QJM: An International Journal of Medicine, 2020, 739–740

doi: 10.1093/qjmed/hcaa104
Advance Access Publication Date: 28 March 2020
Case report

CASE REPORT

Looking beyond Entecavir to discover Gitelman

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Syndrome in a 50 year-old man
M. Simeoni1, V. Columbano1, Y. Suzumoto2, L. Salviano3, G. Capolongo1,
M. Zacchia1, F. Del Vecchio Blanco4, A.F. Perna1, V. Nigro4,5, G. Capasso1,2 and
F. Trepiccione1,2
From the 1Nephrology, Department of Translational Medical Sciences, University of Campania “L.Vanvitelli”,
Naples, Italy, 2Biogem S.c.a.r.l., Institute of Genetic Research “Gaetano Salvatore”, Ariano Irpino, Italy,
3
Department of Health Sciences, Metropolitan University of Santos, Santos, Brazil, 4Department of Precision
Medicine, University of Campania ‘Luigi Vanvitelli’ Naples, Italy and 5Department of Genetics and Medicine,
Telethon Institute, Naples, Italy
Address correspondence to Dr M. Simeoni MD, PhD, Department of Translational Medical Sciences, University of Campania ‘Luigi Vanvitelli’ 80131 Naples,
Italy. email: mariadelina.simeoni@unicampania.it

or secondary) or pseudohyperaldosteronism (genetically deter-

Learning point for clinicians
This case points on the need for a complete evaluation
in differential diagnosis of hypokalemia always extended
to genetically determined tubulopathies, since Gitelman
and Bartter type III syndromes can be underdiagnosed at
the first symptoms presentation.
Introduction
The kidney is crucial for Kþ homeostasis.1 However, disorders of
Kþ balance are life-threating. Hypokalemia results either as a
consequence of very low potassium intake (as in anorexia nerv-
osa) either because of renal or extrarenal loss. Rapid intracellu-
lar shift sustains hormonal dependent or independent
paroxysmal hypokalemic crisis with paralysis. Identification of
the causes of hypokalemia is not always straightforward and
can be challenging, as showed in the following case report.
Urinary fractional excretion of chloride (FeCl %) or urinary Na/
Cl (UNaþ/UCl–) ratio is helpful to discriminate renal from extra-
renal Kþ loss, but the evaluation of acid–base status and blood
pressure are fundamental. Metabolic alkalosis associated to
hypokalemia suggests a state of hyperaldosteronism (primary
mined) when associated with hypertension. However, the con-
current presence of normo-hypotension may suggest a salt-
losing hypokalemic tubulopathy. Finally, hypokalemia can
sometimes be also associated to metabolic acidosis. This occurs
mainly as the consequence of systemic-conditions causing
acid–base disorders (metformin-induced for instance) or be-
cause of renal tubular acidosis (RTA) (genetically induced or sec-
ondary forms). In this scenario, it is a common general practice,
to consider tubulopathies mostly for children and adolescents,
while drug-induced hypokalemia for adults and elderly. As
showed in this case report, this is a simplistic distinction be-
cause hypokalemic syndromes like Gitelman and Bartter type III
manifest usually during adulthood and can be unrecognized for
long time especially in patients with multiple comorbidities on
multi-drugs therapy.
Case report
We present the case of a 50-year-old male patient complaining
of asthenia and hypokalemia (Kþ: 2.4 mM). He referred to his
gastroenterologist because he was affected by HBV (hepatitis B
virus)-related chronic liver disease since he was 34 years old
and since the last 2 years he was on treatment with entecavir, a
direct active antiviral agent (DAA). Hypokalemia was ascribed

Received: 17 March 2020

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739
 740 | QJM: An International Journal of Medicine, 2020, Vol. 113, No. 10
Figure 1. (A) 2D topology model of NCC show the localization sites of patients’ mutations. (B). 3D structure model of human NCC was generated by Swiss-Model protein
structure homology-modelling server (http://swissmodel. expasy.org) using as input the Cryo-EM structure of NKCC1 from Danio rerio (PDB code: 6NPL). Molecular visu-
alization of model structure was performed using PyMol software.
as secondary to DAA and KCl salt supplementation was started.
Because of no substantial improvement, he was referred to the
Nephrology Department. At the clinical interview, the patient
revealed a long-term story of asthenia that prevented him
from hard physical activity. At blood gas analysis, he was
found affected by hypokalemic metabolic alkalosis and a slight
hypomagnesemia (pH 7.45; pCO2 48 mmHg, HCO3 28 mM; Kþ
2.3 mM; Mg2þ 0.72 mM). Since DAA-induced hypokalemia has
been reported to be associated with metabolic acidosis sec-
ondary to proximal RTA,2–4 the role of entecavir was ques-
tioned. Indeed, urinalysis was negative for glycosuria and
phosphaturia, while the presence of hyper-reninemic aldos-
teronism with a low UCa/Creat ratio (0.03 mg/mg) raised the
hypothesis of a Gilteman-like tubulopathy,5 since the patient
denied any use of thiazide diuretic. In order to confirm this
diagnosis, a thiazide administration test was performed as
previously described.6 After oral administration of 50 mg of
hydrochlorothiazide, the increased FeCl from the baseline
was always lower than the diagnostic threshold of 2.3, sug-
gesting the patient was affected by a Gitelman syndrome. The
genetic analysis confirmed the patient was compound hetero-
zygous for two mutations of SLC12A3 gene (NM_000339
c.1001G>A in exon 8, and NM_000339 c.1489A>T in exon 12)
encoding for the NaCl co-transporter, NCC (Figure 1A). By
modeling the NCC structure based on a template of Danio Rerio
NKCC1 cryo-electron microscopy structure, it can be hypothe-
sized that the substitution R334Q (c.1001G>A) can disturb the
hydrogen bond between the R334 and Q432 residues on the
extracellular loop 4, demonstrated by increased atomic dis-
tance from 2.8 to 9.1 Å, while the introduction of a stop codon
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at K497X (c.1489A>T), causes the truncation of the large part
of the C-terminal intracellular domain (Figure 1B).
Ethics
The patient released an informed consent to publication of this
case report.
Conflict of interest: Authors have no conflicts of interest to declare.
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