Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, ...lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values. Conclusion: Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR‐dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis. (HEPATOLOGY 2012)
Background & Aims Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of ...cholestatic patients and activate sensory neurons. Methods Cytosolic free calcium (Ca2+ i ) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative Ca2+ i -inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. Results Transient increases in neuronal Ca2+ i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major Ca2+ i agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls ( P < .0001) and cholestatic patients with versus without pruritus ( P < .0001). Autotaxin activity correlated with intensity of pruritus ( P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or μ-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. Conclusions We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.
Background & Aims Ursodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of ...biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response. Methods PBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase ALP level >40% of baseline level or normal level), Corpechot (ALP level <3-fold the upper limit of normal ULN, aspartate aminotransferase level <2-fold the ULN, bilirubin level <1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels). Results The study included 375 patients, and median follow-up time was 9.7 (range, 1.0–17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria ( P < .001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease. Conclusions Prognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels.
Colesevelam is an anion‐exchange resin with a 7‐fold higher bile acid–binding capacity and fewer side effects than cholestyramine, the current first‐line treatment option for cholestatic pruritus. ...The aim of this trial was to compare the effects of colesevelam and a placebo in patients with cholestatic pruritus. In a randomized, double‐blind, investigator‐initiated, multicenter trial, patients with cholestatic pruritus, both treatment‐naive and previously treated, received 1875 mg of colesevelam or an identical placebo twice daily for 3 weeks. The effect on pruritus was assessed with daily visual analogue scales, quality‐of‐life scores, and evaluations of cutaneous scratch lesions. The predefined primary endpoint was the proportion of patients with at least a 40% reduction in pruritus visual analogue scale scores. Thirty‐eight patients were included, and 35 were evaluable: 17 took colesevelam, 18 took the placebo, 22 were female, 8 were treatment‐naive, 14 had primary biliary cirrhosis, and 14 had primary sclerosing cholangitis. The mean serum bile acid levels were comparable between the groups before treatment (P = 0.74), but they were significantly different after treatment (P = 0.01) in favor of patients treated with colesevelam. Thirty‐six percent of patients in the colesevelam group reached the primary endpoint versus 35% in the placebo group (P = 1.0). There were no significant differences between the groups with respect to pruritus scores, quality‐of‐life scores, and severity of cutaneous scratch lesions. Mild side effects occurred in one colesevelam‐treated patient and four placebo‐treated patients. Conclusion: Although colesevelam significantly decreased serum bile acid levels, this trial was unable to demonstrate that it was more effective than a placebo in alleviating the severity of pruritus of cholestasis. (HEPATOLOGY 2010)
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and ...high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2·4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.
Abstract Purpose This study investigates lipid-modifying therapy (LMT) and LDL-C goal attainment in a real-world, high-cardiovascular-risk population in the Netherlands. Methods From the PHARMO ...Database Network, patients aged ≥18 years with an LDL-C measurement in 2012 (index date) were selected and hierarchically classified into the following mutually exclusive high-cardiovascular-risk categories: familial hypercholesterolemia (FH), recent acute coronary syndrome (ACS), coronary heart disease, ischemic stroke, peripheral arterial disease, and diabetes mellitus. LMT use and LDL-C goal attainment at the index date was assessed. Findings Of 61 839 patients who met the inclusion criteria, 1132 (2%) had FH, 2431 (4%) had recent ACS, 6292 (10%) had coronary heart disease, 2868 (5%) had ischemic stroke, 3017 (5%) had peripheral arterial disease, and 46 099 (75%) had diabetes mellitus. Overall, 67% of patients were receiving LMT. Use of LMT ranged from 77% for recent ACS to 53% for FH, and standard-potency statins were the most prescribed. The percentage attaining an LDL-C goal of <100 mg/dL was 55%, ranging from 23% (FH) to 58% (recent ACS). Among LMT users, 69% taking high-potency statins, 70% taking standard-potency statins, and 20% receiving nonstatin LMTs attained an LDL-C goal of <100 mg/dL. Implications LMT use among high-cardiovascular-risk patients was modest, which contributed to 46% of the cohort failing to reach LDL-C goals <100 mg/dL. Underuse and suboptimal use of LMTs in this cohort represent opportunities for quality improvement programs aimed at reducing the risk of cardiovascular events.
Cellular entry of thyroid hormone is mediated by plasma membrane transporters. We have identified rat monocarboxylate transporter 8 (MCT8) as an active and specific thyroid hormone transporter. The ...MCT8 gene is located on the X-chromosome. The physiological relevance of MCT8 has been demonstrated by the identification of hemizygous mutations in this gene in males with severe psychomotor retardation and elevated serum T3 levels. We have characterized human (h) MCT8 by analysis of iodothyronine uptake and metabolism in cell lines transiently transfected with hMCT8 cDNA alone or together with cDNA coding for iodothyronine deiodinase D1, D2, or D3. MCT8 mRNA was detected by RT-PCR in a number of human cell lines as well as in COS1 cells but was low to undetectable in other cell lines, including JEG3 cells. MCT8 protein was not detected in nontransfected cell lines tested by immunoblotting using a polyclonal C-terminal hMCT8 antibody but was detectable in transfected cells at the expected size (61 kDa). Transfection of COS1 and JEG3 cells with hMCT8 cDNA resulted in 2- to 3-fold increases in uptake of T3 and T4 but little or no increase in rT3 or 3,3′-diiodothyronine (3,3′-T2) uptake. MCT8 expression produced large increases in T4 metabolism by cotransfected D2 or D3, T3 metabolism by D3, rT3 metabolism by D1 or D2, and 3,3′-T2 metabolism by D3. Affinity labeling of hMCT8 protein was observed after incubation of intact transfected cells with N-bromoacetyl-125IT3. hMCT8 also facilitated affinity labeling of cotransfected D1 by bromoacetyl-T3. Our findings indicate that hMCT8 mediates plasma membrane transport of iodothyronines, thus increasing their intracellular availability.
A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The ...aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.
Analysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1(st)) and 1.1.1998-31.12.2007 (2(nd)). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.
A total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1(st): 61, 2(nd): 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1(st): 53.4, 2(nd): 53.8), the mean MELD score 13.9 (1(st):14.5, 2(nd):13.0). The median interval from diagnosis to LTX was 90.5 months (1(st):86.5, 2(nd): 93.5). 69% of patients was treated with UDCA (1(st) 38%, 2(nd) 82%).
Over the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation.
Background and Aims
While some articles describe outcome of pregnancy in autoimmune hepatitis (AIH), there are less data evaluating influence of AIH control on maternal and perinatal outcomes. This ...study analysed outcomes of pregnancy and related possible risk factors in AIH.
Method
A retrospective multicentre cohort study on pregnancy in AIH was performed in 11 hospitals in the Netherlands. Maternal and neonatal outcomes were collected from records and completed by interview. Risk factors—including incomplete response, relapse and cirrhosis—for adverse outcomes were identified using logistic regression analysis.
Results
Ninety‐seven pregnancies in 50 women resulted in 70 deliveries (72%) with a live birth rate of 98.5%. AIH relapse occurred in 6% during pregnancy, and in 27% of post‐partum episodes. Absence of complete biochemical response at conception was identified as risk factor for the occurrence of gestational and post‐partum relapses. Relapse of AIH in the year before conception was a risk factor for the occurrence of both gestational relapses and post‐partum relapses. No complete biochemical response increased the risk for hypertensive disorders during pregnancy and intrahepatic cholestasis of pregnancy (ICP). Cirrhosis was found to be a risk factor for miscarriages, but not for other outcomes.
Conclusion
Pregnancy in AIH is related to an increased incidence of maternal and fetal/neonatal complications; in most cases, outcome is good. Incomplete biochemical response at conception or relapse in the year before conception are risk factors for gestational and post‐partum relapses, for hypertensive disorders and for ICP. Cirrhosis was a risk factor for miscarriages.
Background & Aims Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) differ in clinical, laboratory, and histologic features as well as in response to therapy. A small subgroup of ...patients have an overlap syndrome with features of both diseases, although there is no consensus on its definition or diagnostic criteria. We evaluated the significance of the criteria used to diagnose PBC–AIH overlap syndrome. Methods This retrospective, single-center study included all patients diagnosed with PBC, AIH, or PBC–AIH overlap syndrome, based on the Paris criteria, since January 1990 (n = 134); patients were followed up for 9.7 ± 3.7 years. The 3 groups were compared for their clinical, laboratory, and histologic features. Patients with overlap syndrome or PBC were graded by the revised and simplified AIH scoring systems to assess the ability of this system to identify AIH cases properly. Results The sensitivity and specificity of the Paris criteria for diagnosing the overlap syndrome were 92% and 97%, respectively. The sensitivity and specificity of the AIH scoring systems were considerably lower. Among patients with the overlap syndrome, the 10-year, transplantation-free survival rate was 92%. Conclusions The Paris diagnostic criteria detect overlap syndrome (PBC and AIH) with high levels of sensitivity and specificity. The clinical value of the revised and simplified AIH scoring system is not as reliable. Patients with PBC–AIH overlap syndrome have a 92% rate of 10-year, transplantation-free survival.
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