Common Metabolic Abnormalities DR. SANJAY PANDEYA MD. FRCPC.

Common Metabolic Abnormalities DR. SANJAY PANDEYA MD. FRCPC.

Objectives 1. Review approach to hyponatremia Physiology & pathophysiology review Case-based common clinical questions Three-step process to working up hyponatremia SIADH review 2. Review approach to hypo/hyperkalemia Physiology & pathophysiology review Clinical manifestations & mechanisms Principles of treatment

Hyponatremia

Clinical Case An 84 year-old female from a nursing home is noted to have increasing confusion. She has had a poor appetite over the past year with significant weight loss. Over the past few days, the nurses have also noted some nausea, vomiting with no diarrhea, fever or other complaints. Med review notable for HCTZ and amitryptiline On exam, she has some dry oral mucosa but she is not orthostatic. There is no evidence of CHF, ascites or edema. She is awake, but disoriented. Neuro exam is nonfocal. Labs: Na 121 (130 2 months ago), normal renal/liver function. Serum osm 250, urine osm 280, urine Na 30

Questions we will answer 1. What are the potential causes of hyponatremia in this patient? 2. What other laboratory data is needed? 3. How might her diet be contributing to her hyponatremia? 4. How is the urine Na helpful? What in this case would limit its usefulness? 5. Does her urine osm of under 300 rule out SIADH? 6. How does water intake or inadequately hypertonic fluid intake worsen hyponatremia with SIADH?

Hyponatremia Defined Definition: serum Na+ <135 meq/l Generally associated with decreased osmolality <275 Most common electrolyte abnormality in North America A disorder of water retention Most forms of hyponatremia are associated with elevated ADH (whether appropriate or inappropriate), which concentrates urine and lowers free water excretion

Sodium Physiology Serum Sodium Regulation Stimulation of thirst Secretion of ADH Feedback mechanisms of the renin-angiotensinaldosterone system Renal handling of filtered sodium

Sodium Physiology Thirst Stimulation Osmolality Main driving force Only requires an increase of 2% - 3% Blood volume or pressure is reduced Requires a decrease of 10% - 15% Thirst center is located in the anterolateral center of the hypothalamus Respond to NaCL and angiotensin II

Renal Phsyiology

Hyponatremica: Clinical Manifestations Generally asymptomatic if Na+ level >125 Symptoms often non-specific: Headache, nausea, vomiting, muscle cramps Disorientation, depressed reflexes, lethargy, restlessness Delerium Seizure, coma, brainstem herniation & death More profound when change is large or rapid (hours) Serious complications more commonly seen in young women, pregnancy, after surgery and primary polydipsia

Approach to Hyponatremia Volume overloaded, dry or euvolemic? Osmolality (hyper, iso, or hypo) Is blood concentrated? For hypotonic hyponatremia, continue to 3 rd step: Urinary sodium excretion and FeNa % Is the urine concentrated?

Volume Status Volume status Hypotonic hyponatremia has 3 main groups: Hypovolemic both H2O and Na decreased (ΔH20 < ΔNa) Losses from diarrhea, vomiting, dehydration, malnutrition Euvolemic H20 increased and Na stable SIADH, thyroid disease, primary polydipsia Hypervolemic H20 increased and Na increased (Δ H2O > Δ Na) CHF, cirrhosis, renal failure

Osmolality Serum Osmolality =(2 Na + )+(glucose)+(urea) in mosm/kg Hypertonic - >295 Hyperglycemia, mannitol, glycerol Isotonic - 280-295 Historically pseudo-hyponatremia from elevated lipids or protein. Less common in contemporary laboratory equipment Hypotonic - <280 Xxcess fluid intake, low solute intake, renal disease, SIADH, hypothyroidism, adrenal insufficiency, CHF, cirrhosis, etc. Hypotonic hyponatremia warrants further workup

Urine Studies Urine Studies For euvolemic hyponatremia, check urine osmolality Urine osmolality <100 usually excess water intake Primary polydipsia, tap water enemas, post-turp Urine osmolality >100 - impaired renal concentration SIADH (often >300), hypothyroidism, cortisol deficiency Check urine sodium & calculate FeNa % (Una/Pna)/(Ucr/Pcr) A low urine sodium (<10) and low FeNa (<1%) implies the kidneys are appropriately reabsorbing sodium A high urine sodium (>20) and high FeNa (>1%) implies the kidneys are not reabsorbing sodium

Hyponatermia Isotonic (280-295) mosm/kg of water Hypotonic (<280) mosm/kg of water Hypertonic (>295) mosm/kg of water Plasma Osmolality 2 [Na] + [glucose]/18 +[BUN]/2.8 + [Ethanol]/4.6

Hyponatermia Isotonic (280-295) Lab artifact Absorption of Glycine or Sorbitol in bladder irrigation Hyperlipidemia Hyperproteinemia

Hyponatermia Hypertonic (>295) Excess of another Effective unmeasured Osmoles Radiographic contrast Hyperglycemia 100mg /dl gluà 1.6-2.4 decrease Na Mannitol

Hyponatermia Hypotonic (<280) Hypervolemic Euvolemic Hypovolemic Volume Status orthostatics, JVP, Skin turgor, Mucous membrane, Peripheral edema

Hyponatermia Hypotonic (<280) Hypervolemic Urine Na <10 FENa<1% Urine Na >20 FENa>1% CHF Cirrhosis Nephrotic syndrome Renal Failure

Hyponatermia Hypotonic (<280) Hypovolemic Urine Na>20 FENa >1% Urine Na<10 FENa<1% (Renal loss) Diuretics Adrenal Insufficiency CSW (Extra-renal loss) GI loss Insensible loss Third spacing

Hyponatermia Hypotonic (<280) The most common Euvolemic Urine osm <100 Urine osm >100 Primary polydipsia Low Solute (beer potomania, very low protein + sodium diet) SIADH Adrenal insufficiency Hypothyroidism

Some special attention to the etiologies of the most common cause of hyponatremia which is?

Ellison et al, New Engl J Med 356: 2064-72, 2007 SIADH

SIADH Diagnosis Essential Features Decreased effective osmolality ( <275 mosm/kg of water) Urinary Osmolality > 100 mosm/kg of water Clinical Euvolemia No sign of volume depletion of ECF No orthostasis, tachycardia, decreased skin turgor or dry mucous membrane No sign of excessive volume of ECF No edema or ascites Urinary Na > 40 mmol/l Normal thyroid and adrenal function No recent use of diuretic agents Ellison DH, Berl T, N Engl J Med.356(20):2064-72,2007

Etiologies of SIADH Mitchell H. Rosner. Hyponatremia: An Update on the Management of SIADH. Renal CME.

SIADH Tips for primary care A careful review of medication record can often identify one or more potential contributors to SIADH Judicious changes to medications can correct underlying problem and/or provide very useful information prior to referral Consider imaging studies to rule out malignancy

Hyponatremia: Treatment Approach to treatment Outpatient Treating the underlying cause Fluid +/- sodium restriction Solute intake and urea administration Inpatient Isotonic fluid administration Hypertonic fluid administration Vasopressin receptor antagonist (V 2 R-A)

Clinical Case An 84 year-old female from a nursing home is noted to have increasing confusion. She has had a poor appetite over the past year with significant weight loss. Two weeks ago HCTZ was added. Over the past few days, the nurses have also noted some nausea, vomiting with no diarrhea, fever or other complaints. On exam, she has some dry oral mucosa but she is not orthostatic. There is no evidence of CHF, ascites or edema. She is awake, but lethargic. Neuro exam is nonfocal. Labs: Na 121 (130 2 months ago), normal renal/liver function. Serum osm 250, urine osm 280, urine Na 30. Volume: Euvolemic Osmolality: Serum is hypo-osmotic (250) Urine studies: Urine is inappropriately dilute (280), Urine sodium not low.

Case Questions 1. What are the potential causes of hyponatremia in this patient? Thiazide diuretic Recent n/v and volume loss (although not orthostatic) Poor solute intake/ tea and toast diet (may be why urine osm not as high as expected with classic SIADH) Possible CNS event (stroke, subdural) Underlying SIADH (suggested by inappropriately high urine osm, amitriptyline)

Case Questions 2. What other laboratory data would be needed? TSH AM cortisol level (although not orthostatic) Could consider neuroimaging given underlying dementia and risk for CVA, subdural, etc

Case Questions 3. How might her diet contribute? Each liter of urine requires 50 mosm of solute intake For the `tea and toaster` inadequate solute intake therefore impairs free water clearance Thomas Berl. Impact of Solute Intake on Urine Flow and Water Excretion. JASN 2008 19 (6): 1076-1078

Case Questions 4. How is the urine Na helpful in differentiating SIADH from hypovolemia? What in this case would limit its usefulness? Urine Na should be normal/elevated with SIADH and should be low with hypovolemia Thiazide diuretic use may elevate urine Na

Case Questions 5. Does her urine osm of under 300 rule out SIADH? No; classically urine osmolality is 300 or greater, but the urine osm of 220 in the setting of a serum na of 121 is inappropriately elevated Should be producing maximally dilute urine so anything over 100 is often inappropriate

Case Questions 6. How does water intake or hypotonic fluid intake worsen the hyponatremia with SIADH? Example: patient with SIADH with urine osm of 616. 1 liter of NS has 308 mosmol of NaCl, 1000 ml free water Isotonic Saline NaCl H2O In 308 1000 ml Out 308 500 ml Net 0 +500 ml retained Due to renal handling, the saline bolus actually only provides MORE net free water

Case Questions 7. How would you manage this patient? Discontinue thiazide, amitriptyline Consider water restriction. Need to address both the amount of intake of both free water and solutes in setting of recent vomiting Avoid rapid correction Recheck lytes in in 5-7 days No immediate indication for intravenous resuscitation. If vomitting persisted, consider small amount of normal saline (would be relatively hypertonic to urine osm of 220)

Take Home Points Work-up in 3 important steps 1) Assess volume status 2) Assess serum osmolality 3) Check urine sodium, osmolality

Take Home Points When to Refer Urine Na <125-130 that is persistent or a recent change Often there is the opportunity to try conservative measures before referral: Medication changes, volume correction or restriction What to include in Referral Include medication history and recent changes Labs: Historical sodium values, present serum osm, urine osm, urine Na, lytes, urea creatinine, TSH, random cortisol

References 1. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007 May 17;356(20):2064-72 2. Decaux G. Is Asymptomatic Hyponatremia Really Asymptomatic? The American Journal of Medicine. 2006;119:S79-S82. 3. Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010;123:652-657. 4. Gross P. Treatment of Hyponatremia. Inter Med.2008, 47: 885-891. 5. Ozturk S, Ozsenel E, Kazancioglu R, Turkmen A. A case of fluoxetine-induced syndrome of inappropriate antidiuretic hormone secretion. Nat Clin Pract Nephrol. 2008;4:278-282. 6. Sica DA. Hyponatremia and heart failure--pathophysiology and implications. Congest Heart Fail. 2005;11:274-277. 7. Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis. 2010;56:774-779. 8. Updhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia, Am J Med. 2006 Jul;119(7 Suppl 1):S30-35 9. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations,am J Med. 2007 Nov;120(11 Suppl 1):S1-21

Disorders of Potassium Homeostasis (optional)

Potassium Homeostasis Gastrointestinal absorption of potassium is complete resulting in daily excess intake of about 1 mmol/kg/d Excess potassium is excreted through the kidneys (90%) and through the gut (10%) The most important site of regulation is the distal nephron, under the influence of the renalangiotensin-aldosterone system

Potassium Homeostasis Maintain the osmotic integrity of cells Osmotic pressure in ICF Maintain acid-base balance Potassium-hydrogen exchange Contribute to the reactions that take place in cells Carbohydrate and amino-acid metabolism Involved in excitability of muscle cells

Potassium Homeostasis 98% of potassium is intracellular The remaining 2% is extracellular and tightly regulated between 3.7-5.2 meq/l Hyperkalemia Hypokalemia Mild-to-Moderate 5.5-6.2 meq/l 3-3.4 meq/l Severe >6.5 meq/l and/or symptomatic < 2.5-3 meq/l and/or symptomatic

Hypokalemia: Clinical Manifestations Neuromuscular impairment Muscle weakness, fatigue, cramps, paralysis Gastrointestinal motility Anorexia, nausea, vomitting, paralytic ileus Cardiovascular manifestations Arrhythmias, increased sensitivity to digitalis toxicity Impaired renal transportation function polyuria, impaired bicarb reabsorption, nephropathy Metabolic alkalosis

Hypokalemia: Clinical Manifestations ECG Changes ST segment depression T wave flattening Prominent U wave Prolongation of PR interval

Hypokalemia: Mechanisms 1. Decreased intake Anorexia 2. Excessive loss of K + GI: V/D/laxative Renal 3. K + shift into cells Alkalosis Insulin Catecholamines Hypothermia Hyperthyroid 4. Blood dilution

Hypokalemia: Renal Mechanisms Hyperaldosteronism Primary Secondary Polyuria Diuretics Loop, thiazide, acetozolamide Renal tubular acidosis type I & II Hypomagnesemia Salt-wasting nephropathies Barrter,Gitelman and Liddle s Syndrome Other Black licorice, CAH, Cushing s

Trans-tubular K gradient (TTKG) (Upot/Ppot)/(Uosm/Posm) Appropriate renal response Hyperkalemia TTKG >10 Hypokalemia TTKG < 2 Caveat for interpretation: Una must NOT be <10

Hypokalemia: Principles of Treatment 1. Etiological treatment to correct the underlying disorder including hypomagnesemia 2. Replacement of potassium Oral potassium chloride is preferred to intravenous With hypokalemia and oliguria, extracellular potassium may be driven by shift related to volume depletion and acidosis Generally only replace once confirmed patient is urinating 3. Potassium-sparing diuetics Reasonable to refer if considering these agents

Hyperkalemia: Clinical Manifestations Neuromuscular impairment Muscle weakness and paralysis Cardiovascular manifestations Conduction abnormalities: bundle branch & AV blocks Arrhythmias: bradycardia, asystole, vtach, vfib Impaired renal transportation function Impaired ammonium excretion Metabolic acidosis

Hyperkalemia: Clinical Manifestations ECG Changes Peaked T wave Prolongation of the PR interval ST elevation (which may mimic myocardial infarction) Widening QRS -> sine wave pattern and asystole

Hyperkalemia: Mechanisms 1. Pseudohyperkalemia 2. Release from cells Crush injuries/rhabdo Tumor-lysis syndrome 3. K + shift out of cells Acidosis Insulin deficiency Beta-blockade Exercise Hyperthyroid 4. Reduced renal excretion

Hyperkalemia: Renal Mechanisms Acute and chronic renal disease Impaired sodium and water delivery Hypoaldosteronism Low renin: Diabetes, NSAIDs, drugs Angiotensin inhibitors: ACEi & ARBs Impaired aldosterone secretion: primary hypoaldosteronism, heparin Reduced response to aldosterone Potassium-sparing diuretics Certain antibiotics: trimethoprim, pentamidine

Hyperkalemia: Principles of Treatment Rapid-acting therapies (K>6.5 or with ECG changes): Calcium Calcium gluconate 1000mg over 2-3minutes Insulin with glucose 10 units regular insulin with 1 amp D50 Beta-2 adrenergic agonist Salbutamol 4 puffs q5min x3 or alburerol nebulized Sodium bicarbonate 150mEq in 1L D5W over 4-6 hours

Hyperkalemia: Principles of Treatment 1. Correct the underlying disorder 2. Potassium removal Loop or thiazide diuretics Cation-exchange resins (Kayexelate 30 grams) Dialysis 3. Prevention of future episodes Generally avoid co-administration of ACE-I with ARBs or direct-renin inhibitors (Aliskiren) with ACE-I/ARB Dietary restriction in CKD

References Evans KJ, Greenberg A. Hyperkalemia: a review. J Intensive Care Med. 2005 Sep-Oct;20(5):272-290. Harel Z et al. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: Systematic review and meta-analysis. BMJ 2012 Jan 9; 344:e42. - Hollander JC, Calvert CJ. Hyperkalemia. Am Fam Physician 2006; 73:283-90 Kamel KS, Wei C. Controversial issues in the treatment of hyperkalaemia. Nephrol Dial Transplant. 2003;18:2215-2218. Sood MM, Sood AR, Richardson R. Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clin Proc. 2007 Dec; 82(12):1553-1561 The ONTARGET Investigators. Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events. N Engl J Med 2008; 358:1547-1559

Common Metabolic Abnormalities DR. SANJAY PANDEYA MD. FRCPC.