Clinical profile of functional constipation in Saudi children.

BACKGROUND: Functional constipation (FC) is a common condition in children, and information on the clinical characteristics of FC in Saudi children is scarce. OBJECTIVE: Describe the clinical profile of FC in Saudi children. DESIGN: Retrospective. SETTING: Hospital that provides primary, intermediate and tertiary care. PATIENTS AND METHODS: All children diagnosed with FC according to the Rome IV criteria were included and had at least one follow-up clinic visit. Demographic and clinical data collected from medical records included the age at onset, duration of constipation, clinical features, treatment modalities, and factors associated with clinical response. Descriptive statistics and Pearson's chi-squared test were used in the statistical analysis to see how categorical study variables were linked to clinical response. A P value of ≤.05 was used to report statistical significance. MAIN OUTCOME MEASURE: Compliance and clinical response to polyethylene glycol (PEG) compared with lactulose. SAMPLE SIZE: 370 children from 0.1 to 13 years of age. RESULTS: The median (IQR) age of onset was 4 (5) years and less than one year in 14%. The median (IQR) duration of constipation was 4 months (11) and less than two months in 93/370 (25%). Abdominal pain was the most commonly associated feature (44%). Screening for celiac disease and hypothyroidism was negative. A Fleet enema was the most common disimpaction method (54%) and PEG was the most common maintenance medication (63.4%). PEG was significantly better tolerated (P=.0008) and more effective than lactulose (P<.0001). Compliance was the only variable significantly associated with clinical response. CONCLUSIONS: PEG was better tolerated and more effective than lactulose in our study, a finding in agreement with the literature. Therefore, PEG should be the drug of choice in the initial management of FC in Saudi children. Prospective studies on the causes of noncompliance are needed to improve the response to treatment. LIMITATIONS: The limitations of retrospective design are missing data, recall bias, and hospital-based limitation, such as missing milder cases treated at the outpatient level. However, the sample size of 370 may have minimized these limitations.

Pharmacologic Management of Hepatic Encephalopathy.

Hepatic encephalopathy is a common cause of morbidity and mortality among patients with decompensated liver cirrhosis. In this article, we review the history, mechanism, and evidence for first-line pharmacologic therapies for hepatic encephalopathy including nonabsorbable disaccharides, antibiotics, and electrolyte management. We also review newer, second-line therapies including polyethylene glycol, albumin, branched-chain amino acids, probiotics and fecal microbiota transplant, zinc, and l-ornithine-l-aspartate.

Nontraditional Treatment of Hepatic Encephalopathy.

The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.

Hepatic veno-occlusive disease complicated with extreme hyperammonaemia (920 µmol/L) treated with defibrotide, lactulose, rifampin and haemodialysis.

Hepatic veno-occlusive disease (VOD)/sinusoidal obstructive syndrome (SOS) is a severe complication that can occur following haematopoietic stem cell transplant (HSCT) with high-intensity conditioning chemotherapy regimens. Severe VOD/SOS, often characterised by multiorgan failure, is associated with a high mortality rate. This case report details the complex clinical course of a male patient in his mid-20s, recently diagnosed with B cell acute lymphoblastic leukaemia, who underwent allogeneic HSCT. Based on the 2023 European Society for Blood and Marrow Transplantation (EBMT) criteria, the patient developed very severe VOD/SOS, prompting immediate treatment with defibrotide. Unexpectedly, he developed profound hyperammonaemia exceeding 900 µmol/L, leading to encephalopathy and cerebral oedema. Despite aggressive interventions including defibrotide, lactulose, rifampin and haemodialysis, the patient passed away due to cerebral oedema and pulseless electrical activity arrest. We theorise the hyperammonaemia is disproportionate to his hepatic dysfunction and is possibly secondary to an acquired defect of the urea synthesis consistent with idiopathic hyperammonaemia, a rare complication in patients receiving intense conditioning chemotherapy.

Efficacy of lubiprostone for functional constipation treatment in adolescents and children: Randomized controlled trial.

OBJECTIVES: Adolescent and pediatric functional constipation (FC) is a common clinical problem. Currently, data on lubiprostone for the treatment of pediatric FC are scarce. This study investigated the efficacy and safety of lubiprostone in the treatment of pediatric FC. METHODS: In a single-blinded, randomized controlled study, we included 280 patients aged 8-18 years with FC. Patients were randomized either to a weight-based lubiprostone dose (n = 140) or conventional laxatives (n = 140), including lactulose, bisacodyl, or sodium picosulfate, for 12 weeks, followed by 4 weeks posttreatment follow-up. RESULTS: Improvement in constipation was achieved in 128 (91.4%) patients in the lubiprostone group, and in 48 (34.3%) patients of the conventional therapy group (p < 0.001) and was sustained after treatment discontinuation. One quarter of the lubiprostone group experienced the first spontaneous bowel motion within 48 h after dose initiation. A total of 75.7% of the lubiprostone group could achieve and sustain Bristol stool form of 3 or 4 during the last 4 weeks of therapy and through the 4 weeks of follow-up versus 50 (35.7%) patients in the conventional therapy group (p < 0.001). No life-threatening adverse drug reactions were encountered, and no treatment-related discontinuation. Mild self-limited colicky abdominal pain and headache were the most prevalent side effects in the lubiprostone group. CONCLUSIONS: Lubiprostone is an effective and well-tolerated pharmacotherapy for youthful age and pediatric age groups, which may alter the paradigm of pediatric FC treatment.

Influence of Helicobacter pylori Infection and Eradication on Small Intestinal Bacterial Overgrowth and Abdominal Symptoms.

BACKGROUND: The relationship between Helicobacter pylori (H. pylori) infection and small intestinal bacterial overgrowth (SIBO) has attracted attention recently. AIMS: To analyze the influence of H. pylori infection and eradication on SIBO, IMO, and abdominal symptoms. METHODS: Patients with gastrointestinal symptoms were tested for 13C urea breath test and if positive, treated with bismuth-based quadruple therapy. Lactulose hydrogen methane breath test (HMBT) was performed and symptoms were assessed using gastrointestinal symptom rating scale (GSRS) before and 6 weeks after eradication. RESULTS: Of the 102 subjects, 53 were H. pylori positive. The prevalence of SIBO and IMO were higher in patients with H. pylori infection than in those without infection (49.1% vs 24.5%, P = 0.019 for SIBO; 24.5% vs 8.2%, P = 0.027 for IMO). GSRS scores were similar between H. pylori-infected and uninfected patients (2 (IQR: 1;3) vs 2 (IQR: 1;2), P = 0.211). Patients with SIBO or IMO presented higher GSRS scores than patients with both SIBO and IMO negative (2 (IQR: 2;3), 2 (IQR: 2;3) vs 2 (IQR: 1;2), P = 0.011, 0.001, respectively). For the 50 patients who successfully eradicated H. pylori, the response rates for SIBO and IMO were 66.7% and 76.9%, respectively. GSRS scores also significantly decreased (2 (IQR: 1;3) to 0 (IQR: 0;1), P < 0.001) after eradication. CONCLUSION: Helicobacter pylori infection was associated with higher prevalence of SIBO and IMO, both of which led to more pronounced abdominal symptoms. H. pylori eradication also achieved therapeutic effects on SIBO and IMO, accompanied by relief of abdominal symptoms.

Hepatic Encephalopathy in Children.

Hepatic encephalopathy, characterized by mental status changes and neuropsychiatric impairment, is associated with chronic liver disease as well as acute liver failure. In children, its clinical manifestations can be challenging to pinpoint. However, careful assessment for the development of hepatic encephalopathy is imperative when caring for these patients as progression of symptoms can indicate impending cerebral edema and systemic deterioration. Hepatic encephalopathy can present with hyperammonemia, but it is important to note that the degree of hyperammonemia is not indicative of severity of clinical manifestations. Newer forms of assessment are undergoing further research, and include imaging, EEG and neurobiomarkers. Mainstay of treatment currently includes management of underlying cause of liver disease, as well as reduction of hyperammonemia with either enteral medications such as lactulose and rifaximin, or even with extracorporeal liver support modalities.

Diagnostic Performance of the ICD-10 Code K76.82 for Hepatic Encephalopathy in Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is prevalent and is associated with increased morbidity and mortality among patients with cirrhosis. On October 1, 2022, a new, specific International Classification of Diseases-10 code for HE, K76.82, was introduced. We aimed to analyze the diagnostic accuracy of K76.82. METHODS: Diagnostic performance of K76.82 for HE (sensitivity, specificity, positive predictive ratio, and negative predictive ratio) was evaluated in 2 large health systems compared with lactulose, rifaximin, and K72.90. RESULTS: A total of 2,483 patients were analyzed. The combination term "lactulose or rifaximin" showed the highest sensitivity of >98% while K76.82 demonstrated a specificity of >87% in all cohorts. DISCUSSION: Although K76.82 is promising, the combination term "lactulose or rifaximin" identified patients with HE more accurately.

Hepatic encephalopathy: From novel pathogenesis mechanism to emerging treatments.

Hepatic encephalopathy (HE) is one of the major complications of liver disease and significantly affects the quality of life (QOL) of patients. HE is common and frequently relapses in cirrhotic patients. The management of HE is supportive, and precipitating conditions should be eliminated. Most drugs used to treat HE are conventional and include nonabsorbable disaccharides such as lactulose, and antibiotics such as rifaximin. However, their therapeutic efficacy is still suboptimal, and novel therapeutic agents are urgently needed. In addition, the optimal management and diagnosis of minimal HE/covert HE are under debate. In this review, we focus on novel pathogenetic mechanisms such as central nervous system clearance, and emerging therapeutic targets of HE, such as fecal material transplantation. We also discuss different classifications and etiologies of HE.

A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy.

Background: Hepatic encephalopathy (HE) caused by cirrhosis has severe consequences on an individual's lifespan, leading to long-term liver complications and potentially life-threatening outcomes. Despite recent interest in this condition, the effectiveness of secondary prophylaxis involving rixafimin, lactulose, or L-ornithine L-aspartate (LOLA) may be hindered by the unique microbial profiles each patient possesses. Methods: Thus, in this manuscript, we aimed to search, identify, and gather all randomized controlled trials (RCTs) published between 2000-2023 (November) in four major academic databases such as PubMed, ISI Web of Science, Scopus, and ScienceDirect by using a controlled terminology and web strings that reunite six main keywords. We complementarily retrieved data on the ongoing RCTs. Results: Regardless of the relatively high number of results displayed (n = 75), 46.66% (n = 35) were initially deemed eligible after the first evaluation phase after removing duplicates, n = 40 (53.34%). At the second assessment stage, we eliminated 11.42% (n = 4) studies, of which n = 22 finally met the eligibility criteria to be included in the main body of the manuscript. In terms of RCTs, otherwise found in distinct stages of development, n = 3 target FMT and n = 1 probiotics. Conclusions: Although we benefit from the necessary information and technology to design novel strategies for microbiota, only probiotics and synbiotics have been extensively studied in the last decade compared to FMT.

A specialized HE testing clinic improves rational decision-making for therapy in cirrhosis.

BACKGROUND: Cognitive complaints in cirrhosis are often attributed to HE with reflexive therapy if specialized tests are not performed. The aim was to determine the utility of a specialized HE clinic for management decisions. METHODS: Cirrhosis patients with cognitive complaints were referred through a dedicated consult pathway to a specialized clinic and followed for 6 months. This clinic included detailed history, medication review, standardized tests [Mini-Mental Status Exam (MMSE), Psychometric HE Score, and others], and obstructive sleep apnea screening. Results were communicated with patients and referring providers. A subset was offered repeat testing. RESULTS: A total of 286 patients were tested between 2012 and 2022. Of the 286 patients, 4 patients who showed a Mini-Mental State Exam <25 were referred to neurology. Thirty-nine percent had normal Psychometric HE Score (higher in younger patients, without prior HE, depression, and lower Model for End-Stage Liver Disease-Sodium), while 172 (61%) patients had cognitive impairment. Of the 172 patients, 51 did not want management change, 84 were started on HE therapy, and 37 were considered impaired due to other causes. In 51 without management change, 32 refused lactulose, while the remaining were counseled regarding lactulose titration. Of the 84 patients with HE-therapy initiation, lactulose was initiated in 56 and rifaximin in 28; most therapies continued over 6 months. The ones who were retested improved their Psychometric HE Score. The 37 with other causes (obstructive sleep apnea, mood disorders, substance use, and mild cognitive impairment) led to specialized referrals. No overt HE was found over 6 months in those without HE-related impairment. The clinic was billed for. CONCLUSIONS: A specialized HE clinic for patients with cirrhosis and cognitive complaints established through a dedicated consult pathway showed that 39% of referred patients had normal cognitive performance, while the results guided management changes, including for HE and other causes in the remaining patients.

Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations.

HE is a complication of cirrhosis characterized by neuropsychiatric and motor dysfunction, and results in decreased quality of life and increased mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966, though many questions about its use remain unanswered. Lactulose reverses minimal HE, prevents overt HE, improves quality of life, increases the rate of recovery from overt HE, and improves survival rates. Lactulose's clinical effect appears to be derived from its impact on intestinal microbes, likely a result of its enteric acidifying effect, positive pressure on beneficial taxa, and improvement of gut barrier function. There are several practical considerations with lactulose including (1) a need to avoid excessive bowel movements and subsequent dehydration, (2) treatment titration protocols need further investigation, (3) baseline or treatment-induced gastrointestinal side effects limit adherence in some cases, and (4) the utility of monitoring stool consistency or pH remains unknown. Further research is needed to optimize our use of this effective treatment for HE.

Primary prevention of hepatic encephalopathy post-TIPS: A systematic review and meta-analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) can be an effective treatment for cirrhotic patients who develop variceal bleeding and ascites. However, TIPS placement is associated with an increased risk of developing hepatic encephalopathy (HE). Recently, there have been efforts to use the typical medical therapies prophylactically in patients undergoing TIPS placement to prevent post-TIPS HE. METHODS: We conducted literature searches in MEDLINE, Embase, CINAHL, Scopus, and Cochrane to examine studies that use prophylactic medical therapy for preventing post-TIPS HE. A narrative synthesis and grading of recommendations assessment assessment were done for all studies. Meta-analysis was performed for eligible studies using the Mantel-Haenszel method random-effects model. Nine hundred twenty-one articles were screened and 5 studies were included in the study after 2 levels of screening. The medications studied were rifaximin, lactulose, lactitol, L-Ornithine-L-aspartate (LOLA), albumin, and combination therapies. RESULTS: Narrative results showed that lactulose, lactitol, LOLA and albumin prophylaxis were not associated with reduction in HE occurrence or mortality. A combination of rifaximin and lactulose was found to be associated with lower occurrence of HE, and the results were not different when LOLA was added. Meta-analysis (n = 3) showed that rifaximin treatment was not associated with changes in HE occurrences. CONCLUSION: In conclusion, a vast majority of medications were not found to be effective post-TIPS HE prophylaxis when used alone. A rifaximin and lactulose combination therapy may be beneficial. Overall, there is significant limitation in the current data and more studies are needed to yield more robust meta-analysis results in the future.

Impact of rifaximin use following an initial overt hepatic encephalopathy hospitalization on rehospitalization and costs.

AIM: To assess the impact of rifaximin (± lactulose) use following discharge of an initial overt hepatic encephalopathy (OHE) hospitalization on OHE rehospitalizations and healthcare costs in a real-world setting. METHODS: Adults (18-64 years) with an OHE hospitalization were identified from MarketScan® Commercial claims (Q4'15-Q2'20), classified into two mutually exclusive treatment cohorts (i.e. rifaximin and no rifaximin treatment), and further stratified into four subgroups based on decreasing quality of care (QoC; i.e. Type 1 - rifaximin without delay post-discharge; Type 2 - rifaximin with delay post-discharge; Type 3 - lactulose only post-discharge; Type 4 - no rifaximin/lactulose treatment post-discharge). The impact of rifaximin use on 30-day and annualized OHE hospitalizations and healthcare costs were assessed between cohorts and by the QoC subgroup. RESULTS: Characteristics were similar between the rifaximin (N = 1,452; Type 1: 1,138, Type 2: 314) and no rifaximin (N = 560; Type 3:337, Type 4: 223) treatment cohorts. The 30-day risk of OHE rehospitalization was lower for the rifaximin vs. no rifaximin treatment cohort (odds ratio 0.56, p < .01) and increased with decreasing QoC. The annual rate of OHE hospitalizations was 59% lower for the rifaximin treatment cohort (incidence rate ratio 0.41, p < .01) and increased with decreasing QoC. Compared to the no rifaximin treatment cohort, the rifaximin treatment cohort had higher pharmacy costs, lower medical costs, and no difference in total healthcare costs. LIMITATIONS: This was a claims-based study subject to common data limitations such as billing inaccuracies or omissions in coded claims. Total healthcare costs were reported from a payer's perspective, which do not capture indirect costs associated with patient burden. CONCLUSIONS: Initiation of rifaximin after an OHE hospitalization was associated with reduced OHE hospitalizations both in the 30-days following and annually. Further, reduced medical costs offset increased pharmacy costs, and no annual cost differences were observed between cohorts.

Intestinal flora in the constipation patients before versus after lactulose intervention.

This study aimed to investigate the characteristics of intestinal flora in patients with chronic functional constipation before and after lactulose intervention. Twenty-nine patients with constipation in the treatment group received oral lactulose (15 mL/d) for a month. Twenty healthy subjects served as controls. Stool specimens were collected before and after lactulose treatment. Fecal bacteria were examined by 16SrRNA gene sequencing and bioinformatics analysis. After lactulose treatment, most bacteria in the constipation group, including Bifidobacteria, Bacillus cereus, Prevotella, Bacillus, Anaerostipes, Oribacterium, and Mogibacterium increased as compared to those in the healthy control group. Anaerotruncus declined in the healthy control group after lactulose treatment. Our study shows lactulose can increase the abundance of probiotics, optimize the intestinal microenvironment, and alleviate constipation.

Prevention of dextran sulfate sodium (DSS)-induced ulcerative colitis in mice by a synbiotic approach using probiotic and lactulose.

In this research, the synbiotic effects of the probiotic Lactiplantibacillus plantarum YW11 and lactulose on intestinal morphology, colon function, and immune activity were evaluated in a mouse model of UC induced by dextran sulfate sodium (DSS). The results revealed that L. plantarum YW11 in combination with lactulose decreased the severity of colitis in mice and improved the structure of the damaged colon, as assessed using colon length and disease condition. Moreover, colonic levels of pro-inflammatory cytokines (IL-1ß, IL-6, IL-12, TNF-α, and IFN-γ) were significantly lower and anti-inflammatory factors (IL-10) were significantly higher following the synbiotic supplementation. The synbiotic also exerted antioxidant effects by up-regulating SOD and CAT levels and down-regulating MDA levels in colon tissue. It could also reduce the relative expression of iNOS mRNA and increase the relative expression of nNOS and eNOS mRNA. Western blot confirmed the increased expression of c-Kit, IκBα, and SCF and significantly reduced expression of the NF-κB protein. Therefore, the combination of L. plantarum YW11 and lactulose exerted therapeutic effects mainly through the NF-κB anti-inflammatory pathway, which represented a novel synbiotic approach in the prevention of colonic inflammation.

Clinical study of probiotics combined with lactulose for minimal hepatic encephalopathy treatment.

OBJECTIVE: This study aimed to investigate the clinical effect of probiotics combined with lactulose for minimal hepatic encephalopathy (MHE) treatment. METHODS: A total of 88 patients with MHE were randomly divided into the control ( n  = 44) and combined groups ( n  = 44). The control group was treated with lactulose, while the combined group was treated with probiotics and lactulose. Serum ammonia, liver function [alanine aminotransferase (ALT) and aspartate transaminase (AST)], intestinal mucosal barrier markers [fatty acid-binding protein 2 (FABP2) and advanced glycation end-products (AGEs)] and number connection test A (NCT-A) and digit symbol test (DST) scores were tested and compared between the two groups. RESULTS: The post-treatment in the control and combined groups shows decreased serum ammonia levels, ALT and AST levels, FABP2 and AGEs levels and NCT-A score and increased DST score compared with pre-treatment, with a significant difference ( P  < 0.05). Post-treatment, the serum ammonia level, ALT and AST levels, FABP2 and AGEs levels, NCT-A score decreased and DST score increased in the combined group compared with the control group, with a significant difference ( P  < 0.05). CONCLUSION: Probiotics can promote lactulose in MHE treatment.

Diagnosis and Management of Cirrhosis and Its Complications: A Review.

Importance: Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. Observations: The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective ß-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Conclusions and Relevance: Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.