GASTROENTEROLOGY
1992;102:1080-1085
SELECTED SUMMARIES Mark Feldman, M.D. Selected Summaries Editor Dallas Veterans Administration Medical Service (111) Da!las, Texas 75216
Medical Center
STAFF OF CONTRIBUTORS James L. Achord, Jackson, MS Kim E. Barrett, San Diego, CA Grace H. Elta, Ann Arbor, MI Lawrence S. Friedman, Philadelphia, Hans Fromm, Washington, DC Hans Gerdes, New York, NY Stephen B. Hanauer, Chicago, IL
PA
HAS ANOTHER SURGICAL BEEN REPLACED?
Raymond S. Koff, Framingham, MA Benjamin Krevsky, Philadelphia, PA Loren Laine, Los Angeles, CA William Lee, Dallas, TX Peter F. Malet, Philadelphia, PA Thomas A. Miller, Houston, TX Malcolm Robinson, Oklahoma City, OK
PROCEDURE
Zemel G, Katzen BT, Becker GJ, et al. (Miami Vascular Institute, Baptist Hospital of Miami, Miami, Florida). Percutaneous transjugular portosystemic shunt. JAMA 1991;266: 390-393 (July). The authors created a transjugular intrahepatic portosystemic shunt (TIPS) in eight patients with alcoholic (six patients) or postnecrotic (two patients) cirrhosis by creating a fistula between the hepatic vein and the portal vein and inserting a balloon-expandable stent in the tract. All patients had portal hypertension and varices documented by angiography/hepatic wedge venography and/or liver biopsy/endoscopy. One patient was classified Child A, 5 were Child B, and 2 were Child C. Seven of the patients had bled previously from an upper gastrointestinal source and one from hemorrhoids. The mean wedged pressure gradient of the eight patients was 36 mm Hg. The diameters of the stents were between 8 and 12 mm and lowered the average wedged pressure gradient to 11 mm Hg. Embolization of varices or coronary veins was not done. Upper endoscopy in each patient was said to show complete decompression of the esophageal varices within the week following the procedure. Only the patient with hemorrhoids bled again and was treated by enlarging the stent from 8 to 12 mm. This patient’s portosystemic pressure gradient was reduced from 38 mm Hg to 18 mm Hg with an 8-mm stent and to 8 mm Hg with enlargement of the stent to 12 mm. All shunts were patent at l-9 months’ follow-up (average, 5 months). One patient was found to have developed stenosis of the right hepatic vein 4 months after TIPS that was successfully dilated with balloon angioplasty, reducing the pressure gradient to the original postshunt level of 8 mm Hg. A second patient was incidentally found to have a small portion of the parenchymal tract not covered by the stent during the initial procedure 4 months earlier; it was successfully dilated by balloon angioplasty. Migration of one stent to the left lower lobe pulmonary artery occurred. It was replaced into the inferior vena cava and anchored in place at the bifurcation by expanding its diameter to 18 mm with an angioplasty balloon catheter. (No comment is made concerning replacement of the lost intrahepatic
Mitchell L. Schubert, Richmond, VA Konrad Schulze-Delrieu, Iowa City, IA Fergus Shanahan, Los Angeles, CA Joseph Sweeting, New York, NY Richard C. Thirlby, Seattle, WA M. Michael Wolfe, Boston, MA
stent or of the fate of the parenchymal shunt.) No other complications are reported. “Life-style-limiting” hepatic encephalopathy was not found, but further details are not given. Tense ascites in two patients and mild to moderate ascites in four was improved or resolved after the procedure. Serum bilirubin, albumin, and prothrombin time improved or remained the same 4 months after TIPS in all patients. The hospital stay after the shunt ranged from 1 to 19 days with a mean of 7.7 days. In this preliminary communication involving a very small number of patients, the authors conclude that TIPS appears to be a “safe and effective method of portal decompression for the treatment of variceal hemorrhage” but recognize the need for larger numbers to conclusively establish the safety and longterm effectiveness of this procedure. Comment.
Wire-mesh stents have been in use for the past few years in a number of disciplines. They are made of stainless steel or tantalum and passed encased in a plastic sheath that can be extracted to allow them to expand. They are either self-expanding or expandable to a predetermined size with an angioplasty balloon [Circulation 1991;83(Suppl 2):1122-11361. The mesh density is variable. In the vascular tree, wire stents are unique in that in experimental animals they become covered by ground substance, smooth muscle cells, and a monolayer of endothelial cells within l-2 weeks (Am Heart J 1991;121:1522-1530; Circulation 1991; 83:1788-1798). In the bronchial tree, they become covered with ciliated columnar epithelium (Acta Radio1 1991;32:79-80). Wire stents have found favor with cardiologists in postangioplasty elastic rebound and restenosis [J Am Co11 Cardiol 1991;17(6 Suppl B):155B-159B; Clin Cardiol1991;14:374-91 and have been used in stenotic congenital heart disease (Circulation 1991;83:1923-1939). They have been used for renal artery stenosis (Radiology 1991; 180:367-372) and iliac and femoral and popliteal artery lesions (Radiology 1991;179:449-456; AJR 1991;156:389-393) with somewhat less encouraging results. They have been placed in the tracheobronchial tree both in experimental animals (Acta Radio1 1991;32:79-80) and in human subjects with bronchomalacia [Arch Otolaryngol Head Neck Surg 1990;116:1087-1090), raising the exciting possibility of their use in tracheoesophageal fistulae caused by malignancies. These stents have also been used successfully in urethral obstruction in high-risk patients (Clin Radio1 1990;42:228-232). In the biliary tree, wire stents have been placed endoscopically (Gastrointest Endosc 1990;36:451-457) and transhepatically by both percutaneous (Radiology 1991;179:703-707) and jugular (Radiology 1991;180:579-581) approaches. Early re-
SELECTED SUMMARIES
March 1992
sults show a lower occlusion rate than with plastic stents and largely by tumor growth through the mesh rather than by biliary encrustations (Radio1 Clin North Am 1990;28:1211-1222; Radiology 1990;177:793-797). Wire stents have been used to successfully treat the Budd-Chiari syndrome (Gastroenterology 1991:lOO: 1435-1441). Creating a parenchymal tract between the hepatic and portal system by balloon angioplasty is no great obstacle to today’s invasive radiologist; keeping it open, however, is another matter (Can Med Assoc J 1982;126:267-268). Richter et al. (Radiology 1990;174:1027-1030) used a wire stent to keep the tract open in three patients with cirrhosis, one of whom had hepatorenal syndrome before the shunt and died 11 days later of that syndrome: further details are sparse. In the reviewed preliminary report, Zeme1 et al. show the feasibility of the procedure in a small number of patients. I count two complications (one migrating stent and one acquired stenosis of the right hepatic vein) but no other serious ones. The number of subjects is too small to comment on serious morbidity or mortality, hut even so the results suggest that it is not an extremely hazardous undertaking, especially considering the serious prognosis in this group of patients. It is too early to tell just what the occlusion rate will be, but as demonstrated, these stents can be expanded when necessary by balloon angiography and the channel cleared by various other angiographic techniques. We have known since the early days of surgical portasystemic shunting that ascites can be relieved by shunts, and TIPS is an exciting possibility in certain patients. Further, our efforts to treat acutely bleeding varices should in theory be greatly enhanced by the ability to abruptly lower portal pressure. There is no reason to assume, despite the absence of “life-style-limiting” hepatic encephalopathy in this small number of patients (which suggests that there was some but it was not considered significant by the authors), that an effective portasystemic shunt that directs blood around liver parenchyma by any particular method will avoid encephalopathy. The liver function was not studied in these patients. The serum bilirubin level stayed the same or improved in all subjects; the preshunt mean was 74 Fmol/L (4.3 mg/dL), and the postshunt mean was 42 pmol/L (2.5 mg/dL). Similarly, serum albumin levels and prothrombin times tended to improve. It cannot be concluded that the shunt improved liver function or was responsible for improvement in liver tests, but only that there is no reason to think the liver parenchyma was further impaired by the procedure. This procedure is an exciting development and holds great promise, not only in reducing portal pressure but in several other areas as well. But then so did a lot of others until we systematically and carefully studied them. One may conclude that marked elevation in portal pressure in cirrhosis can be reduced acutely and impressively by this technique and that it has the potential for long-term effectiveness. Because of the apparent relative ease with which this shunt can be placed, the procedure also has a sizable potential for inappropriate use if it becomes readily available. Further careful study of the remote, as well as the direct, effects of this procedure is called for. J. L. ACHORD, M.D.
HEPATOCELLULAR CARCINOMA IN TRANSGENIC MICE: A CONSEQUENCE OF CONTINUED EXPRESSION OF THE HBx GENE? Kim C-M, Koike KK, Saito I, et al. (Laboratory of Virology, Jerome H. Holland Laboratory, American Red Cross, Rockville, Maryland; Laboratory of Hepatitis Viruses, Department of Enteroviruses, National Institute of Health, Tokyo,
Japan). HBx gene of hepatitis B virus induces in transgenic mice. Nature 1991;351:317-320.
1081
liver cancer
To study the role of the hepatitis Bx (HBx) protein in hepatocarcinogenesis, a hepatitis B virus (HBV) DNA fragment containing the coding region for HBx, the transcriptional enhancer, the principal RNA start sites, and the polyadenylation site was placed into the germline of outbred CD1 mice. HBx transgenic mice, with at least one intact copy of the transgene stably integrated into the host genome, were bred out. The HBx transgene was shown to be expressed in liver, kidney, and testis, and HBx protein was detected in liver extracts by immunoprecipitation with anti-HBx or by immunostaining of liver sections. Altered foci of poorly staining, glycogen-rich hepatocytes were detected at 4 months of age, and these expressed relatively high levels of HBx protein. Tumor nodules with the features of hepatocellular adenomas appeared at 8-10 months of age and expressed HBx protein and a-fetoprotein. Serum alanine aminotransferase levels were consistently normal in mice found to have adenomas. Hence, no evidence of chronic hepatitis was observed in association with the development of these tumors. Between 11 and 15 months of age, 80%90% of male transgenic mice died with hepatocellular carcinomas grossly detectable. These carcinomas continued to express HBx protein and a-fetoprotein but did not show accumulated glycogen. In contrast to the observations in male transgenic mice, only 60%-67% of female mice developed hepatocellular carcinoma; female mice developed carcinomas approximately 6 months after their male counterparts. The authors suggest that male and female transgenic mice are equally susceptible; apparent differences in penetrance may simply reflect the earlier age at which males are affected.
Comment. The key mechanisms underlying HBV-associated hepatocarcinogenesis remain enigmatic. Integration of the HBV genome into host hepatocyte DNA is well established and believed to be an important step in the pathogenesis of malignant transformation. HBV-induced amplification of proto-oncogenes or viral or cellular oncogenes may be associated with carcinogenesis. Although transforming oncogenes have been detected near the HBV genome in some hepatocellular carcinomas (Oncogene 1988;3: 537-540), activation of viral or cellular oncogenes by the HBV genome has not been unequivocally proved and homology with the HBV genome has not been established (Hepatology 1988;8:1116-1120). Structural rearrangements of integrated HBV DNA and cellular flanking DNA have been found in HBV-associated malignant hepatocytes (J Virol 1990;64:822-888; Hepatology 1990;11:1017-1023) but may not be present in nonmalignant cells (Hepatology 1990;11:1017-1023). Hence the role of rearrangements, deletions, and other chromosomal alterations (insertional mutagenesis) is uncertain. Could the site of HBV genomic integration be important? Yes, but while integration of the HBV genome within an intron of a human cyclin A gene, a growth-regulatory gene, has been hypothesized to contribute to hepatocarcinogenesis (Nature 1990;343:555-557), this too remains speculative. The possible linkage of HBx and hepatocellular carcinoma was probably first considered when anti-HBx was detected in the sera of patients with HBV-associated primary hepatocellular carcinoma (Science 1985;227:429-433). However, anti-HBx was clearly not specific to hepatocellular carcinoma because it could be detected with some regularity in patients with chronic hepatitis B
1992;102:1080-1085
SELECTED SUMMARIES Mark Feldman, M.D. Selected Summaries Editor Dallas Veterans Administration Medical Service (111) Da!las, Texas 75216
Medical Center
STAFF OF CONTRIBUTORS James L. Achord, Jackson, MS Kim E. Barrett, San Diego, CA Grace H. Elta, Ann Arbor, MI Lawrence S. Friedman, Philadelphia, Hans Fromm, Washington, DC Hans Gerdes, New York, NY Stephen B. Hanauer, Chicago, IL
PA
HAS ANOTHER SURGICAL BEEN REPLACED?
Raymond S. Koff, Framingham, MA Benjamin Krevsky, Philadelphia, PA Loren Laine, Los Angeles, CA William Lee, Dallas, TX Peter F. Malet, Philadelphia, PA Thomas A. Miller, Houston, TX Malcolm Robinson, Oklahoma City, OK
PROCEDURE
Zemel G, Katzen BT, Becker GJ, et al. (Miami Vascular Institute, Baptist Hospital of Miami, Miami, Florida). Percutaneous transjugular portosystemic shunt. JAMA 1991;266: 390-393 (July). The authors created a transjugular intrahepatic portosystemic shunt (TIPS) in eight patients with alcoholic (six patients) or postnecrotic (two patients) cirrhosis by creating a fistula between the hepatic vein and the portal vein and inserting a balloon-expandable stent in the tract. All patients had portal hypertension and varices documented by angiography/hepatic wedge venography and/or liver biopsy/endoscopy. One patient was classified Child A, 5 were Child B, and 2 were Child C. Seven of the patients had bled previously from an upper gastrointestinal source and one from hemorrhoids. The mean wedged pressure gradient of the eight patients was 36 mm Hg. The diameters of the stents were between 8 and 12 mm and lowered the average wedged pressure gradient to 11 mm Hg. Embolization of varices or coronary veins was not done. Upper endoscopy in each patient was said to show complete decompression of the esophageal varices within the week following the procedure. Only the patient with hemorrhoids bled again and was treated by enlarging the stent from 8 to 12 mm. This patient’s portosystemic pressure gradient was reduced from 38 mm Hg to 18 mm Hg with an 8-mm stent and to 8 mm Hg with enlargement of the stent to 12 mm. All shunts were patent at l-9 months’ follow-up (average, 5 months). One patient was found to have developed stenosis of the right hepatic vein 4 months after TIPS that was successfully dilated with balloon angioplasty, reducing the pressure gradient to the original postshunt level of 8 mm Hg. A second patient was incidentally found to have a small portion of the parenchymal tract not covered by the stent during the initial procedure 4 months earlier; it was successfully dilated by balloon angioplasty. Migration of one stent to the left lower lobe pulmonary artery occurred. It was replaced into the inferior vena cava and anchored in place at the bifurcation by expanding its diameter to 18 mm with an angioplasty balloon catheter. (No comment is made concerning replacement of the lost intrahepatic
Mitchell L. Schubert, Richmond, VA Konrad Schulze-Delrieu, Iowa City, IA Fergus Shanahan, Los Angeles, CA Joseph Sweeting, New York, NY Richard C. Thirlby, Seattle, WA M. Michael Wolfe, Boston, MA
stent or of the fate of the parenchymal shunt.) No other complications are reported. “Life-style-limiting” hepatic encephalopathy was not found, but further details are not given. Tense ascites in two patients and mild to moderate ascites in four was improved or resolved after the procedure. Serum bilirubin, albumin, and prothrombin time improved or remained the same 4 months after TIPS in all patients. The hospital stay after the shunt ranged from 1 to 19 days with a mean of 7.7 days. In this preliminary communication involving a very small number of patients, the authors conclude that TIPS appears to be a “safe and effective method of portal decompression for the treatment of variceal hemorrhage” but recognize the need for larger numbers to conclusively establish the safety and longterm effectiveness of this procedure. Comment.
Wire-mesh stents have been in use for the past few years in a number of disciplines. They are made of stainless steel or tantalum and passed encased in a plastic sheath that can be extracted to allow them to expand. They are either self-expanding or expandable to a predetermined size with an angioplasty balloon [Circulation 1991;83(Suppl 2):1122-11361. The mesh density is variable. In the vascular tree, wire stents are unique in that in experimental animals they become covered by ground substance, smooth muscle cells, and a monolayer of endothelial cells within l-2 weeks (Am Heart J 1991;121:1522-1530; Circulation 1991; 83:1788-1798). In the bronchial tree, they become covered with ciliated columnar epithelium (Acta Radio1 1991;32:79-80). Wire stents have found favor with cardiologists in postangioplasty elastic rebound and restenosis [J Am Co11 Cardiol 1991;17(6 Suppl B):155B-159B; Clin Cardiol1991;14:374-91 and have been used in stenotic congenital heart disease (Circulation 1991;83:1923-1939). They have been used for renal artery stenosis (Radiology 1991; 180:367-372) and iliac and femoral and popliteal artery lesions (Radiology 1991;179:449-456; AJR 1991;156:389-393) with somewhat less encouraging results. They have been placed in the tracheobronchial tree both in experimental animals (Acta Radio1 1991;32:79-80) and in human subjects with bronchomalacia [Arch Otolaryngol Head Neck Surg 1990;116:1087-1090), raising the exciting possibility of their use in tracheoesophageal fistulae caused by malignancies. These stents have also been used successfully in urethral obstruction in high-risk patients (Clin Radio1 1990;42:228-232). In the biliary tree, wire stents have been placed endoscopically (Gastrointest Endosc 1990;36:451-457) and transhepatically by both percutaneous (Radiology 1991;179:703-707) and jugular (Radiology 1991;180:579-581) approaches. Early re-
SELECTED SUMMARIES
March 1992
sults show a lower occlusion rate than with plastic stents and largely by tumor growth through the mesh rather than by biliary encrustations (Radio1 Clin North Am 1990;28:1211-1222; Radiology 1990;177:793-797). Wire stents have been used to successfully treat the Budd-Chiari syndrome (Gastroenterology 1991:lOO: 1435-1441). Creating a parenchymal tract between the hepatic and portal system by balloon angioplasty is no great obstacle to today’s invasive radiologist; keeping it open, however, is another matter (Can Med Assoc J 1982;126:267-268). Richter et al. (Radiology 1990;174:1027-1030) used a wire stent to keep the tract open in three patients with cirrhosis, one of whom had hepatorenal syndrome before the shunt and died 11 days later of that syndrome: further details are sparse. In the reviewed preliminary report, Zeme1 et al. show the feasibility of the procedure in a small number of patients. I count two complications (one migrating stent and one acquired stenosis of the right hepatic vein) but no other serious ones. The number of subjects is too small to comment on serious morbidity or mortality, hut even so the results suggest that it is not an extremely hazardous undertaking, especially considering the serious prognosis in this group of patients. It is too early to tell just what the occlusion rate will be, but as demonstrated, these stents can be expanded when necessary by balloon angiography and the channel cleared by various other angiographic techniques. We have known since the early days of surgical portasystemic shunting that ascites can be relieved by shunts, and TIPS is an exciting possibility in certain patients. Further, our efforts to treat acutely bleeding varices should in theory be greatly enhanced by the ability to abruptly lower portal pressure. There is no reason to assume, despite the absence of “life-style-limiting” hepatic encephalopathy in this small number of patients (which suggests that there was some but it was not considered significant by the authors), that an effective portasystemic shunt that directs blood around liver parenchyma by any particular method will avoid encephalopathy. The liver function was not studied in these patients. The serum bilirubin level stayed the same or improved in all subjects; the preshunt mean was 74 Fmol/L (4.3 mg/dL), and the postshunt mean was 42 pmol/L (2.5 mg/dL). Similarly, serum albumin levels and prothrombin times tended to improve. It cannot be concluded that the shunt improved liver function or was responsible for improvement in liver tests, but only that there is no reason to think the liver parenchyma was further impaired by the procedure. This procedure is an exciting development and holds great promise, not only in reducing portal pressure but in several other areas as well. But then so did a lot of others until we systematically and carefully studied them. One may conclude that marked elevation in portal pressure in cirrhosis can be reduced acutely and impressively by this technique and that it has the potential for long-term effectiveness. Because of the apparent relative ease with which this shunt can be placed, the procedure also has a sizable potential for inappropriate use if it becomes readily available. Further careful study of the remote, as well as the direct, effects of this procedure is called for. J. L. ACHORD, M.D.
HEPATOCELLULAR CARCINOMA IN TRANSGENIC MICE: A CONSEQUENCE OF CONTINUED EXPRESSION OF THE HBx GENE? Kim C-M, Koike KK, Saito I, et al. (Laboratory of Virology, Jerome H. Holland Laboratory, American Red Cross, Rockville, Maryland; Laboratory of Hepatitis Viruses, Department of Enteroviruses, National Institute of Health, Tokyo,
Japan). HBx gene of hepatitis B virus induces in transgenic mice. Nature 1991;351:317-320.
1081
liver cancer
To study the role of the hepatitis Bx (HBx) protein in hepatocarcinogenesis, a hepatitis B virus (HBV) DNA fragment containing the coding region for HBx, the transcriptional enhancer, the principal RNA start sites, and the polyadenylation site was placed into the germline of outbred CD1 mice. HBx transgenic mice, with at least one intact copy of the transgene stably integrated into the host genome, were bred out. The HBx transgene was shown to be expressed in liver, kidney, and testis, and HBx protein was detected in liver extracts by immunoprecipitation with anti-HBx or by immunostaining of liver sections. Altered foci of poorly staining, glycogen-rich hepatocytes were detected at 4 months of age, and these expressed relatively high levels of HBx protein. Tumor nodules with the features of hepatocellular adenomas appeared at 8-10 months of age and expressed HBx protein and a-fetoprotein. Serum alanine aminotransferase levels were consistently normal in mice found to have adenomas. Hence, no evidence of chronic hepatitis was observed in association with the development of these tumors. Between 11 and 15 months of age, 80%90% of male transgenic mice died with hepatocellular carcinomas grossly detectable. These carcinomas continued to express HBx protein and a-fetoprotein but did not show accumulated glycogen. In contrast to the observations in male transgenic mice, only 60%-67% of female mice developed hepatocellular carcinoma; female mice developed carcinomas approximately 6 months after their male counterparts. The authors suggest that male and female transgenic mice are equally susceptible; apparent differences in penetrance may simply reflect the earlier age at which males are affected.
Comment. The key mechanisms underlying HBV-associated hepatocarcinogenesis remain enigmatic. Integration of the HBV genome into host hepatocyte DNA is well established and believed to be an important step in the pathogenesis of malignant transformation. HBV-induced amplification of proto-oncogenes or viral or cellular oncogenes may be associated with carcinogenesis. Although transforming oncogenes have been detected near the HBV genome in some hepatocellular carcinomas (Oncogene 1988;3: 537-540), activation of viral or cellular oncogenes by the HBV genome has not been unequivocally proved and homology with the HBV genome has not been established (Hepatology 1988;8:1116-1120). Structural rearrangements of integrated HBV DNA and cellular flanking DNA have been found in HBV-associated malignant hepatocytes (J Virol 1990;64:822-888; Hepatology 1990;11:1017-1023) but may not be present in nonmalignant cells (Hepatology 1990;11:1017-1023). Hence the role of rearrangements, deletions, and other chromosomal alterations (insertional mutagenesis) is uncertain. Could the site of HBV genomic integration be important? Yes, but while integration of the HBV genome within an intron of a human cyclin A gene, a growth-regulatory gene, has been hypothesized to contribute to hepatocarcinogenesis (Nature 1990;343:555-557), this too remains speculative. The possible linkage of HBx and hepatocellular carcinoma was probably first considered when anti-HBx was detected in the sera of patients with HBV-associated primary hepatocellular carcinoma (Science 1985;227:429-433). However, anti-HBx was clearly not specific to hepatocellular carcinoma because it could be detected with some regularity in patients with chronic hepatitis B
