[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

Evaluation of digital construction, production and intraoral position accuracy of novel 3D CAD/CAM titanium retainers.

OBJECTIVES: New opportunities have arisen to manufacture three-dimensional computer-aided design/computer-aided manufacturing (3D CAD/CAM) retainers from titanium blocks by digital cutting technology. These novel technologies need to fulfill requirements regarding digital planning and position accuracy. The aim of the present study was to investigate the digital construction, the CAD/CAM production and the intraoral positioning accuracy of custom-manufactured novel 3D CAD/CAM titanium retainers. MATERIALS AND METHODS: A total of 37 prime4me® RETAIN3R (Dentaurum, Ispringen, Germany) retainers were inserted to stabilize the upper anterior front teeth. Following insertion, an intraoral scan was used to record the position. The intraoral position was compared to the virtual setup using 3D superimposition software. Measurement points were evaluated in all three dimensions (horizontal, sagittal and vertical planes). Data were analyzed using Kruskal-Wallis test followed by Dunn's multiple comparison test. RESULTS: A total of 185 measurements were performed. The horizontal plane and the sagittal plane demonstrated a high level of positioning accuracy between the planned and the intraoral position. Statistically significant deviations between the preceding virtual setup and the intraoral situation were observed in the vertical dimension. Within the retainer, the intraoral positioning accuracy decreased for the measurement points in the direction of the distal retainer segment. CONCLUSION: Based on the results, the present study shows a high level of congruence between the 3D virtually planning and the final intraoral position of the fabricated novel 3D CAD/CAM titanium retainers.

Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany.

Chronic hepatitis C due to HCV genotype 5 and 6 infection is infrequently reported and patients are usually not included in trials. As boceprevir and telaprevir are not approved for these genotypes, pegylated interferon plus ribavirin will remain the treatment of choice for the coming years. Patients infected with HCV genotype 5 or 6 were identified by data base search from an ongoing observational cohort study in Germany. Of the total 23 893 patients, 39 patients (0.2 %) carried a HCV genotype 5 and 39 patients a HCV genotype 6 (0.2 %). Compared to other genotypes patients with genotype 5 were older and more often had a history of blood transfusion. Patients with genotype 6 were more often Asian and showed higher baseline alanine transaminase. Therapy with pegylated interferon alfa-2a and ribavirin was initiated in 24 patients with HCV genotype 5 and 27 patients with HCV genotype 6. After completion of 48 weeks of therapy an end of treatment response was achieved in 79 % and 81 % of treated patients, respectively. Sustained virological response was achieved in 58 % of patients with genotype 5 and in 59 % genotype 6 patients. HCV genotype 5 and 6 infections are rare in Germany. Our findings suggest that most HCV genotype 6 infections are seen in migrants from Asia, whereas HCV genotype 5 infections seem more due to spontaneous local infections. Sustained virological response seems to be better than for patients with genotype 1 or 4 with similar treatment duration.

[Endoscopic therapy for leaks in the gastrointestinal tract, the bile ducts and the pancreas]. / Endoskopische Therapie von Leckagen im Gastrointestinaltrakt, an den Gallenwegen und im Pankreas.

Surgery has been the mainstay of therapy in patients with gastrointestinal perforations, leakage or fistulas. New techniques for endoscopic closure of gastrointestinal perforations provide tools for an effective treatment by less invasive procedures. Temporary placement of covered self-expanding stents is an established therapy for oesophageal perforations and anastomotic leaks. Using conventional endoclips small perforations and leaks in the oesophagus and gastrointestinal tract may be closed. With the new over-the-scope-clips a more effective endoscopic full wall closure is possible in the upper gastrointestinal tract and the rectum. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is an established method for treating rectal leaks and is now increasingly used also in oesophageal leaks. Biliary leakage following endoscopic or surgical interventions is effectively treated with temporary bile stenting in most cases, but closure using metal stents or coiling may be necessary. Pancreatic leaks are a major therapeutic problem and may require multimodal therapies.

[Waiting time for and length of physicianc's consultation define the patient-physician interaction: results of a prospective study in 478 patients with chronic viral hepatitis]. / Wartezeiten und Länge des Arztgesprächs bestimmen aus Patientensicht die Qualität der Arzt-Patienten-Beziehung bei chronischer Hepatitis B und C: Ergebnisse einer prospektiven Studie bei 478 Patienten mit chronischer Virushepatitis.

BACKGROUND: Little is known about the physician-patient interaction in hepatitis B and C. METHODS: This study by the federal competence network hepatitis analysed the physician-patient interaction using the validated FAPI questionnaire. The questionnaire also contained questions concerning demography and disease characteristics. Of the total 1500 questionnaires sent out, 478 were returned (32 %) (20 % HBV vs. 80 % HCV). RESULTS: The FAPI index of patients with HBV/HCV infection (3.10 +/- 0,99) was lower than that in patients with other internal medicine diseases (3.61 +/- 0.92; n = 148). Women had lower values than men (2.98 vs. 3.25; p = 0.005). Patients with active HBV infection showed higher values than those with HCV infection (3.27 vs. 2.97; p < 0.05). Patients with successfully treated hepatitis B/C had higher values than those with active disease (3.36 vs. 3.02; p = 0.004). The index was lower in patients who waited > 2 weeks for the consultation when compared to those with a shorter wait (2.92 vs. 3.31; p < 0.001) and was also lower in patients who waited > 30 min at the consultation day when compared to those with a shorter wait (2.81 vs. 3.39; p < 0.001). The index gradually increased with the consultation length (2.47 < 10 min vs. 2.79 10 - 15 min vs. 3.21 15 - 30 min vs. 3.82 > 30 min; p < 0.001). The index was higher in patients seen by gastroenterologists (3.43) when compared with general practioners (3.10), internists (3.02) and clinical settings (3.13) (p < 0.05). A good information status was associated with higher FAPI values when compared with a bad information status (3.43 vs. 2.76; p < 0.001). Fibrosis, health insurance and age were not associated with FAPI index (p > 0.2). By multivariate analysis a long consultation, a good information status, patients' patience, short waiting times, and providing contact to a patient support group were independently associated with a high index. CONCLUSIONS: The physician-patient interaction in chronic viral hepatitis is worse than in other internal medicine diseases with problems being more pronounced in HCV infection and women when compared to men and HBV infection. Short waiting times and patients' patience ameliorated the interaction as well as the consultation length, the information status of the patient and providing contact to a patient support group. Type of health insurance did not affect either waiting times or physician-patient interaction; thus there is no hint for a two-class medicine in this part of hepatology.

Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.

Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Real-world use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection.

BACKGROUND: Treatment of chronic hepatitis C genotype 3 (GT3) is more challenging compared with other genotypes. Since 2014, several new treatment regimens have been approved but sometimes based on limited data. AIM: To validate the use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection under real-word conditions. METHODS: The German Hepatitis C-Registry is a large national non-interventional real-world study for patients with chronic hepatitis C. A total of 1322 GT3 patients were enrolled (211 untreated and 1111 treated patients). RESULTS: Between February 2014 and September 2015, five different treatment strategies have been used (PegIFN+RBV, PegIFN+RBV+SOF, SOF+RBV, DCV+SOF±RBV, LDV/SOF±RBV). Treatment uptake and use of treatment concepts changed markedly and rapidly during the study influenced by new approvals, guideline recommendations, and label updates. PegIFN-based therapies constantly declined while DCV-based therapies increased with one interruption after the approval of LDV/SOF, which was frequently used until new guidelines recommended not using this combination for GT3. Per-protocol SVR ranged from 80.9% in the PegIFN+RBV group to 96.1% in PegIFN+RBV+SOF treated patients. Treatment-experienced patients with cirrhosis showed a suboptimal SVR of 68% for SOF+RBV but a high SVR of 90-95% for DCV+SOF±RBV. The safety analysis showed more adverse events and a stronger decline of haemoglobin for RBV containing regimens. CONCLUSIONS: Real-world data can validate the effectiveness and safety for treatment regimens that had previously been approved with limited data, in particular for specific subgroups of patients. The present study demonstrates how rapid new scientific data, new treatment guidelines, new drug approvals and label changes are implemented into routine clinical practice today.

Digestive end products release pancreatic enzymes from particulate cellular pools, particularly zymogen granules.

The effects of various amino acids and phosphorylated forms of glucose on the release of digestive enzymes from particulate cellular pools, particularly zymogen granules, were evaluated in rat pancreas. Whole tissue homogenates, as well as zymogen granules isolated either by differential centrifugation in 0.3 M sucrose or by preparation in buffered sucrose and subsequent centrifugation in a Percoll gradient, were studied. The basic amino acids L-arginine and L-lysine, sites of tryptic cleavage, caused the release of trypsinogen, but not chymotrypsinogen, whereas the aromatic amino acids L-phenylalanine and L-tryptophan, sites of chymotryptic cleavage, caused release of both trypsinogen and chymotrypsinogen. Neither led to the release of the starch-splitting enzyme amylase. All effects occurred within the range of normal plasma concentrations for these amino acids in the rat. Two amino acids, L-threonine and hydroxy-L-proline, that are not sites of cleavage by trypsin or chymotrypsin, and a nonmammalian amino acid, aminoadipic acid, did not lead to release of trypsinogen, chymotrypsinogen, or amylase. Two phosphorylated forms of glucose, glucose 1-phosphate and glucose 1,6-diphosphate, caused the release of amylase, but of neither trypsinogen nor chymotrypsinogen. Contrary to previous results, D-glucose was without effect, as was glucose 6-phosphate. We propose that certain digestive end products, by direct action on zymogen granules, cause the selective release of the enzymes involved in their evolution from polymeric substrates during digestion.

Cardiac troponin T in patients with clinically suspected myocarditis.

OBJECTIVES: The present study investigated whether myocyte injury can be assessed sensitively by measurement of serum levels of cardiac troponin T (cTnT) in patients with clinically suspected myocarditis and whether cTnT levels may predict the results of histologic and immunohistologic analysis of endomyocardial biopsy specimens. BACKGROUND: Conventionally used laboratory variables often fail to show myocyte injury in patients with clinically suspected myocarditis, possibly because of a low extent of myocardial injury in these patients. Sensitive variables for myocyte injury have not yet been investigated. METHODS: Eighty patients with clinically suspected myocarditis were screened for creatine kinase (CK) activity, MB isoform of CK (CK-MB) activity and cTnT. Endomyocardial biopsy specimens were examined histologically and immunohistologically. RESULTS: cTnT was elevated in 28 of 80 patients with clinically suspected myocarditis, CK in 4 and CK-MB in 1. Histologic analysis alone of the endomyocardial biopsy specimen revealed evidence of myocarditis in only five patients, all with elevated cTnT levels. Twenty-three of 28 patients with elevated cTnT levels had histologically negative findings for myocarditis. Additional immunohistologic analysis revealed evidence of myocarditis in 26 (93%) of 28 patients with elevated cTnT levels and in 23 (44%) of 52 patients with normal cTnT levels. Mean cTnT levels were higher in patients with myocarditis proved histologically or immunohistologically, or both, than in patients without myocarditis (0.59 +/- 1.68 vs. 0.04 +/- 0.05, p < 0.001). CONCLUSIONS: Measurement of serum levels of cTnT provides evidence of myocyte injury in patients with clinically suspected myocarditis more sensitively than does conventional determination of cardiac enzyme levels. Myocardial cell damage may be present even in the absence of histologic signs of myocarditis. Additional immunohistologic analysis often shows lymphocytic infiltrates in these patients. Elevated levels of cTnT are highly predictive for myocarditis in this group.

Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic liver cirrhosis.

Hypogonadism is common in patients with some liver diseases, such as idiopathic hemochromatosis (IHC) and alcoholic cirrhosis (AC). However, gynecomastia, a typical feature in AC, does not occur in IHC. To determine the hormonal basis for this difference, the following parameters were determined in patients with IHC and AC as well as in normal men: plasma concentrations of androgens and estrogens, metabolic clearance and production rates of androstenedione and testosterone, and the contribution of peripheral conversion of androstenedione and testosterone to the circulating estrogens. Severe impotence in both patients with IHC and those with AC was associated with more than 50% reduction in plasma testosterone. The reduction was due to 63% and 70% decreases in testosterone production in IHC and AC, respectively. The MCRs were less affected in IHC and AC (19% and 37% reductions, respectively). In IHC, the fall in testosterone concentrations was accompanied by decreased production and plasma concentrations of androstenedione, a precursor for estrogen synthesis. In contrast, production and plasma concentrations of androstenedione were significantly increased in AC. Patients with IHC had estradiol und estrone levels similar to those in normal men (mean +/- SD, 16.2 +/- 4.6 vs. 20.3 +/- 3.7 pg/ml; P = NS), whereas in AC, estradiol and estrone were significantly elevated (38.0 +/- 5.3 and 68.5 +/- 17.2 pg/ml, respectively). In IHC, sex hormone-binding globulin levels were in the same range as in the normal men, whereas sex hormone-binding globulin was increased in AC. In IHC, the instantaneous contribution of plasma androstenedione to estrone and estradiol was normal, whereas that of plasma testosterone to plasma estrogens was decreased by about 50%. In contrast, in AC, the instantaneous contribution of plasma androstenedione to estrogens was greatly enhanced, and that of testosterone was in the normal range. Since the MCRs of androgens and the conversion ratios of androgens to estrogens indicate normal peripheral metabolism of sex hormones in IHC, decreased androgen formation implies decreased testicular synthesis. This was confirmed by a significantly decreased LH level in IHC (5.5 +/- 1.9 vs. 10.5 +/- 3.1 mU/ml in normal men), indicating pituitary failure. In AC, however, increased LH (20.0 +/- 2.7 mU/ml) may be indicative of primary testicular failure. These results confirm clinical features of hypogonadism and normal estrogenic activity in patients with IHC.(ABSTRACT TRUNCATED AT 250 WORDS)

Menadione induces both necrosis and apoptosis in rat pancreatic acinar AR4-2J cells.

This study evaluated the action of menadione on cell proliferation and integrity of the rat pancreatic acinar cell line, AR4-2J. Menadione at 1-20 microM dose- and time-dependently inhibited cell proliferation of AR4-2J cells. In contrast, a high concentration of menadione (100 microM) caused rapid cell death (> 90% of cells took up trypan blue within 4-h). While the high concentration of menadione (100 microM) induced DNA smear in electrophoresis indicative of necrosis, lower concentrations (10-20 microM) induced a DNA ladder indicative of apoptosis. Similar results were obtained using a DNA fragmentation ELISA. Glutathione (1 mM), the calcium chelator EGTA (500 microM), and the cysteine protease inhibitor NCO-700 (5 mM) partly inhibited the effect of 1-10 microM menadione on cell proliferation and DNA fragmentation. Menadione at 1-20 microM induced wild-type P53, whereas the 100 microM menadione had a minor effect on wild-type P53. It is concluded that menadione induced necrosis at high concentrations and apoptosis at low concentrations in AR4-2J cells. Apoptosis induced by lower concentrations of menadione may be mediated by wild-type P53, intracellular calcium, and mechanisms which decrease the intracellular concentration of reduced glutathione.

Oxidative injury to isolated rat pancreatic acinar cells vs. isolated zymogen granules.

This study compares the susceptibility of pancreatic acinar cells and zymogen granules against oxidative injury and analyzes the mechanisms involved. Zymogen granules and acinar cells, isolated from rat pancreas, were exposed to a reaction mixture containing xanthine oxidase, hypoxanthine, and chelated iron. Cell function and viability were assessed by various techniques. Trypsin activation was quantified by an Elisa for trypsinogen activating peptide. Integrity of granules was determined by release of amylase. The reaction mixture rapidly generated radicals as assessed by deoxyribose and luminol assays. This oxidative stress caused lysis of granules in a matter of minutes but significant cell death only after some hours. Nevertheless, radicals initiated intracellular vacuolization, morphological damage to zymogen granules and mitochondria, increase in trypsinogen activating peptide, and decrease in ATP already after 5-30 min. Supramaximal caerulein concentrations also caused rapid trypsin activation. Addition of cells but not of granules reduced deoxyribose oxidation, suggesting that intact cells act as scavengers. Caerulein pretreatment only slightly increased the susceptibility of cells but markedly that of granules. In conclusion, isolated zymogen granules are markedly more susceptible to oxidative injury than intact acinar cells, in particular, in early stages of caerulein pancreatitis. The results show that oxidative stress causes a rapid trypsin activation that may contribute to cell damage by triggering autodigestion. Zymogen granules and mitochondria appear to be important targets of oxidative damage inside acinar cells. The series of intracellular events initiated by oxidative stress was similar to changes seen in early stages of pancreatitis.

Experimental acute pancreatitis. In vitro magnetic resonance characteristics.

The effect of pancreatitis on magnetic resonance T1 and T2 relaxation times was evaluated in two different models of acute pancreatitis in the rat. Acute edematous pancreatitis was induced by repetitive intraperitoneal injections of the cholecystokinin-analogue caerulein; acute hemorrhage pancreatitis was induced by retrograde infusion of the bile salt sodium taurocholate into the pancreatic duct. T1 and T2 relaxation times were obtained in vitro from fresh pancreatic specimens at 37 degrees C with a 0.25 resistive spectrometer. In both edematous and hemorrhagic pancreatitis, significant prolongation of T1 and T2 was noted as early as 1.5 hours after the initiation of pancreatitis when compared with normal rat pancreas. Maximal prolongation occurred at 7 hours in the caerulein model with T1 of 966 +/- 46 msec (mean +/- SEM) (normal + 278 +/- 12 msec) and T2 of 75.9 +/- 2.9 msec (normal = 32.8 +/- 3.3 msec), and after 6 hours in the bile salt model with T1 of 798 +/- 40 msec and T2 of 92.5 +/- 3.3 msec. After the time point of maximal prolongation, T1 and T2 gradually decreased toward the normal values. The prolongation of T1 and T2 paralleled each other throughout the time course of pancreatitis in both models. The prolongation of both relaxation times correlated closely with pancreatic weight, water content, and amylase concentration in serum and ascites. The present determination of T1 and T2 relaxation times by in vitro spectrometry suggests that magnetic resonance imaging has the potential for detecting early pathologic changes in acute pancreatitis and thus may be helpful for an early clinical diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of CCK on pancreatic function and morphology.

This report reviews the effects of CCK on the pancreas and in particular analyzes recent studies in which CCK antagonists were used to evaluate the physiological role of CCK in modulating pancreatic function and morphology. CCK is released from endocrine cells of the small intestine in response to a meal. In various animal species there are CCK receptors on pancreatic acinar cells with two sites; occupation of the high affinity site is thought to mediate pancreatic secretion and growth, whereas occupation of the low affinity site by high CCK concentrations is thought to be responsible for supramaximal inhibition of secretion and pancreatitis. Recently, CCK receptors were also found on postganglionic cholinergic neurons in the gastrointestinal tract. Administration of CCK agonists stimulates pancreatic secretion and growth. Although in some previous studies CCK was given at doses that mimic its postprandial increase in plasma, these studies did not prove that the actions of exogenous CCK were physiologically important. In addition, it was unclear if CCK primarily acts as a true hormone or as a neurotransmitter. The development of specific CCK receptor antagonists made it possible to better evaluate the physiological role of CCK. In humans, CCK-A antagonists like loxiglumide or L-364,718 at doses that completely inhibited the action of supraphysiological doses of exogenous CCK reduced meal-stimulated pancreatic enzyme secretion only by approximately 50%. On the other hand, atropine abolished the postprandial increase in pancreatic secretion and in addition markedly reduced the increase in pancreatic secretion due to infusion of "physiological" doses of CCK (i.e., CCK doses that mimic its postprandial increase in plasma). The increase in pancreatic bicarbonate secretion was only slightly reduced by CCK blockade. CCK antagonists failed to reduce the postprandial increase in plasma insulin, but markedly reduced the postprandial PP release. CCK-A antagonists caused slight hypotrophy and hypoplasia of the exocrine pancreas. However, even after 9 months of effective blockade of the CCK-A-receptor, mice had normal body weight and an almost normal pancreas. CCK antagonists were unable to alter short-term changes in pancreatic growth due to feeding and fasting. In some species, CCK agonists induced development of pancreatic nodules and increased the growth of malignant tumors. Studies about the effects of CCK antagonists on induction and growth of pancreatic tumors showed controversial results. In conclusion, CCK may act on the pancreas by three pathways: (1) At low doses it serves as a neurotransmitter by acting on cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Survival and causes of death in hemochromatosis. Observations in 163 patients.

Survival and causes of death were analyzed among 163 patients with hemochromatosis diagnosed between 1959 and 1983. Mean followup was 10.5 +/- 5.6 years (+/- SD). Cumulative survival was 76% at 10 years and 49% at 20 years. Life expectancy was reduced in patients who presented with cirrhosis or diabetes compared to patients who presented without these complications at the time of diagnosis. Patients who could be depleted of iron during the first 18 months of venesection therapy had a markedly better prognosis compared to those patients who could not be depleted during this time period, probably due to greater amounts of excessive iron. Prognosis was not influenced by sex. Patients without cirrhosis or diabetes had a life expectancy that was virtually identical to that of an age-matched normal population. Analysis of the causes of death in 53 patients showed that liver cancer (n = 16) was 219 times more frequent, cardiomyopathy (n = 3) was 306 times more frequent, liver cirrhosis (n = 10) was 13 times more frequent, and diabetes mellitus (n = 3) was seven times more frequent compared to death rates expected for an age-matched normal population. The risk of death from other causes, including extrahepatic cancer (n = 7), did not differ from rates expected. Thus, patients with hemochromatosis diagnosed in a precirrhotic stage and treated by venesection have a normal life expectancy. Cirrhotic patients had a shortened life expectancy and a high risk of death from liver cancer even when complete iron depletion has been achieved.

Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis.

Of 44 male patients with idiopathic hemochromatosis who were diagnosed at an early stage without morphological or biochemical evidence of liver disease, 25% suffered from impotence and 34% manifested glucose intolerance. Impotence was correlated with a 50% reduction in plasma testosterone, resulting from a 63% decrease in testosterone production. Testicular atrophy was caused by insufficient secretion of gonadotropins due to the selective accumulation of iron in gonadotropic cells of the pituitary gland. However, peripheral sexual hormone metabolism, in particular the conversion of androgens to estrogens, remained unaltered. It was therefore possible to employ substitution therapy successfully with testosterone in these men, and hyperestrogenism was not observed as a side effect. The pathogenetic factors in the development of diabetes mellitus in patients with idiopathic hemochromatosis include impaired insulin secretion caused by the selective deposition of iron in B-cells of the pancreas and insulin resistance due to iron accumulation in the liver. In particular, the insulin resistance is markedly improved after depletion of body iron stores by phlebotomy treatment, resulting in lower insulin requirements in patients with insulin-dependent diabetes as well as improvement of carbohydrate metabolisms in about half of the patients with non-insulin-dependent diabetes. We have concluded that hypogonadism and carbohydrate intolerance are caused by the specific distribution pattern of excess iron in the organism, accompanied by functional impairment of affected parenchymal cells.

Long-term effects of CCK-agonist and -antagonist on food intake and body weight in Zucker lean and obese rats.

The present study evaluates long-term effects of the CCK-agonist caerulein and the CCK-A antagonist loxiglumide in obese and lean Zucker rats. Caerulein and loxiglumide altered food intake neither in obese nor in lean rats. By as yet unknown mechanisms, however, weight increase was accelerated by loxiglumide and reduced by caerulein in obese and lean rats. Caerulein increased pancreatic weight only in lean but not in obese rats. Thus, obese rats show a resistance of pancreatic CCK-A receptors. The failure of CCK-agonist and -antagonist to alter food intake suggests that this CCK-resistance is not responsible for obesity in the genetically altered rats.

CCK-resistance in Zucker obese versus lean rats.

Obese Zucker rats are less sensitive to the satiety effect of CCK than lean litter mates. The present studies further characterised this CCK resistance. Subcutaneous injection of the CCK agonist caerulein dose-dependently decreased food intake in Zucker obese and lean rats whereas the CCK-B agonist gastrin-17 did not. Caerulein at 4 microg/kg, which resulted in CCK plasma bioactivity slightly above postprandial levels, decreased food intake in lean rats but not in obese rats. The decrease in food intake was also more marked at higher caerulein doses (20-100 microg/kg) in lean versus obese rats. In lean animals the satiety effects of the "near physiological" 4 microg/kg caerulein dose was abolished after blockade of vagal afferents with capsaicin, whereas the effects of higher caerulein doses were not. CCK-stimulated amylase secretion from pancreatic acini and binding capacity of 125I-labelled CCK-8 were decreased in obese versus lean rats. The CCK-A antagonist loxiglumide at 20 mg/kg, a dose which abolished the action of all caerulein doses on food intake, failed to alter the food intake either in obese or in lean rats when given without an agonist. The results suggest that the satiety effects of "near physiological" doses of caerulein in lean rats are mediated by vagal afferents whereas pharmacological doses act via non-vagal mechanisms. The differences in CCK's satiety effect between lean and obese rats may be due to differences in CCK-receptor binding and action at peripheral vagal sites. However, the failure of the CCK-A antagonist to increase food intake questions whether any of the effects of exogenous CCK are of physiological relevance.

Effects of CCK-receptor antagonist on colonic motor activity in dogs.

This study employed a cholecystokinin (CCK) antagonist to evaluate whether endogenous CCK regulates fasted and fed motor patterns of the colon. Experiments were performed in six conscious dogs, each in duplicate. Motor activity was recorded by four strain gauge transducers implanted on the colon. The effects of the CCK-analogue caerulein and the CCK-antagonist loxiglumide (Rotta, Italy) were studied in fasted and fed states. The motor activity was computed for the area under contractions. Caerulein given as an intravenous bolus of 50 ng kg-1 during a quiescent state caused a burst of phasic and tonic contractions resembling a regular non-migrating motor complex. Physiological doses of 10 ng kg-1 caerulein, which increases plasma CCK-immunoreactivity to postprandial levels, had no effect. Continuous intravenous infusion of 10 mg kg-1 h-1 loxiglumide completely abolished the effects of 50 ng kg-1 caerulein. The motor activity stimulated by the cholinesterase inhibitor neostigmine (10 micrograms kg-1) was not altered by loxiglumide. Loxiglumide given in the fasted state reduced the area under contractions in the proximal colon by 26.8 +/- 12.8% compared to the control without loxiglumide (P < 0.05). The postprandial increase in motor activity in the distal colon, the gastrocolonic response, was significantly inhibited by loxiglumide. Moreover, loxiglumide reduced the area under contractions in the fed state by 25.4 +/- 10.7% and 19 +/- 7.2% in the proximal and distal colon, respectively (P < 0.05). The present results show that loxiglumide acts as a specific antagonist of the actions of CCK on colonic motor activity in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)