Secretin in Refeeding

Study Overview
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Brief Summary
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Patients with restrictive-type anorexia nervosa who are admitted to the hospital for feeding often urinate excessive amounts. Others have changes in the way that they handle acid and base. These issues prolong hospitalizations. Current data suggest that one hormone--named secretin--may control both urine output and how the body handles acid and base. This study will evaluate whether secretin levels are different in anorexic patients who urinate an excessive amount compared to those who urinate normal amounts. For this study, patients will have one extra blood draw before and after one meal during their hospitalization. The blood draw before the meal coincides with a standard of care blood draw. Also after the meal, subjects will be asked to provide one extra urine sample. Information from subject's medical records will also be used.

Detailed Description
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We hypothesize that secretin release and/or response is aberrant in restrictive anorexics. This results in water and salt wasting and/or metabolic alkalosis in many restrictive anorexics during refeeding. We will thus characterize secretin levels and response to a standard meal in 10 restrictive anorexics (5 who have excessive urine output > 3cc/kg/hr and 5 with normal urine output < 2 cc/kg/hr) during refeeding. Refeeding is associated with renal salt and water dumping in a significant proportion of restrictive anorexic patients. This fluid dumping necessitates the administration of as much as an additional 4 to 5 liters of intravenous replacement fluid daily, prolonging hospitalizations by over a week and leading to readmissions. Unfortunately, the pathophysiology of these fluid losses-which are not associated with changes in serum sodium-is poorly understood and treatment aimed at reducing urinary volume by increasing free water retention using arginine vasopressin (AVP) is poorly effective. Importantly, renal fluid dumping is not universal and the factors contributing to its development are not known. Understanding the pathophysiology of fluid losses during refeeding could lead to treatment strategies aimed at reducing hospitalization length and readmissions. During refeeding, some restrictive anorexics also develop a progressive increase in serum bicarbonate. Elevated serum bicarbonate concentrations reflect either a metabolic alkalosis, in which there is retention of bicarbonate by the kidneys, or a respiratory acidosis, in which carbon dioxide is retained by the lungs. Although the acid-base status of restrictive anorexics undergoing refeeding has not been defined, eating, in general, is associated with an alkaline tide in which a surge of bicarbonate temporarily alkalinizes the serum until this tide is excreted by the kidneys. The progressive rise in serum bicarbonate with re-introduction of adequate enteral intake suggests a progressive alkalosis during refeeding in restrictive anorexics. Recent data suggest that renal excretion of the alkaline tide is largely controlled by the enzyme secretin, a gastrointestinal hormone which regulates both acid-base status and salt and water excretion. Gastric acid stimulates secretin release; thus, plasma secretin concentrations increase significantly after meals in healthy individuals. Secretin stimulates the production of pancreatic fluid and bicarbonate secretion into the duodenum. By neutralizing the pH of the duodenal fluid in this manner, secretin optimizes the function of pancreatic amylase and pancreatic lipase. In the kidneys, secretin upregulates pendrin and the CFTR chloride channel in Type B intercalated cells of the cortical collecting duct; these transporters are critical for renal bicarbonate excretion. Independent of its effect on acid-base status and independent of any effect on AVP (which causes electrolyte-free water retention), secretin also increases urinary water and salt excretion. In sum, secretin is critical to maintaining urinary volume, serum tonicity, and acid-base balance, particularly in response to a meal. How secretin is regulated in restrictive anorexics, and whether altered levels or response to this hormone could contribute to water dumping in this condition is unknown. Interestingly, however, neutralization of gastric acid prevents a postprandial rise in plasma secretin concentration and thus, if excessive secretin and/or response mediate the renal fluid losses observed in some restrictive anorexics, low-cost medications such as antacids, could be used to mitigate the fluid and acid-base derangements associated with refeeding. Secretin is an enteral hormone which is released in response to a meal and which regulates fluid homeostasis and renal bicarbonate excretion. Infusion of secretin into healthy volunteers results in significant renal fluid and electrolyte losses. In addition, secretin acts on type B beta intercalated cells in the distal convoluted tubule, stimulate renal bicarbonate excretion at that part of the nephron. Recent data demonstrate that altered response to secretin contributes to alkalosis in individuals with cystic fibrosis; its contribution to alkalosis in other conditions of metabolic alkalosis is unknown. Since secretin is 1) released in response to a meal, 2) regulates renal fluid and electrolyte dumping and 3) regulates renal bicarbonate excretion, altered secretin release or response is an attractive candidate for mediating the fluid losses and progressive increases in serum bicarbonate observed during refeeding in restrictive anorexics. Indeed, our data suggest that a link does exist between these two phenomena as net fluid balance in the first two days of refeeding has a positive correlation with change in serum bicarbonate concentration by day 6 of refeeding. These data suggest that regulation of serum bicarbonate is linked to fluid homeostasis during refeeding in restrictive anorexia and suggest that disordered secretin secretion and/or response could contribute to both phenomena. This pilot study will evaluate the metabolic response-defined by the change in serum secretin, change in serum pH, change in serum bicarbonate, and change in urine bicarbonate excretion-to a standard meal in 10 restrictive anorexics admitted for refeeding. 5 patients with a urine output > 3 cc/kg/hr on the first few hospital days and 5 patients with normal (<2 cc/kg/hr) urine output in the first few hospital days will be recruited for the study. Metabolic responses, as determined by blood measurements of secretin and both blood and urine measurements of acid/base status, will be determined before and after a standard meal on one hospital day (either on day 3 or on day 4 or on day 5 or on day 6 or on day 7). During subjects standard of care blood draw and before a meal, one additional teaspoon of blood will be drawn. Study tests will require one extra blood draw, consisting of 1 extra teaspoon of blood, and one extra urine collection 60 minutes after the meal. Admission BMI, current weight, gender, age, disease duration, and results from subject's standard of care pre feeding blood tests and urinalysis and will be recorded.

Official Title
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Secretin Levels in Refeeding-induced Polyuria (Cross Section)

Conditions
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Anorexia in Adolescence

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group 1: male and female patients age 13-24 years diagnosis of restrictive-type anorexia nervosa hospitalization for nutritional support >4 cc/kg/day of urine output (a.k.a. fluid dumpers; n=5) Group 2: male and female patients age 13-24 years diagnosis of restrictive-type anorexia nervosa hospitalization for nutritional support <2 cc/kg/d of urine output (a.k.a. non-dumpers; n=5) Exclusion Criteria: 5150 hold Anti-depressant, anti-psychotic, or anticonvulsant medications Previous hospitalization within the past 6 months Underlying metabolic disorder not related to anorexia nervosa (including chronic kidney disease, renal tubular disorders, and underlying endocrine disorders) Pregnancy NG or G-tube feeds after day 2 of hospitalization > 10% of nutritional needs from supplemental feeds

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| dumpers<br>male and female patients age 13-24 years diagnosis of restrictive-type anorexia nervosa hospitalization for nutritional support >4 cc/kg/day of urine output (a.k.a. fluid dumpers; n=5) | |
| non-dumpers<br>male and female patients age 13-24 years diagnosis of restrictive-type anorexia nervosa hospitalization for nutritional support <2 cc/kg/d of urine output (a.k.a. non-dumpers; n=5) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in secretin | Change in secretin value from pre- to post- meal | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum bicarbonate | Change in bicarbonate value from pre- to post- meal | 1 hour |