Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.

BACKGROUND: Chronic hepatitis B infection (CHB) is a major health problem in Australia and worldwide. CHB is associated with significant long-term morbidity and mortality. Well tolerated treatment is now available, however the development of resistance is common and the optimal timing of treatment is yet to be determined. Identifying the factors that influence the natural history of CHB may help determine which patients need treatment and when to start it. OBJECTIVE: To determine the demographics, clinical features and virological profile of Australian patients infected with CHB and the influence of these factors on disease activity and severity. STUDY DESIGN: Review of prospectively collected demographic, clinical and virological features of all patients positive for hepatitis B surface antigen (HBsAg) for more than 6 months who were referred to St. Vincent's Hospital liver clinics. Age, sex and ethnicity were correlated with hepatitis B e antigen status (HBeAg), HBV replication status (ALT and HBV DNA), genotype and liver histology. RESULTS: 703 chronic hepatitis B surface antigen positive patients were identified. The patients were predominantly male with an average age of 44. Eighty two percent of patients were born overseas, primarily from Asian (65%) and Mediterranean countries (14%). Two thirds (426) had an elevated ALT (median 79) at presentation. HBeAg was positive in 37%. Active viral replication, defined as abnormal ALT or positive HBVDNA, was present in 74%, 48% of whom were HBeAg negative. In a subset of 103 patients genotyped, 8% had genotype A, 29% B, 41% C and 22% D. Genotype correlated with ethnicity; patients infected with genotypes A were predominantly Caucasian, B and C were Asian, and D were Mediterranean. Of 296 (42%) patients who underwent liver biopsy, 76 (27%) had advanced fibrosis. Advanced fibrosis was associated with increasing age and Mediterranean ethnicity. CONCLUSION AND RECOMMENDATIONS: Perinatal or early childhood transmission is predominant mode of infection in Australia. Two thirds of this cohort had active replication and were at increased risk of developing cirrhosis and/or hepatoma. Advanced disease was associated with age and ethnicity. HBeAg negative CHB accounts for almost half of all those with active viral replication. This parallels the rise in this form of CHB in Asia and the Mediterranean basin. Screening should be offered to people born in, or with parents born in areas of high endemnicity. To detect the development of active disease, patients with positive HBsAg but normal ALT should have liver function tests done 6 monthly and those with elevated ALT should be referred for consideration of therapy, irrespective of HBeAg status.

Purification and characterization of a novel restricted antigen expressed by normal and transformed human colonic epithelium.

A cell surface antigen that is expressed by normal and 95% of transformed colonic epithelium and is recognized by the monoclonal antibody A33 (Welt, S., Divgi, C. R., Real, F. X., Yeh, S. D., Garin-Chesa, P., Finstad, C. L., Sakamoto, J., Cohen, A., Sigurdson, E. R., Kemeny, N., Carswell, E. A., Oettgen, H. F., and Old, L. J. (1990) J. Clin. Oncol. 8, 1894-1906) has been purified to homogeneity from the human colonic carcinoma cell line LIM1215. The A33 protein was purified from Triton X-114 extracts of LIM1215 cells under nondenaturing conditions. These extracts were applied sequentially to Green-Sepharose HE-4BD, Mono-Q HR 10/10, Superose 12 HR 10/30, and micropreparative Brownlee Aquapore RP 300. The purification was monitored by biosensor analysis using surface plasmon resonance detection with a F(ab')2 fragment of the humanized A33 monoclonal antibody immobilized on the sensor surface and Western blot analysis following SDS-polyacrylamide gel electrophoresis (PAGE) under nonreducing conditions using humanized A33 monoclonal antibody. The purified A33 antigen has a Mr on SDS-PAGE of 43,000 under nonreducing conditions. By contrast, the purified protein displayed a Mr of approximately 180,000 under native conditions on both size exclusion chromatography and native PAGE, possibly due to the formation of a homotetramer. N-terminal amino acid sequence analysis of the purified protein identified 34 amino acid residues of a unique sequence: ISVETPQDVLRASQGKSVTLPXTYHTSXXXREGLIQWD. A polyclonal antibody was raised against a synthetic peptide corresponding to residues 2-20 of this sequence. The antipeptide serum recognized the purified protein using Western blot analysis under both nonreducing (Mr 43,000) and reducing (Mr 49,000) conditions.

Dissociation between dyspnea and respiratory effort.

Breathlessness induced by hypercapnia may be related to the sensation of respiratory effort or to the central or peripheral effects of CO2. To examine the relationship among breathlessness, respiratory effort, and hypercapnia, we studied eight normal naive subjects. By using a visual feedback system, subjects maintained a constant ventilation of 50-60 L/min. PETCO2 was held at 40 mm Hg during the first 2 min of each trial (control period), then for 4 min (test period) was either kept at 40 mm Hg or elevated to 50 mm Hg. At the end of each control and test period, subjects were asked to give separate ratings for dyspnea (an unpleasant urge to breathe) and for the sense of respiratory effort (analogous to lifting a weight) on a 50-cm visual analog scale. Hypercapnia was associated with a significant reduction in effort ratings (-7.3 +/- 6.4, mean +/- SD, p < 0.05) and a concomitant increase in dyspnea (+6.6 +/- 6.0, p < 0.05). We conclude that dyspnea associated with hypercapnia is dissociated from changes in respiratory effort, and that CO2 has a direct central effect that leads to breathlessness. Our data also suggest that the sense of effort at a given level of ventilation is less when the ventilation is the result of "reflex" stimuli to breathe rather than "voluntary" signals to the respiratory muscles.

The genetics, epidemiology, and early detection of gastrointestinal cancers.

Current recommendations for screening large populations for colorectal neoplasia have been promulgated by a number of researchers and authorities who generally agree that ongoing screening is justifiable in high-risk groups but not yet in average-risk groups. Nonetheless, it is thought to be justifiable to provide screening for average-risk individuals upon request. Choice of tools for screening remains under discussion. Colonoscopy is generally agreed to be justifiable in those patients with the highest risk, ie, members of families with a clear inherited tendency to develop colorectal cancer or those with a personal history of colorectal neoplasia. There is currently no agreement concerning the recommended tools for those with a weaker family history (one or two affected relatives), but regular fecal occult blood testing with occasional limited endoscopic examination of the bowel is usually favored. The new immunochemical-based occult blood tests show great promise for improved sensitivity and specificity. The evidence of the association between Helicobacter pylori gastritis and gastric cancer has been strengthened by three studies that show that patients with gastric cancer are more likely to have had infection in the years (up to 20) prior to diagnosis. The relative risk for cancer when infected with H. pylori is 3.6 to 6, but many H. pylori-positive individuals do not develop gastric cancer and additional factors must be operative. Probably the most exciting development for gastroenterology in 1991 is the identification of the gene on chromosome 5, designated APC, which is responsible for familial adenomatous polyposis.(ABSTRACT TRUNCATED AT 250 WORDS)

A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter.

Epidermal growth factor (EGF) and transforming growth factor alpha are important determinants of mucosal integrity in the gastrointestinal tract, and they act both directly and indirectly to prevent ulceration in the stomach. Consistent with this physiological role, EGF stimulates transcription of gastrin, a peptide hormone which regulates gastric acid secretion and mucosal growth. EGF stimulation of gastrin transcription is mediated by a GC-rich gastrin EGF response element (gERE) (GGGGCGGGGTGGGGGG) which lies between -54 and -68 in the human gastrin promoter. The gERE sequence also confers weaker responsiveness to phorbol ester stimulation. The gERE sequence differs from previously described EGF response elements. The gERE DNA sequence specifically interacts with a GH4 DNA-binding protein distinct from previously described transcription factors (Egr-1 and AP2) which bind GC-rich sequences and mediate transcriptional activation by growth factors. Furthermore, the gERE element does not bind the Sp1 transcription factor even though the gERE sequence contains a high-affinity Sp1-binding site (GGCGGG).