Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma.

BACKGROUND: Approximately 40-60% of patients with asthma have gastro-oesophageal reflux (GOR) and it has been postulated that this may worsen asthma severity. AIMS: To investigate the effect of the potent gastric acid inhibitor omeprazole 40 mg orally daily on peak expiratory flow rate (PEFR), asthma symptoms and histamine bronchial responsiveness in adult patients with both asthma and GOR. METHODS: This was a double blind, randomised, placebo controlled, crossover study. Upper gastrointestinal endoscopy, 24 hour oesophageal pH measurements, spirometry and histamine bronchoprovocation test (HIT) were performed prior to entry. Phase 1:2 week placebo run-in period, with baseline recording of PEFR, asthma and GOR symptoms, and use of inhaled beta 2-agonist. Phase 2: patients randomised to receive either placebo or omeprazole 40 mg/d for four weeks. Phase 3: placebo for two weeks. Phase 4: patients crossed over to opposite treatment from that of phase 2. Spirometry, and diary cards were assessed at beginning and end of phases 2 and 4. HIT was performed at the end of phase 2 and at the beginning and end of phase 4. RESULTS: Twenty patients (eight female and 12 male) completed the study. The evening but not morning PEFR (% predicted) were significantly higher on omeprazole vs placebo (82 +/- 4% SEM vs 79 +/- 4% SEM; p < 0.05). No significant differences were found in FEV1, FVC, histamine bronchial responsiveness and diurnal variation of PEFR between placebo and omeprazole treatments. Similarly, there were no significant differences during placebo and omeprazole periods in day time wheeze, cough, breathlessness, beta 2-agonist use or night time wheeze and breathlessness. Day and night heartburn symptoms were significantly better on omeprazole vs placebo (p < 0.05). CONCLUSIONS: Omeprazole 40 mg daily improved evening PEFR in asthma patients with GOR. However, asthma symptoms, inhaled beta 2-agonist use and histamine bronchial responsiveness did not change.

High prevalence of duodenal ulcer in Indochinese immigrants attending an Australian university hospital.

Indochinese migrants to Australia appear to have a high prevalence of duodenal ulcer (DU). To examine this hypothesis a 2 year audit of the prevalence of symptomatic DU among patients attending a general hospital was conducted. The last 6 months of this period included a prospective assessment of ulcer risk factors. In Australian-born patients DU prevalence was 8.4 per 1000 admissions. By comparison, prevalence in Indochinese was 24.6 per 1000 admissions (P < 0.001) with an age standardized prevalence of 30.3 per 1000 (P < 0.001). This represented a relative risk in Indochinese of 2.9 using crude data and 3.6 after age standardization. The increased risk was demonstrated only in males: very few DU were diagnosed in female Indochinese. Ulcer prevalence increased in Indochinese for each age decile between 10 and 80 years, with statistical significance (P < 0.01) reached in the age brackets 0-19, 20-39 and 60-79 years. Ulcer prevalence was also increased in some other ethnic groups. However, when referral bias was taken into account (by calculating the ratio of endoscopies to total admissions for each group), a significant increase in DU prevalence could only be confidently demonstrated in Indochinese. Analysis of risk factors showed that among DU patients, Indochinese were significantly less likely to smoke (P < 0.05) and also had a tendency to ingest less non-steroidal anti-inflammatory drugs (NSAID) and to consume less alcohol.

Treatment of reflux oesophagitis with a carbenoxolone/antacid/alginate preparation. A double-blind controlled trial.

Twenty-nine patients were treated with a carbenoxolone/antacid/alginate preparation (Pyrogastrone) and 30 with antacid/alginate alone four times each day for 8 weeks, in a double-blind study, to ascertain the value of carbenoxolone in the treatment of patients with endoscopically confirmed reflux oesophagitis. Symptom review every 2 weeks and endoscopic findings every 4 weeks were converted to a 6-point grading system to facilitate statistical comparison, using a stochastic model for predicting the rate of change in grades during treatment. Carbenoxolone-treated patients showed an 82% improvement in symptom grades over 8 weeks and improved 50% faster (P less than 0.01) than did control patients, who showed a 63% improvement. Endoscopic improvement was not significantly different in the first 4 weeks, although healing was better maintained in carbenoxolone-treated patients during the second 4 weeks (P less than 0.05). At the low doses used (5 X 20 mg daily) no significant side effects of carbenoxolone were encountered. Pyrogastrone should be considered as a therapeutic alternative in patients who fail to respond to routine management with antacids.

High serum levels of alkaline phosphatase are associated with cancer in cholestatic jaundice.

In a prospective study of liver function tests in cholestatic jaundice, the median serum level of alkaline phosphatase (ALP) in 129 patients with cancer involving extrahepatic ducts and liver (556 IU/1) was significantly higher (P less than 0.001) than that in 121 patients without cancer (264 IU/1). Of patients with an ALP level of greater than 10 X N, 88% had cancer whereas serum levels of ALP of less than 3 X N were observed in only 9% of patients with cancer but in 45% of those without cancer, most of whom had bile duct stones. A high serum level of ALP is associated with cancer involving extrahepatic ducts and liver.

Antibodies to liver membrane antigens in chronic active hepatitis (CAH). II. Specificity for autoimmune CAH.

An immunoradiometric assay for IgG class autoantibody to liver membrane antigens, based on serum binding to glutaraldehyde treated monkey hepatocytes, was used to examine sera from patients with chronic active hepatitis (CAH) and other acute and chronic liver diseases. All sera from normals and patients showed binding, up to a titre of 1/2,048. For comparison of assays, results were normalized by selecting two reference sera, one with a high degree of binding, and one from a healthy subject with a low degree of binding: at a dilution of 1/2,048, these sera were given binding values of 100% and 0%. The values for the binding of unknown sera at the same dilution were calculated from these two reference values. For 26 patients with autoimmune CAH, the mean (+/- s.d.) percentage binding value (70 +/- 33%) was significantly higher than the mean value for 26 healthy subjects (10 +/- 15%), and high binding values were significantly associated with biochemically active hepatitis. The mean percentage binding value was moderately increased for eight patients with HBsAg associated CAH (42 +/- 12%), 13 patients with alcoholic hepatitis with cirrhosis (37 +/- 25%) and 45 patients with acute viral hepatitis A (40 +/- 27%) or B (52 +/- 37%). At a cut-off binding value of 65%, the assay as a single diagnostic procedure was shown to have a 70% sensitivity and a 95% specificity for the diagnosis of autoimmune CAH. Better understanding of the pathogenetic significance of antibodies to liver membrane antigens in CAH and other liver diseases will depend upon biochemical analysis of the presumably multiple antigenic determinants on the hepatocyte membrane.

Urinary thromboxane B2 and prostaglandin E2 in the hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors.

Vasodilatory prostaglandins function to maintain renal perfusion in patients with cirrhosis and ascites. To evaluate the potential contribution of the vasodilator prostaglandin E2 and the vasoconstrictor metabolite thromboxane B2 to the development of the hepatorenal syndrome, we measured urinary excretion of these products in 14 patients with hepatorenal syndrome and in control populations with acute or chronic liver or kidney failure. Radioimmunoassay measurements were confirmed by bioassay and by mass spectrometry. Prostaglandin E2 was decreased compared with healthy controls (2.2 +/- 0.3 vs. 6.3 +/- 0.8 ng/h, p less than 0.01) and compared with acute renal failure (9.6 +/- 2.1 ng/h) and with alcoholic hepatitis (9.2 +/- 3.3 ng/h). Thromboxane B2 concentration was normal in patients with alcoholic hepatitis (0.12 +/- 0.02 vs. 0.15 +/- 0.03 ng/ml) and minimally increased in acute renal failure (0.18 +/- 0.15 ng/ml), but markedly elevated in hepatorenal syndrome (0.69 +/- 0.15 ng/ml, p less than 0.001). Urinary thromboxane B2 concentration fell with improved renal function in 3 patients who survived. These data suggest an imbalance of vasodilator and vasoconstrictor metabolites of arachidonic acid in patients with the hepatorenal syndrome.

Hepatocellular carcinoma in a patient with sarcoidosis-associated chronic active hepatitis and the MZ alpha-1-antitrypsin phenotype.

A case of primary hepatocellular carcinoma is described in a patient with long-standing sarcoidosis of the liver associated with chronic active hepatitis, and the MZ alpha-1-antitrypsin phenotype. This association appears to be unique. The respective roles of alpha-1-antitrypsin deficiency, sarcoidosis and chronic active hepatitis in the development of hepatocellular carcinoma in this case are uncertain.

Chronic hepatitis after successive halothane anesthetics.

A woman with cancer of the cervix had over a 4-week period three anesthetics with halogenated anesthetic agents, halothane, enflurane and halothane. 1 day after the third halothane anesthetic she developed fever and jaundice with biochemical evidence of severe hepatitis. Liver biopsy 10 days after the onset of jaundice showed features of acute hepatitis with bridging necrosis and piecemeal necrosis. A second biopsy after 10 months showed quiescent cirrhosis with residual piecemeal necrosis. The case is reported as a further example of halothane hepatitis evolving to cirrhosis of the liver.

Intrahepatic synthesis of immunoglobulin in liver disease.

Patterns of intrahepatic immunoglobulin production were investigated by an in vitro biosynthetic labelling technique which measured the rate of Ig production in liver biopsy fragments. This technique depends on the incorporation of 3H-leucine into proteins synthesized by cells in the biopsy fragment and subsequently released into the culture medium, and precipitation of Ig with monospecific antisera. Intrahepatic Ig production was expressed as counts of radioactivity precipitated/g of liver tissue/24 h. Mean values were high in various inflammatory diseases of the liver, including alcoholic hepatitis (AH) (17 cases), IgG, 87.8, IgA, 105.6 and IgM, 14.7, chronic active hepatitis (CAH) (19 cases), IgG, 86.0, IgA, 56.1 and IgM, 12.6, and acute viral hepatitis (3 cases), IgG, 116.0, IgA, 61.0 and IgM, 32.0, but low in histologically normal livers (6 cases), IgG, 4.5, IgA, 4.8 and IgM, 4.7, alcoholic fatty liver (11 cases), IgG, 9.4, IgA, 11.4 and IgM, 7.1, and miscellaneous non-inflammatory conditions (10 cases), IgG, 8.7, IgA, 11.1 and IgM, 5.0. Photomicrographs were used to measure the density of plasma cells, expressed as cells/mm2 of liver biopsy tissue: mean counts were for AH 5.1, CAH 16.2 and normal liver 0.0. Intrahepatic Ig production in vitro did not correlate with the density of plasma cells in biopsy samples from cases of AH or CAH, nor with serum Ig levels.

Autoantibodies to liver antigens in chronic liver disease. I. A radioimmunoassay for antibody to liver membrane antigens.

A radioimmunoassay using a single cell suspension of glutaraldehyde-treated monkey hepatocytes was developed to measure antibody in human serum to liver membrane antigens. Hepatocytes were exposed to doubling dilutions of test sera in microtitre trays and binding of serum IgG was determined by exposure of the washed cells to 125I-labelled staphylococcal protein A. Specificity of binding was established according to several criteria including use of non-hepatic cells such as monkey kidney cells and various cell lines, IgG depletion of serum, absorption of binding activity by pre-exposure of serum to liver cells, and demonstration that binding was mediated by the F(ab) rather than Fc portions of immunoglobulin molecules. This radioimmunoassay distinguished autoimmune-type chronic active hepatitis (CAH) from other categories of liver disease. It should prove useful for diagnosis and classification of cases of CAH, and could facilitate identification of a liver-specific membrane antigen relevant to pathogenesis of autoimmune hepatitis.

Detection of antibodies to tetanus toxoid: comparison of a direct haemagglutination method with a radioimmunoassay.

Two methods of detecting antibodies to tetanus toxoid were compared, a radioimmunoassay (RIA) employing radiolabelled staphylococcal protein A and a direct haemagglutination (HA) method employing sheep erythrocytes coupled to tetanus toxoid with chromic chloride. These were shown to have a similarly high specificity with the HA method showing slightly higher sensitivity. Haemagglutination offers several additional advantages in terms of simplicity, low cost and less requirement for specialised equipment. The assays were also used to demonstrate a transient IgM response after repeated booster injections with absorbed toxin given to seropositive individuals, and these antibodies were found to be protective in biological tests.

Intrahepatic synthese of immunoglobulin G in chronic liver disease.

A method has been developed to measure the in vitro production of immunoglobulin (Ig) by liver biopsy specimens. Five to 30 mg of liver tissue was cultured for 24 h in Dulbecco's modified Eagle's medium/10% foetal calf serum (FCS) containing radiolabelled leucine (L-[4,5-3H] leucine). The culture medium was collected, centrifuged and the supernatant dialysed to remove labelled leucine. The residual radioactivity was a measure of newly synthesized 3H-labelled proteins released into the medium. The quantity of IgG was determined by immunoprecipitation with monospecific antisera to IgG heavy chains. The presence of IgG in the supernatant was confirmed by chromatography on protein-A Sepharose column. In 6 biopsies without evidence of active inflammation (4 normal and 2 fatty liver by histological criteria) less than 1% of the protein synthesized was IgG. In contrast in the presence of active inflammation in 4 cases of alcoholic hepatitis the IgG percentage ranged from 2 to 6%. Maximal levels of IgG production were detected in 3 cases of chronic active hepatitis (CAH) and ranged from 5 to 30%. The increased Ig synthesis by the liver in alcoholic hepatitis and CAH is presumed to be an index of the intrahepatic host response and may have important implications for mechanisms of liver damage in these diseases.

Diagnosis and management of acute diarrhoea in adults.

Acute diarrhoea is a frequent, worldwide complaint. On any given day, 200 million people suffering from gastroenteritis will pass a volume of diarrhoeal water comparable with the flow of water over the Victoria Falls in one minute. In most attacks, routine microbiological techniques will fail to demonstrate the cause.