Clinical Case Summary

Seronegative enteropathies pose a complex diagnostic challenge, as their histology mimics celiac disease (CeD) (1). We report a 51-year-old patient with hypertension and osteoporosis, referred for abdominal pain, weight loss, and constipation. Blood tests showed no anemia; anti-transglutaminase and anti-endomysium antibodies were negative, but HLA typing was compatible with CeD. Ileocolonoscopy excluded IBD and microscopic colitis, while OEGD revealed villous atrophy (MARSH 3c). Negative anti-enterocyte antibodies, and exclusion of drugs and infections, led to a diagnosis of seronegative CeD. A gluten-free diet was started, but after 1 year, symptoms improved only partially despite good adherence. OEGD showed persistent duodenal damage with increased intraepithelial lymphocytes (IELs), CD3+ and CD8+ T-cells with monoclonal TCR expression (fig. 1), consistent with RCeD type 1, despite no overt malabsorption. The patient began prednisone 50 mg/day, then switched to open-capsule budesonide, with some clinical benefit but persistent atrophy.
A year later, his daughter was diagnosed with CVID and a heterozygous STAT3 variant (c.1252T>C, p.Cys418Arg), somatically acquired in NK-cell leukemia. A luciferase assay confirmed its gain-of-function (GOF) effect (fig. 2). Family studies revealed the same germline variant in the patient. His diagnosis was revised to STAT3 GOF-associated enteropathy. Further investigations revealed hypogammaglobulinemia, splenomegaly, bronchiectasis, and emphysema. Treatment with Ruxolitinib (a JAK1/2 inhibitor) was started, resulting in clinical and histological remission (fig. 3).
STAT3 GOF enteropathy is a very rare condition (2,3) that should be considered in the differential diagnosis of seronegative villous atrophy. Anti-JAK therapy may be effective (4).

References

References of the images:
Figure 1: Histologic aspects at diagnosis
Figure 2: Luciferase assay of STAT3
Figure 3: Histologic aspects after 1 year of therapy

1. Schiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. Gut. 2022 Jun 8;71(11):2218–25.
2. Vogel TP, Leiding JW, Cooper MA, Forbes Satter LR. STAT3 gain-of-function syndrome. Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023.
3. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.
4. Kaneko S, Sakura F, Tanita K, Shimbo A, Nambu R, Yoshida M, et al. Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function. Immunotherapy Advances. 2023;3(1).

Clinical Case Summary

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, was first described in 1951. It is characterized by disseminated necrotizing vasculitis with extravascular granuloma formation, occurring almost exclusively in patients with asthma and tissue eosinophilia. Clinical manifestations typically include marked peripheral eosinophilia, asthma, chronic sinusitis, cardiomyopathy, pulmonary infiltrates, gastrointestinal symptoms, and peripheral neuropathy. However, bowel ischemia is an exceedingly rare manifestation and has been only sporadically reported in the literature.
Case report: We present the case of a 36-year-old patient admitted with diarrhea and abdominal pain. The patient had a known history of asthma. Computed tomography revealed pneumatosis intestinalis in the small bowel. Due to septic presentation, an emergency laparotomy was performed, revealing small bowel ischemia. Ischemic segments were resected, and a temporary ileostomy was constructed. Histopathological examination of the resected bowel revealed vasculitic changes consistent with EGPA. The patient recovered well and, after one week in intensive care, was transferred to a general ward where induction therapy with cyclophosphamide and corticosteroids was initiated.
Conclusion: EGPA is a necrotizing small-vessel vasculitis characterized by asthma, pulmonary infiltrates, extravascular granulomas, and eosinophilia. While gastrointestinal involvement is recognized, bowel infarction is a rare but potentially life-threatening complication. This diagnosis should be considered in patients with asthma or known EGPA who present with abdominal symptoms.

Clinical Case Summary

A 56-year-old Chinese male with chronic history of alcohol consumption presented with mixed derangement of liver function tests(LFTs) (alanine transaminase 227 U/L, asparate transaminase 329 U/L, alkaline phosphatase 472 U/L) and focal swellings in the pancreatic head and body on magnetic resonance imaging(MRI). Liver and biliary tree imaging were unremarkable. Autoimmune workup revealed raised antinuclear antibodies (>1:640), anti-M2 antibody (103 u/mL) but a normal immunoglobin(Ig)G4 (53.9 mg/dL) level. Liver and pancreatic biopsies demonstrated interface hepatitis, bile duct damage and pancreatic fibrosis, consistent with primary biliary cholangitis(PBC) but not diagnostic of autoimmune hepatitis(AIH) or pancreatitis. Ursodeoxycholic acid(UDCA) was started without steroids and rapid LFTs improvement was noted. Alcohol intake was stopped.
At subsequent review two years after (due to defaulting visits), the patient remained asymptomatic but LFTs remained abnormal and IgG4 levels rose to 7051 mg/dL. IgG2 levels were raised at 11558 mg/dL. MRI showed stable pancreatic swelling without any biliary or liver abnormalities. Clinical examination noted proptosis and cranial imaging showed thickened supraorbital nerves. Orbital nerve biopsy confirmed IgG4-related disease(IgG4-RD). He was commenced on prednisolone 40 mg daily with tapering and UDCA was restarted.
Despite steroid therapy, LFTs remained raised. Repeat liver biopsy showed progression of interface hepatitis and bile duct damage. Multidisciplinary review concluded the histology was more consistent with AIH-PBC than IgG4-RD. A final diagnosis of concurrent IgG4-RD with AIH-PBC overlap syndrome was made. Azathioprine and fenofibrate were added with LFTs improvement.
This rare and complex case illustrates the multisystem nature of autoimmune disease in a male phenotype and highlights the risk of overlapping immune-mediated conditions. Timely recognition and management are essential to improving patient outcomes.

References

Image 1: Abdominal magnetic resonance imaging of focal swellings in the pancreatic head and body
Image 2: Initial liver biopsy histological slide image
Image 3: Second liver biopsy histological slide image
Image 4: Computed Tomography scan image of thickened supraorbital nerves
Image 5: Orbital nerve biopsy histological slide image