Introduction

Chronic liver injury ultimately progresses to the development of cirrhosis. Patients with cirrhosis can be in a compensated or decompensated phase, the latter marked by clinical events such as ascites, hepatic encephalopathy and variceal bleeding. These events are associated with significant morbidity and mortality and the management is challenging and labor-intensive. Due to ongoing unhealthy lifestyle factors resulting in chronic liver injury, the burden of cirrhosis on healthcare systems in Europe is increasing. There is however limited data on the impact of cirrhosis on Dutch healthcare resources.

Aims & Methods

We aimed to determine the point-prevalence and claimed health costs of adults (≥ 18 years) registered as patients with cirrhosis at Dutch hospitals. To this end we extracted health claims data (timeframe 2017-2021) from the records of the Dutch health claims database (Vektis), which covers almost all inhabitants of the Netherlands. We used diagnosis codes ‘compensated cirrhosis’ and ‘decompensated cirrhosis’ to identify patients.

Results

The point prevalence of patients with cirrhosis increased from 48,7 patients per 100.000 adult Dutch inhabitants in 2017 to 75,2 per 100.000 in 2021 (+54%). The point-prevalence for cirrhosis was highest in the province of Limburg with 105,6 patients per 100.000 adult Dutch inhabitants. The annual increase in unique new patients for which hospitals claimed costs was n=3.725 in 2018, n=3.840 in 2019 (+3%), n=3.749 in 2020 (-2%) and n=3.695 in 2021 (-1%). The largest increase was observed in the province of Zuid-Holland (approximately 5 new patients per 100.000 adult Dutch inhabitants per year). Total number of hospital admissions increased with 19% from 2.443 admissions in 2017 to 2.899 admissions in 2021. The median length of stay for admitted patients with cirrhosis in 2017-2021 was four days [IQR 2-7 days]. The annual reported costs for patients with cirrhosis increased from €35 million in 2017 to €78 million in 2021 (+120%).

Conclusion

The point-prevalence of Dutch adults registered as a patient with cirrhosis in Dutch hospitals increased by more than fifty percent, with remarkable regional differences. Consequently, the total healthcare costs claimed for these patients more than doubled in less than five years.

Clinical Case Summary

A 67-year-old man initially presented in 2020 with intermittent dysphagia for solid food. An endoscopy of the upper gastrointestinal tract revealed an inflammatory, presumed peptic stenosis at the level of the Z-line. No hiatus hernia was present. A balloon dilatation was performed and therapy with proton pump inhibitors was started. This maintained remission until 2023, when he represented with frequent bolus retention, retrosternal chest pain and regurgitation. A repeat endoscopy appeared normal; however, biopsies revealed lymphocytic esophagitis. A high-resolution oesophageal manometry was performed to clarify the cause of dysphagia. Water swallows showed no abnormal findings; however, the patient had repeated, symptomatic outlet-obstruction during the solid test meal. This finding is often seen in eosinophilic esophagitis.¹ The diagnosis of primary lymphocytic esophagitis, considered to be a variant of this condition,² was proposed. Treatment with oro-dispersible budesonide (1mg bid) was started.
At the same time, an abnormal AV conduction pattern was noted on ECG. Echocardiography and a cardiac stress test were normal; however, CT imaging showed bihilar lymphadenopathy with peri-lymphatic pulmonary nodules. Broncho-alveolar lavage showed lymphocytic alveolitis (29% lymphocytes) and an elevated CD4/CD8 ratio (ratio = 4). ACE (51 U/l) was normal and granulomas were not seen on fine needle aspiration of the lymph nodes; however, the diagnosis of stage 2 pulmonary sarcoidosis was confirmed on PET-CT. Oral prednisolone (30mg od) replaced locally active steroids. The patient was symptom free after one month treatment.
Sarcoidosis is a granulomatous disease that often affects the lungs, skin and lymph nodes; however, involvement of the digestive tract is rare, and secondary lymphocytic esophagitis has hardly ever been described.³ The investigation, primary or secondary aetiology, and management of dysphagia in this case of lymphocytic esophagitis will be discussed.

References

1. Sykes C, Fairlamb G, Fox M, et al. Assessment of Esophageal Motility in Patients With Eosinophilic Esophagitis: A Scoping Review. J Clin Gastroenterol 2023;57:10-30.
2. Greuter T, Straumann A, Fernandez-Marrero Y, et al. Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study. Allergy 2022;77:2520-2533.
3. Brito-Zeron P, Bari K, Baughman RP, et al. Sarcoidosis Involving the Gastrointestinal Tract: Diagnostic and Therapeutic Management. Am J Gastroenterol 2019;114:1238-1247.

Disclosure

None of the authors have any conflict of interest to disclose

Clinical Case Summary

Closure of mucosal defects after endoscopic submucosal dissection (ESD) may reduce the risk of postprocedural perforation and bleeding. However, defect closure with traditional through-the-scope (TTS) or over-the-scope (OTS) clips and OTS suturing devices may be technically limited by defect size and location. The development of a new through-the-scope helix tack suture system (TTSS) has emerged as a promising tool for overcoming these limitations, particularly when combined with TTS clips.

We present two cases of gastric ESD defect closure with TTSS and adjunctive TTS clip application, highlighting the outcomes and main challenges to achieve complete defect closure.

CASE 1: 73-year-old woman with a 15mm Paris 0-IIb dysplastic lesion of the posterior wall of the antrum. En-bloc ESD was performed and the 25mm mucosal defect was closed with TTSS in a ‘Z’ pattern. However, suboptimal tack placement resulted in incomplete closure of the central portion of the scar, leaving two areas of exposed submucosa at the edges. Complete defect closure was accomplished with the additional placement of four TTS clips at the edges, only possible due to the previously achieved proximity.

CASE 2: 55-year-old man referred for ESD of a 13mm Paris 0-IIa dysplastic lesion in the lesser curvature of the antrum. En-bloc ESD was accomplished, and the resulting 25mm mucosal defect was closed using TTSS in a 'Z' pattern. Complete defect closure was achieved with the additional placement of one TTS clip.

Both patients were discharged the following day and presented with no complications at 1-month follow-up.

These cases highlight the potential of TTSS becoming a practical solution for the closure of complex post-ESD defects, allowing earlier patient discharge. While this novel TTSS with adjunctive TTS clip application appears to be effective in the management of sizable defects, proper suture pattern and tack placement are paramount for achieving complete defect closure.

References

1. Kobara H, Tada N, Fujihara S, Nishiyama N, Masaki T. Clinical and technical outcomes of endoscopic closure of postendoscopic submucosal dissection defects: Literature review over one decade. Dig Endosc. 2023 Jan;35(2):216-231.
2. Hernandez-Lara A, Garcia Garcia de Paredes A, Rajan E, Storm AC. Step-by-step instruction: using an endoscopic tack and suture device for gastrointestinal defect closure. VideoGIE. 2021;6(6):243-245.
3. Hernandez A, Marya NB, Sawas T, Rajan E, Gades NM, Wong Kee Song LM, et al. Gastrointestinal defect closure using a novel through-the-scope helix tack and suture device compared to endoscopic clips in a survival porcine model (with video). Endosc Int Open. 2021 Apr;9(4):E572-E577.
4. Canakis A, Dawod SM, Dawod E, Simons M, Di Cocco B, Westerveld DR, et al. Efficacy, Feasibility, and Safety of the X-Tack Endoscopic HeliX Tacking System: A Multicenter Experience. J Clin Gastroenterol. 2024 Jan 29.
5. Canakis A, Deliwala SS, Frohlinger M, Twery B, Canakis JP, Shaik MR, et al. Endoscopic outcomes using a novel through-the-scope tack and suture system for gastrointestinal defect closure: a systematic review and meta-analysis. Endoscopy. Published online March 22, 2024.

Clinical Case Summary

We report the case of a 64-year-old man with preexisting hepatic sarcoidosis complicated by liver cirrhosis, who presented with confusion as an initial manifestation of COVID-19 confirmed by rapid Antigenic test. His Child Pugh score was 8 (Class B) and MELD was 16. Chest radiographs showed bilateral patchy interstitial opacities. Computed tomography (CT) of the brain was normal. Lumbar puncture was not performed because of a marked thrombocytopenia. Urine cytobacteriological examination did not show a urinary tract infection. An abdominal ultrasound showed normal hepatoportal flow and a mild ascites. Ascitic fluid analysis did not show spontaneous bacterial peritonitis. Since the patient was cirrhotic, we have considered the diagnosis of hepatic encephalopathy as a possible explanation for the neurological symptoms, so he started Lactulose and Rifaximin. However, his clinical condition showed no improvement, the neurological disorders remained the same. A brain MRI showed in FLAIR MR sequences a few hyperintensities punctiform in the white matter of the supratentorial region and the subcortical of the left insula region. There were no signs of a cerebral granuloma nor toxoplasmosis. It did not show venous thrombosis. There were no microheamorragies neither ischemic lesions. After careful evaluation by neurologic experts, encephalitis associated with SARS-CoV-2 infection was concluded. The patient was treated by intravenous Dexamethasone and he fully recovered without sequelae. This case illustrates the fact that neurological manifestations associated with COVID-19 infection are not necessarily a reflection of critical illness, and should incite clinicians to actively look for any evidence of COVID-19 infection as a differential diagnosis in patients with preexisting cirrhosis, presenting with neurological symptoms, during the epidemic period of COVID-19.

Introduction

Functional gastrointestinal disorders (FGIDs) are more prevalent in female than in male patients [1,2]. This triggers the question whether this is also reflected in medical care, especially also in self-medication, where often botanicals are used. A potential source of data to address this question is the PhytoVIS study, a pharmacoepidemiological study conducted in Germany in more than 20,000 patients taking herbal medicinal products.

Aims & Methods

To have a large and homogenous data base for a gender-related evaluation, records for a clinically proven herbal medicinal product (HMP) often used in FGIDs, STW 5 [3,4], were evaluated to uncover potential gender-related differences in the pharmacotherapy of FGIDs.

Results

1513 records were evaluated, 71 % of them from females and 29 % from males, i.e. a 4 % higher proportion of females compared to the overall population of the PhytoVIS study. Main criterium for the evaluation was the Clinical Global Impression Scale – Efficacy (CGI-E). No major differences between females and males were found, apart that women perceived a minimally better effect of the therapy. The reported symptoms were differentiated into symptoms associated with functional dyspepsia (FD), irritable bowel syndrome (IBS), or symptoms that can be associated with both. As far as the records allow a differentiation, no gender differences could be observed. This applies also to the perceived efficacy, the tolerability and the onset of action.

Conclusion

So, while there are differences in the prevalence of FGIDs in women and men, there are no therapeutically relevant pharmacoepidemiological differences in patients with functional gastrointestinal diseases treated with a medicinal product indicated in these diseases, so suggesting that there is no gender gap in this highly relevant therapeutic field.

References

1. Kim YS, Kim N. Sex-Gender Differences in Irritable Bowel Syndrome. J Neurogastroenterol Motil. 2018;24:544-558
2. Houghton LA, Heitkemper M, Crowell M, Emmanuel A, Halpert A, McRoberts JA, Toner B. Age, Gender and Women's Health and the Patient. Gastroenterology. 2016; S0016-5085(16)00183-9;
3. Malfertheiner P. STW 5 (Iberogast) Therapy in Gastrointestinal Functional Disorders. Dig Dis. 2017;35 Suppl 1:25-29
4. Madisch A, Vinson BR, Abdel-Aziz H, Kelber O, Nieber K, Kraft K, Storr M. Modulation of gastrointestinal motility beyond metoclopramide and domperidone : Pharmacological and clinical evidence for phytotherapy in functional gastrointestinal disorders. Wien Med Wochenschr. 2017;167:160-168

Disclosure

JW and EC were interns, OK, is employee of Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany, KN und KK have received fees from the same company.

Introduction

Colorectal cancer (CRC) and other bowel diseases is a significant health concern globally. In several countries, the fecal immunochemical test (FIT) is a cornerstone in CRC screening for early detection of cancer in asymptomatic individuals. Moreover, the utility of FIT extends beyond this, as it is increasingly recommended for evaluating symptomatic patients as part of the clinical pathway to render possible or rule out serious bowel pathology. Therefore, we aimed to quantify the findings of serious bowel conditions following a non-screening FIT test in the Danish population.

Aims & Methods

This study investigated use of FIT beyond the national CRC screening program in Denmark. We aimed (1) to assess utilization patterns of FIT in contexts other than screening and (2) to examine ensuing diagnoses. Our goal was to quantify the findings of CRC and other bowel diseases in symptomatic patients, thereby assessing its broader potential.
This cohort study was conducted within the Danish universal public healthcare system, delivered by five administrative regions. National CRC screening using FIT was initiated in 2014, but utilization of FIT for symptomatic patients varies between regions. The cut-off for a positive test is ≥10 µg haemoglobin/g faeces for symptomatic populations.
The study used data from the Danish Civil Registration System, the Danish National Patient Registry covering all Danish hospitals, and the Clinical Laboratory Information Register. The cohort included all patients who underwent FIT between 2014 and 2021 outside the Danish CRC screening program.
We employed descriptive statistics to examine FIT administration and demographic distributions across the Danish regions, as well as fecal haemoglobin levels among tested individuals. In addition, we estimated the cumulative incidence of CRC and inflammatory bowel disease (IBD) diagnoses following FIT, considering death as a competing risk and evaluated the proportion of diagnoses for CRC and IBD during the year following FIT.

Results

We identified 19,787 individuals who underwent FIT outside the national CRC screening program in 2014 to 2021. Of these, 4,283 (22%) individuals had a positive FIT result. Among tested individuals, 10,807 (55%) were female. Median age at testing was 64 years. Use of FIT varied across the regions, with 36% of the study cohort being from the Central Denmark Region, and 1.6% being from the Region of Southern Denmark.
Positive FIT cases had a shorter median time to CRC diagnosis (28 days) and any diagnosis (36 days) compared to negative FIT cases (711 and 58 days, respectively). Within one year of the FIT, 370 (1.9%) individuals were diagnosed with CRC, with higher occurrence for FIT positive individuals (7.9%) than for FIT negative individuals (0.2%) (risk difference: 7.7 percentage points [95% CI: -3.2, 11.1]).
Among individuals with a positive FIT result, 83 (1.9%) were diagnosed with IBD within one year, compared to 51 (0.3%) individuals with a negative FIT (risk difference: 1.6 percentage points [95% CI: -5.8, 7.3]).

Conclusion

We found that FIT used outside the national CRC screening program had over 20% positivity. A positive test indicated higher risk of CRC and IBD. Differences in diagnoses are expected due to varied follow-up procedures after positive and negative FIT results. A negative test, while not definitive, suggests a potential to rule out disease and could reduce unnecessary investigations when assessing symptomatic patients.

Introduction

Non-alcoholic steatohepatitis (NASH) is a common known risk factor for developing hepatocellular carcinoma (HCC). Many patients with NASH are given metformin, a widely prescribed medication for type 2 diabetes and obesity. Its primary mode of action involves the activation of AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis. Beyond its anti-hyperglycemic effects, it also exhibits pleiotropic properties that extend to modulating various cellular processes, including inflammation, metabolism, and immune response. In this similar mechanism, growing evidence indicates that metformin also has anti-cancer properties. It has shown significant synergistic effects in combination with standard chemotherapy and immune check-point inhibitors (ICI). However, its effect on advanced HCC treated with ICI (e.g. atezolizumab + bevacizumab, pembrolizumab, durvalumab) is not well understood.

Aims & Methods

This meta-analysis aims to determine the effect of metformin in the overall survival of diabetic patients with advanced HCC treated with ICIs. Major electronic databases and grey literature sources were searched up to January 2023 for studies assessing the effect of metformin in the survival of diabetic HCC patients on immunotherapy.

Results

The hazard ratios for the overall survival of metformin (experimental) vs non-metformin (control) groups were compared from the studies done by Kang 2022, Lin 2022 and Ramini 2023. Resulting I2 of 0% (p value = 0.54) implies that heterogeneity does not exist. Resulting pooled hazard ratio of 1.08, with a narrow 95% confidence interval 0.85 to 1.38, is not significant (Z = 0.65, p = 0.51), implying no significant difference between the two groups. The forest plot also shows that the diamond market intersects the 1 axis or the line of no effect, suggesting that the hazard ratio is not significant. However, eyeballing the said forest plot, all 3 studies tend toward the non-metformin or control group which signifies a worse prognosis with metformin on HCC patients on ICIs.

Conclusion

The use of metformin has no significant difference in the overall survival in diabetic HCC patients receiving immunotherapy, although trends are leading towards worse prognosis. Hence, physicians must take into consideration the diabetes status of HCC patients on immunotherapy due to its impact on their clinical outcomes and negative prognostic effect of metformin use.

References

Papadakos SP, et al. The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy? Cancers (Basel). 2023 Jun 13;15(12):3161. doi: 10.3390/cancers15123161

Hua, Y., Zheng, Y., Yao, Y. et al. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med 21, 403 (2023). https://doi.org/10.1186/s12967-023-04263-8

Disclosure

No conflict of interest