Colorectal adenomas and diet: a case-control study. Colorectal Adenoma Study Group.

It has been postulated that high intakes of animal fat and protein and low intakes of fiber, calcium, and antioxidants increase the risk of colorectal cancer. Whether specific types of protein such as that from red meat are important, and whether vegetables might be key protective factors will also be considered in this study. Dietary intake over the past year was studied according to the diet history method by means of a case-control study in 184 cases and matched controls. After adjustment for energy, relative weight, and social class, no associations were found for fat or protein in comparison with either control group. Unexpectedly, carbohydrate intake was inversely related with adenoma risk, the RR being 0.29 (0.10-0.81) for quintile 5 versus 1 in comparison with hospital controls. None of the antioxidants showed a significant protective effect except beta-carotene intake in comparison with hospital controls, the RR being 0.24 (0.11-0.50) for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile of intake being 3.6 (1.7-7.5) in comparison with hospital controls and 4.4 (1.6-12.1) in comparison with population controls. Our data support the protective role for carbohydrate intake and of beta-carotene intake in the etiology of colorectal adenomas and show a strong increased risk for developing adenomas in those with high meat intake.

Relation of serum antioxidant vitamins to the risk of colorectal adenoma.

The relation between risk of colorectal adenoma and serum concentrations of vitamins A, C, E and carotene was examined in a population-based case-control study of 105 cases of colorectal adenoma and a similar number of hospital controls showing no polyps at colonoscopy and a second control group of population controls. There were no significant associations with serum concentrations of vitamins C and E and carotene. Serum concentrations of vitamin A were significantly inversely related to the risk of colorectal adenoma when cases were compared with both control groups. After adjustment for energy intake, smoking, alcohol, estrogen therapy, body-mass-index and social class the inverse association between vitamin A and colorectal adenoma was even more marked. For the highest versus the lowest quartile of serum levels the adjusted RR was 0.23 (0.07-0.73) in relation to hospital controls and 0.08 (0.02-0.25) in relation to population controls. These findings suggest that the risk of developing colorectal adenomas is reduced in those with high vitamin A levels.

Alcohol and cigarette smoking and the risk of colorectal adenomas.

Whether alcohol and tobacco can be considered as risk factors for the occurrence of adenomas remains inconclusive. A case-control study was carried out to examine these factors while taking into account possible confounding factors. One hundred eighty-two patients with colorectal adenomas and similar numbers of hospital and population controls were compared as to intake of alcohol and various nutrients including smoking and drug intake. There was a positive association between cigarette smoking and adenoma risk compared with hospital controls, the RR being 2.3 (1.1-4.6). Overall alcohol intake was no risk factor in hospital controls, but drinking liquor was associated with an increased risk, the RR being 4.1 (1.3-13.4) and was especially marked in males [RR 10.2 (2.3-46.2)]. Compared with population controls, there was no increased RR associated with smoking or alcohol intake. None of the risk factors was positively associated with disease risk in those with small or large adenomas. These findings suggest that alcohol and tobacco play no major role in the formation or growth of adenomas.

Long-term use of nonsteroidal antiinflammatory drugs and the risk of colorectal adenomas. The Colorectal Adenoma Study Group.

AIMS: Previous studies have suggested that the regular use of NSAIDs reduces the risk of colorectal adenomas. The aim of this study was to examine this association while taking possible confounding factors into account. METHODS: The intake of drugs including NSAID intake during the last 20 years was assessed by means of a case-control study in 184 cases and matched hospital and community controls. RESULTS: Overall, there were few individuals with a relevant drug intake for more than 5 years. NSAID intake for more than five years was associated with decreased risk in comparison with both control groups. The RR was 0.20 (0.04-1.04) compared with hospital and 0.21 (0.04-0.99) compared with population controls, the latter association being statistically significant. Subgroup analysis by type of drug revealed a significant protective effect only for long-term aspirin intake in relation to hospital controls, the RR being 0.09 (0.01-0.82). CONCLUSION: Our data support the hypothesis that there is a protective effect of NSAID intake of more than 5 years against the development of colorectal polyps.

Helicobacter pylori and the risk of colonic adenomas. Colorectal Adenoma Study Group.

AIMS: Previous studies have found a positive association between Helicobacter pylori infection and colorectal adenomas. The aim of the present study was to examine this association while taking possible confounding factors into account. METHODS: 98 serum samples were available from 182 patients with colorectal adenomas who entered a case-control study of colorectal adenomas and diet. The H. pylori status in patients was compared with a hospital control group and a population control group. RESULTS: H. pylori IgG antibodies were more common in colorectal polyp patients compared with either control group, the prevalence being 79% in cases compared with 62% in both control groups. The corresponding RR was 1.4 (0.76-2.6) compared with hospital controls and 2.1 (1.1-3.9) compared with population controls. After adjusting for possible confounding variables the association between H. pylori status and adenoma risk was even more marked. There was an RR of 1.6 (0.80-3.4) compared with hospital controls and an RR of 2.6 (1.3-5.4) compared with population controls, the latter association being statistically significant. CONCLUSION: These findings suggest a statistically significant association between H. pylori infection and colorectal polyps. A possible mechanism might be increased gastrin levels in H. pylori-infected subjects which exhibit a trophic effect on colonic mucosa.

Antimitochondrial antibody profiles in primary biliary cirrhosis distinguish at early stages between a benign and a progressive course: a prospective study on 200 patients followed for 10 years.

In recent retrospective studies, it was shown that subtypes of antimitochondrial antibodies (AMA) can help to discriminate between a benign [only anti-M9 and/or anti-M2 positive by enzyme-linked immunosorbent assay (ELISA)] and a rather progressive course (anti-M2, -M4 and/or -M8 positive). According to different constellations of these AMA subspecificities in ELISA and complement fixation test (CFT), four AMA profiles (A-D) were defined. In 1984 we started a prospective study based on 200 PBC patients with known AMA profiles in order to correlate the antibody pattern with the clinical outcome. Progression was defined primarily as the necessity of liver transplantation and death due to hepatic failure or variceal bleeding. At entry, 18 (9%) of the 200 patients had AMA profile A (only anti-M9), 57 (29%) profile B (only anti-M2 with or without anti-M9), 74 (37%) profile C (anti-M2 in association with anti-M4/-M8 by ELISA), and 51 (26%) profile D (anti-M2/-M4/-M8 by ELISA and CFT). At the beginning of the study, 177 patients had PBC stage I/II. During the observation period of ten years, ten patients died and in 18 orthotopic liver transplantation (OLT) was performed; all these patients belonged to profile C/D. Furthermore, 44% of the patients with profile C and 31% of the patients with profile D progressed to late stages, as defined by histology and clinical manifestations such as portal hypertension and increase of bilirubin, while only one of the patients with profile B and none of the profile A-patients developed late stage PBC. A significant increase of bilirubin was observed only in C/D-patients. AMA profiles did not change during the follow-up. In conclusion, AMA profiles discriminate between a benign and a progressive course of PBC already at early stages.

Value of an extended monoethylglycinexylidide formation test and other dynamic liver function tests in liver transplant donors.

Measuring monoethylglycinexylidide (MEGX) formation after intravenous administration of lidocaine in potential organ donors (MEGX test) has been advocated as a useful test to select donor livers for transplantation, but some groups have demonstrated a low test efficacy. We, therefore, investigated the value of an extended MEGX formation test and the value of other dynamic liver function tests, in selecting suitable human donor livers. In 51 human multi-organ donors, we measured elimination of galactose, indocyanine green, and lidocaine, as well as formation of MEGX, at 15, 30, and 60 min after administration of the test substances. In the early postoperative period, the function of the transplanted liver was then classified as good or poor, as defined by a prothrombin time above or below 65% by day 4 and fibrinogen concentration above or below 300 mg/dl by day 7. Donor characteristics and preservation modalities were very similar between the two groups. Galactose, indocyanine green, and lidocaine metabolism failed to predict good or poor graft function in the early postoperative period. MEGX serum concentrations, however, were significantly higher in the group of donors whose organs functioned well in the recipients, as compared with donors whose organs functioned poorly in the recipients. This was true for MEGX concentrations at 15 min (117+/-9 vs. 90+/-9 ng/ml; P=0.03), 30 min (108+/-8 vs. 86+/-8 ng/ml; P=0.04), and 60 min (100+/-6 vs. 73+/-5 ng/ml; P=0.006). Extending the MEGX formation test from 15 to 60 min improved test efficacy. Maximal MEGX concentration in 9 or up to 12 consecutive blood samples, drawn between 3 and 120 min after lidocaine infusion, was also significantly higher in donors whose organs functioned well, than in donors whose organs functioned poorly (129+/-10 vs. 101+/-10 ng/ml; P=0.03). Although the groups with good and poor organ function differed significantly with respect to their MEGX serum concentrations, and although efficacy of the MEGX test was improved by extending the test from 15 to 60 min, the overlap in individual MEGX serum concentrations was still so wide that it is virtually impossible to predict early graft function only on the basis of the MEGX test in the donor. Therefore, the MEGX test, although of potential scientific interest, does not predict early graft function with an accuracy necessary for clinical use.

Serial quantitative liver function tests in patients with primary biliary cirrhosis: a prospective long-term study.

Primary biliary cirrhosis (PBC) is a rare chronic cholestatic disorder of unknown origin that can now be treated effectively with ursodeoxycholic acid (UDCA). The clinical course of PBC is very variable, but a significant proportion of patients eventually die or undergo liver transplantation. In this single-center prospective long-term study, we analyzed the effect of UDCA therapy (10 mg/kg b.w./day) on conventional liver function tests and we also investigated whether serial quantitative liver function tests are useful in the clinical management of patients with PBC. Fifteen patients, most of them in an early disease stage, were followed up for either 4 (n = 7) or 5 (n = 8) years. In addition to regular conventional liver function tests, every 12 months quantitative liver function tests were performed. Thus we measured galactose elimination capacity, indocyanine green half-life and lidocaine half-life. Quantitative liver function tests were also performed once in healthy volunteers. Treatment with UDCA significantly improved conventional liver function tests, and this effect was maintained for several years (values in U/l before therapy and 4 years after therapy: AP = 1,346 +/- 317 vs. 516 +/- 93; gammaGT 378 +/- 80 vs. 144 +/- 30; LAP 122 +/- 10 vs. 71 +/- 9; AST 61 +/- 19 vs. 34 +/- 12; ALT 90 +/- 19 vs. 68 +/- 35; GLDH 14.3 +/- 1.9 vs. 8.2 +/- 1.9). Quantitative liver function tests were not significantly different between healthy volunteers and patients (GEC 6.8 +/- 0.3 vs. 7.0 +/- 0.3 mg/kg x min; ICG half-life 4.2 +/- 0.4 vs. 3.7 +/- 0.3 min; lidocaine half-life 75 +/- 8 vs. 79 +/- 6 min). In the patients, results of quantitative liver function tests (GEC, ICG and lidocaine half-lives) were not affected by UDCA therapy and remained constant over time. In the 1 patient who was transplanted, serial quantitative liver function tests did not indicate deteriorating liver function earlier than the patient's progressive symptoms or conventional liver function tests. Thus UDCA therapy markedly improved conventional liver function tests in patients with PBC, and this effect was maintained for at least 4-5 years. Possibly due to the fact that most of the patients were in an early disease stage, serial quantitative liver function tests provided little additional information that was relevant for planning therapy in the individual patient.

Conventional and quantitative liver function tests after hepatic transplantation: a prospective long-term follow-up.

In long-term survivors of liver transplantation, hepatic function is obviously of vital importance. Therefore, we prospectively performed conventional and quantitative liver function tests in patients who had survived a first transplantation for at least 4 years. Compared to 6 months after transplantation, serum bilirubin concentration and gamma GT activity were significantly lower after 3, 4, and 5 years (bilirubin 1.2 +/- 0.2 mg/dl at 6 months vs 1.0 +/- 0.1, 1.0 +/- 0.2, and 0.8 +/- 0.1 mg/dl respectively; gamma GT 106 +/- 0 33 U/l at 6 months vs 56 +/- 17, 67 +/- 35, 39 +/- 10 U/l respectively). At these points in time, blood levels of cyclosporin A were also significantly lower. Other parameters of liver cell function and liver cell integrity (AP, AST, ALT, GLDH, total protein, thromboplastin time, partial thromboplastin time) were unchanged over time. Serial quantitative liver function tests (indocyanine green half-life, galactose elimination capacity, lidocaine half-life, and MEGX formation) also remained stable. Thus, we conclude that hepatic function remains stable in long-term survivors of liver transplantation for at least several years.

[Hemolytic anemia as cause of a marked bilirubin increase in primary biliary cirrhosis]. / Hämolytische Anämie als Ursache eines auffälligen Bilirubinanstieges bei primärer biliärer Zirrhose.

HISTORY AND CLINICAL FINDINGS: 16 years ago a now 53-year-old woman was found to have primary biliary cirrhosis. 5 years later, after bleeding from oesophageal varices, she had a portacaval shunt. For several years she had been taking ursodeoxycholic acid (750 mg daily). Because of steadily increasing jaundice over the past few years she presented for possible liver transplantation. INVESTIGATIONS: There was a discrepancy between the markedly raised serum bilirubin concentration (7.8 mg/dl) and the only slightly raised or normal activities of alkaline phosphatase (247 U/l) and gamma-GT (21 U/l). Further tests confirmed that the patients had not only PBC but also Coombs-negative haemolytic anaemia (haemoglobin 10.7 g/dl, reticulocyte count 122/1000, indirect bilirubin 6.4 mg/dl, haptoglobin not demonstrated, lactate dehydrogenase 316 U/l). She had splenomegaly despite the portacaval shunt. Blood smear revealed spherocytes, but hereditary spherocytosis was not confirmed. TREATMENT AND COURSE: A six-week interruption of taking ursodeoxycholic acid led, as expected, to a rise in the activities of serum alkaline phosphatase and gamma-GT, while haemolysis parameters were not affected. CONCLUSION: Serum bilirubin concentration is a decisive prognostic factor in the course of primary biliary cirrhosis and is therefore of particular relevance for the indication of liver transplantation. The reported case demonstrates the importance of considering other causes of hyperbilirubinaemia.

Mortality in elderly patients with acute renal failure.

In a retrospective study, we identified 55 elderly patients with acute renal failure (ARF) admitted to our hospital during an 8-year period from 1985 to 1993. Information about the etiology, complications, laboratory data, and treatment course were obtained from the clinical history. Of the 200 patients with ARF admitted to the hospital during this period, 28% were patients more than 60 years old (41 male and 14 female) with an average age of 68.5 +/- 7 years. The main causes of ARF were sepsis, volume depletion, low cardiac output, arterial hypotension, nephrotoxicity by antibiotics, and obstructive uropathy. The global mortality of elderly patients with ARF was 53%. The mortality rate of the different types of the ARF were: prerenal 35%, intrinsic 64% (oliguric 76%, nonoliguric 50%), and postrenal 40%. Mortality as a result of sepsis occurred in 18 patients (62%), by cardiovascular disease in 4 patients (13%), by acute respiratory failure in 2 patients (7%), and by other causes in 5 patients (18%). In the cases of sepsis, Pseudomonas was detected in 7 cases (39%), Escherichia coli in 2 cases (11%), Gram-negative nonspecific in 3 cases (17%), Klebsiella in 1 case (5%), and in 5 cases (16%), the hemoculture was negative. The patient survival rate was 47% (26 of 55 patients). Of these patients, 19 recovered their normal renal function (73%), but 7 patients remained with renal failure (27%). In conclusion, the global mortality in the elderly patients without considering the types of ARF was 53%. The oliguric form had the highest mortality rate with 76%. The main causes for mortality were sepsis with 62%, cardiovascular disease with 13%, and other causes 18%.

Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer. Interim analysis of a phase II trial.

PURPOSE: The prognosis of patients with locally advanced esophageal cancer (LAEC) remains poor when treated with local modalities. An intensive preoperative program with chemoradiotherapy was used to evaluate the curative resection rate, pathologic response, and survival of patients with LAEC. PATIENTS AND METHODS: Ninety patients with LAEC were treated preoperatively with chemotherapy (three courses of fluorouracil, leucovorin, etoposide, and cisplatin [FLEP]) followed by concurrent chemoradiotherapy (one course of cisplatin plus etoposide in combination with 40 Gy of radiation). Transthoracic esophagectomy was performed 4 weeks after the end of radiation. RESULTS: Seventy-two patients were included in this evaluation. Forty-four (61%) underwent a complete tumor resection, and 16 (22%) had no tumor in the resected specimen (pathologic complete response [PCR]). The operative mortality rate was 15%. At a median follow-up time of 22 months (range, 12 to 41), the median survival duration of all 72 patients was 17 months (range, 1 to 41+). The calculated survival rates at 3 years were 33%, 42%, and 68% for all patients, patients after complete resection, and patients with PCR, respectively. CONCLUSION: This combined treatment modality is active in LAEC, with a PCR in 33% of the patients undergoing surgery. The results appear improved compared with those reported with surgery alone, by approximately doubling the 3-year survival rate. The high efficacy of preoperative chemoradiation warrants evaluation of the role of surgery in LAEC.

[Primary sclerosing cholangitis: conventional and quantitative liver function tests during long-term therapy with ursodeoxycholic acid]. / Primär sklerosierende Cholangitis: Konventionelle und quantitative Leberfunktionstests unter einer mehrjährigen Therapie mit Ursodesoxycholsäure.

Primary sclerosing cholangitis, a chronic cholestatic liver disease, frequently leads to an impairment of liver function. In nine men and two women, aged 23 to 57 years, we prospectively studied for three to six years the effect of treatment with ursodeoxycholic acid (UDCA) on liver function. 10 mg UDCA/kg bw significantly reduced serum activities of AP, gamma GT, AST and ALT for several years. After three years of treatment, however, serum concentration of bilirubin was higher than before therapy in eight out of eleven patients (1.8 +/- 0.8 versus 0.9 +/- 0.1 mg/dl; p = 0.01). Likewise, serum concentration of bilirubin was higher in eight out of nine patients after four years of treatment (1.3 +/- 0.3 versus 0.9 +/- 0.1 mg/dl; p = 0.03). In most cases, however, the increase was discrete. Parameters of synthetic liver function (coagulation, serum protein concentration, serum activity of cholinesterase) remained constant in the observation time. Quantitative liver function tests (galactose elimination capacity and indocyanine green half-life) also showed little variation in the observation time. We conclude that UDCA treatment significantly improves serum activities of liver enzymes for several years. Nevertheless, serum bilirubin concentration, believed to be of prognostic value in patients with PSC, seems to rise slowly over time. Serial determinations of galactose elimination capacity and indocyanine green halflife are not superior to conventional liver function tests in the timing of liver transplantation in the individual patient.

Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ).

Alpha 1-Antitrypsin deficiency predisposes to pulmonary emphysema, liver cirrhosis and hepatocellular carcinoma. Anecdotal evidence and a large autopsy study suggest that severe lung and liver disease rarely coexist in the same subject, but this has not been studied in patients. Therefore we investigated 27 patients with severe alpha 1-deficiency (Pi ZZ) and pulmonary emphysema for signs of liver disease and impaired hepatic function. A subgroup of 7 patients underwent quantitative liver function tests. On physical examination or ultrasonography, cirrhosis or tumor was not suspected in any patient. Conventional liver function tests were completely normal in 17 patients. Elevated serum activities of gamma-glutamyltranspeptidase and/or aminotransferases were seen in 10 patients. In some, the elevation was only marginal and in none more than twice normal. The serum bilirubin concentration and activity of alkaline phosphatase were increased in 1 patient. Serum protein, albumin, fibrinogen, antithrombin III, alpha 1-fetoprotein concentrations, serum activities of cholinesterase and glutamate dehydrogenase, activated partial thromboplastin time and prothrombin time were normal in all patients. The indocyanine green half-life was abnormal only in 1 of 6 patients, suggesting that hepatic blood flow was not impaired in the study group. However, the lidocaine half-life and galactose elimination capacity, parameters of hepatic metabolization, were impaired in 4 and 6 of 7 patients, respectively. We conclude that liver disease or impaired liver function is not a clinically relevant problem in most patients with pulmonary emphysema due to alpha 1-antitrypsin deficiency. But results of quantitative liver function tests, although performed in only a small group of patients, suggest that hepatic metabolization might be impaired even in those patients who present with pulmonary disease.

Visualization of Surfactants on Nanostructured Palladium Clusters by a Combination of STM and High-Resolution TEM.

Scanning tunneling microscopy (STM) and high-resolution transmission electron microscopy (TEM) have been used to determine the dimensions of a series of palladium clusters stabilized by tetraalkylammonium salts. Electrochemically prepared colloids were used in which the average diameter of the inner metal core was varied between 2 and 4 nanometers, and the size of the ammonium ions was adjusted in the series (+)N(n-C(4)H(9))(4) < (+)N(n-C(8)H(17))(4) < (+)N(n-C(18)H(37))(4). The difference between the mean diameter determined by STM and that measured by TEM allows the determination of the thickness of the protective surfactant layer. On the basis of these studies, a model of the geometric properties of ammonium-stabilized palladium clusters has been proposed. Suggestions for the mechanism of the STM imaging process are also made.

Gastroenterologic manifestations of mastocytosis.

Mastocytosis as a rare disease is usually diagnosed by dermatologists because of urticaria pigmentosa as one of the leading signs. If the triad of urticaria pigmentosa, flush and diarrhea is present diagnosis is easily made. However, urticaria pigmentosa and flush may be less dominant or even absent and gastrointestinal signs may render diagnosis more difficult. Therefore, this review is thought to describe clinical manifestations of mastocytosis from the gastroenterologist's point of view. In addition, on the grounds of a recent classification of mastocytosis practical diagnostic procedures as well as therapeutic approaches are discussed.

[Liver complications in HELLP syndrome]. / Leberkomplikationen des HELLP-Syndroms.

In a 5 years period 5 female patients suffering from a severe HELLP syndrome were treated. The problems concerning diagnostic and treatment are discussed. 3 patients had to be operated on in an emergency state. The operations were performed because of acute and severe abdominal bleeding. Two of the patients needed liver transplantation as an emergency procedure, one of them died after hepatectomy on the list. Another one died 7 weeks after successful transplantation in a state of prolonged sepsis. The two conservatively treated and the one transplanted patient are still alive and well.

[Increased plasma endothelin concentrations in patients after liver transplantation and in liver cirrhosis]. / Erhöhte Plasma-Endothelin-Konzentrationen bei Patienten nach Lebertransplantation und bei Leberzirrhose.

Endothelin, one of the most potent vasoconstrictors known today, is released by the vascular endothelium. Patients after liver transplantation and patients with liver cirrhosis show significantly higher plasma endothelin concentrations and significantly reduced results in the quantitative liver function tests (ICG-HL, GEC, Lidocaine-HL, MEGX) compared with healthy control persons. The plasma endothelin concentrations were better correlated with the more liver bloodflow dependent function tests (ICG-HL, Lidocaine-HL) than with the more metabolic-capacity dependent function tests (GEC, MEGX). As cyclosporine A in vitro can increase the liberation of endothelin, we conclude that in patients after liver transplantation an endothelin mediated cyclosporine induced hepatotoxicity might be the reason for the demonstrated association.