Peter N. Meier

Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis : A single center study

OBJECTIVES:Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with varying severity and progression. This study describes the natural history of PSC patients and evaluates the prognostic significance of clinical, biochemical, and cholangiographic findings constructing a novel prognostic model.METHODS:A population of 273 German PSC patients was studied with a median follow-up time of 76 months (range 1–280 months). Survival curves were analyzed by the Kaplan-Meier method, and prognostic significance of clinical, biochemical, and cholangiographic features recorded at the time of diagnosis was evaluated by multivariate analysis using Cox proportional-hazards regression models.RESULTS:The estimated median survival from the time of diagnosis to death or time of liver transplantation was 9.6 yr. One hundred eight (39.6%) patients underwent liver transplantation. Hepatobiliary malignancies were found in 39 (14.3%) patients of the entire PSC population. Age, low albumin, persistent bilirubin elevation longer than 3 months, hepatomegaly, splenomegaly, dominant bile duct stenosis, and intra- and extrahepatic ductal changes at the time of diagnosis were found to be independent risk factors correlating with poor prognosis and were used to construct a new prognostic model.CONCLUSIONS:A persistent bilirubin elevation for longer than 3 months from the time of diagnosis could be identified as a novel marker correlating with a poor outcome. A new prognostic model was developed to predict progression of PSC, which may be useful in timing of liver transplantation.

Quantitative assessment of intestinal eosinophils and mast cells in inflammatory bowel disease

Previous studies on the frequency of intestinal mast cells and eosinophils in patients with inflammatory bowel disease yielded conflicting results. In the present morphometric study, we quantified mast cells and eosinophils in the lamina propria by histological and immunohistochemical methods in 64 patients suffering from Crohn’s disease (33 cases) or ulcerative colitis (31 cases), and in 29 controls. Histological data from 206 biopsies were related to the presence of mucosal inflammation and clinical parameters. The number of eosinophils was increased in patients with inflammatory bowel conditions (mean ± SE: 331 ± 44/mm2) as compared to controls (258 ± 27/mm2), and was dependent on disease activity and drug treatment. Mean mast cell numbers did not differ between patients and controls. However, a reduced mast cell number was found in toluidine blue‐stained sections of actively inflamed tissue areas (143 ± 16/mm2, versus 206 ± 18/mm2 in non‐inflamed tissue). Immunohistochemical studies using antibodies against the granule proteins tryptase and chymase suggest that this decrease in mast cell numbers is due to mast cell degranulation. The present data show that the number of intestinal mast cells and eosinophils is altered in patients with inflammatory bowel diseases, suggesting that both cell types are involved in the pathogenesis of chronic intestinal inflammation.

Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract

Background and aims: Histamine is known as a regulator of gastrointestinal functions, such as gastric acid production, intestinal motility, and mucosal ion secretion. Most of this knowledge has been obtained from animal studies. In contrast, in humans, expression and distribution of histamine receptors (HR) within the human gastrointestinal tract are unclear. Methods: We analysed HR expression in human gastrointestinal tissue specimens by quantitative reverse transcription-polymerase chain reaction and immunostaining. Results: We found that H1R, H2R, and H4R mRNA were expressed throughout the gastrointestinal tract, while H3R mRNA was absent. No significant differences in the distribution of HR were found between different anatomical sites (duodenum, ileum, colon, sigma, and rectum). Immunostaining of neurones and nerve fibres revealed that H3R was absent in the human enteric nervous system; however, H1R and H2R were found on ganglion cells of the myenteric plexus. Epithelial cells also expressed H1R, H2R and, to some extent, H4R. Intestinal fibroblasts exclusively expressed H1R while the muscular layers of human intestine stained positive for both H1R and H2R. Immune cells expressed mRNA and protein for H1R, H2R, and low levels of H4R. Analysis of endoscopic biopsies from patients with food allergy and irritable bowel syndrome revealed significantly elevated H1R and H2R mRNA levels compared with controls. Conclusions: We have demonstrated that H1R, H2R and, to some extent, H4R, are expressed in the human gastrointestinal tract, while H3R is absent, and we found that HR expression was altered in patients with gastrointestinal diseases.

Reconstructive surgery for ischemic-type lesions at the bile duct bifurcation after liver transplantation.

OBJECTIVE To assess the feasibility, morbidity, mortality, and clinical success rate of surgical reconstruction of the biliary system in patients with ischemic-type biliary lesions in their liver graft. SUMMARY BACKGROUND DATA After liver transplantation, strictures in the biliary tree with secondary sludge formation can occur in the absence of vascular problems. Jaundice, pruritus, and recurrent cholangitis are predominant clinical features leading to considerable morbidity. Interventional measures are the first-line treatment but are frequently only of transient success. Retransplantation is usually considered when interventional treatment is not effective. METHODS Surgical exploration and reconstruction was performed in 17 patients with ischemic-type biliary strictures at a median of 2 years after liver transplantation. Findings during surgery, surgical strategies, and postsurgical courses are described. Clinical symptoms and biochemical parameters of cholestasis and liver function were analyzed in the postsurgical course. RESULTS During surgery, all 17 patients were found to have strictures or sclerotic changes involving the hepatic bifurcation and extrahepatic bile duct. Sludge or stones were present in nine patients. In 14 patients with viable bile ducts proximal to the bifurcation, surgical reconstruction was performed by resection of the bifurcation and hepaticojejunostomy. In three patients with more extensive biliary destruction, portoenterostomy with or without peripheral hepatojejunostomy was performed. The prevalence rate of biliary infection at surgery was 93%; the predominant organisms were Candida and enterococci. The perioperative mortality rate was 0%. Clinical symptoms and biochemical parameters became normal or were considerably improved in 14 of 16 patients (88%). CONCLUSIONS The hepatic bifurcation seems to be a predominant site for ischemic-type biliary changes after liver transplantation. Surgical treatment by resection of the bifurcation and reconstruction by high hepaticojejunostomy is a safe and highly effective approach leading to cure or persistent major improvement in most patients.

Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer

Background and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation. Methods: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation. Results: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma—high grade dysplasia with minimal invasive growth—compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells. Conclusions: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.

Enhanced production of monocyte chemotactic protein 3 in inflammatory bowel disease mucosa

BACKGROUND The β chemokine monocyte chemotactic protein 3 (MCP-3) has chemoattractant and activating capabilities in monocytes, lymphocytes, eosinophils, and basophils. AIMS To investigate MCP-3 expression in inflammatory conditions of the human intestinal mucosa. PATIENTS Forty five colon biopsy specimens from 18 patients with inflammatory bowel disease (IBD; 16 specimens from inflamed and 10 from non-inflamed areas) and 19 control patients were examined. METHODS Immunohistochemical staining and reverse transcription polymerase chain reaction (RT-PCR) were used for MCP-3 detection in tissue sections. Intestinal epithelial cell lines (HT-29, Caco-2, T-84) were stimulated with interleukin (IL) 1β, IL-6, and tumour necrosis factor α (TNF-α) and examined for MCP-3 protein and mRNA expression using immunocytochemistry and RT-PCR, respectively. RESULTS In tissue sections, MCP-3 protein was detected predominantly in epithelial cells, both in patients with IBD and in controls. MCP-3 staining was particularly pronounced at sites of active mucosal inflammation. The intensity of MCP-3 staining was positively correlated with the extent of epithelial destruction. In intestinal epithelial cell lines, MCP-3 mRNA was expressed, whereas MCP-3 protein was not consistently detected. CONCLUSIONS Our data show that MCP-3 protein is present in normal and inflamed intestinal tissue. MCP-3 production is substantially enhanced in areas of active inflammation, suggesting an immunoregulatory role of MCP-3 in intestinal inflammation.

K-ras mutations in the bile of patients with primary sclerosing cholangitis

BACKGROUND AND AIMS The development of cholangiocarcinoma (CCC) is a complication of primary sclerosing cholangitis (PSC). To date, no reliable factors have been described which can define those PSC patients at high risk for the development of CCC and the clinical diagnosis of CCC in PSC patients is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as K-ras mutations, may improve the early diagnosis of CCC or the timing of liver transplantation. METHODS K-ras mutations were analysed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of K-ras mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months. RESULTS In contrast with the control group, 17 (30%) patients with PSC revealed K-ras mutations in bile fluid. The mean Mayo score was not significantly different between PSC patients with (mean score 0.70) and without (mean score 0.13; p=0.2) K-ras mutations. In contrast with the group of PSC patients without K-ras mutations, four CCCs and two dysplasia were diagnosed in the group of patients with K-ras mutations during the follow up investigation (p<0.001). CONCLUSIONS Our results indicate that K-ras mutations in bile fluid of PSC patients represent frequent early events during cholangiocarcinogenesis. However, most of the PSC patients with K-ras mutations remained tumour free after a long follow up investigation which is in agreement with the fact that these mutations are not specific for malignancy but may also occur in normal bile duct mucosa or in dysplasias. Therefore, analysis of K-ras mutations in bile should not be used for diagnosis of CCC in PSC patients. However, the results of our prospective follow up investigation indicate that K-ras mutations in bile fluid of PSC patients have to be considered as risk factors for the development of CCC which may have implications for the timing of liver transplantation.

Transpapillary intraductal ultrasound in the evaluation of dominant bile duct stenoses in patients with primary sclerosing cholangitis

Objective. Primary sclerosing cholangitis (PSC) is associated with the development of cholangiocarcinoma (CC) in approximately 9% of patients. Neither cholangiography nor endoscopic tissue sampling can reliably distinguish between CC and benign dominant bile duct stenosis. The aim of the present study was to assess the value of intraductal ultrasonography (IDUS) in distinguishing between benign and malignant dominant stenoses in PSC patients. Material and methods. Forty PSC patients with dominant bile duct stenoses were studied prospectively. Transpapillary IDUS and endoscopic tissue sampling were performed in addition to endoscopic retrograde cholangiography (ERC). Cholangiography and IDUS findings were classified as malignant or benign by the investigators. Final diagnosis of malignant stenosis was based on positive histology and/or cytology, whereas a benign character was assumed in cases of negative tissue sampling and uneventful extended clinical follow-up. Results. Eight PSC patients (20%) had dominant bile duct stenoses caused by CC, whereas 32 out of 40 patients (80%) had benign dominant bile duct stenoses. IDUS was significantly superior to ERC for detection of malignancy in terms of sensitivity (87.5% versus 62.5%, p=0.05), specificity (90.6% versus 53.1%, p<0.001), accuracy (90% versus 55%, p<0.001), positive predictive value (70% versus 25%, p<0.001), and negative predictive value (96.7% versus 85%, p=0.049). Conclusions. Transpapillary IDUS significantly increases the ability to distinguish malignant from benign dominant bile duct stenoses in patients with PSC.

Characterization and clinical course of hepatobiliary carcinoma in patients with primary sclerosing cholangitis

Objective. Primary sclerosing cholangitis (PSC) confers a high risk of development of hepatobiliary carcinoma (HBC). The aim of the study was to identify indicators and risk factors for developing HBC in PSC patients. Material and methods. Thirty-nine PSC patients with HBC at time of HBC diagnosis were compared with 101 PSC patients without HBC at time of acceptance for liver transplantation. Results. Eighteen of these patients (46.2%) developed HBC within one year after diagnosis of PSC. In PSC patients with HBC male gender, nicotine abuse, long duration of inflammatory bowl disease (IBD), clinical symptoms, elevation of CA 19-9, as well as dominant bile duct stenosis were significantly more frequent (p<0.05) compared with the PSC control group. A cross-validated sensitivity and specificity of 85% and 97%, respectively, for the detection of HBC was obtained using the following parameters: weight loss, elevation of CA 19-9 ≥ 200 kU/l, and dominant bile duct stenosis. Conclusions. HBC is not necessarily a late complication of end-stage PSC. A long history of IBD, male gender, and nicotine abuse are risk factors for the development of HBC. In particular, CA 19-9, body-weight and dominant bile duct stenosis are valuable indicators in detecting HBC in PSC patients.

Percutaneous sonographic gastrostomy: method, indications, and problems

Objectives:This study evaluated the application of ultrasound (US) guidance in the percutaneous placement of gastric feeding tubes in patients in whom endoscopic placement of a nutrition tube is not possible.Methods:Thirty-eight patients with upper gastrointestinal obstruction were entered in a prospective study with US-guided nutrition tube application. Feasibility of placement, side effects, and nutritional states were monitored for a mean follow-up of 4 months.Results:Ultrasound allowed rapid puncture after filling of the stomach with water through a nasal tube in 34/38 cases. In four cases a total upper gastrointestinal obstruction required an initial stomach insufflation through a direct puncture. Puncture-related major complications were not observed. Minor complications during the observation time were one late dislocation, five cases with broken material after about 6 months (four could be changed by using the Seldinger technique), and two minor local infections. The nutrition through feeding tubes stabilized body weight and body composition parameters.Conclusion:The percutaneous sonographic gastrostomy (PSG) is a safe and minimally invasive procedure for enteral nutrition in all cases with upper gastrointestinal obstruction when endoscopic placement of a feeding tube is not possible. Percutaneous sonographic gastrostomy may help to stabilize the nutritional parameters and general condition in patients with malignant diseases.