Clinical Case Summary

Caudate lobe hypertrophy is a common finding in cirrhotic liver, although giant variants are rare. Nevertheless, any lesion on a cirrhotic liver warrants consideration for hepatocellular carcinoma (HCC).
This case involves a 28-year-old male patient irregularly followed up at our center for secondary biliary cirrhosis. With a history of intrahepatic bile duct paucity due to Alagille syndrome since neonatal age, he is a current smoker (10 pack-years) with no alcohol abuse. After three years lost to follow-up, the patient presented with a gradual 4-month onset of jaundice, dark urine, and upper right quadrant discomfort. Laboratory findings revealed worsening liver function tests: total bilirubin 11.5 mg/dl (vs 2.5 mg/dl), predominantly conjugated 7.6 mg/dl (vs 1.7 mg/dl), alkaline phosphatases 3.3x ULN (vs 2.6x ULN), gamma-glutamyl transferase 6.4x ULN (vs 4.5x ULN), aspartate aminotransferase 3.8x ULN (vs 1.7x ULN), alanine aminotransferase 1.5x ULN (vs 1.3x ULN).
The 4-phase CT scan revealed a dysmorphic liver with a large mass spanning segments 4, 5, 6, 7, and 8, measuring 130x100mm. The mass exhibited arterial enhancement without late phase washout and no evidence of a capsule. This mass displaced the hepatic veins and abutted the inferior vena cava and portal branches, without signs of invasion. MRI showed a similar appearance with no diffusion restriction. Initially suspected as HCC, the mass was classified as LIRADS-4. Alpha-foetoprotein level was normal. CT-guided biopsy retrieved multiple 41mm samples. Histopathological findings indicated annular fibrosis with histological cholestasis and no malignant cells. Therefore, the established diagnosis was caudate lobe hypertrophy, following a multidisciplinary team discussion and review of radiological features.
Despite this entity's rarity, biopsy seems crucial to rule out HCC, especially with abnormal vascular behavior like arterial enhancement, to avoid overtreatment.

Introduction

Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) offers advantages over duodenal stenting and surgical bypass. EUS-GE technique, however, remains non-standardized. A parallel enteric tube (PET) facilitates luminal distention, a critical step during EUS-GE.

Aims & Methods

We primarily aimed at standardizing PET-assisted EUS-GE, secondarily assessing reproducibility and outcomes.
Prospective multicenter study on consecutive adult patients with unresectable malignant gastric outlet obstruction undergoing primary EUS-GE between August 2019-April 2021. Hierarchical task analysis predefined procedural steps into tasks and subtasks. Subtasks were further categorized into essential (performed in all centers and in over 85% of the procedures) or optional. Subtask methodology was considered established if performed similarly in all centers or variable if not. Procedure times, injected fluid volume, luminal diameters obtained, accessories used, and clinical outcomes were recorded.

Results

Seven endoscopists performed EUS-GE in 65 patients (50.8% male, median [IQR] age 77.5 [65.7-86.5] years). EUS-GE was categorized into 4 tasks and 10 subtasks (Table 1). Five essential subtasks involved an established methodology (guidewire and PET placement, endoscope exchange, delivery system insertion and LAMS deployment).
Technical and clinical success rates were 98.5% and 83.3%, respectively. AEs occurred in 10 (15.4%) patients (2 mild, 7 moderate, 1 severe). Success and AE rates were not different between expert and non-experts. Median (IQR) procedure time was 26.2 (19.7-37.1) min. The short and long axis of the targeted small bowel loop was 27 (23-30) x 40 (33-60) mm. Procedure time was longer (35 [30.6-43.7] vs 21.8 [16.4-29.5] min, p<0.001) and injected fluid volume higher (510 [439-870] vs 415 [255-480] ml, p=0.01) in non-experts.

Table 1. Proposed taxonomy for the PET-assisted EUS-GE

Conclusion

PET-assisted EUS-GE was standardized, identifying its key steps and technique variants. PET-assisted EUS-GE appears to be a reproducible procedure among advanced endoscopists with different levels of experience. (Clinical Trials Identification Number: NCT04660695).

Disclosure

Carlos Chavarríareceived research and training support by a grant from The Foundation of the Institute of Health Sciences Studies of Castilla y León (IECSCYL).
Vanessa Martín-Álvarezhas nothing to declare.
José Ramón Aparicio is a consultant for Boston Scientific.
Jose Carlos Subtil has nothing to declare.
Francisco Javier Garcia-Alonso has nothing to declare.
Juan J. Vila is a consultant for Boston Scientific and speaker for Cook Endoscopy and Olympus.
Belén Martínez-Moreno has nothing to declare.
Victoria Busto-Bea has nothing to declare.
Ramon Sanchez-Ocaña has nothing to declare.
Carlos de la Serna-Higuera has nothing to declare.
Manuel Perez-Miranda Miranda is a consultant and speaker for Boston Scientific, Olympus, and M.I.Tech.

Clinical Case Summary

Introduction: Inflammatory bowel diseases gather several phenotypes of autoimmune affectation of the GI tract - sometimes they may frame into a polyautoimmune syndrome (PAS).
Case description: We present a 28-year-old man with nephrotic syndrome, autoimmune hepatitis/primary biliary cholangitis overlap syndrome and alopecia areata universalis, who was on cyclosporine and budesonide.
The patient was admitted with chronic bloody diarrhea and weight loss. He had anemia, hypoalbuminemia and increased CRP; fecal calprotectin (FC) was 4500ug/g. CT scan showed concentric colon thickening. Endoscopic studies showed deep, exudative ulcers in the colon and rectum - biopsies showed chronic active colitis.
Previous immunosuppressive therapies were stopped and prednisolone was begun. Biopsies tested positive for CMV and antivirals were started. The patient improved and was discharged home on steroids.
This was assumed to be a case of unclassified inflammatory colitis with concurrent CMV colitis. In the following months, the patient was re-hospitalized 5 times for severe exacerbations with partial response to steroids and new CMV reactivations. Infliximab was started but discontinued due to loss of response; azathioprine therapy was tried but stopped due to adverse reaction.
It was decided to start tofacitinib. After 6 months of therapy, he is asymptomatic, regaining weight and recovering body hair. FC is 1191ug/g, with no other analytical changes.
Genetic tests show a possible pathogenic variant in LRBA gene (linked to immunodeficiency type 8 with autoimmunity). The LRBA deficit study has been expanded.
Conclusion: This case highlights the complexity of patients with PAS and the need for a multidisciplinary approach. It also proves the efficacy of tofacitinib in this patient, having prevented new admissions so far, with important clinical/analytical improvements. If LRBA deficiency is proven, abatacept may be considered for treatment as it is effective in most of these patients.

Introduction

Autoimmune pancreatitis (AIP) is a chronic, relapsing form of pancreatitis, often affecting multiple organs. Although the exact pathomechanism is incompletely understood, plasmacytoid dendritic cells (pDC) and their cytokines IL-33 and interferon alpha-1 (IFNA1) are known to play a central role in AIP pathophysiology. Through activation of IFN-regulatory factors 3 and 7 (IRF3/IRF7) in pDC, IFNA1 transcription is initiated, likely offsetting the inflammatory cascade. AIP often leads to exocrine atrophy and insufficiency, however it is currently unknown whether pDCs affect acinar cell regeneration or their cell death.

Aims & Methods

This study aims to understand the effect of the IFN-cascade offset by pDCs on acinar regeneration capacity and cell death in AIP. The MRL/Mp mouse model for AIP was used to first characterize the immune cell infiltrate in AIP compared to acute pancreatitis (AP) via immunohistochemistry (IHC) staining. To test the impact of pDCs and Ifna1 release on pancreatic acinar cells, pDCs were generated from bone marrow of wild type (WT) and Irf3/7-knock out (Irf3/7-KO) mice and murine acinar cells were incubated with supernatant of WT and Irf3/7-KO pDCs, or pDC-related cytokines IL-33 and IFN-a. Gene expression via qPCR, cell stress via LDH assay and cytokine array were performed to measure the effects on acinar cells.

Results

AIP in MRL/Mp mice exhibited a stronger immune infiltrate in comparison to mice with an AP. The immune infiltrate in AIP was characterized by a dense invasion of CD8+ T cells, presence of CD11c+ cells (pDCs) and complete absence of neutrophils. Furthermore, Irf3 and Irf7 expressions were increased not only in immune but also acinar cells in AIP, whereas decreased in acinar cells and not at all expressed in immune cells in AP. Proliferation markers were not expressed in acinar cells in AIP, whereas showed some expression in acinar cells in AP. Acinar cells treated with pDC supernatant of WT revealed an increase in apoptosis signaling genes, whereas acinar cells treated with pDC supernatant of Irf3/7-KO mice showed a downregulation of apoptotic genes.

Conclusion

This study reveals that pDCs dictate acinar cell death signaling by regulating apoptosis via the IFN-cascade. This might be a distinct feature of AIP, in which the clinical course is moderate and only apoptosis is present, compared to AP, in which the disease course is much more severe and necrosis is a prominent feature. Further studies are needed to examine the role of pDC in necrosis and acinar regeneration.

References

1. Hart PA, Zen Y, Chari ST. Recent Advances in Autoimmune Pancreatitis. Gastroenterology. 2015;149(1):39–51.
2. Watanabe T, Yamashita K, Arai Y, Minaga K, Kamata K, Nagai T, et al. Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells. J Immunol. 2017;198(10):3886–96.
3. Minaga K, Watanabe T, Arai Y, Shiokawa M, Hara A, Yoshikawa T, et al. Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis. J Gastroenterol. 2020;55(5):565–76.

Clinical Case Summary

A 74-year-old, female patient was referred to the study center for pancreatic cysts. Magnetic resonance imaging revealed multiple pancreatic cysts up to 15 mm in size distributed from the pancreatic head to the pancreatic tail and enlargement of the main pancreatic duct diameter to 8 mm. T1- and T2-weighted imaging demonstrated showed a 10 mm mass with iso-intensityin the main pancreatic duct in the pancreatic body with diffusion restriction on diffusion-weighted imaging. Endoscopic ultrasonography also demonstrated a mass located in the main pancreatic duct in the pancreatic body, but determining whether the tumor was located in the pancreatic duct or was an extension of the intraparenchymal lesion into the main pancreatic duct was difficult. On contrast-enhanced abdominal computed tomography, the mass was difficult to identify as a lesion because it showed the same contrast as the surrounding pancreatic parenchyma. Endoscopic retrograde choangiopancreatography revealed enlargement of the duodenal papillary entrance, mucus discharge, and a mass-like, translucent image with an irregular surface in the main pancreatic duct in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration led to the diagnosis of adenocarcinoma, and a distal pancreatectomy was performed on the assumption that the lesion derived from IPMN. Pathological analysis led to the diagnosis of IOPN consisting of papillary cells with an eosinophilic cytoplasm, positive immunostaining for MUC5AC and MUC6, and partially positive staining for MUC1 and HepPar-1. The mass was determined to be within the pancreatic parenchyma by comparing a resection specimen with preoperative images. Fusion gene analysis revealed the presence of ATP1B1-PRKACA, confirming the diagnosis of IOPN.
It is important always to bear in mind the possibility of IOPN if pancreatic cysts are observed. IOPN is relatively rare, and more cases are needed for a better understanding of this disease.

References

Aatur D. Singhi, Laura D.Wood, Emma Parks, Michael S.Torbenson, Matthaus Felsenstein. Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct : Gastroenterology. 2020 Feb ; 158(3) : 573-582.
Eriko Ikeda. Histological Classification of Intraductal Papillary Mucinous Neoplasms of the Pancreas : Journal of Biliary Tract & Pancreas. 2020 ; 41(1) : 27-31