Background & Aims
Altered bile acid (BA) homeostasis is an intrinsic facet of cholestic liver diseases, but clinical usefulness of plasma BA assesment in primary sclerosing cholangitis (PSC) remains ...understudied. We performed BA profiling in a large retrospective cohort of PSC patients and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility.
Approach & Results
Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5‐year risk of hepatic decompensation (HD: defined as ascites, variceal hemorrhage or encephalopathy). There were 400 PSC patients and 302 controls in the derivation cohort (Mayo Clinic) and 108 PSC patients in the validation cohort (Norwegian PSC Research Center). PSC patients had increased BA levels, conjugated fraction and primary‐to‐secondary BA ratios relative to controls. UDCA increased total plasma BA level while lowering cholic acid (CA) and chenodeoxycholic acid (CDCA) concentrations. Patients without inflammatory bowel disease (IBD) had primary‐to‐secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine learning model, PSC‐BAP (bile acid profile) score (C‐statistic, 0.95), predicted HD better than individual measures including alkaline phosphatase and performed well in validation (C‐statistic, 0.86).
Conclusions
PSC patients demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.
Background & Aims
To better understand the pathogenesis of primary sclerosing cholangitis, anti‐ and pro‐inflammatory factors were studied in bile.
Methods
Ductal bile of PSC patients (n = 36) and ...controls (n = 20) was collected by endoscopic retrograde cholangiography. Gallbladder bile was collected at liver transplantation. Bile samples were analysed for cytokines, FGF19 and biliary lipids. Hepatobiliary tissues of PSC and non‐PSC patients (n = 8–11 per patient group) were collected at transplantation and were analysed for IL8 and FGF19 mRNA expression and IL8 localization. The effect of IL8 on proliferation of primary human cholangiocytes and expression of pro‐fibrotic genes was studied.
Results
In PSC patients, median IL8 in ductal bile was 6.6 ng/ml vs. 0.24 ng/ml in controls. Median IL8 in gallbladder bile was 7.6 ng/ml in PSC vs. 2.2 and 0.3 ng/ml in two control groups. IL8 mRNA in PSC gallbladder was increased and bile ducts stained positive for IL8. In vitro, IL8 induced proliferation of primary human cholangiocytes and increased the expression of pro‐fibrotic genes.
Conclusion
Elevation of IL8 in bile of PSC patients, collected at different stages of disease, indicates an ongoing inflammatory stimulus that drives IL8 production. This challenges the idea that advanced PSC is a burned‐out disease, and calls for reconsideration of anti‐inflammatory therapy in PSC.
Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The ...pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MS-based measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes.
Immunosuppression-associated lymphoproliferative disorders can be related to primary as well as acquired immune disorders. Interferon gamma receptor (IFN-γR) deficiency is a rare primary immune ...disorder, characterized by increased susceptibility to mycobacterial infections. Here we report the first case of an Epstein Barr Virus (EBV) related B-cell lymphoma in a patient with complete IFN-γR1 deficiency. The patient was a 20-year-old man with homozygous 22Cdel in
IFNGR1
resulting in complete absence of IFN-γR1 surface expression and complete lack of responsiveness to IFN-γ in vitro. He had disseminated refractory
Mycobacterium avium
complex and
Mycobacterium abscessus
infections. At age 18 he presented with new spiking fever and weight loss that was due to an EBV-positive B-cell non-Hodgkin lymphoma. Two years later he died of progressive lymphoma. IFN-γ plays an important role in tumor protection and rejection. Patients with IFN-γR deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections. As more of these patients survive their early infections, cancer awareness and tumor surveillance may need to become a more routine part of management.
Mycobacterial infections are critically controlled by interferon-γ (IFN-γ) and the cellular responses it elaborates, as shown by patients with mutations in the IFN-γ receptor ligand-binding chain ...(IFN-γR1) who have disseminated nontuberculous mycobacterial infections. The immunologic sequelae of IFN-γR1 deficiency were characterized in 2 unrelated patients from the Indian subcontinent with novel homozygous recessive IFN-γR1 mutations. In vitro, these patients' peripheral blood mononuclear cells produced 10% of normal IFN-γ and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-γ in response to PHA plus IL-12. Tumor necrosis factor-α (TNF-α) production was normal in response to endotoxin and to PHA but was not augmented by the addition of IFN-γ. An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate the critical role that the IFN-γ receptor plays in the regulation of IFN-γ, IL-12, and TNF-α.
We describe two brothers of consanguineous Pakistani parents who lived in Norway and had disseminated infections due to nontuberculous mycobacteria. The first boy developed clinical signs of ...disseminated BCG infection after vaccination. He was successfully treated with antimycobacterial agents. Two and one-half years later, he developed disseminated Mycobacterium avium complex infection and died at 6 years of age. The second boy, born 5 years after the death of his brother, did not receive BCG vaccine. At 2 years of age, he developed disseminated M. avium complex infection. Because he responded only partly to specific chemotherapy, empirical interferon γ treatment was added to the antimycobacterial regimen. After 2 years of combined therapy, his condition is stable. Studies of peripheral blood mononuclear cells from the second boy demonstrated reduced surface expression of the ligand binding chain of interferon γ receptor 1. This defect explains the increased susceptibility to mycobacterial disease in the two brothers.
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