Cellular transplantation in the treatment of experimental hepatic failure.

The survival of Lewis rats with D-galactosamine-induced fulminant hepatic failure was prolonged if they were given intraperitoneal injections of single-cell suspensions of liver or bone marrow cells from normal rats. Suspensions of liver cells were also effective in prolonging the survival of rats with ischemia-induced hepatic necrosis. The liver cells did not act by repopulating the recipient liver.

Biochemical and clinical response of fulminant viral hepatitis to administration of prostaglandin E. A preliminary report.

The effect of PG on patients with fulminant and subfulminant viral hepatitis (FHF) was studied. 17 patients presented with FHF secondary to hepatitis A (n = 3), hepatitis B (n = 6), and non-A, non-B (NANB) hepatitis (n = 8). 14 of the 17 patients had stage III or IV hepatic encephalopathy (HE). At presentation the mean aspartate transaminase (AST) was 1,844 +/- 1,246 U/liter, bilirubin 232 +/- 135 mumol/liter, prothrombin time (PT) 34 +/- 18, partial thromboplastin time (PTT) 73 +/- 26 s, and coagulation Factors V and VII 8 +/- 4 and 9 +/- 5%, respectively. Intravenous PGE1 was initiated 24-48 h later after a rise in AST (2,195 +/- 1,810), bilirubin (341 +/- 148), PT (36 +/- 15), and PTT (75 +/- 18). 12 of 17 responded rapidly with a decrease in AST from 1,540 +/- 833 to 188 +/- 324 U/liter. Improvement in hepatic synthetic function was indicated by a decrease in PT from 27 +/- 7 to 12 +/- 1 s and PTT from 61 +/- 10 to 31 +/- 2 s, and an increase in Factor V from 9 +/- 4 to 69 +/- 18% and Factor VII from 11 +/- 5 to 71 +/- 20%. Five responders with NANB hepatitis relapsed upon discontinuation of therapy, with recurrence of HE and increases in AST and PT, and improvement was observed upon retreatment. After 4 wk of intravenous therapy oral PGE2 was substituted. Two patients with NANB hepatitis recovered completely and remained in remission 6 and 12 mo after cessation of therapy. Two additional patients continued in remission after 2 and 6 mo of PGE2. No relapses were seen in the patients with hepatitis A virus and hepatitis B virus infection. Liver biopsies in all 12 surviving patients returned to normal. In the five nonresponders an improvement in hepatic function was indicated by a fall in AST (3,767 +/- 2,611 to 2,142 +/- 2,040 U/liter), PT (52 +/- 25 to 33 +/- 18 s), and PTT (103 +/- 29 to 77 +/- 44 s), but all deteriorated and died of cerebral edema (n = 3) or underwent liver transplantation (n = 2). These results suggest efficacy of PGE for FHF, and further investigation is warranted.

Metabolic effects of reducing rate of glucose ingestion by single bolus versus continuous sipping.

Modifying the rate of absorption has been proposed as a therapeutic principle of specific relevance to diabetes. To demonstrate clearly the metabolic benefits that might result from reducing the rate of nutrient delivery, nine healthy volunteers took 50 g glucose in 700 ml water on two occasions: over 5-10 min (bolus) and at a constant rate over 3.5 h (sipping). Despite similar 4-h blood glucose areas, large reductions were seen in serum insulin (54 +/- 10%, P less than 0.001) and C-peptide (47 +/- 12%, P less than 0.01) areas after sipping, together with lower gastric inhibitory polypeptide and enteroglucagon levels and urinary catecholamine output. There was also prolonged suppression of plasma glucagon, growth hormone, and free-fatty acid (FFA) levels after sipping, whereas these levels rose 3-4 h after the glucose bolus. An intravenous glucose tolerance test at 4 h demonstrated a 48 +/- 10% (P less than 0.01) more rapid decline in blood glucose (Kg) after sipping than after the bolus. Furthermore, FFA and total branched-chain amino acid levels as additional markers of insulin action were lower over this period despite similar absolute levels of insulin and C-peptide. These findings indicate that prolonging the rate of glucose absorption enhances insulin economy and glucose disposal.

Plasma neutral amino acid ratios in normal man and in patients with hepatic encephalopathy: correlations with self-selected protein and energy consumption.

Plasma amino acid concentrations and the ratios of tryptophan and tyrosine to other large neutral amino acids (NAA) were related to prior food consumption by normal healthy adults and by adults with hepatic encephalopathy. Previous habitual (3-day) energy consumption by 32 healthy subjects correlated inversely with the fasting plasma tyr/NAA (r = --0.40, p less than 0.05), while the proportion of energy consumed as protein was inversely related to plasma trp/NAA (r = -0.63, p less than 0.001). Postprandial plasma trp/NAA of 11 normal subjects at 2 and 4 h also reflected (r = --0.62 and --0.69, p less than 0.05, respectively) the proportion of food energy chosen as protein at a single meal. Similarly, samples obtained from five patients with hepatic encephalopathy showed that when high plasma trp/NAA ratios occur these are likely to be due to the low protein intake prescribed. However, for these patients the tyr/NAA or the tyr and met/branched-chain amino acid ratios were above normal ranges caused by diet. The conclusion of this study is that the plasma trp/NAA ratio is associated with the proportion of dietary energy consumed as protein, whereas the plasma tyr/NAA ratio is associated with long-term total energy consumption.

The importance of dietary protein in the zinc deficiency of uremia.

The pathogenesis of zinc deficiency and its relationship to hypogeusia were studied in three chronic dialysis units in Toronto. The difference between low plasma zinc levels at two of the hospitals compared to the normal levels in the third hospital was significantly related to levels of dietary zinc intake which in turn was due to the levels of dietary protein intake. Thus one cause of zinc deficiency in chronic uremia is dietary protein deprivation. In addition, in the hospital with normal plasma levels there was a small but significant rise in plasma zinc postdialysis in contrast to the other two hospitals where there was no change. Thus slight leaching of zinc from dialysis equipment could help prevent zinc deficiency in such patients. Hypogeusia was more common in zinc-deficient patients.

Autoantibodies in alcoholic liver disease.

PURPOSE: To test the hypothesis that since only a proportion of heavy drinkers develop significant alcoholic liver disease (ALD), an autoimmune pathogenesis is likely. PATIENTS AND METHODS: Autoimmune markers were measured in 47 patients with biopsy-proven ALD and compared to measurements in 20 alcoholics without clinical and hematologic evidence of ALD and 28 patients with autoimmune chronic active hepatitis (CAH). RESULTS: Twenty-two percent of patients with ALD were antinuclear antibody-positive, compared to 71% of patients with CAH. Approximately 60% of patients with ALD had either anti-single-stranded or anti-double-stranded DNA antibodies, slightly more than the patients with CAH. Another marker of autoimmunity, as in systemic lupus erythematosus, is the presence of IgM antibodies to autologous and heterologous lymphocytes, which are cytotoxic at 4 degrees C. Seventy-two percent of patients with CAH had positive antilymphocyte antibodies, compared to 59.6% of patients with ALD. Furthermore, more than 90% of the sera from ALD and CAH patients displayed lymphocytotoxicity. Thirty-two percent and 25.5% of CAH and ALD patients, respectively, had all three autoantibodies present. CONCLUSION: These results suggest that autoimmune mechanisms may indeed play a role in the pathogenesis of ALD in at least some patients.

Muscle sympathetic nerve activity and renal responsiveness to atrial natriuretic factor during the development of hepatic ascites.

PURPOSE: Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive antinatriuretic forces such as the sympathetic nervous system and vasodilatory natriuretic agents such as atrial natriuretic factor (ANF). With the development of refractory ascites, cirrhotic patients become unresponsive to the natriuretic effect of ANF. Animal data suggest that the sympathetic nervous system plays a key role in mediating the refractoriness to ANF. We therefore studied the relationship between sympathetic nerve activity (SNA) and the natriuretic response to ANF in normal subjects and cirrhotic patients. We also attempted to localize the intrarenal site of refractoriness to ANF by lithium clearance. PATIENTS AND METHODS: Twenty-six patients with biopsy-proven cirrhosis and seven age- and sex-matched normal volunteers were studied after a week of 20 mmol/day sodium intake and no diuretics. Muscle SNA was recorded from the peroneal nerve (microneurography) and correlated with responsiveness to a 2-hour ANF infusion. Lithium clearance was used as a marker of sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action. Plasma norepinephrine, renin, and aldosterone levels were also determined. Patients were categorized into three groups: nine patients free of ascites (by ultrasonography), five ascitic patients who responded to a 2-hour ANF infusion (i.e., had a natriuretic response to ANF above 0.83 mmol/hour), and 12 ascitic patients who did not respond. RESULTS: Muscle SNA was greatly increased in the ascitic nonresponder patients compared with the normal subjects (64 +/- 4 versus 27 +/- 7 bursts/minute, p less than 0.001), moderately increased in ascitic responders (47 +/- 6 bursts/minute, p less than 0.05), but not significantly increased in nonascitic patients with cirrhosis (34 +/- 5 bursts/minute). SNA was positively correlated with plasma norepinephrine levels (r = 0.69; p less than 0.005) and inversely correlated with peak sodium excretion during the ANF infusion (r = -0.63; p less than 0.001). Plasma renin activity and aldosterone were markedly elevated in ascitic nonresponders, and normal in ascitic responders and nonascitic patients. Lithium clearance was reduced in ascitic patients compared with nonascitic patients, did not change after the ANF infusion, and correlated inversely with SNA (r = -0.61; p less than 0.01). CONCLUSION: These results support the concept that the sympathetic nervous system is a factor in renal sodium handling in cirrhosis, especially in the initiation of sodium retention and the development of refractory ascites. Refractoriness to ANF might be explained, at least in part, by increased neurally mediated sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action.

Liver disease in Felty's syndrome.

Eighteen patients with Felty's syndrome were examined prospectively for the presence of hepatic abnormalities. Twelve patients had abnormal liver histologic features: five with nodular regenerative hyperplasia and seven with portal fibrosis or abnormal lobular architecture. Only seven of the 12 had abnormal liver chemistry results. Four of the 12 had portal hypertension, and three bled from esophageal varices compared with one of six with normal histologic features. When patients with normal and abnormal liver histologic findings were compared, there was no difference in clinical, serologic, or extra-articular manifestations between the two groups, although there was a tendency for the patients with abnormal findings to have a higher incidence of vasculopathy. All patients with Felty's syndrome should be screened for hepatic abnormalities and portal hypertension as they have an increased likelihood of bleeding from esophageal varices.

Role of atrial natriuretic peptide in the natriuretic response to central volume expansion induced by head-out water immersion in sodium-retaining cirrhotic subjects.

PURPOSE: It is possible that abnormalities in atrial natriuretic peptide may be involved in the pathogenesis of sodium retention in edema states. We performed a study in a group of 12 sodium-retaining cirrhotic subjects to determine the role of this peptide in mediating differences in the natriuretic response to central volume expansion induced by head-out water immersion. PATIENTS AND METHODS: Each patient was maintained for seven days on a 20-mmol sodium intake, and then studied on both control and immersion days. On each day, measurements of the following were obtained: plasma atrial natriuretic peptide, hematocrit, electrolytes, creatinine, plasma renin activity, serum aldosterone, urinary cyclic guanosine monophosphate (cGMP), blood pressure, and pulse rate. RESULTS: In six subjects, immersion resulted in a marked natriuresis sufficient to induce negative sodium balance by the third hour, and these subjects were termed "responders." In these six patients, baseline pre-immersion levels of plasma renin activity and serum aldosterone were all below 3 ng/liter/second and 4 nmol/liter, respectively. In the other six subjects, the natriuretic response to immersion was markedly blunted and insufficient to induce negative sodium balance, and these subjects were termed "non-responders." In these subjects, baseline pre-immersion levels of plasma renin activity and aldosterone were all above 3.5 ng/liter/second and 5 nmol/liter, respectively, and were significantly elevated compared with the responders, and compared with the normal range for control subjects consuming the same sodium intake. In both groups of cirrhotic subjects, baseline levels of plasma atrial natriuretic peptide and cGMP excretion were significantly and comparably elevated compared with the normal range for control subjects ingesting the same sodium intake. Despite the marked difference in the natriuretic response to immersion in both responders and non-responders, there was a significant and comparable further elevation of plasma atrial natriuretic peptide and urinary cGMP excretion during immersion, compared with the control day. CONCLUSION: These results suggest that the relative resistance to the natriuretic action of atrial natriuretic peptide in the non-responders compared with the responders is mediated by anti-natriuretic factors acting at a level parallel with or beyond atrial natriuretic peptide release or coupling to its cGMP-linked receptors.

Acute effects of peritoneovenous shunting on plasma atrial natriuretic peptide in cirrhotic patients with massive refractory ascites.

Plasma immunoreactive alpha-human atrial natriuretic peptide (ANP) was measured in six cirrhotic patients with massive refractory ascites, under strict metabolic conditions, while they were receiving a 20-meq sodium diet, both before and at two-hour intervals for eight hours following peritoneovenous shunting (PVS). The mean preoperative level of ANP was 75 +/- 18 pg/ml, which was found to be significantly higher than the normal range for this laboratory (8 to 24 pg/ml) (p less than 0.05). This value was also significantly higher than the value of 21 +/- 5 pg/ml (p less than 0.05) obtained in six patients with cirrhosis but without ascites. Following shunt insertion, an immediate natriuresis and diuresis were observed in five of the six cirrhotic patients with refractory ascites. In these five, right atrial pressure and ANP rose immediately, followed by a rise in the level of urinary cyclic guanosine monophosphate. The sixth subject had a delayed rise in right atrial pressure, and correspondingly the rise in ANP, the diuresis, and natriuresis were delayed. The changes in ANP following PVS were positively correlated with changes in right atrial pressure (p less than 0.05), urinary cyclic guanosine monophosphate (p less than 0.05), urinary sodium excretion (p less than 0.05), and urine volume (p less than 0.01). These results suggest that ANP may be important in mediating the acute response to PVS.

Allogeneic and xenogeneic hepatocyte transplantation in experimental hepatic failure.

Previous studies have demonstrated the efficacy of syngeneic hepatocyte transplantation in the treatment of D-galactosamine-induced acute hepatic failure in Lewis strain rats. This report describes the efficacy and immunological consequences of allogeneic and xenogeneic hepatocyte transplantation in the same model. The i.p. administration of allogeneic (minor and major histoincompatibility) hepatocytes or xenogeneic (rabbit or porcine) hepatocytes at a dose of 4 x 10(7) cells/rat given at 48 hr after toxin all resulted in significant improvement in survival compared to that of controls, and also comparable to the results obtained with syngeneic hepatocyte transplantation. Sensitization to i.p. allogeneic (WF) hepatocyte administration was demonstrated by in vivo 51Cr release, indirect immunofluorescent technique, and accelerated skin allograft rejection. Similarly, the in vivo 51Cr release assay was able to detect sensitization to porcine hepatocytes. Despite evidence of immunogenicity, redosing with either WF or porcine hepatocytes resulted in no overt toxicity. Furthermore, presensitization by either WF hepatocytes or skin allografts did not adversely affect survival after WF hepatocyte treatment in D-galactosamine-induced hepatic failure in Lewis strain rats. These data demonstrate that histocompatibility is not a constraint to successful hepatocyte transplantation and that repeated treatments are potentially safe and efficacious despite sensitization.

Treatment of primary liver graft nonfunction with prostaglandin E1.

Primary nonfunction following orthotopic liver transplantation is characterized by rapidly rising serum transaminases, minimal bile production, and severe coagulopathy, which can progress to hypoglycemia, hepatic encephalopathy, and acute renal failure. Untreated it has a mortality of over 80% and to date the only treatment has been retransplantation. As a result of the beneficial effect of Prostaglandin E1 infusion in patients with fulminant hepatic failure, this trial was conducted to determine whether PGE1 would be of value in primary nonfunction. We have encountered 16 cases of primary nonfunction in 94 liver transplants, an incidence of 17%. Initially in the program, there were 6 occurrences of nonfunction that did not receive PGE1; 3 underwent retransplantation (2 survivors), 2 died awaiting another liver, and in one recovery of hepatocellular function occurred with supportive care but the patient died of cytomegalovirus infection. Ten patients received PGE1 within 4-34 hr of transplantation. Within 12 hr of treatment, 8 patients responded with a significant fall in the AST (129 U/hr) whereas, in the untreated group, the AST continued to rise (267 +/- 102 U/hr) at the same rate as prediagnosis (337 +/- 95 U/hr). At the conclusion of the infusion (4-7 days) in the 8 responders, there were significant decreases in AST (4386 +/- 546 U/L to 102 +/- 21 U/L), prothrombin time (22 +/- 2 to 12 +/- .4 sec) and partial thromboplastin time (45 +/- 3-29 +/- 4 sec), and significant increases in coagulation factor V (26 +/- 8 to 95 +/- 12%) and factor VII (10 +/- 5 to 61 +/- 4%). No serious side effects occurred, although 2 patients developed diarrhea, and abdominal cramps. Two patients treated with PGE1 were retransplanted at 10-36 hr and were considered nonresponders. Graft survival was 80% in the PGE1-treated group and 17% in the untreated group (P less than 0.05) and patient survival was 90% and 33%, respectively. This study suggests a potential benefit of PGE1 in the treatment of primary nonfunction.

Modification of pulmonary metabolism of noradrenaline in experimental obstructive jaundice.

The pulmonary metabolism of noradrenaline (NA) was measured in lungs removed from 3 day sham-operated rats and from rats whose bile ducts had been ligated 3 days earlier (BDL). The pulmonary metabolism of NA as measured by a single clearance of the radio-labelled 14C-amine was significantly increased in lungs excised from BDL rats as compared to that measured in the sham-operated rats. The change in metabolism was associated with an alteration in the pulmonary uptake of NA and not with the activities of the enzymes monoamine oxidase types A and B and catechol-O-methyl transferase. Moreover, it was not correlated with rises in the bilirubin or cholesterol concentrations in the serum of the BDL rats and occurred independent of any changes in pulmonary pressure. In a second series of experiments, the evolution of this abnormality over the period of one to six days postoperative was investigated. In the sham-operated rats, there was no significant change in the pulmonary metabolism of NA even by the sixth day. In contrast, there were time-dependent increases from one to six days in these metabolic processes in BDL rats with the highest values being at six days. In contrast, the serum concentrations of bilirubin and cholesterol and activities of the enzymes, alanine transaminase and alkaline phosphatase all rose to their maximum by the fourth day and thereafter declined. Although serum albumin levels fell significantly in BDL rats they were not significantly different from sham-controls. Thus, change in pulmonary metabolism of NA with obstructive jaundice increases with time from one to six days and it not related to the blood chemical changes of biliary obstruction or hepatic synthetic function.

Review article: the treatment of alcoholic liver disease.

Over the past 20 years we have moved from a situation in which we had no therapy for alcoholic liver disease, through a period when any therapy we had was purely empirical, to an era where we have specific therapies for different aspects of this disease based upon sound pathogenic principles. In this short review, an attempt has been made to summarize these advances in the understanding of the pathogenesis of alcoholic liver disease. In particular, they explain why patients with severe acute alcoholic hepatitis continue to deteriorate in hospital despite withdrawal from alcohol, why they respond to corticosteroids, why only a small percentage of patients develop cirrhosis, and why propylthiouracil may offer protection.

Effect of insulin on the venoconstrictive response to norepinephrine in normal human subjects: the influence of sodium status.

Hyperinsulinemia and insulin resistance have been implicated in the pathogenesis of essential hypertension, with alterations in insulin-induced vasodilatation as one possible mechanism. The aims of this study were to assess the local vasodilatory action of insulin on a dorsal hand vein and the influence of sodium status on the insulin effect in healthy human subjects. Distensibility of a superficial hand vein and response to norepinephrine, insulin, and nitroglycerine were measured by the linear variable differential technique. Fourteen healthy subjects were studied after a low (20 mmol) and high (200 mmol) sodium diet for 7 days. All subjects gained weight (P < .005) and had higher central venous pressure (P = .003) on a high sodium intake. Baseline mean arterial pressure, heart rate, and fasting plasma glucose levels were not significantly different between the two diets. High sodium diet, however, resulted in a higher calculated insulin/glucose ratio (P = .029) implying reduced tissue sensitivity to insulin. Baseline plasma norepinephrine was significantly higher on the low (1.29 +/- 0.13 nmol/L) compared with the high sodium diet (0.79 +/- 0.11 nmol/L) (P < .005). The dorsal hand vein was significantly more dilated at the baseline level on a low sodium (2.60 +/- 0.12 mm) than on a high sodium diet (2.20 +/- 0.12 mm) (P = .034). However, the maximal constriction achieved with norepinephrine was not significantly different between the two diets. Only an insulin dose of 0.8 mU/min on a low sodium diet was able to significantly dilate the norepinephrine preconstricted vein (77 +/- 9% of baseline diameter versus ED50) (P = .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the prekallikrein-bradykininogen system in liver disease.

The plasma prekallikrein-bradykininogen system was studied in 45 patients with chronic liver disease since its activation with increased liberation of kinin into the plasma could account for some of the clinical manifestations of cirrhosis, namely, vasodilatation, hypotension, and increased capillary permeability.A significant reduction in plasma bradykininogen was found in the cirrhotic patients as compared with control groups of normal subjects and hospital inpatients. The mean plasma prekallikrein was not significantly different and only five patients with liver disease had reduced levels. The most likely explanation for the low plasma bradykininogen was impairment of synthesis by the cirrhotic liver, the usually normal prekallikrein levels making the other possibility of increased activation of bradykininogen to bradykinin in the plasma less likely.

Results and hemodynamic changes after interposition mesocaval shunt.

Forty-seven patients have been treated by interposition mesocaval shunting for portal hypertension and variceal bleeding between December 1973 and March 1980. The average age was 55 years. The underlying diseases were alcoholic cirrhosis in 26 patients (56%), macronodular cirrhosis in 11 patients (23%), and other causes in 10 patients (21%). Thirty-five operations (75%) were performed on an emergency basis for patients who continued to bleed after failure of conservative management. In these patients, the early mortality rate was 43%. Overall survival, rebleeding, and postshunt encephalopathy rates are correlated with the preoperative Child's classification. These figures are similar to those reported for end-to-side portocaval shunts. The improvement in postshunt encephalopathy rates as reported by Drapanas is not borne out by our results. Postshunt angiography was performed in 31 patients and shunt patency was confirmed in 28 (90%). In 26 patients, selective studies to determine portal flow patterns were carried out, and in only three patients was there any evidence of hepatopedal flow. In each of these patients, some kinking of the shunt was noted. Mesocaval shunting is a reasonable alternative to end-to-side portocaval shunts and is associated with similar rates of patency, rebleeding, mortality, and late postoperative encephalopathy. A well-constructed, patent mesocaval shunt totally diverts portal flow.

Reversal of toxic and anoxic induced hepatic failure by syngeneic, allogeneic, and xenogeneic hepatocyte transplantation.

This report describes the efficacy of syngeneic hepatocyte transplantation in an anoxic model and of xenogeneic (rabbit and porcine) hepatocyte transplantation in a toxic model of fulminant hepatic failure in the rat. Lewis strain rats that received 4 X 10(7) hepatocytes intraperitoneally at 48 hours after hepatic artery ligation had a significantly improved survival rate (79%, n = 14) when compared with control animals (38%, n = 21, P less than 0.05). Xenogeneic hepatocytes (4 X 10(7) cells/rat) given intraperitoneally to D-galactosamine-poisoned Lewis rats at 48 hours after toxin administration were able to significantly improve survival rate as compared with controls (71% versus 14%, n = 14, P less than 0.01 for rabbit; and 75%, n = 14 versus 12.5%, n = 16, P less than 0.001 for porcine). Although an increase in in vivo cytotoxicity could be demonstrated after procine hepatocyte transplantation, no adverse clinical effects were observed. The methodology for the harvest and storage of large numbers of hepatocytes from a large animal liver has been developed, and it is now feasible to proceed to the clinical application of hepatocyte transplantation for human fulminant hepatic failure.

Accumulation of macrophages in primary sclerosing cholangitis.

OBJECTIVES: To determine what changes are occurring in patients with primary sclerosing cholangitis (PSC) by examining perisinusoidal macrophages (Kupffer cells) in liver biopsies; 2-to measure transforming growth factor beta (TGFbeta) as a marker of fibrosis in these patients. DESIGN AND METHODS: Transmission electron microscopy and immunohistochemistry of 15 PSC, 26 primary biliary cirrhosis (PBC), 30 alcoholic liver disease (ALD) and 51 with normal histology was used. Five PSC, 30 ALD and 120 normal volunteers were sampled for serum levels of TGFbeta. RESULTS: There was a three-fold increase in relative numbers of Kupffer cells in PSC compared to PBC and to patients whose livers had normal histology. In PSC there was an accumulation of perisinusoidal macrophages, which was not associated with focal necrosis or with cholestasis. The levels of TGFbeta in PSC were 54 +/- 2 in cirrhotic versus 34 +/- 5 in non-cirrhotic patients (p < 0.005). CONCLUSION: The persistent activation of these macrophages may lead to the chronic release of TGFbeta and contribute to chronic inflammation, fibrosis and cirrhosis.

Cytokine network in nonresponding chronic hepatitis C patients with genotype 1: role of triple therapy with interferon alpha, ribavirin, and ursodeoxycholate.

OBJECTIVE: (i) to characterize the profile of tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), IL 10, Fas-ligand and transforming growth factor beta (TGF beta), chronic hepatitis C (HCV) patients with genotype 1; (ii) to determine the influence of triple therapy (TT) with interferon alpha (IFN alpha) + ribavirin + ursodeoxycholic acid on these cytokines and (iii) to establish the relationship between the pro-inflammatory cytokines and the outcome of treatment. DESIGN AND METHODS: 22 patients infected with HCV-genotype 1 a/b and non responsive to IFN-alpha monotherapy were enrolled in the TT. The controls were 49 HCV naïve patients with genotype 1 a/b. Cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline TNF alpha values (pg/mL) in the sustained responders (SRs) (63+/-3) were significantly lower than non-responders (NRs) (140+/-16) (p < 0.001). Baseline Fas (ng/mL) levels were also lower in SRs (4.3+/-0.2) than NRs (5.4+/-0.4) (p < 0.05). CONCLUSIONS: Fas and TNF alpha may be used as serological markers of inflammation and effectiveness of therapy.