Introduction

Lynch syndrome (LS) represents the most prevalent hereditary colorectal cancer (CRC) syndrome, with approximately one in 279 individuals in the general population believed to carry a pathogenic variant. This autosomal dominant condition results from germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). In addition to colorectal cancer, LS encompasses various extracolonic malignancies, such as gastric carcinoma (lifetime risk of 13%) and small bowel cancer (lifetime risk of 8%). Both German and current NCCN guidelines advise upper GI screening using esophagogastroduodenoscopy (EGD) every 2-4 years. However, standard EGD screening often misses lesions in the jejunum, where up to one third of small bowel cancers occur. Consequently, we sought to determine the frequency of jejunal lesion detection with push enteroscopy employing a colonoscope and whether this method maintains the overall diagnostic quality.

Aims & Methods

Patients with a proven pathogenic mutation in a DNA mismatch repair gene were included in a surveillance program at our National Center of Hereditary Tumor Syndromes, where all patients are followed prospectively after signing an informed consent. We assessed endoscopic findings using standard esophagogastroduodenoscopy (EGD) compared to push enteroscopy using a pediatric colonoscope at our center. We implemented the routine use of push enteroscopy in August 2022. The same endoscope was used for the following colonoscopy. Results of endoscopy, histopathology, affected gene were compared.

Results

Between April 2013 and July 2022, a total number of 445 EGDs were performed in 187 patients (range 1-7; 108 (58%) female; median age at endoscopy 48 years), all carrying a pathogenic MMR gene variant (66 MLH1 (35.5%); 86 MSH2 (46%); 25 MSH6 (13%); 9 PMS2 (5%); 1 Epcam (0.05%)).
Between August 2023 and April 2023, a total number of 103 push enteroscopies using a colonoscope were performed in 103 carriers of a pathogenic MMR gene variant (54 (52%) female; median age at endoscopy 48 years; 38 MLH1 (37%); 46 MSH2 (45%); 11 MSH6 (11%); 4 PMS2 (4%); 1 Epcam (1%); 3 MLH1 and MSH2 (3%)).
Using standard EGD, Barrett esophagus was detected in 23 (5%) patients, with three patients exhibiting high-grade dysplasia, whereas push enteroscopy identified Barrett's esophagus in 4 (4%) patients and revealed one case of eosinophilic esophagitis. Helicobacter pylori infection was found in 21 (5%) and 4 (4%) cases, respectively. Intestinal metaplasia was detected in 49 (11%) patients with standard EGD and 23 (22%) patients with push enteroscopy, both revealing one case (MLH1) with dysplasia. Neoplastic and preneoplastic lesions observed included gastric cancer (5; 1%), gastric adenomas (7; 1.6%), duodenal cancer (3 duodenal, 2 ampullary cancers; 1%), and duodenal adenomas (8; 1.8%) with standard EGD, while no neoplastic lesions were found using push enteroscopy. However, push enteroscopy enabled the detection of three jejunal adenomas, including two advanced adenomas.

Conclusion

This prospective endoscopic study demonstrates that monitoring the upper gastrointestinal (GI) tract in Lynch syndrome (LS) patients yields clinically significant findings for a considerable proportion of individuals. The application of push enteroscopy does not impede the identification of pertinent lesions. Notably, we observed an increased detection rate of gastric intestinal metaplasia using this technique.

Introduction

Type 1 AIP is the most common presentation of IgG4-related disease. Serum IgG4 levels are widely used in initial screening and diagnosis, with levels ≥135 mg/dL recommended as part of the diagnostic criteria. However, its diagnostic specificity is limited as it can be elevated in a broad spectrum of neoplastic, infectious, and autoimmune diseases. Histological diagnosis though definitive, remains challenging in real life clinical practice. In recent years, IgG4/IgG ratio has been proposed as a promising alternative serum biomarker.

Aims & Methods

We aimed to study the diagnostic utility of serum IgG4/IgG ratio compared to serum IgG4 alone in the diagnosis of Type 1 AIP. We identified a cohort of patients from 2015 to 2021 who had raised serum IgG4 levels in Tan Tock Seng Hospital, Singapore. Associations between serum IgG4 level and IgG4/IgG ratio were compared to confirmed AIP diagnosis and characteristic computed tomography (CT) and magnetic resonance imaging (MRI) features (diffuse pancreatic swelling, rim-like enhancement). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at IgG4/IgG thresholds of ≥15% and ≥20%.

Results

Our sample included a total of 60 patients with raised serum IgG4 levels. 21 patients had been diagnosed with Type 1 AIP, and 39 patients had not.
The majority of our patients had serum IgG4 ≥135 mg/dL (n=53, 88.3%). However, there was no significant association between the conventional serum IgG4 cut off of ≥135 mg/dL and the diagnosis of AIP (p = 0.687). In contrast, serum IgG4/IgG ratio demonstrated significantly higher values in patients with AIP compared to those without (median 23.2% vs 13.9%; p < 0.001). Analysis by logistic regression of IgG4/IgG ratio showed an acceptable performance with an area under the curve of 0.779, sensitivity of 92.3%, and specificity of 52.4%.

Variable	Type 1 AIP Present (n=21)	Type 1 AIP Absent (n=39)	Test Statistic	p-value
IgG4/IgG ratio	23.2 (24.0 ± 14.2)	13.9 (13.4 ± 4.5)	U = 184	<0.001
Serum IgG4 ≥135 mg/dL	18/21 (85.7%)	35/39 (89.7%)	Fisher's exact	0.687

We performed further analysis to determine a threshold for diagnostic utility of serum IgG4/IgG ratio. A ratio of ≥20% was strongly associated with AIP diagnosis (OR = 13.2, 95% CI: 3.08–56.5; p < 0.001), with high specificity (92.3%) and PPV (78.6%). Reducing the diagnostic threshold to ≥15% increased sensitivity to 76.2% (vs 52.4% at ≥20%) and improved NPV 84.4%, however this reduced specificity to 69.2%.

Subset analysis was performed among patients with Type 1 AIP (n=21) to evaluate for relationship between serum biomarkers and typical imaging findings (diffuse pancreatic swelling, rim-like enhancement). When stratified to a cut off of ≥135 mg/dL, the association between serum IgG4 levels with imaging findings trended towards positivity, but was not statistically significant (OR 3.14, p = 0.0553, φ 0.196). The IgG4/IgG ratio demonstrated a stronger association with typical imaging findings, although still not achieving statistical significance (OR = 1.065, p = 0.129). This subset analysis is likely limited by the small sample size.

Conclusion

This study demonstrates that serum IgG4/IgG ratio is a superior serological marker compared to serum IgG4 alone, particularly in the diagnosis of type 1 AIP. A threshold ratio of ≥20% demonstrated strong association with AIP diagnosis, with high specificity and PPV.
Our findings support the incorporation of IgG4/IgG ratio - particularly at a cut-off of 20% - as a valuable adjunct in diagnosis of suspected type 1 AIP, and we recommend further research in a larger cohort to validate this data.

References

1. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol. 2020;72(1):7–19.
2. Umehara H, Okazaki K, Kawa S, Takahashi H, Yoshino T, Matsui S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-related disease. Mod Rheumatol. 2021;31(3):529–33.
3. Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4-related disease. BMJ. 2020;369:m1067.
4. Uchida K, Okazaki K. Current status of type 1 (IgG4-related) autoimmune pancreatitis. J Gastroenterol. 2022;57(10):695–708.
5. Xia CS, Zhang S, Duan L, Zhao CW, Zhang F. Diagnostic performances of serum IgG4 concentration and IgG4/IgG ratio in IgG4-related disease. Clin Rheumatol. 2017;36(11):2769–74.

Introduction

Acute pancreatitis (AP) is associated with an intense catabolic, local-regional and systemic inflammatory state, which can lead to changes in body composition, with prognostic implications.

Aims & Methods

Aims: To evaluate the body composition by anthropometry, bioelectrical impedance analysis (BIA) and computed tomography (CT) and its influence in AP severity, endocrine insufficiency (EnPI-AP), pancreatic exocrine (EPI-AP) and post-pancreatic enzyme replacement therapy (PERT).
Methods: Prospective longitudinal study of consecutive adult patients diagnosed with first AP episode. EPI-AP patients were randomized to receive PERT (4000IU/meal+20000IU/snack) vs. placebo (clinicaltrials.gov:NCT05480241). Body composition was assessed using anthropometry, BIA (InBody 570) and CT (cross-sectional areas L1/L3). Obesity was diagnosed for body mass index (BMI)≥30Kg/m², waist-to-hip ratio (WHR)>0.9(men)/0.85(women) and percentage total fat mass (TFM)>20%(men)/28%(women). Visceral obesity was defined by abdominal circumference (AC)>94(men)/80(women)cm, visceral fat area (VFA)≥100cm² and visceral/subcutaneous fat ratio (VSFR)≥0.4. Sarcopenia was diagnosed by skeletal muscle mass (SMM)<20(men)/15(women)Kg, SMM index (SMMi)<7.0/5.5Kg/m² and skeletal muscle area index (SMAi)<41(men)/38.5(women)cm². The three methods were correlated using spearman test and Bland-Altman plots.

Results

A total of 105 patients (65.7%(n=69) males; mean age:63.8±17.1yo) were enrolled and followed-up. AP was moderately-severe/severe in 32.4%/16.2%. EPI-AP and EnPI-AP occurred in 47.6%(n=50) and 17.1%(n=18). EPI-AP was persistent (≥6months after AP diagnosis) in 58%. After 6-month post-randomization, 44%(n=11/25) under PERT and 40%(n=10/25) under placebo resolved EPI-AP (p=0.598).
Obesity was diagnosed in 19.0%(n=20) by BMI, 97.1%(n=102)/72.4%(n=76) by WHR in antropometry/BIA, and 57.1%(n=60) by TFM. Visceral obesity was diagnosed in 78.1%(n=82) by AC, in 41.9%(n=44)/ 97.2%(n=103) by VFM in BIA/CT and in 90.5%(n=95) by VSFR. Sarcopenia was diagnosed in 1.0%(n=1) by MMS.
Considering outcomes, moderately-severe/severe AP was strongly associated with WHR by BIA (OR=10.2; p=0.034) and VFA by BIA (OR=1.08; p=0.029) and CT (OR=1.003; p=0.038). EPI-AP was statically associated with WHR by BIA (OR=11.6; p=0.048) and SMMi by BIA (OR=77.4; p=0.048) and TFM (OR=2.3; p=0.048). Severe EPI-AP was strongly associated with VSFR (OR=20;95%CI; p=0.048) and SMMi by BIA (OR=23.2; p=0.003) and CT (OR=2.3; p=0.041). SMMi by BIA (OR=14.1; p=0.030) and CT (OR=1.6; p=0.031) predicted EnPI-AP.
For obesity, TFM by BIA had a strong correlation with BMI (r=0.61; p<0.001) and a weak correlation with WHR by anthropometry (r=0.37; p<0.001). Regarding visceral obesity, VFA by BIA was weakly correlated with WHR by anthropometry (r=0.29; p=0.004) and VFA by CT (r=0.20; p=0.045). For sarcopenia, SMM by BIA was strongly correlated with SMM by CT (r=0.78; p<0.001).
In EPI-AP patients, a significant decrease of WHR (t(52)=2.262; p=0.028) and TFM (t(53)=1.695; p=0.046) by BIA was observed after 6months of PERT.

Conclusion

Body composition is significantly changed in AP, with >2/3 of patients with obesity, especially the visceral component. Obesity, including visceral obesity, correlates with AP severity. Obesity, including visceral obesity and sarcopenia are correlated with the EPI-AP and its severity, while sarcopenia is correlated with EnPI-AP. PERT has led to a significant reduction in obesity markers. Body composition assessment by BIA (TFM, VFA and SMM) and CT (VFA and SMM) were of clinical value and comparable.

References

1. Kim J, Kim S-s, Hwang HK, Kang CM, Kim KS, Kim SH. Body composition assessment using bioelectrical impedance analysis and computed tomography in patients who underwent pancreatoduodenectomy in Korea: a before and after study. Ann Nutr Metab 2023;15(3):72-80.
2. Wang S, Wang M, Jiang L, Zhao X. Low skeletal muscle quality extracted from CT is associated with poor outcomes in severe acute pancreatitis patients. Eur J Radiol 2024;170:111215.
3. Zhou Y, Hao N, Duan Z, Kong M, Xu M, Zhang D, et al. Assessment of acute pancreatitis severity and prognosis with CT-measured body composition. Int J Gen Med 2021;14:3971-3980.
4. Chaigneau T, Morello R, Vannier E, Musikas M, Piquet M-A, Vupont B. Impact of sarcopenic obesity on predicting the severity of acute pancreatitis. Did Liver Dis 2023;55(7):926-932.