Expression of major histocompatibility complex antigens and replacement of donor cells by recipient ones in human liver grafts.

The disappearance of certain cell populations of donor origin and their replacement by recipient-specific cells constitutes a possible explanation for the relatively mild course of acute rejection despite lack of MHC compatibility in human orthotopic liver transplantation (OLT). In the present report, graft biopsies of 12 OLT patients from a total of 42 patients were studied for expression of MHC antigens after transplantation using monoclonal antibodies to HLA-ABC and HLA-DR. The patients were selected based upon donor-recipient mismatching for HLA-A2, B7, Drw52, or DQw1. Monoclonal antibodies to these 4 polymorphic HLA antigens and monoclonal antibodies to HLA-ABC and -DR were applied to frozen tissue sections and visualized using an immunoperoxidase technique. Expression of HLA-ABC and -DR on, respectively, hepatocytes and bile duct epithelium were observed in posttransplant graft conditions such as viral infections, cholangitis, and acute rejection. However, no specific pattern of MHC antigen distribution was observed for these various pathological graft conditions. Disappearance of DR-positive Kupffer cells of donor origin and immigration of recipient ones was encountered in the early posttransplant biopsies. This Kupffer cell replacement coincided with a reversible episode of acute rejection. The disappearance of highly immunogenic cellular components as HLA-DR positive Kupffer cells of graft origin may be one of the mechanisms contributing to the mild rejection response observed in human liver transplantation.

Acute rejection in human liver grafts: a comparative histologic study of cases maintained on azathioprine and prednisone versus cyclosporine A and low-dose steroids.

The morphology of acute rejection (AR) in biopsies of liver allografts obtained in the first 2 weeks after transplantation was analyzed. Material from patients maintained on azathioprine and prednisone (AZA; Groningen, The Netherlands) was compared with that of patients receiving cyclosporine A and prednisone (with or without azathioprine) in low doses (CSA; Minneapolis). Strict selection criteria were applied to exclude circulatory and biliary complications and viral infection in this early observation period after transplantation. Follow-up biopsies ranged from 3 weeks to 1 year after transplantation. Time zero biopsies and/or pretransplant biopsies served as baseline histology, Our data revealed an identical morphologic picture during AR early after transplantation in both patient groups, except for a more marked degree of venous endothelialitis and hepatocyte ballooning in the Minnesota material. The follow-up biopsies suggested a spontaneous resolution of these early rejection episodes without antirejection treatment in six of the ten AZA patients. No differences in the long-term survival rate between the CSA- and AZA-treated patients were observed.

Choledochocholedochostomy, a relatively safe procedure in orthotopic liver transplantation.

The biliary anastomosis has been considered the Achilles heel of liver transplantation, and especially the choledochocholedochostomy has been reported to be ill-fated. However, based on previous experimental experiences we decided to use the choledochocholedochostomy as the biliary anastomosis of preference in orthotopic liver transplantation. A choledochocholedochostomy has been performed in 29 of the 31 patients who have undergone transplantation since 1979. Five complications (17%) were diagnosed, of which one proved to be fatal. Two complications were related to the handling of the T-tube and required simple laparotomy to solve the intraperitoneal bile leakage. The other three complications were major: in one patient the choledochocholedochostomy was stenosed, requiring a conversion into a hepaticojejunostomy, while in two patients the donor common bile duct became necrotic. One of these patients underwent successful retransplantation, while the other died of sepsis. In both patients the hepatic artery anastomosis proved to be thrombosed, while in all patients without biliary complications the hepatic artery anastomosis was patent angiographically or at autopsy. The total incidence of sepsis was 26%, but in only four patients (13%) was sepsis related to the choledochocholedochostomy. The relationship between the necrosis of the donor bile duct and the patency of the hepatic artery anastomosis emphasizes an impeccable surgical technique. The low incidence of biliary complications in our 31 patients characterizes the choledochocholedochostomy as a relatively safe biliary procedure in clinical liver transplantation.

Evaluation of gravimetric assays of the H2O concentration in human serum and urine.

The oven-drying method and the combined freeze- and oven-drying method for gravimetrical measurement of human serum and urine H2O concentration, as well as two reported formulas for the calculation of the serum H2O concentration were evaluated. Day-to-day precision in serum and urine (coefficient of variation (CV) less than 0.95%), and recovery in serum (95-99%) were excellent. Storage at 4 degrees C and at -20 degrees C was safe at least for 3 wk and 2 mth, respectively. For the oven-drying method, which was the most practical, reference values after fasting overnight were determined (n = 47; 99% confidence interval; serum, 48.8-51.6 mol/l; urine, 51.2-53.8 mol/l). Patients in different disease categories were tested (n = 38), and had normal values mostly. Low serum values were found in a patient after hemodialysis with ultrafiltration (47.0 mol/l), and in two patients with an extreme hyperproteinemia (48.8 mol/l) and hypercholesterolemia (48.1 mol/l), respectively. Formulas for calculation of the serum H2O concentration proved unreliable. When direct measurement is impossible, a serum value of 50.5 mol/l can be substituted.

Arterial ammonia with Blood Ammonia Checker II and with indophenol reaction to assess presence of hepatic encephalopathy.

Hepatic encephalopathy (HE) is associated with elevated arterial ammonia levels. The relationship is variable, in part due to ammonia methodology. One method, based on the indophenol reaction (IPh), is interfered with a number of amino acids including all aromatic amino acids. We have determined arterial ammonia simultaneously with the Blood Ammonia Checker II (BAC) as reference method and with the IPh method. The difference BAC-IPh, mumol/l, was assumed to express the interference in the indophenol method (IFI) by amino acids. It may be positive or negative. The aim was to establish the value of BAC in comparison with IPh in the diagnosis of liver disease and overt HE and to assess any added value of IFI. Of two reference groups without disturbances, A (n = 39) had not and B (n = 13) had encephalopathy. Group C consisted of 125 liver patients (34 no cirrhosis, 91 cirrhosis) of which 55 had no manifest HE (C:HE-) and 70 had HE (C:HE+). Median BAC ammonia nitrogen (NH3-N), mumol/l: A 21, B 35, C 80, C:HE - 57 and C:HE+ 98 (A < B < C and A < B < C:HE - < C:HE +, P < 0.001). Median IPh NH3-N, mumol/l: A 27, B 30, C 30, C:HE - 25 and C:HE + 35 mumol/l (A = B = C and C:HE - < C:HE+, P < 0.01). IFI medians: A -6, B 3, C 40, C:HE - 29 and C:HE + 58 mumol/l (A < B (P < 0.05) < C (P < 0.0001); A, B < C:HE - and C:HE+; C:HE- < C:HE + (all P < 0.0001)). While BAC correlated weakly with IPh in the (sub)groups C, C:HE-, C:HE+ (r = 0.3, 0.3, 0.4, P < 0.05), it correlated strongly with IFI (r = 0.9, 0.9, 0.8, P < 0.0001). There was no correlation between IPh and IFI. BAC, as well as IFI, could discriminate all liver patients (C) from both reference groups A and B with 100% positive likelihoods. BAC, IPh and IFI could discriminate between HE- and HE+. To differentiate cirrhosis from non-cirrhosis the specificity of IPh was uniformly high and the sensitivity satisfactory, whereas BAC had a high sensitivity but an insufficient specificity. In conclusion, in blood, BAC is the ammonia determination of choice. It differentiates between reference groups (encephalopathic or not) and liver disease and the more so HE. The combination of BAC and IPh (indicating IFI) may eventually be shown useful to rapidly assess the severity of underlying liver disease in HE patients. In other biological fluids, IPh is excellent when the inhibiting influence of non-protein nitrogen substances is absent or can be eliminated.

Determination of ammonia in ear-lobe capillary blood is an alternative to arterial blood ammonia.

Blood ammonia determination is a laboratory test to diagnose hepatic encephalopathy. Arterial blood is superior to peripheral venous blood ammonia because of ammonia metabolism in muscle. We have compared capillary with arterial whole blood ammonia as capillary sampling is an attractive alternative. Ear-lobe capillary blood ammonia (ECA) was determined in all 173 persons studied, fingertip capillary blood ammonia (FCA) in 46 of these and arterial blood ammonia (AA) in 113. Of the 173, 60 were healthy (H), 64 were patients, not liver diseased (NLD) and 49 had liver disease (LD). Reference values, median and ranges, mumol NH3-N/l: AA, NLD, n = 64: 17 (7-42); ECA, H = NLD (P = 0.9), n = 124: 20 (7-45); FCA, H = NLD (P = 0.8), n = 33: 70 (29-151). Within the NLD group (n = 64) AA values (range 7-42) were little but significantly lower than the ECA values (range 7-45, P = 0.002). FCA NLD > AA NLD (n = 14, P < 0.0001); FCA H+NLD > ECA (n = 33, P < 0.0001). AA correlated very well with ECA, r = 0.87 (n = 113, P < 0.0001) and less well with FCA, r = 0.56 (n = 27, P < 0.01). ECA correlated with FCA, r = 0.51 (n = 46, P < 0.001). Ear-lobe capillary blood ammonia thus accurately reflects arterial ammonia and is an attractive alternative. The higher fingertip ammonia may be due to contamination with ammonia-rich sweat from finger grooves, regardless of the precautions taken.

Gravimetric determination of the water concentration in whole blood, plasma and erythrocytes and correlations with hematological and clinicochemical parameters.

We have assessed gravimetric methods for determination of intravascular water, established whole blood-, plasma- and erythrocyte water reference values in a healthy volunteer group (n = 97, 48 females) and correlated these variables with 30 simultaneous hematological, clinicochemical and body parameters. The water standard was 55.56 mol/kg = 100 mass %. For erythrocyte water determination three methods were evaluated: 2 indirect methods were easy to perform, the third, using a hematocrit centrifuge, was the most reliable. Imprecision (within-batch coefficient of variation (CV), %) was excellent: whole blood 0.2, plasma 0.1, erythrocytes 0.7-2.2 and recoveries (means, %) 99.7-100.1. Serum water was found to be slightly higher than plasma water. Volunteer group, mean reference values, mass %: whole blood water 79.7, plasma water 91.2, erythrocyte water, three methods 66.2, 64.6 and 64.2, respectively. Females had mean 1.6 mass % higher whole blood water and 0.9-1.0 mass % higher erythrocyte water than males with no difference in plasma water. In the volunteer group whole blood water correlated strongly with hematocrit (r = -0.96), hemoglobin (r = -0.94) and erythrocytes (r = -0.85) and centrifuge hematocrit (r = -0.91). Plasma water correlated strongly with plasma total protein (r = -0.74, all correlations P < 0.001). Hemoglobin and hematocrit can serve as surrogate parameters for whole blood water when water determination is not available; total protein reflects plasma water.

Comparison of the precision of seven analytical methods for the H2O concentration in human serum and urine.

In order to calculate a true renal H2O clearance (U X V/P), serum and urine H2O concentrations have to be known. In this investigation we compared the precision (repeatability) and the ease of performance of 7 H2O assays in human serum and urine. The 3 gravimetric assays (oven-drying, freeze-drying or freeze-drying as well as oven-drying) had a very high precision (coefficients of variation (CV) 0.2-0.4%) and were easy to perform. The precision of mass spectrometry, gas chromatography and titrimetry (Karl Fischer) was better in urine than in serum (ranges of CV 1.2-1.5% in urine vs. 2.4-4.3% in serum), but the precision of osmometry was better in serum than in urine (CV 1.0 vs. 1.6%). Accuracy was not determined as storage effects at 4 degrees C and at -20 degrees C caused insuperable logistic problems. Only small sample volumes are used in titrimetry and gas chromatography, making them more suitable for determinations in babies and animal studies. With titrimetry determinations can be done in a short time. The gravimetric assays appear to reflect the true H2O content of serum and urine, thus enabling calculation of the true renal H2O clearance, which can be of clinical importance in liver, renal and cardiac disease.

Whole blood and plasma water in health and disease: longitudinal and transverse observations and correlations with several different hematological and clinicochemical parameters.

In a healthy reference population, hemoglobin (Hgb) and hematocrit (Hct) have been proposed as surrogate markers for whole blood water (WBW). We have extended this study under different physiological and pathological conditions in two longitudinal series, viz. (1) acute hyper- and hypohydration experiments in a healthy individual and (2) three athletes running 5 km each, and in three transverse series, viz. (3) a young reference population (n = 97, 49 females), (4) an old reference population (n = 37, nine females) consisting of inhabitants of a nursing home and (5) cardiac, hematological and renal patients including severe anaemia, polycythaemia and abnormal protein levels (n = 50, 25 females) with suspected hydration disturbances. The only sex difference found was a lower WBW in males in the young reference group. The percentage change of PW was less than that of WBW. In all five groups together (n = 293) WBW correlated closely (P < 0.0001) with Hgb and Hct (both r = -0.95) and with erythrocyte count (r = -0.85), whereas PW correlated with total protein (Tprot) (r = -0.84). In the longitudinally studied groups (1) and (2) WBW also correlated (P < 0.0001) with cholesterol, Ca, Tprot, albumin, platelets, globulin and white blood cells (r +/- 0.98-0.37), while PW correlated (P < 0.0001) not only with the same clinicochemical parameters but also with Hct, Hgb and red blood cells (r +/- 0.98-0.44). The homeostasis of PW is more narrowly regulated than that of WBW. Hgb, Hct and erythrocyte count reflect WBW and Tprot reflects PW also under disease conditions. WBW (mass%) can be calculated from Hgb and Hct using the formulae: -0.09 x Hgb (g/l) + 91.7 and -28.6 x Hct (v/v) + 91.8 and PW (mass%) from Tprot using the formula: -0.09 x Tprot (g/l) + 97.6. Other correlations were observed only in a longitudinal setting and presumably are due to concentration and dilution.

Capillary gas chromatographic determination of cholestanol/cholesterol ratio in biological fluids. Its potential usefulness for the follow-up of some liver diseases and its lack of specificity in diagnosing CTX (cerebrotendinous xanthomatosis).

The concentration ratios of cholestanol/cholesterol in biological materials (serum, cerebrospinal fluid and tendon biopsy) were determined using a capillary gas chromatographic method. The method was validated by gas chromatography-mass spectrometry. The ratio was determined in several groups of patients: (a) patients with cerebrotendinous xanthomatosis (in serum, cerebrospinal fluid and tendon biopsy), before and during chenodeoxycholic acid therapy, (b) patients receiving cholestyramine therapy (in serum), (c) patients suffering from various liver diseases (in serum) and (d) one patient before and after liver transplantation (in serum). It can be concluded that the cholestanol/cholesterol concentration ratio is a potentially useful parameter for monitoring liver diseases but is not specific for establishing the diagnosis of cerebrotendinous xanthomatosis.

Determination of blood ammonia using the Ammonia Checker.

A new diffusion method employing bromocresol green for determination of blood ammonia (Ammonia CheckerR) using disposable reagent test-plates and a pocket-size colorimeter with direct read-out of results was compared with an enzymatic method. The values obtained with the Ammonia Checker were slightly lower than those with the enzymatic method. Instead of arterial blood, capillary blood may be used for ammonia determination, but thorough cleansing of the fingertip used is necessary because of the high ammonia content of sweat.

Composition of human hepatic bile.

To define reference values of human hepatic bile for sodium, potassium, chloride, calcium, iron, copper, urea, creatinine, phosphate, glucose, bilirubin, cholesterol, protein, bile salts, phospholipids, ammonia, pH, PCO2, bicarbonate and osmolarity, bile was obtained via a T-drain from 12 adult patients who underwent cholecystectomy. Bile of females had a higher cholesterol concentration than that of males. The saturation index, however, was not different in both groups.

Choledochocholedochostomy is successful in orthotopic liver transplantation.

The viability of the extrahepatic bile ducts of liver grafts depends on their arterial blood supply, and consequently, on the patency of the arterial anastomosis. Thrombosis of the hepatic artery leads almost inevitably to necrosis of the extrahepatic bile ducts of the liver graft. An impeccable technique of arterial anastomosis is essential to avoid biliary complications resulting from ischemia. The low incidence of biliary complications (17%) in our 31 patients indicates that choledocho-choledochostomy is a relatively safe biliary procedure in clinical liver transplantation, especially when compared with other commonly used biliary anastomoses.

Research into quality of life: a qualitative approach in the evaluation of a liver transplant programme.

This article describes and analyses the psycho-social impact of a liver transplant programme. Through in-depth interviews an inventory has been made of experiences of liver patients/their relatives: those who were on the waiting list, those in the green-light phase, patients who were transplanted (with or without success), patients who were turned down. The article is based on qualitative data. This qualitative approach can provide a better understanding of the problems of the liver transplant technology, and in this way it can contribute to the frame of reference of those who draw up the health policy.

Ammonia kinetics in eight patients with liver disease and in dogs.

Pharmacokinetic parameters of ammonia were calculated from a constant-rate infusion of ammonium chloride in 8 patients with chronic liver disease, and in 19 healthy mongrel dogs. In the animal group, the median half-life of the infused ammonia was approximately 4 minutes (range 3.5-5 minutes). The median ammonia clearance was 4.4 l/min (range 3.3-9.2 l/min). The median volume of distribution was approximately 28 liters. In the animal group, the median half-life of the infused ammonia was one minute (range less than 1-4 minutes). The median clearance was 2.2 l/min (range 1.2-4.2 l/min). The median volume of distribution was 3.1 liters. The short half-life and the high clearance of ammonia underscore the importance of the extrahepatic ammonia removal mechanisms.

Primary biliary cirrhosis (PBC) in an European country--a description of death rates in The Netherlands (1979-1992).

BACKGROUND/AIMS: In 1979, separate liver transplantation (LT) and primary biliary cirrhosis (PBC) death rate registration became available in The Netherlands (15 million inhabitants). The objective of this study was to investigate death rates from 1979-1992 and analyse the impact of LT. PATIENTS AND METHODS: PBC was either a primary or secondary cause of death. Rates were expressed as absolute numbers or per million inhabitants in the corresponding age category. Age classes of 5 years were used. The Netherlands was divided in four regions, North, South, East and West. Standardized mortality ratios (SMR) were used for calculation of regional differences. RESULTS: In the 14 year period between 1979-1992, 417 persons died from and 179 persons died with PBC, totaling 596 PBC patients (6.3 per million inhabitants > or = 35 years). No person younger than 35 died. Eighty-two percent were female, with a corresponding female/male ratio of 4.2 per million females/males inhabitants. In region South there were significantly fewer deaths (SMR 66%, p < 0.001) and in region North significantly more (SMR 141%, p < 0.05). The median age class at death was 70-74 (males and females alike). At age 35-59, death from PBC in 1992 per million was 1.2, and for > or = 65 years 15.7. In age class 80-84, the highest death rate from or with PBC was found with 28 deaths per million inhabitants and with a female/male ratio of 3.6. In 1992, with two deaths only, LT appeared to have nearly eliminated death from PBC in the age category 35-59 years. CONCLUSION: Death from PBC mainly occurs in the old and very old, who may never seek a specialized center. This indicates a more specific management and therapy for this particular group is needed.

Primary biliary cirrhosis: an electronic diagnostic tool trial based on symptoms, (past) history and signs only, using the European database euricterus. The Euricterus PMG.

BACKGROUND/AIMS: Primary Biliary Cirrhosis (PBC) is a relatively rare chronic progressive disease in which a working diagnosis of PBC easily leads to a final diagnosis by testing for anti-mitochondrial antibodies. Liver transplantation is the only effective treatment. The aim of this study was to test an electronic diagnostic tool (tool) for it's ability to include PBC in the working differential diagnosis. METHODOLOGY: In the European Union Euricterus project a large number of (sub)icteric patients in 17 discrete disease categories, PBC being one of them, were gathered prospectively. A tool was developed-using Bayes (B) and Trial Algorithm (TA) pattern-recognition and based on items related to the history, symptoms and signs of all Euricterus patients. We have tested the diagnostic tool on 143 PBC Euricterus patients. RESULTS: PBC was mentioned by the tool in 86% (B) and 91% (TA) of the 143 patients. These figures were higher for patients under 60 and (TA only) females. Females under 60 (n = 89) scored 92% B and 96% TA. A sole diagnosis of PBC was made in 31% (B) and 66% (TA). In the other patients with a PBC probability, 7 other (first) diagnoses were presented by the tool of which non-alcoholic active liver disease and pancreatic or biliary carcinoma were the leaders. These 7 diseases appeared evenly distributed along the percentual probabilities of PBC given by the tool (B) and also along Pugh and Mayo scores (B and TA). PBC was mentioned by the tool in all patients with a Pugh score 10 or higher (advanced disease, class C). In the patients in whom the tool did not mention PBC, the primary diagnoses came from 9 other disease categories. CONCLUSION: This electronic tool has been able to identify PBC as one of the differential diagnostic modalities in the large majority of a present population of PBC patients.

Assessment of liver cirrhosis severity in 1015 patients of the Euricterus database with Campbell-Child, Pugh-Child and with ascites and ascites-nutritional state (ANS) related classifications. Euricterus Project Management Group.

BACKGROUND/AIMS: The assessment of disease stage in cirrhosis is important for the individual patient (prognosis, timing and risk for requiring surgical intervention) and also for population comparisons and trials. There are several established methods, and we have aimed at comparison of the methods within a large cirrhosis population. METHODOLOGY: In the European Union Euricterus database, there are 1015 patients with a "certain" diagnosis of cirrhosis, each of whom in one session had a protocol work-up of history, physical examination and all laboratory investigations needed for this study. The Child-Turcotte (CT), Campbell-Child (C) and Pugh-Child (P) classifications, as well as ascites/no ascites, ascites 1, 2, 3 (no, therapy responsive, nonresponsive) and ascites/nutritional state (ANS, 1-9) scores were used. CT and C have the same 5 variables, P has prothrombin time instead of nutritional state. CT, C and P variables score 1-3 each. C and P furthermore have variable range scores of 5-15. CT, C and P have classes A-C. The variables used were ascites, nutritional state, encephalopathy, bilirubin, albumin and prothrombin time. RESULTS: Only 53 patients (5%) fit within the CT criteria. C and P variable range scores (5-15) correlated strongly (r = 0.84). Cross-over calculation showed slightly different results in the P and C choice of variables, while the variable ranges (1-3) did not matter. Different selection of score ranges for the A-C classes in C and P resulted in 69% class C in P (35% in C) and 3% A in P (19% in C). The patients with ascites (70%) had worse bilirubin, albumin, nutritional states and C and P 5-15 scores (p < 0.0001). Patients with ascites 3 had all variables and also C, P 5-15 scores worse than those with ascites 2 (p < 0.02). ANS scoring showed wasting in 33% of the patients without ascites (ANS 3), 50% of the patients with ascites 2 (ANS 6) and 60% with ascites 3 (ANS 9) (p < 0.0003), and C and P scores were higher in the 3 ANS scores with wasting. CONCLUSIONS: Campbell and Pugh 5-15 scores correlated closely and can be used interachangeably. As C does not contain the more elaborate prothrombin time determination, it probably can be used anywhere in the world. Ascites (degree) and Ascites/Nutritional State (ANS) scoring only use history and physical examination and are, or remain, although less refined, clinically relevant.

Clinical presentation of (subclinical) jaundice--the Euricterus project in The Netherlands. United Dutch Hospitals and Euricterus Project Management Group.

BACKGROUND: From a primary clinical database, we wanted to obtain insight in disease distribution and clinical presentation of adult jaundiced patients in a Western country. MATERIALS AND METHODS: As part of the Euricterus project, 24 Dutch general and academic hospitals in a period of 2 years gathered prospectively 702 patients on a standard proforma. Patient aged 16 years or more (median 61) and with a serum bilirubin of 20 mmol/l or more (median 83) were included. The final diagnosis was established within 3 months. RESULTS: Pancreatic or biliary carcinoma (20%), gallstone disease (13%) and alcoholic liver cirrhosis (10%) were the 3 most frequent diagnoses. Imaging (79%), clinical course (63%) and chemistry/serology (57%) were the most used ascertaining methods. Pancreatic or biliary carcinoma and gallstone disease were more common and age higher in general hospitals (p = 0.0001), and 'immunological' liver disease, non-alcoholic cirrhosis and hepatocellular carcinoma (HCC) more common in academic hospitals (p = 0.001). Patients aged 90 years or older (13%) had pancreatic or biliary carcinoma, liver metastases or heart failure and patients with age less than 20 (0.9%) had acute viral hepatitis, nonalcoholic active liver disease or HCC. Risk factors were more apparent (p < 0.02) in those aged less than 61 years. Feeling unwell (78%), dark urine (67%) and anorexia (57%) were the 3 most frequent symptoms; the 3 most frequent signs were liver enlarged (39%), looking ill (29%) and appearing wasted (23%). CONCLUSIONS: Through Euricterus, fresh clinical knowledge has emerged of symptomatology, age stratification and hospital preponderance of (sub)clinical jaundice in this country. This is important both for teaching and in preparing clinical studies.

Anti-HBc titers and anti-HBc immunoglobulin (M/G) classes in acute, chronic and resolved hepatitis B.

IgM-anti-HBc and IgG-anti-HBc serum titers were determined by indirect immunofluorescence in a prospective longitudinal study of 50 patients with hepatitis B, 43 of whom recovered completely. 37 of the recovered patients and all 7 non-recovering patients were followed up for a median of 5 years. Five of the non-recovering patients were followed up from the initial acute stage of the disease. IgM-anti-HBc was present in the acute stage in 39/43 of the recovery patients. The median maximal titer, 1:1000, was reached during the week before peak SGPT. It always disappeared in recovering patients within a median period of 5 weeks after peak SGPT. IgG-anti-HBc was present in all 43 recovering patients in the acute stage of disease with a median maximal titer of 1:1000, maintained for at least 10 weeks. After 5 years, 28 of 37 recovered patients were still IgG-anti-HBc positive with a median titer of 1:200. All non-recovering patients showed persistent IgM as well as IgG-anti-HBc positivity. In the acute stage the medians of the maximal titers were 1:100 for IgM-anti-HBc and 1:1000 for Igg-anti-HBc. After 5 years they were 1:100 for IgM and 1:10000 for IgG-anti-HBc. The presence of IgM-anti-HBc in a preceding study was considered to be a marker of hepatitis B virus replication. From this study no evidence can be obtained to support the view that the titer level of anti-HBc is reliable in the differentiation between infectious anti-HBc positive blood, as there was no difference (p = 0.4) between the number of patients with an anti-HBc level of 1:1000 after at least five years, who had recovered (9/28) and who had not recovered (3/7).