Small-bowel capsule endoscopy in patients with Meckel's diverticulum: clinical features, diagnostic workup, and findings. A European multicenter I-CARE study.

BACKGROUND AND AIMS: Meckel's diverticulum (MD) may remain silent or be associated with adverse events such as GI bleeding. The main aim of this study was to evaluate indicative small-bowel capsule endoscopy (SBCE) findings, and the secondary aim was to describe clinical presentation in patients with MD. METHODS: This retrospective European multicenter study included patients with MD undergoing SBCE from 2001 until July 2021. RESULTS: Sixty-nine patients with a confirmed MD were included. Median age was 32 years with a male-to-female ratio of approximately 3:1. GI bleeding or iron-deficiency anemia was present in nearly all patients. Mean hemoglobin was 7.63 ± 1.8 g/dL with a transfusion requirement of 52.2%. Typical capsule endoscopy (CE) findings were double lumen (n = 49 [71%]), visible entrance into the MD (n = 49 [71%]), mucosal webs (n = 30 [43.5%]), and bulges (n = 19 [27.5%]). Two or more of these findings were seen in 48 patients (69.6%). Ulcers were detected in 52.2% of patients (n = 36). In 63.8% of patients (n = 44), a combination of double lumen and visible entrance into the MD was evident, additionally revealing ulcers in 39.1% (n = 27). Mean percent SB (small bowel) transit time for the first indicative image of MD was 57% of the total SB transit time. CONCLUSIONS: Diagnosis of MD is rare and sometimes challenging, and a preoperative criterion standard does not exist. In SBCE, the most frequent findings were double-lumen sign and visible diverticular entrance, sometimes together with ulcers.

Unsedated Transnasal Endoscopy: A Safe, Well-Tolerated and Accurate Alternative to Standard Diagnostic Peroral Endoscopy.

Diagnostic unsedated transnasal endoscopy (uTNE) has been proven to be a safe and well-tolerated procedure. Although its utilization in the United Kingdom (UK) is increasing, it is currently available in only a few centers. Through consideration of recent studies, we aimed to perform an updated review of the technological advances in uTNE, consider their impact on diagnostic accuracy, and to determine the role of uTNE in the COVID-19 era. Current literature has shown that the diagnostic accuracy of uTNE for identification of esophageal pathology is equivalent to conventional esophagogastroduodenoscopy (cEGD). Concerns regarding suction and biopsy size have been addressed by the introduction of TNE scopes with working channels of 2.4 mm. Advances in imaging have improved detection of early gastric cancers. The procedure is associated with less cardiac stress and reduced aerosol production; when combined with no need for sedation and improved rates of patient turnover, uTNE is an efficient and safe alternative to cEGD in the COVID-19 era. We conclude that advances in technology have improved the diagnostic accuracy of uTNE to the point where it could be considered the first line diagnostic endoscopic investigation in the majority of patients. It could also play a central role in the recovery of diagnostic endoscopic services during the COVID-19 pandemic.

Mapping the distribution of small bowel angioectasias.

Background: Angioectasias are a prominent cause of small bowel (SB) bleeding frequently identified during capsule endoscopy (CE). Subsequent management depends upon grade/severity and location. There is increasing evidence that the location of SB angioectasias is not random. We aimed to map the distribution of SB angioectasias, and assess whether this impacted clinical outcomes. Materials and methods: Retrospective study examining CEs performed over a 10-year period at a tertiary referral centre. Information regarding number, location, and Saurin classification (P0-2) of SB angioectasias was collected. Clinically significant angioectasias (P1/P2) and active SB bleeding were analysed further. Outcomes of patients with P2 angioectasias or active SB bleeding were recorded. Results: 164 SBCE examinations reported angioectasias. 554 P1-2 angioectasias and active bleeds were seen, 435 (78.52%) within the first tertile of SB transit time (SBTT). 277 (50%) angioectasias were identified within the first 10% of SBTT. 40/75 (53.3%) patients with >1 P2 angioectasia and/or active bleed were referred for intervention. Of initial interventions, 24 patients underwent upper GI endoscopy; 13 underwent double balloon enteroscopy (DBE). 9/37(24.3%) had no identifiable angioectasias on endoscopy. Of those receiving ablative therapy, 20/28 (71.4%) re-presented with iron-deficiency anaemia or bleeding. In this group, average angioectasia position was 15.6% of SBTT, compared with 7.9% in those who did not re-represent (p = 0.344). Patients who re-presented had an average 1.6 additional P1 angioectasias, compared with 7.6 amongst those who did not return (p = 0.017). Conclusions: Clinically significant angioectasias are overwhelmingly located within the proximal SB. The majority are within reach of conventional endoscopy. However, AEs are often multiple and many patients re-present following intervention.

Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites.

BACKGROUND & AIMS: Carvedilol, a non-selective beta-blocker (NSBB) with additional anti-alpha 1 receptor activity, is a potent portal hypotensive agent and has been used as prophylaxis against variceal bleeding. However, its safety in patients with decompensated liver cirrhosis and ascites is still disputed. In this study, we examined whether long-term use of carvedilol in patients with ascites is a risk factor for mortality. METHODS: A single-centre retrospective analysis of 325 consecutive patients with liver cirrhosis and ascites presenting to our Liver Unit between 1st of January 2009 to 31st August 2012 was carried out. The primary outcome was all-cause and liver-specific mortality in patients receiving or not receiving carvedilol as prophylaxis against variceal bleeding. RESULTS: The final cohort after propensity score matching comprised 264 patients. Baseline ascites severity and UK end-stage liver disease (UKELD) score between carvedilol (n=132) and non-carvedilol (n=132) treated patient groups were comparable. Median follow-up time was 2.3years. Survival at the end of the follow-up was 24% and 2% for the carvedilol and the non-carvedilol groups respectively (log-rank p<0.0001). The long-term survival was significantly better in carvedilol than non-carvedilol group (log-rank p<0.001). The survival difference remained significant after adjusting for age, gender, ascites severity, aetiology of cirrhosis, previous variceal bleed, spontaneous bacterial peritonitis prophylaxis, serum albumin and UKELD with hazard ratio of 0.59 (95% confidence interval [CI]: 0.44, 0.80; p=0.001), suggesting a 41% reduction in mortality risk. When stratified by the severity of ascites, carvedilol therapy resulted in hazard ratio of 0.47 (95% CI: 0.29, 0.77; p=0.003) in those with mild ascites. Even with moderate or severe ascites, carvedilol use was not associated with increased mortality risk. CONCLUSION: Long-term carvedilol therapy is not harmful in patients with decompensated cirrhosis and ascites. LAY SUMMARY: The safety of carvedilol and other non-selective beta-blocker drugs in patients with liver cirrhosis and ascites is still debated. In this study, we have shown that carvedilol therapy in these patients was associated with reduced risk of mortality, particularly in those with mild ascites. We concluded that low dose, chronic treatment with carvedilol in patients with liver cirrhosis and ascites is not detrimental.

Clinical outcomes of negative small-bowel capsule endoscopy for small-bowel bleeding: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Small-bowel bleeding is the primary indication for capsule endoscopy (CE). Many experts advocate a "watch-and-wait" policy in negative CE. This meta-analysis examines the odds of rebleeding after negative index CE and the impact on long-term follow-up. METHODS: A comprehensive literature search identified articles examining the rebleeding rate after negative CE. Demographic and clinical information with emphasis on outcomes was retrieved, pooled, and analyzed. Heterogeneity among studies was assessed using the I2 statistic. A random effects model was used as the pooling method because of high heterogeneity. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. The primary outcome evaluated was the pooled odds ratios (ORs) for rebleeding after a negative CE for obscure GI bleeding (OGIB). RESULTS: Twenty-six studies with 3657 patients were included. The pooled rate of rebleeding after negative CE was .19 (95% CI, .14-.25; P < .0001). The pooled OR of rebleeding was .59 (95% CI, .37-.95; P < .001). The effect was more pronounced in studies with a short follow-up (OR, .47; 95% CI, .24-.94; P < .001). There was no statistically significant difference in rebleeding after CE for occult and overt OGIB. Prospective studies showed a lower OR of rebleeding of .24 (95% CI, .08-.73; P = .01). Most studies were high quality. CONCLUSIONS: Our analysis shows that negative CE provides adequate evidence of a subsequently low risk of rebleeding. Such patients can therefore be safely managed with watchful waiting. However, patients who rebleed after 2 years may need to be investigated for a new source of blood loss.

Clinical validity of flexible spectral imaging color enhancement (FICE) in small-bowel capsule endoscopy: a systematic review and meta-analysis.

Patients and methods A comprehensive literature search was conducted. We measured pooled rate of lesion visualization improvement and improvement in lesion detection comparing FICE settings 1 - 3 and WLE, for angioectasias and ulcers/erosions. Pooled results were derived using the random-effects model because of high heterogeneity as measured by I2. Repeated-measures analysis of variance (ANOVA) was used to measure differences in lesion detection between WLE and the three FICE modes. Results 13 studies were analyzed. All studies used the PillCam SB 1 and/or SB 2 devices. Most used experienced readers. Improvement in delineation had been investigated in 4 studies; in the 3 studies entered into the meta-analysis, using FICE setting 1, 89 % of angioectasias and 45 % of ulcer/erosions were considered to show improved delineation. For FICE settings 2 and 3, small proportions of images showed improved delineation. Heterogeneity of studies was high with I2 > 90 % in 4/6 analyses. Lesion detection had been investigated in 10 studies; meta-analysis included 5 studies. Lesion detection did not differ significantly between any of the FICE modes and WLE. Conclusions Overall, the use of the three FICE modes did not significantly improve delineation or detection rate in SBCE. In pigmented lesions, FICE setting 1 performed better in lesion delineation and detection.

The use of hemostatic spray as an adjunct to conventional hemostatic measures in high-risk nonvariceal upper GI bleeding (with video).

BACKGROUND: Endoscopic management of nonvariceal upper GI bleed (NVUGIB) can be challenging. Hemospray is a novel endoscopic hemostatic agent for NVUGIB. Its efficacy in attaining hemostasis in NVUGIB is promising, particularly with respect to technically difficult lesions. However, most of the currently available data are focused on its application as monotherapy. The aim of this study was to evaluate its efficacy as a second agent to adrenaline, or as an addition to the combination of adrenaline with either clips or a thermal device in NVUGIB. METHODS: Consecutive patients with Forrest 1a and 1b ulcer treated with hemostatic spray as an adjunct to conventional endoscopic hemostatic measures between July 2013 and June 2015 were included in this retrospective analysis. The endpoints were initial hemostasis, 7-day rebleeding, 30-day rebleeding, all-cause, and GI-related 30-day mortality. RESULTS: A total of 20 patients (median age, 75 years, 50% men, 60% Forrest 1a ulcer) were treated with hemostatic spray as a second agent to adrenaline, or as an adjunct to the combination of adrenaline with either clips or a thermal device. Hemostatic spray was used as a second agent to adrenaline in 40% and as a third agent to combined dual therapy in 60%. Initial hemostasis was attained in 95% with an overall rebleeding rate at 7 days of 16%. There was no difference between the 7-day and 30-day rebleeding rates. The combination of hemostatic spray and adrenaline resulted in 100% initial hemostasis and 25% 7-day rebleeding. Similarly, initial hemostasis was achieved in 92% with a 9% rebleeding rate when hemostatic spray was used as the third agent to 2 of the conventional measures. All-cause mortality was 15% with 1 GI-related death (3%). CONCLUSIONS: In our single-center retrospective analysis, hemostatic spray appears promising as an adjunct to conventional methods for NVUGIB, although prospective controlled trials are needed to confirm this.

Association Between Fecal Calprotectin Levels and Small-bowel Inflammation Score in Capsule Endoscopy: A Multicenter Retrospective Study.

BACKGROUND: Accurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images. GOALS: Multicenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels. STUDY: Five academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3 months. RESULTS: Overall, correlation between FC and LS was weak (r s: 0.232, P < 0.001). When two clinically significant FC thresholds (100 and 250 µg/g) were examined, the r s between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (P = 0.307). For clinically significant (LS ≥ 135) or negative (LS < 135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76 µg/g with sensitivity 0.59 and specificity 0.41. LIMITATIONS: Retrospective design. CONCLUSIONS: LS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC level ≥ 76 µg/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.

Proteomic profiling of cellular steatosis with concomitant oxidative stress in vitro.

BACKGROUND: Nutrient excess underpins the development of nonalcoholic fatty liver disease (NAFLD). The ensuing metabolic derangement is characterised by increased cellular respiration, oxidative stress and mitochondrial impairment. We have previously recapitulated these events in an in vitro cellular steatosis model. Here, we examined the distinct patterns of protein expression involved using a proteomics approach. METHODS: Human hepatoblastoma C3A cells were treated with a combination of energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N). Proteins extracts were trypsinized and analyzed on a capillary HPLC OrbitrapXL mass spectrometer. Proteins were quantified using a label-free intensity based approach. Functional enrichment analysis was performed using ToppCluster via Gene Ontology (GO) database. RESULTS: Of the 1327 proteins identified, 104 were differentially expressed between LPON and untreated cells (defined as: ≥2 peptides; fold change ≥1.5; p-value <0.05). Seventy of these were upregulated with LPON. Functional enrichment analysis revealed enhanced protein biosynthesis accompanied by downregulation of histones H2A type 1-A, H1.2, H1.5 and H1.0I in LPON cells. Lipid binding annotations were also enriched as well as proteins involved in cholesterol synthesis, uptake and efflux. Increased expression of aldo-keto reductase family 1, member C1 and C3 suggests enhanced sterol metabolism and increased ROS-mediated lipid peroxidation. CONCLUSIONS: The surge of energy substrates diverts free fatty acid metabolism towards pathways that can mitigate lipotoxicity. The histones depletion may represent an adaptation to increased protein synthesis. However, this can also expose DNA to oxidative stress thus should be explored further in the context of NAFLD progression.

Small bowel capsule endoscopy and portal hypertensive enteropathy in cirrhotic patients: results from a tertiary referral centre.

BACKGROUND AND RATIONALE: Portal hypertensive enteropathy (PHE) remains difficult to diagnose in patients with cirrhosis and portal hypertension. Limited test choices exist for the inspection of the small bowel in these patients. Small bowel capsule endoscopy (SBCE) is ideal in this situation but rarely performed. We aimed to determine the prevalence of PHE using SBCE in a cirrhotic patient population and correlate its presence with clinical and CT imaging findings. MATERIAL AND METHODS: We retrospectively analysed data from cirrhotic patients who underwent SBCE at our unit. Studies were evaluated for the presence of cirrhosis-related findings in the oesophagus, stomach and small-bowel. The relationships between PHE and patients' clinical characteristics were evaluated. RESULTS: 53 patients with cirrhosis underwent SCBE. We used PillCam®SB on 36 patients and MiroCam® capsule on 17. Thirty patients were referred for iron deficiency anaemia, 15 for obscure gastrointestinal bleeding, and 4 for other indications. Four data sets were not available for review, leaving 49 patients. Mean age was 61.19 ± 14.54 years (M/F = 27/22). Six SBCE examinations were incomplete. Thirty three patients had evidence of portal hypertensive gastropathy (PHG) and 17 had evidence of oesophageal varices. In total, 29 patients had SCBE evidence of PHE (57%). 28/29 (96.5%) patients with PHE had also evidence of PHG. 13/17 (76.4%) patients with oesophageal varices had also evidence of PHE. CONCLUSIONS: The prevalence of PHE in our study was 57%. SBCE is a useful tool in evaluating PHE in cirrhotic patients irrespective of aetiology.

Microscopic colitis: a misnomer for a clearly defined entity?

In recent years, several endoscopic features of microscopic colitis have been noted. The pickup of these on colonoscopy depends on local expertise, endoscopic technology, and case volume. As the incidence of microscopic colitis has increased, we wanted to draw attention to endoscopists' ability to recognize such findings. We present eight cases of biopsy-proven microscopic colitis which demonstrate the spectrum of endoscopic findings. Endoscopists should actively search for such findings and target their biopsies, as new high-definition colonoscopes with sharper images, zoom capabilities, and high resolution allow a new vision into this syndrome.

The use of domperidone increases the completion rate of small bowel capsule endoscopy: does this come at the expense of diagnostic yield?

BACKGROUND: The completion rate (CR) of small bowel capsule endoscopy (SBCE) has been reported at 81.3% to 84.8%. Prokinetic agents are used to increase CR and (theoretically) diagnostic yield (DY). Domperidone has not been widely used in SBCE; unlike metoclopramide, it lacks extrapyramidal adverse effects. OBJECTIVES: This was a retrospective study. This study aimed to assess gastric transit time (GTT), small bowel transit time (SBTT), and the CR of SBCE when using domperidone. Furthermore, we aimed to compare the CR of 2 different SBCE systems (MiroCam, PillCam). Consecutive SBCE examinations (January 2008 to October 2012) from a tertiary referral center were analyzed. RESULTS: In the aforementioned period, a total of 635 SBCE examinations were performed: 379/635 (59.7%) with PillCamSB and 256 (40.3%) with MiroCam. In 437/635 (68.8%) examinations, liquid domperidone (5 mg) was administered for capsule ingestion, whereas 198 (31.2%) ingested the capsule without any domperidone. Although the 2 groups were comparable, the median age of patients who received domperidone was higher compared with patients who did not receive (58 vs. 48 y, P=0.027). In our cohort, the overall CR of SBCE was 88.9%. The 2 SBCE systems showed equivalent CR (PillCamSB 88.9%, MiroCam 89.1%; P =0.96). The use of liquid domperidone increased CR (91.1% vs. 84.3%; P =0.042). Interestingly, the use of domperidone with PillCamSB was associated with reduced DY for vascular, inflammatory, and polyps/mass-type lesions. This effect was not seen in the MiroCam group. Furthermore, the median GTT and the median SBTT did not differ between the 2 groups (GTT/SBTT with domperidone 26.0'/221.0' and without 29.0'/228.0', respectively; P=0.461/P=0.477). A higher CR was noted when domperidone was used with PillCamSB (93.0% vs. 89.5%, P=0.012) than with MiroCam (84.4% vs. 83.3%, P=0.08). LIMITATIONS: The major limitations of this study were the retrospective design of the study and limited numbers on MiroCam with no domperidone. CONCLUSIONS: In conclusion, the use of domperidone increases the CR of SBCE with PillCamSB. However, this increase does not translate into higher DY. A smart, tailored approach, which may include domperidone, purgatives, and real-time viewers, may be used in the clinical practice to improve DY until technology delivering capsules with much longer battery time becomes available.

Fibrinogen production is enhanced in an in-vitro model of non-alcoholic fatty liver disease: an isolated risk factor for cardiovascular events?

BACKGROUND: Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis. METHODS: Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways. RESULTS: The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05). CONCLUSIONS: In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.

Esophageal capsule endoscopy is a useful tool in patients with hemophilia.

Esophageal capsule endoscopy (ECE) is considered to be an alternative to conventional esophagogastroduodenoscopy (EGD); however, its indications continue to expand. This report presents results from the use of ECE in patients with hemophilia at a tertiary referral academic center over a 7-year period. A total of 16 patients with hemophilia, who were all at risk of new-variant Creutzfeldt-Jakob disease due to previous treatment with UK plasma-derived pooled blood products, underwent a total of 28 ECE examinations. Main outcomes were the diagnostic yield of ECE, requirement for subsequent conventional EGD, and any variceal bleeding episodes during the follow-up period. The overall diagnostic yield was 67.8 % (19 /28 ECEs). Only one patient underwent conventional EGD, for esophageal biopsies. There were no variceal hemorrhage events in any of the patients on variceal screening follow-up. ECE is a useful and acceptable alternative to conventional endoscopy in selected patient groups (i. e. patients with hemophilia). In this group, ECE can eliminate the need for prior administration of clotting factors.

Tailoring follow-up endoscopy in patients with severe oesophagitis.

Objective: We aimed to investigate the clinical utility of follow-up oesophagogastroduodenoscopy (OGD2) in patients with severe oesophagitis (Los Angeles grades C or D) through evaluating the yield of Barrett's oesophagus (BO), cancer, dysplasia and strictures. Second, we aimed to determine if the Clinical Frailty Scale (CFS) may be used to identify patients to undergo OGD2s. Design/method: Patients in NHS Lothian with an index OGD (OGD1) diagnosis of severe oesophagitis between 1 January 2014 and 31 December 2015 were identified. Univariate analysis identified factors associated with grade. Patients were stratified by frailty and a diagnosis of stricture, cancer, dysplasia and BO. Results: In total 964 patients were diagnosed with severe oesophagitis, 61.7% grade C and 38.3% grade D. The diagnostic yield of new pathology at OGD2 was 13.2% (n=51), new strictures (2.3%), dysplasia (0.5%), cancer (0.3%) and BO (10.1%). A total of 140 patients had clinical frailty (CFS score ≥5), 88.6% of which were deceased at review (median of 76 months). In total 16.4% of frail patients underwent OGD2s and five new pathologies were diagnosed, none of which were significantly associated with grade. Among non-frail patients at OGD2, BO was the only pathology more common (p=0.010) in patients with grade D. Rates of cancer, dysplasia and strictures did not vary significantly between grades. Conclusion: Our data demonstrate that OGD2s in patients with severe oesophagitis may be tailored according to clinical frailty and only be offered to non-frail patients. In non-frail patients OGD2s have similar pick-up rates of sinister pathology in both grades of severe oesophagitis.

Metabolism of Acetaminophen by Enteric Epithelial Cells Mitigates Hepatocellular Toxicity In Vitro.

The gut-liver axis is defined by dietary and environmental communication between the gut, microbiome and the liver with its redox and immune systems, the overactivation of which can lead to hepatic injury. We used media preconditioning to mimic some aspects of the enterohepatic circulation by treating the human Caco-2 intestinal epithelial cell line with 5, 10 and 20 mM paracetamol (N-acetyl-para-aminophenol; APAP) for 24 h, after which cell culture supernatants were transferred to differentiated human hepatic HepaRG cells for a further 24 h. Cell viability was assessed by mitochondrial function and ATP production, while membrane integrity was monitored by cellular-based impedance. Metabolism by Caco-2 cells was determined by liquid chromatography with tandem mass spectrometry. Caco-2 cell viability was not affected by APAP, while cell membrane integrity and tight junctions were maintained and became tighter with increasing APAP concentrations, suggesting a reduction in the permeability of the intestinal epithelium. During 24 h incubation, Caco-2 cells metabolised 64-68% of APAP, leaving 32-36% of intact starting compound to be transferred to HepaRG cells. When cultured with Caco-2-preconditioned medium, HepaRG cells also showed no loss of cell viability or membrane integrity, completely in contrast to direct treatment with APAP, which resulted in a rapid loss of cell viability and membrane integrity and, ultimately, cell death. Thus, the pre-metabolism of APAP could mitigate previously observed hepatotoxicity to hepatic tight junctions caused by direct exposure to APAP. These observations could have important implications for the direct exposure of hepatic parenchyma to APAP, administered via the intravenous route.