Page 1 of 32 Endocrine Connections Publish Ahead of Print, published on March 14, 2018 as doi:10.

1530/EC-18-0109

Hypokalaemia: a clinical update

Efstratios Kardalas (1), Stavroula A. Paschou (2), Panagiotis Anagnostis (3), Giovanna

Muscogiuri (4), Gerasimos Siasos (5), Andromachi Vryonidou (6)

(1) Department of Endocrinology and Diabetes, Evangelismos Hospital, Athens, Greece

(2) Division of Endocrinology and Diabetes, “Aghia Sophia” Hospital, Medical School,

National and Kapodistrian University of Athens, Athens, Greece

(3) Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology,

Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

(4) Division of Endocrinology, Department of Clinical Medicine and Surgery, “Federico II”

University of Naples, Naples, Italy

(5) First Department of Cardiology, Hippokration Hospital, Medical School, National and

Kapodistrian University of Athens, Athens, Greece

(6) Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens, Greece

Corresponding author: Dr. Andromachi Vryonidou, MD, PhD, Department of

Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athanasaki 1, 11526 Athens,

Greece, e-mail: [email protected]

Short Title: Hypokalaemia

Keywords: hypokalaemia; potassium; electrolytes; acid-base status; adrenal; kidneys

Word Count: 4,943

Copyright 2018 by Society for Endocrinology and European Society of Endocrinology.

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Number of Tables: 3

Number of Figures: 2

Abstract

Hypokalaemia is a common electrolyte disturbance, especially in hospitalized patients. It can

have various causes, including endocrine ones. Sometimes, hypokalaemia requires urgent

medical attention. The aim of this review is to present updated information regarding: 1) the

definition and prevalence of hypokalaemia, 2) the physiology of potassium homeostasis, 3)

the various causes leading to hypokalaemia, 4) the diagnostic steps for the assessment of

hypokalaemia and 5) the appropriate treatment of hypokalaemia depending on the cause.

Practical algorithms for the optimal diagnostic, treatment and follow-up strategy are

presented, while an individualized approach is emphasized.

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1. Introduction

Hypokalaemia is present when serum levels of potassium are lower than normal. It is a rather

common electrolyte disturbance, especially in hospitalized patients, with various causes and

sometimes requires urgent medical attention (1). It usually results from increased potassium

excretion or intracellular shift and less commonly from reduced potassium intake. Although

many chapters, clinical statements and guidelines refer to hypokalaemia, they do so, mainly

in the context of other clinical entities. The aim of this comprehensive review is to provide

current knowledge regarding definition, prevalence and aetiology of hypokalaemia, as well

as, an individualized guide for the optimal diagnostic management and follow-up strategy.

2. Materials and Methods

In order to identify publications on hypokalaemia, a literature search was conducted in

PubMed and using combinations of the key-terms: “potassium” OR “hypokalaemia” OR

“hypokalaemia” OR “electrolyte disturbances” AND “guide” OR “algorithm” OR

“guidelines”. On the top, a manual search of key journals and abstracts from the major annual

meetings in the fields of endocrinology and nephrology was conducted. This review

collected, analyzed and qualitatively re-synthesized information regarding: 1) the definition

and prevalence of hypokalaemia, 2) the physiology of potassium homeostasis, 3) the various

causes leading to hypokalaemia, 4) the diagnostic steps for the assessment of hypokalaemia

and 5) the appropriate treatment of hypokalaemia depending on the cause.

3. Physiology of potassium homeostasis

3.1 Potassium role in cellular functions

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Potassium (K+) plays a key role in maintaining normal cell function (2). K+ is the main

intracellular kation and almost all cells have the pump called “Na+-K+-ATPase”, which

pumps sodium (Na+) out of the cell and K+ into the cell leading to a K+ gradient across the

cell membrane (K+in>K+out), which is partially responsible for maintaining the potential

difference across membrane. Many cell functions rely on this potential difference,

particularly in excitable tissues, such as nerve and muscle. Two percent of K+ exists in the

extracellular fluid (ECF) at a concentration of only 4 mEq/L (3). Enzyme activities, as well

as, cell division and growth are catalyzed by potassium and are affected by its concentrations

and its alterations.

Of great importance, intracellular K+ participates in acid base regulation through exchange

for extracellular hydrogen ions (H+) and by influencing the rate of renal ammonium

production (4). Counterregulatory mechanisms exist in order to defend against potassium

alterations. These mechanisms serve to maintain a proper distribution of K+ within the body,

as well as to regulate the total body K+ content. Excessive ECF potassium (hyperkalaemia)

decreases membrane potential, while hypokalaemia causes hyperpolarization and non-

responsiveness of the membrane (5). If potassium balance is disrupted (hypokalaemia or

hyperkalaemia), this can also lead to disruption of heart electrical conduction, dysrhythmias

and even sudden death. Potassium balance has a direct negative effect on (H+) balance at

intra- and extracellular level and the overall cellular activity.

3.2. Balance of K+

External potassium balance is determined by the rate of potassium intake (normally

100 mEq/d) and rate of urinary (normally 90 mEq/d) and fecal excretion (normally

10 mEq/d). The distribution of potassium in muscles, bone, liver and red blood cells (RBC)

and ECF has a direct effect on internal potassium balance (6,7) (Figure 1).
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The kidney is primarily responsible for maintaining total body K+ balance. However, renal

K+ excretion is adjusted over several hours; therefore, changes in extracellular K+

concentrations are initially buffered by movement of K+ into or out of skeletal muscle. The

regulation of K+ distribution between the intracellular and extracellular space is referred to as

internal K+ balance. Under normal conditions, insulin and catecholamines play the most

important role in this regulation (8). Potassium controls its own ECF concentrations through

a feedback regulation of aldosterone release. An increase in K+ levels leads to a release of

aldosterone through the renin-angiotensin-aldosterone mechanism or through the direct

release of aldosterone from the adrenal cortex cells, which are stimulated (9). More

specifically, an increase in extracellular potassium concentrations stimulates aldosterone

secretion (via angiotensin II) which in turn increases urinary K+ excretion. In the steady state,

K+ excretion matches intake and approximately 90% is excreted by the kidneys and 10% in

the stool.fairly constant. By contrast, the rate of K+ secretion by the distal nephron varies and

is regulated according to physiologic needs. The cellular determinants of K+ secretion in the

principal cell include the intracellular K+ concentration, the luminal K+ concentration, the

potential (voltage) difference across the luminal membrane, and the permeability of the

luminal membrane for K+. Conditions that increase cellular K+ concentration, decrease

luminal K+ concentration, or render the lumen more electronegative will increase the rate of

K+ secretion. Conditions that increase the permeability of the luminal membrane for K+ will

increase the rate of K+ secretion (8, 9).

Two principal determinants of K+ secretion are mineralocorticoid activity and distal delivery

of Na+ and water. Aldosterone is the major mineralocorticoid in humans and mediates the

renal excretion of K+ and Na+ reabsorption by binding to the mineralocorticoid receptors in

the distal tubules and collecting ducts of the nephron. Aldosterone increases intracellular K+

concentration by stimulating the activity of the Na+-K+-ATPase in the basolateral membrane,

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stimulates Na+ reabsorption across the luminal membrane, which increases the

electronegativity of the lumen, thereby increasing the electrical gradient favoring K+

secretion and lastly has a direct effect on the luminal membrane to increase K+ permeability

(10). Under conditions of volume depletion, activation of the renin-angiotensin system leads

to increased aldosterone release. The increase in circulating aldosterone stimulates renal Na+

retention, contributing to the restoration of extracellular fluid volume, but occurs without a

demonstrable effect on renal K+ secretion. When hyperkalemia occurs, aldosterone release is

mediated by a direct effect of K+ on cells in the zona glomerulosa. The subsequent increase in

circulating aldosterone stimulates renal K+ secretion, restoring the serum K+ concentration to

normal, but does so without concomitant renal Na+ retention. The ability of aldosterone to

signal the kidney to stimulate salt retention without K+ secretion in volume depletion and

stimulate K+ secretion without salt retention in hyperkalemia has been referred to as the

aldosterone paradox (11).

Furthermore, K+ is freely filtered by the glomerulus and almost all the filtered K+ is

reabsorbed in the proximal tubule and loop of Henle. This absorption in the proximal part of

the nephron passively follows that of Na+ and water, whereas reabsorption in the thick

ascending limb of the loop of Henle is mediated by the Na+, K+, 2 Chloride (Cl-) carrier

(NKCC2) in the luminal membrane. The connecting segment, the principal cells in the

cortical and outer medullary collecting tubule, and the papillary (or inner medullary)

collecting duct via luminal potassium channels secrete K+ (12). The renal outer medullary

K+ (ROMK) channel, is one of the two populations of K+ channels, which have been

identified in the cells of the cortical collecting duct and is considered to be the major K+-

secretory pathway. This channel is characterized by having low conductance and a high

probability of being open under physiologic conditions. The maxi-K+ channel (also known as

the large-conductance K+ [BK] channel) is characterized by a large single channel

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conductance and quiescence in the basal state and activation under conditions of increased

flow In addition to increased delivery of Na+ and dilution of luminal K+ concentration,

recruitment of maxi-K+ channels contributes to flow-dependent increased K+ secretion (11,

12).

Returning to the function of the collecting segments, they secrete varying quantities of K+

according to physiologic requirements, and are responsible for most of the urinary potassium

excretion. Secretion in the distal segments is also balanced by K+ reabsorption through the

intercalated cells in the cortical and outer medullary collecting tubules (13). The active H+-

K+-ATPase pump in the luminal membrane acts as a mediator and leads to both proton

secretion and K+ reabsorption. The kidneys are far more capable in increasing than

decreasing K+ excretion. As a result inadequate intake can lead to K+ depletion and

hypokalaemia. Hyperkalemia usually occurs when renal excretion is impaired [Glomerular

Filtration Rate (GFR) <20 mL/min)] .

4. Definition and prevalence of hypokalaemia

Hypokalaemia is an electrolyte characterized by low serum potassium concentrations (normal

range: 3.5-5.0 mEq/L). Severe and life threatening hypokalaemia is defined when potassium

levels are <2.5 mEq/L . In outpatient population undergoing laboratory testing, mild

hypokalaemia can be found in almost 14% (14). Furthermore, as many as 20% of

hospitalized patients are found to have hypokalaemia but only in 4-5% this is clinically

significant (15). Severe hypokalaemia is relatively uncommon. Approximately 80% of

patients who are receiving diuretics become hypokalaemic, while many of patients with

hypokalaemia could also have an associated systemic disease. There are no significant

differences in its prevalence between males and females (16).

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5. Causes of hypokalaemia

Hypokalaemia can be either caused by decreased intake of potassium, or by excessive losses

of potassium in the urine or through the GI tract (17, 18). The later is more common.

Excessive excretion of potassium in the urine (kaliuresis) may result from the use of diuretics

drugs, endocrine diseases such as primary hyperaldosteronism, kidney disorders and genetic

syndromes effecting the renal function (19). Gastrointestinal losses of potassium usually are

due to prolonged diarrhea or vomiting, chronic laxative abuse, intestinal obstruction or

infections. An intracellular shift of the potassium can also lead to severe hypokalaemia.

Insulin administration, stimulation of the sympathetic nervous system, thyreotoxicosis and

familiar periodic paralysis are some of the reasons for this phenomenon (20). Congenital

adrenal hyperplasia due to enzymatic defects, is a genetic syndrome strongly associated with

hypertension and hypokalaemia, resulting from excessive mineralocorticoid effects. Drugs,

such as diuretics and penicillin can be often the underlying cause of hypokalaemia. Finally,

hypomagnesemia is very important. More than 50% of clinically significant hypokalaemia

has concomitant magnesium deficiency and is clinically most frequently observed in

individuals receiving loop or thiazide diuretic therapy. Concomitant magnesium deficiency

has long been appreciated to aggravate hypokalaemia. Hypokalaemia associated with

magnesium deficiency is often refractory to treatment with K+ (21) ( Table 1).

6. Signs and Symptoms

The severity of hypokalaemia’s clinical manifestations tends to be proportionate to the degree

and duration of serum potassium reduction. Symptoms generally do not become present until

serum potassium is below 3.0 mEq/L, unless it falls rapidly or the patient has a potentiating

factor, such as the use of digitalis, in which patients have a predisposition to arrhythmias.
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According to the severity of hypokalaemia, symptoms can vary from absent to lethal heart

arrthymias (22). Symptoms usually resolve with correction of the hypokalaemia.

More specifically, we could categorize the manifestations according to the affected system.

The effects of hypokalaemia regarding the renal function can be metabolic acidosis,

rhabdomyolysis (in severe hypokalaemia) and, rarely, impairement of tubular transport,

chronic tubulointerstitial disease and cyst formation. nervous system is affected, the patient

can suffer from leg cramps, weakness, paresis or ascending paralysis. Constipation or

intestinal paralysis and respiratory failure often present as signs of severe hypokalaemia. Last

but not least, hypokalaemia can have detrimental effects on the cardiovascular system,

leading to electrocardiographic (ECG) changes (U Waves, T Wave Flattening, ST Segment

changes), cardiac arrhythmias (sometimes lethal) and heart failure (23) (Table 2).

7. Laboratory investigation of hypokalaemia

7.1. General diagnostic approach

The undelying cause of hypokalaemia is usually apparent after obtaining a detailed medical

history and physical examination (24). In order to evaluate the severity of hypokalaemia and

to initiate an effective treatment, assessment of serum and urinary potassium levels is needed.

Depending on the above findings, tests and imaging of the endocrine glands are appropriate,

but they should not be first-line tests unless the clinical index of suspicion for such a disorder

is high

A basic biochemical laboratory panel (including serum sodium, potassium, glucose, chloride,

bicarbonate, BUN and creatinine) is the core of screening in patients with hypokalaemia.

Urine electrolytes (potassium and chloride) in spot urine are useful in differentiating renal
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from non-renal causes of hypokalaemia. An arterial blood gas (ABG) analysis should be

performed to detect metabolic acidosis or alkalosis when the underlying cause is not apparent

from the history. As the difference between arterial and vein blood samples, regarding the

potassium levels, is clinically not significant, measurement of potassium in vein blood

sample is not contraindicated in the mergency department. Further urinalysis and urine pH

measurement should follow to assess for the presence of renal tubular acidosis. Serum

magnesium, calcium, and/or phosphorus levels are important to exclude associated

electrolyte abnormalities, especially if alcoholism is suspected. Urinary calcium excretion is

very critical to exclude Bartter syndrome. We should also measure serum digoxin level if the

patient is on digitalis. In cases of high clinical index of suspicion for a disorder, a drug screen

in urine and/or serum for diuretics, amphetamines, and other sympathomimetic stimulants

should be conducted. Assessment of TSH levels is required in cases of tachycardia or clinical

suspicion of hypokalemic periodic paralysis (25).

In general, there are two major components of the diagnostic evaluation: a) assessment of

urinary potassium excretion in order to distinguish renal potassium losses (eg, diuretic

therapy, primary aldosteronism) from other causes of hypokalaemia (eg, gastrointestinal

losses, transcellular potassium shifts) and b) assessment of acid-base status, since some

causes of hypokalaemia are associated with metabolic alkalosis or metabolic acidosis. We

present a diagnostic algorithm for the assessment of hypokalaemia.

7.2. Assesment of urinary potassium excretion

Potassium excretion in a 24-hour urine collection is the best way to asses the urinary

potassium excretion (26). If this excretion is above 15 mEq of potassium per day, this is a

direct indication of inappropriate renal potassium loss (27). Measurement of the potassium

and creatinine concentrations in a spot urine is an alternative, if collection of a 24-hour urine

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is not feasible. A spot urine potassium-to-creatinine ratio greater than 13 mEq/g creatinine

(1.5 mEq/mmol) usually indicates inappropriate renal potassium loss. After determining

whether renal potassium wasting is present, assessment of acid–base status can further

narrow the differential diagnosis (28, 29).

7.3. Assesment of acid base status

Once urinary potassium excretion is measured, the following diagnostic possibilities should

be considered in the patient with hypokalaemia of uncertain origin. A metabolic acidosis with

a low rate of urinary potassium excretion in an asymptomatic patient is suggestive of lower

gastrointestinal losses due to laxative abuse or a villous adenoma. On the other hand, a

diabetic ketoacidosis or type 1 (distal) or type 2 (proximal) renal tubular acidosis can occur

because of a metabolic acidosis with urinary potassium wasting. Furthermore, surreptitious

vomiting (often common in bulimic patients trying to lose weight) or diuretic use can be the

cause of a metabolic alkalosis with a low rate of urinary potassium excretion. In addition,

some patients with laxative abuse present with metabolic alkalosis, rather than with the

expected metabolic acidosis (30).

On the other side, when a metabolic alkalosis with urinary potassium wasting is present and

the patient has a normal bloοd pressure, the diagnosis is diuretic use, vomiting, Gitelman or

Bartter syndrome. In this setting, measurement of the urine chloride concentration is often

helpful, being normal (equal to intake) in Gitelman or Bartter syndrome. On the other hand,

urine chloride concentration is high or low with diuretics, depending upon the duration of

action of the diuretic. In cases of vomiting, this concentration is low at a time when urinary

sodium and potassium excretion may be relatively high due to the need to maintain

electroneutrality as some of the excess bicarbonate is being excreted (31). In the presence of

hypertension, a surreptitious diuretic therapy comes as first in the differential diagnosis in a

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patient with underlying hypertension, renovascular disease, or one of the causes of primary

mineralocorticoid excess (32).

Patients with either Bartter or Gitelman syndrome syndrome may present with constipation,

muscle cramps and weakness non-specific dizziness and fatigue. The biochemical features of

both syndromes can include hypokalemic, hypochloremic metabolic alkalosis associated

with high plasma renin activity and high aldosterone concentration (33). Patients with

Bartter syndrome present in early childhood and the failure to thrive is more severe and with

a great deal of growth retardation.Gitelman syndrome is associated with less severe failure to

thrive and the growth retardation is milder. Symptoms of Gittleman Syndrome are similar to

thiazide diuretic-abusers with salt wasting. Indeed, Gitelman patients are mostly thought to

be asymptomatic (34). They often present for workup of isolated, asymptomatic

hypokalaemia, but when closer questioned, 80% of Gitelman patients complain of dizziness

and fatigue; 70% of the patients complain of muscle weakness and cramps and 50% with

nocturia and polyuria, in whom 90% are subsequently found to be salt wasters. Normal

blood pressure in patients with Bartter syndrome is a feature thought to be different from the

occasional hypotension of Gitelman syndrome. Focal segmental glomerulosclerosis has been

described in Bartter syndrome (35). In contrast, Gitelman patients often complain of nocturia

and polyuria. Persistent hypokalaemia may give rise to interstitial nephritis, signaled by

urinary anomalies. Urinary calcium excretion is important because it distinguishes the two

syndromes. In contrast to the hypocalciuria of Gitelman syndrome, Bartter patients are often

documented to have hypercalciuria. Medical noncompliance to potassium chloride

supplementation and other therapy is an important issue in long-term followup of Bartter and

Gitelman patients (36). Although the chronic hypokalaemia can be mildly symptomatic, it

can be aggravated by diarrhea or vomiting, precipitating prolonged QT interval, increased

risk of rhabdomyolysis, cardiac arrhythmia, syncope, and sudden death. Alcohol abuse,
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cocaine or other drug abuse can also precipitate life-threatening arrhythmia Electrolyte and

fluid repair, oral potassium supplementation, potassium sparing diuretics, cyclo-oxygenase

inhibitors, and renin-angiotensin blockers become life-saving in such emergencies (37).

Finally, in familial cases, both conditions are conveyed by autosomal recessive transmission.

The site of defect in Bartter syndrome is at the thick ascending limb (TAL) of the loop of

Henle, whereas in Gitelman syndrome, the defect resides at the distal convoluted tubule

(DCT) (38).

Liddle syndrome is a rare form of autosomal dominant hypertension with early penetrance

and impressive cardiovascular sequelae. In addition to severe hypertension, many of the

patients have overt hypokalaemia. Despite having the clinical presentation typical of primary

aldosteronism, the actual rates of aldosterone excretion are markedly suppressed, accounting

for the descriptive term “pseudoaldosteronism.” Liddle syndrome is an extreme example of

low renin, volumeexpanded hypertension. In general, inappropriate renal Na1 retention with

subsequent volume expansion, low plasma renin activity and hypertension are the

consequences of “pseudoaldosteronism,” that results from constitutive activation of the

amiloride-sensitive epithelial Na1 channel (ENaC) in the terminal nephron segments.

Cardiovascular and cerebrovascular complications of hypertension are much more common

findings, and the usual cause of death in undiagnosed or untreated patients (39).

A diagnostic approach to a patient with hypokalaemia is presented in Figure 2.

7.4. Endocrine causes of hypokalaemia

Screening for primary aldosteronism (PA) is recommended for any case with spontaneous or

diuretic induced hypokalaemia and hypertension. In such cases, a plasma aldosterone to

plasma renin activity ratio (ARR) should be assessed. If it is higher than 20, further

confirmatory testing is not necessary (oral sodium test, saline infusion test, fludrocortisone
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suppression test, captopril challenge test) (40). Conclusively, in case of patients with

hypertension, who are at high risk for a primary hyperaldosteronism (patients with relatively

high prevalence of PA, including patients with stage I (> 160 - 179/100 - 109 mm Hg), stage

II (> 180/110 mm Hg), or drug-resistant hypertension; hypertension with adrenal

incidentaloma; or hypertension and a family history of early-onset hypertension or

cerebrovascular accident at age younger than 40 years), we should conduct a plasma

aldosterone concentration/plasma renin activity ratio examination. An adrenal computed

tomography scan is recommended in all patients with PA. This test also excludes large

masses that may represent adrenocortical carcinoma. Moreover adrenal venous sampling by

an experienced radiologist is recommended to distinguish between unilateral and bilateral

adrenal disease, when surgical treatment is feasible, and the patient is willing to undergo the

procedure. Genetic testing for Glucocorticoid remediable Aldosteronsim (GRA) is suggested

in patients,whose confirmed PA begins before 20 years of age and in those with a family

history of PA or strokes at 40 years of age or younger This condition is also called familial

hyperaldosteronism type 1. In very young patients with PA, testing for germline mutations in

KCNJ5 is recommended to diagnose familial hyperaldosteronism type 3 (41).

Rare causes of hypertension and hypokalaemia include 11-beta hydroxylase and 17-alpha

hydroxylase deficiency, which are characterized by increased production of cortisol and

aldosterone precursors due to chronic stimulation of the adrenal cortex by ACTH (42). In 11-

beta hydroxylase deficiency, 11-deoxycortisol is markedly elevated in the classic form,

whereas in cases with the non-classic variants, 11-deoxycortisol may be normal and

therefore an ACTH stimulation test is then indicated. In the classic form,

deoxycorticosterone (DOC), urinary 17-ketosteroids, urinary tetra hydrometabolites, adrenal

androgens, testosterone and 17-hydroxyprogesterone are elevated. On the contrast, in 17-

alpha hydroxylase deficiency, 17-hydroxyprogesterone, 11-deoxycortisol cortisol, adrenal

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adrogens and testosterone are all decreased or absent. The urinary metabolites 17-

hydroxylase corticosteroid and 17-ketosteroid also are decreased or absent. The diagnosis is

set by markedly elevated levels of 11-deoxycorticosterone and corticosterone (43). If there

are clinical features of hypercortisolaemia (f.e. Cushing’s syndrome) and after excluding

exogenous corticosteroid use, a diagnostic approach to confirm autonomous cortisol

production is recommended. At least two of the following tests with high diagnostic

accuracy is needed: 24h-urinary cortisol, late night salivary cortisol, 1 mg overnight or 2 mg

48-h dexamethasone suppression test. In some cases, a serum midnight cortisol or

dexamethasone-CRH test may be useful to establish the diagnosis of endogenous

hypercortisolaemia (44).

Apparent mineralocorticoid excess

Apparent mineralocorticoid excess (AME) is an autosomal recessive disease caused by

deficiency of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) (45).

11beta-HSD2 converts cortisol into inactive cortisone and prevents the stimulation of the

mineralocorticoid receptor by cortisol. In patients with AME, an enhanced stimulation of

mineralocorticoid receptors by cortisol in the distal nephron causes an elevated sodium

reabsorption and increased potassium excretion. Sodium retention leads to severe low renin

hypertension. The diagnosis of AME is based on the detection of an increased concentration

of cortisol metabolites and a low or undetectable concentration of cortisone metabolites in

urine (46). Molecular analysis of the HSD11B2 gene confirms the diagnosis. AME is

successfully treated by potassium-sparing diuretics, sometimes in combination with loop

diuretics (furosemide). Mild forms of AME might occur more frequently than is currently

known and should be suspected in patients with hypertension, hypokalaemia and decreased

plasma renin concentration. Since liquorice can induce the clinical symptoms of AME due to
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reversible inhibition of the 11beta-HSD2 enzyme by glycyrrhetinic acid, the active

ingredient of liquorice, patients suspected of having AME should not consume liquorice (47).

Glucocorticoid Resistance Syndrome

Familial glucocorticoid (GC) resistance is a rare syndrome that is characterized by

diminished cortisol action which is mediated by the GC receptor (GR) (48). As a

consequence, a compensatory stimulation of adrenocorticotropic hormone (ACTH) secretion

by the pituitary occurs, resulting in elevated circulating levels of GCs, mineralocorticoids

and androgens. This syndrome is inherited as an autosomal recessive or dominant disease.

Several rare mutations of the GR gene (NR3C1) have been described which were associated

with clinical signs and symptoms of generalized GC resistance. In normal conditions, the

secretion of GCs is regulated by the hypothalamus, which receives stimuli from the central

nervous system Due to GR defects, cortisol has impaired actions through the GR. As a

consequence, the central negative feedback of GCs is diminished, GC production by the

adrenal is elevated, and cortisol binds with high affinity to the mineralocorticoid receptor

(MR). Symptoms in patients with cortisol resistance are the consequence of this

compensatory hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis (49). Due to

elevated ACTH, patients suffer from an overproduction of mineralocorticoids, leading to

hypertension, hypokalaemic alkalosis, and fatigue. Females also show signs of

hyperandrogenism, such as hirsutism, male pattern of baldness and menstrual irregularities

due to higher adrenal production of androgens. In males the gonadal production of androgens

is much higher, which outweighs the increased adrenal androgen production. In

physiological conditions, tissues which have an important mineralocorticoid function (e.g.

the kidneys) are protected from high cortisol levels by the enzyme 11b-hydroxysteroid

dehydrogenase type II, which rapidly converts cortisol to the inactive cortisone. In the

condition of cortisol resistance, cortisol levels exceed the capacity of this enzyme and
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thereby contribute to increased mineralocorticoid effects. However, GC-resistant patients

can also be asymptomatic or suffer from chronic fatigue as the only complaint, which has

been suggested to result from a relative GC deficiency due to insufficient compensation by

the HPA axis.GCs have many functions in physiology and virtually all tissues are affected

by them. These hormones are essential for cardiovascular and metabolic homeostasis and

many functions of the central nervous system. Therefore, the syndrome of (partial) GC

resistance is rare, and complete resistance to GCs is probably not compatible with life (50).

Geller’s Syndrome (Constitutive Activation of the Mineralcorticoid Receptor)

This is an autosomal-dominant condition caused by gain-of-function mutations in the MR

located on chromosome 4q31. The onset of hypertension is before the age of 20 years.

Pregnancy may exacerbate hypertension in patients with this condition because of elevated

progesterone levels and altered specificity of the MR receptor with progesterone and

traditional MR antagonists now acting as potent MR agonists. The biochemical profile

includes normal potassium and low aldosterone, renine and urine aldosterone levels. Genetic

testing of the MR is required, because a missense mutation S810L located in the

hormonebinding domain of the MR has been found in patients, causing hypertension.

Spironolactone as a therapeutic choice, is contraindicated in MR-L810 carriers (51).

8. Further testing

8.1. Imaging

Imaging of the adrenal glands [computerized tomography (CT) or magnetic resonance

(MRI)] if there is a suspicion of mineralocorticoid, glucocorticoid, or catecholamine excess

or MRI of pituitary gland (in order to exclude Cushing’s disease) are useful in establishing

the cause of hypokalaemia. Moreover an abdominal CT scan should be performed if clinical

and laboratory features of VIPoma are present, such as watery diarrhea that persists with
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fasting (stools are tea-colored and odorless with stool volumes exceeding 700 mL/day), mild

or absent abdominal pain, flushing episodes and lethargy, nausea, vomiting, muscle

weakness and muscle cramps (in 20 percent of patients,where symptoms are related to

hypokalaemia and dehydration), if the CT is inconclusive it may be necessary to perform

radiolabeled pentetreotide scintigraphy or endoscopic ultrasound to confirm the diagnosis

(52).

8.2. ECG

An ECG is recommended for all patients with hypokalaemia. Typically, there is suppression

of the ST segment, decrease in the amplitude of the T wave and an increase in the amplitude

of U waves (often seen in the lateral precordial leads V4 to V6). A variety of arrhythmias

may be associated with hypokalaemia, including sinus bradycardia, premature atrial and

ventricular beats, paroxysmal atrial or junctional tachycardia, atrioventricular block,

ventricular tachycardia, or fibrillation (53).

9. Treatment of hypokalaemia

The treatment of hypokalaemia has four aims: a) reduction of potassium losses, b)

replenishment of potassium stores, c) evaluation for potential toxicities and d) determination

of the cause, in order to prevent future episodes, if possible. Major goal of treatment should

be the management of the underlying disease or elimination of the causative factor.

Discontinuation of laxatives, use of potassium-neutral or potassium-sparing diuretics (if

diuretic therapy is required, such as in heart failure), treatment of diarrhea or vomiting, use of

H2 blockers in patients with nasogastric suction and effective control of hyperglycemia, if

glycosuria is present, are some measures in this direction (54).

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Whether oral or intravenous potassium will be administered, this should be decided according

the severity of the hypokalaemia It is important to remember that every 1 mEq/L decrease in

serum potassium, represents a potassium deficit of approximately 200-400 mEq. However,

this calculation could either overestimate or underestimate the true potassium deficit. Patients

with potassium levels of 2.5-3.5 mEq/L (representing mild to moderate hypokalaemia), may

need only oral potassium replacement. If potassium levels are less than 2.5 mEq/L,

intravenous (i.v.) potassium should be given, with close follow-up, continuous ECG

monitoring, and serial potassium levels measurements. The i.v. route should be also our

choice in patients with severe nausea, vomitting or abdominal distress (55). In patients with

renal impairment, potassium should be very cautiously replaced and the renal team should be

also contacted, if the patient is on dialysis or has severe renal impairment. Administration of

oral potassium should be accompanied with plenty of fluid (between 100 and 250 ml of water,

depending on the form of the tablet of potassium) and is better to be given with or after meals

(56). Regarding i.v. therapy, 0.9 % sodium chloride is the preferred infusion fluid, as 5%

glucose may cause trans-cellular shift of potassium into cells. We should prefer pre/mixed i.v.

infusions. It is critical also to correct the levels of serum magnesium, in order to achieve an

adequate treatment of hypokalaemia (57). An extensive description of the treatment of

hypokalaemia can be found in Table 3.

4. Conclusion

In most patients presenting with hypokalaemia, the cause is apparent from the history (eg,

vomiting, diarrhea, diuretic therapy). Two are the major components for the diagnostic

evaluation: a) assessment of urinary potassium excretion in order to distinguish renal

potassium losses (eg, diuretic therapy, primary aldosteronism) from other causes of

hypokalaemia (eg, gastrointestinal losses, transcellular potassium shifts), and b) assessment

 Page 20 of 32

20

of acid-base status, since some causes of hypokalaemia are associated with metabolic

alkalosis or metabolic acidosis. The renal potassium excretion is better assessed by a 24-hour

urine collection. However, the potassium concentration or, preferably, potassium-to-

creatinine ratio on a spot urine are alternatives. Management of the underlying disease or

contributing factors constitutes the cornerstone of therapeutic approach. Potassium should be

gradually replaced, preferably by oral administration if clinically feasible. In cases of

severe/symptomatic hypokalaemia and cardiac complications, i.v. administration with

continunous ECG monitoring is recommended. In some patients, such as in endocrine related

hypokalaemia cases, multidisciplinary diagnostic and therapeutic approach is needed.

Disclosure Statement: The authors have nothing to disclose

Funding: This research did not receive any specific grant from any funding agency in the

public, commercial or not-for-profit sector.

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Figure legends

Figure 1. Potassium homeostasis

Figure 2. Algorithm of the diagnostic approach to a patient with hypokalaemia

Page 27 of 32

Table 1. Causes of hypokalaemia

Gastrointestinal tract • chronic diarrhea, including chronic laxative abuse and

losses bowel diversion
• clay (bentonite) ingestion, which binds potassium and
greatly decreases absorption
• villous adenoma of the colon, which causes massive
potassium secretion (rarely)

Intracellular shift • glycogenesis during total parenteral nutrition or enteral

hyperalimentation (stimulating insulin release)
• Insulin administration
• stimulation of the sympathetic nervous system,
particularly with beta2-agonists (albuterol, terbutaline)
• thyrotoxicosis (occasionally) due to excessive beta-
sympathetic stimulation (hypokalemic thyrotoxic
periodic paralysis)
• familial periodic paralysis

Renal potassium losses • adrenal steroid excess (Cushing’s syndrome)

• primary hyperaldosteronism
• rare renin-secreting tumors
• glucocorticoid-remediable congenital adrenal
hyperplasia.
• ingestion of substances such as glycyrrhizin
• Bartter syndrome
• Gitelman syndrome
• Liddle syndrome
• renal tubular acidosis
• Fanconi syndrome
• hypomagnesemia

Drugs • thiazides
 Page 28 of 32

• loop diuretics
• osmotic diuretics
• laxatives
• amphotericin B
• antipseudomonal penicillins (carbenicillin)
• penicillin in high doses
• theophylline (both acute and chronic intoxication)
Page 29 of 32

Table 2. Symptoms and signs of hypokalaemia

Mild to moderate hypokalaemia asymptomatic or with mild symptomatology,

especially in elderly people or in people suffering
from heart or kidney disease

Severe hypokalaemia Renal system

• metabolic acidosis
• rhabdomyolisis
• hypokalaemic kidney disease (tubular
interstitial nephritis, nephrogenic diabetes
insipidus)

Nervous system
• leg Cramps
• weakness and paresis
• ascending paralysis

Gastrointenstinal System
• Constipation or intestinal Paralysis

Respiratory System
• Respiratory Failure

Cardiovascular system
• ECG changes (U Waves, T Wave
Flattening, ST Segment changes)
• cardiac arrhythmias
• heart failure
 Page 30 of 32

Table 3. Treatment of Hypokalaemia

Hypokalaemia Treatment Comments

Mild potassium tablets (72mmol/day) or i.v.
(3.0 - 3.4 mEq/L) potassium infusion 25ml (75 • usually asymptomatic
mmol/day) • monitor potassium levels daily
and adjust treatment accordingly
• consider i.v. potassium if patient
cannot tolerate oral potassium

Moderate Potassium tablets • no or minor symptoms

(2.5 - 2.9 mEq/L) (96 mmol/day) or i.v. potassium • monitor potassium levels daily
infusion 25 ml (100 mmol/day) and adjust treatment accordingly
• consider i.v. potassium if patient
cannot tolerate oral potassium

Severe Intravenous replacement • Standard infusion rate: 10 mmol/h

(<2.5mEq/L or symptomatic) 40 mmol KCl in 1L 0.9% NaCl • Maximum infusion rate: 20 mmol/h
(glucose 5% may be used) • Check magnesium levels (reported
automatically if K <2.8mEq/L)
• If patient hypomagnesemic:
initially give 4 ml MgSO4 50% (8
mmol) diluted in 10ml of NaCl
0.9% over 20 min, then start first
40 mmol KCl infusion, followed by
magnesium replacement
Page 31 of 32
 Page 32 of 32

24h-urinary potassium excretion

< 15 mmol/d (UK:UCr <1.5) > 15 mmol/d (UK:UCr >1.5)

x Gastrointestinal loss:
vomiting, diarrhea 9 blood pressure ; RU < blood pressure
x Hypokalaemic periodic
paralysis

X aldosterone to renin ratio (ARR), ; aldosterone ; renin Plasma bicarbonate

9 DOGRVWHURQH concentration

If ;: II 9
renal tubular acidosis x gastric loss
Primary hyperaldosteronism
x diuretic use
x adrenal adenoma or hyperplasia
x magnesium
x bilateral adrenal hyperplasia
deficiency
x adrenal carcinoma
x Bartter syndrome
x familial hyperaldosteronism
x 11-beta hydroxylase deficiency x Gitelman
x 17-alpha hydroxylase deficiency syndrome
x apparent mineralocorticoid
excess
x /LGGOH¶V V\QGURPH
x *HOOHU¶V V\QGURPH
x &XVKLQJ¶V V\QGURPH
x Glucocorticoid resistance