Hypercalcemia and Hyponatremia

Santosh Reddy MD FACP Assistant Professor Scott & White/Texas A&M

Etiology of Hypercalcemia

 Hypercalcemia results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone.

 Sources of calcium are most commonly the bone or the gastrointestinal tract Etiology

 Hypercalcemia is a relatively common clinical problem.  Elevation in the physiologically important ionized (or free) calcium concentration.  However, 40 to 45 percent of the calcium in serum is bound to protein, principally albumin; , increased protein binding causes elevation in the serum total calcium. Increased bone resorption

 Primary and secondary hyperparathyroidism  Malignancy  Hyperthyroidism  Other - Paget's disease, estrogens or antiestrogens in metastatic breast cancer, hypervitaminosis A, retinoic acid Increased intestinal calcium absorption  Increased calcium intake  Renal failure (often with vitamin D supplementation)  Milk-alkali syndrome  Hypervitaminosis D  Enhanced intake of vitamin D or metabolites  Chronic granulomatous diseases (eg, sarcoidosis)  Malignant lymphoma  Acromegaly

Pseudocalcemia

 Hyperalbuminemia  1) severe dehydration 2) multiple myeloma who have a calcium- binding paraprotein.  This phenomenon is called pseudohypercalcemia (or factitious hypercalcemia) Other causes

Familial hypocalciuric hypercalcemia  Chronic lithium intake  Thiazide diuretics  Pheochromocytoma  Adrenal insufficiency  Rhabdomyolysis and acute renal failure  Theophylline toxicity

 Immobilization  Total parenteral nutrition

Primary hyperparathyroidism

 Activation of osteoclasts leading to increased bone resorption in primary hyperparathyroidism (also cancer).

 Adenoma (80%)  Hyperplasia (15-20%)  Carcinoma (<1%) Secondary hyperparathyroidism

 Due to increased PTH in response to decreased calcium  Elevated PO4  ESRD Tertiary hyperparathyroidism

 An autonomous nodule develops after longstanding secondary hyperparathyroidism Familial hypocalciuric hypercalcemia (FHH)

 Mutation in the Ca-sensing receptor in parathyroid and kidney which increases the Ca set point

 May also increase the PTH ( parathyroid isn’t sensing Calcium) Malignancy

 PTHrP- PTH related peptide (squamous cell lung cancer, renal, breast, bladder)  Cytokines (TNF, INTERLEUKIN-1)  OAF: Local osteolysis (breast cancer, multiple myeloma)  Tumoral effect (Hogkins / NHL) Vitamin D Excess

 Granulomas (sarcoid, TB, histo) Produce 1-alpha hydroxylase ; that covert inactive Vit D to the active form

 Vitamin D Intoxication

Increased bone turnover

 Hyperthyroidism  Immobilization  Paget’s disease  Vitamin A Miscellaneous

 Thiazides (increase resorption in kidney)  Ca-based antacids (Milk-Alkali Syndrome)  Adrenal insufficiency Clinical Manifestations

 Bones  stones  abdominal groans  psychic moans Bones

 Osteopenia  Osteitis fibrosa cystica (seen in severe hyperparathyroidism only) Osteitis Fibrosa Cystica Cysts, fibrous nodules, salt and pepper appearance on X-ray Stones

 Nephrolithiasis  Nephrocalcinosis  Nephrogenic Diabetes Insipidus Abdominal Groans

 Anorexia  Nausea  Vomiting  Constipation  Pancreatitis  Peptic ulcer disease Psychic Moans

 Fatigue

 Depression

 Confusion

Labs

 Free Calcium Measured or Calculated( Measured Ca+(0.8x(4.0-alb) or use med-math?  PTH (irma assay)  PTH rp  VIT D , VIT A  PO4  URINE CALCIUM- 24 HRS

Treatment

 Normal Saline (4-6L per day) FILL THE TANK  Furosemide-CALCIURESIS Start after patient is intravascularly repleted  Bisphosphonates- Inhibits osteoclast activity(reducing bone resorption and turnover) malignancy and ?Immobilization 28 hrs half-life Bisphosphonates

 Pamidronate 60mg to 90 mg IV lasts 3-4 weeks; Pagets, Metastatic Bone disease,Myeloma

 Zolendronic acid(Zometa); 4 mg IV Can repeat 3-4 weeks same indications except pagets

Treatment

 SQ/IM( not nasal spray)Calcitonin 4 u/kg q12 hrs increase to 8 units q 12 hrs Onset 6-8 hours,duration 2-3 days

 Steroids( targets OAF, 5-A Hydroxylase) Onset 24-48 hrs days Hypercalcemia Quiz

 PTH Increased  Cal Increased  PO4 decreased

What do I have? quiz

 PTH DECREASED  CAL INCREASED  PO4 DECREASED/ INCREASED- EITHER

WHAT IS IT? QUIZ

 PTH DECREASED  CAL INCREASED  PO4 INCREASED

WHAT IS IT? QUIZ

 PTH NORMAL  CAL INCREASED  PO4 DECREASED QUIZ

 PTH INCREASED  CAL DECREASED  PO4 INCREASED QUIZ

 PTH INCREASED  CAL DECREASED  PO4 DECREASED Question 1

 A 66-year-old woman is evaluated in the emergency department for malaise and confusion of 8 days' duration. She has a 40-pack-year smoking history. She takes hydrochlorothiazide for hypertension. Physical examination reveals distant breath sounds. Chest radiograph shows a 1.5-cm mass in the proximal upper lobe of the left lung and infiltrates distal to the mass. A bone scan indicates no evidence of focal or metastatic disease.

 Laboratory StudiesCalcium 15.8 mg/dL  Phosphorus 3.0 mg/dL Chloride 97 meq/L  Intact parathyroid hormone<1.0 pg/mL  Serum protein electrophoresis shows polyclonal gammopathy.

 Which of the following is the most likely cause of the patient's hypercalcemia? Question 1

Which of the following is the most likely cause of the patient's hypercalcemia?  A Humoral hypercalcemia of malignancy  B Multiple myeloma  C Parathyroid adenoma  D Parathyroid hyperplasia  E Thiazide-induced hypercalcemia Question 2

 A 34-year-old man is evaluated in the emergency department for progressive nausea and poor appetite for the past 3 months and a decreased ability to concentrate. The patient has a history of hypertension, sarcoidosis, and nephrolithiasis. Sarcoidosis was diagnosed 5 years ago as a result of lymph node biopsy during an evaluation for fever, generalized lymphadenopathy, and elevated aminotransferase levels. He was treated with corticosteroids with good response; after 6 months the corticosteroids were discontinued. He has not taken corticosteroids for 2 years. evaluation.

 His only medication at this time is metoprolol.

 On physical examination, temperature is 37.7 °C (99.9 °F), blood pressure is 130/80 mm Hg, and heart rate is 68/min. Lymphadenopathy is present in the supraclavicular, epitrochlear, and axillary areas. There is mild hepatosplenomegaly. Question 2

 Laboratory StudiesSodium145 meq/ LPotassium4.9 meq/LChloride103 meq/ LBicarbonate31 meq/LSerum creatinine1.2 mg/dLBlood urea nitrogen34 mg/dL  Calcium12.6 mg/dL  Phosphorus5.1 mg/d  Parathyroid hormone3 pg/mL  1,25-Dihydroxyvitamin D3 168 pg/mL Question2

Which of the following is the most likely cause of this patient's hypercalcemia?

 A Metastatic bone disease  B Primary hyperparathyroidism  C Secondary hyperparathyroidism  D Vitamin D toxicity Question3

 A 48-year-old woman is evaluated in the office for a serum calcium concentration of 11.6 mg/dL discovered on routine screening.  There is no history or evidence of renal stones, bone fracture, cognitive impairment, or fatigue. The intact parathyroid hormone level is elevated at 115 pg/mL. The serum creatinine is 0.9 mg/ dL. Phosphorus is 2.4 mg/dL.  The 24-hour urine calcium excretion is 270 mg (normal for women, <250 mg). Question 3

 A Benign familial hypocalciuric hypercalcemia

 B Humoral hypercalcemia of malignancy

 C Metastatic bone disease

 D Multiple myeloma

 E Primary hyperparathyroidism Hyponatremia

Santosh Reddy MD DEFINITION

 Defined as Serum Sodium less than 136 meq/lt  4 % of hospitalized patients

 NEJM 2000:342:1581-9( Adrogue,Madias) Hyponatremia

 Disorders of sodium are generally due to changes in total body water, not sodium  Hyper- or Hypo- osmolality  watershifts  changes in brain cell volume  changes in mental status, seizures Hyponatremia: pathophysiology

 Excess water compared to sodium, almost always due to increased ADH The increased ADH may be:  Appropriate (e.g. hypovolemia or hypervolemia with too little effective arterial volume)EAV.  Inappropriate (e.g. SIADH) Workup

 Measure plasma osmolality to determine if hypo, hyper, or isotonic hyponatremia  Urine Osmolality  Serum NA  Urine NA

Hypertonic Hyponatremia

 Excess of another effective osmoles, such as mannitol, glucose

 Each 100mg/dL of glucose above 100 causes a decrease in Na by 1.8 mEq/L Isotonic Hyponatremia

 Lab artifact from  hyperlipidemia

 or hyperproteinemia Hypotonic Hyponatremia

 Most common scenario  True excess of water compared to Na Hypotonic Hyponatremia

hypovolemic euvolemic hypervolemic

UNa>20 UNa<10 UNa<10 UNa>20 FeNa<1% FeNa>1% FeNa>1% FeNa<1%

CHF, Renal Renal Extrarenal cirrhosis, failure losses losses nephrosis

Pt’s clinical history Uosm>100 Uosm<100 Uosm var.

SIADH, Primary Reset adrenal insuff, polydipsia, osmostat hypothyroidism low solute Hypovolemic Hypotonic Hyponatremia

 Renal losses: Thiazides or other diuretics, salt-wasting nephropathy, adrenal insufficiency  Extra-renal losses: GI losses (diarrhea), third-spacing (pancreatitis), inadequate intake, insensible losses Euvolemic Hypotonic Hyponatremia

 SIADH pulmonary-pneumonia, asthma, COPD, PTX, +pressure ventilation, small cell lung cancer intracranial-trauma, stroke, hemorrhage, tumors, infection, hydrocephalus drugs-antipsychotics, antidepressants, thaizides misc-pain, nausea, post-op state  Endocrinopathies (adrenal insuff, hypothyroidism)  Reset osmostat ( exercise, seizures)

Low solute

 “tea & toast”, “beer potomania” – increased free water intake with greatly decreased solute load  Maximum rate of water excretion on a normal diet is 10-12 L per day – more than this you overwhelm the excretory capacity of the kidney Hypervolemic Hypotonic Hyponatremia

 CHF: low effective arterial volume (EAV)  ADH  Cirrhosis: ascites causes low EAV ADH  Nephrotic syndrome: hypoalbuminemia causes low EAV  ADH  Advanced renal failure

Methods to increase Na

 Restrict free water range 800-1.2 lt per day  Remove stimulus for ADH (volume replete, increase EAV, treat pulmonary pathology, etc)  Demeclocycline (ADH antagonist) 300MG BID TO QID  Normal saline after NA deficit is calculated Treatment

 NA deficit: HYPOTONIC EUVOLEMIA TBW ( 60 % MEN : 50%) x (DESIRED NA----MEASURED NA )  Ex: 100 kg Man, MEASURED NA 120 TBW 60 MEQ x 12( D--- M sodium) 720 MEQ PER 24 HOURS

Treatment

 0.9 % : 154 meq/ LT  3% : 514 meq / LT

GIVE : 4. 6 LT OF 0.9 % NACL 1.4 LT OF 3 % NACL Treatment of Euvolemic Hyponatremia

 Asymptomatic: correct at rate of < 0.5 mEq/L/hr  Symptomatic: initital rapid correction of Na (2 mEq/ L/hr) until symptoms resolve  Rate of correction should NOT exceed 12mEq in a 24 hour period, or 18mEq in a 48 hour period to avoid Central pontine myelinosis (CNS demyelination  changes in mental status, paralysis, pseudobulbar palsy)  NEPHROLOGY 1994;4:1522-30

Treatment

 Conivaptan( vaprisol): Aquaresis:blocks V1a and V2 the activity of AVP ,free water excretion without losses of NA/K EVEREST trial

IV 20mg per day ; max IV 40mg per day Maximum 4 day therapy Electrolytes q 4-6 hrs

Aquaresis

 Tolvaptan;Samsca;( Salt 1 and 2 trials) V2 receptor antagonist( hypervolemic or Euvolemic)  Euvolemic: start 15mg po daily ,Increase by 15mg po daily; max daily dose 60mg

 Hypervolemic; same dose increments  Monitor electrolytes q 4-6 hrs Question 1

 A 61-year-old woman is hospitalized for a 5-day history of nausea and vomiting and decreased oral intake and a 2-day history of postural lightheadedness. Her creatinine level is 7 mg/dL (creatinine level 1 month ago was 1 mg/ dL). She has a history of hypertension and type 2 diabetes mellitus. Medications are aspirin, glipizide, enalapril, and chlorthalidone.  On physical examination, heart rate is 98/min and blood pressure is 85/60 mm Hg. Skin turgor is decreased. Cardiac and pulmonary examinations are normal. There is no peripheral edema. On neurologic examination, she is alert and oriented and there are no focal neurologic signs. Question 1

 Laboratory Studies  Blood urea nitrogen 85 mg/dL  Creatinine 8 mg/dL  Sodium 120 meq/L  Potassium 3.7 meq/L  Chloride 86 meq/L Bicarbonate 26 meq/L Urinalysis Several hyaline casts/hpf  Urine sodium 4 meq/L Question 1

 Which of the following is the next best step in this patient's management?  A Dialysis  B Fluid restriction

 C Intravenous normal (0.9%) saline

 D Intravenous 3% sodium chloride Question 2

 A 23-year-old man with HIV infection is evaluated in the office during a follow-up examination. He was hospitalized 1 week ago with Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, which is being treated with trimethoprim– sulfamethoxazole and prednisone. During his hospitalization, he was diagnosed with hyponatremia.  He feels well, and his condition has significantly improved since his discharge 3 days ago.

 On physical examination, temperature is 36.6 °C (97.8 °F), heart rate is 84/min, respiration rate is 12/min, and blood pressure is 110/60 mm Hg without orthostatic changes. He appears thin and in no apparent distress. Cardiac examination is normal. The lungs are clear. There is no peripheral edema. Neurologic examination, including mental status, is normal.

Question 2

 Glucose 122 mg/dL Blood urea nitrogen 12 mg/dL Creatinine 0.7 mg/dL  Sodium 111 meq/LPotassium 3.6 meq/L Chloride 96 meq/LBicarbonate 22 meq/L  Serum osmolality 246 mosm/kg H2O  Urine sodium 117 meq/L  Urine osmolality 453 mosm/ kg H2O Question 2

Which of the following is the most likely cause of this patient's hyponatremia?  A Adrenal insufficiency  B Pseudohyponatremia  C Psychogenic polydipsia  D Syndrome of inappropriate antidiuretic hormone secretion  E Volume depletion