Gd-EOB-DTPA-enhanced MRI for the assessment of liver function and volume in liver cirrhosis.

OBJECTIVE: The aims of this study were to use dynamic hepatocyte-specific contrast-enhanced MRI to evaluate liver volume and function in liver cirrhosis, correlate the results with standard scoring models and explore the inhomogeneous distribution of liver function in cirrhotic livers. METHODS: 10 patients with liver cirrhosis and 20 healthy volunteers, serving as controls, were included. Hepatic extraction fraction (HEF), input relative blood flow and mean transit time were calculated on a voxel-by-voxel basis using deconvolutional analysis. Segmental and total liver volumes as well as segmental and total hepatic extraction capacity, expressed in HEFml, were calculated. An incongruence score (IS) was constructed to reflect the uneven distribution of liver function. The Mann-Whitney U-test was used for group comparison of the quantitative liver function parameters, liver volumes and ISs. Correlations between liver function parameters and clinical scores were assessed using Spearman rank correlation. RESULTS: Patients had larger parenchymal liver volume, lower hepatocyte function and more inhomogeneous distribution of function compared with healthy controls. CONCLUSION: The study demonstrates the non-homogeneous nature of liver cirrhosis and underlines the necessity of a liver function test able to compensate for the heterogeneous distribution of liver function in patients with diseased liver parenchyma. ADVANCES IN KNOWLEDGE: The study describes a new way to quantitatively assess the hepatic uptake of gadoxetate or gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid in the liver as a whole as well as on a segmental level.

Altered immunoregulatory profile during anti-tumour necrosis factor treatment of patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) can be treated effectively by anti-tumour necrosis factor (TNF) therapy. We set out to investigate the unclear immunoregulatory mechanisms of the treatment. Thirty-four patients with IBD treated with anti-TNF were included. Lymphocytes from peripheral blood and intestinal biopsies were analysed by flow cytometry. Regulation of antigen-stimulated proliferation was analysed by blocking of interleukin (IL)-10, transforming growth factor (TGF)-ß or depletion of CD25(+) cells in peripheral blood mononuclear cell cultures. No changes in CD4(+)CD25(+), CD25(+)TNF-RII(+) or CD4(+)CD25(+) forkhead box protein 3 (FoxP3(+)) T cells could be observed in peripheral blood after, in comparison to before, 6 weeks of treatment. The suppressive ability of CD4(+)CD25(+) cells did not change. There was an initial decrease of CD4(+)CD25(+) cells in intestinal mucosa after 2 weeks of treatment, followed by an increase of these cells from weeks 2 to 6 of treatment (P < 0·05). This was accompanied by an increased percentage of CD69(+) cells among these cells after 6 weeks of treatment compared to before treatment (P < 0·01). There was also an increase of mucosal T helper type1 cells from weeks 2 to 6 (P < 0·05). In addition, CD25(+)TNF-RII(+) cells in the mucosa were decreased after 6 weeks of treatment compared to before treatment (P < 0·05). Before treatment, peripheral blood mononuclear cell baseline proliferation was increased when IL-10 was blocked (P < 0·01), but not after. In CD25(+) cell-depleted cultures proliferation increased after treatment (P < 0·05). Our data indicate that anti-TNF treatment leads to an induction of effector T cells. Anti-TNF therapy has no significant impact on regulatory T cells in IBD, although the composition of regulatory T cell subsets may change during treatment.

Clinical application of the multigene analysis test in discriminating between ulcerative colitis and Crohn's disease: a retrospective study.

METHODS: The newly described--multigene analysis test (DiBiCol) identifying 7 inflammatory bowel disease (IBD)-specific genes in colonic mucosal biopsy differentiating between ulcerative colitis (UC) and Crohn's disease (CD) with active inflammation--is a new addition to existing methods with a higher stated sensitivity and specificity. Method biopsy material from 78 patients with a complicated course diagnosed as most probably UC in 38, CD in 18 and inflammatory bowel disease unclassified (IBDU) in 22 were investigated by DiBiCol. RESULTS: DiBiCol showed a pattern consistent with CD in 13 patients with UC and led to change of diagnosis in 3 patients and a strong suggestion of CD in 8 patients. A total of 2 patients remained as UC. DiBiCol showed a pattern of UC in 4 patients of 18 with CD leading to a changing of diagnosis to UC in 3 patients, but the fourth remained as CD. In 22 patients with IBDU DiBiCol showed a pattern consistent with UC in 7 cases and with CD in 13 cases. A new evaluation 1 year after the DiBiCol allowed the assessment of clinical diagnosis in 10 patients confirmed in 9 of 10 patients by DiBiCol. In patients with acute flare of colitis the clinical diagnosis corresponded in 10 of 12 UC and in 5 of 6 CD cases. SUMMARY: Adopting the DiBiCol test led to a change of the primary diagnosis in a significant number of patients with the initial diagnosis of UC and CD and suggested a clinically probable diagnosis in most of the patients with IBDU and in those with an acute flare of colitis.

Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County.

BACKGROUND: Several placebo controlled studies have demonstrated the efficacy of infliximab in inflammatory bowel disease (IBD) but the potential toxicity of this new biological compound has been less studied. AIM: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality. PATIENTS: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated. METHODS: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure. RESULTS: A cohort comprising 217 patients was assembled: 191 patients had Crohn's disease (CD), and infliximab was used off label for ulcerative colitis (UC) in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8-79). The mean number of infliximab infusions was 2.6 (0.1) (range 1-11). Forty two severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which two were fatal), opportunistic infections occurred in two patients (one with UC, fatal), and two patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25-79). The overall response rate was 75% and did not differ between the patient groups. CONCLUSIONS: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.

Primary AL-amyloidosis, ulcerative colitis and collagenous colitis in a 57-year-old woman: a case study.

A 57-year-old woman with AL-amyloid deposits in the heart, gastrointestinal tract and the liver developed ulcerative colitis, which was treated with glucocorticosteroids and 5-aminosalicylic acid, with good response. The AL-amyloidosis was successfully treated with high-dose chemotherapy and autologous stem-cell transplantation. The patient was in good clinical condition for 18 months after treatment, until she developed diarrhea, which was found to be due to collagenous colitis. Two years after treatment of amyloidosis, the patient is in excellent condition, the symptoms of heart failure have stabilized and no adverse effects of the treatment regime have been observed. The bowel diseases are in clinical remission.

Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment.

BACKGROUND: The S-mephenytoin hydroxylase is a polymorphic cytochrome P450 (CYP) enzyme, identified as CYP2C19, which catalyses the metabolism of omeprazole and some other drugs. AIM: To determine whether long-term treatment with omeprazole affects serum vitamin B12 levels, and if so to what extent it depends on CYP2C19 activity. METHODS: Serum vitamin B12 levels (pmol/L) were assessed in 179 patients. Genotyping for wild-type (wt) and mutated (mut) CYP2C19 alleles was performed by allele-specific PCR amplification. RESULTS: One-hundred and eleven of the patients received one dose of 20 mg omeprazole. No difference in B12 levels were found between heterozygous (wt/mut) (n = 23) and homozygous (wt/wt) (n = 85) patients (mean +/- s.d., 350 +/- 82 vs. 315 +/- 87 pmol/L, respectively). Three patients were mut/mut, with serum vitamin B12 levels of 303 +/- 50 pmol/L. In the 68 patients on long-term (>1 year) therapy with 20 mg omeprazole daily, serum vitamin B12 levels were lower in the heterozygous (wt/mut) (n = 19) compared to homozygous wt/wt (n = 49) (246 +/- 71 vs. 305 +/- 98 pmol/L, P = 0. 01, respectively). In one patient (mut/mut) who was studied both after a single dose and after long-term (15 months) treatment with omeprazole, serum vitamin B12 decreased from 360 to 178 pmol/L. In the wt/mut, but not in the wt/wt group, serum vitamin B12 levels were significantly lower in patients on long-term therapy compared with those receiving one dose (246 +/- 71 vs. 350 +/- 82 pmol/L, P < 0.0001, respectively). CONCLUSIONS: CYP2C19 polymorphism significantly affected serum vitamin B12 levels in patients on long-term therapy with omeprazole. In the future, genotyping of CYP2C19 may be useful for patients in need of long-term treatment with omeprazole or other proton pump inhibitors.

Comparison of the effect of lansoprazole and omeprazole on intragastric acidity and gastroesophageal reflux in patients with gastroesophageal reflux disease.

BACKGROUND: Lansoprazole (LAN) and omeprazole (OME) heal esophagitis effectively and to similar extents, but LAN has a faster effect on the relief of symptoms of gastroesophageal reflux. However, no strict comparison of the two proton pump inhibitors' effect on acid reflux and gastric acidity has been published. The aim of this study was to compare the effects of LAN and OME on gastroesophageal reflux with simultaneous measurements of gastric acidity in patients with established gastroesophageal reflux disease (GERD) and esophagitis. METHODS: Fourteen patients with endoscopically verified erosive esophagitis and with a pretreatment esophageal 24-h pH measurement showing acid reflux to the esophagus participated in the study. This was a double-blind, randomized study with crossover design. Before (day 0) and on the last day (day 5) of each treatment period with encapsulated 30 mg LAN or 20 mg OME daily, 24-h intraesophageal and intragastric acidity were measured with antimony electrodes connected to an ambulatory pH recording system. RESULTS: Ten of 14 patients completed the study. There were no differences in intragastric or intraesophageal acidity or the number of reflux episodes on day 0 between the two treatments. Both LAN and OME treatments increased the median and nocturnal intragastric pH and decreased the 24-h area under the time curve for intragastric acidity significantly and to about the same extent (79% and 69% acid inhibition by LAN and OME, respectively) (NS). However, the percentage of time with pH below 4 in the esophagus was significantly less during LAN treatment (1.92% +/- 2.29; mean +/- standard deviation) than during OME treatment (4.76% +/- 2.88%) on day 5 (P = 0.002). There were also significantly fewer reflux episodes >5 min during treatment with LAN (1.00 +/- 1.33) than with OME (2.90 +/- 2.42) at the end of the treatment period (P = 0.031). CONCLUSIONS: In this study lansoprazole and omeprazole had a comparable effect on gastric acidity in patients with established GERD with esophagitis. However, 30 mg lansoprazole daily reduced the acidity in the oesophagus and the number of refluxes more effectively than 20 mg omeprazole daily. This might indicate that proton pump inhibitors affect the esophageal clearance and/or influence the lower esophageal sphincter differently.

Twenty-four-hour basal and repetitive pentagastrin-stimulated gastric acid secretion in normal and sham-operated rats and in rats after gonadectomy or treatment with estradiol or testosterone.

BACKGROUND: Studies in different species have suggested, but not established, that sex hormones influence gastric acid secretion. We studied how acid output is affected by the sex hormones estradiol or testosterone in vivo and in vitro. METHODS: In gastric fistula rats that were normal, sham-operated, neonatally gonadectomized, or treated with estradiol or testosterone, 24-h basal and pentagastrin-stimulated acid secretion was measured. The in vitro effects of estradiol and testosterone on histamine-induced aminopyrine accumulation in isolated parietal cells were also determined. RESULTS: Basal acid output was similar in the two sexes, but stimulated secretion was significantly higher (34%; P < 0.01) in males. Ovariectomy did not influence acid output, whereas orchidectomy reduced basal (18%; NS) and stimulated 24-h secretion (P < 0.01). Estradiol decreased (23%; NS) the 24-h basal output in females but not in males. Estradiol suppressed stimulated secretion in females (29%, P < 0.01) and males (42%, P < 0.01) during the day. At night the stimulated secretion increased in both females (17%, NS) and males (32%, P < 0.05). A similar pattern was found when rats were treated with testosterone. In vitro, estradiol and testosterone reduced histamine-stimulated aminopyrine accumulation in both female and male isolated parietal cells. CONCLUSIONS: Estradiol and testosterone both appear to influence gastric secretion in rats, and their action differs between day and night, between the sexes, and between basal and stimulated secretion.

Pregnancy in patients with primary sclerosing cholangitis.

A deterioration of liver function may occur during pregnancy in patients with chronic liver disorder. Primary sclerosing cholangitis (PSC) is a chronic progressive liver disorder with a highly variable and fluctuating course. This study aims at investigating the outcome of pregnancy in patients with PSC and, conversely, the effect of pregnancy on the disease. Thirteen pregnancies in 10 patients with PSC (4 with liver cirrhosis, 6 with mild liver disease) were observed. Seven patients had PSC before pregnancy, 2 developed the disease during pregnancy, and one patient developed PSC 2 months after a normal pregnancy with a normal delivery. Clinical symptoms and biochemical analyses were routinely evaluated during the pregnancy. No gastrointestinal haemorrhage was observed during the pregnancy. Two patients had pruritus and 2 abdominal pain before pregnancy, and these symptoms continued during pregnancy. Abdominal pain was noted in 3 patients lacking this symptom before pregnancy. Four patients without pruritus prior to pregnancy developed this symptom during the pregnancy. In two patients, pruritus was so intense as to bring on premature delivery. Liver tests did not indicate any deterioration during pregnancy. No fetal loss occurred. The outcome for all babies was normal. In patients with PSC pregnancy does not seem to have a negative effect on the disease process, neither mothers nor babies showed any ill effects. PSC has not worsened during the pregnancy in our patients.

Influence of orthotopic liver transplantation on serum vitamin A levels in patients with chronic liver disease.

BACKGROUND: Low serum vitamin A levels are observed in many liver diseases, such as primary biliary cirrhosis (PBC) and alcoholic liver disease. The aim of this study was to investigate serum vitamin A in patients with advanced liver diseases before and after orthotopic liver transplantation (OLT). METHODS: Serum vitamin A (retinol) concentrations were investigated in 54 patients before (OLT) and in 21 patients 1, 2, 3, and 4 weeks and 2 and 3 months after OLT. Ten healthy subjects and 19 patients with inflammatory bowel disease (IBD) served as control groups. RESULTS: The mean serum retinol concentration before OLT was 0.64 +/- 0.1 mumol/l in patients with alcoholic and postnecrotic cirrhosis (n = 24), 1.06 +/- 0.48 mumol/l in patients with PBC (n = 14), 0.96 +/- 0.64 mumol/l in sclerosing cholangitis (n = 7), and 1.02 +/- 0.73 mumol/l in liver cancer (n = 9). These results were significantly lower than in healthy controls (2.34 +/- 0.54 mumol/l) and patients with IBD (2.7 +/- 0.74 mumol/l) (p < 0.001). CONCLUSIONS: After OLT, serum retinol levels increased significantly already after 1 week (1.4 +/- 0.1 mumol/l) (p < 0.001), normalized after 2 weeks (2.2 +/- 0.4 mumol/l), and remained normal during the observation.

Metabolism of vitamin A in inflammatory bowel disease.

The aim of this study was to determine serum retinol levels in patients with inflammatory bowel disease and to attempt to elucidate the mechanism of changes in vitamin A metabolism in these disorders. It was found that in 15 patients with active ulcerative colitis, 14 patients with active Crohn's disease and in 3 operated patients with recurrent Crohn's disease serum retinol levels and retinol-binding protein were significantly lower than in controls. Concentrations of vitamin A did not depend on the localization of inflammatory bowel disease, previous ileal resections, duration of the disease or age and sex of the patients. During successful treatment of active ulcerative colitis normalization of serum retinol levels without substitution of vitamin A was observed. Repeated determinations in patients with Crohn's disease who had low serum retinol levels in an active phase of disease revealed normal vitamin A levels in an inactive phase. The absorption of vitamins A and E in patients with inflammatory bowel disease was normal. The normal serum retinol concentrations in patients with diarrhea due to irritable bowel syndrome, and in those with anorexia nervosa exclude the influence of diarrhea and body weight itself on vitamin A levels. The results of this study indicate that serum retinol levels in patients with active inflammatory bowel disease are secondary to the decreased serum retinol-binding protein concentrations, and probably depend on the increased protein catabolism in these disorders.

GLP-1-(7-36) amide, -(1-37), and -(1-36) amide: potent cAMP-dependent stimuli of rat parietal cell function.

We investigated the effect of glucagon-like peptide 1 (GLP-1)-(7-36) amide and its molecular variants GLP-1-(1-37) and GLP-1-(1-36) amide on enzymatically dispersed enriched rat parietal cells using [14C]aminopyrine accumulation as a measure of H+ production. GLP-1-(7-36) amide was 100 times more potent than GLP-1-(1-37) and GLP-1-(1-36) amide in stimulating [14C]aminopyrine accumulation. At their maximally effective concentrations, GLP-1-(7-36) amide (10(-8) M), GLP-1-(1-37) (10(-6) M), and GLP-1-(1-36) amide (10(-6) M) reached 80-90% of the response to 10(-4) M histamine. However, the peptides were 100-10,000 times more potent than histamine, which induced maximal [14C]aminopyrine accumulation at 10(-4) M. Stimulation by GLP-1 was dependent on the presence of a phosphodiesterase inhibitor and was not altered by pertussis toxin. Ranitidine failed to affect the response to the GLP-1 variants. Stimulation of H+ production by GLP-1 was accompanied by an increase in the formation of adenosine 3',5'-cyclic monophosphate (cAMP) but not by changes in phosphoinositol breakdown. In stimulating [14C]aminopyrine accumulation, the GLP-1 variants acted additively to threshold but not to maximal concentrations of histamine, suggesting that histamine and GLP-1 activate the same cAMP pool. In contrast, in anesthetized rats GLP-1-(7-36) amide (10-500 ng.kg-1.h-1) had no effect on basal and pentagastrin-stimulated acid secretion in vivo. We conclude that GLP-1 exerts a direct stimulatory effect on rat parietal cells. This potent effect is mediated by cAMP and is independent of H2 receptors. In vivo direct stimulation by GLP-1 of the parietal cells might be counterbalanced by indirect inhibitory mechanisms that are excluded in the in vitro cell system.

Serum retinol level in patients with colorectal premalignant and malignant lesions.

Serum retinol levels were determined by a fluorometric method in patients with colorectal cancer or polyps and those with inflammatory bowel disease. Serum retinol levels in patients with benign or malignant colorectal polyps and stage B cancer (modified Dukes' classification) were similar to those found in controls. By contrast, serum retinol levels were significantly lower in patients with Dukes' stage C or D. Among cancer patients that were followed after surgical treatment serum retinol levels did not differ significantly from those found in controls. Patients who died of metastases during follow-up possessed very low serum retinol levels. These findings suggest that a decreased serum retinol level in cancer patients is a consequence rather than a precursor of the neoplastic process. Furthermore, this study suggests that the marked decrease in serum retinol level might be an indicator of poor prognosis in colorectal cancer patients after surgery.