Current consensus on the management of primary sclerosing cholangitis.

Guidelines for the management of primary sclerosing cholangitis (PSC) have recently been published by both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD). The current review focuses on the management of PSC, based on these guidelines. There is no established medical therapy for PSC. The role for UDCA in slowing the disease progression and improving survival is as yet unclear, and there are no specific recommendations for the general use of UDCA in this condition. Guidelines recommend that dominant bile duct strictures with significant cholestasis should be treated with biliary dilatation, with or without stenting. Prospective studies to define type, duration, optimal frequency and long-term effects of endoscopic therapy are needed. Liver transplantation is recommended for end stage disease and has excellent results. PSC patients with dysplasia in biliary brush cytology specimens should also be considered for transplantation. There is no evidence-based algorithm for the follow-up of PSC patients, but some regular investigations are recommended (surveillance colonoscopies in patients with IBD and ultrasound to detect gallbladder mass lesions).

Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes.

Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.

Secondary osteoporosis in liver transplant recipients: a longitudinal study in patients with and without cholestatic liver disease.

BACKGROUND: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation. METHODS: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals. RESULTS: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A. CONCLUSION: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

The use of modified primer competitors to enhance yields and specificity of HLA class I amplification by polymerase chain reaction (PCR).

Various PCR based techniques have been developed for genomic HLA typing. The fidelity of these techniques is highly dependent upon the specificity of the primers for the given HLA locus. Due to the high degree of homology between HLA class I loci, few primer sites that selectively amplify genes at a given HLA class I locus may be identified. To avoid coamplification of homologous loci, we designed and applied primer competitors for PCR amplification of HLA-A, -B and -C loci. Primer competitors identical to the 3' end of the specific primers and completely degenerate in the 5' end were designed and titrated into the respective HLA-locus PCR mixtures. We found that inclusion of primer competitors in the PCR reaction increased the specificity and yields of HLA class I amplifications, in particular when crude DNA preparation was used as template. This was particularly true for DNA preparations of low quality. The method described here may be useful for various protocols for downstream genomic typing of HLA-A, -B and -C alleles. In particular the method is useful when DNA is in scarce supply (i.e., for extensive PCR based allelic typing) or when high yields and locus specificity of amplicons are needed (i.e., sequencing-based typing).

Secondary Osteoporosis in Liver Transplant Recipients: a Longitudinal Study in Patients With and Without Cholestatic Liver Disease.

BACKGROUND: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation. METHODS: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A-chronic cholestatic liver disease (n = 28), and group B-chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-l-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals. RESULTS: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving'cyclosporin A. CONCLUSION: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles.

Susceptibility to primary sclerosing cholangitis (PSC) is associated with HLA-B8, -DR3, -DR2, and -DR6. It is not established whether these HLA genes or closely linked genes confer the primary disease susceptibility. MICA and MICB genes are found in the class I region between HLA-B and DRB. MICA is expressed in gastrointestinal epithelium and activates gammadelta T cells in the gut. Because PSC is strongly associated with inflammatory bowel disease, we investigated whether MICA and MICB contribute to the HLA-associated genetic susceptibility to develop PSC. The study included 130 PSC patients and 306 healthy controls, previously typed for HLA class I and II genes, typed for 5 MICA and 15 MICB microsatellite alleles. The phenotype frequencies of MICA5.1 and MICB24 were significantly increased among PSC patients compared with controls (90% vs. 74%; odds ratio [OR] = 3.2; P(c) = 3 x 10(-3) and 58% vs. 29%; OR = 3.3; P(c) < 1 x 10(-7), respectively). When stratified for B8- or DR3-positive and -negative individuals, the association of these markers to PSC was no longer evident. However, we observed that B8 and DR3 were associated to PSC only in the presence of both MICA5.1 and MICB24 markers. The frequency of individuals carrying all 4 alleles was significantly increased among the PSC patients compared with controls (49% vs. 18%; OR = 4.5; P(c) < 1 x 10(-7)). Our data indicate that PSC is associated to the extended B8-MICA5.1-MICB24-DR3 haplotype.