TEORI KASUS UJIAN

HYPOKALEMIA
Diajukan guna melengkapi Tugas Kepaniteraan Klinik
Bagian Ilmu Penyakit Dalam RSUD Kota Semarang

Oleh :
Rahma Marini Sulwana(406138128)
Fistia Naintriani (406138152)

Pembimbing :
dr.Diana Novitasari, Sp PD

Kepaniteraan Klinik Ilmu Penyakit Dalam

Fakultas Kedokteran Universitas Tarumnagara
Rumah Sakit Umum Daerah Semarang
Periode 11 September-22 November 2014

HYPOKALEMIA
DEFINITION
Hypokalemia, defined as a plasma K+ concentration <3.5 mmol/L, may
result from one (or more) of the following: decreased net intake, shift into
cells, increased net loss.
EPIDEMIOLOGY
The frequency of hypokalemia in the general population is difficult to estimate; however,
probably fewer than 1% of people who are not taking medication have a serum potassium
level lower than 3.5 mEq/L. Potassium intake varies according to age, sex, ethnic
background, and socioeconomic status. Whether these differences in intake produce different
degrees of hypokalemia or different sensitivities to hypokalemic insults is not known.
Up to 21% of hospitalized patients have serum potassium levels lower than 3.5 mEq/L, with
5% of patients exhibiting potassium levels lower than 3 mEq/L. Among elderly patients, 5%
demonstrate potassium levels lower than 3 mEq/L.
Of patients taking nonpotassium-sparing diuretics, 20-50% develop hypokalemia. African
Americans and women are more susceptible. The higher frequency of hypokalemia in the
former group may be from lower intake of potassium in African-American men
(approximately 25 mEq/day) than in their white counterparts (70-100 mEq/day). Risk of
hypokalemia in patients taking diuretics is enhanced by concomitant illness, such as heart
failure or nephrotic syndrome.
Other factors associated with a high incidence of hypokalemia include the following:

Eating disorders (incidence of 4.6-19.7% in an outpatient setting[30, 31] )

AIDS (23.1% of hospitalized patients)[32]
Alcoholism (incidence reportedly as high as 12.6%[33] in the inpatient setting), likely
from a hypomagnesemia-induced decrease in tubular reabsorption of potassium
Bariatric surgery[34]
The frequency of hypokalemia increases with age because of increased use of diuretics and
potassium-poor diets. However, infants and younger children are more susceptible to viral GI
infections; emesis or diarrhea from such infections places them at increased risk for
hypokalemia because the depletion of fluid volume and electrolytes from GI loss is relatively
higher than that in older children and adults.
Hypokalemia generally is associated with higher morbidity and mortality, especially from
cardiac arrhythmias or sudden cardiac death. However, an independent contribution of
hypokalemia to increased morbidity/mortality has not been conclusively established. Patients
who develop hypokalemia often have multiple medical problems, making the separation and
quantitation of the contribution by hypokalemia, per se, difficult.

ETIOLOGY
Table 46-3 Causes of Hypokalemia
I. Decreased intake
A. Starvation
B. Clay ingestion
II. Redistribution into cells
A. Acid-base
1.
Metabolic
alkalosis
B. Hormonal
1. Insulin
2. 2-Adrenergic agonists (endogenous or exogenous)
3. -Adrenergic antagonists
C. Anabolic state
1. Vitamin B12 or folic acid (red blood cell production)
2. Granulocyte-macrophage colony stimulating factor (white blood cell
production)
3. Total parenteral nutrition
D. Other
1. Pseudohypokalemia
2. Hypothermia

3. Hypokalemic periodic paralysis

4. Barium toxicity
III. Increased loss
A. Nonrenal
1. Gastrointestinal loss (diarrhea)
2. Integumentary loss (sweat)
B. Renal
1. Increased distal flow: diuretics, osmotic diuresis, salt-wasting nephropathies
2. Increased secretion of potassium
a. Mineralocorticoid excess: primary hyperaldosteronism, secondary
hyperaldosteronism (malignant hypertension, renin-secreting tumors, renal
artery stenosis, hypovolemia), apparent mineralocorticoid excess (licorice,
chewing tobacco, carbenoxolone), congenital adrenal hyperplasia,
Cushing's syndrome, Bartter's syndrome
b. Distal delivery of non-reabsorbed anions: vomiting, nasogastric suction,
proximal (type 2) renal tubular acidosis, diabetic ketoacidosis, glue-sniffing
(toluene abuse), penicillin derivatives
c. Other: amphotericin
hypomagnesemia

B,

Liddle's

syndrome,

Redistribution into Cells

Movement of K+ into cells may transiently decrease the plasma K + concentration without
altering total body K+ content. For any given cause, the magnitude of the change is relatively
small, often <1 mmol/L. However, a combination of factors may lead to a significant fall in
the plasma K+ concentration and may amplify the hypokalemia due to K + wasting. Metabolic
alkalosis is often associated with hypokalemia. This occurs as a result of K + redistribution as
well as excessive renal K+ loss. Treatment of diabetic ketoacidosis with insulin may lead to
hypokalemia due to stimulation of the Na+-H+ antiporter and (secondarily) the Na+, K+-

ATPase pump. Furthermore, uncontrolled hyperglycemia often leads to K+ depletion from an

osmotic diuresis (see below). Stress-induced catecholamine release and administration of 2adrenergic agonists directly induce cellular uptake of K+ and promote insulin secretion by
pancreatic islet cells. Hypokalemic periodic paralysis is a rare condition characterized by
recurrent episodic weakness or paralysis (Chap. 382). Since K + is the major ICF cation,
anabolic states can potentially result in hypokalemia due to a K + shift into cells. This may
occur following rapid cell growth seen in patients with pernicious anemia treated with
vitamin B12 or with neutropenia after treatment with granulocyte-macrophage colony
stimulating factor. Massive transfusion with thawed washed red blood cells (RBCs) could
cause hypokalemia since frozen RBCs lose up to half of their K+ during storage.
Nonrenal Loss of Potassium
Excessive sweating may result in K+ depletion from increased integumentary and renal K +
loss. Hyperaldosteronism, secondary to ECF volume contraction, enhances K + excretion in
the urine (Chap. 336). Normally, K+ lost in the stool amounts to 510 mmol/d in a volume of
100200 mL. Hypokalemia subsequent to increased gastrointestinal loss can occur in patients
with profuse diarrhea (usually secretory), villous adenomas, VIPomas, or laxative abuse.
However, the loss of gastric secretions does not account for the moderate to severe K +
depletion often associated with vomiting or nasogastric suction. Since the K+ concentration of
gastric fluid is 510 mmol/L, it would take 3080 L of vomitus to achieve a K + deficit of
300400 mmol typically seen in these patients. In fact, the hypokalemia is primarily due to
increased renal K+ excretion. Loss of gastric contents results in volume depletion and
metabolic alkalosis, both of which promote kaliuresis. Hypovolemia stimulates aldosterone
release, which augments K+ secretion by the principal cells. In addition, the filtered load of
HCO3 exceeds the reabsorptive capacity of the proximal convoluted tubule, thereby
increasing distal delivery of NaHCO3, which enhances the electrochemical gradient favoring
K+ loss in the urine.

Renal Loss of Potassium

In general, most cases of chronic hypokalemia are due to renal K + wasting. This may be due
to factors that increase the K+ concentration in the lumen of the CCD or augment distal flow
rate. Mineralocorticoid excess commonly results in hypokalemia. Primary
hyperaldosteronism is due to dysregulated aldosterone secretion by an adrenal adenoma
(Conn's syndrome) or carcinoma or to adrenocortical hyperplasia. In a rare subset of patients,
the disorder is familial (autosomal dominant) and aldosterone levels can be suppressed by
administering low doses of exogenous glucocorticoid. The molecular defect responsible for
glucocorticoid-remediable hyperaldosteronism is a rearranged gene (due to a chromosomal
crossover), containing the 5'-regulatory region of the 11-hydroxylase gene and the coding
sequence of the aldosterone synthase gene. Consequently, mineralocorticoid is synthesized in
the zona fasciculata and regulated by corticotropin. A number of conditions associated with
hyperreninemia result in secondary hyperaldosteronism and renal K + wasting. High renin
levels are commonly seen in both renovascular and malignant hypertension. Renin-secreting
tumors of the juxtaglomerular apparatus are a rare cause of hypokalemia. Other tumors that
have been reported to produce renin include renal cell carcinoma, ovarian carcinoma, and
Wilms' tumor. Hyperreninemia may also occur secondary to decreased effective circulating
arterial volume.

In the absence of elevated renin or aldosterone levels, enhanced distal nephron secretion of
K+ may result from increased production of non-aldosterone mineralocorticoids in congenital
adrenal hyperplasia. Glucocorticoid-stimulated kaliuresis does not normally occur due to the
conversion of cortisol to cortisone by 11-hydroxysteroid dehydrogenase (11-HSDH).
Therefore, 11-HSDH deficiency or suppression allows cortisol to bind to the aldosterone
receptor and leads to the syndrome of apparent mineralocorticoid excess. Drugs that inhibit
the activity of 11-HSDH include glycyrrhetinic acid, present in licorice, chewing tobacco,
and carbenoxolone. The presentation of Cushing's syndrome may include hypokalemia if the
capacity of 11-HSDH to inactivate cortisol is overwhelmed by persistently elevated
glucocorticoid levels.
Liddle's syndrome is a rare familial (autosomal dominant) disease characterized by
hypertension, hypokalemic metabolic alkalosis, renal K+ wasting, and suppressed renin and
aldosterone secretion. Increased distal delivery of Na+ with a nonreabsorbable anion (not Cl)
enhances K+ secretion. Classically, this is seen with proximal (type 2)renal tubular acidosis
(RTA) and vomiting, associated with bicarbonaturia. Diabetic ketoacidosis and toluene abuse
(glue sniffing) can lead to increased delivery of -hydroxybutyrate and hippurate, respectively,
to the CCD and to renal K + loss. High doses of penicillin derivatives administered to volumedepleted patients may likewise promote renal K+ secretion as well as an osmotic diuresis.
Classic distal (type 1) RTA is associated with hypokalemia due to increased renal K+ loss, the
mechanism of which is uncertain. Amphotericin B causes hypokalemia due to increased distal
nephron permeability to Na+ and K+ and to renal K+ wasting.
Bartter's syndrome is a disorder characterized by hypokalemia, metabolic alkalosis,
hyperreninemic hyperaldosteronism secondary to ECF volume contraction, and
juxtaglomerular apparatus hyperplasia. Finally, diuretic use and abuse are common causes of
K+ depletion. Carbonic anhydrase inhibitors, loop diuretics, and thiazides are all kaliuretic.
The degree of hypokalemia tends to be greater with long-acting agents and is dose-dependent.
Increased renal K+ excretion is due primarily to increased distal solute delivery and secondary
hyperaldosteronism (due to volume depletion).
PATHOPHYSIOLOGY
An abnormal potassium balance occurs, for example, if potassium supply is inadequate (!
A1). As intravenous infusion of K+ initially passes into a compartment, namely plasma, that
has a relatively low potassium content;
too rapid K+ administration can lead to a dangerous level of hyperkalemia even if there is a
K+ deficiency. The secretion of K+ in exchange for Na+ in the distal tubules and collecting
duct is the decisive step in the renal elimination of K+ (!A2; see also p. 96ff.). Renal loss of
K+ occurs, for example, in hyperaldosteronism (!p. 266) or if there is an increased
availability of Na+ in the distal tubules (!p. 98 D). Conversely, renal K+ elimination is
decreased
if: 1) Na+ reabsorption is impaired in the distal tubules, as in hypoaldosteronism; 2) diuretics
acting on the connecting tubule and collecting
duct have been administered; or 3) there is a decreased supply of Na+ (e.g., in renal failure).
In alkalosis fewer H+ ions are secreted in the connecting tubule and collecting duct and more
K+ is lost, while conversely acidosis decreases
K+ secretion in the distal nephron. K+ may also be lost via the gut (!A3). If there is an
increased supply of Na+ or in hyperaldosteronism, an increased amount of Na+ is similarly
absorbed in the colon in exchange for K+.

In (extracellular) alkalosis the cells release H+ in exchange for Na+ (Na+/H+ exchangers)
and pump the Na+ out again in exchange for K+ (Na+/K+-ATPase) (!A5). This K+ uptake by
the cells causes hypokalemia. Conversely, acidosis leads to hyperkalemia. Glucose stimulates
the release of insulin that, by activating
Na+/H+ exchangers, Na+-K+-2 Cl cotransporters and Na+/K+-ATPase, stimulates the
uptake of K+ by the cells. In insulin deficiency or hypoglycemia
(when fasting), the cells lose K+. The administration of insulin in diabetic hyperglycemia(!p.
286ff.) or food intake by a starving person may lead to dangerous hypokalemia because the
cells will be taking up K+.
Catecholamines promote the uptake of K+ by the cells via -receptors and the cellular
release of K+ from the cells via "-receptors The effects of changed plasma K+ concentratio
are in part mediated by changes in the membrane potential. Hypokalemia hyperpolarizes
while hyperkalemia depolarizes the K+ equilibrium potential, and thus the membrane
potential of selective cells. In this way hypokalemia reduces the excitability of nerve cells
(hyporeflexia), skeletal muscles (adynamia), and smooth muscles (gut, bladder, etc.) (!A6).
Conversely, hyperkalemia can increase the excitability of the nervous system (hyperreflexia),
smooth muscles (!A7), and skeletal muscles (!p. 306). In contrast, a decrease in K+
concentration reduces the conductance of the K+ channels, thus decreasing the
hyperpolarizing effect of K+ on the membrane potential. This promotes the heterotopic
automaticity of the heart that may even trigger ventricular fibrillation
(!p.188ff.). The reduction of K+ conductance is also responsible for delayed repolarization of
the Purkinje fibers. Hypokalemia often produces a prominent U wave in the
electrocardiogram (ECG) (!A6). Conversely, hyperkalemia increases the K+ conductance, the
action potential is shortened, and correspondingly also the ST segment in the ECG (!A7).
Lack of potassium promotes the cellular retention of H+ and its secretion in the distal tubules.
This results in an alkalosis (!p. 86). Conversely, K+ excess leads to acidosis (!p. 88).
Hypokalemia also causes polyuria (!p.100) and can ultimately lead to irreversible tubular cell
damage. Lastly, the release of a number of hormones is abnormal in K+ deficiency
(especially insulin [!p. 286] and aldosterone [!p. 266]).
Inhibition of Na+-K+-2 Cl cotransporter (!B14) by loop diuretics stops NaCl reabsorption
in the loop of Henle and thus urinary concentration (!p.100). This results in massive
natriuresis and diuresis. Distal tubules and collecting ducts are overwhelmed by Na+ and
reabsorb Na+ in exchange for K+ (see below), leading to kaliuresis and hypokalemia. The
Na+-K+-2 Cl cotransport needs K+ as substrate, which must recirculate via K+ channels
(ROMK; !B15). In K+ deficiency or hypokalemia the K+ channel is closed off and NaCl
reabsorption in the loop of Henle is impaired. A genetic defect in the Na+-K+-2 Cl
cotransporter, Cl or K+ channel are causes of Bartters syndrome which gives rise to
impaired urinary concentration, natriuresis, hypokalemia (except in defects of ROMK), and
lowered blood pressure, despite increased renin, angiotensin and aldosterone formation (!
p.114). Because of the abnormal Na+ reabsorption, the kidney produces large amounts of
prostaglandins that inhibit Na+-reabsorption in more distal nephron segments and thus
aggravate NaCl loss. Furthermore they cause life-threatening peripheral vasodilation. a
hyperactive Na+ channel (Liddles syndrome) leads to Na+ retention and hypertension.

CLINICAL FEATURES
The clinical manifestations of K+ depletion vary greatly between individual patients, and their
severity depends on the degree of hypokalemia. Symptoms seldom occur unless the plasma
K+ concentration is <3 mmol/L. Fatigue, myalgia, and muscular weakness of the lower
extremities are common complaints and are due to a lower (more negative) resting membrane
potential. More severe hypokalemia may lead to progressive weakness, hypoventilation (due
to respiratory muscle involvement), and eventually complete paralysis. Impaired muscle
metabolism and the blunted hyperemic response to exercise associated with profound K +
depletion increase the risk of rhabdomyolysis. Smooth-muscle function may also be affected
and manifest as paralytic ileus.
The electrocardiographic changes of hypokalemia (Fig. 221-16) are due to delayed
ventricular repolarization and do not correlate well with the plasma K+ concentration. Early
changes include flattening or inversion of the T wave, a prominent U wave, ST-segment
depression, and a prolonged QU interval. Severe K + depletion may result in a prolonged PR
interval, decreased voltage and widening of the QRS complex, and an increased risk of
ventricular arrhythmias, especially in patients with myocardial ischemia or left ventricular
hypertrophy. Hypokalemia may also predispose to digitalis toxicity. Hypokalemia is often
associated with acid-base disturbances related to the underlying disorder. In addition, K +
depletion results in intracellular acidification and an increase in net acid excretion or new
HCO3 production. This is a consequence of enhanced proximal HCO 3 reabsorption,
increased renal ammoniagenesis, and increased distal H+ secretion. This contributes to the
generation of metabolic alkalosis frequently present in hypokalemic patients. NDI (see
above) is not uncommonly seen in K + depletion and is manifest as polydipsia and polyuria.

Glucose intolerance may also occur with hypokalemia and has been attributed to either
impaired insulin secretion or peripheral insulin resistance.
DIAGNOSIS

COMPLICATIONS
Cardiovascular complications
Hypokalemia has widespread actions in many organ systems that, over time, may result in
cardiovascular disease. Cardiovascular complications are clinically the most important
harbingers of significant morbidity or mortality from hypokalemia.
Although hypokalemia has been implicated in the development of atrial and ventricular
arrhythmias, ventricular arrhythmias have received the most attention. Increased
susceptibility to cardiac arrhythmias is observed with hypokalemia in the following settings:

Congestive heart failure

Underlying ischemic heart disease/acute myocardial ischemia
Aggressive therapy for hyperglycemia, such as with diabetic ketoacidosis
Digitalis therapy

Methadone therapy
Conn syndrome.
Muscular complications
Muscle weakness, depression of the deep-tendon reflexes, and even flaccid paralysis can
complicate hypokalemia. Rhabdomyolysis can be provoked, especially with vigorous
exercise. However, rhabdomyolysis has also been seen as a complication of severe
hypokalemia, complicating primary hyperaldosteronism in the absence of exercise.
Renal complications
Abnormalities of renal function often accompany acute or chronic hypokalemia. These may
include nephrogenic diabetes insipidus. They also may include metabolic alkalosis from
impaired bicarbonate excretion and enhanced ammoniagenesis, as well as cystic degeneration
and interstitial scarring.
Gastrointestinal complications
Hypokalemia decreases gut motility, which can lead to or exacerbate an ileus. Hypokalemia
also is a contributory factor in the development of hepatic encephalopathy in the setting of
cirrhosis.
Metabolic complications
Hypokalemia has a dual effect on glucose regulation by decreasing insulin release and
peripheral insulin sensitivity. Clinical evidence suggests that the hypokalemic effect of
thiazide is the causative factor in thiazide-associated diabetes mellitus.
TREATMENT
The therapeutic goals are to correct the K+ deficit and to minimize ongoing losses. With the
exception of periodic paralysis, hypokalemia resulting from transcellular shifts rarely requires
intravenous K+ supplementation, which can lead to rebound hyperkalemia. It is generally
safer to correct hypokalemia via the oral route. The degree of K + depletion does not correlate
well with the plasma K+ concentration. A decrement of 1 mmol/L in the plasma K +
concentration (from 4.0 to 3.0 mmol/L) may represent a total body K + deficit of 200400
mmol, and patients with plasma levels under 3.0 mmol/L often require in excess of 600 mmol
of K+ to correct the deficit. Furthermore, factors promoting K+ shift out of cells (e.g., insulin
deficiency in diabetic ketoacidosis) may result in underestimation of the K + deficit.
Therefore, the plasma K+ concentration should be monitored frequently when assessing the
response to treatment. Potassium chloride is usually the preparation of choice and will
promote more rapid correction of hypokalemia and metabolic alkalosis. Potassium
bicarbonate and citrate (metabolized to HCO3) tend to alkalinize the patient and would be
more appropriate for hypokalemia associated with chronic diarrhea or RTA.
Patients with severe hypokalemia or those unable to take anything by mouth require
intravenous replacement therapy with KCl. The maximum concentration of administered K+
should be no more than 40 mmol/L via a peripheral vein or 60 mmol/L via a central vein. The
rate of infusion should not exceed 20 mmol/h unless paralysis or malignant ventricular
arrhythmias are present. Ideally, KCl should be mixed in normal saline since dextrose

solutions may initially exacerbate hypokalemia due to insulin-mediated movement of K + into

cells. Rapid intravenous administration of K+ should be used judiciously and requires close
observation of the clinical manifestations of hypokalemia (electrocardiogram and
neuromuscular examination).

DAFTAR PUSTAKA
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2. Fauci, Braunwald, Kasper, et al. Principal of Internal Medicine;edisi 17; chapter 46.
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methadone treatment.Ann Intern Med. March 2009;150:387-395. [Medline].
4. Born-Frontsberg E, Reincke M, Rump LC, et al. Cardiovascular and cerebrovascular
comorbidities of hypokalemic and normokalemic primary aldosteronism: results of
the German Conn's Registry. J Clin Endocrinol Metab. Apr 2009;94(4):112530. [Medline].

5. Toto A, Takahashi Y, Kishimoto M, Minowada S, Aibe H, Hasuo K, et al. Primary

aldosteronism associated with severe rhabdomyolysis due to profound
hypokalemia. Intern Med. 2009;48:219-223. [Medline].
6. Shafi, T, Appel LJ, Miller III, ER, Klag MJ, et al. Changes in Serum Potassium
Mediate Thiazide-Induced Diabetes. Hypertension. 2008;52:1022-1029.