Secretory Diarrhea Research Articles

The Botanical Drug Substance Crofelemer as a Model System for Comparative Characterization of Complex Mixture Drugs

Crofelemer is a botanical polymeric proanthocyanidin that inhibits chloride channel activity and is used clinically for treating HIV-associated secretory diarrhea. Crofelemer lots may exhibit significant physicochemical variation due to the natural source of the raw material. A variety of physical, chemical, and biological assays were used to identify potential critical quality attributes (CQAs) of crofelemer, which may be useful in characterizing differently sourced and processed drug products. Crofelemer drug substance was extracted from tablets of one commercial drug product lot, fractionated, and subjected to accelerated thermal degradation studies to produce derivative lots with variations in chemical and physical composition potentially representative of manufacturing and raw material variation. Liquid chromatography, UV absorbance spectroscopy, mass spectrometry, and nuclear magnetic resonance analysis revealed substantial changes in the composition of derivative lots. A chloride channel inhibition cell-based bioassay suggested that substantial changes in crofelemer composition did not necessarily result in major changes to bioactivity. In 2 companion papers, machine learning and data mining approaches were applied to the analytical and biological data sets presented herein, along with chemical stability data sets derived from forced degradation studies, to develop an integrated mathematical model that can identify CQAs which are most relevant in distinguishing between different populations of crofelemer.

McKittrick Wheelock Syndrome Treated by Transanal Minimally Invasive Surgery: A Single-Center Experience and Review of the Literature

McKittrick Wheelock Syndrome (MKWS) is a rare syndrome characterized by secretory diarrhea, dehydration, prerenal acute kidney injury, and severe electrolyte abnormalities caused by a large hypersecretory villous adenoma located in the rectum or rectosigmoid junction. Transabdominal (laparoscopic) procedures are the most described procedures in the treatment of MKWS. We report an alternative surgical approach, transanal minimally invasive surgery (TAMIS), to solve this syndrome. All patients who underwent transanal endoscopic microsurgery or TAMIS were included in a prospectively collected database in our center. Between 1996 and 2015, 3 patients were found to have MKWS and treated by TAMIS. Demographics, characteristics of the adenoma, surgery-related data, and outcome were analyzed. The first patient had a villous adenoma 0-12 cm from the anal verge. After TAMIS, she complained of a stenosis that was successfully treated by dilatation. The second patient had an impressive bulky tumor in the rectum. An endoscopic mucosal resection was attempted twice, but incompletely. Pathology analysis showed villous adenoma with high-grade dysplasia and intramucosal carcinoma. One year after TAMIS, a recurrence was detected and treated by an abdominal-perineal resection. A TAMIS was performed in the third patient because of a giant villous circular adenoma, but because of high mucus and fluid production, no proper overview could be obtained. Together with opening of the peritoneum, this prompted us to convert to a laparoscopic Hartmann procedure. Besides this technical difficulty, the patient recovered uneventful. MKWS is a rare syndrome and missed diagnosis could result in life-threatening situations. Different endoscopic and surgical treatments are described to solve this syndrome. TAMIS should be considered as a rectum-preserving surgical treatment option for such extensive adenomas.

Secretory diarrhea and hypokalemia associated with colonic pseudo-obstruction: A case study and systematic analysis of the literature.

Colonic pseudo-obstruction (CPO) is characterized by colonic distention in the absence of mechanical obstruction or toxic megacolon. Concomitant secretory diarrhea (SD) with hypokalemia (SD-CPO) due to gastrointestinal (GI) loss requires further characterization. To perform a systematic review of SD-CPO, report a case study, and compare SD-CPO with classical CPO (C-CPO). We performed a search of MEDLINE, EMBASE, Cochrane, and Scopus for reports based on a priori criteria for CPO, SD and GI loss of potassium. An additional case at Mayo Clinic was included. Nine publications met inclusion criteria, with a total of 14 cases. Six studies had high, three moderate, and our case high methodological quality. Median age was 74years (66-97), with 2:1 male/female ratio. Kidney disease was present in 6/14 patients. Diarrhea was described as profuse, watery, or viscous in 10 patients. Median serum, stool, and urine potassium concentrations (mmol/L) were 2.4 (range: 1.9-3.1), 137 (100-180), and 17 (8-40), respectively. Maximal diameter of colon and cecum (median) were 10.2cm and 10.5cm, respectively. Conservative therapy alone was effective in five out of 14 patients. Median potassium supplementation was 124mEq/d (40-300). Colonic decompression was effective in three out of six patients; one had a total colectomy; three out of 14 had died. The main differences between SD-CPO and C-CPO were lower responses to treatments: conservative measures (35.7% vs 73.6%, P=.01), neostigmine (17% vs 89.2%, P<.001), and colonic decompression (50% vs 82.4%, P=.02). SD-CPO is a rare phenotype associated with increased fecal potassium and is more difficult to treat than C-CPO.

Cellular mechanisms underlying the inhibitory effect of flufenamic acid on chloride secretion in human intestinal epithelial cells

Intestinal Cl− secretion is involved in the pathogenesis of secretory diarrheas including cholera. We recently demonstrated that flufenamic acid (FFA) suppressed Vibrio cholerae El Tor variant-induced intestinal fluid secretion via mechanisms involving AMPK activation and NF-κB-suppression. The present study aimed to investigate the effect of FFA on transepithelial Cl− secretion in human intestinal epithelial (T84) cells. FFA inhibited cAMP-dependent Cl− secretion in T84 cell monolayers with IC50 of ∼8 μM. Other fenamate drugs including tolfenamic acid, meclofenamic acid and mefenamic acid exhibited the same effect albeit with lower potency. FFA also inhibited activities of CFTR, a cAMP-activated apical Cl− channel, and KCNQ1/KCNE3, a cAMP-activated basolateral K+ channel. Mechanisms of CFTR inhibition by FFA did not involve activation of its negative regulators. Interestingly, FFA inhibited Ca2+-dependent Cl− secretion with IC50 of ∼10 μM. FFA inhibited activities of Ca2+-activated Cl− channels and KCa3.1, a Ca2+-activated basolateral K+ channels, but had no effect on activities of Na+–K+–Cl− cotransporters and Na+–K+ ATPases. These results indicate that FFA inhibits both cAMP and Ca2+-dependent Cl− secretion by suppressing activities of both apical Cl− channels and basolateral K+ channels. FFA and other fenamate drugs may be useful in the treatment of secretory diarrheas.

Development and Validation of a Novel Real-time Assay for the Detection and Quantification of Vibrio cholerae.

Vibrio cholerae O1 and O139 has been known for its ability to cause epidemics. These strains produce cholera toxin which is the main cause of secretory diarrhea. V. cholerae non-O1 and non-O139 strains are also capable of causing gastroenteritis as well as septicemia and peritonitis. It has been proven that virulence factors such as T6SS, hapA, rtxA, and hlyA are present in almost all V. cholerae strains. It is imperative that viable but non-culturable cells of V. cholerae are also detected since they are also known to cause diarrhea. Thus, the aim of this study was to develop an assay that detects all V. cholerae regardless of their serotype, culturable state, and virulence genes present, by targeting the species specific conserved ompW sequence. The developed assay meets these goals with 100% specificity and is capable of detecting as low as 5.46 copy number of V. cholerae. Detection is rapid since neither lengthy incubation period nor electrophoresis is required. The assay had excellent repeatability (CV%: 0.24–1.32) and remarkable reproducibility (CV%: 1.08–3.7). Amplification efficiencies in the 89–100% range were observed. The assay is more economical than Taqman-based multiplex real-time PCR assays. Compared to other real-time assays, the ompW assay is specific and sensitive, has better repeatability and reproducibility, and is more economical.

Posterior Reversible Encephalopathy Syndrome Due To Carcinoid Crisis Complicating Transarterial Chemoembolization for Metastatic Carcinoid Tumour

Posterior Reversible Encephalopathy Syndrome Due To Carcinoid Crisis Complicating Transarterial Chemoembolization for Metastatic Carcinoid Tumour

Su1534 - Secretory Diarrhea and Hypokalemia Associated with Acute Colonic Pseudo-Obstruction: A Systematic Review and Meta-analysis of the Literature

Su1534 - Secretory Diarrhea and Hypokalemia Associated with Acute Colonic Pseudo-Obstruction: A Systematic Review and Meta-analysis of the Literature

Identification and characterization of population heterogeneity of Vibrio cholerae in vivo

Vibrio cholerae is a facultative pathogen that is found naturally in aquatic environments around the world. Upon ingestion of contaminated water or food, V. cholerae can colonize the human small intestine and induce profuse secretory diarrhea known as rice water stool (RWS). During the course of the infection V. cholerae undergoes through various transcriptional changes to adapt to the shifting environment. In the early stage of infection, bacteria rapidly replicate and increase expression of key virulence factors. The middle stage of infection is characterized by upregulation of the chemotaxis and flagellar genes. This allows V. cholerae to exit the luminal fluid of the small intestine. Finally in the late stage of infection, chemotaxis becomes repressed as V. cholerae is shed in the RWS. Studies have shown that V. cholerae exiting the mammalian host can enter into a hyperinfectious state. These hyperinfectious bacteria have been implicated to be major contributors in household transmission of the disease. Factors that promote hyperinfectivity are still largely unknown.Other studies have demonstrated that host‐passed bacteria upregulate important late genes that prepare V. cholerae transition into the aquatic environment. For example, several of these late genes are involved in metabolism and are shown to be important for V. cholerae survival in pond water. One such gene is glpK, which encodes for a glycerol kinase and plays an important role in glycerol metabolism. By quantitative real time PCR, previous work has shown that mice‐passaged V. cholerae had an increased expression of glpK by 10‐ to 14‐fold. However, using recombination‐based in vivo expression technology (RIVET), our lab demonstrated that only 27% of the bacterial population exiting the host induces glpk expression. This suggests that glpK is highly expressed during the late stage of infection but only in a quarter of the population. These results led to the idea that the population of V. cholerae leaving the host may be heterogeneous, in which one subset of the population undergoes preparation for survival in the aquatic environment while the other remains hyperinfectious and therefore, can be more fit for rapid transmission to the next host. To examine this heterogeneous population in vivo, we generated a chromosomal GFP‐transcriptional fusion to glpK in the wave three Haiti V. cholerae strain. Using this strain we infected infant rabbits, which serve as an animal model for cholera in humans, and showed that only a subset of the host‐passed vibrios express GFP or glpK. This is consistent with previous RIVET studies. We will use fluorescence‐activated cell sorting (FACS) to separate the two populations and perform RNA‐seq to study their transcriptomes. Analysis of the subpopulation will provide further understanding of the mechanism of transmission and dissemination of V. cholerae.

РЕЗУЛЬТАТИ ФАРМАКОЕКОНОМІЧНИХ ДОСЛІДЖЕНЬ ЛІКУВАННЯ ЕНТЕРИТІВ ВІРУСНОГО ПОХОДЖЕННЯ У ДІТЕЙ (НА ПРИКЛАДІ РЕГІДРАТАЦІЙНОЇ ТЕРАПІЇ)

Мета роботи. Провести фармакоекономічну оцінку ефективності застосування ЛЗ для оральної та парентеральної регідратації та моделювання витрат на регідратаційну терапію секреторних (вірусних) діарей у дітей віком до 5-ти років.Матеріали і методи. У дослідженні було використано метод фармакоекономічного аналізу «мінімізація витрат», а також аналітичний, статистичний, логічний та графічний методи. На прикладі регідратаційної терапії визначено ЛЗ, найбільш доцільні для використання з метою оральної та перантеральної регідратації дітей з позиції мінімізації витрат, а також змодельовано сукупні витрати на регідратаційну терапію секреторних (вірусних) діарей у дітей віком до 5-ти років. Дослідження було здійсненне за створеною методикою проведення фармакоекономічних досліджень ГКІ у дітей. Результати й обговорення. Визначено можливий обсяг витрат на регідратаційну терапію ГКІ вірусної етіології у дітей до 5-ти років на 2017 рік, що склав понад 707 тис. грн, або 26 004 $ (1$ США – 27,19 грн станом на 11.01.17).Висновки. Здійснено розрахунки вартість регідратаційної терапії ГКІ у дітей з використанням методу фармакоекономічного аналізу «мінімізація витрат», а також змодельовано можливі витрати на лікування дітей до 5-ти років з діагнозом ГКІ вірусної етіології. В подальшому отримані результати доцільно використати у процесі вдосконалення фармацевтичного забезпечення дитячого населення, зокрема для попередження та терапії ГКІ.

Human rotavirus strain Wa downregulates NHE1 and NHE6 expressions in rotavirus-infected Caco-2 cells.

Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na+-coupled transport mechanisms at the luminal membrane, including Na+/H+ exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs. Western blotting was employed for protein detection. Furthermore, immunocytochemistry was used to validate the NHE's protein expression. Finally, intracellular Ca2+ concentration was detected by confocal laser scanning microscopy. The results demonstrated that the NHE6 mRNA and protein expressed in the human colon adenocarcinoma cell line (Caco-2). Furthermore, RV-Wa induced decreased expression of the NHE1 and NHE6 in Caco-2 cell in a time-dependent manner. In addition, intracellular Ca2+ concentration in RV-Wa-infected Caco-2 cells was higher than that in the mock-infected cells. Furthermore, RV-Wa also can downregulate the expression of calmodulin (CaM) and calmodulin kinase II (CaMKII) in Caco-2 cells. These findings provides important insights into the mechanisms of rotavirus-induced diarrhea. Further studies on the underlying pathophysiological mechanisms that downregulate NHEs in RV-induced diarrhea are required.

US in Detection and Differentiation of Ileus

Ultrasonography has become increasingly important in the routine diagnostics of gastrointestinal diseases. It is not only assessing the lumen but more important the wall and the surrounding structures of the stomach and bowel. Furthermore, functional processes (peristalsis, blood flow) can be visualized and provide important information about passage and perfusion. With modern high resolution (compressive) sonography the gastroenterologist has an ideal method available complementary to endoscopy. Ultrasonography is an effective diagnostic tool in situation of emergency (ileus, perforation). In emergency indications sonography is the method of first choice achieving a high sensitivity. The same applies to the ileus, which can be diagnosed significantly earlier by sonography than with conservative X-ray. Meanwhile sonography can contribute considerable information to clarify genesis (e.g. invagination, intusception). Signs of mechanical small bowel ileus are dilatated and round bowel loops. In the late phase, the bowel wall is thicker, oedematous and a peristaltic. Hyper peristaltic, pendula peristalsis und atony depend on the stadium. Distal of the stenosis the bowel is empty (“hunger bowel”). Frequent causes are adhesive bands and adhesions (not visible), incarcerated hernias, invaginations (in children) or tumours (seldom foreign bodies or gall stones). Differential diagnostic peritoneal carcinosis has to be excluded as cause of the obstruction. Often the cause for he ileus can be found by detailed examination in conjunction with medical history and clinical symptoms. Differential diagnostic wide, exudate-filled, intestinal loops with hyper-motility in case of endemic sprue, but also other forms of secretory diarrhoea. Most frequently the cause of large bowel ileus is colon cancer. Typical is a lot of gas in the dilated colon. Other reasons are coprostasis, volvulus, peri-diverticulitis and IBD. In paralytic ileus, small bowel loops are enlarged and a peristaltic and also the colon is enlarged. Typical examples are postoperative bowel atony or paralytic situations in pancreatitis, peritonitis and mesenteric ischemia. The published sensitivity of sonography (89 – 97 %) is significant higher than that of X-ray (77 - 85 %). In mechanical small bowel ileus diagnosis with possible US is 6 h earlier then with X-ray. Radiological signs are considerably later apparent as the passage obstruction, detectable by sonography. In large bowel ileus, heavy flatulence of single bowel segments is the main sign, in some cases this can be demonstrated more clearly with a X-ray abdomen overview. But gas filling is usually a late sign of Ileus. Free intraabdominal fluid (interenteric ascites) is also a (late) sign of Ileus.

電解質喪失症候群（EDS）を呈した直腸絨毛腫瘍の1症例

An 82-year-old woman with disturbance of consciousness was admitted to our hospital. Blood examination results showed renal failure, hyponatremia, and hypokalemia. Endocrine function was normal. Abdominal computed tomography images revealed a 53-mm tumor and intussusception in the recto-sigmoid. Contrast enema results revealed a concave pressure defect. Endoscopic examination revealed a continuous circumferential villous tumor located at 5 cm from the lower rectum, which could have intussuscepted due to peristalsis. We diagnosed EDS due to villous tumor of rectum and performed a Hartmann procedure ; the resected specimen showed a 140 × 110 mm circumferential villous tumor, and pathological investigation revealed adenocarcinoma with an adenoma component. EDS is a rare disorder characterized by a villous tumor leading to chronic secretory diarrhea which in turn leads hypokalemia, hyponatremia, and renal failure. Intussusception in adults is rare in comparison with children.

Clostridium Difficile Infection in Children: A Review.

Clostridium difficile is a sporogenic, anaerobic, Gram-positive, emerging enteric pathogen. It represents the most common cause of health care-associated diarrhoea in the United States, with significantly associated morbidity, mortality, and health care costs. Historically regarded as a little more than an innocent coloniser bystander of the gastrointestinal tract of children, C difficile has increasingly demonstrated its behaviour as a true pathogen in the paediatric age groups. This organism may be responsible for a broad spectrum of diseases in children, ranging from self-limiting secretory diarrhoea to life-threatening conditions, such as pseudomembranous colitis, toxic megacolon, intestinal perforation, and septic shock. The incidence and severity of C difficile infection are, however, not completely understood in this population. In particular, although asymptomatic carriage remains high among infants, the clinical significance of detecting C difficile in children aged 1 to 3 years is not fully understood. Moreover, recent epidemiological surveillance has demonstrated a rise in the incidence of C difficile infection, particularly in the community and in low-risk settings. Interestingly, such cases may not show the disease pattern to be associated with typical risk factors, such as recent exposure to antimicrobial drugs or on-going contacts with the health care system.The purpose of the present review is to present the features of C difficile infection that are unique to paediatric patients and to update paediatricians on information and recommendations regarding C difficile infection in children.

Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea: AN ESSENTIAL ROLE FOR PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE (PIP2) SIGNALING IN CHOLERA

Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl- channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl- secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca2+]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl- current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling.

Role of Quercetin in Modulating Chloride Transport in the Intestine.

Epithelial chloride channels provide the pathways for fluid secretion in the intestine. Cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs) are the main chloride channels in the luminal membrane of enterocytes. These transmembrane proteins play important roles in many physiological processes. In this study, we have identified a flavonoid quercetin as a modulator of CaCC chloride channel activity. Fluorescence quenching assay showed that quercetin activated Cl− transport in a dose-dependent manner, with EC50 ~37 μM. Short-circuit current analysis confirmed that quercetin activated CaCC-mediated Cl− currents in HT-29 cells that can be abolished by CaCCinh-A01. Ex vivo studies indicated that application of quercetin to mouse ileum and colon on serosal side resulted in activation of CFTR and CaCC-mediated Cl− currents. Notably, we found that quercetin exhibited inhibitory effect against ANO1 chloride channel activity in ANO1-expressing FRT cells and decreased mouse intestinal motility. Quercetin-stimulated short-circuit currents in mouse ileum was multi-component, which included elevation of Ca2+ concentration through L-type calcium channel and activation of basolateral NKCC, Na+/K+-ATPase, and K+ channels. In vivo studies further revealed that quercetin promoted fluid secretion in mouse ileum. The modulatory effect of quercetin on CaCC chloirde channels may therefore represent a potential therapeutic strategy for treating CaCC-related diseases like constipation, secretory diarrhea and hypertension. The inverse effects of quercetin on CaCCs provided evidence that ANO1 and intestinal epithelial CaCCs are different calcium-activated chloride channels.

Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.

Secretory diarrheas caused by bacterial enterotoxins, including cholera and traveler's diarrhea, remain a major global health problem. Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido-pyrrolo-oxazinedione (R)-BPO-27 inhibits CFTR chloride conductance with low-nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)-BPO-27 for treatment of secretory diarrheas caused by cholera and Escherichia coli enterotoxins. (R)-BPO-27 fully blocked CFTR chloride conductance in epithelial cell cultures and intestine after cAMP agonists, cholera toxin, or heat-stable enterotoxin of E. coli (STa toxin), with IC50 down to ∼5 nM. (R)-BPO-27 prevented cholera toxin and STa toxin-induced fluid accumulation in small intestinal loops, with IC50 down to 0.1 mg/kg. (R)-BPO-27 did not impair intestinal fluid absorption or inhibit other major intestinal transporters. Pharmacokinetics in mice showed >90% oral bioavailability with sustained therapeutic serum levels for >4 h without the significant toxicity seen with 7-d administration at 5 mg/kg/d. As evidence to support efficacy in human diarrheas, (R)-BPO-27 blocked fluid secretion in primary cultures of enteroids from human small intestine and anion current in enteroid monolayers. These studies support the potential utility of (R)-BPO-27 for therapy of CFTR-mediated secretory diarrheas.-Cil, O., Phuan, P.-W., Gillespie, A. M., Lee, S., Tradtrantip, L., Yin, J., Tse, M., Zachos, N. C., Lin, R., Donowitz, M., Verkman, A. S. Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.

CFTR pharmacology.

CFTR protein is an ion channel regulated by cAMP-dependent phosphorylation and expressed in many types of epithelial cells. CFTR-mediated chloride and bicarbonate secretion play an important role in the respiratory and gastrointestinal systems. Pharmacological modulators of CFTR represent promising drugs for a variety of diseases. In particular, correctors and potentiators may restore the activity of CFTR in cystic fibrosis patients. Potentiators are also potentially useful to improve mucociliary clearance in patients with chronic obstructive pulmonary disease. On the other hand, CFTR inhibitors may be useful to block fluid and electrolyte loss in secretory diarrhea and slow down the progression of polycystic kidney disease.

HIV and diarrhoea: what is new?

The review examines the changing causes and the investigation of infectious and noninfectious diarrhoea in individuals with HIV. Despite the excellent prognosis conferred by combination antiretroviral therapy, diarrhoea is still common in HIV-positive individuals and is associated with reduced quality of life and survival. There is increasing interest in the importance of Th17 and Th22 T cells in the maintenance of mucosal immunity within the gut, and in the role of the gut microbiome in gut homeostasis. Bacterial causes of HIV-associated diarrhoea continue to be important in resource-poor settings. In other settings, sexually transmitted enteric infections such as lymphogranuloma venereum and shigellosis are increasingly reported in men who have sex with men. HIV increases the risk of such infections and the presence of antimicrobial resistance. Parasitic causes of diarrhoea are more common in individuals with uncontrolled HIV and low CD4 counts. Noninfectious causes of diarrhoea include all classes of antiretroviral therapy, which is under-recognised as a cause of poor treatment adherence. Pancreatic dysfunction is remediable and the diagnostic workup of HIV-related diarrhoea should include faecal elastase measurements. New antimotility agents such as crofelemer may be useful in managing secretory diarrhoea symptoms. Clinicians looking after patients with HIV should ask about diarrhoeal symptoms, which are under-reported and may have a remediable infectious or noninfectious cause.

Intractable Diarrhea: A Diagnostic Dilemma

As per the American Gastroenterological Association, chronic diarrhea is defined as a decrease in fecal consistency lasting greater than four weeks. Co-morbidities, socio-economic status, family history, diet and immune status must be taken into account when searching for a diagnosis. A 47-year old female with past medical history of DMI with nephropathy, right BKA and hypothyroidism was admitted to the Medical ICU for DKA and septic shock due to HCAP. After a prolonged course complicated by chronic respiratory failure, she was unable to be weaned off the ventilator and underwent tracheostomy and PEG tube placement. Throughout her hospitalization, she was found to have severe, intractable diarrhea, often stooling up to 12 times per day with significant volumes. Differential diagnoses included osmotic diarrhea due to tube feeds vs malabsorption due to bowel edema/ischemia vs secretory diarrhea of unknown etiology. GI was consulted, and work-up included multiple rounds of fecal fat testing, C difficile toxin, celiac antibodies, stool studies, culture and gram stain, all which resulted as normal. Octreotide scan showed no evidence of primary or secondary neuroendocrine tumour. CT Abdomen/Pelvis showed evidence of colitis and the patient underwent colonoscopy with biopsies consistent with ischemic colitis. The patient finished a course of antibiotics, however, continued to have intractable diarrhea for >4 months inpatient duration despite aggressive medical therapy. Concomitantly, she developed a skin rash, which when biopsied, was consistent with small vessel-vasculitis. It was then postulated that this could be the underlying etiology, and she was started on high dose steroids with resolution of rash, however, diarrhea persisted. Eventually when the patient was medically stable, she underwent repeat colonoscopy with colonic biopsies showing regenerative ischemic changes. To this day, there is still no clear consensus among specialists for the cause of the patient's prolonged symptomatology. Chronic diarrhea has a wide differential whose etiology depends largely on the unique characteristics of a patient. It is a difficult entity to diagnose as clinicians are often faced with multiple medical co-morbidities that can easily confound diagnosis. Unfortunately, an ideal strategy for work-up of chronic diarrhea has yet to be established and, ultimately, a cause may never be uncovered, as was the case with our patient.

A systematic literature search and review of sodium concentrations of body fluids

Wide ranges of sodium concentrations for different body fluid losses have been noted with minimal substantiating data and variability among sources, leading to use of "cumulative fluid balance" regardless of composition in hospitalized patients. To define the sodium concentrations of fluid losses from the body. We performed a systematic search and literature review in adult humans using PubMed database. Inclusion criteria were met for 107 full-text articles. Mean sodium concentrations were significantly lower for acidic (mean±SD: 44±12mEq/L) than for alkaline (55±13mEq/L) gastric fluid, higher for bile (185±24mEq/L) or pancreatic fluid (156±3mEq/L) than for all other body fluids, and similar for intact small bowel (119±14mEq/L) and ileostomy outputs (116±25mEq/L). Sodium concentrations were significantly greater for cholera-induced diarrhea (128±18mEq/L) and lower for osmotic-induced diarrhea (28±16mEq/L) than all other causes of diarrhea. For osmotic diarrheas, sorbitol-induced diarrhea sodium concentration was higher (63±17mEq/L) than for carbohydrate malabsorption (43 ± 20mEq/L), lactulose (26±19mEq/L), Idolax (16±13mEq/L), or polyethylene glycol (13±7mEq/L). For secretory diarrheas, sodium concentration for idiopathic causes (53±22mEq/L) was lower than for neuroendocrine and villous tumors (75±13mEq/L) or nonosmotic laxatives (88±33mEq/L). For pleural, peritoneal, and edema fluid, sodium concentrations (137±13mEq/L) were similar to plasma. No data were found for wound fluid. Sodium concentration for sweat was 44±17mEq/L. This is the first in-depth review of verifiable sodium concentrations of body fluids most commonly lost in hospitalized patients. Sodium concentrations are fluid-specific and consistent. Sodium concentrations for diarrhea are associated with specific mechanisms/causes. These data should be useful to more accurately replace sodium and water content for specific body fluid losses. .