- Email: [email protected]
Hepatic and portal vein flow in correlation with intrahepatic fat deposition and liver histology
AASLD A1235
April 1998
time of diagnosis in 25% of the cases and was significantly more frequent in male than in female (p=0.006). CONCLUSION: This first French national epidemiological study showed that the diagnosis of GH is always delayed (mean age : 47 years). Routine blood tests allowed diagnosis nearly in half cases. The most frequent three revealing clinical symptoms are arthralgia, asthenia and cutaneous abnormalities. Familial tracking does not allow to decrease the delay for the diagnosis. L0147 EFFECTS OF THERAPEUTIC PHLEBOTOMIES ON GENETIC HEMOCHROMATOSIS REGARDING A FRENCH NATIONAL EPIDEMIOLOGIC STUDY ON A SAMPLE OF 498 PATIENTS. JM Didelot P Blanc, P Martinez, D Larrey, H Michel. H6pital Saint Eloi. 2, Avenue Bertin Sans. 34295 Montpellier C~dex 5. France. BACKGROUND AND AIM OF THE STUDY: Since 1947, the only treatment of genetic hemochromatosis (GH) is therapeutic phlebotomy. We studied its efficiency on different complications of GH determined by the first national epidemiologic study ever carried out in France on patients with GH. METHOD: Two questionnaires about the clinical symptoms at the onset of the disease were sent in 1997 to 1500 patients with GH of the French Association of Hemochromatosis. 498 patients were selected among 754 who answered the first questionnaire because the diagnosis of GH was definied and performed by either therapeutic phlebotomies during more than one year or liver biopsy or serum transferrin saturation > 60% in men and > 50% in women and serum ferritin concentration > 200 ~tg/l. Among these 498 patients, 371 answered a second questionnaire, more complete about the outset of the disease. The statistical study used a monofactorial analysis of variance followed by a Student's two-tailed t-test. RESULTS: Before treatment, 85% of patients had arthralgia, 80% asthenia, 67% skin abnormalities, 53% hepatomegaly, 39% heart dysfunctions. GH treatment was performed with desferrioxamine in 9% of cases and with therapeutic phlebotomies in 91%. The mean volume of phlebotomies were 413 ml for all, 422 ml in male and 389 ml in female (p=0.0001). They were performed in mean every 10.5 days for all, 9.6 days in male and 12.7 in female (p=0,003). During a mean time of treatment of 7 years, 91% of the patients had no complication of liver disease but 1% had ascitis, 1% jaundice, 2.5% bleeding esophageal varices and 4.5% hepatocellular carcinoma. Therapeutic phlebotomies improved overall condition in 65% of patients. Only 5% of patients worsened. After therapeutic phlebotomies, melanodermia improved in 66%, hepatomegaly in 55% and asthenia in 51%. Arthralgia were not improved by this treatment and were even worse than before treatment. CONCLUSION: Therapeutic phlebotomies allow substantial improvement of symptoms of GH particularly asthenia, melanodermia and hepatomegaly. However, arthralgia remain unchanged. • L0148 LAMIVUDINE TREATMENT FOR ONE YEAR IN PREVIOUSLY UNTREATED U.S. HEPATITIS B PATIENTS: HISTOLOGIC IMPROVEMENT AND HEPATITIS BE-ANTIGEN (HBeAg) SEROCONVERSION. J. Dienstag l, E. Schiff2, T. Wright 3, R. Perrillo 4, H-W. Hann 5, L. Crowther6, M. Woessner6, M. Rubin 6, N. Brown6, and the U.S. Lamivudine Investigator Group. 1Mass General Hospital, Boston, MA; 2U of Miami, Miami, FL; 3VA Medical Center, San Francisco, CA; 4Ochsner Clinic, New Orleans, LA; 5Jefferson Medical College, Philadelphia, PA; 6Glaxo Wellcome, Research Triangle Park, NC.
A controlled Phase III trial was undertaken to assess the efficacy and safety of lamivudine (LAM) in previously untreated U.S. patients (pts) with compensated chronic hepatitis B. Methods: Eligible pts were randomized (1:1) to double-blinded treatment with LAM (100 mg/day) or placebo (PBO), for a period of one year (52 weeks) with post treatment follow-up for 16 weeks. The primary efficacy endpoint of the trial was histologic response, defined as a > 2-point reduction in the Knodell histologic activity index (HAI). Liver biopsies were performed pre-treatment and at Week 52 and were scored, blinded, by an independent histopathologist. A secondary efficacy endpoint of the trial was HBeAg seroconversion (defined as undetectable HBeAg, detectable anti-HBe and undetectable HBV DNA) at Week 52. The Intent-to-Treat patient population was used for the efficacy analysis. Results: Sixty-six pts were randomized to LAM, and 71 to PBO. Treatment groups were well-matched for demographic and disease factors, although baseline serum HBV DNA levels were higher in the LAM group (mean 199 pg/mL) than in the PBO group (mean 107 pg/mL). Histologic response was significantly greater in LAM pts compared to PBO pts (52% vs. 23%, p<0.001). LAM pts had a median HA1 reduction of 3 points at Week 52, while the median change in PBO pts was zero. In blinded "ranked" assessments, PBO pts were more likely to exhibit progression in hepatic fibrosis than LAM pts (20% vs. 5%, p<0.01). In addition, after 52 weeks of treatment, LAM pts were more likely to experience HBeAg seroconversion than PBO pts (17% vs. 6%, p<0.04). HBeAg loss was also more common in LAM pts than PBO pts at Week 52 (32% vs. 11%), and this response was still present in >80% of these patients at Week 68. HBV DNA suppression (44% vs. 16%, p<0.001) and ALT normalization (41% vs. 7%, p<0.001) were also more common in LAM pts than PBO pts. LAM was generally welltolerated with a similar safety profile to PBO. Grade 2 (2.1-3 x baseline) and Grade 3 (3.1-10 x baseline) ALT elevations occurred in a minority (<15%) of patients during treatment on both treatment arms, and no Grade 4 (>10 x baseline) elevations occurred during treatment. Elevated HBV DNA and serum aminotransferases recurred after treatment discontinuation (i.e., after week 52). Grade 3 ALT elevations were more common in LAM pts compared to
PBO (22% vs. 6%) post-treatment. These elevations were infrequently associated with bilirnbin elevations (one patient in each group). Grade 4 ALT elevations were rare (<5%). Conclusion: LAM significantly improves liver histology and increases HBeAg seroconversion rates in previously untreated patients with chronic hepatitis B. This research was funded by Glaxo Wellcome, Research Triangle Park, NC. L0149 HEPATIC AND PORTAL VEIN FLOW IN CORRELATION WITH INTRAHEPATIC FAT DEPOSITION AND LIVER HISTOLOGY. C.F. Dietrich, J.-H. Lee, C. Sarrazin, C. Rees, W.F. Caspary, S. Zeuzem. Med. Klinik II, J.W. Goethe-University Hospital, Frankfurt, Germany.
The flow pattern in hepatic veins depends on cardiac physiology and liver histology. Aim of the present study was to determine the dependence of the flow pattern of hepatic and portal veins in relation to histological grading, staging, and the intrahepatic fat deposition in patients with chronic hepatitis C. Methods: In 135 patients with chronic hepatitis C and normal cardiac function, the Doppler spectrum of the right liver vein was classified as triphasic, biphasic, or monophasic. The flow of the portal vein was characterized according to the undulation (VelocitYmax.min). At the same occasion liver biopsy was performed and biopsy specimens were semiquantitatively evaluated by the histological activity index (HAI) and a score of the hepatic fat content. As controls 75 healthy subjects were investigated. Multiple logistic regression analysis was used to identify the histological features that might contribute to the type of the flow phase. Results: Sufficient analysis of respective flow patterns were achieved in all patients with chronic hepatitis C and in all healthy controls. In patients with chronic hepatitis C no strong correlation was found between the flow pattern of the hepatic veins and the histological activity index (HA1). The hepatocyte fat content was the only variable associated with an independent effect on the type of flow-phase (monophasic versus triphasic; odds ratio, 16.26; 95 percent confidence interval: 6.38 to 41.45; P < 0.0001). A pronounced undulation in the portal vein was associated with portal inflammation but not with other parameters of the HAI or the intrahepatic fat deposition. In healthy controls the flow pattern was triphasic in 56/75 (75%), biphasic in 7/75 (9%), and monophasic in 12/75 (16%), respectively. All healthy controls with a monophasic flow pattern revealed a sonographically bright echotexture of the liver, representing fatty liver. Discussion: The normal flow pattern in the right liver vein is triphasic. The monophasic flow pattern in the right liver vein is mainly caused by intrahepatic fat deposition and less related to inflammatory or fibrotic changes. In contrast, the flow pattern of the portal vein is mainly influenced by portal inflammation. L0150 WITHDRAWN.
1373
• L0151 PERCUTANEOUS INTRAHEPATIC ItEPATOCYTE TRANSPLANTATION WITH FLUOROSCOPIC GUIDANCE. V. Dixit. P. Dong, M. Arthur, J. Roberts, P. Martin, and G. Gitnick. UCLA School of Medicine, Los Angeles, CA.
Current hepatocyte transplantation (Tx) techniques are associated with significant risk because they require major abdominal surgery to expose the portal vein (PV) or spleen, the usual hepatocyte Tx sites. To avoid such complications, we have developed a simple, non-invasive, fluoroscopyguided technique for hepatocyte Tx that involves percutaneous catheterization of the intrahepatic PV. Methods: A #4 French catheter was inserted into the intrahepatic PV of healthy recipient pigs (30 _+6 kg; N=6) by intercostal insertion with fluoroscopy guidance. The cannula was secured and exteriorized at the surface of the chest near the 11th and 12lh ribs. Placement of the catheters was verified by fluoroscopy. In preliminary experiments, we slowly infused 99Tc-labeled (2.5 x 108; 1 mCi) rat hepatocytes into the PV of normal pigs using a syringe pump. Scintigraphy was performed to image the biodistribution of the labeled hepatocytes in the body. In other similar studies (N=3) we measured the portal pressure pre- and post-hepatocyte Tx for a period of two weeks. All animals (N=9) were immunosuppressed with cyclosporine A. Results: All 9 cannulation procedures were carried out without morbidity or mortality. Intraportal cannulas were patent for at least 1 week post-cannulation. Representative fluoroscopy (Fig. 1) showed a definitive transhepatic portagram with proper placement of the catheter in the PV.
Scintigraphy (Fig.2) revealed that the hepatocytes were localized only in the liver. Average pre-Tx portal pressure (PP) was 11/7 mm Hg. Following hepatocyte Tx there was a transient elevation in average PP to 50•35 mm Hg that subsided to 24/11 within 5 minutes. Within 3 days the PP returned to normal pre-Tx levels and remained so until the animals were sacrificed 2 weeks post-Tx. Conclusions: (1) The fluoroscopy-guided hepatocyte transplantation technique described here is safe, quick, and can be performed by an interventional radiologist. (2) This technique will permit the slow infusion of hepatocytes and avoid complications associated with obstruction of portal blood flow.
April 1998
time of diagnosis in 25% of the cases and was significantly more frequent in male than in female (p=0.006). CONCLUSION: This first French national epidemiological study showed that the diagnosis of GH is always delayed (mean age : 47 years). Routine blood tests allowed diagnosis nearly in half cases. The most frequent three revealing clinical symptoms are arthralgia, asthenia and cutaneous abnormalities. Familial tracking does not allow to decrease the delay for the diagnosis. L0147 EFFECTS OF THERAPEUTIC PHLEBOTOMIES ON GENETIC HEMOCHROMATOSIS REGARDING A FRENCH NATIONAL EPIDEMIOLOGIC STUDY ON A SAMPLE OF 498 PATIENTS. JM Didelot P Blanc, P Martinez, D Larrey, H Michel. H6pital Saint Eloi. 2, Avenue Bertin Sans. 34295 Montpellier C~dex 5. France. BACKGROUND AND AIM OF THE STUDY: Since 1947, the only treatment of genetic hemochromatosis (GH) is therapeutic phlebotomy. We studied its efficiency on different complications of GH determined by the first national epidemiologic study ever carried out in France on patients with GH. METHOD: Two questionnaires about the clinical symptoms at the onset of the disease were sent in 1997 to 1500 patients with GH of the French Association of Hemochromatosis. 498 patients were selected among 754 who answered the first questionnaire because the diagnosis of GH was definied and performed by either therapeutic phlebotomies during more than one year or liver biopsy or serum transferrin saturation > 60% in men and > 50% in women and serum ferritin concentration > 200 ~tg/l. Among these 498 patients, 371 answered a second questionnaire, more complete about the outset of the disease. The statistical study used a monofactorial analysis of variance followed by a Student's two-tailed t-test. RESULTS: Before treatment, 85% of patients had arthralgia, 80% asthenia, 67% skin abnormalities, 53% hepatomegaly, 39% heart dysfunctions. GH treatment was performed with desferrioxamine in 9% of cases and with therapeutic phlebotomies in 91%. The mean volume of phlebotomies were 413 ml for all, 422 ml in male and 389 ml in female (p=0.0001). They were performed in mean every 10.5 days for all, 9.6 days in male and 12.7 in female (p=0,003). During a mean time of treatment of 7 years, 91% of the patients had no complication of liver disease but 1% had ascitis, 1% jaundice, 2.5% bleeding esophageal varices and 4.5% hepatocellular carcinoma. Therapeutic phlebotomies improved overall condition in 65% of patients. Only 5% of patients worsened. After therapeutic phlebotomies, melanodermia improved in 66%, hepatomegaly in 55% and asthenia in 51%. Arthralgia were not improved by this treatment and were even worse than before treatment. CONCLUSION: Therapeutic phlebotomies allow substantial improvement of symptoms of GH particularly asthenia, melanodermia and hepatomegaly. However, arthralgia remain unchanged. • L0148 LAMIVUDINE TREATMENT FOR ONE YEAR IN PREVIOUSLY UNTREATED U.S. HEPATITIS B PATIENTS: HISTOLOGIC IMPROVEMENT AND HEPATITIS BE-ANTIGEN (HBeAg) SEROCONVERSION. J. Dienstag l, E. Schiff2, T. Wright 3, R. Perrillo 4, H-W. Hann 5, L. Crowther6, M. Woessner6, M. Rubin 6, N. Brown6, and the U.S. Lamivudine Investigator Group. 1Mass General Hospital, Boston, MA; 2U of Miami, Miami, FL; 3VA Medical Center, San Francisco, CA; 4Ochsner Clinic, New Orleans, LA; 5Jefferson Medical College, Philadelphia, PA; 6Glaxo Wellcome, Research Triangle Park, NC.
A controlled Phase III trial was undertaken to assess the efficacy and safety of lamivudine (LAM) in previously untreated U.S. patients (pts) with compensated chronic hepatitis B. Methods: Eligible pts were randomized (1:1) to double-blinded treatment with LAM (100 mg/day) or placebo (PBO), for a period of one year (52 weeks) with post treatment follow-up for 16 weeks. The primary efficacy endpoint of the trial was histologic response, defined as a > 2-point reduction in the Knodell histologic activity index (HAI). Liver biopsies were performed pre-treatment and at Week 52 and were scored, blinded, by an independent histopathologist. A secondary efficacy endpoint of the trial was HBeAg seroconversion (defined as undetectable HBeAg, detectable anti-HBe and undetectable HBV DNA) at Week 52. The Intent-to-Treat patient population was used for the efficacy analysis. Results: Sixty-six pts were randomized to LAM, and 71 to PBO. Treatment groups were well-matched for demographic and disease factors, although baseline serum HBV DNA levels were higher in the LAM group (mean 199 pg/mL) than in the PBO group (mean 107 pg/mL). Histologic response was significantly greater in LAM pts compared to PBO pts (52% vs. 23%, p<0.001). LAM pts had a median HA1 reduction of 3 points at Week 52, while the median change in PBO pts was zero. In blinded "ranked" assessments, PBO pts were more likely to exhibit progression in hepatic fibrosis than LAM pts (20% vs. 5%, p<0.01). In addition, after 52 weeks of treatment, LAM pts were more likely to experience HBeAg seroconversion than PBO pts (17% vs. 6%, p<0.04). HBeAg loss was also more common in LAM pts than PBO pts at Week 52 (32% vs. 11%), and this response was still present in >80% of these patients at Week 68. HBV DNA suppression (44% vs. 16%, p<0.001) and ALT normalization (41% vs. 7%, p<0.001) were also more common in LAM pts than PBO pts. LAM was generally welltolerated with a similar safety profile to PBO. Grade 2 (2.1-3 x baseline) and Grade 3 (3.1-10 x baseline) ALT elevations occurred in a minority (<15%) of patients during treatment on both treatment arms, and no Grade 4 (>10 x baseline) elevations occurred during treatment. Elevated HBV DNA and serum aminotransferases recurred after treatment discontinuation (i.e., after week 52). Grade 3 ALT elevations were more common in LAM pts compared to
PBO (22% vs. 6%) post-treatment. These elevations were infrequently associated with bilirnbin elevations (one patient in each group). Grade 4 ALT elevations were rare (<5%). Conclusion: LAM significantly improves liver histology and increases HBeAg seroconversion rates in previously untreated patients with chronic hepatitis B. This research was funded by Glaxo Wellcome, Research Triangle Park, NC. L0149 HEPATIC AND PORTAL VEIN FLOW IN CORRELATION WITH INTRAHEPATIC FAT DEPOSITION AND LIVER HISTOLOGY. C.F. Dietrich, J.-H. Lee, C. Sarrazin, C. Rees, W.F. Caspary, S. Zeuzem. Med. Klinik II, J.W. Goethe-University Hospital, Frankfurt, Germany.
The flow pattern in hepatic veins depends on cardiac physiology and liver histology. Aim of the present study was to determine the dependence of the flow pattern of hepatic and portal veins in relation to histological grading, staging, and the intrahepatic fat deposition in patients with chronic hepatitis C. Methods: In 135 patients with chronic hepatitis C and normal cardiac function, the Doppler spectrum of the right liver vein was classified as triphasic, biphasic, or monophasic. The flow of the portal vein was characterized according to the undulation (VelocitYmax.min). At the same occasion liver biopsy was performed and biopsy specimens were semiquantitatively evaluated by the histological activity index (HAI) and a score of the hepatic fat content. As controls 75 healthy subjects were investigated. Multiple logistic regression analysis was used to identify the histological features that might contribute to the type of the flow phase. Results: Sufficient analysis of respective flow patterns were achieved in all patients with chronic hepatitis C and in all healthy controls. In patients with chronic hepatitis C no strong correlation was found between the flow pattern of the hepatic veins and the histological activity index (HA1). The hepatocyte fat content was the only variable associated with an independent effect on the type of flow-phase (monophasic versus triphasic; odds ratio, 16.26; 95 percent confidence interval: 6.38 to 41.45; P < 0.0001). A pronounced undulation in the portal vein was associated with portal inflammation but not with other parameters of the HAI or the intrahepatic fat deposition. In healthy controls the flow pattern was triphasic in 56/75 (75%), biphasic in 7/75 (9%), and monophasic in 12/75 (16%), respectively. All healthy controls with a monophasic flow pattern revealed a sonographically bright echotexture of the liver, representing fatty liver. Discussion: The normal flow pattern in the right liver vein is triphasic. The monophasic flow pattern in the right liver vein is mainly caused by intrahepatic fat deposition and less related to inflammatory or fibrotic changes. In contrast, the flow pattern of the portal vein is mainly influenced by portal inflammation. L0150 WITHDRAWN.
• L0151 PERCUTANEOUS INTRAHEPATIC ItEPATOCYTE TRANSPLANTATION WITH FLUOROSCOPIC GUIDANCE. V. Dixit. P. Dong, M. Arthur, J. Roberts, P. Martin, and G. Gitnick. UCLA School of Medicine, Los Angeles, CA.
Current hepatocyte transplantation (Tx) techniques are associated with significant risk because they require major abdominal surgery to expose the portal vein (PV) or spleen, the usual hepatocyte Tx sites. To avoid such complications, we have developed a simple, non-invasive, fluoroscopyguided technique for hepatocyte Tx that involves percutaneous catheterization of the intrahepatic PV. Methods: A #4 French catheter was inserted into the intrahepatic PV of healthy recipient pigs (30 _+6 kg; N=6) by intercostal insertion with fluoroscopy guidance. The cannula was secured and exteriorized at the surface of the chest near the 11th and 12lh ribs. Placement of the catheters was verified by fluoroscopy. In preliminary experiments, we slowly infused 99Tc-labeled (2.5 x 108; 1 mCi) rat hepatocytes into the PV of normal pigs using a syringe pump. Scintigraphy was performed to image the biodistribution of the labeled hepatocytes in the body. In other similar studies (N=3) we measured the portal pressure pre- and post-hepatocyte Tx for a period of two weeks. All animals (N=9) were immunosuppressed with cyclosporine A. Results: All 9 cannulation procedures were carried out without morbidity or mortality. Intraportal cannulas were patent for at least 1 week post-cannulation. Representative fluoroscopy (Fig. 1) showed a definitive transhepatic portagram with proper placement of the catheter in the PV.
Scintigraphy (Fig.2) revealed that the hepatocytes were localized only in the liver. Average pre-Tx portal pressure (PP) was 11/7 mm Hg. Following hepatocyte Tx there was a transient elevation in average PP to 50•35 mm Hg that subsided to 24/11 within 5 minutes. Within 3 days the PP returned to normal pre-Tx levels and remained so until the animals were sacrificed 2 weeks post-Tx. Conclusions: (1) The fluoroscopy-guided hepatocyte transplantation technique described here is safe, quick, and can be performed by an interventional radiologist. (2) This technique will permit the slow infusion of hepatocytes and avoid complications associated with obstruction of portal blood flow.