The medical literature on pregnancy in primary biliary cirrhosis is restricted; it mostly dates from several decades ago and mostly reports a bad prognosis for the fetus as well as for the liver disease. We report experiences based on four pregnancies in three patients with primary biliary cirrhosis which are at variance with those reported earlier.

Wei G, Bergquist A, Broome U, Lindgren S, Wallerstedt S, Almer S, Sangfelt P, Danielsson A, Sandber-Gertzen H, Loof L, Prytz H, Bjomsson E (Sahlgrenska University Hospital, Gothenburg; Karolinska University Hospital, Huddinge, Stockholm; University Hospital MAS, Malmo; University Hospital, Linkoping; University Hospital, Uppsala; University Hospital, Umea; University Hospital, Orebro; Central Hospital, Vasteras; and University Hospital, Lund; Sweden). Acute liver failure in Sweden: etiology and outcome. J Intern Med 2007; 262: 393-401.Objective. To determine the causes and outcome of all patients with acute liver failure (ALF) in Sweden 1994-2003 and study the diagnostic accuracy of King's College Hospital (KCH) criteria and the model for end-stage liver disease (MELD) score with transplant-free deaths as a positive outcome.Research design and methods. Adult patients in Sweden with international normalized ratio (INR) of >= 1.5 due to severe liver injury with and without encephalopathy at admission between 1994-2003 were included.Results. A total of 279 patients were identified. The most common cause of ALF were acetaminophen toxicity in 42% and other drugs in 15%. In 31 cases (11%) no definite etiology could be established. The KCH criteria had a positive-predictive value (PPV) of 67%, negative-predictive value (NPV) of 84% in the acetaminophen group. Positive-predictive value and negative-predictive value of KCH criteria in the nonacetammophen group were 54% and 63% respectively. MELD score > 30 had a positive-predictive value of 21%, negative-predictive value of 94% in the acetaminophen group. The corresponding figures for the nonacetaminophen group were 64% and 76% respectively.Conclusions. Acetaminophen toxicity was the most common cause in unselected patients with ALF in Sweden. KCH criteria had a high NPV in the acetaminophen group, and in combination with MELD score < 30 predicts a good prognosis in acetaminophen patients without transplantation.

Collagenous colitis (CC) is an inflammatory bowel disease of unknown etiology. It is characterized by watery diarrhoea without blood, normal endoscopic findings but microscopically colonic mucosal ...

BACKGROUND & AIMS There is no medical treatment of proven benefit for primary sclerosing cholangitis. This study aimed at studying the effect of a higher dose of ursodeoxycholic acid than previously used on survival, symptoms, biochemistry, and quality of life in this disease. METHODS A randomized placebo-controlled study was performed in tertiary and secondary gastroenterology units. A total of 219 patients were randomized to 17 to 23 mg/kg body weight per day of ursodeoxycholic acid (n = 110) or placebo (n = 109) for 5 years. Follow-up data are available from 97 patients randomized to ursodeoxycholic acid and for 101 randomized to placebo. Quality of life was assessed by using the Medical Outcomes Study 36-item Short-Form Health Survey. RESULTS The combined end point "death or liver transplantation" occurred in 7 of 97 (7.2%) patients in the ursodeoxycholic acid group vs 11 of 101 (10.9%) patients in the placebo group (P = .368; 95% confidence interval, -12.2% to 4.7%). The occurrence of liver transplantation as a single end point showed a similar positive trend for ursodeoxycholic acid treatment (5/97 [5.2%] vs 8/101 [7.9%]; 95% confidence interval, -10.4% to 4.6%). Three ursodeoxycholic acid and 4 placebo patients died from cholangiocarcinoma, and 1 placebo patient died from liver failure. Alkaline phosphatase and alanine aminotransferase tended to decrease during the first 6 months. There were no differences between the 2 groups in symptoms or quality of life. Analyses of serum ursodeoxycholic acid concentration gave no evidence that noncompliance may have influenced the results. CONCLUSIONS This study found no statistically significant beneficial effect of a higher dose of ursodeoxycholic acid than previously used on survival or prevention of cholangiocarcinoma in primary sclerosing cholangitis.

OBJECTIVE:To elucidate the dynamics of the rectal inflammatory response to rectal gluten challenge in coeliac disease by measuring inflammatory mediators released by activated neutrophils, eosinophils and mast cells/basophils.MATERIAL AND METHODS:The release of myeloperoxidase (MPO), eosinophilic cationic protein (ECP) and histamine was measured continuously during the early challenge period (3-6 h after gluten challenge) in coeliac patients (n = 9) and healthy controls (n = 5). A segmental perfusion technique was used to carry out this part of the study. Another method, the mucosal patch technique, was used to enable studies of the late challenge period (5-48 h after gluten challenge) in coeliac patients (n = 10) and healthy controls (n = 15).RESULTS:During the early challenge period the MPO levels began to increase as early as 3 h after challenge and increased progressively (p < 0.001) during the next 3 h. A decline in MPO levels was seen 15 h after challenge and another phase of increasing levels at 24 h. The MPO values declined 48 h after challenge but still remained significantly increased (p < 0.05). The ECP levels started to increase 4 h after challenge and increased progressively during the next 2 h (p < 0.05). The ECP kinetics during the late challenge period was similar as for MPO but the relative increase in ECP was more modest. No increase in histamine was found except in one patient who had a transient, early increase of histamine (3-5 h after challenge). No signs of inflammatory reaction to gluten were seen in the controls.CONCLUSIONS:There is a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation is apparent 4 h after challenge and remains for at least 48 h. A more modest eosinophil activation defined by ECP levels starts 1-2 h later and also remains for at least 48 h. The biphasic pattern of MPO and ECP after challenge suggests a biphasic inflammatory reaction.

Background: Knowledge of the diagnostic work-up of colorectal cancer is a prerequisite to improve its quality. Family history is one of few known risk factors of the disease and it is therefore important to investigate to what extent this factor is used in routine management. Methods: Copies of records from all health-care suppliers visited during diagnostic work-up were requested for 227/235 (97%) patients with recently diagnosed colorectal cancer in the county of Vastmanland during 1998-99. A first consultation was identified and records and all diagnostic measures related to the initial consultation were scrutinized. A family history of colorectal cancer was known for 179 patients. Results: Most of the patients, 107 (66%) colon and 57 (86%) rectal cancer patients, had consulted with a general practitioner. The median diagnostic work-up time was 42 days (IQ 12-110) for colon and 23 days (IQ 0-49) for rectal cancer. A double-contrast barium enema was the most commonly used diagnostic method for colon cancer. Family history was documented at the first consultation in 2/179 (1%) cases. In patients with right-sided cancer, median diagnostic work-up time was 53 days in patients with a positive result of faecal occult blood test (FOBT) as compared with 448 in patients with a negative result (P < 0.01). Conclusion: Primary care is the key actor in diagnosing rectal cancer. The restricted capacity for X-ray is one of the main obstacles in detection of colon cancer. Family history is rarely documented during diagnostic work-up of colorectal cancer. The benefit of using FOBT in symptomatic patients is questioned.

BACKGROUND AND AIMS:There is a clear need for a rapid, simple, safe, and sensitive method of determining the type and intensity of inflammation in the gut mucosa in clinical practice. In this study, we have evaluated the potential of a new method, the mucosal patch technique, in patients with and without apparent gut inflammation, as assessed by conventional diagnostic procedures. SUBJECTS AND METHODS:The technique tested is based on the idea that inflammatory mediators released from the rectal mucosa can be absorbed by and then extracted from cellulose patches brought into contact with the mucosa by use of an instrument with an inflatable balloon. Measurements were performed in healthy controls (n = 16) and in patients with active (n = 19) and inactive ulcerative colitis (UC, n = 8), collagen colitis (CC, n = 12), coeliac disease (n = 13), and irritable bowel syndrome (IBS, n = 13). RESULTS:Inflammatory mediators from neutrophils (myeloperoxidase (MPO)) and eosinophils (eosinophil cationic protein (ECP)) were increased on average 300- and 10-fold, respectively, in patients with active UC compared with healthy controls and were correlated with the endoscopic score. Patients with inactive UC, CC, coeliac disease, and IBS exhibited no endoscopic signs of inflammation. These patient groups had significantly lower levels of MPO and ECP than the active UC group but showed on average a four- to sevenfold increase in MPO compared with healthy controls. CONCLUSION:The mucosal patch technique was well tolerated by patients and easily applied by the investigator. Pronounced neutrophil and eosinophil involvement in UC was demonstrated. With the high sensitivity of the technique, low degree mucosal neutrophil activation could also be quantified in patients with CC and UC in clinical remission. The finding of increased neutrophil involvement in patients with IBS contributes to the pathophysiological ideas of this disease.

Objectives.  The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT.

BACKGROUND & AIMS Iron overload may be carcinogenic. Patients with hereditary hemochromatosis (HH) are reportedly at a 20-200-fold risk of intrahepatic cancer, but the reported risks for nonhepatobiliary cancers are conflicting. The risk of cancer in heterozygous individuals (estimated allele frequency, 1/10 to 1/20) is unknown. This study aimed to better assess these risks. METHODS We performed a population-based cohort study of 1847 Swedish patients with HH and 5973 of their first-degree relatives using nationwide, population-based health and census registers. We used standardized incidence ratios (SIRs) as relative risk. RESULTS With 62 liver cancers and 128 nonhepatobiliary cancers, patients with HH were at a 20-fold risk of liver cancer (SIR, 21; 95% confidence interval [CI], 16-22) but an almost unaltered risk of all other cancers (SIR, 1.2; 95% CI, 1.0-1.4), including nonelevated risks for several gastrointestinal tract cancers. At 10 years of follow-up, the absolute risk of liver cancer was 6% among men and 1.5% among women. With 21 liver cancers and 508 nonhepatobiliary cancers, first-degree relatives were at an unaltered risk of extrahepatic cancer (SIR, 1.0; 95% CI, 0.9-1.1, including unelevated risks for gastrointestinal cancers) but at a modest and historic increased risk of hepatobiliary cancer (SIR, 1.5; 95% CI, 1.0-2.4), the histopathologic spectrum of which differed from the patients. CONCLUSIONS Patients (particularly men) with HH are at increased risk for hepatocellular cancer, although the magnitude of the risk is lower than previous estimates. Overall cancer risk in first-degree relatives does not seem to be increased.

OBJECTIVES:Collagenous colitis (CC), a condition of unknown ethiology and pathophysiology, is characterized by watery diarrhea and increased amounts of collagen in the colonic mucosa. Basic fibroblast growth factor (bFGF) is a potent multifunctional growth factor that stimulates proliferation and differentiation of fibroblasts that was recently detected in high intraluminal concentrations in patients with ulcerative colitis. In this study we examined the secretion and expression of bFGF in the colorectal mucosa of patients with CC.METHODS:Ten CC patients and 10 control patients underwent colonoscope-based segmental perfusion of the descending colon and rectum. The concentrations of bFGF in perfusate and serum were determined by immunochemical methods, and the expression of bFGF was analyzed immunohistochemically in biopsy samples from colonic mucosa.RESULTS:The median concentrations of bFGF in perfusates from the descending colon and rectum were increased 4-fold in CC patients compared with control patients. The median concentration of bFGF in serum was not significantly different in patients and controls. Immunohistochemical staining of bFGF was located in the colorectal epithelial cells and in exsudate on the luminal side of these cells. In the lamina propria, inflammatory cells and fibroblasts contained bFGF. There were no differences in the intensity of bFGF staining in surface epithelium or lamina propria between patients and controls.CONCLUSION:Local investigation of the colorectal mucosa seems to be crucial when studying the pathophysiology of CC. Increased colorectal mucosal secretion of bFGF in patients with CC may promote differentiation of fibroblasts and thereby lead to increased subepithelial collagen deposition.

Genetic susceptibility to PBC can, at least in part, be ascribed to the major histocompatibility complex. The relevance of immunogenetic markers for the clinical presentation and course, however, is unclear. Thus, the aim of this study was to investigate the contribution of HLA class II genes to susceptibility, clinical presentation and course of disease in PBC patients. HLA genotyping for HLA-DRB1, -DQB1 and -DPB1 was carried out in a total of 99 Swedish PBC patients and 158 controls. Clinical parameters including epidemiologic variables, signs and symptoms of PBC-related liver disease and histologic data were collected and analyzed in 92 patients at study entry and at follow-up five years later. Significant clinical heterogeneity was seen among PBC patients upon study entry. Although a significant disease association was seen for HLA DRB1*08 and DQB1*0402, immunogenetic markers identified neither a particular subset of patients nor an association with the clinical course of the disease. HLA-DRB1*08 and DQB1*0402 provide the strongest immunogenetic influence in PBC. However, this association is not restricted to any particular, clinically defined subgroup of patients and it is not predictive for the course of the disease.

OBJECTIVE:Patients with chronic liver disease (CLD) have an increased prevalence of osteoporosis. The aim of this study was to evaluate prospectively the rate of bone loss and potential predictors of increased bone loss in a cohort of patients with CLD. DESIGN:Bone mineral density (BMD) was measured at baseline and at follow-up by dual-energy X-ray absorptiometry at the lumbar spine and the femoral neck. RESULTS:Forty-three patients (31 female, 12 male) were available for a second measurement of BMD, with a median of 25 months (range 18-41) between the measurements. Mean annual bone loss at the lumbar spine and the femoral neck, respectively, was 0.6 +/- 2.0% and 1.5 +/- 2.4% in females and 0.8 +/- 1.9% and 2.9 +/- 2.0% in males. The BMD Z score decreased significantly over time at the femoral neck (P = 0.005 and P = 0.02 for females and males, respectively). Bone loss was increased significantly at the lumbar spine in patients classified as Child-Pugh B + C compared with those classified as Child-Pugh A (P = 0.04). Serum levels of bilirubin correlated independently and positively, and 25-hydroxy vitamin D3 levels negatively, with bone loss at the femoral neck. CONCLUSIONS:Patients with CLD have increased bone loss at the femoral neck. Advanced liver disease is associated with increased bone loss, and hyperbilirubinaemia and low levels of vitamin D3 are predictors of increased bone loss.

Background/Aims: This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC).Methods: Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months.Results: All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC.Conclusions: Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found. (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

OBJECTIVES/DESIGN:Increased rate of bone loss has been reported in women with primary biliary cirrhosis (PBC) and varying degree of liver dysfunction. Whether bone loss is increased in patients without liver dysfunction is unclear. The aim of this study was to estimate retrospectively the rate of bone loss in postmenopausal women with PBC and well-preserved liver function.SUBJECTS/INTERVENTIONS:Forty-three women with PBC, and classified as Child-Pugh class A, were included. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at the lumbar spine and the femoral neck.RESULTS:Median time between measurements of BMD was 26 months (range, 12-48 months). Twenty women were not receiving any bone protective treatment, i.e. hormone replacement therapy (HRT), bisphosphonates or vitamin D/calcium supplementation, whilst 23 women received such treatment. Mean annual bone loss in the former group was 0.38 +/- 2.56% and 0.42 +/- 2.29% at the lumbar spine and the femoral neck, respectively. Women receiving treatment, however, increased their BMD by 1.92 +/- 3.76% and 0.15 +/- 2.75% at the lumbar spine and the femoral neck, respectively. At the lumbar spine the difference with regard to changes in BMD between untreated and treated women was statistically significant (P = 0.02). Women who received HRT (n = 11) increased their BMD at the lumbar spine by 2.95 +/- 3.91%, P = 0.03 when compared with untreated women.CONCLUSION:Bone loss in postmenopausal women with PBC and well-preserved liver function is not increased above normal. Treatment with bone protective treatment, mainly HRT, improves BMD at the lumbar spine.

Background and Aim: The pathophysiology of osteoporosis complicating chronic liver disease is unknown. Recent animal studies have found leptin to be a potent inhibitor of bone formation. The aim of this study was to investigate the relationship between serum leptin levels and bone mineral density in patients with chronic liver disease.

As ascites is related to liver cirrhosis in 80% of the patients, the present therapeutic guidelines are focused on ascites in liver cirrhosis. A combination of spironolactone and furosemide is recommended as first line therapy in patients with mild to moderate ascites and is effective in 90% of patients. In patients with pronounced or tense ascites, first line treatment is total paracentesis with intravenous infusion of human albumin as colloid replacement. Maintenance therapy for the prevention of recurrent ascites is based on spironolactone with or without furosemide. The indications for peritoneovenous shunt, or transjugular intrahepatic stent-shunt (TIPSS), are limited and only recommended in strictly selected patients with refractory ascites. Ascites in liver cirrhosis is a symptom of advanced liver disease, and liver transplantation should always be considered in eligible patients.

further and easy diagnostic tool to montitor clinical disease activity in ulcerative colitis, which seems to be strongly infuenced by eosinophil granulocytes. 1432

BACKGROUND/AIMS:Insulin-like growth factor-I (IGF-I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF-I levels and BMD in patients with CLD of other causes.METHODS:Fifty-eight patients with CLD were included. Age- and sex-matched normal individuals served as controls. Serum levels of IGF-I and IGF-II and their binding proteins (IGFBP-1-3) were measured by radioimmunoassay. BMD was measured by dual energy X-ray absorptiometry.RESULTS:IGF-I levels were 57+/-33 and 136+/-48 ng/ml; p<0.0001 in patients and controls, respectively. IGF-II and IGFBP-3 levels were lower (p<0.0001) and IGFBP-1 and IGFBP-2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP-2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF-I, IGF-II, IGFBP-1-3 and BMD in either patients or controls.CONCLUSION:Patients with CLD have low levels of IGF-I, IGF-II and IGFBP-3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.

OBJECTIVE: The pathophysiological role of neutrophil and eosinophil granulocytes in relation to steroid enema treatment was studied in patients with distal ulcerative colitis and proctitis. METHODS: The rectal release of the neutrophil (myeloperoxidase, MPO), and eosinophil (eosinophilic cationic protein, ECP and eosinophil peroxidase, EPO) granule constituents were measured in 11 patients using intraluminal segmental perfusion of the rectum. The released amounts of MPO, ECP, and EPO in the perfusion fluids were determined by radioimmunoassays before and during prednisolone enema treatment and related to clinical, endoscopical, and histopathological data in addition to treatment outcome. RESULTS: Clinical activity and particularly endoscopic activity correlated well with intraluminal MPO concentrations both before and during treatment. At the end of the study, eight of 11 patients fulfilled predefined response criteria; all responding patients had significant decrease of MPO concentrations (p < 0.01). This decline of MPO concentration was seen after 7 days of treatment (p < 0.05) in the response group and often occurred before clinical improvement. There was a nonsignificant trend toward a decrease in the concentrations of ECP and EPO at the end of treatment in responders. CONCLUSIONS: In patients with distal ulcerative colitis and proctitis, neutrophil activation determined, as a release of MPO is an early marker of treatment response. Eosinophil activation measured as a release of ECP and EPO correlates with endoscopic activity, but the relationship to treatment outcome is less clear.