Ayush Sharma

Natural history and clinical detection of undiagnosed coeliac disease in a North American community

Coeliac disease is a substantially underdiagnosed disorder, with clinical testing currently guided by case finding.

Open-Capsule Budesonide for Refractory Celiac Disease

Objectives:Refractory celiac disease (RCD) is a rare condition often associated with poor prognosis. Various immunosuppressive medications (IMs) have been used with modest success. We describe outcomes in patients treated with open-capsule budesonide (OB), including those for whom IM treatment failed.Methods:We identified RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. Demographic, serologic, and clinical variables were analyzed.Results:We identified 57 patients who received OB for suspected RCD. Based on clonal T-cell receptor gamma gene rearrangement or aberrant phenotype of intraepithelial lymphocytes (IELs), 13 patients (23%) were classified as having RCD-2 and 43 (75%) as RCD-1. In one patient (2%) TCR gene rearrangement status was unknown. Most patients were women (69%), mean (s.d.) age was 60.5 (3.5) years and body mass index was 28.4 (4.5) kg/m2. The majority had diarrhea (72%), with median of 6 bowel movements per day (range, 4–25). IM treatment (azathioprine, systemic corticosteroids, or regular budesonide) had failed in nearly half. Twenty-four patients (42%) had anemia and 12 (21%) had hypoalbuminemia. All had Marsh 3 lesions on biopsy: 3a (19%), 3b (46%), and 3c (35%). After OB therapy, the majority had clinical (92%) and histologic (89%) improvement. Follow-up biopsy in 7 out of 13 patients with RCD-2 (53%) showed an absence of clonal TCR gamma gene rearrangement/aberrant IEL phenotype previously seen. On follow-up, 2 patients (4%) died of enteropathy-associated T-cell lymphoma.Conclusions:Most patients with RCD show clinical and histopathologic improvement with OB therapy, including those with failure of IMs. OB is a promising therapeutic option for management of RCD.

Recurrent stat3-jak2 fusions in indolent t-cell lymphoproliferative disorder of the gastrointestinal tract

TO THE EDITOR: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (GI TLPD) is a newly recognized entity in the World Health Organization (WHO) classification of lymphoid neoplasms.[1][1] GI TLPD is defined as a clonal T-cell proliferation occurring in the GI tract, most

Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy

Background & Aims Glycogenic hepatopathy, a syndrome characterized by hepatomegaly and increased liver transaminases in patients with type 1 diabetes, has not been well characterized in adults. We describe the clinical, biochemical, and histopathology profile of a cohort of patients with glycogenic hepatopathy. We also examined differences between patients with type 1 diabetes with versus without glycogenic hepatopathy. Methods We performed a case–control study of patients with type 1 diabetes diagnosed with glycogenic hepatopathy and patients with type 1 diabetes without glycogenic hepatopathy (control subjects). Cases were identified in the database of electronic medical records at Mayo Clinic, Rochester from January 1, 1998, through January 1, 2014. Age‐ and sex‐matched control subjects were identified from a Mayo Clinic registry of patients with type 1 diabetes who had normal levels of liver enzymes. Demographic, clinical, laboratory, and histopathology data were collected and compared between cases and control subjects. The primary outcome was difference in frequency of diabetic ketoacidosis episodes and hemoglobin (Hb) A1c levels between cases and control subjects. Results Among the 36 patients diagnosed with glycogenic hepatopathy, 20 had undergone liver biopsy analysis. Most cases were female (n = 28; 77.8%). Abdominal pain was the most common symptom (n = 23; 63.9%); 28 patients (77.8%) had hepatomegaly. All patients had poor control of diabetes (mean HbA1c level, 11.2 ± 2.4%). A higher proportion of cases had recurrent episodes of diabetic ketoacidosis (61%) than control subjects (9%) (P = .009), and cases had a higher mean level of HbA1c (11.2 ± 2.4% vs 9.0 ± 2.2% in control subjects; P = .0004). Adult cases had higher levels of aspartate transaminase (312.5 IU/L; range, 245.5–775 IU/L) than pediatric cases (157; range, 104–267 IU/L; P = .02) and lower serum levels of albumin (3.7 ± 0.5 g/dL vs 4.3 ± 0.4 g/dL for pediatric cases; P = .008). Only 16.7% of pediatric patients with glycogenic hepatopathy had growth retardation. Levels of liver transaminases were normalized at follow‐up examinations of 18 of 21 adult or pediatric patients with glycogenic hepatopathy. Conclusions More than half of patients with glycogenic hepatopathy and type 1 diabetes have recurrent episodes of diabetic ketoacidosis, and these patients have higher levels of HbA1c than patients with type 1 diabetes without glycogenic hepatopathy. We observed growth retardation in only about 17% of pediatric patients with glycogenic hepatopathy.

Risk of Pancreatic Cancer in Patients With Pancreatic Cysts and Family History of Pancreatic Cancer

Background & Aims: A diagnosis of pancreatic cancer in a first‐degree relative increases an individuals’ risk of this cancer. However, it is not clear whether this cancer risk increases in individuals with pancreatic cystic lesions who have a first‐degree relative with pancreatic cancer. The Fukuoka criteria are used to estimate risk of pancreatic cancer for patients with pancreatic cystic lesions: individuals with cysts with high risk or worrisome features (Fukuoka positive) have a higher risk of pancreatic cancer than individuals without these features (Fukuoka negative). We aimed to compare the risk of pancreatic cancer and surgery based on presence or absence of pancreatic cystic lesions and a first‐degree relative with pancreatic cancer. Methods: We performed a retrospective study of patients seen at the Mayo Clinic in Rochester, Minnesota, from January 1, 2000, through December 31, 2012. We identified individuals with: pancreatic cystic lesions and first‐degree relative with pancreatic cancer (group 1, n = 269), individuals with pancreatic cystic lesions but no first‐degree relative with pancreatic cancer (group 2, n = 1195), and individuals without pancreatic cystic lesions but with a first‐degree relative with pancreatic cancer (group 3, n = 720). We compared, among groups, as well among patients with cysts classified according to Fukuoka criteria, proportions of individuals who developed pancreatic cancer or underwent pancreatic surgery within a 5‐year period. Results: A significantly higher proportion of individuals in group 1 developed pancreatic cancer during the 5‐year period than in group 3 (6.64% vs 1.69%; P = .03); there was no significant difference between the percentage of individuals in group 1 vs group 2 who developed pancreatic cancer (6.64% vs 4.05%; P = .41). There was no significant difference in pancreatic cancer development among individuals with Fukuoka‐positive cysts with vs without a family history of pancreatic cancer (P = .39). There was no significant difference in the proportion of patients in group 1 vs group 2 who underwent pancreatic surgery for their pancreatic cyst over the 5‐year period (14.37% vs 11.80%; P = .59). Among patients with Fukuoka‐negative cysts, a significantly higher proportion underwent surgery in group 1 than in group 2 (10.90% vs 5.90%; P = .03). However, among patients with Fukuoka‐positive cysts, there was no difference in proportions of patients who underwent surgery between groups 1 and 2 (P = .66). Conclusions: In a retrospective study of patients with pancreatic cysts and/or cancer, we found that a family history of pancreatic cancer does not affect 5‐year risk of pancreatic cancer in patients with pancreatic cystic lesions. Despite this, among patients with Fukuoka‐negative cysts, a higher proportion of those with a family history of pancreatic cancer undergo surgery than patients without family history of pancreatic cancer.

Epidemiologic Factors, Clinical Presentation, Causes, and Outcomes of Liver Abscess: A 35-Year Olmsted County Study

Objective To report the changing incidence, clinical presentation, microbiologic spectrum, and outcomes of pyogenic liver abscess (PLA) in Olmsted County, Minnesota, over the past 35 years. Patients and Methods The Rochester Epidemiology Project was used to identify residents with PLA from January 1, 1980, through December 31, 2014. The study included all patients older than 18 years, with the diagnosis of PLA confirmed through radiographic review and microbiologic cultures. Results In total, 72 patients received a diagnosis of PLA from 1980 through 2014. The age-adjusted incidence for men was 3.92 cases per 100,000 person-years (95% CI, 2.76-5.09 cases per 100,000 person-years) compared with 1.87 cases per 100,000 person-years (95% CI, 1.15-2.59 cases per 100,000 person-years) for women. Incidence was higher in the period from January 1, 2001, through December 31, 2014, than in the period from January 1, 1980, through December 31, 2000, for women (incidence rate ratio [IRR], 3.8; 95% CI, 1.43-10.09; P=.007) but not for men (IRR, 0.99; 95% CI, 0.55-1.76; P=.96). Fifteen additional patients had postintervention PLA (1980-2000: n=3 of 29 [10.3%] vs 2001-2015: n=12 of 58 [20.6%]). A significant association was seen between age- and sex-adjusted incidence rates of PLA and year of diagnosis (per year since 1980: IRR, 1.04; 95% CI, 1.02-1.07; P<.001) after including postintervention PLA. Streptococcus milleri was the most common organism identified (52.5%). Organisms with multidrug resistance were more common in the period from 2001 through 2014 than in the period from 1980 through 2000 (51% vs 14%; P=.005). The overall mortality rate of PLA was 16.8% (95% CI, 7.6%-25.0%) at 6 months. Conclusion The incidence of PLA is increasing, probably because of increase in frequency of hepatobiliary interventions and organisms with multidrug resistance.

Pancreatic Cancer and Diabetes Mellitus

Purpose of reviewThe relationship between pancreatic ductal adenocarcinoma (PDAC) and diabetes mellitus (DM) is complex. We reviewed the recent medical literature regarding the effect of anti-diabetic medication on PDAC risk and survival, risk of PDAC in DM, and role of DM in early detection of PDAC.Recent findingsStudies report that while some anti-diabetic medications (e.g., metformin) may decrease the risk of PDAC, others (insulin, sulfonylureas and incretin-based therapies) may increase the risk. However, these observations may be subject to protopathic biases. Metformin’s anti-tumor activity may have influence overall survival of PDAC, but epidemiological reports have largely been inconsistent to defend these findings due to heterogeneous methodologies. There is congruent data to support the association between DM and PDAC, with an inverse relationship to DM duration. Older subjects with new-onset DM are the only known high-risk group for PDAC, and strategy using this group for early detection has led to development of clinical risk prediction models that define a very high-risk PDAC group.SummaryRole of anti-diabetic medication in PDAC risk modification or survival is controversial. With successful efforts to distinguish type 2-DM from PDAC-DM using risk-stratifying models, there is an opportunity to initiate screening protocols for early detection of PDAC in a sub-set of DM subjects.

Features of Adult Autoimmune Enteropathy Compared With Refractory Celiac Disease

BACKGROUND & AIMS: Little is known about the features of immune‐mediated non‐celiac villous atrophies, such as autoimmune enteropathy (AIE). We investigated the demographic, clinical, and histologic features of adults with AIE compared to adults with refractory celiac disease type 1. We also report outcomes of treatment with open‐label budesonide. METHODS: We performed a retrospective case–control of patients with AIE (n = 30) seen at the Mayo Clinic (in Rochester, Minnesota) from 2000 through 2015. Patients with refractory celiac disease type 1 who were treated with open‐label budesonide served as controls (n = 42). Biopsy specimens were reviewed for all patients. We collected demographic, clinical, biochemical and histologic data from patients. We also collected data on responses to open‐capsule budesonide from patients with AIE (available from 22 patients) and controls (available from 42 patients); the median duration of follow up was 28 months (range, 0–1421 months). RESULTS: Patients with AIE had a higher proportion of men (60%) and were younger (mean, 44 ± 18 years) than patients with refractory celiac disease type 1 (29% men; P = .002 and mean age, 57 ± 16 years; P = .007). A higher proportion of patients with AIE presented with chronic diarrhea (100%) and weight loss (90%) than patients with refractory celiac disease type 1 (71%; P < .001 and 71%; P = .05, respectively). Based on histologic analysis, there was no significant difference in degree of villous atrophy in intestinal tissues from patients with AIE vs controls (P = .68). However, a greater proportion of patients with RCD had increased intraepithelial lymphocytes (>40 per 100 epithelial cells in 100%) compared with patients with AIE (in 50%) (P = .003). Conventional therapy (systemic steroids) had failed in most patients with AIE (a complete clinical response was reported in only 7 patients) before treatment with open‐capsule budesonide was initiated. A clinical response to open‐capsule budesonide was reported for 85% of patients with AIE (50% complete response, 35% partial response) compared to 92% of controls (68% complete response, 24% partial response). CONCLUSIONS: In a retrospective study of 30 patients with AIE, followed for a median 28 months, we found this disease to have has distinct demographic, clinical, and histologic characteristics compared to refractory celiac disease type 1. Most patients with AIE (85%) have a clinical response to budesonide, all of whom were unsuccessfully treated with conventional therapies.

Clinical Profile of Pancreatic Cystic Lesions in von Hippel-lindau Disease: A Series of 48 Patients Seen at a Tertiary Institution

Objectives Little is known about the association between pancreatic cystic lesions (PCLs) with von Hippel-Lindau disease (VHLD). In this study, we describe the clinical presentation, type of PCLs, and risk for malignancy in PCLs in VHLD. Methods Patients given a diagnosis of both VHLD and PCLs were identified from electronic medical records at Mayo Clinic, Rochester, MN, from January 1, 2000, to January 1, 2016. Various demographic, clinical, and radiologic variables were recorded. Results Forty-eight patients were identified with PCLs and VHLD. Most were female (73%), and mean (standard deviation) age was 35.9 (14.2) years. Most (92%) were asymptomatic. PCLs included simple cysts (n = 34, 69%), serous cystadenoma (n = 14, 29%), branch duct intraductal papillary neoplasm (n = 5, 10%), and cystic neuroendocrine tumors (n = 2, 4%). Eight (19%) had mixed PCLs. Cyst aspiration was performed in 8 (53%) patients who underwent EUS, and all were negative for malignancy. At a median follow-up of 84 months, no PCL-associated cancers were seen. Conclusions Simple cyst is the most common type of PCL found in VHL disease; however, other PCLs were also seen with no malignancy potential. Branch duct intraductal papillary mucinous neoplasms were present in 10%, and this association was not hitherto reported.

Machine Learning in Detection of Undiagnosed Celiac Disease

Celiac disease (CD) has a diversity of presentations that include typical symptoms such as diarrhea and weight loss and atypical symptoms such as elevated liver function tests and fatigue. Current guidelines recommend case finding for diagnosis of CD, a technique in which physicians test individuals thought to be at risk for the disease due to the presence of conditions or symptoms associated with CD. However, CD, particularly cases with atypical symptoms, remains largely undiagnosed. Increasing evidence suggests that case finding may not be effective. Given the morbidity of undiagnosed symptomatic CD, a new method of detection needs to be developed. We therefore sought to build a machine learning model for identifying undiagnosed CD based on permutations of currently accepted indications to test for CD.