Unconjugated bilirubin and an increased proportion of bilirubin monoconjugates in the bile of patients with Gilbert's syndrome and Crigler-Najjar disease.

Bilirubin pigments were studied in the bile of 20 normal adults, 25 patients with Gilbert's syndrome, 9 children with Crigler-Najjar disease, and 6 patients with hemolysis, to determine how a deficiency of hepatic bilirubin UDP-glucuronosyltransferase would affect the end products of bilirubin biotransformation. In the bile from patients with Gilbert's syndrome, a striking increase was found in the proportion of bilirubin monoconjugates (48.6+/-9.8% of total conjugates) relative to that in normal bile (27.2+/-7.8%). This increase was even more pronounced in children with Crigler-Najjar disease, in whom, even in the most severe cases, glucuronide could always be demonstrated in the bile. Furthermore, unconjugated bilirubin-IXalpha was unquestionably present in the bile of these children and amounted to 30-57% of their total bilirubin pigments (<1% in the controls). It was not possible to predict from the biliary bilirubin composition whether a child would respond to phenobarbital therapy or not. Bile composition was normal in patients with hemolysis, except when there was associated deficiency of hepatic glucuronosyltransferase. Therefore, the observed alterations were not a simple consequence of unconjugated hyperbilirubinemia. The present findings suggest that Crigler-Najjar disease represents a more pronounced expression than Gilbert's syndrome of a common biochemical defect. Hepatic bilirubin UDP-glucuronosyltransferase deficiency leads to decreased formation of diconjugates with an ensuing increase in the proportion of bilirubin monoconjugates in bile; in the most severe cases, an elevated content of biliary unconjugated bilirubin is also found.

Bilirubin conjugates in bile of man and rat in the normal state and in liver disease.

Conjugates of bilirubin were studied in normal bile of man and rat, and in bile of liver patients. In general human bile was obtained by duodenal intubation. In addition T-tube bile was examined in patients operated on for mechanical obstruction. The bile pigment compositions of duodenal and T-tube bile were similar in two patients where comparison was possible. Obstruction of the bile duct in rats was used as an animal model for obstructive jaundice. Diazotized ethyl anthranilate was used for determination of total conjugated bile pigment and for thin-layer chromatography (t.l.c.) analysis of the derived azopigments. The available t.l.c. procedures are versatile and allow rapid and quantitative analysis. A variety of conjugated azopigments can be distinguished. With chloroform, negligible amounts of unconjugated bilirubin are extracted from bile of man. Therefore, the percentage of monoconjugated bile pigments present in the initial bile sample can be calculated from the percentage of azodipyrrole found after diazotization. Normal bile from man and rat yields similar azopigment patterns. The dominant component is azopigment-delta (azodipyrrole beta-D-monoglucuronoside). Small amounts of azopigments with complex conjugating structures (gamma-azopigments) are present in both cases. Human bile further yields small amounts of azopigments containing xylose or glucose (called azopigments-alpha(2) and -alpha(3), respectively). Monoconjugated bilirubin (estimated from the percentage of azodipyrrole) amounts of 22% of total bile pigments in human bile and to 39% in murine bile. In both, the bulk of bile pigment is bilirubin diglucuronoside. From bile of patients with acquired liver diseases a new azopigment group (beta-azopigment) was derived. The gamma-azopigment group was increased; the delta-azopigment group (containing azodipyrrole beta-D-monoglucuronoside) was decreased. No differentiation was possible between intra- and extrahepatic cholestasis. The percentage of beta-azopigment showed a positive correlation with serum bilirubin concentration (r = 0.6). Recovery of the diseases was accompanied by normalization of the azopigment patterns. In rats, hydrostatic or mechanical obstruction induced increases in beta- and gamma-azopigments and a decrease in delta-azopigment similar to the changes observed in bile of liver patients. Complete normalization was obtained 6 hr after relieving the hydrostatic obstruction (duration 15-21 hr). In contrast, with man after surgery for extrahepatic obstruction, T-tube bile was not normalized when the T-tube was withdrawn (10 days after operation). Hydrostatic obstruction in rats provides an easy model when postobstructive bile pigment composition and parameters have to be investigated. The present investigations stress the importance of the physiopathological state when studying bilirubin conjugation. Hindrance to bile secretion induced heterogeneity of bilirubin conjugates and stimulated the formation of complex structures.

Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat.

Biliary secretion of 3 alpha-sulfated bile acids has been studied in Wistar rats with an autosomal recessive defect in the hepatic transport of bilirubin. Liver function, established by measurement of various enzymes in plasma, by enzyme histochemical methods, and by electron microscopy, appeared to be normal in these rats. Serum levels of unconjugated, monoglucuronidated, and diglucuronidated bilirubin were 0.62, 1.62, and 6.16 mumol/liter, respectively, compared with 0.17, 0.08, and 0.02 mumol/liter in control rats. Biliary bilirubin secretion was strongly reduced in the mutant animals: 0.21 +/- 0.03 vs. 0.39 +/- 0.03 nmol/min per 100 g body wt in control rats. Despite normal biliary bile acid output, bile flow was markedly impaired in the mutant animals, due to a 53% reduction of the bile acid-independent fraction of bile flow. The transport maximum for biliary secretion of dibromosulphthalein (DBSP) was also drastically reduced (-53%). Biliary secretion of intravenously administered trace amounts of the 3 alpha-sulfate esters of 14C-labeled taurocholic acid (-14%), taurochenodeoxycholic acid (-39%), taurolithocholic acid (-73%), and glycolithocholic acid (-91%) was impaired in the jaundiced rats compared with controls, in contrast to the biliary secretion of the unsulfated parent compounds. Hepatic uptake of sulfated glycolithocholic acid was not affected in the jaundiced animals. Preadministration of DBSP (15 mumol/100 g body wt) to normal Wistar rats significantly impaired the biliary secretion of sulfated glycolithocholic acid, but did not affect taurocholic acid secretion. We conclude that separate transport systems in the rat liver exist for biliary secretion of sulfated and unsulfated bile acids; the sulfates probably share secretory pathways with the organic anions bilirubin and DBSP. The described genetic defect in hepatic transport function is associated with a reduced capacity to secrete sulfated bile acids into bile; this becomes more pronounced with a decreasing number of hydroxyl groups on the sulfated bile acid's molecule.

Review article: non-biological liver support in liver failure.

Liver failure, whether acute or acute-on-chronic, remains an important cause of morbidity and mortality. The lack of liver detoxification, metabolic and regulatory functions of the liver leads to life-threatening complications, such as renal failure, altered immune response, hepatic coma and systemic haemodynamic dysfunction, eventually culminating in multiorgan failure. Current medical therapy involves the management of the precipitating event and treatment of complications until the liver eventually recovers, leaving us with no other treatment options than transplantation if these attempts fail. However, the shortage in cadaveric organs and other transplant-related problems, have prompted the need for alternative methods to provide liver support. As liver failure is often potentially reversible, considerable effort has been invested in the development of liver support systems. Currently, most of the experience is available for non-biological support systems. They represent the focus of this review, which aims to define the goals of liver support, to describe the design of the different existing devices and to analyse the available data to determine their current status in the management of patients with liver failure.

Selection criteria and outcome of patients referred to intestinal transplantation: an European center experience.

Until 1998, intestinal transplantation (SBT) had not been performed in our region of Flanders, Belgium. Potential SBT activity was not known and selection criteria had not been validated. A multidisciplinary SBT program was launched in 1998. We analyzed requests for SBT and outcomes in these patients whether with or without SBT. Listing for SBT was only considered for patients with irreversible short bowel syndrome who had developed life-threatening complications of total parenteral nutrition, but whose general condition was still thought compatible with surgery and immunosuppression. During the study period 1998 to 2004, one third of the requests for SBT (10/31) were deemed suitable. SBT in this group was lifesaving (100% survival) when performed in time. Mortality in this group without SBT was high (67%). Two thirds of the patients (21/31) did not fulfill the SBT inclusion criteria, either because they were "too moribund" to tolerate transplantation or because they were "too well". This preliminary study emphasized the importance of (1) early referral of potential SBT candidates, (2) adherence to strict criteria for listing patients for SBT, and (3) referral of intestinal donors to procurement organizations.

Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD.

BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Diagnosis and treatment of autoimmune hepatitis at age 65 and older.

AIM: To study features in older patients with autoimmune hepatitis, as this was considered mainly a disease of young females. METHODS: Analysis of 28 patients diagnosed at age > or =65 years compared with 84 younger patients. RESULTS: The incidence was similar at all age decades. The ratio M:F was 1:3 (> or =65 years) vs. 1:2 (<65 years). Presenting symptoms were not different when compared with younger patients and consisted of general malaise and fatigue (36%), jaundice +/- other symptoms (50%), or ascites (11%). Antinuclear antibodies (ANA) > or = 1/80 were positive in 93%, smooth muscle antibodies (SMA) > 1/40 in 50%, anti-liver kidney microsomes (anti-LKM) proved always negative. Histology showed acute necrotizing hepatitis in 19%, severe interphase hepatitis in 15%, chronic hepatitis with plasmo-lymphocytic infiltrate in 30%, cirrhosis in 29% (with active inflammation in one-third); biopsy was refused in 11%. The elderly responded very well to low doses of methylprednisolone (< or =8 mg) and azathioprine (1 mg/kg). This schedule obviates side-effects such as infections seen with higher dosages. CONCLUSION: Autoimmune hepatitis has to be also looked for in the elderly with acute and chronic hepatitis. The steroid therapy should be individualized but kept at a low dose.

Liver transplantation using cavoportal transposition: an effective treatment in patients with complete splanchnic venous thrombosis.

Complete venous thrombosis of the splanchnic system remains a major challenge in liver transplantation surgery. Some of these patients have been treated successfully by multivisceral transplantation. Cavoportal transposition is another alternative to treat these patients. We reviewed our single-center experience with this technique. Five patients with operatively confirmed complete splanchnic thrombosis were transplanted with the cava portal transposition technique. All survived the procedure; 60% survived long term. This technique is a useful salvage procedure in moribund patients with diffuse portal thrombosis who would otherwise rapidly succumb.

Does ex vivo vascular resistance reflect viability of non-heart-beating donor livers?

AIMS: The use of non-heart-beating (NHB) donor livers is limited by a higher risk for primary nonfunction and the absence of methods to measure this risk. This study was designed to determine whether ex vivo vascular resistance of livers correlates with the length of warm ischemia (WI), and, thus, with viability of NHB livers. METHODS: Porcine livers were recovered after 0, 45, or 90 minutes WI. Livers were flushed by gravity and cold stored for 3 hours. Thereafter, livers were perfused at 4 degrees C. Portal vein (PV) and hepatic artery (HA) vascular resistance were calculated during liver flush-out and during 24 hours of machine perfusion. RESULTS: During flush-out, PV and HA vascular resistance were higher among livers with longer WI times; however, only in the PV did the results reach statistical significance. During machine perfusion, PV vascular resistance was low from the start and remained fairly constant. In contrast, HA vascular resistance was higher at the start but gradually diminished to reach a more constant value after 4-6 hours. No correlation was observed between HA or PV vascular resistance and WI during machine perfusion. CONCLUSIONS: The vascular resistance during ex vivo machine perfusion of NHB livers does not correlate with the extent of WI damage and, therefore, cannot predict organ viability.

Liver fatty acid-binding protein: an early and sensitive plasma marker of hepatocellular damage and a reliable predictor of graft viability after liver transplantation from non-heart-beating donors.

OBJECTIVE: Liver fatty acid-binding protein (L-FABP) is a small protein (15 kD) involved in the intracellular transport of long-chain fatty acids in the liver. The L-FABP is regarded as a sensitive marker for liver cell damage. In a pig model for liver transplantation (LTx) from non-heart-beating donors (NHBD), we evaluated plasma changes of L-FABP early after reperfusion of grafts exposed to increasing periods of warm ischemia (WI). METHODS: Porcine livers were procured after 0, 15, 30, 45, and 60 minutes' WI. After 4 hours' cold ischemia (CI), LTx was performed. Primary graft nonfunction (PNF) and day 4 survival were recorded. Plasma samples were collected prior to and 15, 60, and 180 minutes after graft reperfusion for determination of L-FABP and aspartate transaminase (AST). RESULTS: Early after reperfusion, levels of L-FABP correlated well with the duration of WI. The PNF developed in 100% of animals after 60 minutes of WI, 50% after 30, and 45 minutes' WI, and was absent after no WI and 15 minutes of WI. Day 4 survival was 100% in 0 minutes' WI, 83% in 15 minutes' WI, 50% in 30 and 45 minutes' WI, and 0% in 60 minutes of WI. CONCLUSIONS: Plasma levels of L-FABP correlated well with WI and concomitant hepatocellular damage in LTx from NHBD. Monitoring of posttransplant L-FABP plasma levels is a valuable new tool to quantify early the extent of parenchymal cell damage of NHBD livers and to predict their viability and function.

Liver transplantation using livers from septuagenarian and octogenarian donors: an underused strategy to reduce mortality on the waiting list.

Shortage of liver grafts is the only limiting factor for application of liver transplantation and causes an increasing mortality on the waiting list. Very old donors (>70 to 80 years old) are rarely referred to transplant centers because of the assumption that these livers will not work properly. Alternatively, transplant teams may be reluctant to use these very old livers due to the risk of poor posttransplant outcome. We reviewed our experience with seven liver transplantations using very old donor livers. We found that the results in terms of graft function and patient survival are adequate. Interestingly, the majority of these donors originated from a single referring donor unit (of more than 20 units who belong to our donor network) that systematically refers all brain-dead donors to the transplant center, independent of the age of the potential donor. This implies that many of these donors are left undetected in other units. In conclusion, very old donors should be referred to transplant centers since results of transplantation with these grafts are favorable.

Serum vitamin D metabolites and their binding protein in patients with liver cirrhosis.

Serum parameters of calcium metabolism were measured in 32 consecutive patients with biopsy-proven cirrhosis due to either hepatitis (n = 13), alcohol abuse (n = 11), Wilson's disease (n = 3), or primary or secondary biliary cirrhosis (n = 5). All measurements were normal in the small group of patients with Wilson's disease. The serum concentrations of albumin, vitamin D-binding protein, total calcium, phosphorus, and 1,25-dihydroxyvitamin D3 (1,25-(OH2)D3) were decreased in the other patients with cirrhosis, but their mean serum concentrations of ionized calcium, 25-hydroxyvitamin D3 (25-OHD3) and free 1,25-(OH2)D3 index were normal. A slight but significant increase in the serum PTH measured using a carboxyl-terminal antiserum was found. A significant correlation was found between the serum concentration of either albumin or vitamin D-binding protein and the serum concentrations of total calcium, 25-OHD3, 1,25-(OH2)D3, and PTH but not with ionized calcium or free 1,25-(OH2)D3 index. The observed abnormalities of calcium metabolism in unselected patients with cirrhosis were mainly due to decreased protein synthesis. Only the patients with severe cirrhosis had decreased concentrations of 25-OHD3 but they were nevertheless able to maintain a normal ionized serum calcium and free 1,25-(OH2)D3 level, possibly by means of compensatory hyperparathyroidism.

Blood antioxidant levels in patients with alcoholic liver disease correlate with the degree of liver impairment and are not specific to alcoholic liver injury itself.

BACKGROUND: Enhanced production of reactive oxygen species may play a pathogenic role in alcoholic liver injury. AIMS: To investigate whether various antioxidant parameters in blood are affected in different stages of alcoholic liver disease and how specific the changes are relative to non-alcoholic cirrhosis. METHODS: Patients with alcohol abuse without cirrhosis (n=14), with alcoholic cirrhosis [Child-Pugh scores A (n=9), B (n=5) and C (n=18)] and with non-alcoholic cirrhosis [Child-Pugh score C (n=6)] and healthy controls (n=13) were studied. Levels of reduced glutathione and glutathione peroxidase activity in blood, erythrocytic superoxide dismutase activity and carotenoids, alpha-tocopherol and malondialdehyde in plasma were measured. RESULTS: Levels of reduced glutathione were significantly decreased in Child-Pugh score C cirrhotics, alcoholic or not in origin, whereas oxidized glutathione and glutathione peroxidase activity were not affected. Superoxide dismutase activity and alpha-tocopherol levels were not significantly different in the various groups. Carotenoid levels were significantly lower in alcoholic cirrhotics (Child-Pugh score C) vs. controls. Malondialdehyde levels were elevated only in cirrhotics Child-Pugh score C, alcoholic or non-alcoholic. CONCLUSIONS: Levels of reduced glutathione and malondialdehyde reflect the degree of liver impairment, more than the relation with alcohol intake. Decreases in several antioxidant levels are not specific to alcoholic liver injury.

Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response.

AIM: To evaluate the efficacy of early interferon alpha-2b in non-post-transfusion acute hepatitis C virus: a prospective study with historical comparison. PATIENTS: Group A: 28 patients prospectively treated for acute hepatitis C virus with daily regimen of interferon 5 million units for 2 months. Group B: historical series of 16 patients with untreated acute hepatitis C virus. RESULTS: There was no significant difference between the two groups with regard to gender, age, icterus, alanine aminotransferase, or genotypes. In group B, hepatitis spontaneously resolved in three of 16 (19%) patients (follow-up 1-7 years). In group A, 21 of 25 patients became sustained viral responders (75%; P = 0.0003 vs. group B). Factors include not predictive of sustained viral response: age, gender, sources of infection, presence of icterus, alanine aminotransferase peak, bilirubin peak, incubation period, presence of hepatitis C virus antibodies at presentation, or genotypes. The time from presentation to the start of therapy was, however, significantly shorter in sustained viral responders (43 +/- 31 days) than in relapsers or non-responders (88 +/- 52 days) (P = 0.016). CONCLUSIONS: Early treatment of acute hepatitis C virus with interferon prevents chronicity. A short waiting time from presentation to treatment appears as the most relevant predictive factor for sustained response.

Simultaneous alpha-1-antitrypsin accumulation in liver and pancreas.

Inclusions positive for periodic acid-Schiff, resistant to diastase, and immunoreactive to alpha-1-antitrypsin (AAT) were found in hepatocytes and pancreatic islet cells of a patient with clinical and pathologic features of AAT deficiency. Alpha-1-antitrypsin was detected in all pancreatic islets, and AAT-positive cells were observed in the excretory pancreatic ducts. These findings suggest that the pancreas synthesizes AAT and possibly serves as a "storage" place in AAT deficiency. Intercalated cells in the excretory pancreatic ducts may be an additional source of AAT.

Endoscopic biliary endoprosthesis in elderly patients with large bile duct stones: long-term follow-up.

OBJECTIVE: To assess the long-term evolution of elderly patients with large or impacted bile duct stones, treated by an endoscopic biliary endoprosthesis. DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: Twenty-three patients with a mean (+/- SD) age of 86 +/- 5 years (range, 77-97 years). On admission, 96% were highly symptomatic. These patients represent 8.4% of a group of 273 elderly patients (greater than or equal to 70 years old) with choledocholithiasis treated by endoscopic sphincterotomy between November 1984 and May 1989. INTERVENTION: Endoscopic insertion of a biliary endoprosthesis. RESULTS: Eight-seven percent (20/23) remained completely free of biliary symptoms and died of unrelated illness (48%) after a mean follow-up of 23 months or are still alive (39%) with a mean follow-up of 52 months. In four cases, this asymptomatic evolution now extends for more than 5 years. CONCLUSION: Insertion of a biliary endoprosthesis offers an effective method for long-term treatment of non-extractable biliary stones in elderly patients.

Percutaneous transhepatic cholecystostomy for acute complicated calculous cholecystitis in elderly patients.

OBJECTIVE: To assess the immediate and long-term outcomes of elderly patients with acute complicated cholecystitis treated by percutaneous cholecystostomy. To assess the results of bile cultures obtained in this group of patients. DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: Thirty-two patients, with a mean (+/- S.D.) age of 78 +/- 8 years (range, 58-92 years), and who presented with acute cholecystitis complicated by empyema formation. Sixty-six percent had associated disorders, which rendered them at high risk for surgical intervention. INTERVENTION: Percutaneous transhepatic catheter drainage of the gallbladder, with a mean drainage time of 20 days (range 0-84 days). In addition, endoscopic sphincterotomy with removal of common bile duct stones was performed in six patients and percutaneous aspiration of an associated liver abscess in four cases. RESULTS: Percutaneous cholecystostomy was followed by rapid regression of clinical symptoms and of radiologic abnormalities in all patients. Sixteen cases (50%) underwent elective cholecystectomy 1-12 weeks after cholecystostomy. One of them died of aspiration pneumonia, whereas 15 had no post-operative problems and were discharged 9 days (mean) after surgery. Forty-four percent (14/32) were considered inoperable: they remained completely free of biliary symptoms and died of unrelated illness (22%) after a mean follow-up of 6 months (range, 1-22 months) or are still alive (22%) with a mean follow-up of 15 months (range, 5-36 months). Bile cultures were positive in 75% of the patients. Escherichia coli, other aerobic Gram-negative micro-organisms, and anaerobic bacterial species accounted for 35% (16/46), 28% (13/46), and 20% (9/46) of the isolated bacteria, respectively. All aerobic Gram-negative species tested in vitro were susceptible to gentamicin and to temocillin. CONCLUSIONS: Percutaneous transhepatic cholecystostomy is a safe and effective procedure in the treatment of elderly high-risk patients with acute cholecystitis complicated by empyema formation. It can be followed by elective cholecystectomy, if possible, or by expectant conservative management in patients who are inoperable because of systemic disease.

Percutaneous transhepatic cholangioscopy for diagnosis and therapy of biliary diseases in older patients.

OBJECTIVE: To describe the use of percutaneous cholangioscopy in older patients with complex diagnostic and therapeutic bile duct disorders. DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: Fourteen patients with a mean age of 74 (SD +/- 9) years (range, 60-91 years) underwent percutaneous cholangioscopy. Eleven of these patients presented with endoscopically irretrievable bile duct stones. These 11 patients represent 4.1% of a group of 342 patients (age > or = 60 years) with a mean age of 76 (SD +/- 9) years who were treated endoscopically because of common bile duct stones between January 1993 and January 1996. Three patients presented with obstructive jaundice resulting from a bile duct stricture. In these three patients, brushing cytology of the strictures had proved to be negative. INTERVENTION: After creation and dilatation of a percutaneous transhepatic tract, cholangioscopy was carried out with a flexible cholangioscope. All procedures were performed under mild sedation and analgesia. Stone disintegration was obtained by electrohydraulic lithotripsy, applied through the working channel of the cholangioscope. RESULTS: Complete stone disintegration and removal was obtained after one to three cholangioscopic sessions in all 11 patients with stones. A histological diagnosis of malignancy was obtained in the three patients with biliary strictures. CONCLUSIONS: Percutaneous cholangioscopy is a well tolerated and promising technique in our diagnostic and therapeutic strategy in older patients with complex biliary disorders not responsive to peroral endoscopic diagnosis or treatment.

Hepatitis B surface antigen (HBsAg) in the liver of patients with hepatitis; a comparison with serological detection.

Chronic hepatitis was diagnosed on liver biopsy of 76 patients; 52 (68%)had HBsAg. Of the 52 patients with HBsAg, 23% had HBsAg shown by immunofluorescence on the liver, while it could not be detected with radioimmunoassay on the serum; 77% had HBsAg detectable in liver and in serum, and none had HBsAg in serum only. HBsAg was detected more frequently in chronic aggressive hepatitis and active cirrhosis than in chronic persistent hepatitis and cirrhosis with little activity. No correlation was found in the different forms of chronic hepatitis between the HBsAg status on the one hand, and levels of transaminases, gammaglobulins, and auto-antibodies on the other. Acute hepatitis was diagnosed on liver biopsy of 24 patients; 50% had HBsAg. Liver tissue positivity was very low in the fully developed stage compared to serum positivity. In 146 patients with other liver ailments, both liver and serum were negative for HBsAg.

Distribution patterns of hepatitis B surface antigen (HBsAg) in the liver of hepatitis patients.

One hundred liver biopsies from 100 hepatitis patients were examined by the indirect immunofluorescent technique for the detection of HBsAg. Of the 60 positive specimens 52 were diagnosed as various types of chronic hepatitis and 8 were acute hepatitis. Four main distribution patterns of HBsAg were obtained: full cytoplasmic fluorescence with diffuse lobular distribution; cytoplasmic fluorescence with spotty distribution; peripheral fluorescence in the cell membrane and/or cell peripheries; and focal cytoplasmic positivity. There was an inverse relationship between the number of positive hepatocytes and the extent of liver cell necrosis. The distribution patterns of HBsAg were distinctive in each type of chronic hepatitis and in acute hepatitis. Homogeneous full cytoplasmic fluorescence, distributed diffusely in the whole liver lobule, was observed in chronic persistent hepatitis and in cirrhosis with little activity whereas peripheral liver cell membrane and/or peripheral cytoplasmic fluorescence associated with cytoplasmic positivity in a smaller number of hepatocytes was a characteristic finding in chronic aggressive hepatitis, active cirrhosis, and acute hepatitis with possible transition to chronicity. Focal cytoplasmic fluorescence was observed in acute hepatitis and a group of biopsies in chronic hepatitis in which HBsAg was detected in the liver but no antigen was detectable in the serum. The results show that the different patterns of distribution of HBsAg in the liver biopsy are helpful for the histological diagnosis of different types of HBAg positive viral hepatitis and are consistent with the hypothesis of the role of specific immune response in the pathogenesis of type B viral hepatitis.