More on glucose transporters: The acinar organization for hepatic glucose transport

The “erythroid/brain” glucose transporter (GT) isoform is expressed only in a subset of hepatocytes, those forming the first row around the terminal hepatic venules, while the “liver” GT is expressed in all hepatocytes. After 3 d of starvation, a three- to fourfold elevation of expression of the erythroid/brain GT mRNA and protein is detected in the liver as a whole; this correlates with the expression of this GT in more hepatocytes, those forming the first three to four rows around the hepatic venules. Starvation-dependent expression of the erythroid/brain GT on the plasma membrane of these additional hepatocytes is lost within 3 h of glucose refeeding; however, by immunoblotting we show that the protein is still present. Its loss from the surface is possibly explained by internalization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38356/1/1840130432_ftp.pd

Hepatology elsewhere

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38403/1/1840180637_ftp.pd

Spironolactone and canrenoate: Different antialdosteronic diuretic agents

Plasma levels of canrenone and androgen receptoractive materials (ARM) were determined during long-term oral K-canrenoate or spironolactone therapy in cirrhotics with chronic recurrent ascites. Mean plasma canrenone level was approximately 3 times higher under K-canrenoate than under spironolactone treatment; moreover, the levels were not dose related. Either type of treatment did not affect plasma aldosterone and testosterone concentrations. Plasma ARM during K-canrenoate treatment did not change, whereas in the spironolactone group a 3-fold increase of ARM occurred (p 0.05). Our study questions the traditional view that the mode of action of spironolactone is via its metabolite canrenone. The two antialdosterone drugs, although equally effective in clearing ascites from cirrhotics, appear to act through partially different metabolites. The lower incidence of antiandrogenic or estrogen-like side effects during K-canrenoate seems to be related to metabolites other than canrenone itself.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38359/1/1840130531_ftp.pd

Brown pigment gallstones: The role of bacterial hydrolases and another missed opportunity

The bile acids in brown pigment stones and gallbladder bile were fractionated into free acids, glycine and taurine conjugates, and sulfates, using diethylamino-hydroxypropyl-Sephadex LH-20 (DEAPLH-20) column chromatography, and were quantitated by gas chromatography. Twenty-eight cases of brown pigment stones were studied and divided into two groups: those with and those without bacteria possessing bile acid-deconjugating activity. In the former, free bile acid amounted to 62 ± 34% of the total bile acid, while in the latter, only 0.1% of total bile acid was free bile acid. The fraction of total bile acid made up of free bile acids was found to be consistently higher in brown pigment stones than in the corresponding bile, irrespective of the presence or absence of biliary infection. Free bile acid is present in negligible amounts in normal bile. Total bile acid concentration in the bile of patients with brown pigment stones was significantly less than that of controls (13 vs. 50 mg/ml). Biliary infection is almost always present in cases with brown pigment stones. These findings suggest that bacterial infection is present at the initiation of brown pigment stone formation as well as during the period of ensuing stone growth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38351/1/1840130335_ftp.pd

Is the multidrug resistance an ATP channel?

The multidrug resistance ( mdr1 ) gene product, P-glycoprotein, is responsible for the ATP-dependent extrusion of a variety of compounds, including chemotherapeutic drugs, from cells. The data presented here show that cells with increaed levels of the P-glycoprotein release ATP to the medium in proportion to the concentration of the protein in their plasma membrane. Furthermore, measurements of whole-cell and single-channel currents with patch-clamp electrodes indicate that the P-glycoprotein serves as an ATP-conducting channel in the plasma membrane. These findings suggest an unusual role for the P-glycoprotein.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38396/1/1840180131_ftp.pd

Therapy of acute hepatitis C with interferon: How good is it really?

To test whether interferon can prevent acute non-A, non-B hepatitis from becoming chronic, a prospective controlled trial was conducted in 25 patients; 11 were treated for an average of 30 days with a mean of 52 megaunits of interferon and 14 acted as controls. 4 patients in the treatment group who continued to have raised serum aminotransferase concentrations after a year's follow-up were given a second course of interferon. Follow-up at 3 years has revealed that all but 1 of those treated showed normal serum aminotransferase, whereas only 3 controls showed such change (p < 0.02). Serum hepatitis C virus RNA became undetectable in 10 of 11 treated and in only 1 of 12 control patients, which suggests that interferon prevents the progression of acute non-A, non-B hepatitis to chronicity by eradicating HCV.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38380/1/1840160232_ftp.pd

Thyroxine-binding globulin, hyperthyroxinemia and hepatocellular carcinoma

To determine serum thyroxine-binding globulin (TBG) levels, we used radioimmunoassay, and compared the results obtained with other tests in 231 patients with chronic hepatitis B virus infection to evaluate its clinical implications. All of these patients were hepatitis B surface antigen (HBsAg)-positive. Among them, 38 patients had hepatocellular carcinoma (HCC), 18 had chronic persistent hepatitis, 70 had chronic lobular or active hepatitis (grouped as CAH), 31 had active cirrhosis (AC), 25 had inactive cirrhosis, 20 had decompensated cirrhosis, and 29 were “healthy” HBsAg carriers. Twenty-seven patients with acute hepatitis, 12 with cancer metastasis to the liver, and 81 normal adults served as disease or normal controls. The results showed that serum TBG level increased significantly in patients with CAH, AC, or HCC. Serum TBG did not correlate with albumin or bilirubin level, but correlated with alanine aminotransferase (ALT) positively in patients with CAH ( p < 0.001) and negatively in patients with HCC ( p < 0.01) (slope difference p < 0.05). Serial determination of serum TBG and ALT also showed parallel changes in 15 patients with CAH, but not in nine patients with HCC. In contrast, the fall and rise of serum TBG levels in patients with HCC coincided with tumor resection and recurrence. The data suggest that serum TBG elevation in patients with hepatitis activity is the result of hepatocellular damage, whereas that in patients with HCC is due to increased synthesis. Whether serum TBG elevation without concomitant rise of ALT could be used as a marker of HCC awaits further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38358/1/1840130434_ftp.pd

DNA integration sites and hepatocellular carcinoma

This study is part of an ongoing analysis of woodchuck hepatitis virus integration sites in the host genome of hepatocellular carcinomas. The study of woodchuck hepatitis virus-DNA integration sites may shed light on the oncogenic mechanisms involved in cellular transformation and tumor formation. Viral integration enhancing cellular proto-oncogene expression is one such mechanism and has been well documented for oncogenic retroviruses such as mouse mammary tumor virus and interleukin-1. By cloning a woodchuck hepatitis virus integration site from a woodchuck hepatocellular carcinoma the authors were able to identify a new member of the myc gene family, N- myc -2. Examination of 30 additional woodchuck hepatomas revealed viral integration commonly occurred near N- myc loci with an additional five woodchuck hepatitis virus integrants near the N- myc -2 gene and one viral integrant near N- myc -1. Three of these N- myc -2 viral integrations were further evaluated and found to be localized within 200 bp of the translation stop codon. This 3′ noncoding region has recently been identified as a common site of murine leukemia virus integration in virally induced T-cell lymphomas and results in increased expression of the N- myc gene. Similar mechanisms can be proposed for hepatocellular carcinoma formation. Woodchuck hepatitis virus integration near cell-growth related protooncogenes, such as N- myc , can juxtapose viral enhancer elements and growth-regulatory genes. Virally induced overexpression of proto-oncogene messenger RNA could result from enhanced transcription or increased messenger RNA stability. To search for such effects the authors analyzed N- myc -2 RNA levels in 30 woodchuck hepatitis virus-related hepatomas. Increased levels of N- myc -2 RNA were found in 18 of 30 tumors, whereas nontumorous portions of the same livers had no detectable N- myc -2 RNA. Taken together these findings suggest that woodchuck hepatitis virus integration can result in altered N- myc -2 gene expression in a significant proportion of woodchuck hepatocellular carcinomas. The deregulation of N- myc gene expression could result in cellular transformation and ultimately tumor formation. Such examples of hepadnavirus-specific oncogenic mechanisms lend credence to theories of hepatitis B virus-induced tumorigenesis and provide models to design molecular investigations of human hepatocellular carcinoma formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38347/1/1840130229_ftp.pd

Treatment of hepatocellular carcinoma

Fifty-one patients with unresectable hepatocellular carcinoma were treated by embolization of the hepatic artery with Gelfoam powder, contrast material and three chemotherapeutic agents (doxorubicin, mitomycin, cisplatin). Twelve patients (24%) had a partial response with a decrease in the tumor diameter by at least 50%, 13 patients (26%) had only minor responses, 12 (24%) had stabilization of disease and the remainder had progressive disease. Tumor liquefaction was noted on computed tomographic scanning in 70% of patients, and 23 of 34 patients with elevations in serum alphafetoprotein values had a greater than 50% reduction following treatment. The median patient survival time from treatment was 207 days. Most patients experienced transient pain, fever, nausea and elevations in serum aminotransferase activities as a result of therapy. Ascites developed in 14 patients. There were two treatment-related deaths: one from tumor hemorrhage and one from liver failure. Chemoembolization therefore appears to have significant activity in patients with hepatocellular carcinoma and is relatively well tolerated. This study reports the results of resection in 72 cirrhotic patients with hepatocellular carcinoma from Europe. One and 3 year survival rates were 68% and 51% respectively. Survival was significantly higher in Child's class A than in class B or C patients. Patients with a thickly encapsulated tumor lived longer than those with an infiltrating tumor and also had a significantly lower recurrence rate. There was no relationship between the size of the tumor or the presence of symptoms and survival. These data suggest that good results can be achieved by resection of hepatocellular carcinoma in European cirrhotic patients. A thickly encapsulated tumor and good liver function are the main determinants of low cancer recurrence and high survival.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38355/1/1840130431_ftp.pd

Aplastic anemia and hepatitis C: Molecular biology exonerates another suspect

Objective. – To test the hypothesis that the rare, often fatal, syndrome of hepatitis-associated aplasia is associated with hepatitis C virus infection. Design. – Case series. Setting.-Tertiary referral centers in the United States, Japan, Italy, and Germany. Patients. – Twenty-eight patients with onset of aplastic anemia within 90 days after seeking medical attention for jaundice, or having serum transaminase levels 150% or more of normal (hepatitis-associated aplasia patients) and three patients who developed aplastic anemia following liver transplantation for non-A, non-B, hepatitis. Outcome Measures. - Presence of hepatitis C in serum, bone marrow, and liver samples, detected by the polymerase chain reaction; antibody testing; and percentage of activated peripheral cytotoxic T lymphocytes determined by immunophenotyping. Results. – Hepatitis ribonucleic acid was present in the serum samples of 10 (36%) patients with hepatitis-associated aplasia. However, hepatitic C virus viremia was associated with transfusions received after the onset of aplasia: seven (58%) of 12 patients with hepatitis-associated aplasia who had received 21 or more units of blood products at the time of serum sampling were viremic, compared with only three (19%) of 16 patients with hepatitis-associated aplasia who had received 20 or less units of blood products ( P <.05). Hepatitis C virus was not found in blood and bone marrow samples of three National Institutes of Health case patients tested at the time of diagnosis. None of three livers from non-A, non-B hepatitis patients who developed aplastic anemia after liver transplantation contained hepatitis C virus ribonucleic acid. Activated CD8 + T lymphocytes were elevated three- to 20-fold early in the course of hepatitis-associated aplasia. Conclusions. – Our results implicate a novel, non-A, non-B, and non-C agent in both hepatitis-associated aplasia and fulminant hepatitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38390/1/1840170227_ftp.pd