Non-pharmacological strategies to treat irritable bowel syndrome: 2022 update.

Irritable bowel syndrome (IBS) is a chronic functional disorder characterized by abdominal pain associated with changes in stool frequency or form, in absence of organic disease. The treatment of IBS is often challenging and should be individually adjusted according to the prevalent symptomatology. Pharmacological treatment for IBS with diarrhea includes peripheral opioid agonists, bile acid sequestrants and antibiotics, while IBS with constipation can be treated with soluble fibers, osmotic agents or prokinetics. In case of abdominal pain, the available pharmacological options are antispasmodics, peripheral opioid agonists or antidepressants. Along with pharmacotherapy, non-pharmacological interventions should be considered as they can play an important role in symptom control. The first-line approach includes lifestyle modifications and dietary advice. Microbiota manipulation through probiotics, prebiotics and symbiotics is a widely used strategy, although the evidence upon the most effective among these in specific IBS subtypes is still unclear. Fecal microbiota transplantation is still in experimental phase for IBS, but it is giving promising results. Psychological therapies may be effective in patients with IBS, despite their application can be limited by long duration, high costs and poor patient's acceptance. Alternative medicine approaches, such as acupuncture, body relaxation techniques, dietary supplements or Chinese herbs, have been proposed; however, the evidence upon their efficacy and safety is still controversial.

Serum glypican-3 for the prediction of survival in patients with hepatocellular carcinoma.

BACKGROUND: Glypican-3 (GPC-3) is a heparan sulfate proteoglycan overexpressed by hepatocellular carcinoma (HCC) cells. Several studies highlighted the diagnostic and prognostic value of GPC-3 expression in liver tissue, while data on the reliability of serum GPC-3 are limited and conflicting. We aimed to evaluate the prognostic value of serum GPC-3 in patients with HCC. METHODS: A total of 449 patients (91 F and 358 M; median age 65 [38-86] years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were retrospectively analyzed. All patients had cirrhosis and the main underlying etiology was viral (N.=323, 72%). Barcelona Clinic Liver Cancer (BCLC) staging system was adopted for patients' classification (BCLC 0/A, N.=293, 65% vs. B/C/D, N.=156, 35%) and treatment allocation. Response to therapy was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). RESULTS: Median overall survival (OS) after HCC diagnosis was 30 months (95% confidence interval [CI]: 27-34). Patients with serum GPC-3>150 pg/mL showed lower overall survival (16; 95%CI: 13-24 months) compared to those with GPC-3≤150 pg/mL (36; 95%CI: 30-56 months) (Log-rank test, P<0.001). At multivariate Cox proportional-hazard regression analysis, presence of ascites (adjusted Hazard Ratio [aHR]=1.84; 95%CI: 1.23-2.74, P=0.003), BCLC stage (aHR=1.65; 95%CI: 1.39-1.97, P<0.001), mRECIST (aHR=0.33; 95%CI: 0.21-0.51, P<0.001) and GPC-3>150 pg/mL (aHR=2.02; 95%CI: 1.47-2.78, P<0.001) resulted significantly associated to overall survival. CONCLUSIONS: Serum GPC-3 resulted an independent prognostic factor for patients with HCC irrespectively from tumor stage and response to therapy.

Risk of recurrence after local resection of T1 rectal cancer: a meta-analysis with meta-regression.

BACKGROUND: T1 rectal cancer (RC) patients are increasingly being treated by local resection alone but uniform surveillance strategies thereafter are lacking. To determine whether different local resection techniques influence the risk of recurrence and cancer-related mortality, a meta-analysis was performed. METHODS: A systematic search was conducted for T1RC patients treated with local surgical resection. The primary outcome was the risk of RC recurrence and RC-related mortality. Pooled estimates were calculated using mixed-effect logistic regression. We also systematically searched and evaluated endoscopically treated T1RC patients in a similar manner. RESULTS: In 2585 unique T1RC patients (86 studies) undergoing local surgical resection, the overall pooled cumulative incidence of recurrence was 9.1% (302 events, 95% CI 7.3-11.4%; I2 = 68.3%). In meta-regression, the recurrence risk was associated with histological risk status (p < 0.005; low-risk 6.6%, 95% CI 4.4-9.7% vs. high-risk 28.2%, 95% CI 19-39.7%) and local surgical resection technique (p < 0.005; TEM/TAMIS 7.7%, 95% CI 5.3-11.0% vs. other local surgical excisions 10.8%, 95% CI 6.7-16.8%). In 641 unique T1RC patients treated with flexible endoscopic excision (16 studies), the risk of recurrence (7.7%, 95% CI 5.2-11.2%), cancer-related mortality (2.3%, 95% CI 1.1-4.9), and cancer-related mortality among patients with recurrence (30.0%, 95% CI 14.7-49.4%) were comparable to outcomes after TEM/TAMIS (risk of recurrence 7.7%, 95% CI 5.3-11.0%, cancer-related mortality 2.8%, 95% CI 1.2-6.2% and among patients with recurrence 35.6%, 95% CI 21.9-51.2%). CONCLUSIONS: Patients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resection techniques. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status.

Assessment of glomerular filtration rate in patients with cirrhosis: Available tools and perspectives.

Renal dysfunction often complicates the course of liver disease, resulting in higher morbidity and mortality. The accurate assessment of kidney function in these patients is essential to early identify, stage and treat renal impairment as well as to better predict the prognosis, prioritize the patients for liver transplantation and decide whether to opt for simultaneous liver-kidney transplants. This review analyses the available tools for direct or indirect assessment of glomerular filtration rate, focusing on the flaws and strengths of each method in the specific setting of cirrhosis. The aim is to deliver a clear-cut view on this complex issue, trying to point out which strategies to prefer in this context, especially in the peculiar setting of liver transplantation. Moreover, a glance is given at future promising tools for glomerular filtration rate assessment, including new biomarkers and new equations specifically modelled for the cirrhotic population.

Diarrhea due to parasites: a short, updated point of view from the clinical setting.

Diarrhea represents a common manifestation of several gastrointestinal diseases. Infectious agents are the most common causes of diarrhea in developing countries, where the inadequate sanitation and hygiene are prevalent. In these countries, the scarcity of preventive measures as well as the limited health resources cause a substantial increase in incidence, morbidity and mortality due to infectious diseases, including diarrhea. Currently, with the availability of rapid and inexpensive air transportation millions of people travel for tourism, work and immigration from developing countries to industrialized countries and vice versa. This leads to a high number of imported pathogens such as parasites causing infectious diarrhea. Importantly, while most cases of parasitic diarrhea are short, mild and self-limited, other cases may be associated with chronic diarrhea and serious morbidity and mortality. The aim of the current review was to provide an update, from a clinician's point of view, of the main parasites causing diarrhea, with a focus on their diagnosis and management in the clinical setting.

The small intestine: barrier, permeability and microbiota.

In recent years, there has been growing interest in the comprehension of the physiology of intestinal permeability and microbiota; and how these elements could influence the pathogenesis of diseases. The term intestinal permeability describes all the processes that allow the passage of molecules as water, electrolytes and nutrients through the intestinal barrier by the paracellular or the transcellular transport systems with several implications for self-tolerance and not-self immunity. An increased permeability might induce a more significant interaction of the immune system with unknown external antigens. This might favor the onset of several immune-related extra-intestinal diseases including coeliac disease, diabetes mellitus type 1, bronchial asthma and inflammatory bowel diseases. Furthermore, the intestinal permeability interacts every day with microbiota, the complex system of mutualistic inhabitants and commensal microorganisms living in the healthy gut. Microbiota is implicated in physiological functions by actively participating in digestion, absorption, synthesis of vitamins and protection from external aggressions. The critical site where these processes occur is the small intestine to which this updated review is dedicated. Understanding its anatomy, its barrier structure and permeability modulation and its microbiota composition is the essential skill to comprehend the complex pathogenesis of several - not only gastroenterological - diseases.

Peripheral neuropathy after viral eradication with direct-acting antivirals in chronic HCV hepatitis: A prospective study.

BACKGROUND: HCV-related extra-hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence-based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct-acting antiviral agent (DAA) treatment. METHOD: Ninety-four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro-QoL). RESULTS: At T0, sensory-motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P < .05 compared to T0). Scores for MRC, questionnaires and Euro-QoL improved significantly (P < .05). CONCLUSION: Our study confirms the high prevalence of clinical and subclinical peripheral sensory-motor neuropathy in patients with HCV infection and indicates improvement after eradication by DAA. These results support the need for larger intervention studies.

Helicobacter pylori eradication with a clarithromycin-based triple therapy in elderly patients.

BACKGROUND: Helicobacter pylori (H. pylori), main agents of several gastroduodenal diseases, represents a therapeutic challenge. Since the influence of age on the success of bacterial treatment remains uncertain, in this case-control study we assessed the efficacy of a standard H. pylori eradication therapy among elderly patients. METHODS: In this retrospective study, a total of 361 naïve patients (194 males, mean age 79.8±3.4 years) aged more than 65 years and treated with a triple therapy regimen comprising a standard dose of omeprazole twice daily, amoxicillin 1g twice daily and clarithromycin 500 mg twice daily, for 7, 10 or 14 days, were included. They were compared with naïve patients, younger than 65 years (mean age 43±2.7 years). Since in the year 2017, we began to use the three-in-one single capsule bismuth-containing quadruple therapy, the search was ended on 31 December 2016. RESULTS: Overall, H. pylori eradication rate in the intention-to-treat (ITT) analysis, was 70.9% (256/361) among elderly patients versus 70.9% (256/361) among young patients. Dividing by treatment duration, among elderly patients, eradication was obtained in 78.1% (50/64), 69.1% (139/201) and 69.7% (67/96) elderly patients within 7-day, 10-day and 14-day regimens, respectively, without statistical difference. Out of 361 elderly patients, 11 were excluded from the per protocol (PP) analysis because of discontinuations (7 for adverse events). One subject discontinued treatment among young patients. Also, the PP analysis showed no statistical difference, with an eradication rate of 73.1% (256/350) among elderly patients versus 71.1% (256/360) among young patients. CONCLUSIONS: In conclusion, elderly does not affect efficacy or safety of a clarithromycin-based triple therapy for H. pylori eradication.

Liver involvement in adult-onset Still's disease: our experience in a third level liver unit and review of the literature.

BACKGROUND: Adult-onset Still's Disease (AOSD) is a systemic inflammatory condition, mainly characterized by high spiking fevers, leukocytosis, skin rash, arthralgia and myalgia. Liver involvement is a frequent feature, usually presenting with hepatomegaly and mild liver enzymes abnormalities, which usually normalize after treatment with anti-inflammatory or immunomodulatory drugs given for AOSD. Although uncommon, the onset of severe acute hepatitis and even of life-threatening liver failure is possible and requires a prompt diagnosis and an aggressive therapy and, in some cases, an emergency liver transplantation. The differential diagnosis of the cause of the liver injury can be very challenging in these patients. METHODS: We reviewed the charts of all consecutive patients admitted for acute hepatitis, between January 2019 and December 2019, to the unit of Gastroenterology and Hepatology, Molinette Hospital, Turin, Northern Italy, searching for episodes AOSD-related. RESULTS: In this period, 21 cases of acute hepatitis were recorded with one among them diagnosed as due to AOSD. The incidence was 5% (1/21). This patient was a woman with a recent diagnosis of AOSD who developed a severe acute seronegative biopsy-proven autoimmune hepatitis. She was successfully treated with high-dose methylprednisolone, with a full and stable recovery from the liver injury. CONCLUSIONS: We discuss the incidence, etiology, pathophysiology, diagnosis, and standard of treatment in the clinical management of AOSD with a special attention and a systematic review on the available therapies for severe liver involvement associated with AOSD.

The impact of direct-acting antiviral treatment on glycemic homeostasis in patients with chronic hepatitis C.

INTRODUCTION: There is robust epidemiological evidence suggesting the link of chronic hepatitis C virus (HCV) infection with type 2 diabetes mellitus (DM). Viral clearance achieved by direct acting antiviral agents (DAAs) has been associated to significant improvements in glycometabolic control but data on the long-term effect of sustained virological response (SVR) on diabetic disease are limited. The aim of this review is to evaluate the influence of SVR after DAA-based therapy on insulin resistance (IR) and DM incidence in non-diabetic patients, on the glycemic homeostasis in diabetic patients and on their long-term hepatic and metabolic outcomes. EVIDENCE ACQUISITION: An electronic search of Embase, PubMed, MEDLINE, Ovid and the Cochrane Database of Systematic Reviews was performed for papers regarding the effect of DAA-induced SVR on the glycometabolic control and clinical outcomes of HCV-positive diabetic patients up to September 30, 2020. EVIDENCE SYNTHESIS: Among non-diabetic patients, a significant reduction in the risk of IR and DM was reported by the vast majority of the studies; the glycometabolic control significantly improved in diabetic patients during and immediately after the end of antiviral treatment. However, whether this beneficial effect is long lasting is still matter of debate. Furthermore, at variance with data obtained during the Interferon era, DM does not seem to be an unfavorable predictive factor of hepatocellular carcinoma in cured patients. CONCLUSIONS: A favorable influence of DAA-induced SVR on IR and DM incidence and on glycemic control is reported by several studies. However, the long-term biochemical, metabolic and clinical impact of this endocrine benefit remains largely unknown.

Transjugular intrahepatic portosystemic shunt in refractory ascites: clinical impact of left ventricular diastolic dysfunction.

BACKGROUND AND AIMS: Left ventricular diastolic dysfunction (LVDD) in cirrhotics are associated with circulatory dysfunction, hepatorenal syndrome (HRS) and heart failure in stressful conditions. Transjugular intrahepatic portosystemic shunt (TIPS) exacerbates the hyperdynamic circulation and challenges cardiac function. We evaluated the incidence and the impact of LVDD in cirrhotic candidates to TIPS for refractory ascites. METHODS: Among 135 patients who underwent TIPS for refractory ascites, 63 cases (child B/C 53/10, Na-model for end-stage liver disease 16.5 ± 0.9) who had 2D-transthoracic-echocardiography with tissue-Doppler-imaging pre-TIPS were retrospectively analysed (group A); in 23 cases cardiac and hormonal assessment before and after TIPS was available. 41 cirrhotics without refractory ascites treated by banding ligation for variceal re-bleeding were used as controls (group B). RESULTS: The prevalence of LVDD was higher in group A (59%; 22% with grade ≥2) as compared to group B (35%; 7% with grade ≥2) (P < 0.01 and P < 0.03). A lack of clinical response to TIPS occurred in 10 patients, all with LVDD (P < 0.03 vs. no LVDD) and in patients with grade ≥2 LVDD mostly (P < 0.02 vs. grade 1). Central venous pressure >20 mmHg after TIPS and left ventricular end-diastolic volume at basal were predictors of no response to TIPS (P = 0.01 and P = 0.004, respectively), which was an independent predictor of death. Elevated levels of NT-proBNP 3 days after TIPS were associated with advanced cardiac dysfunction (P = 0.005). CONCLUSION: NT-proBNP and careful LVDD investigation are useful to better select patients and to predict clinical response and mortality after TIPS.

Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents.

BACKGROUND AND AIMS: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.

Elastography for characterization of focal liver lesions: current evidence and future perspectives.

Focal liver lesions (FLLs) are a common finding during routine abdominal ultrasound (US). The differential diagnosis between diverse types of FLLs, especially between benign and malignant ones, is extremely important and can often be particularly challenging. Radiological techniques with contrast administration and/or liver biopsy are mostly necessary for establishing diagnosis, but they have several contraindications or complications. Due to limitations of these tools, there is urgent and still unmet need to develop a first line, non-invasive and simple method to diagnose FLLs. Elastography is an US-based imaging modality that provides information about the physical parameter corresponding to the tissue stiffness and can be considered a virtual biopsy. Several elastographic approaches have been developed, such as transient elastography, strain imaging and share wave imaging, which include point shear wave elastography and 2D shear wave elastography. These tools are already in use for evaluating liver fibrosis and in the assessment of focal lesions in other organs, like breast and thyroid gland. This review aims to assess the current evidence of different techniques based on elastography in the setting of FLLs, in order to evaluate accuracy, limitations and future perspectives. In particular, we focused on two contexts: the ability of discriminating between benign and malignant lesions, especially hepatocellular carcinoma and liver metastasis, and the surveillance after percutaneous therapy. This could have a high clinical impact making elastography crucial to identify the appropriate management of FLLs.

Gastroesophageal reflux disease: key messages for clinicians.

Gastroesophageal reflux disease (GERD) is a chronic common disorder for which patients often refer to specialists. In the last decades, numerous studies helped to clarify the pathophysiology and the natural history of this disease. Currently, in the clinical setting, GERD is defined by the presence of symptoms that, when endoscopic investigation is required, permit to distinguish between cases with or without associated esophageal mucosal injuries. These conditions are called erosive reflux disease and non-erosive reflux disease (NERD), respectively. The latter is the most common manifestation of GERD. Symptoms are defined typical, as heartburn and regurgitation, and atypical (also called extra-esophageal), as coughing and/or wheezing, hoarseness, sore throat, otitis media, and dental manifestations. In this context, it is crucial for clinicians to investigate the presence of features of suspected malignancy, as unexplained weight loss, anemia, dysphagia, persistent vomiting, familiar history of cancer, long history of GERD, and beginning of GERD symptoms after the age of 50 years. The presence of these risk factors should induce to perform an endoscopic examination. Particular attention should be given to functional conditions that can mimic GERD, such as functional heartburn and hypersensitive esophagus as well as, more rarely, eosinophilic esophagitis. The former ones have different pathophysiology and this explains the frequent non-response to proton pump inhibitor drugs. This narrative review provides to clinicians a useful and practical overview of the state-of-the-art on advancements in the knowledge of GERD.

Management of functional dyspepsia in 2020: a clinical point of view.

Dyspepsia is a disorder that refers mainly to central upper abdominal pain or discomfort. When a cause of this symptom is not identified the condition is termed functional dyspepsia (FD), that affects a large part of the general population. The relevance of FD is due to its high prevalence, but also to its chronic or intermittent course. This induces a significant burden for each national healthcare system. The pathogenesis of FD is complex and multifactorial, depending on cultural, environmental, and biological factors. Although considered of main importance in the pathophysiology of several gastroduodenal diseases, in the context of FD Helicobacter pylori (H. pylori) infection plays a limited role. The diagnosis of FD requires the exclusion of organic gastroduodenal diseases as well as H. pylori infection. Thus, the diagnostic workup includes a complete anamnesis, biochemical tests, and endoscopy with biopsy (when requested), and the satisfaction of clinic criteria recommended by the Rome IV consensus. The treatment of FD is also challenging, in fact more and more studies focused on a wide range of different therapies, with a multitude of results. The aim of this literature review is to provide an update of the new evidences useful for diagnosis and management of FD.