Follow-up magnetic resonance imaging/3D-magnetic resonance cholangiopancreatography in patients with primary sclerosing cholangitis: challenging for experts to interpret.

BACKGROUND: In patients with primary sclerosing cholangitis follow-up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI-based definitions of primary sclerosing cholangitis related complications are, however, lacking. AIM: To investigate how primary sclerosing cholangitis experts interpret follow-up MRI/MRCP with a focus on conclusions that may impact clinical decision-making in primary sclerosing cholangitis. METHODS: Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real-life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2-weighted liver MRI/3D-MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple-choice questionnaire. An inter-rater reliability calculation (Fleiss' kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed-effect models. RESULTS: Forty-four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11-0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants' recommendations contrasted the real-life management and outcome. CONCLUSIONS: In primary sclerosing cholangitis, the interpretation of follow-up MRI/3D-MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI-based definitions of primary sclerosing cholangitis-related complications are urgently needed.

Autoimmune hepatitis 2013 and beyond.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease leading to cirrhosis and its complications if left untreated. Clinical features include elevated transaminases, elevated immunoglobulin G and the presence of autoantibodies. A liver biopsy is necessary for the establishment of the diagnosis. If treated properly and timely, prognosis of AIH is excellent. Standard treatment today consists of azathioprine and prednisolone and leads to remission in the vast majority of patients. Intolerance to standard treatment or incomplete remission as well as special patient groups such as pregnant patients or elderly patients require second- or sometimes even third-line treatments. For those patients, a number of effective drugs are available off-label and induction of remission will be possible in the vast majority of patients. Choice of drug regimen is important as drug-drug-interactions, concomitant diseases, age and gender of the patients have to be taken into account to achieve a tolerable side effect profile and good quality of life in patients. Mycophenolate mofetil is the drug of first choice in azathioprine intolerance. Other treatments may include the use of cyclosporine, tacrolimus, cyclophosphamide or biologicals such as rituximab or infliximab. Close monitoring of the patients will be necessary as side effects may occur.

[Autoimmune liver diseases]. / Autoimmunerkrankungen der Leber.

Autoimmune hepatitis (AIH) can occur in all age groups. AIH affects women more commonly than men (3:1). Clinical presentation may be an acute hepatitis up to fulminant liver failure, but can also be asymptomatic. AIH is characterized by lymphoplasmacellular infiltrates on liver biopsy, elevated liver enzymes in serum and the absence of active viral markers. Patients characteristically present with hypergammaglobulinemia, elevated serum levels of IgG and autoantibodies. Corticosteroids are the drug of choice for induction of remission, azathioprine the drug of choice for maintenance of remission. Rapid response to immunosuppressive treatment supports the diagnosis and leads to a good long-term prognosis.Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are immune mediated diseases affecting bile ducts. While PBC has a slow progression to cirrhosis and complications mostly will be limited to complications of cirrhosis, PSC additionally carries a high risk of developing cholangiocellular carcinoma. The treatment of choice in PBC and PSC is oral ursodeoxycholic acid which may slow progression of liver disease and may ameliorate lab findings.

Delirium and persistent dyskinesia induced by a lithium-neuroleptic interaction.

We report the case of a bipolar patient developing severe delirium and extrapyramidal signs shortly after initiation of a lithium-neuroleptic combination therapy. Clinical presentation, EEG changes and lithium plasma levels showed a close correlation. The delirium was reversible when all drugs were stopped; however, dyskinesia was found to be persistent after a period of 6 months. This rare syndrome is difficult to differentiate from lithium intoxication and neuroleptic malignant syndrome. Given the additional use of valproate and biperiden in this patient, valproate encephalopathy and anticholinergic delirium are further differential diagnoses. To avoid this serious pharmacodynamic drug interaction, patients should be closely monitored when lithium-neuroleptic comedication is started.

Ca2+ influx induced by store release and cytosolic Ca2+ chelation in Ht29 colonic carcinoma cells.

Cl- secretion in HT29 cells is regulated by agonists such as carbachol, neurotensin and adenosine 5'-triphosphate (ATP). These agonists induce Ca2+ store release as well as Ca2+ influx from the extracellular space. The increase in cytosolic Ca2+ enhances the Cl- and K+ conductances of these cells. Removal of extracellular Ca2+ strongly attenuates the secretory response to the above-mentioned agonists. The present study utilises patch-clamp methods to characterise the Ca2+ influx pathway. Inhibitors which have been shown previously to inhibit non-selective cation channels, such as flufenamate (0.1 mmol.l-1, n = 6) and Gd3+ (10 micromol.l-1, n=6) inhibited ATP (0.1 mmol.l-1) induced increases in whole-cell conductance (Gm). When Cl- and K+ currents were inhibited by the presence of Cs2SO4 in the patch pipette and gluconate in the bath, ATP (0.1 mmol.l-1) still induced a significant increase in Gm from 1.2 +/- 0.3 nS to 4.7 +/- 1 nS (n = 24). This suggests that ATP induces a cation influx with a conductance of approximately 3-4 nS. This cation influx was inhibited by flufenamate (0.1 mmol.l-1, n = 6) and Gd3+ (10 micromol.l-1, n = 9). When Ba2+ (5 mmol.l-1) and 4,4'-diisothiocyanato-stilbene-2-2'-disulphonic acid (DIDS, 0.1 mmol.l-1) were added to the KCl/K-gluconate pipette solution to inhibit K+ and Cl- currents and the cells were clamped to depolarised voltages, ATP (0.1 mmol.l-1) reduced the membrane current (Im) significantly from 86 +/- 14 pA to 54 +/- 11 pA (n = 13), unmasking a cation inward current. In another series, the cation inward current was activated by dialysing the cell with a KCl/K-gluconate solution containing 5-10 mmol.l-1 1,2-bis-(2-aminoethoxy)ethane-N,N,N',N'-tetraacetic acid (EGTA) or 1,2-bis-(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA). The zero-current membrane voltage (Vm) and Im (at a clamp voltage of +10 mV) were monitored as a function of time. A new steady-state was reached 30-120 s after membrane rupture. Vm depolarised significantly from -33 +/- 2 mV to -12 +/- 1 mV, and Im fell significantly from 17 +/- 2 pA to 8.9 +/- 1.0 pA (n = 71). This negative current, representing a cation inward current, was activated when Ca2+ stores were emptied and was reduced significantly ( Im) when Ca2+ and/or Na+ were removed from the bathing solution: removal of Ca2+ in the absence of Na+ caused a Im of 5.0 +/- 1.2 pA (n = 12); removal of Na+ in the absence of Ca2+ caused a Im of 12.8 +/- 3.5 pA (n = 4). The cation inward current was also reduced significantly by La3+, Gd3+, and flufenamate. We conclude that store depletion induces a Ca2+/Na+ influx current in these cells. With 145 mmol.l-1 Na+ and 1 mmol.l-1 Ca2+, both ions contribute to this cation inward current. This current is an important component in the agonist-regulated secretory response.

Forskolin and PMA pretreatment of HT29 cells alters their chloride conductance induced by cAMP, Ca2+ and hypotonic cell swelling.

HT29 cells were preincubated with forskolin (10(-5) mol/l, FORHT) or phorbol 12-myristate 13-acetate (PMA) (10(-7) mol/l, PMAHT) for 20 h, which has been shown previously and is also shown here, to upregulate and downregulate, respectively, the expression of the cystic fibrosis transmembrane conductance regulator (CFTR). CFPAC-1 cells underwent the same protocols. HT29 cells were examined by slow (SWC) and fast (FWC) whole-cell patch-clamp techniques. The results of SWC and FWC were indistinguishable and were pooled. CFPAC-1 cells were examined with FWC. The membrane voltage (V) of FORHT was -41.8 +/- 1.4 mV (n = 77) and that of PMAHT was -43.6 +/- 2.4 mV (n = 76). The conductance (G) of FORHT (9.4 +/- 0.9 nS, n = 77) was significantly larger than that of PMAHT (3.7 +/- 0.4 nS, n = 76). Acute application of forskolin (10(-5) mol/l, FOR) plus 0.5 mmol/l 8-(4-chlorophenylthio)-cAMP (cAMP) depolarized V by 12 (FORHT) and 8 (PMAHT) mV, respectively. The acute increase of G by FOR plus cAMP was by 7.6 +/- 1.9 nS for FORHT (n = 22) and only 2.2 +/- 1 nS for PMAHT (n = 13). ATP (10(-4) mol/l) depolarized V in both types of cells. It enhanced G by 16.7 +/- 4.1 nS in FORHT (n = 14) and significantly less (by 5.5 +/- 1.2 nS, n = 14) in PMAHT. Also the G increase lasted longer in FORHT. Neurotensin (NT, 10(-8) mol/l) also had a stronger and longer lasting effect in FORHT.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase in cytosolic Ca2+ regulates exocytosis and Cl- conductance in HT29 cells.

Increases of cytosolic Ca2+, as occur with agonists such as ATP, neurotensin (NT), hypotonic cell swelling and ionomycin, enhance the membrane conductance (GM) and hence the input conductance (GI) of HT29 cells. In the present study we have examined whether these increases in GM are paralleled by exocytosis. To this end the membrane capacitance (CM) of HT29 cells was measured by patch clamp techniques. Two methods to monitor CM were used: a direct method (DM) and a phase tracking method (PTM). With the DM the following results were obtained. NT (10(-8) mol/l, n = 9) increased GM and CM significantly from 2.4 +/- 0.3 nS and 23.5 +/- 3 pF to 32 +/- 8 nS and 27.3 +/- 3.1 pF respectively. ATP (10(-4) mol/l, n = 29) had a very similar effect. GM and CM were increased from 5.7 +/- 1 nS and 36 +/- 4.4 pF to 111 +/- 21 nS and 44 +/- 5.4 pF respectively. Hypotonic cell swelling (160 mosmol/l, n = 18) had a comparable effect: GM and CM were increased from 4.9 +/- 1 nS and 30 +/- 4.1 pF to 46 +/- 10 nS and 37 +/- 4.9 pF respectively. Ionomycin (10(-7) mol/l, n = 4) gave similar results. With the PTM it was possible to monitor the rapid changes in GM and CM, as they were induced by ATP (n = 42) and NT (n = 29), with high time resolution.(ABSTRACT TRUNCATED AT 250 WORDS)