An epidemiological study of precursor lesions of esophageal cancer among young persons in a high-risk population in Huixian, China.

The occurrence of chronic esophagitis, considered a precursor condition for esophageal cancer, among persons 15 to 26 yr of age and risk factors for the disease were investigated in Huixian, Henan Province, a high-risk area for esophageal cancer in the People's Republic of China. The 538 study subjects underwent an esophagoscopy with guided biopsies and cytology, a physical examination, an interview with a questionnaire including known and suspected risk factors for esophageal lesions, and collection of a 10-ml blood sample and overnight urine. One-third of the subjects was selected from households with a case of esophageal cancer in the past 6 yr and two-thirds came from control households. Histologically confirmed very mild, mild, and moderate esophagitis was observed in 31.6%, 10.7%, and 1.1% of 354 male and 30.4%, 4.3%, and 1.1% of 184 female subjects, respectively. In the multivariate case-control analysis of mile and moderate esophagitis compared with very mild esophagitis and normal subjects, the prevalence of mild and moderate disease was found to be positively associated with the consumption of burning hot beverages [odds ratio (OR) = 4.7], the prevalence of esophagitis among siblings (OR = 4.4), and family history of esophageal cancer (OR = 1.8) and negatively associated with the frequent consumption of fresh fruits (OR = 0.3) and wheat flour products (OR = 0.4). Weaker associations were seen for cigarette smoking and the use of cottonseed oil as the main cooking oil. Univariate associations seen with a clinical diagnosis of oral leukoplakia (OR = 2.7) and seborrheic dermatitis (OR = 3.7) are probably due to common risk factors such as smoking and nutritional deficiency. The present findings suggest that exposures early in life to environmental risk factors and nutritional deficiency may be responsible for inflammation and a weakened esophageal epithelium, resulting in a condition possibly more favorable for the development of esophageal cancer.

Taurine and glycine conjugation and sulfation of lithocholate in primary hepatocyte cultures.

Rat primary liver cells were used to study taurine and glycine conjugation and sulfation of lithocholate. After addition of [14C]lithocholate to the tissue culture medium, synthesis and excretion of amidated and/or sulfated products were investigated for up to 24 h. After incubation for 1 h, more than 83% of the labeled bile salt was amidated but not sulfated and between 5 and 11% was sulfated, with more than 80% of the sulfated bile salts being also amidated. After 24 h, the proportion of sulfated lithocholate had increased to about 23% and more than 99% of the lithocholate sulfate was additionally conjugated with glycine or taurine. Both sulfates and non-sulfates were preferably amidated with taurine. We conclude that in primary rat hepatocytes, (1) lithocholate is rapidly and almost completely conjugated with glycine or taurine (amidated), whereas sulfation of lithocholate (and its amidates) proceeds slowly and even after 24 h represents only a small proportion of the total lithocholate metabolites, and (2) sulfated and unsulfated bile salts are both preferably amidated with taurine.

Micronuclei in esophageal cells of Chinese youths in a high-incidence area for esophageal cancer in China.

An epidemiologic survey among 538 young persons between 15 and 26 years of age in a high-risk area for esophageal cancer in the People's Republic of China revealed a high prevalence of esophagitis. Histologically confirmed very mild, mild, and moderate esophagitis was observed in 31.6%, 10.7%, and 1.1% of 354 male and 30.4%, 4.3%, and 1.1% of 184 female subjects. The prevalence of micronuclei in esophageal smears was assayed in a subsample to investigate its possible association with esophagitis and with risk factors for esophageal lesions. Of the 186 subjects, 2.7% had mild or moderate esophagitis, 19.9% had very mild esophagitis, and 77.4% were normal. The frequency distribution of micronucleated cells in the esophageal mucosa was similar for the three diagnostic groups. Mean percentages of micronucleated cells did not differ by diagnosis of esophagitis, household status, current smoking status, presence of oral leukoplakia, or consumption of burning hot beverages or fresh fruit. Higher mean percentages were observed in the older age group of both sexes, but the difference was not statistically significant. The results suggest that if esophagitis is considered an important precursor state in the development of esophageal cancer, the scoring of micronuclei does not appear to be an efficient test for mild forms of esophagitis.

Prevalence of Helicobacter pylori infection and gastritis among young adults in China.

To investigate the prevalence of gastritis and H. pylori infection among young Chinese in Henan Province, a high incidence area for oesophageal cancer in China, the gastric mucosa was examined in 194 asymptomatic subjects, aged 15-26 years, in the course of an epidemiological study of precursor lesions of oesophageal cancer. Histopathological grading of gastritis and determination of H. pylori infection were performed on haematoxylineosin and Warthin-Starry stained section. An enzyme-linked immunosorbent assay was used to detect the presence of serum IgG antibodies to H. pylori. A very high prevalence of gastritis (93.8%) was found: 71 subjects (36.6%) presented with superficial gastritis (14 active), 94 (48.5%) with diffuse gastritis (92 active) and in 17 cases (8.8%) diffuse gastritis (16 active) was accompanied by focal atrophy. Silver staining detected H. pylori in 166 (85.6%) of the study participants. However, serological techniques identified H. pylori in only 109 (56.2%). H. pylori was seen in all the 119 cases showing histological signs of active gastritis, in 41 of the 63 cases (65%) without activity, and also in 50% (6/12) of histologically normal subjects. H. pylori infection was found to be associated with a 2.5-fold higher prevalence of chronic atrophic gastritis compared with non-atrophic gastritis. A family history of stomach cancer, consumption of pickled vegetables more than twice a month, and a high monthly salt consumption (> 500 g/month) also showed a positive association.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of bile acid glucuronides in urine: group separation on a lipophilic anion exchanger.

A chromatographic separation of glucuronidated bile acids using the anion exchanger diethylaminohydroxypropyl Sephadex LH-20 (DEAP LH-20) is described. Group separation of non-sulfated, non-glucuronidated bile acids, bile acid glucuronides, bile acid monosulfates, and bile acid disulfates was obtained. The method allowed analysis of all these bile acid derivatives in the urine of 15 patients with cirrhosis of the liver and cholestasis. The patients excreted in mean 30.4 mumol/24 h non-sulfated, non-glucuronidated bile acids, 90.3 mumol bile acid monosulfates, and 10.2 mumol bile acid glucuronides. Glycine- or taurine-conjugated were 68% of the non-sulfated, non-glucuronidated bile acids, 96% of bile acid sulfates, and 81% of bile acid glucuronides.

Gilbert's syndrome: diagnosis by typical serum bilirubin pattern.

Analysis of serum unconjugated and conjugated bilirubin fractions by routine diazo procedures does not allow a definite diagnosis of Gilbert's syndrome. By the alkaline methanolysis procedure of Blanckaert followed by thin-layer chromatography we were able to discriminate Gilbert's syndrome even in the presence of normal serum bilirubin concentrations from healthy subjects, patients with chronic persistant hepatitis and patients with chronic hemolysis. The relative proportion of unconjugated bilirubin in serum was 95 +/- 2% in patients with Gilbert's syndrome (n = 28), 84 +/- 5% in healthy subjects (n = 29), 75 +/- 6% in patients with chronic persistant hepatitis (n = 7) and 85 +/- 3% in patients with chronic hemolysis (n = 9). The difference between Gilbert's syndrome and the control groups with normal or elevated serum bilirubin was highly significant (p less than 0.001). In Gilbert's syndrome, unconjugated bilirubin ranged between 90 and 99%, in healthy subjects between 72 and 90%, in patients with chronic persistant hepatitis between 68 and 85% and in patients with chronic hemolysis between 81 and 89% of total. An overlap was only seen in one patient with Gilbert's syndrome and in 2 healthy subjects at the 90% level. We conclude that in most patients with Gilbert's syndrome provocation tests are no longer necessary.

Biliary excretion of iron in healthy man and in patients with alcoholic cirrhosis of the liver.

We measured the biliary excretion of iron in 11 patients with alcoholic cirrhosis of the liver and in 10 healthy controls using an intestinal perfusion technique. In the patients with cirrhosis increased amounts of iron in liver tissue were present. The concentrations of iron in the bile samples were determined by atomic absorption spectrometry. The biliary excretion of iron in the healthy controls was 0.32 +/- 0.09 mumol/h and in the patients with cirrhosis it was 0.45 +/- 0.14 mumol/h. The biliary excretion of iron in the patients with cirrhosis was not reduced, indicating that other mechanisms than a reduced biliary excretion of iron must be responsible for the accumulation of iron in liver tissue in alcoholic cirrhosis.

Serum hepatocyte growth factor levels in primary biliary cirrhosis.

BACKGROUND: Recent studies have shown that serum levels of hepatocyte growth factor, a potent mitogen for hepatocytes, are increased in patients with fulminant liver failure and with advanced stages of liver cirrhosis. DESIGN: Retrospective study. METHODS: Serum levels of hepatocyte growth factor (HGF) were determined in 26 patients with advanced stages of liver cirrhosis by means of an enzyme-linked immunosorbent assay. In 23 of these patients, liver biopsies were obtained before treatment with ursodeoxycholic acid and investigated for hepatocyte expression of the proliferating cell nuclear antigen (PCNA) and the Ki-67 antigen by immunocytochemical methods. RESULTS: In 25 of the 26 patients, serum HGF levels did not differ from those of patients with histologically normal livers. Levels did not vary between the different stages of primary biliary cirrhosis but increased moderately when re-evaluated after a period of 24 +/- 4.9 months or 54 +/- 10.7 months. An abnormally increased serum HGF level was observed in only one patient, who had end-stage liver cirrhosis before liver transplantation. Both PCNA and Ki-67 antigen labelling indices were significantly higher at all stages of primary biliary cirrhosis than in normal liver, indicating increased hepatocyte proliferation, but the labelling indices did not correlate with the HGF concentrations in serum. CONCLUSION: Serum HGF levels in almost all patients with primary biliary cirrhosis were within normal limits despite increased hepatocyte proliferation. The results support the hypothesis that HGF serum levels may reflect liver dysfunction rather than active hepatocyte proliferation.

Biliary excretion of mezlocillin in patients with hepatic disease.

In three patients with liver disease (2 patients with alcoholic liver cirrhosis and 1 patient with chronic cholangitis) total, renal, biliary and metabolic clearance of the acylureidopenicillin mezlocillin was examined under steady state conditions. Mezlocillin was infused for 6 hours at a constant infusion rate of 10 mg/min. Renal clearance was calculated based on urinary excretion rates. Duodenal perfusion and marker dilution technique was applied to determine biliary excretion rates of the drug. Clearances were estimated by dividing the excretion rate by the respective plasma concentration. Total clearance was calculated by dividing the infusion rate by the plasma concentration. Biliary clearance was markedly reduced in the patients compared to the data of 8 healthy controls (0.65 +/- 0.33 ml/min vs 98.6 +/- 42.5 ml/min). Total and renal clearance were diminished (total clearance: 121.4 +/- 21.6 ml/min vs 286.5 +/- 54.6 ml/min, renal clearance, 65.4 +/- 1.0 ml/min vs 137.6 +/- 32.6 ml/min). In contrast, metabolic clearance was not changed (53.3 23.1 ml/min vs 50.3 +/ 24.2 ml/min). As mezlocillin is well tolerated and has a wide margin of safety we do not recommend reduced dosage. On the contrary, it might even be necessary to increase the dose when treating biliary tract infections in patients with cholestasis in order to assure effective drug concentrations in the bile.

Biliary excretion of benzbromarone and its hydroxilated main metabolites in humans.

Hepatic metabolism of the uricosuric drug benzbromarone results in the formation of two hydroxilated main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxybenzbromarone). As urinary excretion of benzbromarone and its metabolites is very low, we investigated biliary and plasma concentrations of the parent drug and the metabolites after oral administration of a single 100 mg dose of benzbromarone in 6 patients requiring diagnostic gastroduodenoscopy. Benzbromarone, M1 and M2 were detectable in bile samples 12 hours after drug application. No dehalogenated derivatives (bromobenzarone, benzarone) were present in the bile. 12h, 24h, and 36h plasma concentrations of the parent drug and the main metabolites varied substantially. Our data provide direct evidence of biliary excretion of benzbromarone and its hydroxilated main metabolites 1'-OH-bzbr (M1) and 6-OH-bzbr (M2) and demonstrate the lack of excretion of debrominated products.

Biotransformation and uric acid lowering effect of benzbromarone in patients with liver cirrhosis - evidence for active benzbromarone metabolites?

The disposition of benzbromarone and its uric acid lowering effect were investigated in 8 patients with compensated liver cirrhosis in order to obtain evidence whether dose requirements differ from subjects with normal liver function. Following a single oral dose of 100 mg benzbromarone, the plasma concentrations of the parent drug and the two hydroxylated main metabolites M1 and M2 as well as uric acid were determined up to at least 72 h. All patients were found to be rapid benzbromarone eliminators. In patients 2-8 the extent of systemic availability of benzbromarone, as estimated by the average AUC(0-infinite), was similar to previous observations in healthy individuals, whereas the values of both metabolites M1 and M2 tended to be lower in patients with liver cirrhosis. Cmax of benzbromarone and M1 also were lower in patients, M2 was equivalent to the data in subjects with normal liver function. tmax and the plasma elimination half-life t(1/2) varied within the same range as previously observed in healthy individuals. One patient exhibited much higher values in AUC(0-infinite); and Cmax of benzbromarone and both metabolites, and in addition of the elimination half-life of M1 and M2, whereas the plasma elimination of benzbromarone itself was not delayed. An effect of altered liver function cannot be excluded in this patient. Ten hours after benzbromarone administration the mean plasma uric acid in patients 2-8 was reduced by 31.5% and in patient 1 by 44.2% as compared to pretreatment values. Baseline levels were not regained until 72 h. These data are compatible with a prolonged uric acid lowering effect of an active benzbromarone metabolite. Altogether, the present observations do not suggest dose adjustment to be necessary in patients with compensated liver cirrhosis Child A and B.

Treatment of active and postactive ileal and colonic Crohn's disease with oral pH-modified-release budesonide. German Budesonide Study Group.

BACKGROUND/AIMS: Budesonide is a glucocorticoid with a high topical anti-inflammatory but low systemic activity due to its rapid hepatic inactivation. The aim of this open, multicenter study was to investigate efficacy and safety of oral pH-modified-release budesonide in patients with active Crohn's disease of the ileum and colon and in maintaining budesonide-induced remission in postactive Crohn's disease. MATERIALS AND METHODS: 81 patients (intention-to-treat) received 3 x 3 mg budesonide/day for 6 weeks, followed by 3 x 2 mg budesonide for another 6 weeks in case of response to initial treatment. Clinical and laboratory parameters were assessed at study entry as well as after 2, 4, 6 and 12 weeks of treatment. RESULTS: On an intention-to-treat basis remission was induced in 54.3% of 81 patients with active Crohn's disease, 71.4% of 35 patients stayed in remission after the acute-phase treatment until the end of the trial. Typical steroid-related side effects were observed during the acute-phase treatment in only 18% of the patients. Duration, severity and extent of disease at study entry played no significant role in the outcome of the trial, but there was a tendency towards better results during the acute-phase treatment in patients with moderate disease activity and affection of the terminal ileum and proximal colon. CONCLUSIONS: Budesonide could be an alternative to conventional steroid treatment in patients with active Crohn's disease.

Biliary lipids, lithogenic index and biliary drug concentrations during etofibrate and bezafibrate treatment.

Hypolipidemic drugs like etofibrate and bezafibrate may induce lithogenic bile and increase the risk of gallstone formation. In this study, biliary lipids, lithogenic index and biliary drug concentrations were investigated in 6 hyperlipidemic patients after cholecystectomy. Patients were treated once daily for 5 days with either 500 mg/day etofibrate or 400 mg/day bezafibrate. Hepatic bile was collected for 6 days via T-drainage in 4 hourly aliquots. In the patients treated with etofibrate, the range of the lithogenic index remained stable with 0.89-1.69 before and 0.78-1.51 after 5 day drug therapy. In the bezafibrate group, the range of the lithogenic index rose from 0.81-1.40 to 1.26-1.66 mainly as a result of an increase of biliary cholesterol concentrations. Biliary drug concentrations were substantially higher under bezafibrate treatment than under etofibrate treatment. In conclusion, the fibrate drugs, etofibrate and bezafibrate, are different with regard to lithogenicity of bile and extent of biliary excretion. The safety profile of etofibrate may be preferably compared to other fibrate drugs.

[Traveler's diarrhea in Turkey. Prospective randomized therapeutic comparison of charcoal versus tannin albuminate/ethacridine lactate]. / Reisediarrhö in der Türkei. Prospektiv randomisierter Therapievergleich Kohle versus Tanninalbuminat/Ethacridinlactat.

In most cases traveler's diarrhea is a self-limiting disease not requiring professional assistance. As data on self-treatment are very limited, a prospective randomized trial was performed in 620 German tourists spending a two week-holiday in Turkey. 31.6% of these travelers developed diarrhea and 186 were assigned to two treatment groups, receiving either medical coal or a combination of tannalbuminate and ethacridinlactate (TA/EL). In the TA/EL group stool frequencies significantly earlier returned to normal and complaints of moderate to severe abdominal pain were recorded less frequently (50 vs. 82.2%) than in patients receiving charcoal preparations. Both medications were well tolerated and TA/EL appeared more efficient for self medication of uncomplicated traveler's diarrhea.

[Assessment of the efficacy and safety of the phytopharmacon STW 5 versus metoclopramide in functional dyspepsia--a retrolective cohort study]. / Wirksamkeit und Unbedenklichkeit des Phytopharmakons STW 5 versus Metoclopramid bei funktioneller Dyspepsie unter Praxisbedingungen--eine retrolektive Kohortenstudie.

AIM: The objective of this study was to assess the efficacy and safety of the phytopharmacon STW 5 versus metoclopramide in functional dyspepsia. METHODS: A retrolective, epidemiological cohort study with parallel groups in 23 randomised centres where both drugs were used routinely was performed. The main outcome variable was improvement of 10 dyspepsia-specific symptoms of a valid gastrointestinal symptom score (GIS) during therapy. For inclusion, patients had to suffer from at least three of these symptoms before therapy. Secondary outcome variables were change of single symptoms, time till complete symptom relief, investigators' judgement of efficacy and tolerability, duration of inability to work and occurrence of adverse events. RESULTS: The per protocol collective comprised 490 STW 5 and 471 MCP patients. Anamnestic data were comparable. 439 of patients had taken MCP as drops. There was no relevant difference in median treatment duration. Significantly more patients were symptom-free after STW 5 treatment (71.6 vs. 62.8% p = 0,012). Additionally, the extent of symptom improvement (excluding nausea and vomiting) and median duration of inability to work (1 vs. 3 days) were significantly different in favour of STW 5. More physicians assessed STW 5 as effective (71.6 vs. 63.1% p<0.01) and very well tolerated (90 vs. 70.6% p<0.001). Adverse drug reactions were documented only under MCP. CONCLUSION: The present study illustrates a comparable to higher efficacy of STW 5 vs. MCP with better tolerability in treating functional dyspepsia under practice conditions, especially regarding complete symptom improvement, symptom duration and quality of life. The study confirms the results of prospective trials for STW 5 as being an appropriate alternative to the frequently administered antacids and prokinetics.

Ileal excretion of bile acids: comparison with biliary bile composition and effect of ursodeoxycholic acid treatment.

The amount of bile acid excreted via an ileostomy at the end of the ileum should give an estimate of the amount of bile acid transported to the colon. In the present study, 8 patients with ileostomies at the end of the ileum but without disease or resection of the small intestine excreted 1690 +/- 205 mumol/day (mean +/- SEM) of bile acids from the ileostomies. In comparison with duodenal bile, cholic acid was increased at the end of the ileum and chenodeoxycholic acid decreased; in addition, bile acid sulfates were increased and bile acid glucuronides were decreased. When ursodeoxycholic acid, a bile acid that decreases biliary cholesterol saturation and dissolves gallstones, was administered at a dose of 500 mg to each subject, 59% +/- 8% (mean +/- SEM) of this bile acid was excreted within 24 h from the ileostomies. It is apparent from these studies that absorption of ursodeoxycholic acid from the small intestine is slower than previously anticipated and involves the entire small intestine and probably also the colon.

Passage of a large bilirubin stone through a narrow papillotomy.

Large stones in the bile are generally considered to be a contraindication for endoscopic papillotomy (EPT). In the case described a large biliary stone passed spontaneously into the lumen of the gut after EPT. It is speculated that pure pigment stones are less "rigid" than cholesterol stones and are therefore able to pass through narrower channels than cholesterol stones.

Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids.

The effects of ursodeoxycholic acid and chenodeoxycholic acid on the small-intestinal absorption of endogenous bile acids were studied in patients with ileostomies who served as a model to investigate small-intestinal absorption in humans. In the control period, the eight patients excreted 327 +/- 91 (mean +/- standard error of the mean) mumol/8 h cholic acid and 214 +/- 38 mumol/8 h chenodeoxycholic acid by their ileal fluid. Following ursodeoxycholic acid administration (500 mg), ileal excretion of cholic acid increased to 517 +/- 96 mumol/8 h, and that of chenodeoxycholic acid increased to 337 +/- 42 mumol/8 h, indicating decreased absorption of these bile acids. Following chenodeoxycholic acid administration (500 mg), no significant increase of cholic acid excretion was observed, whereas chenodeoxycholic acid excretion increased as expected. It is concluded that following ursodeoxycholic acid administration the absorption of common bile acids from the small intestine decreases markedly. This effect of ursodeoxycholic acid on intestinal absorption of common bile acids probably is responsible for the decrease of their plasma concentrations, the reduction of their pool sizes, the increase of their fractional turnover rates, and most likely also contributes to the increased hepatic synthesis of cholic acid.

Increased sulfation of lithocholate in patients with cholesterol gallstones during chenodeoxycholate treatment.

Chenodeoxycholate was administered to 13 patients with cholesterol gallstones. During the treatment period the bile composition changed markedly. Chenodeoxycholate increased from 42.9% of the total bile salts before treatment to 79.3% after 8 weeks of treatments. Ursodeoxycholate increased from 2.3 to 12.6% and lithocholate from 1.1 to 3.3%. In contrast, cholate decreased from 40.3% of the total bile salts to 3.1% and deoxycholate decreased from 12.5 to 2.5%. Less than 5% of chenodeoxycholate, ursodeoxycholate, cholate and deoxycholate in bile were sulfate esters. In contrast, considerable amounts of lithocholate were sulfated. The sulfation of lithocholate increased from 32.8% of the total lithocholate before treatment to 73.9% after 8 weeks of treatment. Sulfated lithocholate is more rapidly eliminated in feces and urine than the nonsulfated compound. Furthermore, sulfated lithocholate is less toxic. Therefore, the increase in the sulfation of lithocholate observed in most of our patients represents a protective mechanism.