Abstract
Liddle syndrome (LS) is an autosomal dominant genetic disorder characterized by early onset hypertension, hypokalemia, and low plasma aldosterone or renin concentration. It is caused by mutations in subunits of the epithelial sodium channel (ENaC). The clinical phenotypes of LS are variable and nonspecific, making it prone to both misdiagnosis and missed diagnosis. Genetic analysis is necessary to confirm the diagnosis of LS. Herein, we report the case of a 42-year-old male with LS and a 30-year history of hypertension. He was being treated for possible primary aldosteronism (PA) over the preceding 7 years; however, his hypertension was poorly controlled despite intensive combination therapy. His 13-year-old son served as a proband for a diagnosis of LS, as he had hypertension, hypokalemia, and a significant family history of hypertension. Genetic testing revealed a heterozygous pathological variant in the SCNN1B gene. This led to a diagnosis of LS, as the father was found to harbor the same mutation. Both were treated with ENaC inhibitors and a salt-restricted diet, which improved their symptoms markedly. The son’s genetic diagnosis facilitated the subsequent proper diagnosis and treatment of his father. LS causes early onset hypertension; hence, its early diagnosis and treatment can prevent complications. Hereditary hypertension should be considered in cases of early onset hypertension with a significant family history. Patients diagnosed with PA using outdated criteria may have concomitant LS and require careful evaluation of biochemical and endocrine tests according to the current criteria.
Introduction
Liddle syndrome (LS) is an autosomal dominant disorder that typically manifests as early onset severe hypertension, hypokalemia, hyporeninemia, hypoaldosteronism, and metabolic alkalosis. It was first reported by Liddle in 1963 [1]. The diverse and nonspecific phenotypes of LS make it prone to misdiagnosis and missed diagnosis. Hypertension with hypokalemia is observed in several disorders—including LS, renal vascular hypertension, primary aldosteronism, Cushing’s syndrome, apparent mineralocorticoid excess (AME), and congenital adrenal hyperplasia. Herein, we report the case of a 42-year-old man diagnosed with LS by a proband, his 13-year-old son, who was found to have a heterozygous pathological variant of the SCNN1B gene.
Case Presentation
A 42-year-old man was first diagnosed with hypertension at the age of 10 years. His father had hypertension and died of subarachnoid hemorrhage at age 42. His mother had hypertension and died of a cerebral hemorrhage at age 51. His sisters both had hypertension and hypokalemia (Fig. 1). At age 27, he was treated with imidapril hydrochloride, an angiotensin-converting enzyme (ACE) inhibitor, and amlodipine besilate, a calcium channel blocker, to control his hypertension (blood pressure, 168/112 mmHg). At age 34, he had persistent hypertension (152/96 mmHg) and was found to have hypokalemia (3.2 mEq/L) as well. He was suspected to have primary aldosteronism (PA), based on a plasma aldosterone concentration (PAC) of 59.1 pg/mL (using the radioimmunoassay), a plasma renin activity (PRA) of <0.1 ng/mL/hr, and an aldosterone-renin ratio (ARR) of >200 after discontinuing imidapril hydrochloride for 2 months. A captopril challenge test was positive, a saline infusion test was negative, and a furosemide test was attempted but discontinued owing to the patient’s physical condition (Table 1). Based on the “Guidelines for the diagnosis and treatment of primary aldosteronism 2009” by the Japan Endocrine Society, the patient was diagnosed with suspected primary aldosteronism. He underwent a contrast-enhanced computed tomography scan that showed no adrenal adenoma. Adrenal venous sampling (AVS) was suggested but could not be performed because he was reluctant to undergo invasive testing. Therefore, imidapril hydrochloride was restarted and an oral potassium supplement, potassium L-aspartate, was prescribed. At age 41, he was also prescribed imidapril hydrochloride 5 mg/day, amlodipine besilate 7.5 mg/day, and potassium L-aspartate 900 mg/day. However, his blood pressure (135/91 mmHg) and serum potassium level (3.4 mEq/L) did not normalize, and his PAC (<4.0 pg/mL using the chemiluminescent enzyme immunoassay) and PRA (0.3 ng/mL/hr) were still suppressed.
Fig. 1
Family pedigree. The black arrow indicates the proband. Black filled symbols indicate Liddle syndrome diagnosed by genetic testing: II-4, III-5. Grey filled symbols indicate suspected cases of Liddle syndrome due to hypertension and hypokalemia, but no genetic testing was done: II-1, II-3; Slash indicates passed away due to cerebrovascular accident: I-1, I-2; Siblings of the proband are 17 and 11 years old, respectively, with no hypertension or hypokalemia: III-4, III-6.
Table 1 Results of PA screening and confirmatory tests at age 34
|
Results |
Criteria for positive results in the 2009 guidelines |
| Screening test |
PAC 59.1 pg/mL, PRA <0.1 ng/mL/hr, ARR >200 |
ARR >200 |
| Captopril challenge test |
After 60 min ARR 242 (PAC 48.4 pg/mL, PRA 0.2 ng/mL/hr)
After 90 min ARR >371 (PAC 37.1 pg/mL, PRA of ≤0.1 ng/mL/hr) |
After 60 min/90 min, ARR >200 |
| Saline infusion test |
After 4 h PAC 22.1 pg/mL |
After 4 h, PAC >60 pg/mL |
| Furosemide-upright test |
Discontinued due to physical condition |
After 2 h, PRA <2.0 ng/mL/hr |
He was suspected of having PA because the 2009 guidelines only had ARR >200 as the positive criteria for PA screening. Since 2016, high PAC in addition to high ARR has been included in the screening positive criteria, so he does not meet the new positive criteria. PAC as measured by RIA. PA: primary aldosteronism, PAC: plasma aldosterone concentration, PRA: plasma renin activity, ARR: aldosterone-renin ratio.
Meanwhile, his 13-year-old son was referred to the hospital with complaints of hypertension (166/109 mmHg), hypokalemia (3.2 mEq/L), and lower-limb weakness. He had been found to have a systolic blood pressure of 130 mmHg at 10 years of age, and hypokalemia at age 12. His PAC and PRA were too low to be measured (PAC was measured using the chemiluminescent enzyme immunoassay), and no metabolic alkalosis was observed (Table 2). The blood samples were obtained at 9 in the morning in the supine position after overnight fasting. He had no history of vomiting, diarrhea, or taking laxatives or licorice. There was no evidence of cortisol over-abundance or abnormal urinary cortisol metabolite levels. We suspected LS based on his clinical presentation and his significant family history of hypertension. We conducted a genetic testing for kidney disease using a next-generation sequencing (NGS) panel, which was requested and performed at Institute of Science Tokyo (Science Tokyo) [2]. The research received approval from the Institutional Review Board of Science Tokyo (approval number G2000-081) and was conducted in accordance with the Declaration of Helsinki. All participants in the study provided written informed consent and agreed to the use of their DNA in research aimed at identifying genetic risk variants for kidney function. Additionally, all participants consented to the publication of their genetic and medical data in academic journals, provided that the data were anonymized. Genetic testing revealed a heterozygous nonsense mutation, c.1969C>T:p. R566X, in exon 13 of the SCNN1B gene, leading to a diagnosis of LS. The boy became the proband of his father’s illness, as this also led to a correct diagnosis of LS in his father, who was found to harbor the same nonsense mutation.
Table 2 Laboratory data of the proband at age 13
| Hematology |
Hormone levels in serum |
| WBC |
4,290/μL |
FT4 |
1.03 ng/dL |
| RBC |
4.83 × 106 g/dL |
TSH |
0.616 μU/mL |
| Hb |
14.5 g/dL |
ACTH |
22.3 pg/mL |
| Plt |
26.3 × 104 /μL |
cortisol |
2.6 μg/mL |
|
|
PRA |
<0.2 ng/mL/hr |
| Biochemistry |
PAC |
<4.0 pg/mL |
| AST |
24 U/L |
Adrenaline |
21 pg/mL |
| ALT |
15 U/L |
Noradrenaline |
117 pg/mL |
| LDH |
184 U/L |
Dopamine |
7 pg/mL |
| BUN |
8.6 mg/dL |
|
|
| Cr |
0.63 mg/dL |
|
|
| Glu |
105 mg/dL |
urine biochemistry |
| Na |
142 mEq/L |
K |
68 mEq/L |
| K |
3.2 mEq/L |
Cr |
234 mg/dL |
| Cl |
104 mEq/L |
|
|
| |
|
| venous blood gas |
|
|
| pH |
7.435 |
|
|
| pO2 |
62 mmHg |
|
|
| pCO2 |
44.7 mmHg |
|
|
| HCO3– |
29.4 mEq/L |
|
|
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Plt: platelet, AST: asparate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, Cr: creatinine, Glu: glucose, Na: sodium, K: potassium, Cl: chloride, pH: potential hydrogen, pO2: partial pressure of oxygen, pCO2: partial pressure of carbon dioxide, HCO3–: bicarbonate ion, PRA: plasma renin activity, PAC: plasma aldosterone concentration
We initiated a tailored therapy for both patients. The father discontinued imidapril hydrochloride and potassium L-aspartate and started triamterene (100 mg/day), an epithelial sodium channel (ENaC) blocker that acts as a K+-sparing diuretic as well as a salt-restricted diet. His plasma potassium levels normalized the day after the treatment change. After 9 days of treatment with triamterene, his amlodipine besilate dose was reduced to 2.5 mg/day and his blood pressure improved to 110/80–85 mmHg. His son was also started on triamterene (50 mg/day) and a salt-restricted diet. His plasma potassium levels increased after 2 weeks of this tailored therapy. His triamterene dose was gradually increased to 150 mg, and his blood pressure normalized. The dose was then reduced to 100 mg, and his blood pressure remained stable. He had no complications resulting from hypertension, such as left ventricular hypertrophy or hypertensive retinopathy. The siblings of the proband, aged 17 and 11, did not have hypertension or hypokalemia. The other members of the family who had died of cerebrovascular disease might have had LS as well; however, this was impossible to assess. Other living family members with hypertension and hypokalemia were also suspected of having LS; however, we were unable to reach them for examination.
Discussion
We report a case in which a 42-year-old man who had been treated for hypertension as a possible PA for many years was diagnosed with LS after his son was diagnosed with LS. A tailored treatment approach soon led to better blood pressure control in both patients.
Hypertension is the most frequent modifiable risk factor for cardiovascular disease, and affects approximately 1 billion people worldwide. Approximately 30–50% of the individual risk comes from genetic factors, and a family history of hypertension increases the risk of developing hypertension by four-fold. Most monogenic forms of hypertension are caused by gain- or loss-of-function mutations, resulting in alterations in mineralocorticoid, glucocorticoid, or sympathetic pathways [3]. Approximately 50–80% of childhood hypertension cases are secondary hypertension, with renal parenchymal, renal vascular, and endocrine causes being the most common. Because some diseases (such as LS) are inherited, genetic factors should be considered and family histories should be obtained when initiating treatments [4]. In particular, a family history of hypertension that begins in childhood is an important finding suggestive of hereditary hypertension such as LS. In some cases, a family member is diagnosed with LS as a result of their child’s diagnosis [5]. LS is a genetic disorder that causes early onset hypertension. However, it is also unfamiliar to many clinicians, and its prevalence in the population of patients with hypertension remains unknown. Two studies investigating the prevalence of LS confirmed by genetic testing in younger Chinese patients with hypertension reported that the prevalence of LS was 1.52% (5/330) in hypokalemic patients aged 14–40 years [6] and 1.72% (7/407) in hyporeninemic ones diagnosed before age 30 [7]. Even in these more targeted studies, the frequency of LS was only 1.5%. As a result, it is generally assumed that LS is extremely rare among cases of hypertension. Clinicians should be aware that early onset hypertension, such as LS, can be inherited.
The heterozygous nonsense mutation c.1969C>T:p. R566X in exon 13 of the SCNN1B (p.Arg566*, R566X, previously reported as Arg564) identified in our cases has already been reported to be the LS gene [8, 9]. This mutation is a stop codon that deletes the PY motif of the protein’s β-subunit. Molecular characterization of the p.R566X protein-truncating mutation has revealed deletion of the last 75 amino acids and removal of the cytoplasmic carboxyl tail [10].
The typical clinical manifestations of LS are early onset hypertension, hypokalemia, and metabolic alkalosis—similar to those of mineralocorticoid excess. A systematic review of reported LS cases revealed that hypertension was present in 92.4% of patients, hypokalemia in 71.8%, and hypoaldosteronemia in 58.2%. This variability was observed not only between unrelated patients carrying different mutations, but also between affected members of the same family. Both environmental and genetic factors, including Na+ intake and polymorphisms in the genes involved in Na+ handling, can influence the phenotypic manifestations of LS [11]. Extremely severe phenotypes and mild forms of the disease can coexist, with some patients carrying a causative mutation and remaining normotensive, and other patients only being diagnosed with LS later in life [12]. The proband’s father did not reveal a suppressed PAC at the initial examination. Notably, the phenotype of LS varies; LS cannot be ruled out even if the PAC is not suppressed.
The pathologies of LS and PA are similar, and it is important to distinguish between them. In fact, LS that was misdiagnosed as PA has already been reported at least twice in the literature [13, 14]. In both of these reports, PA was suspected on the basis of hypokalemia and hypertension. Peng et al. reported a case of misdiagnosis of PA made on the basis of a false-positive saline infusion and captopril challenge tests. They also mentioned the importance of the combination of ARR and high PAC when screening for PA [13]. Yaling et al. reported a case of misdiagnosis of PA made on the basis of a false-high aldosterone measurement. The accuracy of aldosterone levels for diagnosing this condition differs for different assays. The accuracy and precision of biochemical tests are important because aldosterone levels and ARR are critical to making a differential diagnosis between PA and LS [14]. False positive or false negative ARR can occur because many antihypertensive medicines affect renin and aldosterone concentrations. Treatment with diuretics, dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. Beta-blockers suppress renin, raising the ARR with the potential for false positives. Therefore, if possible, diuretics should be discontinued at least 6 weeks before the ARR measurement and other interfering drugs at least 2 weeks before [15, 16]. The 2009 Japanese PA guidelines require a PAC/PRA ratio of >200 to merit further evaluations. However, since 2016, high PAC values have become more critical and a radioimmunoassay PAC result of ≥120 pg/mL was added. Later, the standard PAC testing method was changed from the radioimmunoassay to the chemiluminescent enzyme immunoassay (CLEIA), and a PAC of 60 pg/mL by CLEIA comprised the criterion in the 2021 update of the guidelines [17]. Our patient (the father of the proband) had an elevated ARR but normal PAC (59.1 pg/mL) at 34 years of age. In other words, he was diagnosed with PA according to the 2009 guidelines, but not under the 2021 guidelines. The fact that the patient was already undergoing treatment for high blood pressure complicated the matter further, as this meant that his test results needed to be evaluated with some caution—as such treatments can affect both PAC and PRA. The proband’s father was receiving a calcium channel blocker at the initial examination but he had stopped ACE inhibitors for 2 months. His PRA was suppressed, with probably no effect of medication on the test results. Some patients diagnosed with PA before 2016 may have LS and should be reconsidered using the new criteria if their response to treatment is poor, and genetic testing should be performed if indicated.
Appropriate diagnosis and treatment can prevent hypertension-related complications and improve patient prognoses. Hereditary hypertension should be considered in cases of early onset hypertension where a patient has a significant family history of hypertension. Particularly, genetic diagnosis is beneficial for tailored therapy and diagnosis. A definitive diagnosis of a genetic disease should lead to a screening of other family members who may also be at risk. Although several inherited hypertension types exist, the phenotypic variability of LS needs to be recognized; LS cannot be ruled out despite normal PAC. Biochemical and endocrine tests should be carefully evaluated when diagnosing PA. Possibly, some patients might have been misdiagnosed with PA following older guidelines, and if blood pressure is poorly controlled, the possibility of other diseases should be considered.
Disclosure
None of the authors have any potential conflicts of interest associated with this research.
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