This document discusses chloride losing diarrhoea (CLD), a rare genetic condition caused by mutations in the SLC26A3 gene. It causes watery diarrhoea from birth and metabolic alkalosis due to excessive chloride loss. It can lead to dehydration, electrolyte abnormalities, and long-term complications affecting the kidneys and male fertility if not managed properly. Treatment involves oral and intravenous salt replacement therapy with sodium chloride and potassium chloride to prevent dehydration and metabolic alkalosis. Additional treatments including proton pump inhibitors, oral butyrate, and cholestyramine may help reduce diarrhoea. With prompt treatment and management of electrolyte losses, outcomes have improved from fatal to now treatable

1. Chloride Losing
Diarrhoea
Dr Prakash. I

2. Introduction
 Rare
 Difficult to diagnose and manage
 AR inheritance
 1945-Holmberg, Wedejoja et al- watery diarrhoea + high chloride
content of stool + metabolic alkalosis: “metabolic alkalosis with
diarrhoea” or “congenital chloridorrhea”
 Finland 1960s- Finland- “CLD/ CCD”
 genetic origin
 Treatment

3. Incidence
• Kuwait- 1/3200 Single cases may appear world wide
• Saudi Arabia -1/5000 Mutation analysis –in low incidence countries
• Finland-1/30,000-40,000
• Poland -1/200,000

4. Pathophysiology
 Function of chloride
 Regulate cell volume
 Fluid secretion
 Acid base balance
 Defect: SLC26A3 (solute carrier
protein), loss of SLC26A3
mediated transport
 Diarrhoea
 Secretory (large volume,
NPO no effect)
 Osmotic (low volume)

5. Pathophysiology cont…..
 SLC26A3 gene (family of 26 member, >30 mutations) encodes for
a trans-membrane protein {apical epithelial (Cl⁄HCO3)
exchanger}
 Result:
 defective Gut absorption of Cl and secretion of HCO3
 The coupled epithelial Na+⁄H+ transport through the
Na+⁄H+ exchangers (NHE2 and⁄ or NHE3) is defective
& leads to
 intestinal loss of both NaCl, fluid
 watery Cl rich diarrhoea.

6. At birth
 Distended abdomen
 Visible peristalsis
 Most are LBW
 d/d: intestinal obstruction
 D1: Profuse watery diarrhea
?????urine, misdiagnosed as
delayed passage of meconium

7. CCD Vs GI obstruction
 Family history (AR)
 Local demographics
 Normal peristalsis
 ANSS:
 Generalized dilatation of gut
with polyhydramnious
 Increase chloride in AF

8. Diagnosis
 Typical clinical picture:
 Watery diarrhea since birth
 Metabolic alkalosis
 High fecal chloride >90 mmol/L
 fecal pH between 4 and 6
 Genetic testing for mutation
 If excessive fluid loss and salt depletion*:
 ↓diarrhea & low faecal Cl of even 40 mmol/L
 Repeat faecal samples for diagnosis
 >3 months of life:
 diagnosis by high fecal chloride concentration

9. In the 1st hour after birth
Dehydration, Hypochloremia, Hyponatremia,
Activate renin-angiotensin system
Hyperaldosteronism (compensatory mechanism) →K+ depletion and metabolic
alkalosis
Laboratory findings (untreated): hypochloraemia, hypokalemia and metabolic
alkalosis

10. Immuno-histochemical staining of the congenital chloride
diarrhea protein. A) Normal colon (left). B.) CCLD (right).

11. Complications
 Diarrhoea and fecal incontinence-
 Life long
 No of stools: 2-7L/day
 Renal injury-
 Major complication
 Chronic hypovolemia →secondary effects
 ↑ renin, aldosterone with secondary hyperaldosteronism
 Vascular changes –hypertensive changes (±BP)
 Chronic K+ loss→ impaired function of renal tubular and
intestinal absorptive cells

12. Complications……..
 Male subfertility –
 low concentration of poorly motile spermatozoa
 abnormal morphology +
 high seminal chloride with low pH
 large bilateral spermatoceles
 Hyperuricaemia & gout –
 age dependent increasing risk
 Sweat gland-
 increased chloride (similar to CF)

13. Management
 Neonatal period: NaCl and KCl added to IV
maintenance fluids
120-300 mL/day (patients aged 0-7 days)
500-700 mL/day (patients aged more than
7days)
Bicarbonate free fluid
 IV → PO: Q8/Q6 H
Salt substitution therapy (NaCl and KCl)

14. Salt replacement therapy
 ↑ intestinal absorption (mechanisms-not known)
 Inhibits development of hypochloraemic and hypokalaemic metabolic
alkalosis
 Despite t/t:
 Diarrhoea is persistent (defective SLC26A3-mediated anion transport
remains in the intestine)
 ↑ age: ↓ in amount of stools & electrolytes, but continuous loss of Cl
 Insufficient replacement: Cl-free urine*
 Adequate salt replacement: excretion of Cl in urine, ± electrolyte and
acid base status
The rationale:

16. Proton pump inhibitor (Omeprazole)
 Inhibition of gastric chloride secretion
protect endogenous chloride stores
reduce the amount of chloride presented to the
intestine
 ↓ in volume and frequency of stools
 Cessation of incontinence

17. Oral Butyrate
 Short-chain FA
 Easily administered
 Prevent severe dehydration episodes
 Stimulates intestinal water and ion absorption (activation of a
parallel Cl-/butyrate and Na+/H+ exchanger, inhibit both basal
and adenosine 3’,5’-cyclic monophosphate–stimulated Cl
secretion)
 Trophic effects : mediated through circulatory, hormonal, and
neural mechanisms

18. Cholestyramine
 Binds bile acids → reduces intestinal secretion
 Moderate reduction in diarrhoea (for 2 to 4
weeks)

19. Outcome
 From fatal → treatable disease
 Prompt recognition and management of
electrolyte loss
↓Constant dehydration
↓Dys/Hypoelectrolytemia
↑growth and development
↓Renal involvement
↓Activation of renin aldosterone system