This is a mechanism module, not a specific disease. It models one conserved mechanism - loss of an apical intestinal electrolyte-transport step producing luminal electrolyte retention - and is the deliberate complement of diet_induced_osmotic_diarrhea, which models loss of a substrate-specific step handling an ingested NUTRIENT. The two are kept separate because the current CODE nosology separates them (PMID:29654747), and the separation is operational, not cosmetic: diet-induced diarrhea has a high stool osmotic gap and remits on eliminating the offending nutrient, whereas the diarrhea modelled here has a low stool osmotic gap and persists through complete bowel rest. A disorder must not conform to both for the same node. Note that the older "secretory" label for this class is imprecise and is avoided here: in both curated conformers the primary lesion is failure of ion ABSORPTION, not active anion secretion, and PMID:29654747 makes exactly this point in proposing the electrolyte-transport-related term. Active secretion does contribute in the GUCY2C arm, where excess cyclic GMP hyperactivates CFTR, but even there it is additional to, not a substitute for, the absorptive failure. This module also excludes the enterocyte-structural and trafficking enteropathies (microvillus inclusion disease, congenital tufting enteropathy), where ion-transporter abnormalities are real but are downstream consequences of losing or disorganising the apical membrane rather than the primary lesion; and it excludes immune-mediated enteropathy and barrier injury, which intestinal_barrier_dysfunction covers. Key disease-specific substitutions: congenital chloride diarrhea substitutes DRA/SLC26A3, luminal chloride, and the alkalotic arm; congenital sodium diarrhea substitutes NHE3/SLC9A3 (or its constitutive inhibition by activating GUCY2C), luminal sodium, and the acidotic arm. Modules bind GO and CL terms only and do not use chemical (CHEBI) or disease (MONDO) term bindings; ion and drug chemistry is described in prose, except in the treatments block where the therapeutic agent carries a CHEBI/NCIT identifier per the treatment schema.
Loss of an Apical Intestinal Electrolyte Transport Step
trigger
The shared upstream lesion. A single electrolyte-transporting activity is lost from the apical membrane of the ileal or colonic epithelium, while the mucosa remains structurally intact and the rest of the absorptive machinery continues to work. Two transporter identities are curated. Loss of the sodium-independent chloride/bicarbonate exchanger DRA abolishes the major chloride-absorbing step of the distal intestine. Loss of the sodium/proton exchanger NHE3 abolishes the principal route of electroneutral sodium absorption; notably this can arise either from direct loss-of-function variants in the exchanger or from an activating variant in guanylate cyclase C upstream, because NHE3 is a downstream target of GC-C and excess cyclic GMP inhibits it. That a gain-of-function lesion and a loss-of-function lesion converge on the same failed step is what establishes this node as a functional rather than a genetic category.
Downstream
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Luminal Electrolyte Retention and Failure of Net Ion Absorption
Show evidence (3 references)
"A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate."
Establishes the chloride/bicarbonate arm of this trigger as a major intestinal transport function whose loss causes disease.
"SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger."
Establishes the sodium/proton arm of this trigger and identifies NHE3 as the major brush-border exchanger.
"This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD"
Supports treating NHE3 loss-of-function and upstream GC-C gain-of-function as one functional lesion, since NHE3 is a downstream target of GC-C.
Luminal Electrolyte Retention and Failure of Net Ion Absorption
central effector
The rate-limiting, disorder-agnostic node and the key conformance target. Whichever transporter is lost, the ion it handled accumulates in the intestinal lumen because no alternative route can clear it at physiological rates. The critical property distinguishing this node from its counterpart in diet_induced_osmotic_diarrhea is the source of the retained solute: it is an ion secreted and recycled by the body itself, not a nutrient that arrives only with feeding. Luminal ion load is therefore set by endogenous secretion and total salt turnover rather than by any single dietary constituent, which is why withholding feeds does not stop the diarrhea and why no elimination diet is therapeutic. In the GUCY2C arm, cGMP-driven CFTR hyperactivation adds actively secreted chloride to the retained load.
Downstream
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Obligated Water Loss and Feeding-Independent Watery Diarrhea
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Ion-Specific Systemic Depletion and Acid-Base Derangement
Show evidence (2 references)
"We prefer to use the term electrolyte-transport-related diarrhea. Examples include congenital chloride or sodium diarrheas."
Names the class this module models and gives its two members - exactly the module's conformers - as the defining examples. Evidence source is OTHER because this is a review proposing the current CODE classification.
"it does not describe the watery high-salt diarrheas caused by defects in intestinal sodium absorption"
Supports the module's insistence that the lesion is failure of ion ABSORPTION rather than active secretion, which is why the older "secretory" label is avoided here.
Obligated Water Loss and Feeding-Independent Watery Diarrhea
effector
Retained luminal ions are osmotically active and obligate water, giving high-volume watery stool from the perinatal period. Fluid loss typically begins before birth, so both conformers can present prenatally with polyhydramnios and dilated fetal bowel loops that mimic intestinal obstruction. The stool osmotic gap is low - the measured stool osmolality is largely accounted for by the retained electrolytes themselves - which is the laboratory finding that separates this class from the diet-induced diarrheas at the bedside.
Show evidence (2 references)
"The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content."
Documents the chloride arm of this node - lifelong watery diarrhea whose ion content reflects the retained luminal electrolyte.
"perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion"
Documents the sodium arm of this node with the same structure - persistent watery stool carrying a disproportionate load of the retained ion.
Ion-Specific Systemic Depletion and Acid-Base Derangement
effector
The second output, and the one that makes the module clinically discriminating. Continuous stool loss depletes the ion the failed transporter handled, and the acid-base consequence follows from that transporter's coupling partner rather than from the diarrhea itself. DRA absorbs chloride in exchange for secreted bicarbonate; when it fails, chloride is lost in stool and bicarbonate is retained, which with volume-contraction-driven secondary hyperaldosteronism gives a hypochloremic, hypokalemic metabolic ALKALOSIS. NHE3 absorbs sodium in exchange for a secreted proton; when it fails, sodium is lost and the proton is retained, giving hyponatremia with metabolic ACIDOSIS. The two conformers therefore diverge in opposite acid-base directions from one shared mechanism - a genuinely predictive consequence of the module rather than a descriptive coincidence, and the fastest way to tell the two disorders apart before genetic results return.
Downstream
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Electrolyte Crisis, Growth Failure and Long-Term Morbidity
Show evidence (2 references)
"secondary volume contraction with the development of metabolic alkalosis, electrolytes imbalance, failure to thrive"
Documents the alkalotic arm of this node in the chloride conformer.
"hyponatremia, metabolic acidosis, and low-to-normal urinary sodium concentrations"
Documents the acidotic arm of this node in the sodium conformer, with low-to-normal urinary sodium confirming the loss is enteric. Together with the alkalosis evidence above this establishes the mirror-image relationship the node asserts.
Electrolyte Crisis, Growth Failure and Long-Term Morbidity
consequence
The clinical output. Untreated, both conformers are fatal in infancy from volume contraction and electrolyte imbalance; treated, both cause failure to thrive and carry long-term morbidity from chronic hypovolemia and electrolyte disturbance, including renal impairment. The therapeutic asymmetry is instructive and is preserved by the module's node structure: replacing the lost ions corrects the systemic arm and is life-saving, but does nothing to the luminal retention node, so stool volume is unchanged and the daily burden of diarrhea persists. Only an intervention acting on the transport step itself, such as butyrate in chloride diarrhea, reduces stool output.
Show evidence (2 references)
"Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition."
States the early mortality risk of this node and the enteral adaptation achievable by survivors.
"The quality of life in CLD patients is negatively influenced by the elevated number of evacuations a day and the fecal incontinence"
Documents the residual disease burden that persists once electrolytes are corrected, supporting the therapeutic asymmetry this node describes.
Oral Electrolyte Substitution
Platform:
Other
The shared, life-saving supportive treatment across the class: oral or parenteral replacement of the ion lost in stool, with correction of the accompanying acid-base derangement - chloride and potassium salts in congenital chloride diarrhea, sodium with correction of acidosis in congenital sodium diarrhea. It is deliberately modelled as acting on the systemic node rather than the central effector, because that is precisely its scope and its limit: it normalises electrolytes and transforms survival while leaving luminal electrolyte retention, and therefore stool volume, untouched.
Sodium Butyrate (Transporter-Directed Therapy)
Platform:
Small molecule
The one curated intervention that acts on the transport step itself rather than compensating for its consequences, and therefore the only one that reduces stool volume. In congenital chloride diarrhea, oral sodium butyrate increases SLC26A3 expression and reduces DRA mistrafficking and misfolding while also stimulating alternative chloride-absorbing transporters. Efficacy is genotype-dependent, best where a residual mutant protein exists to be rescued. This pattern is specific to the chloride conformer: no equivalent transporter-directed therapy is established for the sodium conformer, and conforming disorders do not inherit it.