Prevalence of HLA-A and -B antigens, anti-HBc and -HBs antibodies in alcoholic hepatopathies

The frequency of 26 HLA-A and B antigens and of antibodies to the hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs) has been studied in 150 alcoholic patients divided into 3 groups: I) n = 50, isolated hepatic steatosis; II) n = 50, acute alcoholic hepatitis +/- cirrhosis; III) n = 50, cirrhosis without acute alcoholic hepatitis. For the control group 184 blood donors were selected. In all these subjects, as in all the alcoholic patients, the Alsatian origin of four grand parents was proved. An increased frequency of HLA-B15 was observed in group III (34 p. 100) compared to the control group (9.8 p. 100) (corrected p less than 0.001). There was no significant difference between the four groups for all the other HLA antigens. In group III, the prevalence of anti-HBc and/or anti-HBs was higher in patients with HLA-B15 (64.7 p. 100) than in patients without this antigen (15.1 p. 100) (p less than 0.001). In groups I and II, there was no significant difference. These results suggest that there is a genetic predisposition to cirrhosis without acute alcoholic hepatitis, dependent on HLA-B15 antigen. This predisposition could involve the hepatitis B virus.     

Primary biliary cirrhosis: associations with class II major histocompatibility complex antigens

Tissue injury in primary biliary cirrhosis is thought to be mediated by immune mechanisms. Various Class II antigens of the major histocompatibility complex are associated with autoimmune diseases and their differing clinical manifestations. Thus, the aim of this study was to examine the relationship between primary biliary cirrhosis, its clinical manifestations and serologically defined Class II antigens (HLA-DR and HLA-DQ). Typing for these antigens was performed in 114 primary biliary cirrhotic patients and 171 controls by lymphocytotoxicity. There was a 6-fold increase in the frequency of HLA-DRw8 in primary biliary cirrhosis as compared to controls [30.1 vs. 4.7% (p less than 0.0001)]. In contrast, HLA-DR5 had a decreased frequency in primary biliary cirrhosis as compared to controls [9.8 vs. 25.2% (p less than 0.02)]. We examined the relationship between Class II antigens and the following prognostic indicators in primary biliary cirrhosis: serum bilirubin; 24-hr urine copper; serum albumin; prothrombin time; platelet count; ascites, and histologic stage (I to IV). Patients who are positive for HLA-DRw52 (n = 82) had a 2-fold increase in serum bilirubin compared to those who are negative (n = 32) for this antigen (p less than 0.05). Conversely, patients who are positive for HLA-DR2 had less than half the serum bilirubin values of those negative for this antigen (p less than 0.02). In conclusion, we found different Class II antigens to be associated with a prognostic indicator in primary biliary cirrhosis (serum bilirubin), while HLA-DRw8 is strongly associated with the disease itself.(ABSTRACT TRUNCATED AT 250 WORDS)     

Distribution of HLA histocompatibility antigens, ABO blood groups and Rh antigens in alcoholic liver disease.

The distribution of 16 antigens of the HLA-A and 15 antigens of the HLA-B series of HLA system, the blood groups ABO, and Rh antigens were studied in 40 alcoholics with cirrhosis, 18 alcoholics without cirrhosis, and in normal control subjects. The group of alcoholics with cirrhosis showed a significantly high frequency of HLA-B13 (corrected P less than 0.01) when compared with normal subjects, while the frequency of HLA-B13 was similar to normal in alcoholics without cirrhosis. On the basis of these findings, its seems that the carriers of HLA-B13 are more susceptible to liver damage caused by alcohol. Both groups of alcoholics and the normal controls had a similar distribution of ABO blood groups and Rh antigens.     

Apolipoprotein AI and alcoholic liver disease

A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100 controls in order to describe the changes of apolipoprotein AI according to the different stages of the alcoholic liver disease, to correlate the changes to serum liver tests and to estimate its diagnosis and prognostic value. Results showed that apolipoprotein AI concentration is highly related to the degree of liver injury, reaching a maximum in patients with steatosis (229 +/- 90 mg per dl), beginning to decrease in patients with fibrosis (188 +/- 88 mg per dl) and reaching a minimum in patients with severe cirrhosis (91 +/- 46 mg per dl). Apolipoprotein AI had an independent and discriminative value for the diagnosis of fibrosis (p less than 0.001) vs. steatosis and for the diagnosis of cirrhotic vs. noncirrhotic fibrosis (p less than 0.001) or vs. acute alcoholic hepatitis without cirrhosis (p less than 0.001). Cirrhotic patients with apolipoprotein AI less than 100 mg per dl had a lower survival rate at 1 year (62 +/- 7%) than patients with greater value (80 +/- 6%; p less than 0.05), but this prognostic value disappeared in multivariate analysis when other known prognostic factors were taken into account.     

Hepatitis B virus, serological markers of viral infections and humoral immunity in alcoholic cirrhosis

In order to define the role of hepatitis B virus (HBV) in alcoholic liver disease and to study the relationship between HBV and other common viruses, the serological markers of viral disease (HBV, Rubella, Polio, Herpes, and Cytomegalovirus-CMV) were compared in 163 patients with alcoholic cirrhosis (group C), 100 patients with alcoholic steatosis (group S) and in 168 non-alcoholic control subjects (group NA). A significantly increased prevalence of HBV markers in group C was related to the presence of anti-HBc antibodies, in 10.5 p. 100 of cirrhotic patients, vs. 1.2 p. 100 in group S and 1 p. 100 in group NA (p less than 0.01). In cirrhotic patients with HBV markers (HBV +) incidence of alcoholic hepatitis was 4 times lower and the total duration of alcohol overconsumption was significantly lower than in cirrhotic patients without these markers (HBV-). Hepatic function tests were not different in HBV + and HBV- cirrhotic patients, excepted for the ASAT/ALAT ratio (1.55 +/- 0.10 vs. 1.92 +/- 0.12; p less than 0.05). Prevalence of anti-CMV antibodies, and anti-herpes greater than 1/100 antibodies, was significantly increased in S and C groups (p less than 0.01). Anti-Rubella, Polio, and CMV antibody titers were higher (p less than 0.05) in HBV + than in HBV- cirrhotic patients. In cirrhotic subjects, titers of these 3 anti-virus antibodies were not related to alcoholic hepatitis or to IgG and IgM concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased spontaneous and lymphokine-conditioned IgA and IgG synthesis by B cells from alcoholic cirrhotic patients.

Immunoglobulin secretion by B lymphocytes is a complex process in which lymphokines secreted by T lymphocytes play an important regulatory role. Increased serum levels of IgA and IgG have been characteristically detected in patients with alcoholic cirrhosis. We have studied the functional alterations of T and B lymphocytes implicated in the physiopathology of this common immunoglobulin abnormality. After activation with phytohemagglutinin, purified T cells from alcoholic cirrhotic patients showed significantly enhanced secretion of B-cell differentiation factors for IgG and IgA with respect to those secreted by T cells from healthy controls (p less than 0.05). Simultaneously, normal secretion of B-cell differentiation factor for IgM was demonstrated in T lymphocytes from these patients. The pattern of secretion of the lymphokines involved in the regulation of the B-cell differentiation pathway found in alcoholic cirrhotic patients was different from that of the primary biliary cirrhotic patients studied. Purified B cells from patients with alcoholic cirrhosis secreted significantly higher amounts of IgA and IgG than did those found in healthy controls, both spontaneously (p less than 0.05) and after sequential activation with immunoglobulin ligands (Staphylococcus aureus Cowan I) and a standard B-cell differentiation factor preparation (p less than 0.05). By contrast, the IgM secretion and regulatory pathway were normal in alcoholic cirrhotic patients. These results support a physiopathological explanation for the characteristic hyperimmunoglobulinemia found in patients with alcoholic cirrhosis.     

Clinical and prognostic implications of HLA B8 in corticosteroid-treated severe autoimmune chronic active hepatitis

To assess the clinical and prognostic implications of human leukocyte antigen B8 in corticosteroid-treated severe autoimmune chronic active hepatitis, 81 consecutive patients were tested for histocompatibility antigens on the A and B loci, treated with corticosteroids, and followed prospectively for 111 +/- 8 mo. The 47 patients with HLA-B8 were younger (38 +/- 2 yr vs. 48 +/- 2 yr; p less than 0.01), had higher serum levels of aspartate aminotransferase (658 +/- 60 U/L vs. 465 +/- 49 U/L; p = 0.02) and bilirubin (7 +/- 1 mg/dl vs. 2.8 +/- 0.4 mg/dl; p = 0.003), and more commonly had histologic features of bridging necrosis, multilobular necrosis, and cirrhosis (85% vs. 56%; p less than 0.01) at presentation than the 34 patients without HLA-B8. Remission (79% vs. 71%), relapse after drug withdrawal (76% vs. 71%), treatment failure (13% vs. 6%), progression to cirrhosis (46% vs. 32%), and death from liver failure (6% vs. 3%) occurred as frequently in patients with and without HLA-B8. Importantly, HLA-B8-negative patients with HLA-A1 relapsed less frequently than HLA-B8-positive patients with and without HLA-A1- and HLA-B8-negative counterparts without HLA-A1. It is concluded that HLA-B8-positive patients are younger and have more severe disease at presentation than HLA-B8-negative patients. The HLA-B8 phenotype does not influence the response to corticosteroid therapy. HLA-B8-negative patients with HLA-A1 relapse less frequently than other phenotypes.     

Transferrin metabolism in alcoholic liver disease

The metabolism of transferrin was studied using purified 125I-labeled transferrin in 11 alcoholic patients; six with fatty liver and five with cirrhosis. Six healthy subjects whose alcohol intake was les than 40 gm daily were studied as a control group. There were no significant differences in the mean fractional catabolic rate and plasma volume in the alcoholic groups when compared with control subjects. A significantly decreased mean serum transferrin concentration was found in the alcoholic cirrhotic patients (1.8 +/- 0.3 gm per liter vs. 2.9 +/- 0.2; p less than 0.01), resulting from diminished total body synthesis (0.9 +/- 0.2 mg per kg per hr vs. 1.8 +/- 0.2; p less than 0.01). In contrast, in the patients with alcoholic fatty liver, the mean total body transferrin synthesis (2.4 +/- 0.3 mg per kg per hr) was significantly increased when compared with controls (p less than 0.05). For all the alcoholic patients, the serum transferrin correlated with transferrin synthesis (r = + 0.70; p less than 0.01) but the serum iron did not. These results suggest that, in alcoholic cirrhosis, transferrin synthesis is decreased, probably reflecting diminished synthetic capacity by the liver. In contrast, in patients with alcoholic fatty liver, transferrin turnover is accelerated.     

Insulin action in cirrhosis

In vivo insulin sensitivity and adipocyte insulin binding and action were assessed in 16 patients with histologically proven hepatic cirrhosis and 11 age-, weight- and sex-matched normal control subjects. The cirrhotic group displayed impaired oral glucose tolerance, despite an exaggerated serum immunoreactive insulin response, and in vivo insulin resistance as assessed both by the euglycemic hyperinsulinemic clamp and the glucose-insulin infusion techniques. Adipocytes of the cirrhotic patients bound significantly less insulin than those of the control subjects (2.21 +/- 0.12% vs. 2.64 +/- 0.13%; p less than 0.05). Although the adipocytes from the cirrhotic patients were less sensitive to insulin stimulation in vitro (half-maximal stimulation at 60.0 +/- 8.0 vs. 21.8 +/- 3.3 pM; p less than 0.001), they exhibited higher maximum rates of lipogenesis. Comparison of the responses of the alcoholic, primary biliary cirrhosis and cryptogenic subgroups suggested pronounced differences in the maximum rates of lipogenesis. There were significant negative correlations between specific binding to adipocytes and both fasting serum immunoreactive insulin and in vivo insulin resistance as assessed by glucose-insulin infusion. Monocyte insulin binding was normal in the cirrhotic group and did not correlate with in vivo insulin resistance. It is concluded that both binding and postbinding defects in insulin target organ cells contribute to the marked in vivo insulin resistance of hepatic cirrhosis.     

In vitro demonstration of a deficit in suppressor T-cell function in alcoholic cirrhosis. Role of hepatitis B virus infection

The T lymphocyte suppressor cell activity has been evaluated in 33 alcoholic patients compared with 16 normal controls, using an in vitro test. Suppressor T cells were activated with concanavalin A, and suppressor effect was quantified by the inhibition of an autologous B cell culture response to Pokeweed Mitogen. When compared with controls, cirrhotic patients showed a significant defect of suppressor cell activity on B cell production of IgG (20 +/- 3 vs 46 +/- 5 p. 100, p less than 0.001) and IgM (26 +/- 4 vs 56 +/- 8 p. 100, p less than 0.05). In cirrhotic patients, defect of T cell suppressor function was independent of sex and severity of the cirrhosis (Child's staging). This defect was more marked in cirrhotics with serological markers of hepatitis B virus (HBV) infection (n = 11) than in cirrhotics without markers (n = 22) (9 +/- 5 vs 25 +/- 3 p. 100, p less than 0.05; 16 +/- 6 vs 30 +/- 5 p. 100, p less than 0.05 respectively for IgG and IgM production suppression). These results suggest that HBV and lymphocytes interact directly. This interaction could increase the T suppressor cell defect, and explain the promoting role of HBV infection in the constitution of the cirrhosis in alcoholics even when viral replication is not serologically apparent.     

Gonadal dysfunction and changes in sex hormones in postnecrotic cirrhotic men: a matched study with alcoholic cirrhotic men.

To investigate the gonadal dysfunction and changes in sex hormones in male patients with postnecrotic cirrhosis, and to compare them with those in alcoholic cirrhotic men, three age-matched groups of men (hepatitis B virus-related postnecrotic cirrhosis 27, alcoholic cirrhosis 21, normal controls 30) were studied. Twelve of the 21 (57%) alcoholic cirrhotics and 16 of the 27 (59%) postnecrotic cirrhotics had a history of impotence. Both alcoholic and postnecrotic cirrhotic patients had significantly lower basal testosterone, but higher estradiol and prolactin levels than the control group (p less than 0.05). However, no differences were noted between the two cirrhotic groups. The degree of reduced testosterone and increased prolactin levels correlated with the severity of the cirrhosis. Despite the low testosterone concentration, basal levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were not increased in the cirrhotic patients. All the three groups studied had normal FSH and LH responses to the stimulation of exogenous gonadotropin releasing hormone. On the basis of these results, we conclude that: (1) impotence and low testosterone level are not infrequent findings in men with hepatitis B virus-related postnecrotic cirrhosis, especially in those with decompensated liver function. (2) The liver disease per se is important for the development of male sexual dysfunction. (3) The derangement of hypothalamic-pituitary function may play a role in the sexual dysfunction and changes in sex hormones in male patients with cirrhosis.     

Psoriatic arthritis: clinical subgroups and histocompatibility antigens.

Histocompatibility antigens were determined in 60 patients with psoriatic arthritis. The patients were divided into clinical subgroups according to axial or peripheral joint involvement, disease severity based on number of peripheral joints involved, and the presence or absence of bone erosions. The total group showed a significant increase in frequency of HLA-A1, B17, B27, and DR7 when compared with a control population. The subgroup with spondylitis had a significant increase in frequency of HLA-B27 when compared with patients with peripheral arthritis (p less than 0.001). The subgroup with peripheral arthritis alone had a higher frequency of HLA-DR7 than the control group (p less than 0.001). There were also significant associations between HLA-DR7 and chronic severe disease (p less than 0.001) and between HLA-DR4 and the presence of erosions (p less than 0.05).     

HLA associations with rheumatoid arthritis in African blacks

The HLA-A, B, C and DR antigens were determined in a group of 100 blacks with classical or definite rheumatoid arthritis (RA) in Durban, South Africa. Fifty-six of these patients were also tested for the DQ antigens. There was a significant association of HLA-DR4 with RA (chi 2 = 77.2; p less than 0.0001). The frequency of DR4 in RA was 44% in comparison with 10% in controls (relative risk 7.4). An unusual finding was a significant increase in the frequency of HLA-B8 in 35% of patients with RA compared to 12.5% of controls (p less than 0.001; relative risk 3.8). There was no linkage disequilibrium between DR4 and B8 to explain the latter association.     

Histocompatibility antigens in patients with alcoholic liver disease in Scotland and northeastern England: failure to show an association.

A study of HLA-A and B antigens in 248 patients with biopsy diagnosed alcoholic liver disease was conducted to examine for a genetic predisposition to alcohol related liver injury. No statistically significant differences were established for 8 HLA-A and 16 HLA-B antigens between normal healthy controls (n = 342) and patients with alcoholic fatty liver (n = 86), alcoholic hepatitis (n = 63), active alcoholic cirrhosis (n = 64) and inactive alcoholic cirrhosis (n = 35). It is concluded that no HLA-A or B locus genetic susceptibility to alcoholic related injury could be shown.     

HLA-DR3 and HLA-DR5 associated thyrotoxicosis--two different types of toxic diffuse goiter

One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.     

Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease.

In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations, elevated concentrations of oestrone and sex hormone binding globulin (SHBG) and reduced levels of 5 alpha-dihydrotestosterone (DHT), while women with non-alcoholic cirrhosis had significantly elevated concentrations of SHBG and reduced levels of oestrone sulphate, DHT, androstenedione and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded.     

Neuropsychological Aspects of Portal-Systemic Encephalopathy

An extensive psychometric test program was performed in 96 patients with proven liver cirrhosis and clinical signs of portal hypertension as well as in 20 patients with alcoholic pancreatitis, in 19 patients without cirrhosis but with alcoholic cerebral atrophy and in 163 normal controls. The study population comprised six groups of subjects as follows:Group 1. 27 patients with non-alcoholic cirrhosis and normal EEG pattern " 2. 48 patients with alcoholic cirrhosis and normal EEG pattern " 3. 21 patients with cirrhosis and minimal EEG changes " 4. 20 patients with alcoholic pancreatitis " 5. 19 patients without cirrhosis but with alcoholic cerebral atrophy " 6. 163 normal controls.A one way analysis of variances comparing asymptomatic patients (group 1, 2 and 4) with controls (group 6) revealed no significant differences between patients with alcoholic and non-alcoholic cirrhosis, both cirrhotic groups scoring significantly lower than patients with alcoholic pancreatitis and normal controls, who did not differ significantly. Comparing symptomatic patients (group 3 and 5) with normal controls both patient groups scored significantly lower than controls, the cirrhotic group (group 3) scoring significantly lower than patients with alcoholic cerebral atrophy. A two way analysis of variances revealed that in clinically asymptomatic patients cerebral functional defects revealed by psychometry are only due to cirrhosis and that in patients with clinical evidence of cerebral impairment the factors alcohol and cirrhosis are additive - not synergistic. A multiple group stepwise discriminant analysis revealed that tests evaluating psychomotor functions contributed most to the discrimination. Especially line tracing proved to be most sensitive and most specific followed by dexterity, steadiness, aiming, digit symbols in sensitivity and by reaction time, steadiness and dexterity in specificity. A test program for clinical use is proposed.     

Energy metabolism in patients with acute and chronic liver disease

Energy expenditure and substrate oxidation rate for fat, glucose and protein were evaluated by indirect calorimetry in 20 normal individuals, 35 patients with acute hepatitis and 22 patients with biopsy-proven alcoholic cirrhosis in the postabsorptive state. Measurements were done in the resting state after an overnight fast (10 to 12 hr). Oxygen consumption (ml/min/1.73 m2) in normal subjects, in patients with acute hepatitis and in patients with cirrhosis was 206.5 +/- 4.0 (mean +/- S.E.M.), 216.4 +/- 4.7 and 228.8 +/- 7.1 (p less than 0.05 vs. controls), respectively. When related to body surface area (kcal/min/1.73 m2), resting energy expenditure did not differ between normal subjects (0.98 +/- 0.02), patients with acute hepatitis (1.03 +/- 0.02) and cirrhotic patients (1.06 +/- 0.03). However, when related to 24-hr urinary creatinine excretion as an estimate of lean body mass, energy expenditure was increased in cirrhosis (p less than 0.0001). In cirrhosis an inverse association between the severity of liver disease according to Pugh and oxygen consumption and resting energy expenditure was found. In cirrhotic patients the percentages of total calories derived from fat (86% +/- 5%), carbohydrate (2% +/- 4%) and protein (12% +/- 1%) were different from those of normal controls who metabolized 45% +/- 4%, 38% +/- 4%, 17% +/- 1%, respectively. In acute hepatitis no alterations in metabolism could be found apart from a decreased protein oxidation rate. In conclusion no appreciable changes in energy metabolism exist in acute hepatitis. The pattern of fuel use in cirrhosis resembles that in starvation.(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA-DR antigens and disease patterns of rheumatoid arthritis

HLA-DR antigens were determined in 111 patients with classic or definite rheumatoid arthritis. HLA-DR4 was significantly (P corr. less than 10(-6] increased in patients with rheumatoid arthritis (54%) compared with controls (23.2%). HLA-DR 5 was decreased in rheumatoid arthritis (12.6% vs 26.4% of controls); however, the corrected P value was not significant. There were no significant differences with regard to various clinical, radiological and serological parameters between HLA-DR 4 positive and negative patients. However, a milder course of rheumatoid arthritis was observed in DR 7 positive patients: Patients with this antigen were associated significantly with seronegativity and low titers of IgM-rheumatoid factor. Despite a similar disease duration patients with DR 7 had a significantly lower number of joints with inflammatory arthritis (synovitic swelling with limitation of movement) and developed less frequently severe radiological changes as joint ankylosis than DR 7 negative patients. In addition to the well known association between rheumatoid arthritis and HLA-DR 4, our data indicate that HLA-DR 7 may have a protective effect on the course of rheumatoid arthritis.