Acute giardiasis and Chapman reflexes: Musculoskeletal symptoms preceding, during and after infection

Giardiasis is an acute infection caused by Giardia lamblia, which produces profuse secretory diarrhea that can lead to dehydration and electrolyte derangement. Musculoskeletal manifestations resulting because of giardiasis occur due to prolonged inflammation and viscero-somatic reflexes of the pathophysiology for this disease process. By treating the parasitic infection with an antiparasitic agent, as well as treating the somatic dysfunctions with osteopathic manipulative treatment, analgesics and a home exercise program, the patient in the following article experienced an uneventful course of treatment and a complete recovery including resolution of the pain.

Chloride transport modulators as drug candidates

Chloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride transporting proteins with expression in cell plasma or intracellular membranes, which include chloride channels, exchangers and cotransporters, some having broad anion specificity. Loss of function mutations in chloride transporters cause a wide variety of human diseases, including cystic fibrosis, secretory diarrhea, kidney stones, salt wasting nephropathy, myotonia, osteopetrosis, hearing loss and goiter. While impactful advances have been made in the past decade in drug treatment of cystic fibrosis using small molecule modulators of the defective cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, other chloride channels and solute carrier proteins (SLCs) represent relatively underexplored target classes for drug discovery. New opportunities have emerged for development of chloride transport modulators as potential therapeutics for secretory diarrheas, constipation, dry eye disorders, kidney stones, polycystic kidney disease, hypertension and osteoporosis. Approaches to chloride transport-targeted drug discovery are reviewed herein, with focus on chloride channel and exchanger classes in which recent preclinical advances have been made in the identification of small molecule modulators and in proof of concept testing in experimental animal models.

Caco-2/HT29-MTX co-cultured cells as a model for studying physiological properties and toxin-induced effects on intestinal cells

Infectious gastrointestinal diseases are frequently caused by toxins secreted by pathogens which may impair physiological functions of the intestines, for instance by cholera toxin or by heat-labile enterotoxin. To obtain a functional model of the human intestinal epithelium for studying toxin-induced disease mechanisms, differentiated enterocyte-like Caco-2 cells were co-cultured with goblet cell-like HT29-MTX cells. These co-cultures formed a functional epithelial barrier, as characterized by a high electrical resistance and the presence of physiological intestinal properties such as glucose transport and chloride secretion which could be demonstrated electrophysiologically and by measuring protein expression. When the tissues were exposed to cholera toxin or heat-labile enterotoxin in the Ussing chamber, cholera toxin incubation resulted in an increase in short-circuit currents, indicating an increase in apical chloride secretion. This is in line with typical cholera toxin-induced secretory diarrhea in humans, while heat-labile enterotoxin only showed an increase in short-circuit-current in Caco-2 cells. This study characterizes for the first time the simultaneous measurement of physiological properties on a functional and structural level combined with the epithelial responses to bacterial toxins. In conclusion, using this model, physiological responses of the intestine to bacterial toxins can be investigated and characterized. Therefore, this model can serve as an alternative to the use of laboratory animals for characterizing pathophysiological mechanisms of enterotoxins at the intestinal level.

A Rare Case of Chronic Diarrhea in a Pediatric Patient

Background: VIPoma, also known as Watery Diarrhea-Hypokalemia- achlorhydria (WDHA) Syndrome is a rare manifestation of multiple endocrine neoplasia syndrome type 1 (MEN1). Vasoactive intestinal peptide, part of the secretin-glucagon family, may be overexcreted in tumors associated with MEN1 and results in diarrhea that persists while fasting, resulting in massive secretion of water and electrolytes. First-line treatment is surgical resection. Clinical Case: We present a 13-year-old male with a past medical history of chronic diarrhea for four years who was transferred from an outside hospital for severe diarrhea and associated electrolyte derangements, including hypokalemia of <1.0 mmol/L (3.5-5.0 mmol/L), sodium of 120 (135-145 mmol/L), and chloride of 84 mmol/L (101-110 mmol/L). Family history was significant for pancreatic, breast, thyroid, stomach, parathyroid, and uterine cancer, as well as hyperparathyroidism and nephrolithiasis. The patient had been admitted to the hospital before for a similar episode of acute on chronic diarrhea but was treated for infectious diarrhea during that admission. CT enterography was obtained during this hospitalization and it revealed multiple solid and heterogeneous appearing pancreatic masses in the head and tail of the pancreas. Work-up was significant for pancreatic polypeptide of 1,523 pg/mL (92-752 pg/mL) and vasoactive intestinal peptide of 1,105 pg/mL (<75 pg/mL). Pancreatic biopsy revealed a grade 2 pancreatic neuroendocrine tumor. Genetic testing revealed a known pathogenic mutation in the menin gene p.R526 (c. 1579>T, pArg527). A pylorus-preserving total pancreatectomy, duodenectomy, cholecystectomy, and splenectomy was performed and surgical pathology revealed a well-differentiated grade 1 neuroendocrine tumor in the head of the pancreas and a well-differentiated grade 2 neuroendocrine tumor in the tail of the pancreas. Since the surgery, the patient currently has no signs of other neuroendocrine tumors associated with MEN1 but continues to follow-up for regular screening for other tumors associated with MEN1. Clinical Lessons: 1. VIPoma, also known as Watery Diarrhea- Hypokalemia- Achlorhydria Syndrome, is characterized by secretory diarrhea that persists while fasting. 2. VIPoma should be considered in patients with a history of chronic diarrhea and a significant family history of neuroendocrine tumors.

SOME CLINICAL ASPECTS AND COMPARATIVE CHARACTERISTICS OF ENTEROPATHOGENIC AND ENTEROINVASIVE ESCHERICHIA COLIINFECTIONIN CHILDREN

The clinical course of enteropathogenic (EPEC) and enteroinvasive escherichiosis (EIEC) in children was studied and their comparative characteristics were carried out. We examined 82 sick children with early age Escherichiosis, caused in 28 byenteroinvasive, in 54 with enteropathogenic strains. In children with EPEC, secretory diarrhea was observed, and EIEC —colitis. A more pronounced manifestation of intoxication syndrome was observed in children with EPEC. The manifestations of diarrheal syndrome and electrolyte disturbances, assessed by the degree of dehydration, are more typical for children with EPEC. If in children with EPEC such complications as hypovolemic shock and acute renal failure were encountered, then in children with EIEC in the form of complications of infectious toxic shock, neurotoxicosis and disseminated intravascular coagulation.

Tannins extract from Galla Chinensis can protect mice from infection by Enterotoxigenic Escherichia coli O101

Background Enterotoxigenic Escherichia coli (ETEC) is classically associated with acute secretory diarrhea, which induces 2 million people death in developing countries over a year, predominantly children in the first years of life. Previously, tannins (47.75%) were extracted from Galla Chinensis and prepared as Galla Chinensis oral solution (GOS) which showed significant antidiarrheal activity in a castor oil-induced diarrhea in mice. Whether the tannins extract were also effective in treatment of ETEC-induced diarrhea was determined in this study. Methods Mice were randomly divided into 6 groups (n = 22). The mice in the normal and untreated groups were given normal saline. Three GOS-treated groups were received different concentrations of GOS (5, 10 and 15%, respectively) at a dose of 10 mL/kg. Mice in the positive control group were fed with loperamide (10 mg/kg). The treatment with GOS started 3 days before infection with ETEC and continued for 4 consecutive days after infection. On day 3, mice were all infected with one dose of LD50 of ETEC, except those in the normal group. Survival of mice was observed daily and recorded throughout the study. On days 4 and 7, samples were collected from 6 mice in each group. Results GOS could increase the survival rate up to 75%, while in the untreated group it is 43.75%. The body weights of mice treated with 15% GOS were significantly increased on day 7 in comparison with the untreated group and the normal group. GOS-treatment recovered the small intestine coefficient enhanced by ETEC-infection. The diarrhea index of mice treated with GOS was significantly decreased. GOS increased the levels of IgG and sIgA in the terminal ileum and decreased the levels of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β, IL-6 and IL-8) in serum. GOS could increase the amount of intestinal probiotics, Lactobacilli and Bifidobacteria. GOS could alleviate colon lesions induced by ETEC-infection. GOS showed higher potency than loperamide. Conclusions GOS could be a promising drug candidate for treating ETEC infections.

A59 SEVERE CHEMOTHERAPY-INDUCED SECRETORY DIARRHEA

Background Diarrhea is one of the most common side effects of chemotherapy, estimated to occur in up to 40% of all patients undergoing cancer therapy. Non-complicated chemotherapy-induced diarrhea (CID) can be managed with loperamide, whereas complicated CID should be treated with continuous infusion of octreotide. Octreotide is usually effective within 48hs of administration. Options for patients that do not respond to loperamide or octreotide include atropine, oral budesonide and cholestyramine. Aims To describe the case of an 18 yo girl with acute myeloid leukemia (AML) who developed severe secretory diarrhea during her treatment course. Methods Retrospective case report. Results The patient was initially treated with Cytarabine, Daunorubicin and Etoposide, and on her third cycle, Gemtuzumab was added. Four weeks later she presented with watery diarrhea up to 6 L/day. She continued with high output despite no oral intake, which was consistent with secretory diarrhea. Infectious workup was negative, and she received Loperamide. Her output decreased to 1 L for 2 days but then increased again to 6 L. She deteriorated and loperamide was switched to octreotide 0.8mcg/Kg/h. The dose was increased to 1.2mcg/Kg/h and she presented blood in the stools. Her stool output was still 4 L/day and octreotide was stopped after one week. Flex sigmoidoscopy showed proctocolitis with friability. Biopsy showed architectural distortion with loss of the superficial epithelium. She was emotionally distressed due to many days of no oral intake, hence Pediasure peptide was introduced, with no changes in the output. Rice was introduced but her diarrhea worsened, and oral intake was stopped again. Four weeks after the onset of diarrhea, her stool output was still above 2 L/day, and cholestyramine 4g once daily was started. Four days later her output decreased and diet was slowly introduced. Two weeks later she had a normal stool output. Cholestyramine was stopped and she was discharged home. Finding the culprit for this case is a challenge, but important to avoid this drug in the future as prior history of CID is a risk factor for a new-onset. Gemtuzumab is a relatively new anti-CD33 antibody used in AML, and results from a meta-analysis showed that adding it to induction chemotherapy may increase the incidence of diarrhea. Her diarrhea started four weeks after the dose of Gemtuzumab, and we believe this new agent might have played an important role in her case. To our knowledge, there are no cases in the literature associating Gemtzumab with such prolonged and severe diarrhea. Conclusions This was a challenging case of CID that did not respond to Loperamide or octreotide and caused a lot of emotional distress for the patient and her providers. Since she responded well to cholestyramine, we recommend its use when the loperamide and octreotide have failed, or in addition to octreotide in severe cases. Funding Agencies None

Vasoactive intestinal peptide producing pheochromocytoma and intracardiac thrombosis

A case of pheochromocytoma producing vasoactive intestinal peptide (VIP) and left ventricular thrombus in the absence of cardiomyopathy or wall motion abnormalities on echocardiogram is presented along with a review of the relevant literature. A 30-year-old female of Afghani descent with past medical history of panic attacks presented with fever, cough, sore throat, vomiting, and was found to have an 11 cm adrenal mass consistent with primary adrenocortical adenoma versus carcinoma. Her tumor elicited catechols and vasoactive intestinal peptide. Her hospitalization was complicated by left ventricular thrombosis leading to an embolic injury to her right kidney, respiratory failure, need for transient dialysis and urinary tract infections. She developed a profuse secretory diarrhea and decision was made to treat with empiric octreotide infusion and imodium with improvement in symptoms. She underwent coil and particle embolization followed by resection. Followup PET gallium scan showed no evidence of residual disease or metastasis. VIP producing pheochromocytoma associated with intracardiac thrombosis is rare. Outcomes depend on prompt diagnosis of the pheochromocytoma and multidisciplinary approach to management.