Faculty Bibliography

Celiac disease (CD) is a chronic autoimmune disorder that affects the small intestine in genetically predisposed individuals. Previous studies have investigated the potential link between CD and cardiovascular disease (CVD); however, the findings have been inconsistent. We aimed to provide an updated review of the literature on the association between CD and CVD. PubMed was searched from inception to January 2023 using keywords including CD, cardiovascular disease, coronary artery disease, cardiac arrhythmia, heart failure, cardiomyopathy, and myocarditis. We summarized the results of the studies, including meta-analyses and original investigations, and presented them according to the different forms of CVD. Meta-analyses published in 2015 provided mixed results regarding the relationship between CD and CVD. However, subsequent original investigations have shed new light on this association. Recent studies indicate that individuals with CD are at a higher risk of developing overall CVD, including an increased risk of myocardial infarction and atrial fibrillation. However, the link between CD and stroke is less established. Further research is needed to determine the link between CD and other cardiac arrhythmias, such as ventricular arrhythmia. Moreover, the relationship between CD and cardiomyopathy or heart failure, as well as myopericarditis, remains ambiguous. CD patients have a lower prevalence of traditional cardiac risk factors, such as smoking, hypertension, hyperlipidemia, and obesity. Therefore, it is important to discover strategies to identify patients at risk and reduce the risk of CVD in CD populations. Lastly, it is unclear whether adherence to a gluten-free diet can diminish or increase the risk of CVD among individuals with CD, necessitating further research in this area. To fully comprehend the correlation between CD and CVD and to determine the optimal prevention strategies for CVD in individuals with CD, additional research is necessary.

OBJECTIVES/OBJECTIVE:The US Preventive Services Task Force lowered the recommended starting age for colorectal cancer (CRC) screening in average-risk adults from 50 to 45 years. We aimed to estimate the global burden and trends of colorectal cancer in adults aged 20-49 years (early-onset CRC). METHODS:This is an analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). The GBD 2019 estimation methods were used to describe the incidence, mortality, and disability-adjusted life years (DALYs) of early CRC from 1990 to 2019. Data from 204 countries and geographic areas were available. RESULTS:The global incidence rate of early-onset CRC increased from 4.2/100 000 to 6.7/100 000 from 1990 to 2019. Mortality and DALYs of early-onset CRC also increased. The CRC incidence rate increased faster in younger adults (1.6%) than in adults aged 50-74 years (0.6%) as measured by the annual percentage change. The increase in early-onset CRC incidence was consistently observed in all five socio-demographic index (SDI) regions and 190 out of 204 countries and territories. Middle and high-middle SDI regions had faster annual increases in early-onset CRC, which warrants further attention. CONCLUSIONS:The global incidence, mortality, and DALYs of early-onset CRC increased from 1990 to 2019. The increase in early-onset CRC incidence was prevalent worldwide. Several countries were found to have higher incidence rates than the United States or fast increase in early-onset CRC, which warrants further attention.

BACKGROUND & AIMS/OBJECTIVE:Understanding the epidemiology of bleeding and thromboembolism (clotting) in liver cirrhosis provides important data for future studies and policymaking; however, head-to-head comparisons of bleeding and clotting remain limited. METHODS:This is a populational retrospective cohort study using the US National Readmission Database of 2018 to compare the incidence and outcomes of bleeding and clotting events in patients with liver cirrhosis. The primary outcomes were the 11-month incidence proportion of bleeding and clotting events. RESULTS:Of 1 304 815 participants, 26 569 had liver cirrhosis (45.0% women, mean age 57.2 [SD, 12.7] years). During the 11-month follow-up, in patients with cirrhosis, for bleeding and clotting events, the incidence proportions was 15.3% and 6.6%; the risk-standardized all-cause mortality rates were 2.4% and 1.0%; the rates of intensive care intervention were 4.1% and 1.9%; the rates of rehabilitation transfer were .2% and .2%; the cumulative length of stays were 45 100 and 23 566 days; total hospital costs were 147 and 84 million US dollars; total hospital charges were 620 and 365 million US dollars. Compared to non-cirrhosis, liver cirrhosis was associated with higher rates of bleeding (adjusted hazard ratio, 3.02 [95% CI, 2.85-3.20]) and portal vein thrombosis (PVT) (18.46 [14.86-22.92]), and slightly lower risks of other non-PVT venous thromboembolic events (.82 [.75-.89]). CONCLUSIONS:Bleeding is more common than thromboembolism in patients with liver cirrhosis, causes higher morbidity, mortality and resource utilization. Liver cirrhosis is an independent risk factor for bleeding and PVT, but not non-PVT thromboembolism including venous thromboembolism, acute myocardial infarction and ischemic stroke.

Introduction: Signet ring cell carcinoma accounts for about one percent of all colorectal cancers. It is an aggressive subtype of adenocarcinomas with the tendency for intramural spread and peritoneal carcinomatosis. Here, we reported a middle-aged male with circumferential colonic stenosis and inconclusive histology, found to have stage 4 colorectal signet ring cell carcinoma (SRCC). Case Description/Methods: A 41-year-old male without significant past medical history was referred to a gastroenterology clinic with bright red blood per rectum. Colonoscopy showed ulcerative rectosigmoiditis with rectal bleeding, and there was stricture in the rectum, in the recto-sigmoid colon, and from anus to descending colon (Figure A). Biopsy was obtained from the stricture. The pathology revealed granulation tissue and abundant fibrinopurulent exudate showing small clusters, and individual atypical cells stained positive for CDX-2 immunostain. Unfortunately, the patient subsequently lost follow-up. Three months later, the patient was hospitalized for small bowel obstruction. CT showed markedly enlarged heterogeneous and edematous rectum, an abnormal mass within the posterior pelvis/rectum, retroperitoneal and pelvic lymphadenopathy with thickening and nodularity of the peritoneum. Biopsy was obtained from an inguinal lymph node with histological examination showing metastatic adenocarcinoma composed of poorly cohesive signet-ring cells (Figure B). Immunostains revealed that the neoplastic cells were strongly and diffusely positive for CDX2 and CK20 while negative for CK7, confirming a colorectal primary. Accordingly, the diagnosis of colorectal signet ring cell carcinoma was made.
Discussion(s): The colonoscopic findings of colorectal SRCC could be nonspecific as diffuse circumferential thickening, stricture, or ulcerations. Typical pathological features may not appear on the initial biopsy sample. Immunohistochemical testing could help increase diagnostic yield and early identification of cancer cells. Our case hallmarked the importance of close follow-up for abnormal diffuse stricture and ulcerations in the colorectal area. These lesions may need to be rebiopsied, co-screened with abdominal imaging, and undergo an immunohistochemical investigation to characterize pathology further

Introduction: Gastrointestinal bleeding from vascular malformation is hard to treat. Thalidomide has been shown with therapeutic effects in several studies. We performed a meta-analysis for its efficacy on GI bleeding due to vascular malformation.
Method(s): MEDLINE, the Cochrane Library, and EMBASE were searched up to June 5th. The following keywords were used: "Arteriovenous Malformation", "AVM", "Angioectasia", "Angiodysplasia", "Vascular Malformation", "Telangiectasia", "Thalidomide", "Contergan", "Thalomid", "a-Phthalimidoglutarimide". Observational studies and clinical trials that utilized Nivolumab for refractory esophageal cancer were included. Bleeding cessation rates were studied as primary outcomes. Data were analyzed with STATA version 16.0 (Stata Corp, College Station, TX, USA).
Result(s): A total of 405 manuscripts were identified and four observational or clinical studies with 194 patients meeting inclusion criteria. Patient median or mean ages were more than 50 in all 4 studies and 89 (45.4%) individuals were male. The dose of thalidomide ranged from 50 mg to 200 mg per day. The duration was from 3 months to 45 months. For patients with gastrointestinal bleeding from vascular malformation, thalidomide has a bleeding cessation rate of 41% (95%, 28%-60%) in 6-12 months.
Conclusion(s): Many of the studies claimed that thalidomide was able to decrease bleeding cessation rates significantly, while our meta-analysis with all available studies did not show a significant decrease in bleeding cessation rates compared to the non-thalidomide group reported by Wang's study (41% vs 46%) (Figure). Several studies showed that thalidomide was helpful in the yearly bleeding episodes, yearly red blood cell transfusion requirement, transfusion dependence, overall and bleeding-related hospitalization rate, endoscopic treatment requirement, and hemoglobin level changes, but none of the above topics had enough data to perform a meta-analysis. Therefore, further studies are needed to evaluate the efficacy of thalidomide on Gastrointestinal bleeding from vascular malformation, besides the bleeding cessation rates

Introduction: The United States Preventive Services Taskforce lowered the recommended starting age for colorectal cancer (CRC) screening in average-risk adults from 50 to 45 years due to a rapid increase in young CRC incidence and overall favorable benefit-to-burden ratio in the US. This recommendation has not been widely adopted by other countries partially because the burden of young CRC in these countries is unclear compared to the United States Methods: The incidence rates of early-onset CRC in young adults (defined as the onset of CRC in individuals aged between 20 to 49 years) from 1990 to 2019 were collected from the Global Health Data Exchange (GHDx) results tool (available at https://vizhub.healthdata.org/gbd-results). Data from 204 countries and geographic areas were available. The socio-demographic index (SDI) was used to categorize countries and geographic areas by development (low, low-middle, middle, high-middle, and high).
Result(s): The global incidence rate of young CRC increased from 4.2/100,000 to 6.7/100,000 from 1990 to 2019, with an annual percentage change (APC) of 1.6%. The increase in CRC incidence rate was faster in young adults than in individuals aged 50-74 years (APC 0.6%). In the high HDI region, the CRC incidence rate decreased in adults aged 50-74 years old while it increased in adults 20-49 years old from 1995 to 2019 (Table). The increase in young CRC incidence rate was consistently observed in all five SDI regions and 185 out of 204 countries and territories (Figure a). Middle (120.8%), high-middle (98.5%), and lowmiddle (63.7%) SDI regions experienced the most rapid increase in young CRC incidence rate, while the high SDI region had the highest incidence rate by 2019 (11.5 per 100,000). By 2019, nine countries and territories (Taiwan, Monaco, Portugal, Andorra, Japan, China, Bulgaria, Hungary, and Slovakia) had higher young CRC incidence rates than the United States (Figure b); CRC screening for average-risk adults aged 45-49 years should be studied in these countries. A concerning 142 countries had a higher annual percentage increase of young CRC than the United States, which warrants further attention and investigation. (Table) (Figure a/b)
Conclusion(s): The global incidence, mortality, and DALYs of young CRC increased from 1990 to 2019. The increase in young CRC incidence was prevalent in most countries worldwide. Several countries were found to have higher incidence rates or faster increase in young CRC, which warrants further attention

Introduction: Nonalcoholic fatty liver disease (NAFLD) is causing an emerging global epidemic. The global burden of disease (GBD) study estimates the burden of NAFLD in 203 countries and geographic areas across the world, providing a unique opportunity to understand the landscape of this disease.
Method(s): Prevalence, mortality, and disability-adjusted life years (DALYs) of NAFLD from 1990 to 2019 by region and country in all sex and age groups were collected from the Global Health Data Exchange (GHDx) results tool (Available from http://ghdx.healthdata.org/gbd-results-tool). DALYs are the sum of years lost due to premature death and years lived with disability. The socio-demographic index (SDI) categorizes countries and geographic areas by development (low, low-middle, middle, high-middle, and high).
Result(s): Between 1990 to 2019, the global prevalence of NAFLD increased from 10.9% to 16.6% (increased by 52.6%; linear regression beta-coefficient 0.2, P < .001). In 2019, an estimated 1.3 billion people were affected by NAFLD worldwide. Mortality attributed to NAFLD increased from 93,000 to 169,000. DALYs of NAFLD increased from 2.7 million years to 4.4 million years. Significant uptrends were observed in all SDI regions, more prominent in the middle SDI regions (Table). Changes in the prevalence of NAFLD by countries are depicted in Figure. All but three countries demonstrated an increase in the prevalence of NAFLD. More notable increases (>=10%) were mostly observed in North African and Middle Eastern countries.
Conclusion(s): NAFLD's prevalence increased by more than 50% globally from 1990 to 2019. The mortality and DALYs also increased. The increase in NAFLD prevalence is more prominent in countries with middle SDI and countries in North African and Middle Eastern regions, possibly due to changes in lifestyle in these areas over the past 30 years. (Figure Presented)

Introduction: Inborn errors of immunity are a group of primary immunodeficiency disorders caused by over 400 genetic defects. Enteropathy has been common in PID patients, which presents with chronic diarrhea, malabsorption, growth delay, iron deficiency, and failure to thrive. This article systemically reviewed the clinical presentations, treatments, and genetic defects of enteropathy observed in PIDD.
Method(s): We have reviewed published cases with the clinical diagnosis of both enteropathy and PIDD using 3 databases (Pubmed, Scopus, EMBASE). A total of 346 cases met our inclusion criteria.
Result(s): The most common enteropathy-associated PIDD is common variable immunodeficiency (32.4%), IPEX (21%), selective IgA deficiency (18.1%), and hypogammaglobulinemia (7.9%; Figure). Celiac disease (26.2%) is the most common enteropathy presentation in PIDD, followed by IPEX (20.7%), autoimmune enteropathy (6.4%), and CVID enteropathy (5.8%). Selective IgA deficiency and CD/Celiac like disease were also frequently reported. More than half of documented PIDD-related CD showed positive serology test results and histopathological findings. Eighty-eight percent of PIDD-related CD cases are responsive to a gluten-free diet. FOXP3 mutation (70) was the most common gene mutation in PIDD, followed by CTLA-4 (17), CD55 (8), NFKB1 (8), GoF-STAT1 (5), GoF-STAT3 (5), and C1-INH (4; Table)). CTLA-4 mutation was found related to CVID, hypogammaglobulinemia, and autoimmune enteropathy. NFKB1was found mainly linked to CVID. We observed frequent giardiasis (21), norovirus (3), CMV (4), Candidiasis (2), and histoplasmosis (2) infections causing enteropathy in PIDD. No significant difference in treatments of the enteropathy between PIDD and non-PIDD was noticed.
Conclusion(s): Enteropathy can be common clinical presentations in IEIs. With early recognition of clinical manifestations and enteropathy-associated gene mutation, PIDD can be diagnosed and treated timely, preventing complications and mortalities

Introduction: Biloma is an extrahepatic bile collection secondary to iatrogenic or traumatic biliary tree disruption. It is a rare complication of laparoscopy cholecystectomy with an incidence rate of approximately 2.5%. Without proper management, biloma can become infected and cause life-threatening complications such as peritonitis, biliary fistula, bilhemia and hemobilia. Here we described a case of complicated biloma after laparoscopic cholecystectomy. Case Description/Methods: The patient was a 24-year-old female with a past medical history of hypertension, obesity, and recent laparoscopic cholecystectomy complicated by hepatic subcapsular biloma. It was managed by biliary stent placement via endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous drainage during the previous hospitalization. However, 6 days later, she presented with fever, chills, nausea, and right upper quadrant pain. Vital signs were fever 102.3 F and tachycardia 110 to 120 per min. The CT abdomen revealed decreased size in perihepatic fluid collection with air bubbles (14 x 11 x 18 cm; Figure). It also showed a common bile duct stent in place and a percutaneous drainage catheter tip in the inferior aspect of the collection. Lab results showed leukocytosis to 10.3, normal AST/ALT, total/direct bilirubin 2.1/12 mg/dL, and GGT 152 U/L. Broad-spectrum antibiotics were given in ED. The surgery team performed a laparoscopic lavage and discovered that the drain was not connected with the biloma. Two new drains were placed during the operation. She was discharged with PO antibiotics, and an outpatient follow-up was scheduled for drain removal.
Discussion(s): The management of biloma depends on the severity of the disease. Endoscopic therapy, such as a transpapillary biliary stent placement, can decrease the transpapillary pressure gradient, thus allowing preferential transpapillary bile flow rather than accumulation at the leaking site. However, given that stent placement does not reabsorb formed collection, patients failing ERCP should undergo percutaneous drainage or bile duct repair.Iatrogenic biloma can be detected by post-operational physical exams and image studies. Laparoscopic lavage with drainage should be considered in unresolved or infected biloma due to the high risk of peritonitis

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases are both highly prevalent conditions around the world, and emerging data have shown an association between them. This review found several longitudinal and cross-sectional studies showing that NAFLD was associated with coronary artery disease, cardiac remodeling, aortic valve remodeling, mitral annulus valve calcifications, diabetic cardiomyopathy, diastolic cardiac dysfunction, arrhythmias, and stroke. Although the specific underlying mechanisms are not clear, many hypotheses have been suggested, including that metabolic syndrome might act as an upstream metabolic defect, leading to end-organ manifestations in both the heart and liver. Management of NAFLD includes weight loss through lifestyle interventions or bariatric surgery, and pharmacological interventions, often targeting comorbidities. Although there are no Food and Drug Administration-approved nonalcoholic steatohepatitis-specific therapies, several drug candidates have demonstrated effect in the improvement in fibrosis or nonalcoholic steatohepatitis resolution. Further studies are needed to assess the effect of those interventions on cardiovascular outcomes, the major cause of mortality in patients with NAFLD. In conclusion, a more comprehensive, multidisciplinary approach to diagnosis and management of patients with NAFLD and cardiovascular diseases is needed to optimize clinical outcomes.