69-Year-Old Woman With Confusion and Fatigue

Abstract

A 69-year-old woman presented to her primary care physician with a 4-day history of fatigue and dizziness. She was 45 minutes late for her appointment because she had trouble driving to the office. She reported no motor or sensory deficits but had difficulty with coordination. Review of systems was positive for dysuria and urinary frequency. She did not have fever, chills, weight or appetite changes, respiratory, cardiac, or gastrointestinal symptoms, or recent head trauma. The patient's medical history was remarkable for hypertension, hyperlipidemia, type 2 diabetes mellitus, osteoporosis, and gastroesophageal reflux disease. Medications included metoprolol tartrate, lisinopril with hydrochlorothiazide, lovastatin, cholecalciferol, and as-needed calcium carbonate. She had smoked half a pack of cigarettes per day for 40 years but had quit smoking 6 years previously. She did not use alcohol or illicit drugs. On examination, the patient was afebrile with a blood pressure of 104/67 mm Hg, heart rate of 76 beats/min, respiratory rate of 17 breaths/min, oxygen saturation of 94% while breathing room air, and body mass index (calculated as weight in kilograms divided by height in meters squared) of 39 kg/m2. She was alert and oriented to person, place, and time. Her speech was dysarthric, and she had difficulty following simple commands. Her coordination was impaired with symmetric dysmetria on finger-to-nose testing, heel-knee-shin testing, and rapid alternating movements. Cranial nerves II through XII were intact. Results of motor and sensory examinations were within normal limits. Reflexes were symmetric. Lymph node, thyroid, cardiac, respiratory, gastrointestinal, musculoskeletal, and skin examinations identified no abnormalities.1.Which one of the following is the best initial step in evaluating this patient's presenting neurologic symptoms?a.Arterial blood gas measurementb.Lumbar puncturec.Comprehensive metabolic paneld.Computed tomography of the heade.Toxicology screen This patient presented with global neurologic dysfunction as evidenced by confusion, slurred speech, and symmetric difficulty with coordination. Further work-up in this setting is guided by the patient's history of present illness, medical history, current medications, and physical examination findings. Arterial blood gas measurement would likely not be helpful because this patient had no dyspnea, tachypnea, or history of respiratory disease. Lumbar puncture was not indicated because the patient was afebrile and without meningeal signs. A comprehensive metabolic panel (including sodium, potassium, chloride, bicarbonate, serum urea nitrogen, creatinine, glucose, total calcium, phosphorus, albumin, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and bilirubin) and complete blood cell count should be included among the initial laboratory studies for all patients. Importantly, these initial laboratory tests should include more than the basic electrolyte panel. Screening for total calcium, phosphorus, and hepatic abnormalities should be included. In this patient with dysuria and frequency, urinalysis would be indicated as well. Computed tomography of the head would not be necessary at this time because the patient had no focal neurologic signs or history of head trauma.1Inouye S.K. The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients.Am J Med. 1994; 97: 278-288Abstract Full Text PDF PubMed Scopus (497) Google Scholar A toxicology screen is less helpful as an initial test because results take several hours and will not affect initial management. Although the patient had no history of medication/drug abuse or known access to pain medications, iatrogenic illness related to medications and other chemicals is common and should remain on the differential diagnosis even when a patient denies their use. Initial blood tests revealed the following (reference ranges provided parenthetically): sodium, 137 mmol/L (135-145 mmol/L); potassium, 3 mmol/L (3.6-4.8 mmol/L); chloride, 96 mmol/L (98-107 mmol/L); bicarbonate, 30 mmol/L (23-29 mmol/L); serum urea nitrogen, 22 mg/dL (7-19 mg/dL); creatinine, 1.2 mg/dL (0.6-1.3 mg/dL); glucose, 149 mg/dL (70-139 mg/dL); total calcium, 16.4 mg/dL (8.9-10.1 mg/dL); albumin, 4.5 g/dL (3.5-5.0 g/dL); phosphorus, 3.0 mg/dL (2.5-4.5 mg/dL); and alanine aminotransferase, 25 U/L (7-45 U/L). Results of the complete blood cell count were within normal limits. Urinalysis findings were consistent with urinary tract infection. Chest radiography revealed no abnormalities.2.In addition to antibiotics for urinary tract infection, which one of the following is the most appropriate next step in management?a.Furosemideb.Intravenous isotonic salinec.Intramuscular or subcutaneous calcitonind.Zoledronic acide.Methylprednisolone This patient had marked hypercalcemia, with a total calcium level of 16.4 mg/dL. In patients with total calcium concentrations greater than 14 mg/dL, immediate aggressive treatment is indicated because they are at risk for coma and cardiac arrest. In patients with moderately elevated total calcium levels (12-14 mg/dL), treatment is also necessary, but the urgency of treatment is guided by the presence of symptoms or end-organ dysfunction. Signs and symptoms of hypercalcemia may be gastrointestinal (anorexia, nausea and vomiting, constipation), cardiac (hypertension if intravascular volume is maintained, shortened QT interval), renal (polyuria, polydipsia, nephrocalcinosis, acute kidney injury), and/or neurologic (cognitive difficulties, drowsiness, obtundation, coma).2Bilezikian J.P. Management of acute hypercalcemia.N Engl J Med. 1992; 326: 1196-1203Crossref PubMed Scopus (243) Google Scholar Because this patient had confusion, immediate treatment would be indicated even if her total calcium level was in the moderately elevated range. Loop diuretics such as furosemide block calcium reabsorption in the thick ascending limb of the nephron and are sometimes used to augment treatment of severe hypercalcemia. However, volume expansion must precede the administration of loop diuretics because their efficacy depends on the delivery of calcium to the ascending limb.2Bilezikian J.P. Management of acute hypercalcemia.N Engl J Med. 1992; 326: 1196-1203Crossref PubMed Scopus (243) Google Scholar Although use of loop diuretics such as furosemide is common practice in the treatment of hypercalcemia, a review of the literature from 1950 to 2007 revealed a lack of evidence to support this practice. Furosemide did not consistently provide rapid normalization of total calcium levels.3LeGrand S.B. Leskuski D. Zama I. Narrative review: furosemide for hypercalcemia; an unproven yet common practice.Ann Intern Med. 2008; 149: 259-263Crossref PubMed Scopus (139) Google Scholar The first step in the management of hypercalcemia is fluid resuscitation with intravenous isotonic saline. Hypercalcemia induces diuresis, and affected patients are generally volume depleted. Further, if they are confused, they may have decreased oral intake. Fluid resuscitation not only reverses the increased total calcium concentration due to volume contraction but also increases renal clearance of calcium. The rate of fluid administration is based on the severity of the hypercalcemia, the extent of hypovolemia, and the patient's cardiovascular tolerance of volume expansion.2Bilezikian J.P. Management of acute hypercalcemia.N Engl J Med. 1992; 326: 1196-1203Crossref PubMed Scopus (243) Google Scholar A standard regimen consists of isotonic saline at a rate of 200 to 300 mL/h, adjusted to maintain a urinary output of 100 to 150 mL/h. Calcitonin is a peptide hormone that decreases bone resorption and increases renal calcium excretion. It is sometimes used intramuscularly or subcutaneously to rapidly reduce total calcium concentrations by up to 2 mg/dL. Calcitonin has a fast onset of action (4-6 hours) and rapid offset (48 hours because of the development of tachyphylaxis), making it useful for the initial management of patients with severe hypercalcemia.4Bilezikian J.P. Clinical review 51: management of hypercalcemia.J Clin Endocrinol Metab. 1993; 77: 1445-1449PubMed Google Scholar Notably, nasal application is not efficacious for the treatment of hypercalcemia.5Dumon J.C. Magritte A. Body J.J. Nasal human calcitonin for tumor-induced hypercalcemia.Calcif Tissue Int. 1992; 51: 18-19Crossref PubMed Scopus (22) Google Scholar Bisphosphonates such as zoledronic acid block osteoclast-mediated bone resorption, thus inhibiting calcium release. In comparison to calcitonin, the nadir in total calcium level after intravenous administration of bisphosphonates is later (usually 2-4 days) and total calcium–lowering effects are longer lasting and more robust.4Bilezikian J.P. Clinical review 51: management of hypercalcemia.J Clin Endocrinol Metab. 1993; 77: 1445-1449PubMed Google Scholar Intravenous bisphosphonates are preferred over oral formulations for their potency and duration of effect. They are only effective in lowering the total calcium concentration if excessive bone resorption is the mechanism of hypercalcemia. Glucocorticoids such as methylprednisolone are used to treat hypercalcemia related to overexpression of extrarenal 1α-hydroxylase by mononuclear cells in granulomatous disease. This enzyme converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which increases gastrointestinal absorption of calcium. Glucocorticoids decrease the enzymatic activity of renal 1α-hydroxylase.4Bilezikian J.P. Clinical review 51: management of hypercalcemia.J Clin Endocrinol Metab. 1993; 77: 1445-1449PubMed Google Scholar The treatment of hypercalcemia often involves a combination of the aforementioned options, especially when the cause is unclear and laboratory results are pending. However, the first step is always fluid resuscitation. Our patient was transferred from her primary care physician's office to the hospital for treatment and additional evaluation. On admission, isotonic saline was initiated at a rate of 200 mL/h and one dose of intranasal calcitonin was administered because the intramuscular form was unavailable. The patient was later given 2 doses of intramuscular calcitonin when it became available.3.Which one of the following is the best initial test to evaluate the cause of this patient's hypercalcemia?a.Parathyroid hormone (PTH) measurementb.PTH-related peptide (PTHrP) measurementc.Serum protein electrophoresisd.25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D measuremente.Angiotensin-converting enzyme (ACE) measurement As with any condition, the first step in the evaluation of hypercalcemia is careful history taking and physical examination. This first step includes assessment of symptom development. For example, a long-term history of stable mild hypercalcemia without symptoms or weight loss is most consistent with a diagnosis of primary hyperparathyroidism. A recent increase in serum calcium concentration and weight loss points toward a malignant neoplasm. One should also inquire about a family history of hypercalcemia and medication/supplement use (thiazides, large doses of vitamins A or D, lithium, theophylline, or large amounts of calcium carbonate). Physical examination may identify conditions that may suggest the underlying etiology—tumor masses, lymphadenopathy, or hepatosplenomegaly that could be associated with malignant disease, hyperpigmentation indicative of Addison disease, or goiter that is common in thyrotoxicosis.6Lafferty F.W. Differential diagnosis of hypercalcemia.J Bone Miner Res. 1991; 6: S51-S59PubMed Google Scholar The best initial laboratory test is measurement of PTH to determine whether hypercalcemia is PTH dependent or PTH independent. A high or inappropriately normal PTH level in the setting of hypercalcemia is diagnostic of primary hyperparathyroidism, which is the most common cause of hypercalcemia. Typically, primary hyperparathyroidism is discovered incidentally on routine laboratory tests as an asymptomatic mild hypercalcemia in an outpatient. Other causes of hypercalcemia suppress PTH to below normal or very low in the normal range. A low PTH level in the setting of hypercalcemia indicates a PTH-independent process. The most common PTH-independent cause of hypercalcemia is malignant disease.6Lafferty F.W. Differential diagnosis of hypercalcemia.J Bone Miner Res. 1991; 6: S51-S59PubMed Google Scholar Hypercalcemia due to malignant disease is usually more severe and typically presents with more symptoms of hypercalcemia than are seen with primary hyperparathyroidism. The 3 major mechanisms by which malignant disease causes hypercalcemia include osteolytic metastases with local release of cytokines (eg, multiple myeloma), tumor secretion of PTHrP (eg, squamous cell lung cancer), and tumor production of 1,25-dihydroxyvitamin D (eg, lymphoma).7Stewart A.F. Hypercalcemia associated with cancer.N Engl J Med. 2005; 352: 373-379Crossref PubMed Scopus (194) Google Scholar With this patient's smoking history, she is at risk for squamous cell lung cancer–related secretion of PTHrP. However, serum protein electrophoresis (to screen for multiple myeloma) and measurement of PTHrP and 1,25-dihydroxyvitamin D are generally performed only after determining that PTH is suppressed. Other causes of PTH-independent hypercalcemia include vitamin D intoxication, granulomatous disorders (eg, sarcoidosis or histoplasmosis), hyperthyroidism, adrenal insufficiency, and immobilization. Thus, measurement of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and ACE levels, fungal serologies, and measurement of thyrotropin and morning cortisol levels can be considered after documentation that PTH levels are low. This patient's PTH was low at less than 6.0 pg/mL (15-65 pg/mL), suggesting a PTH-independent process. Thus, additional studies were ordered and revealed a PTHrP level of 0.3 pmol/L (<2.0 pmol/L), serum protein electrophoresis without a monoclonal protein spike, a 25-hydroxyvitamin D concentration of 43 ng/mL (20-50 ng/mL), a 1,25-dihydroxyvitamin D concentration of 17 pg/mL (18-78 pg/mL), and a thyrotropin level of 1.7 mIU/L (0.3-5.0 mIU/L). ACE level, fungal serologies, and morning cortisol measurement were not obtained. By hospital day 3, the patient's mentation, coordination, and speech had returned to baseline and her total calcium level was 10.7 mg/dL. She was dismissed from the hospital and presented to her primary care physician for follow-up 1 week later. She continued to feel well. Her calcium level remained normal at 9.5 mg/dL.4.Which one of the following is the most likely cause of this patient's hypercalcemia?a.Malignant diseaseb.Multiple myelomac.Milk-alkali syndromed.Vitamin D intoxicatione.Granulamatous disease At this point, malignant disease cannot be completely ruled out but is unlikely because the patient had normal chest radiographic findings, PTHrP was within the reference range, and her total calcium level remained normal despite 1 week without active treatment. Multiple myeloma is improbable because her hemoglobin and creatinine levels were within normal limits and serum protein electrophoresis did not reveal a monoclonal protein spike. The most likely cause of this patient's hypercalcemia is milk-alkali syndrome. This diagnosis is usually made in patients with hypercalcemia, alkalosis, and renal impairment who have a history of ingesting large amounts of calcium and absorbable alkali and in whom other causes of hypercalcemia have been excluded. On presentation, this patient had a slightly elevated bicarbonate level, a creatinine concentration at the high end of the normal range, and a history of calcium carbonate ingestion. It was later found that she was taking up to 21 tablets of calcium carbonate per day the week before her hospitalization, equivalent to 6.3 g of elemental calcium. In milk-alkali syndrome, hypercalcemia results when the input of calcium (intake and intestinal absorption) exceeds the output (primarily renal excretion). The amount of calcium carbonate that has been reported to induce milk-alkali syndrome has ranged from 4 to 60 g/d.8Felsenfeld A.J. Levine B.S. Milk alkali syndrome and the dynamics of calcium homeostasis.Clin J Am Soc Nephrol. 2006; 1: 641-654Crossref PubMed Scopus (71) Google Scholar Calcium is absorbed from the intestine via 2 mechanisms: a transcellular active transport process mediated by the action of 1,25-dihydroxyvitamin D and a paracellular passive process.9Bronner F. Mechanisms of intestinal calcium absorption.J Cell Biochem. 2003; 88: 387-393Crossref PubMed Scopus (203) Google Scholar When calcium is consumed in excess, there is compensatory suppression of PTH, which leads to decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and decreased active intestinal absorption of calcium. Some individuals may not adequately suppress PTH in response to large doses of calcium, hindering their ability to regulate active intestinal absorption of calcium. Additionally, the primary mechanism of calcium absorption is through passive intestinal absorption without regulation.10Patel A.M. Goldfarb S. Got calcium? welcome of the calcium-alkali syndrome.J Am Soc Nephrol. 2010; 21: 1440-1443Crossref PubMed Scopus (69) Google Scholar Prerenal acute kidney injury results from hypercalcemia-induced vasoconstriction and diuresis. Diuresis occurs when filtered calcium activates the calcium-sensing receptor in the medullary thick ascending limb of the nephron. This process inhibits the Na-K-2Cl cotransporter, which leads directly to natriuresis and indirectly to diuresis (there is reduction in the medullary concentration gradient and impairment of antidiuretic hormone–dependent water reabsorption in the collecting duct).11McMillan D.E. Freeman R.B. The milk alkali syndrome: a study of the acute disorder with comments on the development of the chronic condition.Medicine (Baltimore). 1965; 44: 485-501Crossref PubMed Scopus (55) Google Scholar Metabolic alkalosis results from direct ingestion of absorbable alkali and increased renal tubular absorption of bicarbonate (in the setting of reduced glomerular filtration, renal tubular cells increase bicarbonate absorption).11McMillan D.E. Freeman R.B. The milk alkali syndrome: a study of the acute disorder with comments on the development of the chronic condition.Medicine (Baltimore). 1965; 44: 485-501Crossref PubMed Scopus (55) Google Scholar Vitamin D intoxication can be ruled out because the patient's 25-hydroxyvitamin D level was not elevated. Although ACE measurements and fungal serologies were not obtained, granulomatous disease is an unlikely cause of the patient's hypercalcemia because her 1,25-dihydroxyvitamin D level was not elevated, chest radiography identified no abnormalities, she reported no respiratory symptoms, and she did not have lymphadenopathy on examination. In this patient, there were other factors driving hypercalcemia in addition to excessive calcium consumption. These factors included thiazide diuretic use causing increased renal reabsorption of calcium and ACE inhibitor use causing decreased glomerular filtration rate/calcium filtration.5.In addition to measuring the calcium level, which one of the following would be the best test to confirm the diagnosis at this time?a.Phosphorus measurementb.Creatinine measurementc.24-Hour urinary calcium measurementd.Ionized calcium measuremente.PTH measurement There is no specific test that diagnoses milk-alkali syndrome. The diagnosis is made on the basis of history, resolution of hypercalcemia after removing calcium supplementation or provoking medications, and follow-up documenting a normal total calcium concentration. Repeated measurements of phosphorus, creatinine, 24-hour urinary calcium excretion, and ionized calcium would not be helpful in supporting the diagnosis of milk-alkali syndrome. However, in addition to measuring the total calcium level after treatment, it may be helpful to measure the PTH level because some patients experience rebound elevation in serum PTH.12Beall D.P. Scofield R.H. Milk-alkali syndrome associated with calcium carbonate consumption: report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia.Medicine (Baltimore). 1995; 74: 89-96Crossref PubMed Scopus (112) Google Scholar In milk-alkali syndrome, PTH is suppressed, resulting in negligible physiologic drive to hold onto calcium. Thus, when calcium supplementation and provoking medications are discontinued and hypercalcemia is treated with fluid resuscitation, normocalcemia may be overshot and hypocalcemia may ensue. The PTH level subsequently increases to correct for this hypocalcemia. Also of note is that in the setting of primary hyperparathyroidism and familial hypocalciuric hypercalcemia, PTH secretion remains calcium responsive.13Khosla S. Ebeling P.R. Firek A.F. Burritt M.M. Kao P.C. Heath III, H. Calcium infusion suggests a “set-point” abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism.J Clin Endocrinol Metab. 1993; 76: 715-720PubMed Google Scholar Therefore, in acute illness, the calcium level can become high enough to suppress PTH. In this situation, when the calcium concentration is lowered, even if still above normal, the PTH level will increase and reveal the underlying parathyroid disorder. At follow-up 1 week after hospital dismissal, the patient's PTH level was normal at 16 pg/mL. She likely did not experience rebound elevation in serum PTH because she was never hypocalcemic. She was instructed to restrict her calcium intake and discontinue hydrochlorothiazide. At 6-month follow-up, her serum calcium level remained normal at 9.6 mg/dL. Milk-alkali syndrome was first described in the early 1900s when peptic ulcer disease was treated with the Sippy regimen, an antacid regimen including hourly administration of milk or cream with Sippy powders (magnesium carbonate and sodium bicarbonate alternating with bismuth subcarbonate and sodium bicarbonate).14Sippy B.W. Gastric and duodenal ulcer: medical cure by an efficient removal of gastric juice corrosion.JAMA. 1915; 64: 1625-1630Crossref Scopus (83) Google Scholar With the introduction of new therapies for peptic ulcer disease, milk-alkali syndrome virtually disappeared, and by 1985, it was considered the cause of less than 1% of cases of hypercalcemia.15Jamieson M.J. Hypercalcaemia.Br Med J (Clin Res Ed). 1985; 290: 378-382Crossref PubMed Scopus (30) Google Scholar However, with the more recent emphasis on calcium therapy for prevention and treatment of osteoporosis, the easy availability of over-the-counter calcium carbonate preparations, and the use of calcium carbonate to minimize secondary hyperparathyroidism in patients with chronic kidney disease, there has been a resurgence of milk-alkali syndrome. Between 1998 and 2003, it was the cause of hypercalcemia in over 8.8% of all patients with non–end-stage renal disease admitted to a university hospital with hypercalcemia, making it the third leading cause of hypercalcemia after primary hyperparathyroidism and malignant disease.16Picolos M.K. Lavis V.R. Orlander P.R. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.Clin Endocrinol (Oxf). 2005; 63: 566-576Crossref PubMed Scopus (79) Google Scholar The most common clinical presentation of milk-alkali syndrome is an asymptomatic patient who is incidentally found to have hypercalcemia, alkalosis, and renal impairment. Less commonly, patients present with acute symptomatic hypercalcemia consisting of nausea, vomiting, weakness, and mental changes or chronic symptomatic hypercalcemia consisting of polyuria, polydipsia, muscle aches, and pruritis.17Burnett C.H. Commons R.R. Albright F. Howard J.E. Hypercalcemia without hypercalcuria or hypophosphatemia, calcinosis and renal insufficiency—a syndrome following prolonged intake of milk and alkali.N Engl J Med. 1949; 240: 787-794Crossref PubMed Scopus (87) Google Scholar The diagnosis of milk-alkali syndrome is based on the findings of hypercalcemia, alkalosis, and renal impairment in the setting of ingestion of calcium- and alkali-rich medications and the exclusion of other causes of hypercalcemia. Treatment involves withdrawal of the offending agent and administration of isotonic saline, and possibly furosemide, after adequate hydration is achieved. In the future, patients with non–end-stage renal disease should limit their intake of elemental calcium to 1.2 to 1.5 g/d and avoid ingesting alkali.10Patel A.M. Goldfarb S. Got calcium? welcome of the calcium-alkali syndrome.J Am Soc Nephrol. 2010; 21: 1440-1443Crossref PubMed Scopus (69) Google Scholar Of note, this is a more stringent limitation than that recommended by the Institute of Medicine for the average population. In the average population, the recommended upper intake of elemental calcium is 2.5 g/d for 19- to 50-year-old adults and 2 g/d for adults older than 50 years.18Committee to Review Dietary Reference Intakes for Vitamin D and CalciumTolerable upper intake levels: calcium and vitamin D.in: Ross A.C. Taylor C.L. Yaktine A.L. Del Valle H.B. Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press, Washington, DC2011: 403-455Google Scholar