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Long-Term Clinical Outcome in Patients With Congenital Chloride Diarrhea

Hihnala, Satu MD*; Höglund, Pia MD, PhD*; Lammi, Laura DDS; Kokkonen, Jorma MD, PhD; Örmälä, Timo MD, PhD§; Holmberg, Christer MD, PhD*

Journal of Pediatric Gastroenterology and Nutrition: April 2006 - Volume 42 - Issue 4 - p 369-375
doi: 10.1097/01.mpg.0000214161.37574.9a
Original Articles: Gastroenterology

Objectives: Congenital chloride diarrhea (CLD) is a rare, autosomal recessive disorder of intestinal Cl/HCO3 exchange caused by mutations in the SLC26A3 gene and characterized by persistent Cl rich diarrhea from birth. Treatment is symptomatic and replacement therapy with NaCl and KCl has been shown to be effective in children, but the long-term prognosis remains unclear. We studied the largest known cohort of patients to evaluate the long-term outcome of CLD and to search for extraintestinal manifestations.

Methods: This is a cross-sectional clinical evaluation and retrospective analysis of medical history of 36 Finnish patients with CLD, born in the 1960s (n = 8), 1970s (n = 7) and 1980s (n = 21).

Results: Early diagnosis and aggressive salt replacement therapy were associated with normal growth and development, in addition to significantly reduced mortality rates among the groups of patients born in the different decades, respectively (P = 0.001). No deaths due to CLD were observed after 1972. Enuresis, slight soiling and hospitalizations for gastroenteritis were common, especially in childhood, but 92% of the patients found their health excellent or good. Complications documented were end-stage renal disease (n = 1) and hyperuricemia (n = 4), novel findings possibly associated with CLD being male subfertility (n = 3), spermatoceles (n = 3), intestinal inflammation (n = 2), inguinal hernias (n = 4) and increased concentrations of sweat Cl in 12% of the patients.

Conclusions: When early diagnosed and adequately treated, the long-term prognosis of CLD is favorable. A putative role of a primary anion exchange defect of SLC26A3 in male subfertility and the decline of renal function due to chronic dehydration deserve further characterization.

*Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; the †Institute of Dentistry, University of Helsinki, Helsinki, Finland; the ‡Department of Pediatrics, University of Oulu, Oulu, Finland; and the §Department of Pediatrics, University of Kuopio, Kuopio, Finland

Received October 5, 2005; accepted January 11, 2006.

Address correspondence and reprints requests to Satu Hihnala, MD, Hospital for Children and Adolescents, P.O. Box 280 (Lastenlinnantie 11 C 22), FI-00029, Helsinki University Hospital, Finland. (e-mail:

Supported by a grant from the Foundation of Pediatric Research, Helsinki, Finland.

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Congenital chloride diarrhea (CLD; OMIM 214700), previously known as congenital alkalosis with diarrhea, is an autosomally recessively inherited disorder of the ileal and colonic epithelial Cl/HCO3 exchange, resulting in watery Cl rich diarrhea, hypochloremia, hypokalemia and metabolic alkalosis (1-3). Diarrhea begins in the uterus causing polyhydramnios and prematurity. Worldwide, about 260 cases have been reported with higher incidence in Finland (1:20,000-1:43,000), Poland, Saudi Arabia and Kuwait (4).

CLD is caused by at least 30 different mutations in the solute carrier family 26 member 3 gene (SLC26A3, alias CLD or DRA), and the V317del mutation has been found in 98% of all Finnish CLD-associated chromosomes (5-7). So far, no evidence of the phenotype-genotype correlation has been found (8). SLC26A3 encodes for a transmembranic Cl/HCO3 (or OH) exchanger mainly expressed in the apical brush border of the ileal and colonic epithelium (9). Extraintestinal expression of SLC26A3 has been found in the sweat gland and male seminal vesicle (10).

High fecal Cl concentration (>90 mmol/L) is the standard for diagnosis of CLD, although DNA analysis is also available (11). CLD is usually lethal if untreated, and those who survive with an undiagnosed disease are likely compensating their diarrheal losses by salty diet (11,12). Lifelong peroral replacement of salt and water remains the only treatment shown to be effective in larger series of patients (13). When combined with cholestyramine, temporary reduction of the diarrhea has been documented (14,15). In the late 1960s, the first patients treated by KCl substitution remained alkalotic, developed renal vascular changes and had high plasma renin and aldosterone activities (16). A combination of NaCl and KCl, introduced in the early 1970s, resulted in clear improvement in all parameters, and Cl doses of 6-8 mmol/kg/d for infants and 3-4 mmol/kg/d for older patients were found to be optimal for normal growth and development (13).

Renal injury is the major complication of inadequate therapy during childhood (16,17). Solitary reports of mental subnormality and hyperuricemia, teeth anomalies (deciduous teeth hypoplasia and other enamel defects) and an increased resistance to dental caries in patients with CLD have been published (18-20).

Today, all adequately treated patients with CLD reach adult life, but the long-term prognosis of this rare disease is unknown. In Finland, CLD is more common than elsewhere resulting in experience of treatment and follow-up of these patients. The major aims of this study were to describe the long-term prognosis of CLD and to search for other manifestations of this disease based on the extraintestinal expression of the SLC26A3 gene.

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We ascertained 46 Finnish patients with CLD and aged over 7 years through our previous genetic studies and in collaboration with the pediatric gastroenterologists of the university clinics. Of these, 7 refused to participate, 2 had been lost to follow-up and 1 had died accidentally. The remaining 36 patients, 20 females (56%) and 16 males (44%) with a median age of 20.5 (range, 10-38) years, were included. They belonged to 27 families, of which 4 families had 2 affected children and 3 families had 3 affected children. They all met the major diagnostic criteria for CLD with a typical clinical picture (prematurity, watery diarrhea from birth, tendency to hypochloremic metabolic alkalosis) and a high Cl content (>90 mmol/L) in feces. Molecular genetic analyses of the SLC26A3 gene were available in 31 patients (86%): 30 had a homozygous V317del genotype and 1 had a heterozygous V317del/344delT genotype.

The patients were divided into 3 subgroups according to their decade of birth (Fig. 1). Group 1960s (n = 8) included the first patients, and group 1970s (n = 7) the patients born in the 1970s, who were collectively treated at the Children's Hospital of the University of Helsinki until the age of 16. The youngest patients up to 21 years (group 1980s, n = 21) were born in 1980-1991 and had been individually treated by their closest university pediatric clinic.

FIG. 1

FIG. 1

All patients were interviewed and examined at the pediatric units of the university hospitals in Helsinki (n = 17, mean age of 22.6 years), Oulu (n = 12, mean age of 20.8 years) or Kuopio (n = 7, mean age of 25.0 years). Investigations included a 24-hour blood pressure registration, chest x-ray, electrocardiography (ECG) and renal ultrasound. Laboratory tests were total blood count, erythrocyte sedimentation rate, Astrup analysis, serum K+, Na+, Cl, uric acid, creatinine, urea nitrogen and aldosterone concentrations and plasma renin activity. For 2 different methods of aldosterone analysis (DiaSorin RIA and DPC RIA), a comparison was performed in the laboratory of the Helsinki University Hospital. Fecal K+, Na+ and Cl concentrations were measured (single specimen). Urine analyses (24-hour collection) included concentrations of K+, Na+ and Cl. A quantitative sweat test, stimulated by pilocarpine iontophoresis, was performed to document the Cl excretion by the sweat glands.

Current heights and weights were measured, and height standard deviation (SD) scores were compared with the Finnish standard values (21). In adults, body mass index (BMI) 19-25 kg/m2 was regarded as normal. In children, BMI cutoff points for overweight were determined according to the age and sex, and BMI <15th percentile was classified as underweight (22).

Twenty-eight patients participated in oral and dental examinations. Dental health was recorded by using the decayed, missed, filled surfaces of teeth index, and periodontal health was recorded by using the community periodontal index of treatment needs. The quality of dental enamel was visually evaluated and panoramic radiographs of dentition were obtained.

Medical data of the patients were collected from birth, including information on diagnosis, therapy, growth and clinical symptoms. The patients completed a questionnaire including experiences of therapy, compliance and dietary factors, assessment of their general state of health (5-step scale: excellent, good, satisfactory, relatively poor and poor), marital status, children, education and employment.

Numeric data were analyzed by using the Statistical Package for Social Sciences (SPSS) 10.0 statistical software. Differences between the data were determined 2 groups at a time by performing Mann-Whitney U test. Fisher exact test was performed to compare the differences in mortality between the groups. Calculated 2-tailed values of P < 0.05 were regarded as statistically significant.

The study protocol was approved by the Ethics Committee of the Hospital for Children and Adolescents, University of Helsinki. Informed consent was obtained from the patients and, when appropriate, from parents.

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Survival, Diagnosis, History of Therapy and Follow-Up

No deaths because of CLD were observed after 1972 (Fig. 1), and the mean age at the diagnosis of CLD was 2.7 (range, 0-59) months (Fig. 2). According to the past clinical guidelines, the patients born in the 1960s were treated with KCl during their first 4-10 years of life, whereas younger patients received increasing doses of NaCl and KCl from their diagnosis (Table 1). Most patients (81%) took their substitution therapy regularly, but 6 had frequent breaks (>2 weeks), which often coincided with the time when they took responsibility for the therapy themselves, at the mean age of 12.9 years. Most patients (97%) had been annually followed by a pediatrician until 20 years, but later 10 patients (28%) had irregular follow-up.

FIG. 2

FIG. 2



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Growth during the first 10 years of life is presented in Figure 3, and the mean current heights and BMIs are presented in Table 2. Mean relative height for all patients was +0.07 SD, the mean expected height being +0.17 SD. Altogether, 10 patients (28%) were slightly overweight and 5 patients (14%) were underweight; an 18-year-old female with severe malnutrition had a BMI of only 11.7 kg/m2.

FIG. 3

FIG. 3



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Diarrhea, Soiling and Enuresis

At the time of the study, all patients reported watery diarrhea 2-7 (mean 3.6) times a day. No correlation could be found between the age, number of stools, daily amount of peroral Cl substitution (0.9-5.3 mmol/kg) or fecal concentrations of electrolytes (Table 2). Short courses of cholestyramine (dose 2 g twice a day) were reported by 4 patients, all with a subjective reduction of the diarrhea for 2-4 weeks. Of dietary factors, bulk was reported to reduce the diarrhea by 14% of the patients.

Soiling was a common finding in all age groups: 53% aged under 20 years and 32% over 20 years reported occasional soiling during night time or during physical exertion. However, soiling was only mild, leading to slight wetting of pants but not to change of bed linen. Occasional enuresis was reported by 33% of the patients at school age, 28% at the age of 11 and 8% at the age of 15.

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Patients with CLD are vulnerable to dehydration and hypoelectrolytemia during acute gastroenteritis (AGE), and all but 1 patient had been hospitalized for AGE. Five patients (14%) had experienced at least 1 faint or convulsion associated with dehydration and hypokalemia, the most severe episode had resulted in outpatient resuscitation. Hospitalizations for AGE were most common in early childhood with a mean 3.6(SD = 2.7) episodes during the first 5 years of life. Later in life, the incidence was 2.1 (SD = 2.6) hospitalizations between 6 and 10 years and 1.5 (SD = 2.0) hospitalizations between 11 and 20 years. In adulthood, only 4 patients had required hospitalization due to AGE.

Urinary tract infections (range, 1-16 per patient) were documented in 13 patients (36%), of them 5 belonged to group 1960s, 3 belonged to group 1970s and 6 belonged to group 1980s. The mean number of urinary tract infections per patient during the first 10 years of life was significantly higher in group 1960s than in group 1980s (P < 0.01).

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Current Laboratory Data and Substitution Therapy

The youngest patients (group 1980s) had the most optimal electrolyte and acid-base balance, reflected by the finding that there were no hypokalemic, hypochloremic or alkalotic patients in this group, and all had adequate secretion of Cl in the urine (Table 2). Of other laboratory tests, total blood counts were normal but elevated erythrocyte sedimentation rates (>30 mm/h in 4 patients) were found in 10 patients. Serum creatinine and urea nitrogen were normal in all but the single patient with a renal transplant, creatinine concentration of 455 μmol/L and urea nitrogen of 45 mmol/L.

Current daily doses of Cl were 0.9-5.3 mmol/kg/d, the mean being 2.8 mmol/kg/d, and no differences were observed between the groups. The number of substitution doses per day ranged from 2 to 5, taken as a ready-made solution (n = 26) of NaCl 18 g/L (308 mmol/L) and KCl 19 g/L (255 mmol/L) or as individual dose bags (n = 10) diluted in a glass of water. Substitution therapy was well tolerated; only 2 patients (6%) reported occasional intestinal complaints after ingestion of salt.

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Extraintestinal Problems

Other diseases are summarized in Table 3.



One patient had developed an end-stage renal disease and needed renal transplantation. He had hypertension, gouty arthritis and a serum urate level of 548 μmol/L despite allopurinol medication. Three additional patients in group 1960s were hyperuricemic (364, 484 and 576 μmol/L) without clinical manifestations of gout, but renal calcifications were seen in ultrasound in 2 of them. The mean concentration of serum urate was significantly lower in group 1980s as compared with group 1960s (P < 0.05) and 1970s (P < 0.05).

As a decline in renal function and elevated plasma renin levels are thought to predispose these patients to hypertension, we performed a 24-hour blood pressure registration, chest x-ray and ECG. Only the patient with a renal transplant showed mild hypertension with a mean blood pressure of 124/89 mm Hg and pulse rate of 79 beats per minute despite carvedilol therapy. Chest x-rays and ECGs were normal in all patients.

Sweat test was performed because of the expression of SLC26A3 in the sweat gland (10). Mean Cl concentration was 36 (range, 8-70) mmol/L; 64% had a concentration below 40 mmol/L, 24% between 40 and 60 mmol/L and 12% above 60 mmol/L. When screening cystic fibrosis with the sweat test, a concentration <40 mmol/L is regarded as negative, and >60 mmol/L is regarded as consistent with the disease (24).

Only 2 of the 8 adult males had children, 1 after in vitro fertilization, and 3 males reported infertility. Altogether, 7 women had 14 healthy children after uneventful pregnancies.

Previous report suggested that patients with CLD may have better dental and oral health, perhaps due to flushing effect of peroral solutions (20). We found good dental and oral health in our patients with low decayed, missed, filled surfaces of teeth index (10.1) and community periodontal index of treatment needs figures, indicating a good periodontal state. Moderate enamel defects, such as pits or isolated hypoplastic defects, were seen in 43%, minor forms including opacities were seen in 25% and faultiness of dental enamel were seen in 32%. Three patients had a permanent tooth congenitally missing and a 37-year-old female had a sialolith in the right submandibular duct.

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Quality of Life

According to the questionnaires, 31% regarded their health as excellent and 61% as good. Two patients defined their health as satisfactory and only 1 as poor. Most patients had adjusted to their diarrhea experiencing only minimal social disadvantage, and only 3 young adults (8%) with frequent soiling problems found the diarrhea disturbing. None had marked abdominal distention.

Most patients (89%) had followed general education, and indications for some special education in comprehensive school were moderate learning difficulties (n = 3) and mild sensorineural hearing loss (n = 1). At the time of this study, 11 patients (30.6%) attended comprehensive school, 20 (55.6%) had vocational studies or education and 5 (13.8%) were university students or had an academic degree. One patient was unemployed. Of 19 adult patients, 6 (32%) were married and 6 (32%) lived in a permanent relationship.

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During the last 40 years, CLD has changed from a mostly fatal disorder to a treatable disease with an established genetic basis. This is the first report of the long-term outcome of CLD, based on a cross-sectional clinical and laboratory evaluation and a retrospective analysis of the medical data of 36 Finnish patients. The patients represented 80% of all Finnish patients aged over 7 years and were divided into 3 groups according to their decade of birth. High infant mortality (45%) in the 1960s and refusal (23%) in the 1970s were the most substantial reasons for nonparticipation and modulated the final sampling from each subgroup, which were 40%, 54% and 95% of the patients born in the 1960s, 1970s and 1980-1991, respectively (Fig. 1).

After the introduction of the salt substitution in the late 1960s, only 2 infants have died of probable CLD in Finland (Fig. 1). If undiagnosed, CLD is usually lethal, and only 2 Finnish patients are known to have survived undiagnosed to 1 year of age. In Finland, CLD is nowadays easily recognized by pediatricians and obstetricians based on polyhydramnios and fluid-filled intestinal loops in the ultrasonic investigation (25). Consequently, the diagnoses have been made significantly earlier during the last decades (Fig. 2). Diagnostic pitfalls include food allergies (as in one of our patients), intestinal obstruction (as Hirschsprung disease), malabsorption syndromes, infectious diarrheas and other inherited diseases with osmotic diarrhea (26-29).

The main goal of the salt substitution is to maintain normal growth, acid-base and electrolyte balance and excretion of Cl into urine. Earlier, "KCl-only" therapy poorly met these requirements, and early growth retardation was common in the 1960s (Fig. 3). However, normalization of growth was observed in all compliant patients when therapy consisted of a combination of NaCl and KCl. We found that salt replacement therapy has become more aggressive during the last decades, especially in childhood, although the increase of dosage during rapid growth and later in life is often missed. Therefore, the current mean dose of Cl in our patients was only 2.8 mmol/kg/d, whereas the recommended dose for adults is 3-4 mmol/kg/d (13). Consequently, signs of undersubstitution were common: growth was slightly retarded in 22%, abnormal laboratory values were observed in 60% (Table 2) and one fourth reported consumption of salty food. Accordingly, we increased the mean daily dose of Cl in 24 (67%) patients to a minimum dose of 3.0 mmol/kg/d or over if low urinary Cl, low serum K+ or metabolic alkalosis were observed.

Therapies for the diarrhea itself have turned out to be imperfect. Cholestyramine has been shown to reduce the diarrhea but the effect fades during a few weeks (14,15). This was also observed by our patients, of which 4 reported occasional use of cholestyramine, for example, in situations when they want to be sure not to soil. However, severe soiling problems seem to disappear before adulthood, and 92% of our patients found their general health as excellent or good. Omeprazole has also been tried for therapy, but often with a less clear effect on the amount of the diarrhea, provided the dose of concurrent salt substitution has been optimized (8,30). Recent report of butyrate therapy in a single Italian patient showed significant reduction of stool volumes and deserve further characterization among larger set of patients with CLD (31). Butyrate is formed in the large intestine by fermentation of diet fiber, and it may increase the absorption of water and electrolytes in the intestinal epithelium (32). In this study, 14% of the patients found that bulk reduces their diarrhea, but whether additional diet fiber plays a role in the reduction of the diarrhea in CLD remains to be clarified.

Altogether, 10 patients (28%) had an elevated erythrocyte sedimentation rate (>30 mm/h in 4 patients), indicating an inflammatory response without a clear focus. Only solitary cases of intestinal inflammation were found, and the link with CLD remains unsure. One female had Crohn disease and infliximab treatment, and another had unspecified colitis, frequent watery diarrhea (6-7 times/d),soiling problems, enuresis and weight deficit (BMI 11.7 kg/m2) requiring intermittent parenteral nutrition. Despite extensive investigations, no other disease than CLD and unspecified colitis had been diagnosed in this 18-year-old female with a common homozygous V317del mutation of the SLC26A3 gene, as found also in her sister with totally uneventful course of CLD.

None of our patients had developed malignancy, although a slightly elevated risk to gastrointestinal malignancies has been proposed (33). Instead, AGEs may be potentially life-threatening in patients with CLD due to a susceptibility to rapid dehydration, hypokalemia and alkalosis, and this tendency was found to persist throughout life, although with less frequent episodes. During AGE, most patients have learned to take an extra substitution dose per day to prevent dehydration.

Without adequate therapy for CLD, chronic intravascular contraction is known to lead to hyperaldosteronism, hyperreninism and reduced glomerular filtration rate (13,16,17). We found slight hyperreninism and/or hyperaldosteronism in 7 patients, but serum creatinine and urea nitrogen were within normal limits in all but 1 patient who had developed terminal uremia.

Hyperuricemia has been previously reported in a single patient and was found to be common among older patients in this study; however, only 1 patient had gouty arthritis (19).

Dental and oral health was good agreeing with our previous report from early childhood, but as the prevalence of dental caries has decreased in Finland during the past decades and considering the wide range of age of the studied patients, it is difficult to say how much the studied group differ from their present day peers (20).

Allergic diseases including hay fever, asthma and atopic eczema were common, but not related with CLD, as the prevalence of atopic disease is high in Finnish population (34).

As novel complications of CLD, we found inguinal hernias and spermatoceles more common than in the general population (35,36). Four of 16 males had been operated for inguinal hernia, 3 of them in infancy, giving figures 10 times higher than in an unselected pediatric population. Intra-abdominal pressure is a likely contributor in the pathogenesis of hernias, but for the spermatoceles, found in 3 adult males, the pathogenesis is less evident.

For the first time, we found evidence for extraintestinal manifestations of CLD, probably caused by loss of functional SLC26A3 in the male reproductive tract and in the sweat gland, where its expression has been reported previously (10). Altogether, 38% of the adult males in this study reported infertility, and a primary role for SLC26A3 in male reproduction is yet to be characterized in detail, but an analogous defect in water and electrolyte transport in reproductive tissues expressing SLC26A3 is possible. Similarly, we found increased concentrations of sweat Cl among 12% of the patients, suggestive for a minor role for SLC26A3 in the sweat gland. The cystic fibrosis transmembrane conductance regulator is the major protein mediating thermoregulation and salt retention through the sweat glands, and thus any minor loss of salt due to defective function of SLC26A3 is likely to be compensated. This is especially true at rest but may require notification on physical exertion, reflected by the patients who have found it beneficial to add salt substitution during excessive sweating. As the incidence of cystic fibrosis is very low in Finland (1:25,000), screening for cystic fibrosis transmembrane conductance regulator mutations because of these abnormal values of the sweat test is not indicated (37).

It is worth remembering that our results are related to a highly homogenous population of Finnish patients with identical genetic background of CLD. There has been no evidence of phenotype-genotype correlation of CLD so far, but it has not been excluded that patients with CLD and other than the Finnish V317del mutation may have a different clinical course of the disease (8).

In conclusion, our results emphasize the importance of early diagnosis and adequate treatment of CLD, allowing normal growth and development. Renal pathology and male subfertility need to be further studied, and a favorable effect of butyrate on the diarrhea needs to be tested in a larger population. Meanwhile, patients with CLD, their families and physicians can be assured that normal life is expected with adequate salt substitution therapy and compliance.

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We regret to say that during the publication process, Dr. Jorma Kokkonen passed away. The authors thank Päivi Ollila, Panu Rantonen and Sinikka Pirinen for helping in dental examination and analysis, and Esa Hämäläinen for comparison of aldosterone measurements.

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Congenital chloride diarrhea; SLC26A3; Prognosis; Treatment outcome

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