Hypokalemia

Case 14-1: Hypokalemia With Paralysis

A 45-year-old man developed profound weakness in both his lower and upper extremities over the past few hours. He had two similar episodes in the preceding two months. Prior to each of these episodes, he had a very large intake of sweetened soft drinks. He was not taking any medications, including diuretics or laxatives. He has no family history of hypokalemia, periodic paralysis, or hyperthyroidism. On physical examination, he was alert and oriented. His BP was 150/70 mm Hg, his heart rate was 124 beats/min, and his respiratory rate was 18 breaths/min. The only neurologic finding was symmetrical flaccid paralysis with areflexia in all four limbs. The pH and PCO ₂ values shown in the table below were from an arterial blood sample, whereas all other data were from a venous blood sample. The ECG showed sinus tachycardia and prominent U waves. Tests of thyroid function were normal.

Case 14-2: Hypokalemia With a Sweet Touch

A 76-year-old Asian man became very weak this morning and was unable to walk for the past 6 hours. He denied nausea, vomiting, or diarrhea. He did not take diuretics or laxatives. Hypokalemia (P _K 3.3 mmol/L) and hypertension were noted by his family physician about 1 year ago but were not investigated further. He had no previous history or family history of similar episodes. His BP was 160/96 mm Hg, and his heart rate was 70 beats/min. The only positive finding on physical examination was symmetric flaccid paralysis with areflexia. His ECG showed prominent U waves and prolonged Q-T interval. The laboratory data on admission are presented in the following table:

The patient was given a large quantity of KCl; his weakness improved when his P _K rose to 2.5 mmol/L. Over the following 2 weeks, his P _K and his BP returned to normal levels and his body weight decreased from 78 to 74 kg. When the results became available, his P _Renin mass was low, his P _Aldosterone was low, and the concentration of cortisol in his plasma (P _Cortisol ) was in the normal range.

Case 14-3: Hypokalemia in a Newborn

A young boy, who is now 2 years of age, is the first child of a consanguineous marriage (his parents are first cousins). Pregnancy was complicated by severe polyhydramnios, for which amniocentesis was performed on two occasions early in the course of pregnancy. Delivery occurred in the 26th week; he weighed 2.2 lb (1 kg). His urine volume was very large, which resulted in a loss of more than 20% of his weight in the first 24 hours. The concentration of Na ⁺ ions in his urine (U _Na ) was very high (98 mmol/L; expected, <10 mmol/L). His P _K was high (5.5 mmol/L), but after aggressive infusion of isotonic saline, hypokalemia was consistently present (P _K ∼3.3 mmol/L).

During the first month of life, he required a large daily fluid volume to replace his urine output (∼250 mL/kg/day). There was also a huge excretion of NaCl (∼12 mmol/kg/day), and he required supplements of NaCl to maintain hemodynamic stability. He was treated with a prostaglandin synthesis inhibitor (indomethacin), and his renal salt wasting largely disappeared. Notwithstanding, this seemed to have uncovered a second abnormality because he developed water diuresis with large urine volume and urine osmolality (U _Osm ) of less than 100 mosmol/kg H ₂ O. In response to the administration of 1-deamino 8-D-arginine vasopressin (desmopressin [dDAVP]), his urine flow rate did not fall and his U _Osm did not rise. The laboratory data in the following table are typical of measurements done during his first week of life:

Clinical Implications

There are a number of clinical implications from the understanding of this physiology of the distribution of K ⁺ ions between the ECF and ICF compartments. An acute shift of K ⁺ ions into cells occurs when insulin is given to a patient with diabetic ketoacidosis (DKA). In patients with DKA who present with a P _K of less than 4 mmol/L, it is suggested that the administration of insulin be delayed for 1-2 hours and aggressive therapy with the administration of intravenous KCl be promptly started to bring the P _K to a value that is close to 4 mmol/L to avoid the risk of a severe degree of hypokalemia and possible cardiac arrhythmia when insulin is given. As a general rule, in patients with a severe degree of hypokalemia, KCl should not be administered in a solution that contains glucose, because even a small degree of an acute shift of K ⁺ ions into cells due to the release of insulin can be dangerous in this setting. Although not supported by data, the notion that a high carbohydrate load is a risk factor for development of an acute attack in patients with hypokalemic periodic paralysis may be explained by a spike in blood insulin level that triggers a shift of K ⁺ ions into cells.

In patients with a severe degree of hypokalemia and acidemia due to metabolic acidosis, the P _K should be raised to at least 3 mmol/L before administering NaHCO ₃ , because even a small degree of an acute shift of K ⁺ ions into cells can be dangerous in this setting (see margin note).

An acute shift of K ⁺ ions into cells may occur in conditions associated with an adrenergic surge (e.g., acute myocardial infarction, acute pancreatitis, subarachnoid hemorrhage, and traumatic brain injury; see discussion of Case 14-1 ). Acute hypokalemia may also occur in patients who are given a large dose of β ₂ -agonists (e.g., albuterol for treatment of bronchial asthma, amphetamine for weight loss). Because large doses of caffeine result in an adrenergic surge, acute hypokalemia may be also seen in this setting. Nonselective β ₂ -antagonists are suggested in the treatment of patients with acute hypokalemia precipitated by an adrenergic surge.

Patients with catabolic states such as DKA have a deficit of K ⁺ ions and phosphate anions because these ions were released from cells and lost in the urine. A shift of K ⁺ ions into cells occurs when patients with DKA are treated with insulin and phosphate anions are provided from the diet. Hence, hypokalemia may develop if a sufficient amount of K ⁺ ions is not given. A similar situation arises in cachectic patients when they are treated with parenteral nutrition and in patients with pernicious anemia early in the course of therapy with vitamin B ₁₂ .

Secretion of K ⁺ Ions in the CDN

The process of secretion of K ⁺ ions by principal cells in the CDN has two elements. First, a lumen-negative transepithelial voltage must be generated by the electrogenic reabsorption of Na ⁺ ions (i.e., reabsorption of Na ⁺ ions without their accompanying anions, which are largely Cl ⁻ ions) via the epithelial sodium ion channel (ENaC). Second, open renal outer medullary K ⁺ ion (ROMK) channels must be present in the luminal membrane of principal cells.

Aldosterone actions lead to an increase in the number of open ENaC units in the luminal membrane of principal cells in the CDN and hence the rate of electrogenic reabsorption of Na ⁺ ions. Aldosterone binds to its receptor in the cytoplasm of principal cells, and the hormone–receptor complex enters the nucleus, leading to the synthesis of new proteins, including the serum and glucocorticoid regulated kinase-1 (SGK-1). SGK-1 increases the number of open ENaC in the luminal membrane of principal cells via its effect to phosphorylate and inactivate the ubiquitin ligase, Nedd 4-2 (see Chapter 13 , Fig. 13-9 ).

The concentration of cortisol in plasma is at least a hundred times higher than that of aldosterone. Moreover, cortisol binds to the intracellular aldosterone receptor with the same avidity as aldosterone. Nevertheless, cortisol does not normally act as a mineralocorticoid because it is converted to an inactive form (cortisone) by the 11 β-hydroxy steroid dehydrogenase (11 β-HSDH) 1 and 2 enzyme system before it can reach the receptor for aldosterone (see Chapter 13 ). There are three circumstances, however, when cortisol acts as a mineralocorticoid: first, when 11β-HSDH is congenitally lacking (e.g., in patients with apparent mineralocorticoid excess syndrome); second, when 11β-HSDH is inhibited (e.g., by glycyrrhizinic acid in licorice); and third, when the activity of 11β-HSDH is overwhelmed by a large excess of cortisol (e.g., in a patient with an ACTH-producing tumor).

An electroneutral NaCl transport in the CCD seems to be mediated by the parallel activity of the Na ⁺ -independent $\text{C}{\text{l}}^{-}/{{\text{HCO}}_{\text{3}}}^{-}$ anion exchanger (pendrin) and the Na ⁺ -dependent $\text{C}{\text{l}}^{-}/{{\text{HCO}}_{\text{3}}}^{-}$ anion exchanger (NDCBE) (see Chapter 13 , Fig. 13-10 ). An increase in luminal fluid concentration of ${{\text{HCO}}_{\text{3}}}^{-}$ ions and/or an alkaline luminal fluid pH seem to increase the amount of K ⁺ secreted in the CDN. An increase in luminal ${{\text{HCO}}_{\text{3}}}^{-}$ ion concentration may inhibit pendrin, and hence NDCBE, and thereby the electroneutral NaCl reabsorption. In addition, an increase in luminal fluid ${{\text{HCO}}_{\text{3}}}^{-}$ ion concentration may increase the abundance and activity of ENaC in the luminal membrane of principal cells. This may also lead to a higher rate of electrogenic reabsorption of Na ⁺ ions and hence secretion of K ⁺ ions, providing that open ROMK are present in the luminal membrane of principal cells.

In addition to control by the lumen-negative voltage, the secretory process for K ⁺ in principal cells is dependent on having a sufficient number of open ROMK channels in the luminal membrane of principal cells. Regulation of these channels is via phosphorylation/dephosphorylation-induced endocytosis/exocytosis of ROMK. This involves a complicated mixture of kinases and phosphatases including the With No Lysine (WNK) kinases, protein tyrosine kinases, and SGK-1. Angiotensin II (ANG _II ), via increasing the expression of protein tyrosine kinase, leads to phosphorylation of ROMK, which results in its endocytosis. The ratio of the kidney-specific form of WNK1 (KS-WNK1) to the long form of WNK1 (L-WNK1) is decreased by dietary K ⁺ ion restriction, which leads to endocytosis of ROMK.

It seems that in humans, the number of open ROMK channels may not limit the net secretion of K ⁺ ions unless the P _K falls to the range of 3.5 mmol/L. Because there is a time lag before a sufficient number of open ROMK channels are reinserted into the luminal membrane of principal cells in the CDN following chronic hypokalemia, hyperkalemia may develop with aggressive K ⁺ ion replacement therapy in this setting.

K ⁺ reabsorption occurs primarily in the medullary collecting duct (MCD) (see Chapter 13 , Fig. 13-13 ). It is stimulated by K ⁺ ion depletion, and the transporter is an H ⁺ /K ⁺ -ATPase. This exchange is electroneutral and requires the presence of a sufficient number of H ⁺ ion acceptors in the luminal fluid (i.e., ${{\text{HCO}}_{\text{3}}}^{-}$ ions and/or NH ₃ ).

Clinical Implications

In a patient with hypokalemia, a higher than expected rate of excretion of K ⁺ ions in the urine indicates a more negative voltage in the lumen of the CDN. This greater lumen-negative voltage is due to a higher rate of electrogenic versus electroneutral Na ⁺ ion reabsorption in the CDN because of an increased number of open ENaC units in the luminal membrane of principal cells in the CDN. This could be due to one of two groups of disorders. The first is a secondary increase in ENaC activity due to the release of aldosterone in response to a low EABV. The second group of disorders consists of conditions that lead to a primary increase in ENaC activity (e.g., primary hypereninemic hyperaldosteronism, primary hyperaldosteronism, disorders in which cortisol acts as a mineralocorticoid in the CDN, constitutively active ENaC in the luminal membrane of principal cells in the CDN).

Tools Used In The Clinical Assessment Of The Patient With Hypokalemia

Deal with Emergencies

The major emergencies related to hypokalemia are cardiac arrhythmias and respiratory muscle weakness leading to respiratory failure ( Flow Chart 14-1 ). Because the administration of a large, rapid dose of K ⁺ ions is likely required, the concentration of K ⁺ ions in the administered intravenous fluid will need to be high. Therefore, K ⁺ ions may have to be administered via a large central vein; cardiac monitoring is essential in this setting.

Anticipate and Prevent Dangers Due to Therapy

Because one does not know in any individual patient to what degree hypokalemia is due to a shift of K ⁺ ions into cells versus a total body deficit of K ⁺ ions, in the absence of an emergency related to hypokalemia, one should not replace the deficit of K ⁺ ions rapidly because of the risk of causing acute hyperkalemia. Therapy should not contain compounds that may cause K ⁺ to shift into cells. Hence, the initial infusion should not contain glucose or NaHCO ₃ , and β ₂ -adrenergic agonists should be avoided. In patients who also have hypomagnesemia, hypokalemia may be refractory to the administration of KCl until supplements of magnesium salts are given. This is particularly important in patients with a cardiac arrhythmia.

There are a number of reasons why the administration of KCl may cause a rapid or excessive rise in the P _Na and hence the risk of osmotic demyelination in a patient with chronic hyponatremia. In terms of body tonicity, Na ⁺ ions (the main ECF cations) and K ⁺ ions (the main ICF cations) are equivalent. During the development of hypokalemia caused by the loss of K ⁺ ions, K ⁺ ions are lost mainly from the ICF compartment. Some of these K ⁺ ions in the ICF compartment are replaced by Na ⁺ ions from the ECF compartment. When K ⁺ ions are administered, K ⁺ ions enter cells, and Na ⁺ ions that entered these cells to replace the K ⁺ ions that were lost from cells will exit from these cells. Therefore, the administration of K ⁺ ions will cause a rise in body tonicity, which will be reflected by a rise in P _Na similar to that with the administration of an equivalent amount of Na ⁺ ions, if there is no change in total body water. Furthermore, because Na ⁺ ions are retained in the ECF compartment, EABV may become expanded and a water diuresis may ensue. This is of particular concern because patients with hypokalemia are at high risk for the development of osmotic demyelination. Therefore, the administration of K ⁺ ions should be in a solution that is isotonic to the patient. For example, if the patent has a P _Na of 120 mmol/L, a solution of half normal saline (0.45% NaCl, or 77 mmol/L) with 40 mmol of KCl/L will have a concentration of Na ⁺ + K ⁺ ions that is reasonably close to the patient’s P _Na . Administration of dDAVP to prevent the occurrence of a water diuresis may be considered.

Determine if the Major Basis for Hypokalemia is an Acute Shift of K ⁺ Ions Into Cells ( Flow Chart 14-2 )

A low rate of excretion of K ⁺ ions in the urine and the absence of a metabolic acid-acid base disorder provide clues to suggest that the major basis of the hypokalemia is an acute shift of K ⁺ ions into cells.

We begin by examining the rate of excretion of K ⁺ ions in the urine. The expected renal response in a patient with hypokalemia that is due to a shift of K ⁺ ions into cells is to decrease the rate of excretion of K ⁺ ions in the urine to the minimum, that is, 15 mmol/day).

We use the U _K /U _Creatinine ratio in a spot urine sample to assess the rate of excretion of K ⁺ ions in the urine. In a patient with acute hypokalemia due solely to a shift of K ⁺ ions into cells, and assuming a usual rate of creatinine excretion of 1 g (∼10 mmol/day), U _K /U _Creatinine should be less than 15 mmol of K ⁺ ions/g creatinine or less than 1.5 mmol of K ⁺ ions/mmol creatinine.

There are possible caveats in using the U _K /U _Creatinine to determine if the basis of hypokalemia is an acute shift of K ⁺ into cells. This ratio may be low in a patient with chronic hypokalemia due to extrarenal loss of K ⁺ ions or a renal loss of K ⁺ ions that have occurred in the recent past without an ongoing loss of K ⁺ ions in the urine. In both of these settings, however, it is likely that a metabolic acid–base disorder will be present.

If we have established that the major basis of hypokalemia is an acute shift of K ⁺ ions into cells, the next step is to determine whether an adrenergic surge is its cause. In these settings, tachychardia, a wide pulse pressure, and systolic hypertension are often present. It is very important to recognize this group of patients because the administration of nonselective β-blockers (e.g., propranolol) can lead to a rapid rise in P _K without the need for a large infusion of KCl, and hence avoid the risk of development of rebound hyperkalemia when the stimulus for the shift of K ⁺ ions into cells abates.

Patients with hypokalemia due to an acute shift of K ⁺ ions into cells caused by an adrenergic surge can be divided into two groups based on whether there is an exogenous or endogenous source of the β ₂ -adrenergic effect. There are several exogenous causes of β ₂ adrenergic effect. Amphetamines may be used to suppress appetite and induce weight loss or to increase alertness. A shift of K ⁺ ions may be provoked by the repeated use of large doses of β ₂ -agonists (e.g., albuterol) to relieve bronchospasm in a patient with bronchial asthma. Hypokalemia due to use of clenbuterol, a β ₂ -adrenergic agonist, has been reported in body builders, who use the drug as an alternative to anabolic steroids, and also in users of heroin that was adulterated with clenbuterol. The intake of a very large quantity of caffeine (e.g., coffee, caffeinated soda, cocoa, or a very large intake of chocolate) can cause a large surge of catecholamines, which may induce a shift of K ⁺ ions into cells. The source of the β ₂ -adrenergic effect may also be endogenous. For example, hypokalemia may occur in acute stress states (e.g., head trauma, subarachnoid hemorrhage, myocardial infarction, acute pancreatitis, alcohol withdrawal). Another example is thyrotoxic periodic paralysis (TPP), which is more commonly seen in young males of Asian or Hispanic descent. Other disorders with a long-acting endogenous adrenergic surge that can induce an acute shift of K ⁺ ions into cells such as hypoglycemia due to an insulin overdose, the release of insulin from an insulinoma, or a β ₂ -adrenergic effect in a patient with a pheochromocytoma.

In the absence of a high adrenergic state, suspect familial periodic paralysis, more commonly seen in Caucasians, sporadic periodic paralysis, a rapid anabolic state if a sufficient amount of K ⁺ ions is not given (e.g., patients recovering from DKA, patients who are treated with parenteral nutrition, and patients with pernicious anemia early in the course of their therapy with vitamin B ₁₂ ), or the presence of a K ⁺ ion channel blocker (e.g., ingestion of barium sulfide).

Clinical Approach to the Patients With Chronic Hypokalemia

The first step to the diagnosis of the cause of hypokalemia in the patient with chronic hypokalemia is to examine the acid–base status in plasma.

Subgroup with metabolic acidosis

The group of patients with chronic hypokalemia and metabolic acidosis (usually hyperchloremic metabolic acidosis) can be divided into two categories by examining the rate of excretion of ammonium ( ${{\text{NH}}_4}^{+}$ ) ions in the urine ( Flow Chart 14-3 ). The rate of excretion of ${{\text{NH}}_4}^{+}$ ions can be estimated using the calculation of the urine osmolal gap (see Chapter 2 ).

Subgroup with metabolic alkalosis

The first step in this subgroup of patients is to determine whether the site of loss of K ⁺ ions is renal or extrarenal based on assessment of the rate of excretion of K ⁺ ions in the urine. This can be done with the use of the U _K /U _Creatinine ratio. Patients who have hypokalemia, metabolic alkalosis, and a U _K /U _Creatinine ratio that is <15 mmol of K ⁺ ions/g of creatinine (<1.5 mmol of K ⁺ ions/mmol of creatinine) are likely to have a condition associated with the loss of K ⁺ ions via a nonrenal route, such as in sweat (e.g., patients with cystic fibrosis) or via the intestinal tract (e.g., patients with diarrhea associated with decreased activity of the colonic downregulated in adenoma [DRA] $\text{C}{\text{l}}^{-}/{{\text{HCO}}_{\text{3}}}^{-}$ anion exchanger; see Chapter 4 ). Notwithstanding, the U _K /U _Creatinine ratio may be low in patients with a remote renal loss of K ⁺ ions (e.g., due to prior use of diuretics)

On the other hand, patients who have hypokalemia, metabolic alkalosis, and a U _K /U _Creatinine ratio that is higher than these values have a condition associated with a renal loss of K ⁺ ions. The steps to take to determine the underlying pathophysiology in this group of patients are outlined in Flow Chart 14-4 . In essence, we are trying to determine the cause of a higher rate of electrogenic reabsorption of Na ⁺ ions in the CDN. The primary pathophysiology is an increased number of open ENaC units in the luminal membrane of principal cells in the CDN. This could be due to two groups of disorders. Patients in the first group have low EABV causing the release of aldosterone, and hence an increased number of open ENaC units in the luminal membrane of principal cells in the CDN. These patients are not likely to have high BP. The most common causes are protracted vomiting or the use of diuretic agents. In some patients, a diuretic effect may be due to an inherited disorder affecting NaCl reabsorption in the medullary thick ascending limb (TAL) of the loop of Henle (i.e., Bartter syndrome) or in the DCT (i.e., Gitelman syndrome). Ligands that occupy the calcium-sensing receptor in the medullary TAL of the loop of Henle (e.g., calcium in a patient with hypercalcemia, drugs [e.g., gentamicin, cisplatin], and possibly cationic proteins [e.g., cationic monoclonal immunoglobulins in a patient with multiple myeloma]) may result in a clinical picture that mimics Bartter syndrome. The use of urine electrolytes in the differential diagnosis of hypokalemia in a patient with a contracted EABV is summarized in Table 14-1 .

TABLE 14-1

Urine Electrolytes in the Differential Diagnosis of Hypokalemia in a Patient With a Contracted EABV

Adjust Values of the Urine Electrolyte Concentration When Polyuria Is Present

	Urine Electrolyte
Condition	Na +	Cl −
Vomiting
Recent	High	Low
Remote	Low	Low
Diuretics
Recent	High	High
Remote	Low	Low
Diarrhea or laxative abuse	Low	High
Bartter or Gitelman syndrome	High	High

High, > mmol/L; Low, < 15 mmol/L.

Patients in the second group have conditions that are associated with a primary increase in ENaC activity. The EABV in these patients is not low, and the BP is commonly high. These disorders include primary hypereninemic hyperaldosteronism (e.g., renal artery stenosis, malignant hypertension, renin secreting tumor), primary hyperaldosteronism (e.g., adrenal adenoma, bilateral adrenal hyperplasia, glucocorticoid remediable aldosteronism [GRA]), disorders in which cortisol acts as a mineralocorticoid in CDN (e.g., apparent mineralocorticoid excess syndrome [AME], inhibition of 11β-HSDH by glycyrrhizinic acid, ACTH-producing tumor), and conditions with constitutively active ENaC in the luminal membrane of principal cells in the CDN [e.g., Liddle syndrome]). The measurement of P _Renin and P _Aldosterone are helpful in this differential diagnosis in this group of patients ( Table 14-2 ).

TABLE 14-2

Plasma Renin and Aldosterone to Assess the Basis of Hypokalemia due to a Lesion With Primary Active ENaC

	Renin	Aldosterone
Primary hyperaldosteronism	Low	High
Glucocorticoid remediable hyperaldosteronism	Low	High
Renal artery stenosis	High	High
Malignant hypertension	High	High
Renin-secreting tumor	High	High
Liddle syndrome	Low	Low
Disorders in which cortisol acts as a mineralocorticoid	Low	Low

In some patients, a decreased rate of electroneutral reabsorption of Na ⁺ ions may contribute to the increased rate of electrogenic reabsorption of Na ⁺ ions and enhanced kaliuresis. This may be the case when Na ⁺ ions are delivered to the CDN with a small amount of Cl ⁻ ions (e.g., delivery of Na ⁺ ions with ${{\text{HCO}}_{\text{3}}}^{-}$ anions in a patient with recent vomiting or with anions of a drug [e.g., penicillin]).

Magnesium (Mg ²⁺ ) deficiency is frequently associated with hypokalemia. This relationship is likely due to the underlying disorders that cause both Mg ²⁺ and K ⁺ ions loss (e.g., diarrhea, diuretic therapy, Gitelman syndrome). K ⁺ ion secretion in the CDN is mediated by ROMK, a process that is inhibited by intracellular Mg ²⁺ ions. A decrease in intracellular concentration of free Mg ²⁺ ions, caused by Mg ²⁺ ion deficiency, releases the inhibition of ROMK. Mg ²⁺ ion deficiency alone, however, does not necessarily cause hypokalemia, because an increase in the rate of electrogenic reabsorption of Na ⁺ ions is required to enhance the rate of secretion of K ⁺ ions.

Pathophysiology

An increased Na-K-ATPase activity due to excess thyroid hormones, which can lead to a greater shift of K ⁺ ions into cells in the presence of a stimulus that would not cause acute hypokalemia in normal subjects, has been implicated in the pathogenesis of thyrotoxic periodic paralysis (TPP). Recent studies have shown that susceptibility to TPP can be conferred by loss-of-function mutations in the skeletal muscle–specific inward rectifying K ⁺ ion (Kir) channel, Kir2.1. The dual hits of increased intracellular K ⁺ ion influx because of increased numbers of activated Na-K-ATPase units and decreased K ⁺ ion efflux because of defective Kir channels lead to hypokalemia with decreased muscle excitability in these patients.

Familial periodic paralysis is inherited as an autosomal dominant disorder. Genetic analyses in patients with familial periodic paralysis have suggested that the abnormality in many of these patients is linked to the gene that encodes for the α-subunit of the dihydropyridine-sensitive calcium ion channel in skeletal muscles; it is not clear how this leads to periodic hypokalemia and paralysis.

Clinical Picture

The dominant finding is recurrent, transient episodes of muscle weakness that may progress to paralysis in association with a severe degree of hypokalemia (P _K is often <2.0 mmol/L). In Asian and Hispanic populations, it is commonly associated with thyrotoxicosis, although signs and symptoms of thyrotoxicosis are often subtle.

Diagnosis

The first step is to determine if the hypokalemia is acute (caused by a shift of K ⁺ ions into cells) or chronic (caused by a total body deficit of K ⁺ ions). A low rate of excretion of K ⁺ ions in the urine as assessed by the U _K /U _Creatinine ratio and the absence of a metabolic acid-acid base disorder provide clues to suggest that the major basis of the hypokalemia is an acute shift of K ⁺ ions into cells. The presence of tachycardia (systolic hypertension with wide pulse pressure) suggest that the basis of the acute shift of K ⁺ ions into cells is an acute adrenergic surge or hyperthyroidism. Hypophosphatemia is usually present in both the thyrotoxic and the familial forms of hypokalemic periodic paralysis. The signs of hyperthyroidism may be present in patients with thyrotoxic periodic paralysis but more often are subtle; the diagnosis is made by finding elevated levels of thyroid hormones in plasma.

Differential Diagnosis

The clinical and laboratory findings help to differentiate patients with hypokalemic periodic paralysis from patients with chronic hypokalemia due to K ⁺ ion loss who may also have a component of their hypokalemia due to an acute shift of K ⁺ ions into cells. One other point helps in the differential diagnosis. Patients with hypokalemic periodic paralysis usually need far less KCl supplementation to bring their P _K to a safe level (∼3 mmol/L) than do patients who have chronic hypokalemia with total body K ⁺ ion deficit (∼1 vs. >3 mmol of KCl/kg body weight).

Therapy

During an acute attack, patients are treated with the administration of KCl. The rate of administration of KCl should not exceed about 10 mmol/hr unless there is a cardiac arrhythmia. There is, however, the risk of development of rebound hyperkalemia as K ⁺ ions move back into the ECF compartment. In retrospective case-controlled studies, rebound hyperkalemia (P _K >5.0 mmol/L) was observed in 30% to 70% of patients with thyrotoxic hypokalemic periodic paralysis if more than 90 mmol of KCl were given in a 24 hour period or at a rate higher than 10 mmol/hr. Patients with thyrotoxic hypokalemic periodic paralysis have been successfully treated with the administration of a nonselective β-blocker (propranolol, 3 mg/kg orally) without the administration of KCl resulting in rapid reversal of weakness and hypokalemia and without the development of rebound hyperkalemia. The administration of a nonselective β-blocker may also be useful to treat other conditions of acute hypokalemia that are associated with a high adrenergic surge (e.g., intake of amphetamines or large doses of caffeine). Hyperthyroidism, if present, is treated in the usual fashion. To prevent recurrence of attacks, patients are usually advised to avoid carbohydrate-rich meals and vigorous exercise. In the longer term, administration of nonselective β-blockers may reduce the number of the attacks of paralysis but seems to have little effect on the degree of fall in the P _K during an attack. Acetazolamide (250 to 750 mg/day) has been used successfully to reduce the number of attacks in some patients with familial hypokalemic periodic paralysis. The mechanism of the beneficial effect of this carbonic anhydrase inhibitor in this condition is not clear.

Pathophysiology

Hypokalemia, which can be severe at times, is commonly seen in patients with distal renal tubular acidosis that is due to a low net rate of secretion of H ⁺ ions. This low rate of net H ⁺ ion secretion could be caused of a defect affecting the H ⁺ -ATPase in the distal nephron (e.g., an inherited disorder, an acquired defect in a number of autoimmune disorders, or dysproteinemias), or a defect resulting in the secretion of ${{\text{HCO}}_{\text{3}}}^{-}$ ions in the distal nephron (e.g., in patients with Southeast Asian ovalocytosis and a second mutation affecting the $\text{C}{\text{l}}^{-}/{{\text{HCO}}_{\text{3}}}^{-}$ anion exchanger, causing it to be mistargeted to the luminal membrane of α-intercalated cells) (see Chapter 4 for more discussion of this topic). The accelerated secretion of K ⁺ ions could be due to an effect of ${{\text{HCO}}_{\text{3}}}^{-}$ in the lumen of the CDN to diminish the electroneutral NaCl transport via pendrin/NDCBE, which may lead to an increase in the rate of electrogenic reabsorption of Na ⁺ ions and the magnitude of the lumen-negative voltage in the CDN.

Diagnosis

The clinical features include the presence of hypokalemia, metabolic acidemia with a normal value of the anion gap in plasma (P _{Anion gap} ), a low rate of excretion of ${{\text{NH}}_4}^{+}$ ions, and a high value of the urine pH (∼7.0). Many patients with this disorder present with recurrent calcium phosphate stones or nephrocalcinosis.

Therapy

K ⁺ ions should be given as a KCl preparation if the patient has a significant degree of hypokalemia. NaHCO ₃ must not be administered until the P _K is raised to a safe level (i.e., >3 mmol/L) because its administration may induce a shift of K ⁺ ions into cells, and hence a more severe degree of hypokalemia may develop. The administration of K ⁺ ions with a precursor of ${{\text{HCO}}_{\text{3}}}^{-}$ ions (e.g., citrate anions) seems rational to correct both the hypokalemia and metabolic acidemia. This therapy, however, may lead to a further increase in urine pH and hence in the fraction of the total amount of phosphate in the urine that is in the form of divalent phosphate, which may increase the risk of precipitation of calcium phosphate stones. Nevertheless, the incremental increase in the concentration of divalent phosphate with further rise in the urine pH above a value of 7.0 is small (see Chapter 4 , Table 4-8 ). This risk may be outweighed by the possible benefit from increasing the rate of excretion of citrate anions in the urine, as a result of correcting the acidemia and hypokalemia, resulting in decreasing the concentration of ionized calcium in the urine.

Pathophysiology

Metabolism of toluene leads to the production of hippuric acid (see Figure 3-2 ). The excretion of hippurate anions in the urine at a rate that exceeds that of ${{\text{NH}}_4}^{+}$ ions leads to loss of Na ⁺ ions and contraction of the EABV. Hpokalemia results from excessive loss of K ⁺ ions in the urine because of a high rate of secretion of K ⁺ ions in the CDN as a result of a more negative lumen voltage in the CDN. This higher lumen-negative voltage is caused by a higher rate of electrogenic reabsorption of Na ⁺ ions in the CDN. This is because of the presence of more numbers of open ENaC units in the luminal membrane of principal cells in the CDN due to the actions of aldosterone released in response to low EABV and the delivery of Na ⁺ ions with hippurate anions, which are not reabsorbed in the CDN.

Diagnosis

Diagnosis is based on the presence of hypokalemia, metabolic acidosis with a normal P _{Anion gap} , and a high rate of excretion of ${{\text{NH}}_4}^{+}$ ions in the urine with anions other than Cl ⁻ . One can deduce that the anions excreted in the urine with ${{\text{NH}}_4}^{+}$ ions are hippurate anions from their high fractional excretion rate because hippurate anions are freely filtered and are also secreted in the PCT.

Therapy

If the patient presents with a significant degree of hypokalemia, K ⁺ ions must be given as a KCl preparation. The administration of NaHCO ₃ should be delayed until the P _K is raised to a safe level (i.e., >3 mmol/L).

Patients With Secretory Diarrhea