Electrolyte Disorders Case File
Eugene C. Toy MD, Donald Briscoe, MD, FA AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA AFP, FACG
Case 17
A 58-year-old woman presents to your office for follow-up of an emergency department visit. She was seen 1 week earlier in the emergency department for abdominal pain and was diagnosed with nephrolithiasis. Ultimately, she was sent home with pain medications and given instructions to strain her urine for stones and to follow up with her primary care physician. Today, she is asymptomatic. She takes no medications on a regular basis. Her family history is significant only for a father with high blood pressure. She had several routine laboratory tests drawn in the emergency department, copies of which she brings with her. Upon your review of the laboratory values, you note the following (normal values are in parenthesis): sodium 142 mEq/L (135-145); potassium 4.0 mEq/L (3.5-5.0); chloride 104 mg/dl (95-105); bicarbonate 28 mEq/L (20-29); blood urea nitrogen (BUN) 20 mg/dl (7-20); creatinine 0.9 mg/dl (0.8-1.4); calcium 12.5 mg/dl (8.5-10.2); albumin 4.2 g/dl (3.4-5.4). The complete blood count (CBC) was within normal limits.
The renal calculus was detected by helical computed tomography (CT) scanning without contrast and was located in the right mid ureter.
Your patient has brought with her the stone that she has strained from the urine. Upon questioning, you learn that she has had multiple episodes of "kidney stones" in the past 2 years. You send the stone to the laboratory for analysis and order a repeat serum calcium level. The results show that the stone is made of calcium oxalate; the serum calcium is still elevated at 11.9 mg/dl.
⯈ What is your diagnosis?
⯈ What is the most likely cause?
⯈ What is the next step?
ANSWER TO CASE 17:
Electrolyte Disorders
Summary: This is a 58-year-old woman with a history of recurrent nephrolithiasis, presenting for follow-up and found to have calcium oxalate stones. She had an initial serum calcium level that was elevated, as was the repeat serum calcium 1 week later. At the time of her follow-up, she was completely asymptomatic. She takes no medications, and has a family history only significant for hypertension.
- Diagnosis: Hypercalcemia and recurrent nephrolithiasis
- Most likely cause: Hyperparathyroidism
- Next step: Further laboratory workup, including serum parathyroid hormone (PTH) level
ANALYSIS
Objectives
- Be able to list common causes of calcium, sodium, and potassium disorders.
- Describe the workup and management of common electrolyte disorders.
Considerations
This patient illustrates one common presentation of hypercalcemia. Many times, patients with hypercalcemia are asymptomatic and an elevated calcium level is found unexpectedly on routine laboratory studies. The diagnostic workup begins with a careful review of the patient's history, as clues to its etiology may often be elicited here. The diagnostic workup is designed to distinguish parathyroid dysfunction from other etiologies so that optimal treatment and management can be pursued.
Approach To:
Electrolyte Disorders
DEFINITIONS
HYPERPARATHYROIDISM: Condition of elevated parathyroid hormone usually due to excessive production by the parathyroid glands, leading to hypercalcemia.
SECONDARY HYPERPARATHYROIDISM: Condition as the parathyroid glands overproduce PTH to respond to low serum calcium levels. This may occur as a response to low dietary calcium intake or a deficiency of vitamin D.
TERTIARY HYPERPARATHYROIDISM: Elevated PTH in patients who have renal failure.
CLINICAL APPROACH
Pathophysiology of Calcium Homeostasis
Before discussing the differential diagnosis of hypercalcemia, it is essential to review the basic mechanism by which normal calcium levels are maintained in the body. Most of the calcium in the body is found in the skeleton (approximately 98% ). The remaining calcium is found in circulation. Of this remaining 2%, about half is bound to albumin and other proteins, and half is "free;' or ionized. It is the ionized calcium that has physiologic effects. Because the serum calcium is partially bound to albumin, abnormally low serum albumin levels will affect the measurement of calcium, thus causing a misinterpretation of an abnormal calcium level. With patients found to have a concomitant hypoalbuminemia, the ionized calcium can be measured directly. However, there is a useful formula that can correct this error. A "corrected" serum calcium is provided by the formula:
"Corrected" serum calcium= [0.8 x (Normal albumin) - (Patient's albumin level)] +
(Serum calcium)
PTH, calcitonin, and 1,25-dihydroxyvitamin D3 (calcitriol) are responsible for regulating calcium levels and maintaining calcium homeostasis. Causes of hypercalcemia include an increase in calcium resorption from bone, decreased renal excretion of calcium, or an increase in calcium absorption from the gastrointestinal tract. When calcium levels increase, calcitonin, produced by the thyroid parafollicular cells, attempts to lower calcium levels through renal excretion of calcium and by opposing osteoclast activation. When calcium is excreted through this pathway, phosphate is also excreted. Conversely, low levels of circulating calcium normally result in PTH secretion. This promotes osteoclast activation, which mobilizes calcium from bone and effects calcium resorption at the kidneys, thereby retaining circulating calcium. While PTH will increase the calcium in the blood, it has the opposite effect on serum phosphate levels. PTH also increases calcitriol levels, which act at the gastrointestinal tract to promote both calcium and phosphate absorption.
HYPERCALCEMIA
Etiology
Any process that increases gastrointestinal calcium absorption, decreases renal excretion, or activates osteoclastic activity will raise serum calcium levels. If this occurs beyond the normal bounds of maintaining calcium homeostasis, hypercalcemia will occur. The most common cause of hypercalcemia in the ambulatory patient is hyperparathyroidism. Cancer is the second leading cause. Hyperparathyroidism and cancer combined account for 90% of hypercalcemia cases. It is useful to categorize the etiologies of hypercalcemia into five main areas: parathyroid hormone related, malignancy, renal failure, high bone turnover, and those related to vitamin D (Table 17-1).
Clinical Manifestations of Hypercalcemia
Normal values of serum calcium range from 8 to 10 mg/dL. Levels of serum calcium between 10.5 and 12 mg/dL are classified as mild hypercalcemia and patients
are typically asymptomatic at these levels. As calcium levels increase, physical manifestations may become apparent. The classic mnemonic "stones, bones, psychic groans, and abdominal moans" is useful to categorize the constellation of physical symptoms associated with hypercalcemia (Table 17-2). Other clinical manifestations include the cardiac sequelae of shortening QT interval and arrhythmias.
Diagnostic Approach
The first step in the evaluation is a careful history to try to establish a cause and to assess for manifestations. The history should include family history of calcium disorders, such as renal stones or malignancy. The patient's risk factors for malignancy, such as smoking, should be investigated. The chronicity of symptom should
be taken in account; more acute symptoms suggest malignancy over hyperparathyroidism and vice versa. A careful review of medications should also take place, to include not only prescription medications but also over-the-counter supplements. Dietary intake of vitamin D and calcium should be questioned. Furthermore, history of immobilization secondary to hospital stay or recent injury should be looked into as prolonged immobilization can cause massive bone demineralization and hypercalcemia. At this point, if the hypercalcemia is mild and the patient is asymptomatic, it is acceptable to stop any suspect medication( s) and repeat the serum calcium level.
If a causative medication is not found, serum intact PTH level should be measured. This level will either be suppressed, normal, or elevated. As with many endocrine disorders, it is useful not to think of normal or abnormal values; rather, one should understand what is appropriate for a given situation. For example, in normal subjects, an increased calcium load will normally depress the PTH hormone level, thus a low PTH level in this situation is normal, or appropriately suppressed. If a patient has an elevated calcium level and the PTH is "normal;' it is said to be inappropriately normal, because in the face of hypercalcemia it should be low, or suppressed.
If a patient with hypercalcemia has a normal or elevated PTH level, then the normal feedback loop is not responding. This defines hyperparathyroidism. Primary hyperparathyroidism occurs when the parathyroid gland overproduces PTH and does not respond to the negative feedback of elevated calcium levels. The vast majority of primary hyperparathyroidism is caused by an adenoma (benign tumor) of one of the four parathyroid glands.
Secondary hyperparathyroidism occurs as the parathyroid glands overproduce PTH to respond to low serum calcium levels. This may occur as a response to low dietary calcium intake or a deficiency of vitamin D. Tertiary hyperparathyroidism occurs in patients who have renal failure. Patients in renal failure initially present with hypocalcemia, hyperphosphatemia, and low vitamin D levels. If untreated, it leads to hyperplasia of the parathyroid glands, an increased PTH secretion, and subsequent hypercalcemia.
There is a condition that can produce inappropriately high PTH levels unrelated to the parathyroid production. This is familial hypocalciuric hypercalcemia (FHH), a genetic disorder related to a defect in a gene that codes for a calcium sensing receptor. Consequently, simply measuring PTH alone may confound this diagnosis, which may be mistaken for primary hyperparathyroidism. To distinguish these entities, a 24-hour urinary calcium level is obtained. In hyperparathyroidism, the kidneys spill calcium into the urine at a normal or elevated level. With FHH, the urinary calcium level is low.
A PTH level that is low with elevated serum calcium suggests that the parathyroid gland is responding appropriately to the high calcium environment. This is seen when tumors produce a hormone that mimics the active site of the PTH molecule. This molecule is called parathyroid hormone-related peptide (PTH-rP). PTH-rP is produced by lung cancers, squamous cell cancers of the head and neck, and renal cell cancer. PTH-rP effects osteoclastic bone resorption, increases calcitriol, and promotes calcium resorption from the kidneys, resulting in increased levels of serum calcium. The continued production of PTH-rP effectively takes the parathyroid gland out of the loop in calcium homeostasis. Because cancer is a common etiology for hypercalcemia, the search for malignancy is paramount at this step in diagnosis, before other, less common, disorders are considered.
If a malignancy is not found, other etiologies must be considered. These fall into the category of endocrine disorders other than parathyroid and include hyperthyroidism, adrenal insufficiency, and acromegaly. The workup thus includes thyroid-stimulating hormone (TSH), a cortisol level, and a pituitary imaging study, respectively.
TREATMENT OF HYPERCALCEMIA
The treatment of hypercalcemia is directed at the underlying disorder. Patients with mild hypercalcemia may be treated with preventative measures aimed at avoiding aggravating factors. These measures include adequate hydration (dehydration aggravates nephrolithiasis), avoiding thiazide diuretics or other offending medications, encouraging physical activity, and avoiding prolonged inactivity.
For the treatment of primary hyperparathyroidism, surgical parathyroidectomy is the definitive treatment. Surgery is appropriate for patients with symptomatic hyperparathyroidism. Surgery may be an option for selected asymptomatic patients, including those who have developed osteoporosis or renal insufficiency, who have markedly elevated calcium levels, or who are younger than age 50.
Approach to Urgency in Acute Hypercalcemia
The most serious manifestations of hypercalcemia occur in the form of dysrhythmias and coma. In situations like these, it is imperative to correct the hypercalcemia while simultaneously doing workup to understand the etiology. Management includes rehydration as the first step with IV 0.9% saline 4 to 6 L in 24 hours. After rehydration, IV bisphosphonates should be used, keeping in mind that the dose and time over which these are administered must be decreased in renally impaired patients.
SODIUM DISORDERS
Hyponatremia
Hyponatremia is defined as a plasma [Na+] less than 135 mEq/L. It is a disorder of water balance that primarily causes neurologic symptoms due to a lowered serum osmolality that promotes water movement into brain cells. In hyponatremic states, total body sodium and total body water can be low, normal or high, so assessment of the patient's overall volume state and osmolality is critical to the diagnosis and management. Although most patients with hyponatremia are asymptomatic, early symptoms may manifest as nausea, vomiting, lethargy in acute cases. As most cases of hyponatremia present with a low serum osmolality ( <280 mOsm), evaluation of the patient's volume status will help determine possible causes and guide therapy, as presented below:
1. Hypovolemic hyponatremia-Exhibits signs of volume depletion on physical examination with urinary sodium levels less than 20 mEq/L. Common causes include cerebral salt wasting, skin loss, diuretic use, gastrointestinal (GI) losses, mineralocorticoid deficiency, and third-spacing of fluids. The treatment is volume repletion with normal saline and addressing the underlying condition. Severe symptomatic hyponatremia, which can manifest as confusion, coma, or seizures, are usually observed with serum sodium less than 125 mEq/L and warrants urgent treatment with hypertonic (3%) saline. Often, very small corrections in serum sodium will improve the symptoms. It is recommended to correct the sodium level slowly to avoid the risk of osmotic demyelination, which can result in permanent neurologic injury and death.2. Hypervolemic hyponatremia - Exhibits signs of volume expansion on examination due to decreased renal excretion of water. Common causes include heart failure, cirrhosis, and nephrosis. The treatment is use of diuretics and restriction of fluid and sodium intake.3. Euvolemic hyponatremia - Antidiuretic hormone (ADH) is normally secreted in response to low volume states, resulting in retention of free water. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs when ADH is secreted independently of volume status, resulting in the inappropriate retention of free water with resultant hyponatremia and hypotonicity. SIADH is a common complication of many conditions, including infections, malignancies, medications, and central nervous system disorders (See Table 17-3). The treatment of SIADH involves fluid restriction and, when possible, correction of the underlying condition. Other, less common causes of euvolemic hyponatremia include water intoxication, hypothyroidism, and low solute intake.
Another cause of low plasma [Na+] that should also be considered is pseudohyponatremia. In this scenario, the observed low sodium levels may be appropriate for the given clinical situation, such as in the setting hyperglycemia, hypertriglyceridemia, hyperproteinemia, laboratory errors, or mannitol use. In this situation, patients usually have a normal volume status with normal osmolality.
Hypernatremia
Hypernatremia is defined as a plasma [Na+] greater than 145 mEq/L, and reflects a state of increased serum osmolality that promotes water movement out of cells. The condition is usually due to net water loss that is often associated with an impaired thirst response or restricted access to water ( eg, in the elderly, young infants, and intubated patients). Symptoms are primarily neurologic, just like hyponatremia,
Abbreviations: ADH, antidiuretic hormone; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin
reuptake inhibitors.
Reproduced, with permission, from Papadakis MA, McPhee SJ, Rabow MW. Current Medical Diagnosis & Treatment.
New York, NY: McGraw-Hill Education; 2015. Table 21-2.
and manifest as anorexia, muscle weakness, nausea, vomiting, and lethargy, which may lead to seizures and coma in severe cases.
The most important first step in assessing patients with hypernatremia is to check the urine osmolality. A high urine osmolality ( >400 mOsm/kg) suggests the body's ability to conserve water is intact and that water losses are due to hypotonic fluid loss (eg, excessive sweating, GI losses, etc). A low urine osmolality ( <300 mOsm/kg) suggests pure water loss as seen in diabetes insipidus (DI), which is further broken down into nephrogenic DI (renal resistance to action of antidiuretic hormone) and central DI (lack of antidiuretic hormone production). Treatment involves correcting the underlying condition and the deficit in water. As with hyponatremia, hypernatremia should be cautiously corrected, as rapid correction leads to cerebral edema due to intracellular fluid shifts.
POTASSIUM DISORDERS
Hypokalemia
Hypokalemia is defined as a plasma (K+] less than 3.5 mEq/L. The potential causes of hypokalemia are numerous, but are generally broken down into several categories: decreased net intake, intracellular shifts (eg, alkalosis, excess insulin), and renal losses or extrarenal losses (see Table 17 -4).
Patients present with fatigue, muscle aches, ascending muscular weakness, or cramps that, in severe cases, can lead to paralysis or rhabdomyolysis. ECG changes may be seen in hypokalemia but are not well-correlated with serum potassium concentration. Hypokalemia can lead to ST-segment depression, flattened T waves, and prominent U waves. The therapeutic goals are to prevent life-threatening complications (eg, arrhythmias, respiratory failure), to correct the potassium deficit, and to identify and treat the underlying condition. In most cases, potassium deficits are best corrected by oral potassium replacement. IV potassium should be reserved for profound deficits and for persons unable to take oral medications.
Hyperkalemia
Hyperkalemia is defined as a plasma (K+] greater than 5.0 mEq/L. Causes of hyperkalemia are commonly caused by the following:
- Medications including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and potassium-sparing diuretics
- Shifts from intracellular to extracellular spaces including acidosis, insulin deficiency, and burns
- Reduced renal excretion of potassium including renal insufficiency/failure, Addison disease, and renal tubular acidosis type IV
It is also important to consider pseudohyperkalemia as a possible cause of elevated plasma potassium, especially in the setting of possible laboratory error, hemolysis, or traumatic venipuncture.
Symptoms that may be present in true hyperkalemia include weakness, ascending flaccid paralysis, paresthesias, areflexia, ileus, and in severe cases, can lead to
Reproduced, with permission, from Papadakis MA, McPhee SJ, Rabow MW. Current Medical Diagnosis & Treatment.
New York, NY: McGraw-Hill Education; 2015. Table 21-3.
respiratory failure. The most serious effect of hyperkalemia is the risk of cardiac arrhythmias. ECG changes that are characteristic to hyperkalemia include peaked T waves, flattening of P waves, and widening of QRS complexes.
Acute management of hyperkalemia in the setting of ECG changes, rapid rise in plasma potassium levels, and the presence of significant acidosis include (1) stabilizing the myocardium with IV calcium to decrease the risk of arrhythmias; (2) shifting potassium into cells to decrease plasma concentration by the administration of glucose and insulin; and (3) eventually lowering total body K+ with Kayexalate, loop diuretics, or dialysis. Long-term treatment of hyperkalemia should address the underlying cause (such as discontinuation of a suspect medication), patient counseling on low-potassium diets, and use of diuretics to promote excretion of potassium.
CASE CORRELATION
- See also Case 10 (Acute Diarrhea).
COMPREHENSION QUESTIONS
17.1 A 56-year-old Asian woman with history of hypertension, diabetes, and newly diagnosed polycystic kidney disease presents for follow-up for hypertension. Routine laboratory work shows elevated calcium of 13 mg/dL and an elevated phosphate level. The patient denies weight loss, is taking only metoprolol for her blood pressure, and denies recent history of immobilization. Given as above, which etiology of hypercalcemia would you be most concerned about in this patient?
A. Primary hyperparathyroidism as this is the most common etiology of hypercalcemiaB. Iatrogenic hypercalcemia secondary to medicationsC. A primary vitamin D deficiency given her ageD. Secondary hyperparathyroidism due to renal disease
17.2 A 48-year-old man presents for follow-up of an elevated calcium level of 12.3 mg/dL found on routine screening laboratory tests at his last wellman visit. He takes no medications other than an occasional antihistamine for allergies. He recently started smoking a half-pack of cigarettes per day. He was prompted to attend to his well-man visit by his wife who claims that he has become forgetful, has a decreased appetite, and has had a 10-lb weight loss over the past 2 months. As part of his follow-up laboratory tests, you obtain a serum PTH, which comes back within the normal range. Which of the following is the next step in diagnosis?
A. Chest x-rayB. Repeat calcium after hydrationC. Measurement of PTH-rP levelsD. Measurement of urinary calcium excretion
17.3 An 80-year-old woman is brought to the emergency room (ER) with altered mental status and fever. She is awake and cooperative but is not oriented to time or place. Her blood pressure is normal, her pulse is normal, and her temperature is 101°F. She is found to have pneumonia. Laboratory testing reveals a sodium level of 130 mEq/L but otherwise normal electrolytes. Which of the following is the most appropriate treatment for her?
A. IV antibiotic onlyB. IV antibiotic and aggressive rehydration with IV normal salineC. IV antibiotic and fluid restrictionD. IV antibiotic and IV 3% saline
17.4 A 65-year-old dialysis patient is found to have a serum potassium level of 6.8 mEq/L, which is verified on a STAT repeat level. An ECG shows peaked T waves and a widened QRS complex. What is the first intervention that should be made at this point?
A. IV glucose and insulin administrationB. Arrangement for a dialysis treatmentC. Oral Kayexalate givenD. IV furosemideE. IV calcium
ANSWERS
17.1 D. Secondary hyperparathyroidism occurs in patients with early renal disease when due to hyperphosphatemia, hypocalcemia, and impaired production of 1,25-dihydroxyvitamin D by the failing kidneys, PTH levels increase abnormally, causing in turn elevated levels of calcium. In this disorder therefore you would see increased PTH and increased calcium, signaling a disruption of the normal feedback cycle.
17.2 D. This patient has symptomatic hypercalcemia. He has an inappropriately normal PTH level, which should be suppressed with this degree of hypercalcemia. The next step is to measure a 24-hour urinary calcium excretion to determine if this condition represents primary hyperparathyroidism (most common) or familial hypocalciuric hypercalcemia (rare).
17.3 C. This is a common presentation of SIADH due to pneumonia. This patient is euvolemic, so aggressive rehydration is not necessary. Treatment of the underlying pneumonia is key, so antibiotics must be given. With a sodium level of 130 mg/dL, the use of 3% saline is not necessary. The electrolyte abnormality should correct with treatment of the pneumonia and with fluid restriction.
17.4 E. This patient has hyperkalemia with cardiac changes-an acute, life threatening condition. The first intervention should be to give IV calcium to stabilize the cardiac membranes and reduce the risk of arrhythmia. After this, interventions can be made to lower the potassium level.
CLINICAL PEARLS
⯈ Be sure to question any patient with hypercalcemia regarding all medications- both prescription and over-the-counter-as both megadose vitamins (A and D) and excessive use of calcium carbonate antacids may play a role.
⯈ Hypercalcemia with a suppressed PTH should be considered malignancy until you can prove otherwise.
⯈ Assess the volume status in patients with hyponatremia to help determine the cause and guide therapy.
⯈ ECG Changes in the setting of hyperkalemia require urgent treatment.
REFERENCES
Bartstow C, Braun M, Psyzocha N. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
Calvert J, Hollander-Rodriguez J. Hyperkalemia. Am Fam Physician. 2006;73:283-290.
Carroll M, Schade D. A practical approach to hypercalcemia. Am Fam Physician. 2003;67:1959-1966.
Chow KM, Szeto CC. An unusual cause ofhypercalcemia. South Med]. 2004;97(6):588-589.
Potts JT, Jiippner H. Disorders of the parathyroid gland and calcium homeostasis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill Education; 2015. Available at: http://accessmedicine.mhmedical. com. Accessed May 9, 2015.
Society for Endocrinology, Emergency Endocrine Guidance. Acute hypercalcaemia. Available at: http:/ /www.endocrinology.org/ policy I docs/ 13-02_EmergencyGuidance-AcuteHypercalcaemia. pdf. Accessed May 9, 2015.
Taniegra ET. Hyperparathyroidism. Am Fam Physician. 2004;69:333-340.
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