[Gastroenterology - accusations and errors in treatment: evaluation of the completed expertise process in internal medicine of the expert committee of North Rhineland for the years 2001 to 2005]. / Gastroenterologie - Vorwürfe und Fehler bei der Behandlung: Auswertung der abgeschlossenen Begutachtungsverfahren der Inneren Medizin der Gutachteerkommission Nordrhein der Jahre 2001 bis 2005.

Since three decades the extrajudical expertise procedures of the Expert Committee and Arbitration Group has served to pacify the doctor-patient relationship. Systematic analyses of accusations and errors provide valuable data that help to avoid treatment errors and liability disputes against physicians. Disease of the gastrointestinal tract were found ex post to be the main diagnosis in 10 % of the patients entering complaints. The most common benign diseases were bile duct diseases (1.5 %), acute appendicitis (1.2 %) and diverticulosis (0.9 %); malignant tumours of the digestive organs were found in 1.8 %. About one-third of the procedures were directed internists; with 25 % the quota of treatment errors was less than the general average of one third. With an overproportional frequency (56 %) diagnosis errors were confirmed for the occurrence of appendicitis. Diagnostic and therapeutic endoscopic examinations were the subject of the claimed erroneous treatment by internists in 34 % of the cases: perforations and postinterventional pancreatitis were frequent reasons for filing a complaint. For the resultant injuries, including 4 fatalities, the internists were found to be liable for damages in a total of 17 % of the cases.

5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial.

BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrences and improves survival. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up study in comparison with the effects of 5-FU plus levamisole in the prospective multicenter trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected stage III (International Union Against Cancer) colon cancer were stratified according to tumor, node and grading category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days, plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred and eighty (96.9%) of 702 patients enrolled into this study were eligible. To date, 261 patients have died, 117 on arm A and 144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU plus leucovorin combination significantly improved disease-free survival [79.8 months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly increased median overall survival (88.9 months in arm A versus 78.6 months in arm B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSIONS: After curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated. This long-term follow-up study demonstrates that adjuvant treatment with 5-FU plus leucovorin given for 12 cycles is significantly more effective than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and improving survival.

Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01.

PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

[Liver damage caused by drugs]. / Leberschädigung durch Medikamente.

The liver has a central role in the metabolism of many drugs, since this organ is the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs have a small volume of distribution and can be eliminated unchanged in the urine. By contrast, lipid-soluble drugs have a larger volume of distribution and require conversion to water-soluble metabolites for their elimination in urine or bile. The liver with its specific receptors, transporters and enzymes is responsible for the uptake, transformation and excretion of the lipophilic drugs. While most of the drugs are transformed into stable metabolites, other drugs form reactive, potentially toxic, metabolites producing liver cell damage. Liver injury caused by drugs may mimic almost any kind of liver disease. Clinical findings are gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic liver injury with jaundice and pruritus of severe inflammatory and cirrhotic liver damage with signs of liver failure, encephalopathy and cerebral edema. The morphological changes vary from hepatitis, cholestasis, fatty liver, granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic alterations and vascular lesions and tumors. The most commonly used drugs causing severe liver injury are discussed in detail. These are anabolics, oral contraceptives, antituberculous and antifungal agents, nonsteroidal anti-inflammatory drugs, ring substituted amphetamins ("designer drugs"), antiarrhythmics and antibiotics.

Polyunsaturated phosphatidyl-choline and interferon alpha for treatment of chronic hepatitis B and C: a multi-center, randomized, double-blind, placebo-controlled trial. Leich Study Group.

BACKGROUND/AIMS: Polyunsaturated phospatidyl-choline (PPC) has been shown to reduce serum aminotransferases in experimental hepatitis. This multi-center, randomized, double-blind, placebo-controlled trial evaluated the effects of PPC in patients with chronic hepatitis B and C in combination with interferon alpha 2a or 2b. The diagnosis of chronic viral hepatitis was based on an abnormal serum alanine aminotransferase (ALT) value (more than twice the upper value of normal), viral replication and chronic hepatitis found on liver biopsy. METHODOLOGY: Patients received 5 million I.U. (Hepatitis B) and 3 million I.U. (hepatitis C) interferon s.c. thrice weekly for 24 weeks, respectively, and were randomly assigned to additional oral medication with either 6 capsules of PPC (total daily dose: 1.8 g) or 6 capsules of placebo per day for 24 weeks. Biochemical response to therapy was defined as a reduction of ALT by more than 50% of pre-treatment values. The responders were treated for further 24 weeks after cessation of interferon therapy with either PPC or placebo. RESULTS: 176 patients completed the study protocol (per-protocol population: 92 in the PPC and 84 in the placebo group). A biochemical response (> 50% ALT reduction) was seen in 71% of patients who were treated with PPC, but only in 56% of patients who received placebo (p < 0.05). PPC increased the response rate in particular in patients with hepatitis C: 71% of those patients responded in the PPC group versus 51% in the placebo group (p < 0.05). Prolonged PPC therapy given to responders beyond the cessation of interferon therapy tended to increase the rate of sustained responders at week 48 in patients with hepatitis C (41% versus 15% in the control group; p = 0.064). In contrast, PPC did not alter the biochemical response to interferon in patients with hepatitis B. PPC did not accelerate elimination of HBV-DNA, HBeAg and HCV-RNA. CONCLUSIONS: In conclusion, PPC may be recommended in patients with chronic hepatitis C in combination with interferon and after termination of interferon in order to reduce the high relapse rate. PPC may not be recommended for patients with chronic hepatitis B. In contrast to IFN and other antiviral agents PPC does not carry major risks and is tolerated very well.

Controlled trial of antituberculous chemotherapy in Crohn's disease: a five year follow up study.

BACKGROUND: It has been suggested that Mycobacterium paratuberculosis is the cause of Crohn's disease. In a previous report the immediate effect of two years treatment with antituberculous chemotherapy showed no clinical benefit. AIMS: To assess both the immediate and longer term effect of treatment on the disease. METHODS: Patients were followed for five years from their date of entry to the study. One hundred and thirty patients entered the initial study, and of these 111 (81%) were followed regularly. RESULTS: Overall, there was no evidence of consistent benefit or disadvantage from antituberculous chemotherapy in any of the assessments made, including the number of acute relapses, surgical episodes, hospital admissions, disease activity, blood tests, or medication required for Crohn's disease during the follow up period. CONCLUSION: The absence of any benefit at the end of the initial two year trial period, and during the three year subsequent follow up, fails to support the hypothesis that mycobacteria play an important part in the pathogenesis of Crohn's disease, or that antituberculous chemotherapy may be of benefit.

Screening for hemochromatosis and iron deficiency in employees and primary care patients in Western Germany.

BACKGROUND: Many physicians still believe that iron overload (hemochromatosis) is an uncommon disorder. OBJECTIVE: To estimate the frequency of iron overload and iron deficiency in a group of employees and a group of outpatients. DESIGN: Prospective screening study. SETTING: Western Germany. PARTICIPANTS: 3012 asymptomatic employees and 3027 outpatients of nine practitioners. MEASUREMENTS: Serum ferritin levels and transferrin saturation were measured. Participants with repeatedly abnormal results had thorough clinical evaluations to identify the cause of iron deficiency or overload. RESULTS: Gross iron overload (elevated transferrin saturation and ferritin levels) was proven by liver biopsy and phlebotomy treatment in 28 participants (0.4% of female outpatients, 0.7% of male outpatients, 0.2% of female employees, and 0.4% of male employees) and in six siblings of these participants. Of the 34 participants with iron overload, 30 were precirrhotic. Because 60% of an unselected group of employees with elevated transferrin saturation but normal ferritin levels were assumed to have early hemochromatosis, the prevalence of hemochromatosis was estimated to be 1.8% among patients (1.9% in women and 1.6% in men) and 1.0% among employees (1.1% in women and 1.0% in men). Iron deficiency was found in 6.8% of female patients, 2.4% of male patients, 6.0% of female employees, and 0.5% of male employees. CONCLUSIONS: Iron deficiency was more common in women, and iron overload was more common in men. Among male employees, iron overload was almost as common as iron deficiency.

Diminished plasma levels of vitamin E in patients with severe viral hepatitis.

RRR-alpha-Tocopherol (Vitamin E) was assayed in plasma of 48 patients with viral hepatitis and of 32 healthy controls. In patients with highly elevated serum transaminases (ALT > 100 U/L) vitamin E plasma levels were significantly lower (17.5 +/- 4.8 mumol/L) than in controls (22.7 +/- 4.2 mumol/L, p < 0.01). The vitamin E/lipid ratios (3.12 +/- 0.63 mumol/g) in these patients were 33% lower than those of the controls (4.68 +/- 0.54 mumol/g). The lowered vitamin E levels in patients with acute or chronic viral hepatitis with high activity of disease may be due to free radical-mediated liver injury.

Synergistic stimulatory effects of tumour necrosis factor alpha and interferon gamma on replication of human immunodeficiency virus type 1 and on apoptosis of HIV-1-infected host cells.

Differential and sometimes contradictory effects have been described for tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) on replication of human immunodeficiency virus type 1 (HIV-1). The authors examined individual and coordinate action of these cytokines on HIV-1 expression, and on apoptosis of HIV-1-infected host cells by determination of reverse transcriptase activity in cell culture supernatant, expression of HIV-1-RNA and production of p24 antigen in the promonocytic cell line U937 and its persistently HIV-1-infected clone U1. Apoptosis was demonstrated by typical cleavage of cellular DNA at internucleosomal regions in promonocytic and T-lymphocytic cell lines. TNF-alpha alone markedly stimulated HIV-1 replication in U1 cells at the transcriptional and on the translational level. Exclusive application of IFN-gamma only slightly enhanced HIV-1 expression, whereas it synergistically potentiated stimulatory effects of TNF-alpha. Both cytokines also synergistically induced apoptosis in HIV-1-infected host cells. Co-ordinate action of TNF-alpha and IFN-gamma is suggested to represent an important mechanism for disease progression in HIV infection. These findings demonstrate that cytokine effects on viral expression may vary depending on their single or combined application.

Long-term survival in patients with hereditary hemochromatosis.

BACKGROUND & AIMS: The course of hereditary hemochromatosis may depend on the degree of iron overload and the time of therapeutic intervention. This analysis evaluates the impact of early diagnosis and iron removal on survival and complications in hereditary hemochromatosis. METHODS: A Cohort of 251 patients with hemochromatosis was followed up for 14.1 +/- 6.8 years. RESULTS: Survival was reduced in the total group of patients when compared with a matched normal population. Survival in noncirrhotic and nondiabetic patients and in patients diagnosed between 1982 and 1991 was identical with rates expected. Survival was reduced in patients with severe iron overload vs. those with less severe overload. The percentage of early diagnoses increased threefold between 1947 and 1969 to that between 1970 and 1981; there was only a further 20%-25% increase in the last decade. Deaths caused by liver cancer, cardiomyopathy, liver cirrhosis, and diabetes mellitus were increased as compared with expected rates. Liver cancers were associated with cirrhosis and amount of mobilizable iron but not with hepatitis B or C markers. CONCLUSIONS: Prognosis of hemochromatosis and most of its complications, including liver cancer, depend on the amount and duration of iron excess. Early diagnosis and therapy largely prevent the adverse consequences of iron overload.

Comparison between intraluminal multiple electric impedance measurement and manometry in the human oesophagus.

Conventional oesophageal manometry and intraluminal electrical impedance measurement were simultaneously applied in eight healthy volunteers to study the effect of wet and semisolid bolus viscosities on oesophageal motility and bolus transit. Contraction front velocity measured by electrical impedance and manometry were identical for wet and semisolid swallows and highly associated. Bolus front velocity as measured by electrical impedance was significantly faster than contraction front velocity in both wet and semisolid swallows. Bolus front velocity during semisolid swallows was significantly slower compared to wet swallows. It is concluded that intraluminal electrical impedance measurement is a reliable technique to detect oesophageal motility as well as to differentiate between transit of wet and semisolid bolus consistencies.

Prospective study on the detection of insulinomas by endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: The correct localization of insulinomas using endoscopic ultrasonography (EUS) has been reported to be as high as 80% in multicenter patient cohorts. PATIENTS AND METHODS: Over 24 months, we prospectively investigated 14 patients (11 women, three men) with a definite biochemical diagnosis of endogenous hyperinsulinism prior to surgical exploration and removal of an insulinoma. The endoscopic investigator was not aware of any other imaging results if they had been performed in referring hospitals. RESULTS: The overall sensitivity of EUS in the detection of pancreatic insulinomas was 57% (eight of 14 tumors); the sensitivity for insulinomas in the head of the pancreas was 83% (five of six); and 37% (three of eight) for tumors in the tail of the pancreas. The actual median diameter of undetected tumors was 11 x 9.5 mm, the median volume 0.66 ml (range 0.13 - 2.6 ml). The median diameter of correctly detected tumors was 16 x 11 mm, the median volume 1.37 ml (range 0.7 - 6.3 ml), the differences not being significantly different. In two patients, false-positive results were caused by peripancreatic lymph nodes. CONCLUSIONS: The sensitivity of EUS in the detection of pancreatic insulinomas depends on the location of the tumor, and possibly on the size of the tumors. Tumors not detected by EUS were likely to be smaller than detected tumors, and were likely to be located in the tail of the pancreas.

-Cardiomyopathy as the cause of death in genetic hemochromatosis-. / Kardiomyopathie als Todesursache bei genetischer Hämochromatose.

Hemochromatosis is an autosomal-recessive disease which causes iron-overload of various organs including liver, pancreas and heart. This report analyzes the course of hemochromatosis in two patients (a 28-year-old man and a 57-year-old woman) in whom hemochromatosis was detected because of severe cardiomyopathy. Initial symptoms were edema, anasarca and dyspnea. Further examinations showed pleural effusion, decreased left-ventricular-function, skin pigmentation, diabetes mellitus and liver cirrhosis. Although phlebotomy treatment and iron-chelation therapy with deferoxamine initially resulted in some improvement, both patients died from cardiomyopathy three months after diagnosis. The reports of these two cases underline that hemochromatosis-associated cardiomyopathy is often irreversible if severe congestive heart failure is present. In cardiac decompensation heart transplantation has to be considered as early as possible.

Effect of intestinal resection on serum antibodies to the mycobacterial 45/48 kilodalton doublet antigen in Crohn's disease.

Interest in the role of mycobacterial infection in Crohn's disease has been revived by the cultural detection of Mycobacterium paratuberculosis in patients with Crohn's disease. This hypothesis was examined serologically using assays with high specificity for Crohn's disease. The effect of intestinal resection on serum antibodies specific for Crohn's disease was investigated with an immunoblot assay and an enzyme linked immunosorbent assay using the 45/48 kilodalton doublet antigen of Mycobacterium tuberculosis. Antibodies were detected in 64.7% of patients with Crohn's disease (n = 17), 10% of patients with ulcerative colitis (n = 10), 5% of patients with carcinoma of the colon (n = 20), and none of 10 healthy subjects with the immunoblot assay. Statistical comparison of the Crohn's disease patients with each control group resulted in p = 0.0000236. Immunoglobulin G was essentially unchanged 75 days (mean) after surgery. After more than 180 days, however, the antibody response was reduced in all of five patients studied, and was no longer demonstrable in two of them (40%). Simultaneously, the Crohn's disease activity index (CDAI) decreased. Both the high specificity of this assay for Crohn's disease and the diminished antibody response after intestinal resection in parallel with decreased CDAI support a mycobacterial aetiology of Crohn's disease.

[Diagnosis and therapy of autoimmune hepatitis]. / Diagnose und Therapie der autoimmunen Hepatitis.

Thorough differential diagnosis in patients with autoimmune hepatitis is important since other liver disorders need different treatment regimen. Elevated transaminases and gamma-globulines and autoantibodies should make one think of autoimmune hepatitis. Liver biopsy is helpful but usually not a definitive proof of the diagnosis. Immunosuppressive therapy has to be administered for years and possibly leads to serious side effects. Therapy should only be discontinued if a complete remission is induced. Relapses after cessation of medical treatment occur frequently. If no remission is achieved lifelong immunosuppressive therapy has to be given. In decompensated disease liver transplantation offers a treatment with good prognosis.

Serum levels of stem cell factor are increased in asymptomatic human immunodeficiency virus-infected patients and are associated with prolonged survival.

Cytopenia is a common complication of human immunodeficiency virus (HIV) infection and can affect different hematopoietic lineages, including erythropoiesis, lymphopoiesis, thrombopoiesis, and granulopoiesis. Stem cell factor (SCF), a cytokine expressed by bone marrow stromal cells, is a multipotential growth factor acting on early progenitor cells of most hematopoietic lineages. Therefore, we investigated the serum SCF levels in 74 HIV-infected persons without active secondary infection at different stages of HIV infection [Centers for Disease Control (CDC) stages A through C]. Circulating SCF levels were determined by enzyme-linked immunosorbent assay and were found to be significantly elevated in CDC stage A as compared with normal controls (7.18 +/- 1.94 ng/mL v 3.95 +/- 0.91 ng/mL, P = .04). However, in CDC groups B and C, SCF levels were lower than in CDC group A (3.29 +/- 0.75, P = .162, and 1.95 +/- 0.39, P = .005, respectively). Serum levels greater than 1.8 ng/mL were associated with a longer survival (P = .0037) in 74 HIV type 1 (HIV-1)-seropositive patients monitored for up to 114 weeks, suggesting that this cytokine may be directly associated with the disease course. A Cox proportional hazards model showed SCF to be an independent prognostic factor for survival (risk ratio for death, 0.73; 95% confidence interval, 0.56 to 0.95; P = .019). Serum SCF levels decreased on follow up in 24 of 38 patients or remained below 0.4 ng/mL in 10 of 38 patients from whom a second blood sample was collected after a mean interval of 44 weeks. To determine potential regulatory factors of SCF expression by stromal cells, we exposed cultured fibroblasts to various cytokines. Only interleukin-4 (IL-4) upregulated SCF mRNA. As IL-4 is modulated during early HIV disease, it may be a key regulator of SCF secretion. Further studies are required to elucidate the mechanism of SCF action and regulation in patients with HIV infection.