0021-7557/02/78-03/251 Jornal de Pediatria - Vol. 78, Nº3, 2002 251 Jornal de Pediatria Copyright © 2002 by Sociedade Brasileira de Pediatria

CASE REPORT

Liddle’s syndrome: late diagnosis of a rare cause of arterial

Ana Cristina Simões e Silva,1 Eduardo A. Oliveira,1 Camila Romano Gomes,2 Flávio Souza Lima,3 José S.S. Diniz4

Abstract Objective: the aim of this article is to highlight the importance of a rare disease that causes severe arterial hypertension in children. It is important to advise pediatricians to measure arterial pressure in children in order to avoid late diagnosis and renal insufficiency. Description: we report a case of a 13-year-old patient that presented typical clinical and laboratorial features of Liddle’s syndrome. The diagnosis was established based on the clinical picture associated with the presence of chronic , increase of urinary excretion with retention and reduction of plasma activity, and circulating levels of II and . In a spite of the initial therapeutic response to triamterene, the patient developed progressive renal failure due to the delay in the diagnosis and the poorly controlled hypertension. Comments: Liddle’s syndrome consists of a form of pseudoaldosteronism characterized by arterial hypertension, hypokalemia, and failure to thrive. Some aspects regarding physiopathology, diagnosis and treatment are discussed.

J Pediatr (Rio J) 2002; 78 (3): 251-54: Liddle’s syndrome, arterial hypertension, chronic renal insufficiency.

Introduction In 1963, Liddle et al. described a congenital renal stated that the alterations observed could be produced by a disease with clinical and laboratory characteristics similar primary abnormality regarding the renal transport of sodium, to primary , however it presented low with an increase in the permeability to this ion and, aldosterone excretion rate.1 Acute hypertension, expansion consequently, hypervolemia and potassium loss. Today, the of the extracellular volume and hypokalemia are symptoms syndrome is considered an autosomal dominant disease that characterize this condition. At that moment, Liddle with variable clinical expression, whose main alteration occurs in the sodium channels, secondary to mutations in their beta or gamma subunits.2 Physicians should consider this diagnosis in patients

1. Associate Professor, Department of Pediatrics, School of Medicine, presenting persistent hypertension, , polydipsia, Universidade Federal de Minas Gerais (UFMG). positive family history, hypokalemic alkalosis, 2. Pediatrics Resident, Hospital das Clínicas, Universidade Federal de hyporeninemia, normal level and insignificant level Minas Gerais. 3 3. Undergraduate student. Probationer, Nephrology Unit. of aldosterone. After confirming the diagnosis, we 4. Emeritus Professor, Department of Pediatrics, School of Medicine, recommend the treatment with triamterene or amiloride, Universidade Federal de Minas Gerais (UFMG). which diminishes tubular cell permeability to sodium by Manuscript received Nov 03 2001. Accepted for publication Mar 27 2002. inhibiting the amiloride-sensitive channels.4,5

251 252 Jornal de Pediatria - Vol. 78, Nº3, 2002 Liddle’s syndrome:... - Simões e Silva AC et alii

The diagnosis of Liddle’s syndrome carries important had been seen by several pediatricians and endocrinologists consequences, especially when a late diagnosis is performed (due to his low stature). The patient was admitted to hospital, or when it is not established by the physician. Also, we and was initially given slow-release nifedipine and captopril, would like to point out the importance of genetic counseling, with partial control of blood pressure levels. His hypertensive in addition to research regarding other family members, condition was then investigated, revealing biochemical since it is a congenital disease. Renal, cardiovascular and alterations such as hypokalemia and residual levels of the growth sequelae can be observed, although appropriate upper normal limit, in addition to heart enlargement (chest treatment usually causes significant improvement of clinical x-ray), overload of the left ventricle (ECG) associated with and laboratory conditions. Thus, the purpose of this case hypertrophy and mild aortic insufficiency (echocardiogram). report is to highlight the importance of a disease that, albeit Hypertensive retinopathy was detected on ophthalmologic rare, causes severe hypertension in children. examination, while abdominal ultrasonography revealed kidneys with diffusely increased echogenecity and loss of the cortical and medullary differentiation. The longitudinal, Case Report transversal and anteroposterior dimensions of the kidneys FJTS, 13 years old, male, was admitted to the Service of were as follows: right (73 x 30 x 27 mm) and left Pediatric Nephrology due to retardation of weight/height kidney (77 x 33 x 38 mm). growth rate. The patient’s mother reported that since his After the partial control of blood pressure levels, the birth, in February 1984, the child has presented polyuria, patient was discharged from hospital and continued to be polydipsia, repeated fever episodes and growth retardation, treated with nifedipine and captopril. Deeper investigations with weight and height often below the 3rd percentile. The were performed. The Doppler ultrasound of renal vessels patient was submitted to multivitamin treatments, but with did not show any abnormalities. The determination of no positive effects. With regard to the gestational period urinary electrolytes, plasma renin activity (PRA) and and delivery, the mother presented hemorrhage at the sixth circulating levels of angiotensin [angiotensin I - Ang I, month, and the child was premature. His birthweight was angiotensin II – Ang II and angiotensin-(1-7) – Ang-(1-7)] 1,480 grams and he was 36 cm long; as a result, he stayed and aldosterone respectively showed an increase in the three months in the intensive care unit. There was no urinary excretion of potassium together with the reduction register of blood pressure measurement while the patient of sodium loss, in addition to a decrease in PRA, circulating stayed in the intensive care unit. There was a presumptive levels of Ang II and serum aldosterone (see Table 1). The diagnosis of congenital toxoplasmosis, which was not hypothesis of Liddle’s syndrome was suggested based on confirmed. However, the child was treated for a long period these clinic conditions and laboratory alterations. Thus, the of time. Regarding family history, the patient’s mother therapeutic scheme was replaced with a rigid association of reported that the child had three older brothers. All of them triamterene (150 mg/day), hydrochlorothiazide (150 mg/ were healthy, even though the mother had had three day) and potassium chloride (2.4 g/day), with a positive miscarriages of unknown cause. therapeutic response. Considering the patient’s age, arterial When the patient was admitted to hospital at the age of blood pressure was normal (120 x 85 mmHg, percentile < 13, he was short (123.5 cm – percentile < 3) and did not 90th for gender and height). During follow-up, there was a present any symptoms; however, his blood pressure was reduction in polyuria and polydipsia associated with the 220 x 160 mmHg. His mother reported that his blood stabilization of arterial blood pressure, potassium, and pressure had never been checked before, even though he nitrogen residual levels.

Table 1 - Circulating components of the renin-angiotensin-aldosterone system

Reference values Specific values

PRA (RV: 0.40 ± 0.22 ng Ang I/ml/h) 0.08 ng Ang I/ml/h Ang I (RV: 26.4 ± 13.7 pg/ml) 27.8 pg/ml Ang II (RV: 21.4 ± 8.7 pg/ml) 16.2 pg/ml Ang-(1-7) (RV: 16.1 ± 7.9 pg/ml) 15.5 pg/ml Aldosterone (RV: 5-30 ng/dl) 4 ng/dl Liddle’s syndrome:... - Simões e Silva AC et alii Jornal de Pediatria - Vol. 78, Nº3, 2002 253

The patient interrupted the follow-up visits for about Hypertension is the main clinical alteration observed in two years, and returned presenting uncontrolled blood the patients with Liddle’s syndrome. This symptom can be pressure levels (260 x 140 mmHg) and severe deterioration initially explained by the expansion of the extracellular of renal function, which was detected through the significant fluid caused by renal retention of sodium. This process increase in residual levels (urea = 160 mg/dl, and creatinine causes a reduction in the circulating levels of renin, Ang I, = 5.9 mg/dl). The patient’s mother reported that during the Ang II and consequently, in aldosterone levels as well.3,4 interruption of the clinical follow-up, there was an irregular In this case, there was no decrease in Ang I levels, as shown use of medication and blood pressure levels became out of in Table 1. Moreover, this increase in blood pressure control, so that hospital admissions were necessary. The occurs due to an increase in peripheral vascular resistance patient was admitted to Hospital das Clínicas of Universidade related to the greater sodium influx into the cell, with the Federal de Minas Gerais, where he spent one week and mobilization of intracellular calcium and, consequently, received several hypotensive drugs at high doses: nifedipine vasoconstriction.3,8 This shows that the mechanisms of retard – 120 mg/day, captopril - 150 mg/day, triamterene – sodium transportation through the membrane are not working 300 mg/day, hydrochlorothiazide – 300 mg/day and properly. Such abnormal function was already detected in minoxidil – 15 mg/day. Besides the management of blood studies involving erythrocytes, and is responsible for the pressure levels, a conservative treatment was also increase in vascular response.8 implemented to control renal dysfunction, especially through diet management. After these measures, the patient’s arterial Similarly to this case, patients with Liddle’s syndrome blood pressure was controlled (130 x 85 mmHg), and the also present hypokalemia and growth retardation.3-7 urea and creatinine levels were kept around 168 mg/dl and Considering the laboratory tests, we observe an increase in 5.2 mg/dl, respectively. The laboratory assessment during the urinary excretion of potassium together with sodium follow-up is shown in Table 2. retention (Table 2). These alterations are similar to those caused by primary hyperaldosteronism. The basic difference, however, is related to the circulating levels of aldosterone, Discussion which are reduced in this disease classified as Some aspects regarding this case report should be pseudoaldosteronism.1,2,7 In addition to the determination highlighted. First of all, it is remarkable that the patient’s of aldosterone levels, reduced levels of PRA associated blood pressure had never been checked until he was 13 with normal circulating levels of cortisol may be used as years old. This led to a late diagnosis, with all the clinical auxiliary diagnostic tools, even though they suggest other consequences caused by a chronic and severe increase of possibilities.9 Therefore, besides Liddle’s syndrome, blood pressure. It is interesting to observe that the cases glucocorticoid remediable aldosteronism (GRA) and the reported in the literature had their diagnosis established at syndrome of apparent mineralocorticoid excess (AME) different ages,3-7 ranging from 10 months6 to 72 years.4 should be considered.9,10

Table 2 - Laboratory exams during diagnosis and patient’s clinical follow-up

Exam/ Date 02/ 97 01/ 98 04/ 00 09/ 01

Urea (RV:15-40) 55 mg/dl 71 mg/dl 74 mg/dl 168 mg/dl Creatinine (RV:0.5-1.0) 1.1 mg/dl 1.2 mg/dl 1.9 mg/dl 5.2 mg/dl Na+ (RV: 135-145) 129 mEq/L 143 mEq/L – 139 mEq/L K+ (RV: 3.5-5.5) 2.2 mEq/L 2.7 mEq/L 2.9 mEq/L 2.7 mEq/L Cl- (RV: 98-106) 97 mmol/l 96 mmol/l 97 mmol/l 96 mmol/l pH (RV: 7.35-7.45) 7.42 7.46 7.33 7.34 HCO3- (RV: 22-26) 33 31.7 30.3 27.5 BE (RV: -2 a + 2) +9 +7.6 +3.1 +1.5 Urinary volume 2.900 ml 2.550 ml 3.200 ml – CrCl (RV: 88 - 166) 34.9 ml/min 38.2 ml/min 31 ml/min – FE Na+ (RV < 1%) 0.4 % 2.6 % – – FE K+ (RV: 14.5 ± 8.9) 94 % 73.7 % – – Proteinuria (RV: 1-15) 130 mg/dl 128 mg/dl –

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All these diseases present reduced levels of PRA.9,10 The evolution of this patient was atypical if compared to The definitive diagnosis is established through the patients’ other cases of this disease described in the literature.3-7 genetic study2 or through the measurement of urinary Generally, there is no loss of renal function. However, late metabolites of cortisol. However, such tests are not widely diagnosis, poor treatment adherence and uncontrolled blood available in Brazil. Some clinical and laboratory findings pressure levels might have contributed to the progression of may suggest either GRA or AME. GRA is a rare type of the renal damage. A similar clinical history was reported by autosomal dominant aldosteronism, which occurs due to an Botero-Velez et al. in a patient who was submitted to renal abnormal response of the adrenal glomerular area to the transplantation at the age of 16.3 endogenic adrenocorticotrophic (ACTH).10 In Finally, the current report clearly highlights the these patients, the ACTH stimulates the aldosterone synthesis importance of monitoring children’s blood pressure on a in an anomalous manner, increasing its circulating levels, routine basis. This information may be an initial clue for the hypertension, hypokalemia and decreasing PRA. AME, on diagnosis of diseases that require specific treatment and the other hand, constitutes an alteration of the aldosterone genetic counseling such as Liddle’s syndrome. receptor and the metabolism of cortisol in the renal tubular cells. Such disorder causes a decrease in cortisol degradation and lengthens its extended half-life, establishing an anomalous mineralocorticoid activity.2 Thus, the patients present hyperaldosteronism, with normal or slightly decreased circulating levels of aldosterone.2 The diagnosis may be established through the detection of abnormal References urinary excretion of cortisol metabolites. In case of GRA as 1. Liddle GW, Bledsoe T, Coppage WS. A familial renal disorder well as AME, the treatment must include the administration simulating but with negligible aldosterone of glucocorticoids () associated with secretion. Trans Assoc Am Physicians 1963; 76:199-213. aldosterone antagonists, such as .9,10 There 2. Warnock DG. Liddle syndrome: an autossomal dominant form of is no positive response to the use of triamterene on these human hypertension. Kidney Int 1998; 53:18-24. diseases. In this case, the severe decrease in aldosterone 3. Botero-Velez M, Curtis JJ, Warnock DG. Brief report: Liddle’s levels associated with the positive response to the use of syndrome revised – a disorder of sodium reabsorption in the distal tubule. N Engl J Med 1994; 330:178-81. triamterene reinforces the diagnosis of Liddle’s syndrome, 4. Nakada T, Koike H, Akika T, Katayama T, Kawamata S, Takaya 5 which leads to the rejection of the other two possibilities. K, et al. Liddle’s syndrome, an uncommon form of hyporeninemic Linkage studies have shown that the gene responsible : functional and histopathological studies. J Urol 1987; 137:636-40. for this disease is located in a small segment of chromosome 5. Wang C, Chan TK, Yeung RTT, Coghlan JP, Scoggins BA, 16. The mutations in this gene cause alterations in the beta Stockigt JR. The effect of triamterene and sodium intake on and gamma subunits of sodium epithelial channels, affecting renin, aldosterone, and erythrocyte sodium transport in Liddle’s regulatory sites and producing increased ion transportation. syndrome. J Clin Endocrinol Metab 1981; 52:1027-32. A continuous activation of these channels occurs without 6. Vania A, Tucciarone L, Mazzeo D, Capodaglio PF, Cugini P. feedback mechanisms.2,3 Even though, from the genetic Liddle’s syndrome: a 14-year follow-up of the youngest diagnosed case. Pediatr Nephrol 1997; 11:7-11. point of view the disease is apparently similar among the 7. Hyman PE, Shalafi RI, Tan SY, Hintz R. Liddle syndrome. J members of the same family, there are different phenotypic Pediatr 1979; 95:77-8. 2,3 expressions. It is important to point out that, although 8. Gardner JD, Lapey A, Simopoulos AP, Bravo EL. Abnormal linkage studies have contributed to the understanding of membrane sodium transport in Liddle’s syndrome. J Clin Invest this disease, this kind of analysis is not easily available in 1971; 50:2253-8. Brazil. Albeit useful, it is not always essential for the 9. Yiu VWY, Dluhy RG, Lifton RP, Guay-Woodford LM. Low diagnosis, as shown in this case report. peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997; 11:343-6. The patient’s response to the use of triamterene is 10. Warnock DG. Low renin hypertension in the next millennium. typical of Liddle’s syndrome, and may be explained through Semin Nephrol 2000; 20:40-6. the direct action of the medication on sodium channels, reducing the excessive reabsorption of this ion, and, consequently controlling hypertension and hypokalemia.5,6 The disease does not involve hormonal stimuli, differently from GRA and AME. In patients with GRA, there is an increase in aldosterone levels as a reaction to an anomalous Correspondence: stimulus caused by the ACTH, with a positive response Dr. Eduardo A. Oliveira either to the administration of dexamethasone or to the use Rua Patagônia, 515 / 701 of spironolactone. In patients with AME, there is also a CEP 30320-080 – Belo Horizonte, MG, Brazil response to the antagonism of aldosterone receptors.10 E-mail: [email protected]