Background

Gitelman's syndrome (GS), also called Gitelman's variant of Bartter's syndrome, is an autosomal recessive renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. GS is caused by inactivating mutations in the thiazide-sensitive sodium chloride cotransporter gene (NCCT). It is also known as the "milder" form of Bartter's syndrome, as patients with GS are usually diagnosed in adulthood during routine investigation. Symptoms reported in the literature range from asymptomatic, to mild symptoms of cramps and fatigue, to severe manifestations such as tetany, paralysis, and rhabdomyolysis. This is the first systematic evaluation of a large group of patients with genetically defined GS.

Methods

We evaluated the symptoms and quality of life (QOL) in 50 adult GS patients with confirmed mutations in NCCT, using a standardized questionnaire. This cohort was compared with 25 age- and sex-matched controls.

Results

GS patients were significantly more symptomatic than controls. The most common symptoms were salt craving, with musculoskeletal symptoms such as cramps, muscle weakness, and aches and constitutional symptoms such as fatigue, generalized weakness and dizziness, and nocturia and polydipsia. Forty-five percent of GS patients consider their symptoms a moderate to big problem. Measures of health-related QOL were significantly lower in GS patients compared with controls, particularly in terms of role limitations caused by physical health, emotion, level of energy, and general health perception.

Conclusions

This descriptive study indicates that GS is not an asymptomatic disease and adversely affects QOL in these patients. Further studies are needed to assess the impact of therapy on symptoms and QOL.

METHODS

Patients

The study population consisted of 50 adult GS patients from 36 kindreds in the United States, Canada, and England. They represent a cohort of patients diagnosed with GS referred to our institution between July 1, 1994, and November 30, 1997, for testing for mutations in NCCT, in whom such mutations were identified (discussed later in this article). Of the 50 GS patients, 44 were on some form of therapy for their disease at the time of the study. Such therapy included potassium (N = 44) and magnesium (N = 35) supplements, potassium-sparing diuretics (N = 24), nonsteroidal anti-inflammatory agents (N = 2), and angiotensin-converting enzyme inhibitors (N = 3), and several patients were on a combination of agents. The control group consisted of 25 normal volunteers from the Yale New Haven Medical Center area, matched for age and sex. The demographic characteristics of both groups are shown in Table 1.

Table 1 - Demographic characteristics of study population.

Full table

Symptom questionnaire

A standardized 117-item symptom questionnaire was administered by telephone interview in similar fashion to all participants by one of the investigators (A.J.S.), and the results of this survey form the substance of this report. Referring physicians were asked to provide information regarding patient symptoms at the time blood samples were submitted to our laboratory for genetic testing. Based on a review of over 200 clinical information sheets, the questionnaire was constructed to include all symptoms described therein. The questionnaire included an assessment of both frequency and severity of symptoms. Patients were asked in the questionnaire about their urinary habits. In order to compare the prevalence of symptoms between GS patients and controls, the following definitions were made a priori. Polyuria was defined as voiding urine at least five times during the daytime. Nocturia was defined as voiding at least once during sleeping hours; enuresis was defined as bedwetting past the age of 10 years. Polydipsia was defined as a self-reported fluid intake of "considerably more fluid than other people around him/her." A detailed dietary recall of the subject's food and fluid intake on the day prior to the interview was used to quantitatively estimate daily fluid intake^29,30. All percentages reported in Table 3 are based on the symptom questionnaire, with the exception of carpopedal spasm/tetany and paralysis. These were considered as specific medical conditions that can be correctly identified by only trained medical personnel; therefore, the prevalence of these two symptoms was based on physician reporting.

Table 3 - Prevalence of symptoms in Gitelman's syndrome.

Full table

Quality of life according to the patient's own perception was assessed using the RAND health survey, which comprised 36 items within the questionnaire^31,32,33. QOL scores range from 0 to 100, with higher scores reflecting a better QOL^31,32,33,34.

Genetic tests

Genomic DNA was prepared from venous blood samples by standard procedures³⁵. The mutations in NCCT were identified by single-stranded conformation polymorphism, using polymerase chain reaction (PCR) primers designed from intronic sequences surrounding all 26 NCCT exons, as previously described². The deletion of exons 1 through 7 in two subjects in this report was determined by the absence of PCR amplification of exons 1 through 7 using intronic NCCT primers and was confirmed by Southern hybridization of genomic DNA digested with Bgl II and hybridized to a ³²P-labeled cDNA probe corresponding to exons 1 through 7 of the NCCT gene. The mutations in this study population are listed in Table 2. These included missense variants (N = 57 alleles), splice site variants (N = 22 alleles), premature termination codons (N = 7 alleles), frame shift variants (N = 4 alleles), and deletion of exons 1 through 7 (N = 3 alleles). We identified only a single mutant allele in 7 out of 50 patients (patients 15, 31, 33, 35, 36, 47, and 50). The variants in these seven patients are present in at least one other GS patient tested in our laboratory and have not been detected in any of 160 chromosomes from unrelated Caucasian control subjects. Twelve of the patients in this study are homozygous for a specific variant Table 2, while the rest are compound heterozygotes. Six of the GS kindreds represented in this group have been previously reported².

Table 2 - Mutations in the thiazide-sensitive Na-Cl cotransporter gene (NCCT) in 50 patients with Gitelman's syndrome.

Full table

Laboratory tests

Gitelman's syndrome patients had laboratory values for plasma potassium, magnesium, bicarbonate, and urine calcium/creatinine ratios provided to the investigators at the time their blood samples were submitted for genetic testing. All patients exhibited hypokalemia (mean, 2.6 0.5 mmol/L), hypomagnesemia (mean, 1.2 0.2 mg/dL), and metabolic alkalosis (mean, 31.6 2.7 mmol/L). The mean urine calcium/creatinine ratio was 0.10 0.09 mmol/mmol. All control subjects had routine laboratory tests, including serum potassium levels, done in the course of their routine general medical care, and none have a history of hypokalemia.

Statistical analysis

The data are presented as mean SD, unless otherwise stated, or as percentages, where appropriate. QOL scores and symptoms in the GS and control groups were compared using Student t test for continuous variables, and chi square for categorical variables, with two-tailed P values. A similar analysis was performed comparing male and female GS patients.

The relationship between laboratory values (serum potassium, magnesium, and bicarbonate) and QOL was explored utilizing the Pearson correlation coefficient. In addition, GS patients were grouped into tertiles of serum potassium, magnesium, and bicarbonate levels. The QOL scores of lowest and highest tertile groups for each of these laboratory parameters were compared using the Student t test. To determine whether GS patients with more severe degrees of hypokalemia/hypomagnesemia/metabolic alkalosis are more symptomatic than other GS patients, symptom prevalence between the lowest and highest tertile groups of laboratory values were compared using chi square analysis.

Calculations were performed using SPSS 6.1 for Macintosh (SPSS Inc, Chicago, IL, USA). A P value of < 0.05 was considered statistically significant.

RESULTS

Symptoms

The prevalence of symptoms in this study is shown in Table 3. GS patients were more symptomatic than the controls for most complaints. Prevalence rates are based on the questionnaire, with the exception of carpopedal spasm, tetany, and paralysis, which are specific medical diagnoses and therefore based solely on physician reporting. The most common symptoms were salt craving, musculoskeletal symptoms such as cramps, muscle weakness, and pain, generalized weakness, and dizziness.

Musculoskeletal

The overall prevalence of cramps among our cohort of GS patients is 84%. Among these patients, approximately half experience these muscle cramps frequently, most commonly involving the legs and arms. Thirty-two percent of GS patients describe their cramps as being "moderate to very severe" in intensity. These cramps most commonly occur at night (26% of patients) or with moderate physical activity (17%), although there is no apparent precipitating factor in 33% of subjects. Similarly, muscle weakness affects mainly the legs (33%) and arms (16%), but many patients describe a "generalized" weakness. Three patients have presented with muscle paralysis at the time of diagnosis. Although the overall prevalence of fatigue was not significantly different between GS patients and control subjects Table 3, both the frequency and severity of the fatigue were worse in the GS patients. In terms of frequency, 22% of patients suffer from fatigue "all of the time," while none of the controls did so. In terms of severity, many GS patients also rated their fatigue as a "big problem," while none of the controls did this. Over half of the GS subjects suffered from joint pains, however, this was not significantly different from controls. Joint pains in GS patients affected mostly affecting the hands/fingers (25%) or knees (22%). Although chondrocalcinosis has been reported to occur in patients with GS^36,37,38, none of the current cohort had this condition.

Sixty-five percent of GS patients interviewed for this study had been brought to the emergency room (ER) for their symptoms. The most common symptoms prompting ER visits were cramps, generalized weakness, muscle paralysis, and vomiting. Of these patients, up to 82% had received intravenous potassium and/or magnesium at least once for their symptoms. Between 16 and 18% of our interviewed subjects had been to the ER five or more times for intravenous potassium and/or magnesium therapy. The four most severely affected patients described the following: going to the ER once a week for intravenous magnesium for "many" years (N = 1), going to the ER for intravenous potassium and/or magnesium every two to three weeks for three years (N = 2), and presenting to the ER three to four times per year with severe muscle weakness/"paralysis" (N = 1). These four patients reported compliance with their medical therapy. Whether intercurrent illness played a role could not be ascertained from the questionnaire.

Renal

Gitelman's syndrome patients voided urine more frequently than did control patients both during daytime hours (5.4 2.5 vs. 2.6 1.3 times/day, respectively, P < 0.001) and sleeping hours (2.6 1.1 vs. 1.2 0.4 times/night, respectively, P < 0.001). The prevalence of polyuria and nocturia in GS patients, as defined in Methods section, was 50 and 80%, respectively, significantly higher than controls Table 3. Three fourths of the GS patients reported feeling thirsty frequently. Sixty-five percent said they drink more than other people around them, which is represented in Table 3 as polydipsia. Their mean estimated daily fluid intake was higher than that of controls (2.43 1.28 vs. 1.89 0.42 L/day, respectively, P = 0.01). This intake was also higher than mean fluid intake in a large national health survey (NHANES III, 1.85 1.0 L/day)²⁹. Salt craving was also prominent in GS patients. When asked to describe food cravings, 64% of GS patients reported food habits such as drinking pickle brine, salting cucumbers, and craving for oranges and tomatoes, starting in childhood and persisting into adulthood. Four patients described salting lemons and sucking on them. Two patients described licking salt blocks used for livestock when they were young children.

Other

Paresthesias and palpitations occurred with some frequency in these GS patients. Overall, 45% of GS patients consider their constellation of symptoms as a moderate to big problem, with fatigue, cramps, and polyuria considered particularly bothersome by 20 to 36% of the subjects. Other symptoms volunteered by the patients included heat intolerance, forgetfulness, "decreased ability to concentrate," headache, and dyspnea. Four patients had seizures at least once in their lifetime, but to their knowledge, these were not directly attributed to their GS.

There was no significant difference in prevalence of symptoms between men and women. Because of anecdotal experience suggesting that symptomatology in women with GS is affected by their hormonal status, we included questions regarding this aspect. At the time of interview, 22 of the female GS patients were still having monthly menstrual periods. Of these, eight patients reported that their symptoms were worse during their menstrual period. A few of the women in this study are prescribed a "sliding scale" for their electrolyte supplements by their physicians, with a higher dose taken during their menstrual period. Of the 13 nonmenstruant women, 2 reported that their symptoms were better after menopause. Twenty of the women had children, of whom seven had complicated pregnancies. These complications included the need for intravenous fluids for dehydration, the need for intravenous potassium and/or magnesium administration, severe cramping, Sheehan's syndrome (infarction of the pituitary gland after substantial blood loss during childbirth), gestational diabetes, miscarriages in the first trimester, premature delivery, polyhydramnios, preeclampsia, and abruptio placenta. Other than the first two items, it is unclear whether any of these complications were related to GS. Six women were advised by their physicians to avoid future pregnancies because of their GS.

Gitelman's syndrome patients in the lowest tertile of serum potassium and magnesium were more likely to be diagnosed with hypotension (82 vs. 36%, lowest and highest tertile, respectively, P = 0.03). In addition, GS patients in the lowest tertile of serum potassium were more likely to have a moderate to big problem with cramps (73 vs. 18%; lowest and highest tertile, respectively, P = 0.01).

Quality of life

Measures of QOL were significantly lower in GS patients compared with controls, particularly in terms of role limitations due to physical health, and level of energy Table 4. Their self-assessment of general health was also quite low. A few patients noted that the cost of their medications and the large number of pills they had to take contributed in part to their low perception of their QOL. There was no significant difference in QOL between men and women with GS.

Table 4 - Quality of life health survey.

Full table

The relationship between laboratory values in GS patients and QOL scores was analyzed using Pearson correlation. There was no significant correlation between laboratory values and any of the QOL measures examined in this report. There was also no significant difference in QOL scores between patients at the lowest and highest tertile of laboratory values.

DISCUSSION

Gitelman's syndrome is often described as the milder adult form of Bartter's syndrome. Individuals affected with this disease are usually first diagnosed in adulthood, as opposed to "true" Bartter's syndrome, which usually presents in childhood^21,39. Review articles and editorials on this disease have noted that the syndrome is "characterized by a relatively mild course," that it is "often ... first discovered in adults during routine investigation," and that "many subjects are asymptomatic"^9,21,23. Case reports and series vary, however, from having "no symptoms of magnesium or potassium deficiency," "mild nonspecific symptoms," "mild weakness," "minor neuromuscular symptoms" to "frequent tetanic episodes, muscular weakness, or both"^{4,14,17,23,25}. Similarly, 15% of physicians who have referred their patients to us for genetic screening in NCCT have reported their patients as "asymptomatic," yet the current survey of GS patients presents a different picture. This descriptive study is the first to evaluate symptomatology and QOL in patients with genetically proven GS in a standardized comprehensive manner from the viewpoint of the patient.

Our findings indicate that the prevalence of patient-reported symptoms in GS is high and that this is not an "asymptomatic" disease Table 3. In fact, none of the patients interviewed were completely asymptomatic. This is in stark contrast to physician-reported symptoms, in which the prevalence of salt craving, cramps, and fatigue were 5, 13, and 17%, respectively, and as many as 15% were noted to have "no symptoms" (unpublished data). The frequency of symptoms is variable, and this may account in part for the discrepancy between patient- and physician-reported symptom prevalence. However, a significant percentage of patients rate their symptoms as being a moderate to big problem, again emphasizing the discrepancy between physician and patient perception. The most common symptoms are salt craving, musculoskeletal complaints, fatigue, and dizziness. Nocturia, polydipsia, polyuria, paresthesias, and palpitations are also prominent symptoms. Interestingly, fatigue and dizziness are also commonly reported side effects with hydrochlorothiazide therapy for hypertension⁴⁰. NCCT is the site of action of these diuretics, and the laboratory features of GS are similar to that of a patient on thiazides. GS patients rated fatigue, cramps, and polyuria as particularly problematic. However, many patients appear to adapt well to their symptoms, with the majority able to work full-time or part-time Table 1, probably contributing to the perception that this is an asymptomatic disease. The patients' description of their food cravings suggests that they compensate in part by self-selecting a diet high in sodium and potassium content. Although our results do not support a difference in symptoms between men and women, they do support the observation that premenopausal or postmenopausal status may have some effect on symptoms in women. The mechanism for the latter is not clear. Animal studies have shown a difference in NCCT density and thiazide diuretic response between genders⁴¹. Our study population has a large proportion of women, which may limit the detection of a gender difference. A study in ovariectomized rats showed an enhancing effect of estradiol on NCCT density in the distal tubule⁴². Our observations in humans may be relevant for future studies. GS also appears to be a disease that has an impact on health care costs, with a significant percentage of patients making ER visits, several on multiple occasions. One of the patients in our cohort was confined briefly in a psychiatric ward for suspected diuretic abuse². We noted a modest correlation between symptoms and laboratory values, in that patients with more severe degrees of hypokalemia and hypomagnesemia had a higher prevalence of hypotension and had a bigger problem with cramps. It is likely that the patients with more severe salt wasting have lower blood pressures and greater stimulation of the renin-aldosterone axis. We hypothesize that the greater degree of salt wasting results in delivery of a larger amount of sodium to the epithelial sodium channel in the cortical collecting tubule, with greater loss of potassium in exchange for sodium under the influence of aldosterone in this nephron segment. The role of magnesium in this setting is not clear.

Interestingly, QOL, never previously evaluated in patients with GS, appears to be adversely affected by this disease. GS patients have particularly low scores in terms of role limitations caused by physical health, emotion, level of energy, and general health perception Table 4. In fact, QOL is similar in range to that described for more "significant" diseases such as hypertension, diabetes, congestive heart failure, and coronary artery disease Table 5^{33,40,43,44,45,46}. It is also comparable to "chronic" lung and gastrointestinal disease in terms of physical function, pain, and general health perception, and slightly worse with respect to role limitation due to physical health, emotion, and social function⁴⁴. Perhaps this decreased QOL is related to the cost of medications, the large number of pills required to maintain their electrolytes within reasonable range, as suggested by some patients, and the limited understanding of their disease, among other factors. Looking at QOL in hypertensive patients with thiazide diuretics, GS patients had lower scores Table 5. This is not surprising since thiazide therapy appears to improve QOL in hypertension^40,46. Interestingly, we did not find a correlation between QOL measures and potassium or magnesium levels. Perhaps these analyses are limited by the number of subjects. Approximately 60% of patients noted that knowing the genetic basis for their disease has helped them cope with their illness, and have also improved their interaction with healthcare providers. When asked about their opinion on genetic research, almost all interviewees said they would recommend participating in a genetic study to other patients.

Table 5 - Quality of life in Gitelman's syndrome and other chronic diseases.

Full table

Although our study provides an insight to the spectrum of symptoms in GS, it is obviously limited to the symptoms of the participants, who all reside within the United States, Canada, and England. However, there is no apparent reason why their symptoms would be unique to these specific geographic areas only. We cannot exclude a selection bias; that is, patients who are more symptomatic may be more likely to be referred for genetic testing. However, since the referring physicians describe 15% of the patients as "asymptomatic" or "as incidental diagnosis," this implies that some of these patients were not being referred for genetic testing specifically because they were more symptomatic. Another limitation of the study is the use of a control group of normal volunteers from the New Haven area, which may not be representative of normal volunteers in other geographic areas. Although the ideal control group would be unaffected siblings who are homozygous wild-type for NCCT, this would be a difficult study to perform. Recognizing the limitations of our control group, the current study nevertheless provides valuable insight into the prevalence of symptoms in GS, from the patient's viewpoint. Further study is needed to determine the impact of treatment on the symptoms of this disease.

In summary, our findings demonstrate that GS is not an asymptomatic disease. It adversely affects QOL in these patients, to at least the same degree as more "significant" diseases like hypertension, diabetes, and cardiac conditions. These findings provide further insight and understanding of a disease that was previously dismissed as a "mild" disorder, and add a new dimension in the care of the patient with GS.

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Appendices

APPENDIX

The standardized questionnaire is available at the following Web site: http://www.kidney.med.yale.edu/Appendix.html.

Acknowledgments

The authors thank our patients for their invaluable contribution to this project; Drs. J.W. Balfe, D. Clive, H. Cushner, T. Dornan, J. Gill, H. Gitelman, S. Gluck, B Hoffbrand, K. Kamel, D. Kem, A. Moss, M. Parmar, D. Roer, R. Ruvalcaba, S. Soroka, M. Thorner, M. Turman, R. Unwin, and G. Wilkins for providing clinical data; Laura Burleson and Helen Brickel for their assistance with Website design, data collection and processing; and Carol Nelson-Williams for management of the DNA database. R.P.L. is an investigator of the Howard Hughes Medical Institute. The authors also thank the other members of the Yale Gitelman's and Bartter's Syndrome Collaborative Study Group, who are listed in the following website: http://www.kidney.med.yale.edu/acknowledgments.html.