Groove pancreatitis (GP) is a rare focal form of chronic pancreatitis that frequently mimics pancreatic head or duodenal malignancy, often leading to unnecessary pancreaticoduodenectomy. We report the case of a 47-year-old man with heavy alcohol use who presented with severe gastric outlet obstruction (GOO) due to a mass-like duodenal lesion. Clinical, endoscopic, and radiologic features initially suggested primary duodenal malignancy. However, characteristic imaging, negative biopsies, and multidisciplinary review confirmed segmental GP. The patient achieved complete resolution of GOO and the duodenal lesion within 7 days using conservative management alone (alcohol cessation, nasogastric decompression, proton-pump inhibitors, pancreatic enzymes, and nutritional support). This unusually rapid and morbidity-free response highlights that, when malignancy is reliably excluded, pragmatic conservative therapy can safely prevent major pancreatic resection and its associated costs. Greater awareness of GP and early multimodal assessment can reduce overtreatment in ambiguous pancreaticoduodenal masses.

Poor outcomes in pancreatic neuroendocrine neoplasms (pNENs) partially result from the inability to identify early-stage disease in patients. Prevention strategies have focused on identifying high-risk patients through genetic susceptibility genes. This study aims to report the incidence of pathogenic germline variants (PGVs) in pNEN. 129 pNEN patients that underwent germline testing with Invitae between September 5, 2019, and February 15, 2022, were retrospectively analyzed. PGVs were found in 14.7% (19/129) of pNENs. PGVs in pancreatitis genes were detected in 7.7% (3/39) of the 39 pNEN patients with an available pancreatitis panel. CFTR alterations were the most common pancreatitis-associated gene identified (5.1%, 2/39). MUTYH alterations were the most frequently detected (3.9%, 5/129) PGV in pNENs. DNA or base repair PGVs were found in 7.8% (10/129). Our findings suggest that germline testing may play a role in the standard-of-care management of pNEN. MUTYH alterations merit further evaluation as a potential risk factor for pNEN.

Hyperuricemia (HUA) is implicated in various metabolic and inflammatory diseases. Its role in the pathogenesis of acute pancreatitis (AP), particularly in gut-pancreas crosstalk and the underlying molecular mechanisms, remains poorly understood. This study integrates clinical epidemiology (UK Biobank cohort and the Third Xiangya Hospital cohort), (L-arginine-induced AP mouse models), and multi-omics analyses (RNA sequencing, fecal metabolomics, and gut microbiome profiling) to elucidate the role and mechanistic pathways of uric acid in the onset and severity of AP. Key molecular targets and regulatory relationships identified were further validated via in vitro cellular experiments using pancreatic acinar cells and bone marrow-derived macrophages. In the UK Biobank cohort, over a median follow-up period of 13.69 years, participants in the highest uric acid quartile exhibited a significantly increased risk of developing AP compared to the lowest quartile (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.10-1.43). In the Third Xiangya Hospital cohort, AP patients with elevated serum uric acid levels exhibited more severe symptoms. The combination of uric acid and calcium demonstrated superior predictive capability for AP severity (AUC 0.9504). In the preclinical models, HUA aggravated AP progression, as demonstrated by increased pancreatic histopathological damage, elevated serum amylase levels, multi-organ dysfunction, and higher mortality. Mechanistically, HUA exacerbated AP in mice via cannabinoid receptor 1 (CNR1)-mediated retrograde endocannabinoid signaling, which enhanced macrophage-derived IL-1β and IL-6 production. Metabolomics revealed that the gut-derived flavonoid maesopsin exerted a protective anti-inflammatory effect in the context of HUA-augmented AP. Additionally, Limosilactobacillus genus, particularly Limosilactobacillus reuteri D, was enriched in the HUA + AP group and strongly associated with maesopsin levels. Uric acid exacerbates AP progression via CNR1 driven inflammatory signaling and modulates gut microbiota composition and metabolism. Serum uric acid, especially when combined with calcium, may be integrated into routine clinical assessment for AP risk stratification and severity prediction, while CNR1 and gut microbiota-related targets provided potential directions for the developing adjunctive therapies for HUA-associated AP.

ApoB is the structural protein of all atherogenic lipoproteins, including VLDLs (very-low-density lipoproteins), IDLs (intermediate-density lipoproteins), LDLs (low-density lipoproteins), chylomicron remnants, as well as Lp(a) (lipoprotein[a]). Because each lipoprotein particle contains a single apoB molecule, plasma apoB concentration reflects the number of circulating atherogenic particles. Genetic, epidemiological, and randomized clinical trial evidence consistently demonstrate that, on a per-particle basis, apoB is a more accurate causal determinant of atherosclerotic cardiovascular disease risk than LDL cholesterol alone. Beyond atherosclerosis, apo B48-containing chylomicrons play a central role in severe hypertriglyceridemia and, importantly, contribute to the risk of triglyceride-mediated acute pancreatitis. Most established therapies that reduce major cardiovascular events, including statins, ezetimibe, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, and bempedoic acid, act primarily by enhancing LDL receptor-mediated clearance of apoB-containing particles. Other currently available therapies reduce LDL cholesterol as well as apoB through LDL receptor-independent mechanisms. Lomitapide, an inhibitor of MTP (microsomal triglyceride transfer protein), and evinacumab, a monoclonal antibody targeting ANGPTL3 (angiopoietin-like protein 3), reduce LDL cholesterol in homozygous familial hypercholesterolemia by decreasing triglyceride-rich apoB-containing lipoproteins upstream of LDL particle formation. Emerging therapeutic strategies targeting the angiopoietin-like protein axis, apo CIII, Lp(a), CETP (cholesteryl ester transfer protein), hepatic lipid flux, and incretin signaling expand the therapeutic landscape for modulating apoB-containing lipoproteins. Gene-targeted approaches, including gene editing, epigenome editing, small interfering RNA, and antisense oligonucleotides, as well as novel oral or injectable agents and combination therapies, further broaden opportunities for durable apoB modulation. Transitioning from an LDL cholesterol-centric to an apoB-centric framework may represent a biologically integrated strategy to reduce both atherosclerotic cardiovascular disease and triglyceride-mediated pancreatitis risk.

IgG4-related disease (IgG4-RD) is a relatively recently described condition whose etiology and pathophysiology remain unclear. Histopathological features include dense lymphoplasmacytic tissue infiltration with numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Most individuals with IgG4-RD are asymptomatic; however, the disease can affect nearly any organ, leading to a wide range of clinical presentations. The four most common patterns are hepatopancreatobiliary disease, systemic disease, head and neck disease, and retroperitoneal disease. Diagnosis is challenging due to diverse organ involvement and is most often confirmed by biopsy. Elevated serum IgG4 concentration can support the diagnosis, though high IgG4 levels are neither highly sensitive nor specific for IgG4-RD. Immunohistochemical IgG4 staining is crucial, especially in patients without elevated serum IgG4. Differential diagnosis is necessary, as IgG4+ plasma cell infiltration is also seen in inflammatory and malignant conditions. First-line treatment consists of glucocorticoids (prednisone), although favorable outcomes have also been achieved with rituximab. Prognosis varies: the disease may resolve spontaneously or follow a relapsing-remitting course. If left untreated or undertreated, IgG4-RD can cause irreversible organ damage and even death. Finally, correlations have been made between IgG4 and different allergic reactions.

Acyl-CoA-binding protein (ACBP, encoded by diazepam binding inhibitor, DBI) is an abundant intracellular regulator of lipid metabolism that also circulates systemically, yet the mechanisms governing its release and its relationship to organ injury remain unresolved. Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death-driven liberation of intracellular ACBP/DBI as a unifying mechanism underlying its elevation in disease. In a cohort of 1198 hospitalized adults, among whom 75% were acutely infected by SARS-CoV-2, plasma ACBP/DBI tightly correlated with inflammatory markers and biochemical signatures of cardiac, hepatic, renal, metabolic and hematologic dysfunction. SomaScan proteomics further revealed that ACBP/DBI co-varies with organ-enriched proteins, particularly those originating from skeletal muscle and pancreas, implicating tissue injury as a major determinant of its circulating abundance. Multiple forms of acute organ damage in mice, including hepatic or renal ischemia-reperfusion, bile duct ligation, pancreatitis and rhabdomyolysis, triggered rapid and robust increases in plasma ACBP/DBI. Using defined in vitro paradigms, we demonstrate that apoptosis, ferroptosis and necroptosis each cause loss of intracellular ACBP/DBI and its release upon plasma membrane permeabilization, independent of the upstream lethal pathway. These mechanistic insights translated in vivo: hepatocyte apoptosis, ferroptosis and necroptosis each elevated circulating ACBP/DBI in a manner attenuated by pathway-specific inhibitors. Finally, meta-analysis of >100,000 individuals across diverse populations revealed that elevated plasma ACBP/DBI consistently associates with systemic and organ-specific disease and predicts future morbidity. Together, our findings identify cell death-driven ACBP/DBI release as a conserved mechanism linking organ injury to increased plasma ACBP/DBI, positioning this molecule as an integrative biomarker of tissue damage across species, organs, and cell death modalities.

Familial chylomicronemia syndrome (FCS) (OMIM #238600) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and chylomicronemia due to profound reduction of lipoprotein lipase (LPL). Here, we report 2 unrelated cases of FCS caused by novel homozygous variants in the LPL gene, expanding the known mutational spectrum of this condition. The first case involved a 43-year-old man with longstanding severe hypertriglyceridemia and recurrent acute pancreatitis. Genetic analysis revealed a novel homozygous frameshift variant, c.1172_1173insTCCACAAATAAGA (p.Leu392ProfsTer25), in the LPL gene predicted to result in loss of function. The second case was a female infant presenting with extreme neonatal hypertriglyceridemia, in whom a homozygous missense variant, c.296T>C (p.Leu99Pro), in the LPL gene was identified. Both variants were absent from population databases and identified as novel candidate variants. These cases underscore that phenotypic variability in FCS, ranging from severe neonatal presentation to adult-onset recurrent pancreatitis, is shaped by both the type of the variant and the functional domain involved. Our findings underscore the significance of domain-specific interpretation in genotype-phenotype correlations and identify novel candidate variants for future functional validation.