- Email: [email protected]
Transient hepatofugal portal blood flow in alcoholic cirrhosis with acute alcoholic hepatitis
306
LETTERS TO THE EDITOR
References I. Tine F, Magrin S, Craxi A, Pagliaro L. Interferon for non-A, non-B chronic hepatitis. J Hepatol 1991; 13: 192-9. 2. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: a multicenter randomized controlled trial. N Engl J Med 1989; 321: 1501-6. 3. Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alpha therapy for chronic hepatitis C. A randomized double-blind placebo-controlled trial. N Engl J Med 1989; 321; 1506-10.
4_ Shindo M, Di Bisceglie AM, Hoofnagle JH. Long-term followup of patients with chronic hepatitis C treated with alfa-interferon. Hepatology 1992; 15: 1013-6. 5. Chau KH, Dawson G J, Mushahwar IK, et al. lgM antibody response to hepatitis C virus antigens in acute and chronic post-transfusion non-A, non-B hepatitis_ J Virol Methods 1991; 35: 343-52. 6. Brillanti S, Masci C, Ricci P, et al. Significance of IgM antibody to hepatitis C virus in patients with chronic hepatitis C. Hepatology 1992; 15: 998-1001.
Transient hepatofugal portal blood flow in alcoholic cirrhosis with acute alcoholic hepatitis Spontaneous reversal of portal blood flow is considered a rare irreversible condition which occurs in advanced cirrhosis (I). We report three cases in which Duplex Doppler ultrasound (DUS) demonstrated a transient reversal of portal flow. The only event which can explain this reversal was an associated acute alcoholic hepatitis. The three patients had been alcohol abusers for 10 years. Serological tests for infection by hepatitis A, B, C, cytomegalovirus, EpsteinBarr virus, for antibodies to smooth muscle, mitochondria, nuclei and microsomes, were negative. The main patient characteristics are shown in Table 1.
Case 2
A 40-year-old woman with alcoholic cirrhosis was hospitalized for jaundice. Liver biopsy revealed cirrhosis associated with fatty changes and inflammatory infiltration. Ultrasound demonstrated hepatofugal portal flow with large spleno-renal and coronary veins. Four weeks later, when the patient had stopped drinking and her clinical condition had improved, DUS demonstrated hepatopetal portal flow. Liver biopsy showed slighter fatty change.
Case 1
Case 3
A 37-year-old woman was referred for jaundice. Liver biopsy showed cirrhosis associated with massive macrovesicular steatosis, Mallory bodies and inflammatory infiltration. The first DUS examination showed hepatosplenomegaly and hepatofugal. portal flow in the portal vein. The second, 10 days later, showed hepatopetal portal flow as the patient's clinical condition had improved.
A 32-year-old man was referred for jaundice. Liver biopsy revealed cirrhosis associated with fatty change, hepatocyte necrosis with Mallory bodies and inflammatory infiltration. DUS showed hepatosplenomegaly, minimal ascites and hepatofugal portal flow with large spleno-renal and coronary veins. Nine weeks later, when the patient had stopped drinking and his clinical condition had improved, DUS showed hepatopetal portal flow.
TABLE 1 Main characteristics of the three patients at the time they bad hepatofugal portal blood flow compared to characteristics at the time hepatopetal portal blood flow was regained Patient I
Patient 2
Patient 3
Weeks without alcohol intake Direction of portal flow
0 Hepatofugal
1.5 Hepatopetal
0 Hepatofugal
4 Hepatopetal
0 Hepatofugal
9 Hepatopetal
Ascites Encephalopathy Leukocyte count (per mm 3) Serum bilirubin (/.tmol/l) AST/ALT (IU/1) Alkaline phosphatase (IU/I) Serum GGT (IU/1) Prothrombin activity (%) Endoscopic varices Echographic collaterals Hepatic pressure gradient (mmHg)
No No 13 900 82 162/51 464 530 61 No No 16
No No 9380 50 76/20 219 262 60 No No ND
No No 8000 126 80/25 344 76 36 grade 2 Yes 20
No No 3800 108 40/16 166 46 38 ND Yes 18
Minimal No l 0 000 158 130/39 132 125 37 grade 2 Yes 24
No No 6400 53 36/6 l l6 37 52 ND Yes 21
Ranges of normal values were: serum bilirubin: 0-17 ,umol/I; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST): 5-21 IU/1; alkaline phosphatase: 73-207 IU/I; serum gamma-glutamyltranspeptidase (GGT): 5-28 IU/I; free-wedged hepatic vein gradient: 2-4 mmHg. Grading of varices according to the endoscopic rules proposed by the Japanese Research Society for Portal Hypertension. ND: not done.
LETfERS TO THE EDITOR
307
Liver biopsy showed lower inflammatory infiltration and clearance of fatty change and Mallory bodies.
Transient change in portal flow direction in cirrhotic patients is rare. One case (2) studied by percutaneous transhepatic portography has been attributed to alcoholic hepatitis, but the validity of the procedure was questioned because the injection of contrast material in the portal vein could create artificial hepatofugal flow (3). In the cases reported here, the Doppler trace was recorded by the same skilled operator after deep inspiration and during expiration by the patient to identify possible biphasic flow related to the respiratory cycle. The only change in the patients' condition that could be related to changes in hepatic hemodynamics was the improvement of alcoholic hepatitis. In alcoholic cirrhosis, associated acute alcoholic hepatitis has been shown to increase portal hypertension evaluated by the gradient between wedged and free hepatic venous pressures (4). In the cases in this study, as in the case previously reported (2), the existence of a gradient variation was questionable, since wedged hepatic vein pressure is significantly higher than portal vein pressure when reversal of portal flow occurs (2,5). This could have led to an over-estimation of the first gradient measurement when portal flow was hepatofugal. The reversal of portal flow develops in patients with cirrhosis when the intra-hepatic pressure becomes greater than the pressure in portosystemic collaterals. In Cases 2 and 3, the absence of a marked change in the portal hypertension gradient made an increase in hepatic arterial blood flow or increase in sinusoidal pressure seem unlikely. Although the fact that a slight pressure variation might have reversed an already sluggish flow, these two observations suggest
that a decrease in the resistance of porto-systemic collaterals was the major factor responsible for this event. Th6ng Dao, Isabelle Lecointe, Marie-Astrid Piquet, Isabelle JardinGrimaux, Nicole Bouvard, Jean-Claude Verwaerde and Andr~ Valla Services d'H~pato-gastroenterologie et de mOdecine nuclOaire, Centre Hospitalier Universitaire de Caen, 14000 Caen, France.
References I. Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S, Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients. Gastroenterology 1991; 100: 160--7. 2. Boyer TD, Triger DR, Horisawa M, Redeker AG, Reynolds TB. Direct transhepatic measurement of portal vein pressure using a thin needle. Comparison with wedged hepatic vein pressure. Gastroenterology 1977; 72: 584-98. 3. Moreno AH, Burchell AR, Reddy RV, Steen JA, Panke WF, Nealon TF. Spontaneous reversal of portal blood flow: the case for and against its occurrence in patients with cirrhosis of the liver. Ann Surg 1975; 181: 346-58. 4. Poynard T, Degott C, Munoz C, Lebrec D. Relationship between degree of portal hypertension and liver histologic lesions in patients with alcoholic cirrhosis. Effects of acute alcoholic hepatitis on portal hypertension. Dig Dis Sci 1987; 32: 337-43. 5. Rector WG, Hoefs JC, Hossack KF, Everson GT. Hepatofugal portal flow in cirrhosis : observations on hepatic hemodynamics and the nature of the arterioportal communications. Hepatology 1988; 8: 16-20.
Inhibition of hepatitis B virus replication by adenine arabinoside monophosphate coupled to lactosaminated albumin. Efficacy and minimal active dose In a pilot study (1) in patients with chronic hepatitis B virus (HBV) infection, adenine arabinoside monophosphate (ara-AMP) coupled to lactosaminated human serum albumin (L-HSA) was found to inhibit virus replication in a daily dose 3-6 times lower than that of the free drug.
TABLE 1 Characteristics of the patients at beginning of treatment Patient no.
Sex Age Histology
1 2 3 4 5 6 7 8 9 10
M M M M M F F M M M
19 19 23 65 21 29 37 32 50 30
HBV DNA (Log genomes/ml)
MHL 9 MHL <9 --7 CAH/cirrhosis 9 CLH 9 CPH 8 --8 CAH 8 CPH 8 --9
ALT (mU/ml) 120 140 115 118 98 86 160 77 33 40
MHL=Minimal histological lesions. CAH=Chronic active hepatitis. CLH=Chronic Iobular hepatitis. CPH=Chronic persistent hepatitis. ---=Biopsy not performed. HBV=hepatitis B virus. ALT=alanine aminotransferase.
To confirm this finding and define the minimum effective daily dose, L-HSA-ara-AMP was administered to ten patients with chronic type B hepatitis. The conjugate was given by a 30M.5-min intravenous infusion at 17.5 or 35 mg/kg per day. Patient characteristics are reported in Table 1. In a daily dose of 17.5 mg/kg (corresponding to 0.75 mg/kg of ara-AMP), the conjugate given to patients 1 and 2 for 7 days had little or no effect on viremia_ In a daily dose of 35 mg/kg (=1.5 mg/kg of ara-AMP), the conjugate markedly (1-4 logs) lowered viremia in all treated patients (Fig. 1). This dosage was three to six times lower than the doses of free drug used in the treatment of chronic type B hepatitis (2). The marked difference in efficacy of the two doses of conjugate cannot be explained at present. The levels of HBV DNA rapidly rebounded after the conjugate was discontinued, as observed after short-term treatment with free araAMP (3). The conjugate did not produce neurotoxic side effects (which also were not observed after only 7 days' treatment with free araAMP) or other adverse reactions_ Antibodies binding to the conjugate were not detected in tested patients (nos_ 1, 2, 4 and 7). The plasma levels of L-HSA-conjugated ara-AMP were measured (4) in patients I-4, 6 and 7. Twenty-four hours after conjugate administration, small amounts of coupled ara-AMP (0.1-3.9 /,tg/ml) were still detectable in plasma. This is in contrast to previous determinations in which a different procedure for measuring the conjugated drug was used. The slow removal of coupled araAMP from the bloodstream supports the observation of Marshall
LETTERS TO THE EDITOR
References I. Tine F, Magrin S, Craxi A, Pagliaro L. Interferon for non-A, non-B chronic hepatitis. J Hepatol 1991; 13: 192-9. 2. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: a multicenter randomized controlled trial. N Engl J Med 1989; 321: 1501-6. 3. Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alpha therapy for chronic hepatitis C. A randomized double-blind placebo-controlled trial. N Engl J Med 1989; 321; 1506-10.
4_ Shindo M, Di Bisceglie AM, Hoofnagle JH. Long-term followup of patients with chronic hepatitis C treated with alfa-interferon. Hepatology 1992; 15: 1013-6. 5. Chau KH, Dawson G J, Mushahwar IK, et al. lgM antibody response to hepatitis C virus antigens in acute and chronic post-transfusion non-A, non-B hepatitis_ J Virol Methods 1991; 35: 343-52. 6. Brillanti S, Masci C, Ricci P, et al. Significance of IgM antibody to hepatitis C virus in patients with chronic hepatitis C. Hepatology 1992; 15: 998-1001.
Transient hepatofugal portal blood flow in alcoholic cirrhosis with acute alcoholic hepatitis Spontaneous reversal of portal blood flow is considered a rare irreversible condition which occurs in advanced cirrhosis (I). We report three cases in which Duplex Doppler ultrasound (DUS) demonstrated a transient reversal of portal flow. The only event which can explain this reversal was an associated acute alcoholic hepatitis. The three patients had been alcohol abusers for 10 years. Serological tests for infection by hepatitis A, B, C, cytomegalovirus, EpsteinBarr virus, for antibodies to smooth muscle, mitochondria, nuclei and microsomes, were negative. The main patient characteristics are shown in Table 1.
Case 2
A 40-year-old woman with alcoholic cirrhosis was hospitalized for jaundice. Liver biopsy revealed cirrhosis associated with fatty changes and inflammatory infiltration. Ultrasound demonstrated hepatofugal portal flow with large spleno-renal and coronary veins. Four weeks later, when the patient had stopped drinking and her clinical condition had improved, DUS demonstrated hepatopetal portal flow. Liver biopsy showed slighter fatty change.
Case 1
Case 3
A 37-year-old woman was referred for jaundice. Liver biopsy showed cirrhosis associated with massive macrovesicular steatosis, Mallory bodies and inflammatory infiltration. The first DUS examination showed hepatosplenomegaly and hepatofugal. portal flow in the portal vein. The second, 10 days later, showed hepatopetal portal flow as the patient's clinical condition had improved.
A 32-year-old man was referred for jaundice. Liver biopsy revealed cirrhosis associated with fatty change, hepatocyte necrosis with Mallory bodies and inflammatory infiltration. DUS showed hepatosplenomegaly, minimal ascites and hepatofugal portal flow with large spleno-renal and coronary veins. Nine weeks later, when the patient had stopped drinking and his clinical condition had improved, DUS showed hepatopetal portal flow.
TABLE 1 Main characteristics of the three patients at the time they bad hepatofugal portal blood flow compared to characteristics at the time hepatopetal portal blood flow was regained Patient I
Patient 2
Patient 3
Weeks without alcohol intake Direction of portal flow
0 Hepatofugal
1.5 Hepatopetal
0 Hepatofugal
4 Hepatopetal
0 Hepatofugal
9 Hepatopetal
Ascites Encephalopathy Leukocyte count (per mm 3) Serum bilirubin (/.tmol/l) AST/ALT (IU/1) Alkaline phosphatase (IU/I) Serum GGT (IU/1) Prothrombin activity (%) Endoscopic varices Echographic collaterals Hepatic pressure gradient (mmHg)
No No 13 900 82 162/51 464 530 61 No No 16
No No 9380 50 76/20 219 262 60 No No ND
No No 8000 126 80/25 344 76 36 grade 2 Yes 20
No No 3800 108 40/16 166 46 38 ND Yes 18
Minimal No l 0 000 158 130/39 132 125 37 grade 2 Yes 24
No No 6400 53 36/6 l l6 37 52 ND Yes 21
Ranges of normal values were: serum bilirubin: 0-17 ,umol/I; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST): 5-21 IU/1; alkaline phosphatase: 73-207 IU/I; serum gamma-glutamyltranspeptidase (GGT): 5-28 IU/I; free-wedged hepatic vein gradient: 2-4 mmHg. Grading of varices according to the endoscopic rules proposed by the Japanese Research Society for Portal Hypertension. ND: not done.
LETfERS TO THE EDITOR
307
Liver biopsy showed lower inflammatory infiltration and clearance of fatty change and Mallory bodies.
Transient change in portal flow direction in cirrhotic patients is rare. One case (2) studied by percutaneous transhepatic portography has been attributed to alcoholic hepatitis, but the validity of the procedure was questioned because the injection of contrast material in the portal vein could create artificial hepatofugal flow (3). In the cases reported here, the Doppler trace was recorded by the same skilled operator after deep inspiration and during expiration by the patient to identify possible biphasic flow related to the respiratory cycle. The only change in the patients' condition that could be related to changes in hepatic hemodynamics was the improvement of alcoholic hepatitis. In alcoholic cirrhosis, associated acute alcoholic hepatitis has been shown to increase portal hypertension evaluated by the gradient between wedged and free hepatic venous pressures (4). In the cases in this study, as in the case previously reported (2), the existence of a gradient variation was questionable, since wedged hepatic vein pressure is significantly higher than portal vein pressure when reversal of portal flow occurs (2,5). This could have led to an over-estimation of the first gradient measurement when portal flow was hepatofugal. The reversal of portal flow develops in patients with cirrhosis when the intra-hepatic pressure becomes greater than the pressure in portosystemic collaterals. In Cases 2 and 3, the absence of a marked change in the portal hypertension gradient made an increase in hepatic arterial blood flow or increase in sinusoidal pressure seem unlikely. Although the fact that a slight pressure variation might have reversed an already sluggish flow, these two observations suggest
that a decrease in the resistance of porto-systemic collaterals was the major factor responsible for this event. Th6ng Dao, Isabelle Lecointe, Marie-Astrid Piquet, Isabelle JardinGrimaux, Nicole Bouvard, Jean-Claude Verwaerde and Andr~ Valla Services d'H~pato-gastroenterologie et de mOdecine nuclOaire, Centre Hospitalier Universitaire de Caen, 14000 Caen, France.
References I. Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S, Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients. Gastroenterology 1991; 100: 160--7. 2. Boyer TD, Triger DR, Horisawa M, Redeker AG, Reynolds TB. Direct transhepatic measurement of portal vein pressure using a thin needle. Comparison with wedged hepatic vein pressure. Gastroenterology 1977; 72: 584-98. 3. Moreno AH, Burchell AR, Reddy RV, Steen JA, Panke WF, Nealon TF. Spontaneous reversal of portal blood flow: the case for and against its occurrence in patients with cirrhosis of the liver. Ann Surg 1975; 181: 346-58. 4. Poynard T, Degott C, Munoz C, Lebrec D. Relationship between degree of portal hypertension and liver histologic lesions in patients with alcoholic cirrhosis. Effects of acute alcoholic hepatitis on portal hypertension. Dig Dis Sci 1987; 32: 337-43. 5. Rector WG, Hoefs JC, Hossack KF, Everson GT. Hepatofugal portal flow in cirrhosis : observations on hepatic hemodynamics and the nature of the arterioportal communications. Hepatology 1988; 8: 16-20.
Inhibition of hepatitis B virus replication by adenine arabinoside monophosphate coupled to lactosaminated albumin. Efficacy and minimal active dose In a pilot study (1) in patients with chronic hepatitis B virus (HBV) infection, adenine arabinoside monophosphate (ara-AMP) coupled to lactosaminated human serum albumin (L-HSA) was found to inhibit virus replication in a daily dose 3-6 times lower than that of the free drug.
TABLE 1 Characteristics of the patients at beginning of treatment Patient no.
Sex Age Histology
1 2 3 4 5 6 7 8 9 10
M M M M M F F M M M
19 19 23 65 21 29 37 32 50 30
HBV DNA (Log genomes/ml)
MHL 9 MHL <9 --7 CAH/cirrhosis 9 CLH 9 CPH 8 --8 CAH 8 CPH 8 --9
ALT (mU/ml) 120 140 115 118 98 86 160 77 33 40
MHL=Minimal histological lesions. CAH=Chronic active hepatitis. CLH=Chronic Iobular hepatitis. CPH=Chronic persistent hepatitis. ---=Biopsy not performed. HBV=hepatitis B virus. ALT=alanine aminotransferase.
To confirm this finding and define the minimum effective daily dose, L-HSA-ara-AMP was administered to ten patients with chronic type B hepatitis. The conjugate was given by a 30M.5-min intravenous infusion at 17.5 or 35 mg/kg per day. Patient characteristics are reported in Table 1. In a daily dose of 17.5 mg/kg (corresponding to 0.75 mg/kg of ara-AMP), the conjugate given to patients 1 and 2 for 7 days had little or no effect on viremia_ In a daily dose of 35 mg/kg (=1.5 mg/kg of ara-AMP), the conjugate markedly (1-4 logs) lowered viremia in all treated patients (Fig. 1). This dosage was three to six times lower than the doses of free drug used in the treatment of chronic type B hepatitis (2). The marked difference in efficacy of the two doses of conjugate cannot be explained at present. The levels of HBV DNA rapidly rebounded after the conjugate was discontinued, as observed after short-term treatment with free araAMP (3). The conjugate did not produce neurotoxic side effects (which also were not observed after only 7 days' treatment with free araAMP) or other adverse reactions_ Antibodies binding to the conjugate were not detected in tested patients (nos_ 1, 2, 4 and 7). The plasma levels of L-HSA-conjugated ara-AMP were measured (4) in patients I-4, 6 and 7. Twenty-four hours after conjugate administration, small amounts of coupled ara-AMP (0.1-3.9 /,tg/ml) were still detectable in plasma. This is in contrast to previous determinations in which a different procedure for measuring the conjugated drug was used. The slow removal of coupled araAMP from the bloodstream supports the observation of Marshall