Primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome associated with inflammatory bowel disease: A case report and systematic review.
ABSTRACT: BACKGROUND:A previously healthy 22-year-old woman presented with abdominal pain and jaundice. She had a reagent antinuclear factor (1:640, with a homogeneous nuclear pattern) and hypergammaglobulinemia (2.16 g/dL). Anti-smooth muscle, anti-mitochondrial and anti-liver-kidney microsomal antibody type 1 antibodies were negative. Magnetic resonance cholangiography showed a cirrhotic liver with multiple focal areas of strictures of the intrahepatic bile ducts, with associated dilations. Liver biopsy demonstrated periportal necroinflammatory activity, plasmocyte infiltration and advanced fibrosis. Colonoscopy showed ulcerative pancolitis and mild activity (Mayo score 1), with a spared rectum. Treatment with corticosteroids, azathioprine, ursodeoxycholic acid and mesalamine was initiated, with improvement in laboratory tests. The patient was referred for a liver transplantation evaluation. AIM:To report the case of a female patient with autoimmune hepatitis and primary sclerosing cholangitis (PSC) overlap syndrome associated with ulcerative colitis and to systematically review the available cases of autoimmune hepatitis and PSC overlap syndrome. METHODS:In accordance with preferred reporting items for systematic reviews and meta-analysis protocols guidelines, retrieval of studies was based on medical subject headings and health sciences descriptors, which were combined using Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE (PubMed), Biblioteca Regional de Medicina, Latin American and Caribbean Health Sciences Literature, Cochrane Library for Systematic Reviews and Opengray.eu. Languages were restricted to English, Spanish and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. RESULTS:The search strategy retrieved 3349 references. In the final analysis, 44 references were included, with a total of 109 cases reported. The most common clinical finding was jaundice and 43.5% of cases were associated with inflammatory bowel disease. Of these, 27.6% were cases of Crohn's disease, 68% of ulcerative colitis, and 6.4% of indeterminate colitis. Most patients were treated with steroids. All-cause mortality was 3.7%. CONCLUSION:PSC and autoimmune hepatitis overlap syndrome is generally associated with inflammatory bowel disease and has low mortality and good response to treatment.
Project description:In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.
Project description:BACKGROUND:The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for progressive liver injury in nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic viral hepatitis. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC). METHODS:We prospectively recruited 178 PSC patients (112 male, age range 17-75 years, 55 with liver cirrhosis, 94 with ulcerative colitis, 48 transplanted during follow-up). PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using dedicated TaqMan assays. Associations between genotypes, biochemical and clinical phenotypes were analyzed using contingency tables. RESULTS:Allele and genotype distribution of both variants were consistent with Hardy-Weinberg equilibrium. No significant differences in the genotype distribution of PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) were observed between patients with cirrhosis and patients without cirrhosis. Serum liver enzyme activities were not modified by the presence of PNPLA3 (ALT P = 0.88, AST P = 0.77) or TM6SF2 (ALT P = 0.92, AST P = 0.49) risk variants. Increasing number of risk alleles had no impact on serum liver enzyme activities, as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) risk alleles (P>0.05). No impact of PNPLA3 or TM6SF2 risk variants was detectable in patients with PSC and ulcerative colitis, and none of the variants increased the odds of transplantation. CONCLUSIONS:Neither PNPLA3 nor TM6SF2 polymorphisms seem to contribute significantly towards an increased risk for deterioration of liver function in patients with PSC. These results underscore the divergent mechanisms of liver damage in cholestatic conditions as compared to metabolic and viral liver diseases.
Project description:Trimethylamine-N-oxide (TMAO) is produced in the liver from trimethylamine, which is exclusively generated by gut bacteria.The objective of this article is to investigate the relationship between TMAO and primary sclerosing cholangitis (PSC) and its clinical characteristics.Serum TMAO was measured in 305 PSC patients, 90 ulcerative colitis patients and 99 healthy controls.In PSC patients with normal liver function (n?=?197), TMAO was higher in patients reaching liver transplantation or death during follow-up than those who did not, with an optimal TMAO cut-off of 4.1?µM (AUC?=?0.64, p?<?0.001). PSC patients with high TMAO (>4.1?µM, n?=?77) exhibited shorter transplantation-free survival than patients with low TMAO (n?=?120, log-rank test: p?<?0.0001). High TMAO (>4.1?µM) was associated with reduced transplantation-free survival (HR 1.87, p?=?0.011), independently of the Mayo risk score (HR 1.74, p?<?0.001). Overall, PSC patients demonstrated reduced TMAO values compared with ulcerative colitis and healthy controls, mainly caused by PSC patients with reduced liver function (INR?>?1.2), suggesting impaired oxidation of trimethylamine to TMAO. PSC patients with and without inflammatory bowel disease had similar TMAO levels.In PSC patients with normal liver function, elevated TMAO was associated with shorter transplantation-free survival, potentially reflecting clinically relevant metabolic changes resulting from dietary interactions with the gut microbiota.
Project description:BACKGROUND: Patients with ulcerative colitis have an increased risk of colorectal cancer. Duration, age, and extent of the disease at diagnosis are the only established risk factors. Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have been reported to have a higher frequency of colonic DNA aneuploidy and/or dysplasia than expected, findings indicating an increased risk of colorectal cancer compared with other patients with ulcerative colitis. METHODS: A population based cohort consisting of 125 patients with a verified diagnosis of PSC was followed up by linkage to the Swedish Cancer Registry for the occurrence of colorectal cancer. RESULTS: There were 12 colorectal cancers. Six cancers were diagnosed prior to the diagnosis of PSC. Among the 104 patients with an intact colon at the time of the diagnosis of PSC there was a cumulative risk for colorectal cancer of 16% after 10 years. Among the 58 patients with a diagnosis of ulcerative colitis and colorectal cancer prior to the diagnosis of PSC, there were five colorectal cancers corresponding to a cumulative risk of 25% after 10 years. CONCLUSIONS: Patients with ulcerative colitis and concomitant PSC seem to constitute a subgroup with a high risk for colorectal cancer.
Project description:Background:Some patients exhibit features of both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Similarly, patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) may share histological features with PSC. Case report:We report the case of a 22-year-old man who, since he was 5 years of age, has presented with pruritus, an approximately ninefold elevation of aminotransferases, and γ-glutamyl transferase levels ~10 times the upper limit. Initially he was diagnosed with an overlap syndrome of small duct PSC plus AIH. However, fluctuations in liver enzymes were observed over the following years. Analysis of the ABCB4 gene indicated the diagnosis of PFIC3, revealing a mutation not previously reported. Conclusion:With this case report we aim to describe a new mutation, raise awareness of this rare pathology and highlight the importance of genetic testing of the ABCB4 gene in patients with autoimmune liver disease (mainly small duct PSC) with incomplete response to immunosuppressive treatment. LEARNING POINTS:Autoimmune liver diseases have a wide spectrum of manifestations.Cholangiopathies such as ABCB4 deficiency have histological features quite similar to those seen in small duct primary sclerosing cholangitis.The new mutation of the ABCB4 gene described in this article is compatible with the diagnosis of progressive familial intrahepatic cholestasis type 3, which is probably less rare than usually thought.
Project description:Objectives:The clinical/colonoscopic features of ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC), the prognostic impact of UC, and the utility of UC screening in PSC patients are unknown. We characterized UC associated with PSC and assessed UC's impact on the prognosis of PSC and the importance of colonoscopic UC screening in PSC patients. Methods:We retrospectively analyzed the cases of 77 patients treated for PSC at a single center (April 2000-July 2019). We reviewed the clinical/colonoscopic profiles of the concurrent UC patients and compared the clinical profiles, survival, and primary causes of death between the patients with/without UC (n = 35/n = 42). The details of all patients' colonoscopies were reviewed. Results:The concurrent UC group: 17 men, 18 women, diagnosed with PSC at the mean (SD) age of 36 (17) years; 21 patients (60%) had no UC symptoms. Colonoscopy revealed pancolitis in all patients, predominantly affecting the right-sided colon in 30 patients (86%). Lesions were scattered. Backwash ileitis (n = 13, 37%) and rectal sparing (n = 18, 51%) were observed. Most patients had mild UC; some had moderate or more severe UC (median Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 2; range, 1-5). Ludwig's stage determined by liver biopsy did not correlate with the Mayo endoscopic score for UC. The patients with UC were diagnosed with PSC at a significantly younger age than those without UC (mean (SD), 36  years vs. 55  years, p < 0.0001) and had a significantly higher 5-year survival rate (97.1% vs. 70.5%, p = 0.0028). UC was detected in 19 of 34 asymptomatic patients (56%) who underwent colonoscopy screening. Conclusions:Our cohort's clinical/colonoscopic features of UC associated with PSC are more moderate or severe UC than previous cases. The coexistence of UC might affect the prognosis of PSC. In this regard, colonoscopy in PSC patients is an important examination for determining prognosis. There is also asymptomatic UC in patients with PSC. In this regard, screening for colonoscopy in PSC patients is essential. When a diagnosis of PSC is made, immediate colonoscopy is a priority with UC complications in mind.
Project description:Primary sclerosing cholangitis (PSC) is a progressive disease of the liver characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts, leading to fibrosis and ultimately liver failure, cirrhosis and an increased risk of malignancy. The etiology of PSC is unclear. It is often associated with the inflammatory bowel diseases (IBD), particularly Ulcerative Colitis (UC); up to 75% of PSC patients have UC. PSC is more prevalent in men than in women. Ursodeoxycholic acid (UDCA) has been extensively studied in PSC in randomized clinical trials but failed to show a positive impact on the natural course of the disease. Currently, there is no effective medical therapy for PSC, and the majority of patients will eventually require liver transplantation. PSC is one of the leading indications for liver transplantation. In this paper, we review the current research on the potential therapeutic agents for the treatment of PSC.
Project description:OBJECTIVE: Acoustic radiation force impulse (ARFI) is a new software-based technique that evaluates liver stiffness during B-mode ultrasonography. The purpose of this study was to evaluate the accuracy of ARFI in distinguishing patients with chronic autoimmune liver disease from healthy subjects. MATERIAL AND METHODS: We enrolled 9 adult patients (8 women, 1 man; age 48.1 ± 12.8 years) with chronic autoimmune disease (primary biliary cirrhosis (PBC, n = 3), autoimmune hepatitis (AIH, n = 2), primary sclerosing cholangitis (PSC, n = 1) and overlap syndromes, (n = 3) who underwent a liver biopsy and 11 healthy volunteers (age 34.7 ± 10.4 years; 7 women, 4 men). Liver stiffness was evaluated and expressed as the shear wave velocity (SWV) in m/sec. We used a US scanner Siemens-Acuson S2000, evaluating the right liver lobe and the left liver lobe. RESULTS: THE SWV WAS SIGNIFICANTLY HIGHER IN CASES (RIGHT LOBE: 1.51 ± 0.44; left lobe: 1.57 ± 0.40) than in controls (right lobe: 1.08 ± 0.10; left lobe: 1.12 ± 0.13) (right lobe: P = 0.002; left lobe: P = 0.013). We found no significant correlation between right and left lobe SWVs in cases (P = 0.779) or controls (P = 0.385). The SWV cut-off that best distinguished cases from controls was 1.25 m/sec (accuracy: AUC=0.885; sensitivity: 70.6%; specificity: 95.5%). CONCLUSIONS: ARFI elastography is a noninvasive ultrasonographic technique that can differentiate healthy subjects from patients with fibrotic stages of chronic liver disease.
Project description:The gut-liver axis describes the complex interactions between gut microbiota, the small and large bowel, the immune system and the liver. Current evidence associates abnormalities within the gut-liver axis with liver disease such as primary sclerosing cholangitis (PSC). PSC is believed to be an immune-mediated disease though the exact mechanism of its pathogenesis remains unknown. Here, we report a case of a 66 -year-old woman with treatment-resistant ulcerative colitis and PSC which continued to be active following subtotal colectomy. Interestingly, her PSC achieved full remission after proctectomy for treatment-resistant proctitis in the rectal stump. This case report supports existing hypotheses that PSC is an immune-mediated disease triggered by antigens within the gut. More notably, it suggests the yet unidentified pathogens may be localised to the lower gastrointestinal tract including the rectum.
Project description:Primary sclerosing cholangitis [PSC] is an idiopathic chronic disorder of the hepatobiliary system associated with inflammatory bowel disease [IBD], mainly ulcerative colitis [UC]. Colitis in patients with PSC and UC [PSC-UC] exhibits characteristic features and is linked to increased colon cancer risk. Genetic studies have identified immune-related susceptibility genes that only partially overlap with those involved in IBD. These observations suggest that PSC-UC may represent a distinct form of IBD. It remains to be elucidated whether different immune mechanisms are involved in colitis in these patients. We aimed to evaluate systemic and intestinal T cell and innate lymphoid cell [ILC] responses, previously associated with IBD, in patients with PSC-UC compared with patients with UC and healthy controls.Blood samples and colorectal biopsies were collected from patients with PSC-UC, patients with UC, and healthy controls. T cell and ILC phenotypes were analysed by multicolour flow cytometry.Chemokine receptor [CCR] profiling of circulating T cells showed decreased CCR6-CXCR3+ Th1 cells in PSC-UC, but increased CCR6-CCR4+ Th2 cells only in UC, whereas increased CCR6+CCR4+ Th17 cells were found in both patient groups compared with healthy controls. Increased frequencies of IFN-? secreting T cells were found in the colon of patients with PSC-UC compared with UC. Interestingly, we observed accumulation of ILC in the colon in PSC-UC.Our study suggests that PSC-UC represents a different immunological disorder from UC, characterised by increased intestinal Th1 and ILC responses. These results provide further evidence that PSC-UC may represent a distinct form of IBD.