001) and although the latter were significantly more often radiopaque (p < 0.0001), we found no clear-cut correlation between the cholesterol content or computed tomography density and the degree of fragmentation of the stones. The most important variable which limited successful disintegration was the total stone volume. In stones with a mean total volume of 0.83 ml ± 0.25 S.E. (diameter for single stones = 11.5 ± 0.9 mm), none of the fragments exceeded 2 mm, whereas in stones with a mean volume of 3.6 ml ± 0.64 (diameter = 17.2 ± 1.5 mm) at least one fragment larger than 2 mm remained (p < 0.002). Under the in vitro conditions, fragmentation was similar in multiple and solitary stones, provided the volume of the stones was comparable.

These data show that, in general, the number and size of the stones, i.e. their total volume, and much less significantly their chemical composition are the major determinants of fragmentation by extracorporeal shock waves.
Pathologic analysis of liver transplantation for primary biliary cirrhosis
Authors: Demetris Anthony J. , Markus Bernd H. , Esquivel Carlos , Van Thiel David H. , Saidman Susan , Gordon Robert , Makowka Leonard , Sysyn Gregory D. , Starzl Thomas E.
Published: March 2007

A retrospective histopathologic review of all pathologic specimens from 394 adult liver transplant patients was undertaken with clinical correlation to determine if primary biliary cirrhosis has affected the posttrans-plant course compared to all other indications for liver transplantation and if recurrent primary biliary cirrhosis has occurred after liver transplantation. We also compared the histopathologic features seen in native livers with primary biliary cirrhosis to failed allografts with chronic rejection. One hundred six of the 394 adult patients transplanted during this time (1981 to July, 1986) fulfilled clinicopathologic criteria for a diagnosis of primary biliary cirrhosis. Neither the incidence nor any qualitative pathologic feature of histologically documented acute cellular rejection differentiated subjects transplanted for primary biliary cirrhosis vs. other diseases. No correlation between the titers of antimitochon-drial antibody and the presence of posttransplant hepatic dysfunction based on liver enzyme profiles or the development of chronic rejection was seen in patients transplanted for primary biliary cirrhosis. Minor differences noted in the posttransplant course of primary biliary cirrhosis patients as compared to other conditions (higher incidence of chronic rejection as a cause of graft failure) was seen, but this did not significantly affect graft or patient survival. Recurrent primary biliary cirrhosis could not be diagnosed with certainty in any patient. A comparison of failed chronically rejected allografts vs. native hepatectomies obtained from patients with primary biliary cirrhosis revealed the presence of chronic obliterative vasculopathy, centrilobular cholestasis, and lack of granulomas, cirrhosis, cholan-giolar proliferation, copper-associated protein deposition and Mallory’s hyalin in specimens with chronic rejection. In contrast, livers removed from patients with primary biliary cirrhosis demonstrated a mild vasculopathy, cirrhosis, granulomas, copper-associated protein deposition, Mallory’s hyalin and periportal cholestasis. Both conditions demonstrated a nonsuppurative destructive cholangitis with bile duct paucity.
Hepatic cytoprotection by prostaglandins: Theories unlimited
Authors: Levine Robert A.
Published: March 2007

16,16 Dimethyl prostaglandin E2 (dmPGE2), a known cytoprotective agent, was examined for its ability to alter the course of fulminant hepatitis in an experimental model of fulminant viral hepatitis, murine hepatitis virus type 3 (MHV-3). Fully susceptible BALB/cJ mice, infected with 100 50% lethal doses (LD50) of MHV-3 developed histologic and biochemical evidence of fulminant hepatitis, as evidenced by massive hepatic necrosis with hypoglycemia, metabolic acidosis, and a markedly elevated serum alanine aminotransferase (ALT) (mean, 1,402 ± 619 IU/liter). In contrast, animals treated with dmPGE2 either before or after infection (up to 48 h) demonstrated a marked reduction in both histologic and biochemical evidence of liver damage as characterized by normal blood glucose, total CO2, and ALT determinations (mean ALT, 63 ± 40 IU/liter). Treatment of infected mice with PGF2 demonstrated no cytoprotective effects. High titers of infectious virus were recovered from the livers of both dmPGE2-treated and -untreated animals throughout the course of infection.

In a parallel in vitro study, dmPGE2 (10−4-10−8 M) demonstrated a similar cytoprotective effect on monolayers of isolated cultured hepatocytes from fully susceptible BALB/cJ mice infected at a multiplicity of infection of 0.1, 1.0, and 10.0. In addition, splenic macrophages recovered from infected and untreated BALB/cJ mice demonstrated a marked augmentation in procoagulant activity (PCA) from a basal 10 ± 5 mU/106 splenic macrophages to a maximum of 615 ± 102 mU/106 splenic macrophages, whereas no increase in macrophage PCA was detected in infected animals treated with dmPGE2. These results suggest that dmPGE2, without detectably altering viral replication or infectivity in vivo, confers a marked cytoprotective effect on hepatocytes both in vivo and in vitro, and prevents the induction of macrophage PCA in vivo in fully susceptible BALB/cJ mice after murine hepatitis virus type 3 infection.
Is primary sclerosing cholangitis a progressive disease or not?
Authors: Wiesner Russell H. , Grambsch Patricia , Larusso Nicholas F. , Dickson Rolland E.
Published: March 2007

The clinicopathologic features and natural history of primary sclerosing cholangitis were reviewed in 53 patients followed at the Yale Liver Center during the past 30 yr. At presentation, the mean age of patients was 46 yr, and the male to female ratio was 1.4:1. Biliary sclerosis was limited to the intrahepatic ductal system in 21% of the patients. Fifty-three percent of the patients had mild disease without portal hypertension at presentation, and 25% had no symptoms attributable to their liver disease. Long-term follow-up was available for 42 patients and averaged 56 mo. Over this period, 16 patients remained mildly symptomatic, and 11 were asymptomatic. Survival was calculated by a Kaplan-Meier life-table analysis and demonstrated that 75% of the patients were alive 9 yr after the diagnosis of primary sclerosing cholangitis. A multivariate analysis of clinical features revealed that hepatomegaly and a serum bilirubin level > 1.5 mg/dl at the onset of disease were independent discriminators of a poor prognosis. Patients referred to this university medical center displayed different clinical characteristics than previously reported in primary sclerosing cholangitis. A higher percentage were older, female, and asymptomatic, and more had disease limited to the intrahepatic ductal system. Survival was also considerably improved in this group of patients and suggests that long-term prognosis for patients with primary sclerosing cholangitis may be considerably better than previously believed.

The natural history and prognostic factors of primary sclerosing cholangitis (PSC) are poorly defined. We reviewed our experience with PSC to determine its natural history and whether any factors on presentation or during follow-up were indicative of a favorable or unfavorable prognosis. Thirty-eight patients were followed up for 75.1 ± 58.7 months; 17 (45%) had a poor outcome, defined as the occurrence of death (11 patients [29%]), variceal hemorrhage, hepatic encephalopathy, or hepatic transplantation. We found the following: (1) the rate of progression of PSC is highly variable; (2) an asymptomatic presentation may not indicate a more favorable outcome or prolonged survival; (3) a serum bilirubin value of four times or more the upper limit of normal, particularly if sustained so as to exclude a reversible cause, is indicative of late-stage disease with a likelihood of subsequent poor outcome and death; and (4) variceal hemorrhage may occur before the terminal stage of the disease.
The emergence of biliary sludge, a new clinical entity
Authors: Holzbach Thomas R.
Published: March 2007

Biliary sludge is a collection of mucus, calcium bilirubinate, and cholesterol crystals that is usually recognized by characteristic echoes on ultrasonography. Its pathogenesis, clinical significance, and ultimate prognosis remain uncertain. We therefore studied the origin of biliary sludge ultrasonic echoes, using an ex vivo liver-gallbladder preparation, and determined the outcome of a group of patients identified to have gallbladder sludge by ultrasonography. Echoes were not generated by either an increase in the total solid concentration or by the graded addition of partially purified mucus glycoprotein. Cholesterol monohydrate crystals (>50 μm) mixed with mucus produced echoes that were indistinguishable from gallbladder sludge observed in patients. To determine the natural evolution of gallbladder sludge in patients, we prospectively followed 96 patients found to have biliary sludge for a mean of 37.8 mo by serial ultrasound scans every 6 mo. In 17 patients (17.7%) biliary sludge disappeared and did not recur for at least 2 years, in 58 patients (60.4%) biliary sludge disappeared and reappeared, and in 8 patients (8.3%) asymptomatic gallstones developed. There were 12 cholecystectomies performed: six were done for symptomatic gallstones (6.3%) and the other six for sludge associated with severe biliary pain attacks with or without recurrent acute pancreatitis. The finding of sludge represented precipitates being formed in bile. In some patients, it was a precursor form of gallstone disease.
Control of hepatitis B virus among alaskan natives
Authors: Kane Mark A.
Published: March 2007

In 1983, a comprehensive programme was introduced to halt the spread of hepatitis B virus (HBV) infection and to reduce mortality from hepatocellular carcinoma (HCC) in Alaskan Natives, in whom the incidence of HBV infection was high. This programme includes: serological screening of all Alaskan Natives; immunization of susceptible persons, including all newborn babies, with hepatitis B vaccine; and testing HBsAg-positive carriers twice a year for α-fetoprotein (AFP) to detect HCC at an early stage. By October, 1986, over 53,000 Alaskan Natives (84% of the total Native population) had been tested for HBV serological markers and 80% of the identified susceptibles had been or were being vaccinated against HBV. After complete immunization of 90% of the susceptibles in the area with the highest infection rates in Alaska, the annual incidence of acute symptomatic HBV infection decreased from 215 to 14 cases per 100,000 population. After the introduction of AFP screening, the 1-year-case-fatality rate for HCC fell from 100% to 50%.
Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats
Authors: Olsen Peter Skov , Boesby Steen , Kirkegaard Preben , Therkelsen Kim , Almdal Thomas , Poulsen Steen Seier , Nexø Ebba
Published: March 2007

The role of epidermal growth factor on liver regeneration after partial hepatectomy in rats was investigated. After a 70% hepatectomy in rats, the concentration of epidermal growth factor in portal venous blood was unchanged compared with unoperated controls. However, small amounts of epidermal growth factor could be identified in portal venous blood after intestinal instillation of epidermal growth factor. Brunner’s glands and the submandibular glands secrete epidermal growth factor. Extirpation of Brunner’s glands decreased liver regeneration, whereas removal of the submandibular glands had no effect on liver regeneration. Epidermal growth factor antiserum reduced liver regeneration significantly. Oral or s.c. administration of epidermal growth factor had no effect on liver regeneration, whereas epidermal growth factor enhanced the effect of insulin and glucagon on liver regeneration.

The results suggest that endogenous epidermal growth factor participates in stimulation of liver regeneration after partial hepatectomy in rats. Epidermal growth factor given together with insulin and glucagon had a synergistic effect on liver regeneration which suggests that liver regeneration in the rat is controlled by multiple regulatory peptides.
Cellular interactions promote tissue-specific function, biomatrix deposition and junctional communication of primary cultured hepatocytes
Authors: Goulet Francine , Normand Claire , Morin Odette
Published: March 2007

Hepatocytes, prepared from normal adult rat liver, were seeded onto a collagen substratum and cultured alone or in the presence of rat liver endothelial cells. When hepatocytes were cultured alone in a hormonally defined serum-free medium, decreased albumin production and rapid morphological deterioration of bile canaliculi structures and gap junctions occurred within 4 to 5 days. In contrast, hepatocytes cocultured with liver mesenchymal cells remained morphologically intact and biochemically functional for at least 4 weeks. They reorganized into small islands, continued to secrete high levels of albumin, did not express α-fetoprotein (a fetal marker), and remained strongly dye coupled. All of the hepatocytes synthesized albumin and retained their gap junctional channels. No junctional communication was observed between hepatocytes and endothelial cells. Long fibers containing fibronectin, Type I collagen and laminin distributed over the hepatocytes were induced in coculture but never appeared in hepatocytes cultured alone. Moreover, supplementation of the hormonally defined medium with phenobarbital and dimethyl sulfoxide, both of which improve the life span and functional activities of cultured hepatocytes, failed to induce reticulin fiber formation in pure culture of hepatocytes. The modulation of albumin secretion, biomatrix deposition and junctional communication observed in hepatocytes cultured with sinusoidal liver cells was also obtained when hepatocytes were in association with various epithelial or mesenchymal cells [rat liver epithelial cells (T51B), mouse embryonic fibroblasts (NIH 3T3), human or rat dermal fibroblasts and bovine aorta endothelial cells (AG 4762)].
Galactose elimination capacity and liver volume in aging man
Authors: Marchesini Giulio , Bua Vincenzo , Brunori Alessandra , Bianchi Giampaolo , Pisi Paolo , Fabbri Andrea , Zoli Marco , Pisi Emilio
Published: March 2007

The galactose elimination capacity, a measure of the functional liver cell mass, and liver volume were measured in 50 normal subjects of five different age groups (<50, 51 to 60, 61 to 70, 71 to 80 and >81 years). The volume of the liver was evaluated by ultrasonography. All subjects had normal routine liver function tests and no history of liver disease. Galactose elimination progressively decreased from 3.05 ± 0.58 (S.D.) mmoles per min in younger subjects to 1.83 ± 0.24 mmoles per min in subjects over 81 (p < 0.00003), without any change in the apparent volume of distribution of the sugar. Similarly, the estimated volume of the liver decreased from 110 ± 14 units to 75 ± 13 units with increasing age (p < 0.0002). Both galactose elimination capacity and the estimated liver volume inversely correlated with age (r = 0.728 and r = −0.579, respectively) whereas a positive correlation was observed between galactose elimination and the estimated liver volume (r = 0.520). Part correlation analysis confirmed that age, when entered in a multiple regression already containing body weight and estimated liver volume as independent variables, had a significant effect on liver function, whereas no significant independent effect of liver volume was present. Both age and body weight had a significant independent effect on the estimated liver volume.

The maximum functional capacity of the liver, measured by galactose elimination, is reduced in the elderly. Although several factors may play a role, our data suggest that aging is associated with a slight decline in the intrinsic metabolic activity of the hepatic parenchyma.
Assessment of hepatic encephalopathy with visual evoked potentials compared with conventional methods
Authors: Sandford Neville L. , Saul Ronald E.
Published: March 2007

Thirty-six patients with advanced chronic liver disease of predominantly alcoholic etiology and with a documented history or current physical evidence of hepatic encephalopathy were studied and compared to 30 healthy controls. Assessment was made of their mental state, number connection test, venous blood ammonia, electroencephalography and visual evoked potentials with both pattern reversal and flash stimuli. Because of considerable inter- and intraindividual variation in waveform, visual evoked potentials from flash stimuli were considered unreliable. In pattern reversal visual evoked potentials, the latency of the N1 and P1 waves was significantly longer (p < 0.05) in patients than in controls; however, the wave latencies did not correlate with the mental state score. The mental state score correlated with the number connection test (r = 0.69, p < 0.001), asterixis (r = 0.36, p < 0.05), electroencephalography mean dominant frequency (r = 0.44, p < 0.01) and blood ammonia (r = 0.60, p < 0.01). In 14 patients studied sequentially, change in the mental state score correlated with change in the number connection test (r = 0.80, p < 0.01) and asterixis (r = 0.75, p < 0.01) but not with change in the electroencephalography, blood ammonia or visual evoked potential wave latencies. Although visual evoked potentials are abnormal in patients with alcoholic cirrhosis and encephalopathy, they are less accurate in assessing the level of consciousness than simple bedside evaluation with a number connection test.
A prospective evaluation of bacteremic patients with chronic liver disease
Authors: Barnes Peter F. , Arevalo Cecilia , Chan Linda S. , Wong Sandra F. , Reynolds Telfer B.
Published: March 2007

We prospectively studied 51 consecutive bacteremic patients with chronic liver disease in order to evaluate their clinical presentation and to assess the relationship of various clinical parameters to mortality. Forty-two patients had alcoholic liver disease and 40 were in Class C, by the Pugh modification of Child’s criteria.

Soft tissue infections were the most common source of bacteremia, followed by pneumonia, spontaneous bacterial peritonitis and urinary tract infection. Gram positive organisms were isolated in 69% of cases, and Gram negative ones in 31%. In nine patients, no source of bacteremia was detected. Leukocytosis occurred in 59% of patients and bandemia in only 41%.

Although appropriate antibiotic therapy was begun in all cases on admission, 17 patients (33%) died in the hospital. Of 38 clinical parameters evaluated, multivariate analysis revealed that the three variables contributing the most independent information toward predicting in-hospital mortality were the absence of a history of fever, an elevated serum creatinine and marked leukocytosis. Improved understanding of the pathophysiologic relationship between these parameters and patient outcome may enable us to improve the therapy of bacteremic patients with chronic liver disease.
Ascitic fluid analysis in malignancy-related ascites
Authors: Runyon Bruce A. , Hoefs John C. , Morgan Timothy R.
Published: March 2007

A prospective study identified 45 patients with malignancy-related ascites among 448 ascites patients (10% of the total). Patients were categorized into five subgroups based on the pathophysiology of ascites formation. Each subgroup had a distinctive ascitic fluid analysis. Patients with peritoneal carcinomatosis but without massive liver metastases (53.3% of the patients with malignancy-related ascites) had a uniformly positive ascitic fluid cytology, high ascitic fluid protein concentration and low serum-ascites albumin gradient. Patients with massive liver metastases and no other cause for ascites formation (13.3% of the series) had a negative cytology, low ascitic fluid protein concentration, high serum-ascites albumin gradient and markedly elevated serum alkaline phosphatase. Those with peritoneal carcinomatosis and massive liver metastases (13.3% of the series) had a nearly uniformly positive ascitic fluid cytology, variable protein concentration, high serum-ascites albumin gradient and markedly elevated serum alkaline phosphatase. Chylous ascites (6.7%) was characterized by a milky appearance, negative cytology and an elevated ascitic fluid triglyceride concentration. Patients with hepatocellular carcinoma superimposed on cirrhosis (13.3%) had negative ascitic fluid cytology, low ascitic fluid protein concentration, high serum-ascites albumin gradient and elevated serum and ascitic fluid α-fetoprotein concentration. Two-thirds of patients with malignancy-related ascites had peritoneal carcinomatosis; 96.7% of patients with peritoneal carcinomatosis had positive ascitic fluid cytology. Ascitic fluid analysis is helpful in identifying and distinguishing the subgroups of malignancy-related ascites.