Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats.

A maternal high-fat/sucrose diet, in the presence of maternal obesity, can program increased susceptibility to obesity and metabolic disease in offspring. In particular, nonalcoholic fatty liver disease risk is associated with poor maternal nutrition and obesity status, which may manifest via alterations in gut microbiota. Here, we report that in a preclinical model of diet-induced maternal obesity, maternal supplementation of a high-fat/sucrose diet with the prebiotic oligofructose improves glucose tolerance, insulin sensitivity, and hepatic steatosis in offspring following a long-term high-fat/sucrose dietary challenge compared with offspring of untreated dams. These improvements are associated with alterations in gut microbial composition and serum inflammatory profiles in early life and improvements in inflammatory and fatty-acid gene expression profiles in tissues. Serum metabolomics analysis highlights potential metabolic links between the gut microbiota and the degree of steatosis, including alterations in 1-carbon metabolism. Overall, our data suggest that maternal prebiotic intake protects offspring against hepatic steatosis and insulin resistance following 21 wk of high fat/sucrose diet, which is in part due to alterations in gut microbiota.-Paul, H. A., Collins, K. H., Nicolucci, A. C., Urbanski, S. J., Hart, D. A., Vogel, H. J., Reimer, R. A. Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats.

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection.

BACKGROUND: Suggested mechanisms for SARS-CoV-2 direct liver infection have been proposed by others to involve both cholangiocytes and hepatocytes. Early clinical studies have highlighted abnormal liver biochemistry with COVID-19 infection as often not being severe, with elevated liver enzymes <5X the upper limit of normal. METHODS: Liver enzymes were evaluated and compared in patients admitted with a diagnosis of COVID-19 in a deidentified Internal Medicine-Medical Teaching Unit/hospitalist admission laboratory database. Comparisons in the incidence of severe liver injury (alanine aminotransferase >10 times upper limit of normal) were made for patients with pre-Omicron SARS-CoV-2 (November 30, 2019, to December 15, 2021) and Omicron SARS-CoV-2 (December 15, 2021, to April 15, 2022). Comprehensive hospital health records were also reviewed for the 2 patient cases discussed. One patient had a liver biopsy that was evaluated with H&E and immunohistochemistry staining using an antibody against COVID-19 spike protein. RESULTS: The evaluation of a deidentified admissions laboratory database found the incidence of severe liver injury was 0.42% with Omicron versus 0.30% with pre-Omicron variants of COVID-19. In both patient cases discussed, abnormal liver biochemistry and a negative comprehensive workup strongly suggest COVID-19 as the cause of severe liver injury. In the one patient with liver biopsy, immunohistochemistry staining suggests SARS-CoV-2 presence in the portal and lobular spaces in association with immune cell infiltration. CONCLUSIONS: The Omicron variant of SARS-CoV-2 should be considered in the differential diagnosis of severe acute liver injury. Our observation suggests that this new variant, either through direct liver infection and/or mediating immune dysfunction, can result in severe liver injury.

High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

BACKGROUND: Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS: Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION: High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

Increasing incidence rates, distribution and histological characteristics of primary gastrointestinal non-Hodgkin lymphoma in a North American population.

BACKGROUND: The incidence of primary extranodal non-Hodgkin lymphoma (NHL) of the gastrointestinal (GI) tract has been on the rise. OBJECTIVES: To determine the incidence of primary GI NHL and distribution according to site and histological type in a large North American adult population over a 10-year period. METHODS: All diagnoses of GI NHL made between January 1999 and January 2009 were reviewed using a regional pathology database. Patients ≥18 years of age living within health region boundaries were included. Age- and sex-adjusted incidence rates of GI NHL according to GI site and histological type over a 10-year period were calculated and compared. RESULTS: A total of 149 cases of primary GI NHL were identified during the study period. Age- and sex-adjusted yearly incidence rates ranged from 0.13 per 100,000 in 1999, to 2.39 per 100,000 in 2007. Histological distribution (47% diffuse large B cell lymphoma, 24% extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type, 8% follicular and 5% mantle cell) and site distribution (47% stomach, 26% small bowel, 17% colon) were obtained with increasing annualized incidence rates for each of these sites over time. Remaining cases included multiple GI sites of involvement (9%) and esophagus (0.7%). DISCUSSION: Population-based GI NHL incidence rates in the present study were higher than those described elsewhere in North America and Europe. Nearly one-half showed high-grade (diffuse large B cell lymphoma) histology at diagnosis. Incidence rates for the colon exceed those described in other studies worldwide. CONCLUSION: Because the majority of GI NHL are diagnosed on endoscopic biopsy, clinicians and pathologists must be vigilant of this entity.

Evaluation of endoscopist and pathologist factors affecting the incidence of microscopic colitis.

BACKGROUND: Microscopic colitis (MC) is an umbrella term for collagenous colitis (CC) and lymphocytic colitis (LC). The incidence of these diseases is increasing for unclear reasons. OBJECTIVE: To identify factors that may impact diagnosis rates of MC in a North American population. METHODS: Population-based pathology and endoscopy databases were searched to identify all cases of MC and the number of lower endoscopy (LE) procedures performed over a five-year period (January 2004 to December 2008) in a catchment area of 1.2 million people. Endoscopist characteristics were compared with diagnostic rates. RESULTS: MC incidence increased from 1.68 per 10,000 in 2004, to 2.68 per 10,000 in 2008, with an average annual increase of 12% per year (95% CI 7% to 16%; P<0.0001). The incidence rate of LC increased but the rate of CC remained stable over the study period. Approximately one-half of the cases were probable and one-half were definite based on pathologists' reports - a proportion that remained stable over time. The number of LEs per population increased by 4.6% annually over the study period (95% CI 2.8% to 6.4%; P<0.0001), and biopsy rates in LE for MC indications (eg, unexplained diarrhea, altered bowel habits) increased over time (3.4% annual increase [95% CI 1.8% to 6.0%]; P<0.001). Endoscopists with an academic practice, gastroenterologists and those with lower annual endoscopy volumes were more likely to make a diagnosis of MC. CONCLUSION: The incidence of MC is rising due to increased diagnosis of LC, while CC incidence remains stable. Patients with MC symptoms have stable endoscopy rates but are being biopsied more often. Physician training, practice type and endoscopy volume impact the diagnostic rates of MC.

Percutaneous endoscopically assisted transenteric full-thickness gastric biopsy: initial experience in humans.

BACKGROUND: GI neuromuscular diseases (GINMD) can cause severe dysmotility and symptoms. Full-thickness biopsy specimens may help diagnose these disorders histologically. OBJECTIVE: To assess a novel percutaneous endoscopically assisted transenteric (PEATE) biopsy method for obtaining full-thickness gastric tissue in patients with suspected GINMD. DESIGN: Prospective proof-of-concept case series. SETTING: Tertiary care gastroenterology unit. PATIENTS: Ten patients (8 women, mean [standard deviation] age 43 [10] years) with gastroparesis-like symptoms (mean [standard deviation] gastroparesis cardinal symptom index 3.28 [1.46] out of 5) and/or clinical findings suggestive of a gastric GINMD. INTERVENTIONS: All patients underwent PEATE biopsy during standard gastroscopy as an outpatient procedure. Tissue was stained for histology and immunohistochemistry of gut wall elements. Interstitial cells of Cajal (ICC) counts were compared with archived normal gastric tissue from control gastrectomies. MAIN OUTCOME MEASUREMENTS: Biopsy success, complications, histopathological findings according to the London Classification of GINMD. RESULTS: Full-thickness antral tissue suitable for analysis was obtained in 9 in 10 patients (90%). PEATE biopsy was well tolerated by all patients without complications. Histology suggested GINMD in 4 of 9 cases (44%), with possible degenerative leiomyopathy in 2, probable inflammatory leiomyopathy in 1, and abnormal ICC networks (>50% reduction in ICC counts) in 1 patient. LIMITATIONS: PEATE biopsy specimen size is smaller than a standard laparoscopic full-thickness biopsy. CONCLUSIONS: PEATE full-thickness gastric biopsy is a simple and safe method of assessing histopathological abnormalities in gastric GINMD without the need for laparoscopy or general anesthesia.

Association of Mycobacterium avium subspecies paratuberculosis with Crohn Disease in pediatric patients.

OBJECTIVES: The aim of the present study was to determine the prevalence of Mycobacterium avium subsp paratuberculosis (MAP) DNA in intestinal biopsies from pediatric patients with granulomatous Crohn disease (CD) or ulcerative colitis (UC), and matched control subjects without inflammatory bowel disease (IBD). PATIENTS AND METHODS: DNA was extracted from formalin-fixed paraffin-embedded colonic and ileal biopsies from patients with CD (n = 22) or UC (n = 20), and from controls without IBD (n = 21). IS900 nested polymerase chain reaction was performed in triplicate to determine the presence of MAP-specific DNA. RESULTS: In mucosal biopsies from terminal ileum, IS900 amplicons were detected in 1 of 19 (5.2%) control subjects, 1 of 20 (5%) patients with UC, and 7 of 20 (35%) patients with CD (P < 0.05 vs controls, odds ratio 9.6). In colonic biopsies, IS900 amplicons were detected in 0 of 19 control subjects, 1 of 19 (5.2%) patients with UC, and 5 of 19 (26.3%) patients with CD (P < 0.05 vs controls, odds ratio 14.8). In patients with CD, there was no correlation between disease activity and the presence of IS900. CONCLUSIONS: Our technique enabled sensitive and specific detection of MAP DNA in archival endoscopic biopsy specimens. Although MAP-specific DNA can be detected in about 5% of intestinal biopsies from children with UC or controls without IBD, its presence was significantly associated with pediatric granulomatous CD, being particularly prevalent in ileal tissue. This easily defined clinical subset of patients may be useful for additional studies to determine the role of MAP in CD.

ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice.

Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.

A novel method of full-thickness gastric biopsy via a percutaneous, endoscopically assisted, transenteric approach.

BACKGROUND: Pathologic changes of the enteric nervous system of the stomach have been described in gastroparesis. Because the enteric nervous system lies within the myenteric plexus between the muscle layers of the stomach, it is not accessible by standard biopsy forceps. Thus, tissue must be obtained by laparoscopy or laparotomy. Obtaining full-thickness biopsies with a less-invasive method would be an ideal alternative. OBJECTIVE: To assess the safety and feasibility of a novel method of gastric, full-thickness biopsy by using a percutaneous, endoscopically assisted, transenteric approach. DESIGN: Experimental pilot study in 3 dogs, approved by the animal care committee. INTERVENTION: Under general anesthesia, dogs underwent gastroscopy, and a suitable biopsy area was chosen, based on indentation of the anterior stomach wall by external finger pressure on the abdominal skin and by endoscope transillumination. Using sterile technique, we made a 3-mm incision through the abdominal skin, and a spring-loaded, 14-gauge biopsy needle was used to take 4 separate antral biopsies from each dog, with no mucosal or abdominal closure intervention. MAIN OUTCOME MEASUREMENTS: Feasibility of obtaining enteric nervous system tissue; morbidity and mortality at 4 weeks; gross pathology at necropsy. RESULTS: The procedure was well tolerated by the dogs, with no morbidity or mortality at any time, up to 4 weeks after the procedure. Adequate tissue specimens were obtained for histologic analysis of all layers of the stomach, including enteric nervous system elements. LIMITATIONS: Biopsy size was smaller than a surgical biopsy size. CONCLUSION: The percutaneous, endoscopically assisted, transenteric approach, full-thickness biopsy technique is safe and obtains enteric nervous tissue in a simple, minimally invasive manner.

Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy.

BACKGROUND AND AIMS: Liver stiffness measurement (LSM) by transient elastography (TE) is widely used for the noninvasive assessment of fibrosis. Our objectives were to examine the prevalence, risk factors and causes of discordance between fibrosis estimated by TE and liver biopsy. METHODS: Two hundred and fifty-one patients with hepatitis B, C and nonalcoholic fatty liver disease underwent LSM by TE and liver biopsy. Predictors of discordance (≥2 fibrosis stages) between measures, which occurred in 14% of patients (n=35), were identified by comparing patient, TE and biopsy characteristics of discordant and nondiscordant cases. RESULTS: According to predefined criteria, 40% of discordances were attributed to TE error and 23% to biopsy error; 37% were indeterminate. In multivariate analysis, mild fibrosis (F0-2 vs. F3-4), and higher body mass index (BMI), ALT and LSM variability [assessed by the ratio of the interquartile range to median LSM (IQR/M)] were independently associated with discordance. Discordance was three-fold more common in patients with obesity (28 vs. 9%), ALT ≥60 U/L (20 vs. 7%) and IQR/M ≥0.17 (22 vs. 7%; all P<0.005). Based on these variables, a discordance risk score assigning 1 point to each factor was developed. The prevalence of discordance in patients with 0, 1, 2 and 3 factors were 2, 7, 20, and 55% respectively (P<0.0005). CONCLUSIONS: Discordance between liver fibrosis estimated by TE and biopsy occurs in one in seven patients. In assessing the validity of TE results, clinicians must recognize risk factors for discordance and in at-risk patients, consider alternative measures including biomarkers and possibly biopsy.

Oncogenic HBV variants and integration are present in hepatic and lymphoid cells derived from chronic HBV patients.

The hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC), partly driven by viral integration and specific oncogenic HBV variants. However, the biological significance of HBV genomes within lymphoid cells (i.e., peripheral blood mononuclear cells, PBMCs) is unclear. Here, we collected available plasma, PBMC, liver, and tumor from 52 chronic HBV (CHB) carriers: 32 with HCC, 19 without HCC, and one with dendritic cell sarcoma, DCS. Using highly sensitive sequencing techniques, next generation sequencing, and AluPCR, we demonstrate that viral genomes (i.e., HBV DNA, RNA, and cccDNA), oncogenic variants, and HBV-host integration are often found in all sample types collected from 52 patients (including lymphoid cells and a DCS tumor). Viral integration was recurrently identified (n = 90 such hits) in genes associated with oncogenic consequences in lymphoid and liver cells. Further, HBV genomes increased in PBMCs derived from 7 additional (treated or untreated) CHB carriers after extracellular mitogen stimulation. Our study shows novel HBV molecular data and replication not only liver, but also within 63.8% of lymphoid cells analysed (including a representative lymphoid cell malignancy), that was enhanced in ex vivo stimulated PBMC.

Acoustic Radiation Force Impulse and Conventional Ultrasound in the Prediction of Cirrhosis Complicating Fatty Liver: Does Body Mass Index Independently Alter the Results?

We investigated whether ultrasound (US) could quantify steatosis and fibrosis in non-alcoholic fatty liver disease (NAFLD). Estimates of fat by gray-scale, hepatorenal index (HRI) and fibrosis by acoustic radiation force impulse (ARFI) were made using the interquartile range (IQR)/median for ARFI quality. Biopsy was the gold standard. US fat assessment correlated with histologic grade and predicted steatosis. HRI predicted steatosis but did not improve accuracy. ARFI of good quality was highly sensitive toward severe fibrosis. The median ARFI value depended linearly on body mass index (BMI). Poor quality ARFI data had higher histologic steatosis, leading to higher mean steatosis grades in rejected data (p = 0.018). The ARFI quality cut with IQR/median >0.15 or >0.3 excluded many more patients with severe steatosis versus normal, influenced by increasing BMI. By combining the baseline US with ARFI, patients can be concurrently diagnosed for steatosis and fibrosis, two of the key pathologies of NAFLD and non-alcoholic steatohepatitis (NASH). However, severe steatosis and high BMI may falsely alter ARFI results.

Optimization of In vivo Imaging Provides a First Look at Mouse Model of Non-Alcoholic Fatty Liver Disease (NAFLD) Using Intravital Microscopy.

Non-alcoholic fatty liver disease is a spectrum of liver pathology ranging from simple steatosis to steatohepatitis and can progress to diseases associated with poor outcomes including cirrhosis and hepatocellular carcinoma (HCC). NAFLD research has typically focused on the pathophysiology associated with lipid metabolism, using traditional measures such as histology and serum transaminase assessment; these methods have provided key information regarding NAFLD progression. Although valuable, these techniques are limited in providing further insight into the mechanistic details of inflammation associated with NAFLD. Intravital microscopy (IVM) is an advanced tool that allows for real-time visualization of cellular behavior and interaction in a living animal. Extensive IVM imaging has been conducted in liver, but, in the context of NAFLD, this technique has been regularly avoided due to significant tissue autofluorescence, a phenomenon that is exacerbated with steatosis. Here, we demonstrate that, using multiple imaging platforms and optimization techniques to minimize autofluorescence, IVM in fatty liver is possible. Successful fatty liver intravital imaging provides details on cell trafficking, recruitment, function, and behavior in addition to information about blood flow and vessel dynamics, information which was previously difficult to obtain. As more than 30% of the global population is overweight/obese, there is a significant proportion of the population at risk for NAFLD and complications due to NAFLD (liver decompensation, cirrhosis, HCC). IVM has the potential to elucidate the poorly understood mechanisms surrounding liver inflammation and NAFLD progression and possesses the potential to identify key processes that may be targeted for future therapeutic interventions in NAFLD patients.

Microscopic colitis-defining incidence rates and risk factors: a population-based study.

BACKGROUND & AIMS: The burden and determinants of microscopic colitis (MC) in North America are inadequately defined. We determined the incidence rate of and risk factors for MC in a well-defined North American population. METHODS: A population-based cohort study was conducted between April 1, 2002, and March 31, 2004. All adults with a pathologic diagnosis of MC were identified and comprehensive chart review was undertaken to confirm the diagnosis and identify risk factors. Category-specific risks for developing MC were reported as rate ratios (RRs) with exact 95% confidence intervals (CIs). RESULTS: MC was identified in 164 individuals for an annual incidence rate of 10.0 per 100,000 person-years (lymphocytic colitis, 5.4; collagenous colitis, 4.6 per 100,000). Patients older than the age of 65 were more than 5 times more likely to develop MC (RR, 5.6; 95% CI, 4.0-7.7). Women were at higher risk of acquiring MC for both collagenous colitis (RR, 3.44; 95% CI, 2.07-5.97) and lymphocytic colitis (RR 6.29; 95% CI, 3.21-13.74). Elderly women with a history of malignancy were associated with a higher risk of MC (RR, 3.59; 95% CI, 1.68-7.01), as were patients with celiac disease (RR, 7.9; 95% CI, 4.0-14.2) and hypothyroidism (RR, 6.1; 95% CI, 3.5-10.0). CONCLUSIONS: This was a large population-based cohort study of MC and our incidence rates were consistent with previously reported population-based studies in North America and Europe. An increased incidence of MC was observed in several disease states with the novel finding of an increased risk of MC with malignancy.

Changing epidemiology and risk factors for gastrointestinal non-Hodgkin's lymphoma in a North American population: population-based study.

OBJECTIVES: To assess the incidence, risk factors, and endoscopic presentation of gastrointestinal non-Hodgkin's lymphoma (GI NHL) in a large predominantly urban adult population sample. METHODS: A comprehensive database review of all diagnoses of GI NHL in the Calgary Health Region over a 5-yr period (1999-2003) was undertaken. Longer-term data from a population-based HIV database (1985-2004) were also reviewed. A regional pathology database was used to corroborate case identification. All patients 18 yr of age or older were included. Age- and gender-adjusted incidence rates were calculated. Within the HIV-positive population, incidence rates were compared over time. Endoscopic appearances were assessed and compared. RESULTS: Fifty-six GI NHL cases occurred during the study period. The age- and gender-adjusted annual incidence of GI NHL was 1.73 per 100,000 in the study population. The majority were diffuse large B-cell histology (54%), followed by lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (29%). Increasing age, history of kidney transplant, and H. pylori positivity in MALT lymphoma were identified as risk factors. Within the HIV-positive population, a highly significant drop in GI NHL was seen over time, with an incidence of 3.86 per 1,000 patient-years in 1985-1989 compared to zero cases in 2000-2004, despite a greater prevalence of HIV disease (P < 0.0001 for trend). MALT lymphoma was less likely to manifest as a mass on endoscopy versus other presentations (P < 0.05). CONCLUSIONS: Population-based GI NHL incidence rates in Calgary are higher than those described elsewhere in North America or in Britain. The incidence of GI NHL within the HIV population has virtually disappeared, presumably due to the advent of highly active retroviral therapy.

The risk of microscopic colitis in solid-organ transplantation patients: a population-based study.

BACKGROUND: Microscopic colitis (MC) has not been recognized as a complication of transplantation because patients are on immunosuppressant medications. The objective of this work was to describe the risk of developing MC after solid-organ transplantation. METHODS: This population-based cohort study identified all cases of MC diagnosed after kidney, kidney and pancreas, or liver transplantation using pathology and transplantation databases. The annual incidence and point prevalence of MC after transplantation was calculated. The incidence rate of MC among transplantation patients was compared with the general population and presented as a Standardized Incidence Ratio (SIR) with 95% confidence intervals. RESULTS: Seven cases (0.9%) of MC were diagnosed in kidney (n=2), kidney and pancreas (n=1), and liver (n=4) transplantation recipients. The point prevalence of MC was 8.8 per 1000 transplantation recipients. The annual incidence rate of MC in solid-organ transplantation patients was 5.0 cases per 1000 person-years. The SIR of developing MC after transplantation was 50.5 (95% confidence interval 13.6-131.8). The average age of diagnosis of MC was 49.4+/-5.3 years, average time of onset from transplantation was 67.4+/-27.0 months, and the average latency period was 30.1+/-9.0 months. Once diagnosed, all patients responded to MC-specific therapy. CONCLUSION: Physicians should have a low threshold to investigate for MC in solid-organ transplantation recipients who present with chronic diarrhea because this population is at an increased risk of developing MC.

Evaluation of classical and novel autoantibodies for the diagnosis of Primary Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome (PBC-AIH OS).

BACKGROUND AND AIMS: Up to 20% of Primary Biliary Cholangitis (PBC) patients are estimated to have features that overlap with Autoimmune Hepatitis (AIH). Patients with PBC-AIH overlap syndrome (PBC-AIH OS) have been reported to exhibit suboptimal responses to ursodeoxycholic acid therapy, and are more likely to progress to cirrhosis. Anti-double stranded DNA (anti-dsDNA) and anti-p53 have been previously suggested to be potential autoantibodies for identifying patients with PBC-AIH OS. In our well defined PBC patient cohorts, a comprehensive assessment of various classical and novel autoantibodies was evaluated for their utility in identifying PBC-AIH OS patients. METHODS: PBC-AIH OS was classified according to the Paris criteria and PBC as per the European Association for the Study of the Liver guidelines. Biobanked serum samples from 197 patients at the University of Calgary Liver Unit and the University of Alberta were analyzed for classical and novel autoantibodies. Anti-dsDNA was measured by the Crithidia luciliae immunofluorescence (CLIFT) assay (1:20 dilution) and chemiluminescence (CIA: QUANTA Flash®, Inova Diagnostics, San Diego). Anti-p53, anti-Ro52/TRIM21, anti-YB 1, anti-GW182, anti-Ge-1, and anti-Ago 2 were measured by either an addressable laser bead immunoassay (ALBIA) or line immunoassay (LIA). Autoantibodies against MIT3, gp210, sp100, LKM1, SLA, and the novel autoantibodies Hexokinase-1 (HK-1), and Kelch like protein 12 (KLHL-12) were measured using QUANTA Lite® ELISA assays. We applied non-parametric methods to compare the biomarkers frequencies between study groups. We used multivariate adjusted models and AUROC to compare the diagnostic accuracy of the different autoantibodies alone or in combination with serum biochemistry. RESULTS: 16 out of 197 PBC patients (8.1%) were classified as PBC-AIH OS. Compared to PBC patients, PBC-AIH OS patients were similar in age (median: 59 vs. 63, P = 0.21) and female predominance (94% vs. 89%, P = 1.00). Anti-dsDNA-by CLIFT (37.5% in PBC-AIH OS vs 9.9% in PBC alone, P <0.01) was the only autoantibody associated with PBC-AIH OS; a finding consistent with previous reports. Significant elevation in serum ALT (62 IU/L in PBC-AIH OS vs 37 IU/L in PBC alone, P < 0.01), and serum IgG (17.6 g/L in OS vs 12.1 g/L in PBC alone, P <0.01) were observed in patients with PBC-AIH OS receiving medical/immunosuppressive therapy. In a multivariate model, positive anti-dsDNA by CLIFT, ALT and IgG were significant predictors of PBC-AIH OS with an area under the receiver operator curve (AUROC) value of 0.84. CONCLUSIONS: Consistent with previous findings, the presence of anti-dsDNA by CLIFT is associated with PBC-AIH OS. Contrary to previous reports, anti-p53 was not associated with PBC-AIH OS. Our comprehensive evaluation of various classical and novel autoantibody biomarkers including Ro52/TRIM21, anti-p53, anti-KLHL-12 and anti-HK-1 were not significantly associated with PBC-AIH OS. Our findings highlight the ongoing need for the research and development of new autoantibody biomarkers to aid in the diagnosis of PBC-AIH OS.

Ischemic colitis during pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

Rare cases of ischemic colitis associated with interferon-alpha (IFN-alpha) treatment for chronic hepatitis C (HCV) infection and metastatic cancer have been reported. The present study describes the first case of ischemic colitis attributable to pegylated IFN-alpha and ribavirin combination therapy in an HCV-infected patient after 34 weeks of treatment. The clinical presentation, endoscopic appearance and histopathology of the colon were consistent with ischemic colitis, and the patient's symptoms rapidly resolved with cessation of therapy. The association between the therapy and the pathogenesis of ischemic colitis is unclear, but immunoregulatory, vasospastic and procoagulant mechanisms have been proposed. Physicians should be aware of this complication, and should consider it in any HCV-infected patient taking pegylated IFN-alpha and ribavirin who develops abdominal discomfort and gastrointestinal bleeding.

Rofecoxib-induced hepatotoxicity: a forgotten complication of the coxibs.

Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Although the coxibs are generally well-tolerated, rofecoxib was recently withdrawn from the market due to concerns regarding cardiovascular safety. Rare cases of hepatic injury attributable to the coxibs have been reported. In the present study, two additional cases of severe hepatotoxicity are described in patients with cholestatic symptoms and abnormal liver biochemistry, shortly following the initiation of rofecoxib for arthritic complaints. In both cases, liver histology was compatible with drug-induced hepatotoxicity, and rapid clinical and biochemical improvements were observed following rofecoxib discontinuation. With new coxibs and expanding indications on the horizon, physicians in all areas of practice must be aware of this disorder and consider it in any patient who develops hepatic dysfunction after taking a coxib.

The spectrum of pulmonary mucinous cystic neoplasia : a clinicopathologic and immunohistochemical study of ten cases and review of literature.

We describe 10 new cases and review 66 previously reported cases of primary pulmonary mucinous cystic neoplasia (PMCN). The 3 men and 7 women were 44 to 73 years old (mean, 60.0 years) at diagnosis. Lesions were found by chest radiograph (featuring a solitary, lobulated nodule with soft tissue density that enlarged slowly), or patients had major bronchial occlusion by mucus or hemoptysis. Tumors were well-circumscribed, lobulated soft masses with a central cavity filled with gray to greenish translucent mucus and were 1.5 to 5.5 cm in greatest dimension (mean, 3.3 cm). Microscopically, confluent lakes of mucin characterized all cases. Tumor epithelium ranged from bland to focal cytologic atypia to frankly malignant. The adjacent lung parenchyma was stretched, compressed, or showed an inflammatory reaction to dissected mucin. After 1- to 10-year follow-up (mean, 3.7 years), 3 patients died of metastasis and 1 of amitriptyline toxic effects; 6 were alive without tumor. Combined analysis of our cases and previously reported cases suggests a histologic spectrum from benign cystadenoma to mucinous cystic tumor with atypia to well-differentiated mucinous cystadenocarcinoma. The histomorphologic criteria derived from this analysis can help distinguish PMCN from other types of primary or metastatic mucinous tumors and predict outcome.