Extracellular Calcium Dictates Onset, Severity, and Recovery of Diarrhea in a Child with Immune-Mediated Enteropathy

Abstract

Diarrhea causes monovalent and divalent ion losses that can influence clinical outcome. Unlike the losses of monovalent ions, such as Na⁺, K⁺, Cl^-, and [Formula: see text], which are generally large in quantity (osmoles) and therefore determine the severity of diarrhea, the losses of divalent ions are relatively small in osmoles and are often overlooked during diarrheal treatment. Studies now suggest that despite divalent ions being small in osmoles, their effects are large due to the presence of divalent ion-sensing receptors and their amplifying effects in the gut. As a result, losses of these divalent ions without prompt replacement could also significantly affect the onset, severity, and/or recovery of diarrheal disease. Herein, we report a case of a malnourished child with an immune-mediated enteropathy who developed episodes of "breakthrough" diarrhea with concurrent hypocalcemia while on appropriate immunotherapy. Interestingly, during these periods of diarrhea, stool volume fluctuated with levels of blood Ca²⁺. When Ca²⁺ was low, diarrhea occurred; when Ca²⁺ levels normalized with replacement, diarrhea stopped. Based on this and other observations, a broader question arises as to whether the Ca²⁺ lost in diarrhea should be replaced promptly in these patients.

Keywords: calcium; calcium metabolism; calcium-sensing receptor; diarrhea; immune-mediated enteropathy; inflammatory bowel disease; intestinal barrier function; ion transport.

Figure 1

Diarrhea response and fluctuation of laboratory values prior to and post calcium replacement. Stool output (A) does not vary with blood levels of tacrolimus (C) but fluctuates with blood concentrations of Ca²⁺ ([Ca²⁺]) (B) on three occasions and via two routes of administration. Upon switch to a dairy-free diet, [Ca²⁺] reduces and diarrhea occurs. With intravenous CaCl₂, [Ca²⁺] rises and stool output declines. With oral CaCO₃, [Ca²⁺] rises again and stool output yet declines again. The corresponding alterations in other laboratory values are shown in (D,E). The values between the upper lines (upper normal limits) and lower lines (lower normal limits) are normal, whereas the values above the upper lines are elevated and those below the lower lines are reduced. The two gray areas illustrate the periods in which the patient was receiving calcium therapies. The form of calcium salts and their doses administered are indicated in the black boxes. It is likely that under a negative status of calcium balance, the diarrhea-combating ability of the divalent mineral is compromised, and the responsiveness to immunomodulators is lost. As a result, disease is “flared up” and the patient becomes diarrheic. Diarrhea will temporarily be halted upon normalization of calcium level. However, the disease will relapse and will not enter a permanent remission state unless a normal positive calcium balance is restored.

Figure 2

The correlation between serum Ca²⁺ concentrations ([Ca²⁺]) and daily stool outputs. The total serum [Ca²⁺] is shown. The linear regression was performed using Microsoft Excel 2016 for Windows, while the statistical analysis was performed using GraphPad Prism version 6.07 for Windows (GraphPad Software, San Diego, CA, USA). The fluctuation in stool output is correlated significantly with the change in total (r = −0.5818, P = 0.0181) and ionized (r = −0.8396, P = 0.0365, data not shown) serum [Ca²⁺] in a negative manner.