[Chronic diarrhoea: when is it celiac disease and when not?] / Chronische Durchfälle: Wann ist es eine Zöliakie und wann nicht?

Patients who come to clinical consultation for chronic diarrhoea (i.e., diarrhoea lasting for more than four weeks) may suffer from a wide range of clinical conditions. The possible diagnoses range from a misunderstanding of what can be considered normal and what pathological in terms of daily bowel movements, to a severe malabsorption syndrome. Since the list of possible causes of chronic diarrhoea can be puzzling, the physician's approach needs to be systematic and structured in order to allow the correct diagnosis and treatment. This article proposes an algorithm for the diagnosis of chronic diarrhoea and discusses in detail the key clinical aspects of celiac disease, which is considered a paradigmatic disease as regards chronic malabsorptive diarrhoea.

Patient-derived enteroids provide a platform for the development of therapeutic approaches in microvillus inclusion disease.

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.

Intestinal Disaccharidase Deficiency in Adults: Evaluation and Treatment.

PURPOSE OF REVIEW: Disaccharidase deficiency in adults causes carbohydrate malabsorption, resulting in symptoms which significantly overlap with irritable bowel syndrome (IBS). This article discusses the diagnosis and treatment of disaccharidase deficiency within the context of recent literature. RECENT FINDINGS: Disaccharidase deficiency in adults is more common than previously thought, which includes lactase, sucrase, maltase and isomaltase enzymes. Deficiency in disaccharidases, which are produced by the intestinal brush border, will interfere with the breakdown and absorption of carbohydrates and may result in abdominal pain, gas, bloating and diarrhea. Patients deficient in all 4 disaccharidases are known as having "pan-disaccharidase" deficiency, which has a distinct phenotype with more reported weight loss than patients deficient in one enzyme. IBS patients who do not respond to low FODMAP dietary restriction may have undiagnosed disaccharidase deficiency and may benefit from testing. Diagnostic testing methods are limited to duodenal biopsies, which is the gold standard, and breath testing. Dietary restriction and enzyme replacement therapy have been shown to be effective treatments in these patients. Disaccharidase deficiency is an underdiagnosed condition in adults with chronic GI symptoms. Patients who do not respond to traditional treatment strategies for DBGI may benefit from testing for disaccharidase deficiency. Further studies delineating the distinctions between disaccharidase deficient patients and those with other motility disorders are needed.

Malabsorption Syndromes and Food Intolerance.

Feeding intolerance is ubiquitous in neonatal intensive care units with as many signs and symptoms as possible diagnoses. Optimizing nutrition is paramount in both preterm and term infants. Determining the cause of feeding intolerance and adjusting nutrition interventions is an important part of the daily care of newborns. This review discusses the role of malabsorption and food intolerance as possible causes of nutrition difficulties in the newborn.

Gastrointestinal Conditions: Malabsorption Syndromes.

Malabsorption syndromes are a heterogenous group of conditions that can cause distressing gastrointestinal symptoms. Celiac disease is most common and is triggered by exposure to gluten. Tissue transglutaminase immunoglobulin A is the diagnostic test of choice; management is gluten avoidance. Lactose intolerance is caused by absence or declining levels of the enzyme lactase. Diagnosis typically is clinical, but breath tests can be helpful if diagnosis is uncertain. Management is lactose avoidance. Bile acid malabsorption results in unabsorbed bile acids in the colon, leading to diarrhea. The 75selenium homotaurocholic acid test is most accurate but is not widely available. Therefore, a trial of bile acid sequestrants (typically cholestyramine) is a reasonable alternative when the diagnosis is suspected. Exocrine pancreatic insufficiency is caused by decreased production of pancreatic enzymes, typically occurring in patients with preexisting pancreatic damage from alcohol, surgery, radiation, diabetes, or cystic fibrosis. Diagnosis involves fecal fat or fecal elastase-1 tests. Management is pancreatic enzyme replacement. Small intestinal bacterial overgrowth is caused by pathologic overgrowth of the small bowel microbiome. Diagnosis is by jejunal biopsy or, more commonly, breath tests. Antibiotics (typically rifaximin) are the initial management. Other options include dietary changes, probiotics, and prokinetic drugs.

Incidence, Diagnosis and Management of Malabsorption Following Oesophagectomy: a Systematic Review.

BACKGROUND: Survival following oesophagectomy for cancer is improving, resulting in increased focus on quality of life and survivorship. Malabsorption syndrome is multifactorial and includes exocrine pancreatic insufficiency (EPI), small intestinal bacterial overgrowth (SIBO) and bile acid malabsorption (BAM). The aim of this study was to evaluate the reported incidence and management of malabsorption syndromes post-oesophagectomy. METHODS: A systematic search of PubMed, EMBASE, MEDLINE, Scopus and the Cochrane Library evaluating incidence, diagnosis and management of malabsorption was performed for studies published until December 2021. RESULTS: Of 464 identified studies, eight studies (n = 7 non-randomised longitudinal studies) were included where patients were identified with malnutrition following oesophagectomy. Studies included a combined sample of 328 (range 7-63) patients. Malabsorption syndromes including EPI, SIBO and BAM occurred in 15.9-100%, 37.8-100% and 3.33-100% over 21 days-60 months, 1-24 months and 1-24 months respectively. There was no consensus definition for EPI, SIBO or BAM, and there was variation in diagnostic methods. Diagnostic criteria varied from clinical (gastrointestinal symptoms or weight loss), or biochemical (faecal elastase, hydrogen breath test and Selenium-75-labelled synthetic bile acid measurements). Treatment modalities using pancreatic enzyme replacement, rifaximin or colesevelam showed improvement in symptoms and weight in all studies, where investigated. CONCLUSIONS: Malabsorption syndromes following oesophagectomy are under-recognised, and thus under-reported. The resultant gastrointestinal symptoms may have a negative effect on post-operative quality of life. Current literature suggests benefit with outlined therapies; however, greater understanding of these conditions, their diagnosis and management is required to further understand which patients will benefit from treatment.

Small Intestinal Bacterial Overgrowth-Pathophysiology and Its Implications for Definition and Management.

The concept of small intestinal bacterial overgrowth (SIBO) arose in the context of maldigestion and malabsorption among patients with obvious risk factors that permitted the small bowel to be colonized by potentially injurious colonic microbiota. Such colonization resulted in clinical signs, symptoms, and laboratory abnormalities that were explicable within a coherent pathophysiological framework. Coincident with advances in medical science, diagnostic testing evolved from small bowel culture to breath tests and on to next-generation, culture-independent microbial analytics. The advent and ready availability of breath tests generated a dramatic expansion in both the rate of diagnosis of SIBO and the range of associated gastrointestinal and nongastrointestinal clinical scenarios. However, issues with the specificity of these same breath tests have clouded their interpretation and aroused some skepticism regarding the role of SIBO in this expanded clinical repertoire. Furthermore, the pathophysiological plausibility that underpins SIBO as a cause of maldigestion/malabsorption is lacking in regard to its purported role in irritable bowel syndrome, for example. One hopes that the application of an ever-expanding armamentarium of modern molecular microbiology to the human small intestinal microbiome in both health and disease will ultimately resolve this impasse and provide an objective basis for the diagnosis of SIBO.

Fructose malabsorption: causes, diagnosis and treatment.

This review intends to act as an overview of fructose malabsorption (FM) and its role in the aetiology of diseases including, but not limited to, irritable bowel syndrome (IBS) and infantile colic and the relationship between fructose absorption and the propagation of some cancers. IBS results in a variety of symptoms including stomach pains, cramps and bloating. Patients can be categorised into two groups, depending on whether the patients' experiences either constipation (IBS-C) or diarrhoea (IBS-D). FM has been proposed as a potential cause of IBS-D and other diseases, such as infantile colic. However, our knowledge of FM is limited by our understanding of the biochemistry related to the absorption of fructose in the small intestine and FM's relationship with small intestinal bacterial overgrowth. It is important to consider the dietary effects on FM and most importantly, the quantity of excess free fructose consumed. The diagnosis of FM is difficult and often requires indirect means that may result in false positives. Current treatments of FM include dietary intervention, such as low fermentable oligo-, di-, monosaccharides and polyols diets and enzymatic treatments, such as the use of xylose isomerase. More research is needed to accurately diagnose and effectively treat FM. This review is designed with the goal of providing a detailed outline of the issues regarding the causes, diagnosis and treatment of FM.

Urinary Diversion: Core Curriculum 2021.

Urinary diversion after cystectomy has been a historical standard for the treatment of numerous benign and malignant diseases of the bladder. Since the first published description in the early 1900s, improvements in surgical technique and a better understanding of the metabolic sequelae postoperatively have greatly enhanced patient outcomes. Both continent and incontinent diversions are available to patients after cystectomy. In appropriately selected patients, orthotopic neobladder reconstruction can offer preservation of body image and continence, and continent cutaneous diversions represent a reasonable alternative. Conduit diversion, which remains the most commonly performed diversion technique, is ideal for patients who would benefit from a less morbid surgical procedure that negates the need for self-catheterization. This installment of the Core Curriculum in Nephrology outlines numerous aspects of urinary diversion, in which a multidisciplinary approach to postoperative management at the intersection of nephrology and urology is required to effectively optimize patient outcomes. This article includes a discussion of the various reconstructive options after cystectomy as well as a comprehensive review of frequently encountered short-term and long-term metabolic abnormalities associated with altered electrolyte and acid-base homeostasis.

Small and Large Intestine (I): Malabsorption of Nutrients.

Numerous disorders can alter the physiological mechanisms that guarantee proper digestion and absorption of nutrients (macro- and micronutrients), leading to a wide variety of symptoms and nutritional consequences. Malabsorption can be caused by many diseases of the small intestine, as well as by diseases of the pancreas, liver, biliary tract, and stomach. This article provides an overview of pathophysiologic mechanisms that lead to symptoms or complications of maldigestion (defined as the defective intraluminal hydrolysis of nutrients) or malabsorption (defined as defective mucosal absorption), as well as its clinical consequences, including both gastrointestinal symptoms and extraintestinal manifestations and/or laboratory abnormalities. The normal uptake of nutrients, vitamins, and minerals by the gastrointestinal tract (GI) requires several steps, each of which can be compromised in disease. This article will first describe the mechanisms that lead to poor assimilation of nutrients, and secondly discuss the symptoms and nutritional consequences of each specific disorder. The clinician must be aware that many malabsorptive disorders are manifested by subtle disorders, even without gastrointestinal symptoms (for example, anemia, osteoporosis, or infertility in celiac disease), so the index of suspicion must be high to recognize the underlying diseases in time.

The role of histopathology in the diagnosis and management of coeliac disease and other malabsorptive conditions.

Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well-known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten-free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.

Common Diarrheal Illnesses in the Elderly.

Diarrhea is a fairly common problem among the elderly that has a higher morbidity and mortality compared with the general population. There are multiple reasons for diarrhea in the elderly that can be stratified by different mechanisms: infectious, osmotic, secretory, inflammatory, and malabsorptive. Oral hydration and dietary management are the basic management principles for all forms of diarrhea but specific treatment should address the root cause of diarrhea in order to improve outcomes.

Effect of Fat-Soluble Vitamins A, D, E and K on Vitamin Status and Metabolic Profile in Patients with Fat Malabsorption with and without Urolithiasis.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

Challenges of Microvillus Inclusion Disease in the NICU.

Mutations in the myosin 5ß, syntaxin-binding protein 2, and syntaxin 3 genes lead to microvillus inclusion disease (MVID), an autosomal recessive congenital enteropathy. This rare disease is characterized by lack of microvilli on the surface of enterocytes in the small intestine, the presence of pathognomonic intracellular microvillus inclusions, and vesicular bodies within these enterocytes. This pathology leads to the characteristic intractable, life-threatening, watery diarrhea. In the more common early-onset form, affected patients present in the first few days after birth, whereas in the late-onset form, clinical manifestations appear at approximately 2 to 3 months of age. Genetic testing can confirm the diagnosis, but the infant's medical history, clinical presentation, and small intestinal biopsy results are strongly suggestive of the diagnosis. The prevalence of MVID is thought to be higher in countries with a high degree of consanguinity. Patients with MVID cannot tolerate feedings and require continuous total parenteral nutrition. Mortality is extremely high in the early-onset type with reports of survival in patients treated with small intestinal transplantation. Medical counseling for parents of infants with MVID needs to reflect our current understanding of the various genetic forms of this disease, the feasible management, and anticipated outcomes.

Intestinal failure-associated liver disease (IFALD): insights into pathogenesis and advances in management.

Premature infants and children with intestinal failure (IF) or short bowel syndrome are susceptible to intestinal failure-associated liver disease (IFALD, previously referred to as parenteral nutrition-associated liver disease, or PNALD). IFALD in children is characterized by progressive cholestasis and biliary fibrosis, and steatohepatitis in adults, and is seen in individuals dependent upon prolonged administration of PN. Many factors have been proposed as contributing to the pathogenesis of IFALD. In recent years, the focus has been on the potential synergistic roles of the intestinal microbiome, increased intestinal permeability, activation of hepatic innate immune pathways, and the use of intravenous soybean-oil-based intravenous lipid emulsions (SO-ILE). In vitro and in vivo studies have identified stigmasterol, a component of the plant sterols present in SO-ILE, as playing an important role. Although various strategies have been adopted to prevent or reverse IFALD, most suffer from a lack of strong evidence supported by well-designed, prospective clinical trials with clearly defined endpoints. Reduction in the amount of SO-ILEs or replacement with non-SO-ILEs has been shown to reverse IFALD although safety and long-term effectiveness have not been studied. Medical and surgical modalities to increase intestinal adaptation, advance enteral feedings, and prevent central line bloodstream infections are also important preventative strategies. There is a continued need to conduct high-quality, prospective trials with clearly define outcome measures to ascertain the potential benefits of these strategies.

Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

BACKGROUND: In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA). OBJECTIVE: To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption. METHODS: Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (≥88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured. RESULTS: Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), α-linolenic acid (+56%), and total FA (+20%) (p≤0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p≤0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA. CONCLUSIONS: Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group.

Intestinal Failure: A Description of the Problem and Recent Therapeutic Advances.

Pediatric intestinal failure occurs when gut function is insufficient to meet the nutrient and hydration needs of the growing child. The commonest cause is short bowel syndrome with maldigestion and malabsorption following massive bowel loss. The remnant bowel adapts during the process of intestinal rehabilitation. Management promotes the achievement of enteral autonomy while mitigating the risk of comorbid disease. The future of care is likely to see expansion of pharmacologic methods for augmenting bowel adaptation, tissue engineering techniques enabling immune suppression-free autologous bowel transplant, and the development of electronic health record tools for efficient, collaborative study and care improvement.

Use of a mobile application for self-management of pancreatic enzyme replacement therapy is associated with improved gastro-intestinal related quality of life in children with Cystic Fibrosis.

BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback. METHODS: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module). RESULTS: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001). CONCLUSIONS: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms.