Introduction

A male patient in his twenties presented with clinical aspects of primary sclerosing cholangitis (PSC), chronic cholestatic liver disease, and hypothyroidism. PSC is a rare, chronic cholestatic liver disease characterized by biliary strictures and peribiliary fibrosis (1). Susceptible loci were identified in GWAS but the correlation between genetic background and disease pathogenesis needs further investigation (2). In the index patient we identified a heterozygote candidate variant in the ABCC6 gene (c.2279G>A, p.(Arg760Gln)). Dysfunctional ABCC6 was described to cause ABCB11 and ABCG5/G8 genes overexpression, leading to imbalanced bile composition resulting in gallstone formation and cholestasis (3). ABCC6 variants were previously described in cases with low phospholipid-associated cholelithiasis (LPAC) and intrahepatic cholestasis of pregnancy (ICP)(4-6) . Subsequently, we aimed to investigate rare variants in ABCC6 gene in whole exome sequencing (WES) results from patients with suspected cholestatic liver disease.

Aims & Methods

Variant evaluation and annotation analysis was carried out on WES data, with focus on loss of function and missense variants, presenting allele frequency (AF) of ≤1% based on gnomAD database (https://gnomad.broadinstitute.org). Variants were filtered to include only those in genes relevant to the patients’ clinical phenotype. For each rare variant, a comprehensive in silico assessment was performed using tools such as REVEL, AlphaMissense, EVE, SIFT, and MetaLR to evaluate potential pathogenicity. Filtered were prioritized and interpreted using ACMG-AMP guidelines. This systematic approach ensured a clinically meaningful and evidence-based evaluation of the identified variants.

Results

Nine different rare heterozygote variants were identified in fifteen samples of 247 WES results. Among these, the missense variants c.179G>A, p.(Arg60Gln) and c.3139C>T, p.(Arg1047Cys) were found in two LPAC patients. Additionally, the c.1171A>G, p.(Arg391Gly) variant was observed in two related cases: a mother with ICP and her child with elevated gamma-glutamyl transferase (GGT) levels and jaundice. Moreover, this variant was also detected in another patient with elevated transaminases. c.3871G>A, p.(Ala1291Thr) and c.955A>G, p.(Ile319Val) were seen in patients with ICP and cholestasis, respectively. Three other variants were also identified in patients with liver disease of unknown etiology (c.1540G>A, p.(Val514Ile) and c.2707G>C, p.(Glu903Gln) and c.4397G>A, p.CYS1466Tyr). Additionally one splicing variant (c.37-1G>A, p,?) was also detected in a patient with cholangiocarcinoma (CCA). All variants were observed in heterozygote state and classified as variants of uncertain significance (VUS).

Conclusion

An in-depth analysis of WES data led to the identification of several potentially disease-relevant variants in the ABCC6 gene. These variants may play a contributory role in the observed hepatic phenotypes, suggesting a broader functional involvement of ABCC6 beyond its well-established association with pseudoxanthoma elasticum (PXE). Our findings highlight the importance of integrating genetic data with detailed clinical phenotyping to enhance understanding of genotype–phenotype correlations and reveal novel roles for known genes in atypical or organ-specific presentations.

References

1. Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 2021;75(3):634-46.
2. Goode EC, Fachal L, Panousis N, Moutsianas L, McIntyre RE, Bai BYH, et al. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun. 2024;15(1):9594.
3. Ibold B, Faust I, Tiemann J, Gorgels T, Bergen AAB, Knabbe C, et al. Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues. Lipids Health Dis. 2019;18(1):2.
4. Liu X, Lai H, Xin S, Li Z, Zeng X, Nie L, et al. Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study. BMC Pregnancy Childbirth. 2021;21(1):110.
5. Liu X, Zheng J, Xin S, Zeng Y, Wu X, Zeng X, et al. Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy. Front Genet. 2022;13:941027.
6. Romeo M, Dallio M, Federico A. Is it time to reconsider the MRP6 role in bile secretion and LPAC genetic signature? J Hepatol. 2023;79(4):e152-e4.

Disclosure

The authors declare that they have no conflict of interest.

Introduction

Pain is the hallmark and most disabling symptom of chronic calcific pancreatitis (CCP), often severe and significantly impairing patients' quality of life. Its pathophysiology involves increased intraductal pressure, chronic inflammation, and neuropathic changes.

Aims & Methods

This study aimed to assess the prevalence of pain in CCP and to identify factors associated with its occurrence and severity.
This was a retrospective analytical study including patients followed for CCP. We collected data on disease duration, etiology, clinical manifestations, complications, analgesic treatments (AT), and symptom evolution under treatment. Pain intensity and impact on quality of life were assessed using the Izbicki Score (IS), which categorizes pain as mild (0–20), moderate (21–40), severe (41–60), or very severe (>60). Incomplete records that prevented IS calculation were excluded. Data were entered and analyzed using SPSS software, with statistical significance set at p < 0.05.

Results

We included 22 patients (14 men and 8 women), with a mean age of 55.6 years [27–80 years]. The most common symptoms were epigastric pain (n=18), weight loss (n=13), and chronic diarrhea (n=6). The mean delay between symptom onset and diagnosis was 25 months [1–120 months]. Etiologies included hyperparathyroidism (n=6), alcohol use (n=2), pancreas divisum (n=2), autoimmune causes (n=2), and were undetermined in 10 cases. The IS ranged from 0 to 93.75, with a mean of 40.22. Eight patients had an IS >40. Morphine was required in four cases; paracetamol was prescribed for 12 patients, and tramadol for two. Endoscopic treatment was indicated in three cases, while one patient underwent a Wirsungojejunostomy.
In univariate analysis, alcohol consumption was significantly associated with the occurrence of epigastric pain (p=0.01). Smoking and alcohol use were both linked to a higher IS (>50) (p=0.04). Smoking cessation was associated with a better analgesic response (p=0.04). Morphine use was significantly more frequent among alcoholic patients (p=0.01), and their treatment response was often unfavorable (p=0.02).

Conclusion

In our cohort, 80% of patients with CCP experienced pain, which was severe to very severe in nearly half the cases. Pain intensity was significantly associated with tobacco and alcohol consumption, while cessation improved treatment response. These findings underscore the importance of therapeutic education focused on smoking and alcohol cessation, in addition to analgesic management, to slow disease progression and improve pain control.

Introduction

Diabetes is a known risk factor for pancreatic cancer (PC), potentially mediated by mechanisms such as hyperinsulinemia, insulin resistance, chronic inflammation, and hyperglycemia. Prediabetes shared many of these pathophysiological features; however, its association with PC remains inconclusive.

Aims & Methods

We aimed to evaluate the association between prediabetes and risk of PC and to determine whether changes in glycemic status modify the subsequent PC risk. This retrospective cohort study used data from a territory-wide electronic healthcare database. Adults (≥18 years) with at least one hemoglobin A1c (HbA1c) or fasting glucose (FG) measurement between January 2007 and December 2022 were included. Baseline glycemic status was classified as: (1) normoglycemia (HbA1c <5.7% or FG <5.6 mmol/L), (2) prediabetes (HbA1c 5.7-6.4% or FG 5.6-6.9 mmol/L), or (3) diabetes (HbA1c ≥6.5% or FG ≥7 mmol/L). The index date was the date of first recorded HbA1c or FG. Patients were followed until PC, pancreatectomy, death, or study end date (December 31, 2022). Exclusion criteria included prior PC, immunoglobulin G4-related disease, and type 1 diabetes. To minimize reverse causality between diabetes and PC, individuals with PC diagnosed within two years of the index date or with less than two years of follow-up were excluded. The primary outcome was incident PC. Covariates included demographic factors, body mass index, smoking status, alcohol use disease, metabolic and cardiovascular comorbidities, diabetes-related complications, and concomitant medications (including aspirin, non-steroidal anti-inflammatory drugs [NSAIDs] statins, and antidiabetic agents). Adjusted hazard ratios (aHRs) were estimated using multivariable Cox regression. Among individuals with normoglycemia or prediabetes at baseline, glycemic trajectories over the first 2 years were categorized as: (1) persistent normoglycemia, (2) reversion from prediabetes to normoglycemia, (3) persistent prediabetes, and (4) progression from prediabetes to diabetes, with PC risk evaluated accordingly.

Results

A total of 1,977,149 individuals were included (median age:55.3 [IQR:45.0-65.0] years; 44.5% male), with 1,295,290 (65.5%) classified as normoglycemia, 469,236 (23.7%) as prediabetes, and 212,623 (10.8%) as diabetes at baseline. Over a median follow-up of 8.8 (IQR:5.4-11.6) years, PC developed in 1,419 (1.26/10,000 person-years) normoglycemic, 859 (2.19/10,000 person-years) prediabetic, and 551 (2.92/10,000 person-years) diabetic individuals. The 14-year cumulative PC incidence among three groups was shown in Figure 1 (log-rank P <0.001). Compared with normoglycemia, prediabetes and diabetes were associated with 27% (aHR:1.27; 95%CI:1.17-1.39) and 56% (aHR:1.56; 95%CI:1.40-1.75) higher PC risk, respectively. Each 1% increase in HbA1c was associated with an 11% increased risk (aHR:1.11; 95%CI:1.07–1.15). At year 2, of those with prediabetes at baseline, 68,268 (14.5%) progressed to diabetes, 81,122 (17.3%) reverted to normoglycemia, and 319,846 (68.2%) remained prediabetic. Among normoglycemics, 81,122 (6.3%) remained persistently normoglycemic. Compared with persistent normoglycemia, PC risk was higher in persistent prediabetes (aHR:1.37; 95%CI:1.22-1.53) and prediabetes progressing to diabetes (aHR:2.22; 95%CI:1.91-2.59), but not in those reverting to normoglycemia (aHR:1.17; 95%CI:0.96-1.42).

Conclusion

Prediabetes was independently associated with an increased risk of PC compared with normoglycemia. Early intervention to revert prediabetes to normoglycemia may be a modifiable oncopreventive strategy to reduce PC risk.

Introduction

One possible treatment option for Eosinophilic Esophagitis (EoE) is Protone Pump Inhibitor (PPI) therapy. The possible mechanisms of action discussed include acid suppression and a direct anti-inflammatory effect. However, only up to 50% of EoE patients respond to PPI therapy. Predicting the therapeutic response is challenging, so the aim of this study was to identify potential predictors for a response to such therapy.

Aims & Methods

Patients with active EoE (defined as the presence of esophageal symptoms and simultaneous detection of >15 eosinophilic granulocytes per high-power field [HPF] in at least one biopsy from the esophagus) were retrospectively identified from the hospital database of a tertiary university referral center over 5 years. These patients had received sufficient PPI therapy (defined as double standard dose for at least four weeks). The analysis focused on their therapeutic response and potential predictors including clinical, histological and functional parameters of treatment success.

Results

151 EoE patients were screened and of them 57 patients (mean age: 41 years; 81% male; mean maximum eosinophil count: 55/HPF) who had received PPI therapy at double standard dose for at least 4 weeks (mean duration: 62 days) were finally included. Histopathological complete remission (defined as <5 eosinophils/HPF) was achieved in 18 of 57 patients (31.6%) following PPI treatment, while partial remission (defined as <15 eosinophils/HPF) was observed in 25 of 57 patients (43.9%). No response to PPI therapy was noted in 14 of 57 patients (24.6%). There were no significant differences of the assessed predictors in EoE patients with and without PPI response, although patients with PPI response showed a distally emphasized esophageal eosinophilia and a higher acid exposure time in pH-metry (both non-significant).

Conclusion

No definitive predictors for the response to PPI therapy in EoE patients could be identified. However, a distally predominant esophageal eosinophilia and higher acid exposure time in patients responding to PPI therapy may suggest a contributory role of gastroesophageal reflux in this cohort.

References

No definitive predictors for the response to PPI therapy in EoE patients could be identified. However, a distally predominant esophageal eosinophilia and higher acid exposure time in patients responding to PPI therapy may suggest a contributory role of gastroesophageal reflux in this cohort.