Disorders of Potassium: Hypokalemia

Cause

Mechanism

1. Dietary

Low K⁺ diet

Combination of low dietary K⁺ and its obligatory loss in urine

Eating disorders

Low oral intake and total body K⁺ depletion

High carbohydrate intake with alcohol

Low K⁺ intake and shift into cells

2. Transcellular distribution

Insulin

Shift of K⁺ into cells

β₂-agonists (albuterol, clenbuterol)

Same as above

Alkalosis

Same as above

B₁₂ injections

Consumption of K⁺ in protein synthesis

Familial hypokalemic periodic paralysis

Mutation in the gene encoding the α₁-subunit of skeletal muscle L-type Ca²⁺ channel (60–70 % cases) or mutation in the gene encoding skeletal muscle Na⁺ channel

Thyrotoxic hypokalemic periodic paralysis

Hyperthyroidism

3. Renal loss

Drugs (diuretics, penicillins, amphotericin B, lithium, cisplatin, licorice, gentamicin, amikacin, tobramycin)

Renal K⁺ wasting

Hypokalemic-hypertension disorders

Activation of renin-AII-aldosterone

Malignant hypertension

Same as above

Renovascular hypertension

Same as above

Renin secreting tumors

Excess aldosterone production by adrenals

Primary aldosteronism

Mutation in ENaC

Liddle syndrome

Excess aldosterone production

Glucocorticoid-remediable aldosteronism

Deficiency of 11β-hydroxysteroid dehydrogenase enzyme

Apparent mineralocorticoid excess syndrome

Mutation in mineralocorticoid receptor

Activating mutations of the mineralocorticoid receptor

Deficiency of 11β- and 17α-hydroxylase enzymes

Congenital adrenal hyperplasia

Renal K⁺ wasting

Hypokalemic-normotensive disorders

Renal tubular acidosis (types 1 and 2)

Renal K⁺ wasting

Bartter syndrome

Mutations in Na/K/2Cl cotransporter and ROMK channel

Gitelman syndrome

Mutation in distal tubule Na/Cl cotransporter

Hypomagnesemia

Renal K⁺ wasting

Cushing syndrome

Same as above

4. Gastrointestinal loss

Diarrhea

K⁺ loss in stools

Vomiting

Renal K⁺ wasting

5. Skin loss

Excessive heat

Skin loss

Strenuous exercise

Renal loss

ENaC epithelial sodium channel, ROMK renal outer medullary potassium channel

Some Specific Causes of Hypokalemia

Hypokalemic Periodic Paralysis (HypoPP)

There are two major types of hypokalemic periodic paralysis: familial and thyrotoxic.

Familial

Familial HypoPP is an autosomal dominant form. A genetic test in the context of symptoms is the gold standard for diagnosis.

The most familial form of HypoPP results in 60–70 % of cases from mutation in the gene encoding the α₁-subunit of skeletal muscle L-type Ca²⁺ channel. In the remaining 10–20 % cases, the mutation occurs in the gene that codes for muscle Na⁺ channel.
Hypokalemia is entirely due to movement of K⁺ from extracellular fluid (ECF) to intracellular fluid (ICF) compartment.
Onset is usually before 20 years of age, and the prevalence is 1 per 100,000 people.
Symptoms include severe muscle weakness, progressing at times to flaccid paralysis. A discrete attack may last hours to days.
Triggers or stimuli of attacks are high carbohydrate meal (insulin release), cold exposure during rest period following strenuous exercise (β₂-adrenergic surge), and administration of glucocorticoids
Treatment:
- In acute attacks, patients are treated with either oral or i.v. KCl. The rate of administration should not exceed 10 mEq/h, as there is a risk for rebound hyperkalemia.
- Acetazolamide (250–750 mg/day) to prevent the frequency of attacks. The mechanism is unrelated to inhibition of carbonic anhydrase.
- Diet that is high in K⁺, low in Na⁺ and carbohydrate may reduce the frequency and severity of attacks.

Thyrotoxic

Thyrotoxic HypoPP is the acquired form that is precipitated by subclinical or clinical hyperthyroidism.
Excess stimulation of Na/K-ATPase activity by thyroid hormones, and reduced K⁺ efflux from skeletal muscle seem to be responsible for acute attacks of HypoPP.
Asian and Hispanic males (20–50 years of age) are at increased risk for this disorder.
Symptoms and triggers are similar to the familial type.
Treatment includes KCl (oral or i.v., as indicated) and propranolol. Antithyroid medications are part of long-term management in these patients.

Hypokalemic-Hypertensive Disorders

Malignant Hypertension

A disorder of high renin-AII-aldosterone.
Characterized by hypertension (HTN), hypokalemia, and metabolic alkalosis.
Hyponatremia due to pressure natriuresis is occasionally seen.

Renal Artery Stenosis

It is similar to malignant HTN with high renin-AII-aldosterone.

Patients present with severe hypokalemia, HTN, and metabolic alkalosis.
Stenosis is caused by fibromuscular dysplasia in the young and atherosclerosis in the elderly.
Removal of stenosis by stents or surgery improves hypokalemia and HTN.
Hyponatremia due to pressure natriuresis is occasionally seen.

Primary Aldosteronism

Caused by autonomous secretion of aldosterone by adrenal adenoma or hyperplasia of the adrenal gland.
Characterized by hypokalemia, HTN, and metabolic alkalosis.
Plasma renin levels are low because of aldosterone-induced Na⁺ reabsorption and volume expansion. Despite volume expansion, aldosterone levels are high.
Removal of adenoma or treatment with K⁺-sparing diuretics (spironolactone) corrects metabolic abnormalities and HTN.

Liddle Syndrome

An autosomal dominant disorder, caused by mutations in the ENaC.
Characterized by Na⁺ reabsorption, hypokalemia, and low renin-aldosterone HTN.
Amiloride is the drug of choice (see questions in case 3 for more details).

Glucocorticoid Remediable Hyperaldosteronism (GRA)

Also called familial hyperaldosteronism type 1.
Caused by fusion of two enzymes: aldosterone synthase and 11β-hydroxylase.
Patients with GRA may have hypokalemia, HTN, and metabolic alkalosis.
Plasma renin is suppressed, but aldosterone levels are increased.
Aldosterone secretion is stimulated by adrenocorticotropic hormone (ACTH) and not by angiotensin II. Therefore, administration of glucocorticoid suppresses excessive aldosterone secretion and improves hypokalemia and HTN (see questions in case 3 for more details).

Apparent Mineralocorticoid Excess Syndrome (AME)

Cortisol, in addition to aldosterone, binds to mineralocorticoid receptor (MR) , and promotes Na⁺ reabsorption. Therefore, endogenous cortisol is converted into inactive cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2.
Mutations in 11β-hydroxysteroid dehydrogenase type 2 reduce its activity and prevent the conversion from cortisol to cortisone. As a result, cortisol exerts mineralocorticoid actions.
Patients with AME present with hypokalemia, metabolic alkalosis, HTN, and low plasma renin-aldosterone levels.
Treatment with spironolactone or amiloride improves hypokalemia and HTN (see questions in case 3 for more details).
AME can also be acquired. Ingestion of licorice, chewing tobacco, bioflavonoids or carbenoxolone can cause AME. These agents contain glycyrrhetinic acid, which is a competitive inhibitor of 11β-hydroxysteroid dehydrogenase type 2.
Clinical manifestations are similar to the genetic type of AME.
Glycyrrhetinic acid has been suggested as a potential therapy for hyperkalemia in dialysis patients.

Activating Mutations of the Mineralocorticoid Receptor

A mutation in an MR gene causes conformational change that allows nonmineralocorticoids such as progesterone or spironolactone to act as potent agonists.
Subjects with this mutation develop HTN before the age of 20 with hypokalemia, and low renin-aldosterone levels.
Pregnancy exacerbates HTN without proteinuria, edema, or neurologic changes because of high progesterone levels.
Spironolactone is contraindicated for hypertensive management in nonpregnant subjects (see questions in case 3 for more details).

Table 15.2 summarizes plasma renin and aldosterone levels in hypokalemic conditions associated with HTN.

Table 15.2

Plasma renin and aldosterone levels in hypokalemic-hypertensive states

Disorder	Renin	Aldosterone
Malignant hypertension	↑	↑
Renovascular hypertension	↑	↑
Renin secreting tumor	↑	↑
Primary aldosteronism	↓	↑
Liddle syndrome	↓	↓
GRA	↓	↑
AME	↓	↓
Licorice ingestion	↓	↓
Activating mutations of MR receptor	↓	↓

GRA glucocorticoid remediable hyperaldosteronism, AME apparent mineralocorticoid excess syndrome, ↑ increase, ↓ decrease

Hypokalemic-Normotensive Disorders

Renal Tubular Acidosis (RTA)

Both type 1 (distal) and type 2 (proximal) RTAs cause hypokalemia because of K⁺ wasting in the urine due to high aldosterone levels.

Bartter Syndrome

As shown in Table 3.1, there are five types of Bartter syndrome, which are caused by genetic defects in the apical or basolateral membrane transport systems of the thick ascending limb of Henle’s loop.
Bartter syndrome behaves similar to a patient on loop diuretics.
All of them are characterized by hypokalemia, metabolic alkalosis, and normal blood pressure (BP) or at times hypotension.
Bartter syndromes occur in perinatal period or early in life.
Treatment includes supplementation of K⁺. Spironolactone, amiloride, ACE-inhibitors, and nonsteroidal anti-inflammatory drugs have been tried with variable results

Gitelman Syndrome

As shown in Tables 3.1 and 15.1, Gitelman syndrome is caused by mutations in distal tubule Na⁺ channel (ENaC).
Gitelman syndrome behaves similar to a patient on thiazide diuretic.
Characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and normal BP. Although, these manifestations are similar to Bartter syndrome, Gitelman syndrome occurs at any age (1–70 years), but is diagnosed in young adults.
The only way one can distinguish Gitelman syndrome from Bartter syndrome is urinary Ca²⁺ excretion. In Gitelman syndrome, urinary excretion of Ca²⁺ is low (hypocalciuria), whereas in Bartter syndrome it is normal or high (hypercalciuria).
Hypocalciuria is due to proximal tubule reabsorption of Ca²⁺, and hypomagnesemia is probably related to downregulation of Mg²⁺ channel in the distal collecting tubule.
Treatment includes lifelong liberal salt intake, K⁺ and Mg²⁺ supplementation (KCl, MgCl₂) as well as K⁺-sparing diuretics (spironolactone, amiloride, spironolactone-receptor blocker).

Hypokalemia due to Aminoglycosides

Gentamicin, amikacin, tobramycin are cationic drugs that bind to the Ca²⁺-sensing receptor on the basolateral membrane of the thick ascending limb of Henle’s loop , and inhibit Na/K/2Cl cotransporter with resultant inhibition of ROMK channel. As a result, K⁺ secretion into the lumen is inhibited, causing renal salt, K⁺, Ca²⁺, and Mg²⁺ wasting. Other cationic drugs, such as cisplatin, can act in a similar fashion.
Discontinuation of these drugs improves the electrolyte abnormalities.

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Jun 20, 2017 | Posted by admin in NEPHROLOGY | Comments Off

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Disorders of Potassium: Hypokalemia