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.
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).
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.
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.
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.
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.
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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Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
Congenital chloride diarrhea; SLC26A3; Prognosis; Treatment outcome