Differential Diagnosis in Internal Medicine

From Symptom to Diagnosis

Bearbeitet von Walter Siegenthaler

1. Auflage 2007. Buch. 1144 S. Hardcover ISBN 978 3 13 142141 8 Format (B x L): 19,5 x 27 cm

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Water, Electrolyte, 30 and Acid−Base Disorders

T. Fehr and R. P. Wuethrich 30

892

30.1 Disorders of Sodium and Water Hypokalemia and Hyperkalemia 909 Homeostasis 895 Definition, Diagnosis, and Clinical Features 909 Hypokalemia (PK 3.5 mmol/L) 910 Physiologic Principles 895 Hypokalemia Due to Reduced Potassium Intake 910 Fluid Compartments 895 Hypokalemia Due to Transcellular Principles of Osmoregulation 896 Shifts (Disorders of Internal Balance) 911 Principles of Volume Regulation 896 Hypokalemia Due to Enhanced Potassium Loss 911 Disorders of Volume Homeostasis (Extracellular Volume Contraction and Hyperkalemia (PK 5.0 mmol/L) 912 Expansion) 899 Hyperkalemia Due to Excessive Potassium Intake 912 Definition, Diagnosis, and Clinical Features 899 Hyperkalemia Due to Transcellular Extracellular Volume Contraction (with Shifts (Disorders of Internal Balance) 912 Primarily Normal Serum Sodium) 900 Hyperkalemia Due to Reduced Extracellular Volume Expansion (with Potassium Excretion 913 Primarily Normal Serum Sodium) 900 30.3 Disorders of Acid−Base Disorders of Water Homeostasis and Homeostasis Osmoregulation (Hyponatremia and 915 Hypernatremia) 901 Physiologic Principles 915 Definition, Diagnosis, and Clinical Features 901 Basics of Acid−Base Metabolism 915 Hyponatremia (PNa 135 mmol/L) 901 Hypovolemic Hyponatremia 902 Levels of Acid−Base Regulation 915 Euvolemic Hyponatremia 903 Regulation of Renal Acid Excretion 916 Hypervolemic Hyponatremia 904 Acidosis and Alkalosis 917 Hypernatremia (PNa 145 mmol/L) 905 Hypovolemic Hypernatremia 905 Definition, Diagnosis, and Clinical Features 917 Euvolemic Hypernatremia 905 Metabolic Acidosis 920 Hypervolemic Hypernatremia 906 Pathogenesis and Use of the Serum Anion Gap (SAG) 920 30.2 Disorders of Potassium Normochloremic Metabolic Acidosis Homeostasis (with Increased SAG) 920 907 Hyperchloremic Metabolic Acidoses (with Normal SAG) 921 Physiologic Principles 907 Metabolic Alkalosis 922 Potassium Distribution and Internal Pathogenesis and Importance of the Potassium Balance 907 Urine Chloride Concentration 922 Potassium Excretion and External Chloride-Sensitive Metabolic Alkaloses 923 Potassium Balance 907 Chloride-Resistant Metabolic Alkaloses 924 Steroid Biosynthesis 908 Metabolic Alkalosis via Exogenous Alkali Intake 924

893

Respiratory Acidosis 925 Disorders of Phosphate Homeostasis 937 Acute and Chronic Disorders 925 Definition, Diagnosis, and Clinical Features 937 Differential Diagnosis of Respiratory

3- Acidosis 926 Hypophosphatemia (PPO4 1 mmol/L) 939 Respiratory Alkalosis 928 Hyperparathyroid Status 939 Acute and Chronic Disorders 928 Reduced Intestinal Absorption of Vitamin D and PO 3- 939 Differential Diagnosis of Respiratory 4 3- Alkalosis 928 Transcellular PO4 Shifts 940 Renal Phosphate Loss 940

30.4 Disorders of Calcium, Phosphate, 3- Hyperphosphatemia (PPO4 1.5 mmol/L) 941 and Magnesium Homeostasis 928 Hypoparathyroid Status 941 Increased Intestinal Absorption of PO 3- or Vitamin D 941 Physiologic Principles 928 4 3- Transcellular PO4 Shifts 941 Particular Properties of Calcium, Renal Phosphate Retention 941 Phosphate, and Magnesium 928 Disorders of Magnesium Homeostasis 942 Regulation of Calcium and Phosphate Homeostasis 929 Definition, Diagnosis, and Clinical Features 942 Disorders of Calcium Homeostasis 930 Hypomagnesemia (PMg 0.7 mmol/L) 942 Reduced Intake 942 Definition, Diagnosis, and Clinical Features 930 Transcellular Magnesium Shifts 942 Hypocalcemia (PCa 2.1 mmol/L) 932 Extrarenal Magnesium Loss 943 Hypoparathyroid Status 932 Renal Magnesium Loss 943 Vitamin D Deficiency 933 Hypermagnesemia (PMg 1.2 mmol/L) 944 Calcium Sequestration in Bones and Increased Intake 944 Tissues 933 Transcellular Magnesium Shifts 944 Renal Calcium Loss 934 Renal Magnesium Retention 944 Hypercalcemia (PCa 2.6 mmol/L) 934 Hyperparathyroid Status 934 Vitamin D Excess 935 Increased Bone Resorption 935 Renal Calcium Retention 935 Other Causes 935

894

30.1 Disorders of Sodium and Water Homeostasis

Physiologic Principles

Disorders of sodium and water homeostasis result in changes of volume status, serum osmolality, and serum Intake sodium concentration. Basic knowledge of physiologic principles is fundamental for understanding these disorders. Some of these principles are briefly described Sensed parameter ECS ICS below. for regulation: plasma concentration

Transcellular shift Plasma Fluid Compartments

Excretion General Pathogenesis of Electrolyte Disorders. The human body consists of different fluid compartments, renal extrarenal and each of them has a characteristic electrolyte profile (Tab. 30.1). Electrolyte disorders, which are usually Fig. 30.1 Fundamental pathogenesis of electrolyte disorders. measured in the serum, can occur by three different Electrolyte disorders principally arise in three different ways: by mechanisms (Fig. 30.1): by a net change in intake,bya altered intake, by internal shifts (mainly between intracellular shift between different compartments, and by a net space [ICS] and extracellular space [ECS]), and by altered excre- change in excretion. tion. The kidney is the main organ responsible for excretion of electrolytes. Therefore, the differential diagnosis Size of Fluid Compartments. On average, the human usually distinguishes between renal and extrarenal dis- body consists of 60 % water and 40 % solid substances. orders of electrolyte excretion/loss. The renal excretion Based on a body weight of 70 kg, the total body water is of a substance X can be estimated by determination of distributed as follows (Fig. 30.2): the fractional excretion (FE) in spot urine. The fractional ➤ intracellular volume (ICV): 40 % (28 L) excretion is defined as the amount of a substance X ex- − blood cells: 3 % (2 L) creted via urine divided by the total amount of glomeru- ➤ extracellular volume (ECV): 20 % (14 L) lar filtration of X. In this chapter the concentration of a − intravascular compartment (plasma): 5 % (3.5 L) substance X in the plasma/serum or in the urine is de- − interstitial compartment: 15 % (10.5 L).

scribed as PX or UX, respectively. The fractional excretion of X can then be calculated as follows: The blood volume consists of the combined volume of blood cells and plasma. It represents about 8 % of body (UX ×PCreatinine) FEX = weight. (PX ×UCreatinine)

Fig. 30.2 Distribution of water and cations in the adult body; Solid tissue ~40% water in percent of body weight Extracellular Intracellular (BW), cations in percent of total “Third space” space space body stores. (ECS) (ICS) ~20% BW ~40% BW – Pericardium K+ + + – Pleural cavity – Na ~98% – Na ~2– 3 % + + – Peritoneum –K ~2% –K ~97–98% – Retroperi- + toneum Na – Intestinal 5% + + lumen ~ Na -K -ATPase – Skin

– Muscles 15 % Interstitial space ~ Plasma

Capillary basement membrane Cell membrane

895

Table 30.1 Electrolyte profiles in various fluid compartments (in mEq/L) Ions Plasma Interstitial fluid Intracellular fluid Cations Sodium 142 145 12 Potassium 4.3 4.4 140 Calcium (ionized) 2.5 2.4 4 Magnesium (ionized) 1.1 1.1 34 Anions Chloride 104 117 4 Bicarbonate 24 27 12 Phosphate 2.0 2.3 40 Proteins 14 0 50 Others 5.9 6.2 84

In particular clinical situations sequestration of large Feedback Loop of Osmoregulation. The feedback loop of volumes of fluid is observed in serous cavities (pleural, osmoregulation is shown in Fig. 30.3. Osmolality is pericardial, peritoneal space) or in traumatized tissue sensed in specialized cells of the hypothalamus (affer- (muscle, retroperitoneal space). This is described as a ent part of the loop). Regulation of osmolality then oc- transcellular third space. Under physiologic conditions, curs via a change in water intake and water excretion in this volume is negligible, but it can consist of several the kidney. Two effector mechanisms are mainly re- liters of fluid in certain disease states, and therefore, sponsible (efferent part of the loop): considerably influence volume homeostasis. ➤ Hyperosmolality stimulates thirst and leads to in- Each fluid compartment has a characteristic electro- creased water intake. lyte profile, which is summarized in Tab. 30.1. Under ➤ Hyperosmolality induces the secretion of vasopressin physiologic conditions, the sum of osmotic and oncotic (antidiuretic hormone [ADH]) in the hypothalamus. pressure is identical in all the compartments, which al- Vasopressin activates the vasopressin receptor type 2

lows stable volume homeostasis. However, it is impor- (V2 receptor), which reduces renal water excretion. In tant to understand that the regulation of volume and contrast, hypoosmolality suppresses vasopressin osmolality are fundamentally different and independ- secretion, which leads to activation of water chan- ent of each other. Each of these is regulated by different nels (aquaporins) in the collecting duct and in- hormone systems. creased water excretion.

The daily urine output can be regulated between 0.5 Principles of Osmoregulation and 15−20 L, which allows stable serum osmolality, independent of water intake. Variability of serum osmolality remains within Ȁ 2%. Intracellular and extracellular spaces are separated by the cell membrane, which is permeable to water and urea, but impermeable to electrolytes and proteins. The osmotic pressure within a compartment can be deter- Principles of Volume Regulation mined by the total concentration of all soluble constitu- ents and is described as serum osmolality. In the steady state it is identical in all the compartments and highly Feedback Loop of Volume Regulation. The maintenance correlated with the serum sodium concentration. The of the extracellular volume (ECV) to allow for stable osmolality (Osm) is tightly regulated (285−290 mOsm/ circulation and adequate perfusion of vital organs is one L) and can be approximately calculated by the following of the most fundamental principles of water homeosta- formula: sis. The feedback loop of volume regulation is depicted in Fig. 30.4. Since the ECV cannot be measured directly, P =(2×P )+P +P Osm Na Glucose urea it is determined indirectly by arterial baroreceptors, If there is a considerable difference between calculated which are located in the carotid sinus, aortic arch, and and effectively measured osmolality, this is referred to left ventricle (afferent part of the loop). These receptors as an osmotic gap. Substances which are not included in the formula above (e. g., alcohol, glycol, and certain drugs) may be responsible for this difference (see Me- tabolic Acidosis, below). Fig. 30.4 Scheme of the feedback loop of volume regulation. ୴ ANP = atrial natriuretic peptide. 896

Hypothalamic osmoreceptors: sensor for osmolality

Hypothalamic thirst region: stimulation of water intake Posterior pituitary gland: secretion of vasopressin (ADH)

V2 receptor V1 receptor

Renal water retention Vasoconstriction

Fig. 30.3 Scheme of the feedback loop of osmoregulation. V1/V2 receptor: vasopressin receptor type 1 (on blood vessels) and 2 (on collecting duct cells).

Sympathetic nervous system

Vasomotor center

Cardiac atrium: Adrenal medulla: ANP catecholamines Adrenal cortex: Aldosterone Baroreceptors in the arterial vasculature: sensor for effective circulating volume Renin/ (= filling status of the Angiotensin II arterial circulation)

Renal water retention Vasoconstriction

897

measure the effective circulating volume, therefore the directly and indirectly to secretion of catecholamines filling status of the arterial circulation, which is deter- and consecutive increase of vascular tone. In addi- mined by ECV and vascular tonus. Under physiologic tion, catecholamines increase sodium reabsorption conditions ECV and the effective circulating volume are in the proximal tubule. highly correlated, but in certain pathophysiologic situa- ➤ Hypovolemia leads to renal hypoperfusion, which tions they can be highly discrepant (e. g., edematous triggers renin secretion in the juxtaglomerular ap- disorders with an increase of ECV, but a decrease in the paratus of the kidney. Renin stimulates the synthesis effective circulating volume). of bioactive angiotensin II and ultimately al- The ECV is determined by the total body sodium, dosterone. Angiotensin II is a potent vasoconstrictor which is mainly located in the ECV. An increase of total and also stimulates sodium reabsorption in the prox- body sodium leads to volume expansion, whereas a imal tubule. In contrast, aldosterone leads to sodium decrease leads to volume contraction. Therefore, reabsorption and potassium secretion in the collect- volume regulation occurs mainly by variation of renal ing duct. sodium excretion (efferent part of the feedback loop). ➤ Hypervolemia induces secretion of atrial natriuretic The following hormone systems regulate renal sodium peptide (ANP) in the heart. ANP leads to renal sodium excretion: excretion by increasing glomerular filtration and in- ➤ Hypovolemia activates baroreceptors, which stimu- hibition of sodium reabsorption in the proximal late the sympathetic nervous system, which leads tubule.

Overview of Volume and Osmoregulation

The fundamental principles of volume and osmoregula- Therefore, disorders of sodium and water homeostasis tion are summarized in Tab. 30.2 and can be described as can be classified as follows: follows: ț extracellular volume contraction (with primarily nor- ț The kidney regulates the ECV via renal sodium ex- mal serum sodium concentration) cretion. The clinical parameter is the urine sodium ț extracellular volume expansion (with primarily normal

concentration UNa. Volume contraction leads to serum sodium concentration) sodium retention. Volume expansion leads to in- ț hyponatremia creased natriuresis. ț hypernatremia. ț The kidney regulates serum osmolality via renal water excretion. The clinical parameter is the serum

sodium concentration PNa. Hyperosmolality leads to renal water retention. Hypoosmolality leads to increased renal water excretion.

Table 30.2 Overview of volume and osmoregulation Volume regulation Osmoregulation What is measured? (input) − effective circulating volume − plasma osmolality Sensor (afferent part of the loop) − arterial baroreceptors (left ven- − hypothalamic osmoreceptors tricle, aortic arch, carotid sinus) What is regulated? (output) − renal sodium excretion − renal water excretion − water intake Effector (efferent part of the − proximal sodium reabsorption − water retention in the collecting loop) via catecholamines and angi- duct via vasopressin otensin II − water intake via stimulation of − sodium reabsorption in the col- thirst lecting duct via aldosterone

898

Disorders of Volume Homeostasis (Extracellular Volume Contraction and Expansion)

Definition, Diagnosis, and Clinical Diagnosis. In the case of volume expansion an increased Features heart size, pulmonary congestion, and pleural effusions can be seen in the chest radiograph. In intensive care Increase or Decrease of Total Body Sodium and Water to units measurement of the central venous pressure al- the Same Extent. Disorders of volume homeostasis lead lows reliable assessment of volume status. to expansion or contraction of the ECV, which manifests Laboratory parameters can be helpful in the case of in the typical cardiopulmonary symptoms of hy- volume contraction. An increase of hematocrit or serum povolemia or fluid overload. These disorders are partic- albumin level is not very reliable by itself, but can be ularly frequent in clinical routine, and therefore the used for follow-up investigations under therapy. Since clinical evaluation of the volume status of a patient is of volume contraction leads to renal sodium retention, a utmost importance for differential diagnosis. Chest decrease in urine sodium level is a reliable parameter

radiograph and certain laboratory parameters can give for a volume deficit. In spot urine, UNa is usually some additional guidance. These symptoms and signs 20 mmol/L and UOsm 600 mOsm/L. The fractional ex- are summarized in Tab. 30.3. cretion of sodium, FENa, allows differentiation between prerenal and parenchymal acute renal failure in the Clinical Features. Volume contraction manifests with or- oliguric patient and is below 1 % in the case of volume

thostatic hypotension, tachycardia, collapse of central depletion. FENa is calculated as follows: veins, dry skin and mucosal surfaces, oliguria, and dis- (U ×P ) orientation. In contrast, volume expansion leads to hy- FE = Na Creatinine Na (P U ) pertension, increased body weight, peripheral edema, Na × Creatinine dyspnea, and crackles over the base of the lungs.

Table 30.3 Signs of extracellular volume contraction or expansion Volume contraction Volume expansion Clinical signs cardiopulmonary system − orthostatic hypotension ( 15−20 mmHg − hypertension systolic) − distended central veins, positive hepato- − orthostatic increase in heart rate jugular reflux ( 15−20 beats/min) − pulmonary congestion on auscultation − collapsed central veins (at 45° back inclination) − shock in case of severe volume depletion skin and mucosal surfaces − reduced skin turgor − peripheral edema − dry mucosal surfaces − increased body weight Chest radiograph heart − small heart silhouette − heart silhouette Ȇ lungs and pleura − diffuse pulmonary vasculature, peri- bronchial cuffing, lung edema − pleural effusion Laboratory parameters blood − hematocrit Ȇ − hematocrit ȇ − serum albumin Ȇ − serum albumin ȇ urine − UNa 20 mmol/L − fractional sodium excretion FENa 1% Hemodynamics pressures − central venous pressure ȇ − central venous pressure Ȇ − pulmonary−capillary wedge pressure ȇ − pulmonary−capillary wedge pressure Ȇ − mean arterial pressure ȇ − mean arterial pressure Ȇ cardiac output − cardiac output ȇ − heart failure: cardiac output ȇ − others: cardiac output Ȇ peripheral resistance − peripheral resistance Ȇ − peripheral resistance ȇ

899

Table 30.4 Differential diagnosis of volume depletion mineralocorticoid deficiencies (see Disorders of Extrarenal causes Renal causes Potassium Homeostasis, p. 907). The differential diagnosis of volume depletion is summarized in Tab. 30.4. (UNa 20 mmol/L) (UNa 20 mmol/L) − Insufficient salt and − Osmotic diuresis water intake − severe hyperglycemia − Fluid sequestration in − Drugs Extracellular Volume Expansion (with the third space − chronic diuretic Primarily Normal Serum Sodium) − crush injury, rhabdo- abuse myolysis − Renal salt wasting − internal bleeding − tubulointerstitial If the net intake of sodium and water overcomes excre- − pancreatitis, peritoni- nephropathies tion, the ECV expands. ECV expansion over 2−4 L leads tis, ileus, sepsis − postobstructive to peripheral edema. Based on pathophysiology, two − Gastrointestinal loss diuresis fundamentally different situations can be distinguished − vomiting, nasogastric − renal tubular acidosis (Tab. 30.5): tube − congenital salt- ➤ − diarrhea, fistulas wasting disorders concomitant increase of ECV and the effective circu- − bleeding (Bartter syndrome lating volume as a consequence of increased sodium − Skin loss etc.) and water intake and/or reduced renal excretion − intense sweating − Mineralocorticoid defi- ➤ increase of ECV associated with reduced effective − burns ciency (see Tab. 30.12) circulating volume in the context of classical edema- − External bleeding tous disorders (heart failure, liver cirrhosis, nephrotic syndrome).

Volume expansion, as a consequence of increased intake, Table 30.5 Differential diagnosis of volume expansion occurs in the context of infusion therapy, but usually ECV Ȇ, effective ECV Ȇ, effective only in situations where excretion is also reduced. This is circulating volume Ȇ circulating volume ȇ mainly the case in patients with acute or chronic renal − Primary renal disease − Edematous disorders failure. The renin−angiotensin−aldosterone system is − acute glomerulo- with secondary hyper- suppressed in these patients, and they are hypertensive nephritis aldosteronism due to an increase in the effective circulating volume. − acute and chronic − heart failure The same is the case in patients with primary miner- renal failure − nephrotic syndrome alocorticoid excess (e. g., Conn syndrome). These dis- − Mineralocorticoid excess − liver cirrhosis eases are usually associated with disorders in potassium (see Tab. 30.11) − severe hypoal- homeostasis (see below). buminemia (nutri- In the case of classical edematous disorders a primary tive) underfilling of the arterial circulation is observed. In the case of heart failure this is a consequence of reduced cardiac output, whereas in patients with nephrotic syndrome it is due to hypoproteinemia and consecutive Extracellular Volume Contraction (with fluid shifts into the interstitial space. In the case of liver Primarily Normal Serum Sodium) cirrhosis, the reduced effective circulating volume occurs as a consequence of splanchnic vasodilatation and ascites. All of these patients have an activated renin− Volume contraction with consecutive decrease in the ef- angiotensin−aldosterone system (secondary hyperal- fective circulating volume occurs with combined net dosteronism), and they manifest with hypotension due loss of sodium and water. Three basic mechanisms can to a reduction of the effective circulating volume. Renal be responsible and are not mutually exclusive: hypoperfusion and hyperaldosteronism lead to renal ➤ insufficient intake of sodium and water sodium and water retention, and therefore, edema for- ➤ fluid shift with sequestration in the third space mation. Concomitant hyponatremia is often observed, ➤ increased renal or extrarenal loss. because the reduction of the effective circulating volume leads to nonosmotic stimulation of vasopressin Renal loss occurs in the context of primary renal dis- secretion. This is particularly dangerous in the context eases with tubulointerstitial damage, but also indirectly of therapy with thiazide diuretics (see below). as a consequence of osmotic diuresis and in all forms of

900

Disorders of Water Homeostasis and Osmoregulation (Hyponatremia and Hypernatremia)

Definition, Diagnosis, and Clinical clinical example is the accumulation of urea in the con- Features text of azotemia. Tab. 30.6 shows an overview of these particular situations and underlines the importance of measuring serum osmolality in patients with unclear Increase or decrease of the serum sodium concentra- hyponatremia. tion represents disorders in water homeostasis and osmoregulation. Hyponatremia (PNa 135 mmol/L; Clinical Features. Disorders of serum osmolality and severe: 125 mmol/L) occurs due to an excess of serum sodium lead to a volume shift between the intra- water, and hypernatremia (PNa 145 mmol/L; severe: cellular and the extracellular space. As a consequence, 155 mmol/L) due to a water deficit, always in rela- cellular swelling occurs with hyponatremia and cellular tion to the concomitant total body sodium. Both dis- shrinking with hypernatremia. Because the brain is lo- orders can be associated with a net increase or cated in a fixed volume, it is primarily affected by shifts decrease of total body water. For differential diagnosis, in cellular volume due to disorders in serum sodium it is therefore of critical importance to also assess the concentration or quick therapeutic correction measures. volume status of such patients (see above). Neurologic and psychiatric symptoms and signs are therefore very typical in both situations, e. g., headache, Diagnosis. Until recently, the serum sodium concentra- nausea and vomiting, confusion, delirium, lethargy, and tion was measured by means of flame photometry of eventually coma. Hyponatremia is also associated with total plasma samples (therefore including plasma lipids muscle weakness, whereas hypernatremia results and proteins). As a consequence, massive hyperlipi- rather in spasticity and hyperreflexia. demia (e. g., with triglycerides) or hyperproteinemia (e. g., with paraproteins) led to artificially low sodium Acute brain edema is observed with acute hy- concentrations due to expansion of total plasma volume ponatremia and also with a too rapid correction of (so-called pseudohyponatremia). The serum osmolality severe hypernatremia, and can result in the death of is normal in these cases. With the introduction in the patient. laboratories of ion-selective electrodes, for determining ion concentrations, this discrepancy has disappeared. The accumulation of osmotically active, nonpermea- ble substances in the extracellular space leads to a net shift of water from the intracellular to the extracellular Hyponatremia (PNa 135 mmol/L) space as an attempt to correct hyperosmolality. The serum sodium concentration decreases; so-called trans- Hyponatremia indicates water excess in the extracellu- location hyponatremia. In these patients serum osmolal- lar space. For differential diagnosis the volume status ity is increased. The most important clinical example is has to be considered at the same time. Three different severe hyperglycemia. Finally, it is important to notice clinical situations can be distinguished as follows that the accumulation of osmotically active, permeable (Tab. 30.7): substances does not alter the serum sodium concentra- ➤ hypovolemic hyponatremia: deficiency in total body tions, since these substances distribute equally between water and sodium with an excess loss of salt com- the intracellular and the extracellular space, but the pared to water serum osmolality is increased. The most important

Table 30.6 Osmotically active substances, serum sodium, and serum osmolality Group 1 Group 2 Group 3 Serum osmolality normal increased increased Serum sodium decreased decreased normal Examples − lipids (hypertriglyceridemia) − glucose − urea (azotemia) − proteins (paraproteinemia) − mannitol − alcohols (methanol, ethanol, − glycine isopropanol) − maltose (with intravenous − glycols (ethylene glycol) immunoglobulin) Classification isotonic hyponatremia, hypertonic hyponatremia, hyperosmolality with normal “pseudohyponatremia”* “translocational hyponatremia” serum sodium

* Observed with older methods of sodium measurement such as flame photometry; is not currently a problem with ion-selective electrodes. 901

Table 30.7 Differential diagnosis of hypotonic hyponatremia Hypovolemic hyponatremia Euvolemic hyponatremia Hypervolemic hyponatremia Third space Excessive water intake Edematous diseases with secondary − crush injury, rhabdomyolysis − primary psychogenic polydipsia hyperaldosteronism − pancreatitis, peritonitis, ileus, sepsis − cardiac failure Syndrome of inappropriate ADH − nephrotic syndrome Extrarenal loss secretion (SIADH) − liver cirrhosis − skin: severe burns − CNS diseases: tumors, inflammatory − gastrointestinal tract: vomiting with conditions (meningitis, encephalitis, Acute and chronic renal failure metabolic alkalosis, diarrhea abscess), brain trauma, ischemic or hemorrhagic stroke, Guillain−Barré Renal loss syndrome, acute psychosis − osmotic diuresis: glucosuria, − malignancies: lung and pancreas ketonuria, bicarbonaturia carcinoma, lymphomas − diuretics: mainly thiazides! − pulmonary diseases: inflammatory − renal salt wasting: interstitial conditions (pneumonia, abscess, nephropathies, cystic kidney dis- tuberculosis, aspergillosis), asthma, eases, proximal renal tubular acido- cystic fibrosis, respiratory insuffi- sis, congenital tubular disorders ciency − cerebral salt wasting − drugs: ADH analogues (desmopres- − mineralocorticoid deficit (see sin DDAVP, oxytocin), chlor- Tab. 30.12) propamide, vincristin, cyclo- phosphamide, carbamazepin, tricy- clic antidepressive and antipsychotic drugs, NSAIDs − postoperative state, other stress and/or painful situations Endocrine diseases − glucocorticoid deficit − hypothyroidism Reset osmostat − pregnancy − chronic malnutrition

➤ ➤ euvolemic hyponatremia: moderate excess in total UNa 20 mmol/L suggests extrarenal losses via body water without edema formation and clinically gastrointestinal tract, via skin with severe burns, or normal volume status into a third space with sepsis, pancreatitis, or peri- ➤ hypervolemic hyponatremia: excess of total body tonitis. ➤ water and sodium with retention of more water than UNa 20 mmol/L suggests renal sodium and water salt. loss. Main causes are either secondary due to osmotic diuresis, mineralocorticoid deficiency (see It is important for the understanding of hypovolemic below), or diuretics. Alternatively, this condition can hyponatremia, as well as hypervolemic hyponatremia occur in the context of primary renal diseases (inter- (in the context of edematous disorders with secondary stitial nephritis, polycystic kidney disease, or hyperaldosteronism), to know that a decrease in the ef- nephropathy in the contest of analgesic abuse). fective circulating volume leads to nonosmotic stimulation of vasopressin secretion. This is an expression of the Diuretics. In clinical settings, hypovolemic hyponatremia body’s priority for volume regulation over osmoregula- is most often observed following the use of diuretics. It tion. In these cases, the main therapeutic principle is mainly occurs when the dosage of these drugs is not ad- correction of the volume status or the effective circulat- justed with reduced water and salt intake or when in- ing volume (e. g., treatment of low cardiac output), creased losses occur in the context of acute diseases (e. g., whereas euvolemic hyponatremia is mainly treated by diarrhea). Risk is highest with the use of thiazide diuret- water restriction. ics. Thiazide diuretics block sodium transport in the distal tubule. As for all other diuretics, urinary dilution is com- promised due to sodium loss. However, the interstitial Hypovolemic Hyponatremia concentration gradient is unchanged, since it is built up in the loop of Henle. In contrast, loop diuretics block Causes. Either renal or extrarenal losses of sodium and sodium transport directly in the loop of Henle and there- water can be responsible for this disorder. For differen- fore interfere with urinary dilution and concentration by

tial diagnosis UNa is a good parameter to measure: inhibiting the establishment of an interstitial concentra- 902

tion gradient. If hypovolemia results in nonosmotic vaso- Low serum uric acid is a sensitive parameter for the dis- pressin stimulation, water retention is much more effi- tinction of SIADH and subclinical volume depletion cient in the context of thiazide medication than with (e. g., in the context of diuretics or a renal or cerebral loop diuretics, which can result in severe hyponatremia salt-wasting syndrome). The latter is associated with in very short time! hyperuricemia. It is important to recall that any postoperative state is associated with inappropriate ADH secretion. Therefore, Euvolemic Hyponatremia volume repletion with glucose or hypotonic salt infusion immediately after an operation bears a high risk of Causes. The most frequent cause of this disorder is the acute severe hyponatremia. Young women after gyneco- so-called syndrome of inappropriate anti-diuretic hor- logic or obstetric operations represent a patient group mone (ADH) secretion (SIADH, Schwartz−Bartter syn- with a particularly high risk! drome). The differential diagnosis includes diseases of the central nervous system, pulmonary diseases, malig- Differential Diagnosis. For diagnosis of SIADH, certain nancies, and drugs, which stimulate ADH secretion or endocrine disorders should be excluded, particularly hy- mimic the effect of ADH. The common denominator in pocortisolism and hypothyroidism. The pathogenesis of all these situations is impaired water excretion due to hyponatremia in these diseases is unclear. Another con- enhanced vasopressin activity. The typical laboratory dition with identical laboratory results constellation to signs are: SIADH is called reset osmostat. These patients have ➤ hyponatremia stable mild hyponatremia in the range of 125− ➤ low serum osmolality 130 mmol/L. Typical causes are pregnancy (via human ➤ impaired urinary dilution (UOsm 300 mOsm/L) chorion gonadotropin secreted in the placenta) and ➤ hypouricemia. chronic malnutrition.

Diagnostic Approach to Hyponatremia

The differential diagnosis in patients with hyponatremia are the serum osmolality, assessment of volume status, is depicted in Fig. 30.5. The most important parameters urinary osmolality, and urinary sodium concentration.

Fig. 30.5 Diagnostic P approach to hy- Na POsm Isotonic hyponatremia (“pseudohyponatremia”) hyperproteinemia, hyperlipidemia ponatremia. ECV = extracellular volume, EABV = ef- Hypertonic hyponatremia fective arterial blood (translocational hyponatremia) volume. hyperglycemia, mannitol/glycine

Hypotonic hyponatremia

Volume status Uosm < 100 Water intake Euvolemia mosm/l psychogenic polydipsia (ECV , no edema) Uosm > 300 Water excretion mosm/l • SIADH • endocrine disorders (hypothyroidism, hypocortisolism)

True volume deficit (EABV , ECV ) Edematous diseases (EABV , ECV )

U Na > 20 mmol/l U Na < 20 mmol/l U Na > 20 mmol/l U Na < 20 mmol/l

Renal loss Extrarenal loss Acute/chronic • heart failure • osmotic diuresis • gastrointestinal renal • liver failure • diuretics (thiazides!) • skin insufficiency • nephrotic • renal/cerebral salt “Third space” syndrome wasting • mineralocorticoid deficit

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Table 30.8 Differential diagnosis of hypernatremia Hypovolemic hypernatremia Euvolemic hypernatremia Hypervolemic hypernatremia Extrarenal losses Reduced water intake Increased salt intake

− skin: intense sweating, severe burns − patients with no access to water − hypertonic infusions (e. g., NaHCO3) − gastrointestinal loss: diarrhea, fistu- (children, severely ill and elderly − hypertonic dialysis las and tubes patients) − NaCl tablets − disturbed thirst sensation Renal losses (hypothalamic organic lesion) Endocrine diseases − osmotic diuresis: severe hypergly- − primary hyperaldosteronism cemia with diabetes mellitus, Extrarenal losses − hypercortisolism osmotic and loop diuretics − lungs: hyperventilation with meta- − renal salt wasting: interstitial and bolic acidosis, fever and mechanical cystic nephropathies, polyuria after ventilation obstruction or acute renal failure − skin: intense sweating

Renal losses with central diabetes insipidus − congenital/genetic: dominant: vasopressin gene mutation recessive: Wolfram syndrome (DID- MOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness) − acquired: CNS diseases (trauma, tumor, inflammatory and granulo- matous diseases, aneurysm, Guillain−Barré syndrome)

Renal losses with nephrogenic diabetes insipidus − congenital/genetic:

X-linked: vasopressin V2 receptor gene mutation recessive: aquaporin 2 gene mutation − acquired: interstitial nephropathies (analgesics, cystic kidney diseases, obstruction, myeloma kidney, sarcoidosis), chronic renal insufficiency, electrolyte disorders (hypokalemia, hypercalcemia), drugs (lithium, tetracyclines, amphotericin)

Renal losses with gestational diabetes insipidus (placenta-derived vasopressinase secretion)

SIADH should be distinguished from primary poly- Hypervolemic Hyponatremia dipsia. Water intake 15−20 L per day exceeds the renal capacity for water excretion and will lead to hy- This condition is usually associated with edematous dis- ponatremia. This condition is easily distinguished from orders e. g., heart failure, nephrotic syndrome, and liver SIADH by measurement of the urinary osmolality, cirrhosis. The pathogenesis includes secondary hypoal- which is below 100 mOsm/L in the case of polydipsia, dosteronism and nonosmotic stimulation of vasopressin but 300 mOsm/L in the case of SIADH. secretion, as a consequence of reduced effective circula-

tory volume, and results in low UNa. The differential diagnosis is usually easy in the clinical context of a given patient.

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Hypernatremia (PNa 145 mmol/L) Water DDAVP restriction Hypernatremia indicates water deficit in the extracellular space in relation to the total body sodium and is al- 1000 ways associated with hyperosmolality. Similar to hyponatremia, we can distinguish three different conditions based on the volume status of the patient. The 800 differential diagnosis is summarized in Tab. 30.8: ➤ hypovolemic hypernatremia: deficiency in total body 600 water and sodium with an excess loss of water com-

pared to sodium (mOsm/L) ➤ euvolemic hypernatremia: moderate excess in total Osm 400 body sodium without edema formation and clini- U cally normal volume status ➤ hypervolemic hypernatremia: excess of total body 200 water and sodium with retention of more salt than water. 0 275 280 285 290 295 300 Hypernatremia is a rare disorder, since the thirst mech- POsm (mOsm/L) anism is a very efficient compensation of water loss through skin, gastrointestinal tract, and respiration. 6 Therefore, mainly patients with impaired access to free water intake (e. g., small children, elderly, severely ill 5 patients) and patients with hypothalamic lesions affecting the thirst mechanism are affected. 4

Hypovolemic Hypernatremia 3

Either renal or extrarenal causes can lead to this disorder, 2 normal

Urine volume (mL/min) Urine volume partial CDI which is characterized by an excess of water loss com- complete CDI pared to salt loss. Extrarenal losses occur via the 1 partial NDI gastrointestinal tract (diarrhea, vomiting, fistulas) or complete NDI the skin (sweating, burns) and are associated with UNa 0 20 mmol/L. Renal losses are observed in the context of 275 280 285 290 295 300 ketoacidosis or hyperosmotic diabetic coma, but also POsm (mOsm/L) with primary renal diseases (e. g., postobstructive renal disease or the polyuric phase of acute renal failure). Fig. 30.6 Scheme for interpretation of a thirst test. The thirst test is used for differential diagnosis between central (CDI) and nephrogenic (NDI) diabetes insipidus. The change of urine Euvolemic Hypernatremia osmolality and urine volume is shown after a period with water restriction and subsequent application of a synthetic analogue If only water is lost with stable total body sodium, the of vasopressin (DDAVP). volume status remains stable. Water shifts occur from the intracellular to the extracellular space in order to

maintain ECV and the effective circulatory volume. In trarenal losses urine is concentrated, with UOsm the differential diagnosis a differentiation is made be- 800 mOsm/L, whereas in the case of diabetes in- tween inadequate water intake and renal and/or ex- sipidus urine is diluted, with UOsm 300 mOsm/L. trarenal water losses. Diabetes Insipidus. Diabetes insipidus is caused by a lack Causes. As described above, inadequate intake is only of vasopressin activity and results in polyuria and poly- seen in patients with impaired access to free water (“too dipsia. We can distinguish between central diabetes in- small, too old, too sick”) and in patients with hypo- sipidus (CDI) with a lack of ADH secretion and nephro- thalamic lesions affecting the thirst mechanism. Ex- genic diabetes insipidus (NDI) with a lack of ADH effect at trarenal water losses occur via the lungs and the skin the target organ. The former occurs as a congenital form (hyperventilation with metabolic acidosis, fever, sweat- (e. g., mutation in the vasopressin gene) or acquired in ing), whereas renal losses are caused by various forms of the context of central nervous system diseases. It can be diabetes insipidus. These two situations can be distin- corrected with exogenous application of vasopressin

guished by measurement of UOsm. In the case of ex- (e. g., the synthetic desmopressin, DDAVP). In contrast, 905

NDI does not respond to desmopressin. It also occurs as Hypervolemic Hypernatremia a congenital disease (mutations in the genes for the vasopressin receptor or the water channel). Acquired This disorder is mostly caused by iatrogenic infusion of forms of NDI are observed with various chronic renal hypertonic salt solutions. This can occur by excess of

diseases (e. g., interstitial and cystic nephropathies), in NaHCO3 in the context of metabolic acidosis or car- the context of electrolyte disorders, e. g., hypokalemia diopulmonary reanimation, but also with hypertonic and hypercalcemia, and it can also be caused by certain dialysis. drugs (e. g., lithium). A particular form of diabetes in- Endocrine disorders, e. g., hyperaldosteronism or hy- sipidus is described during pregnancy, when placental percortisolism, should also be considered. secretion of an enzyme, called vasopressinase, can lead to accelerated degradation of vasopressin.

The differential diagnosis between central and nephrogenic diabetes insipidus can be made by ex- perimental increase in serum osmolality by water restriction and subsequent application of 5 IU vasopressin (“thirst test”).

Typical results of such a test are shown in Fig. 30.6.

Diagnostic Approach to Hypernatremia

The differential diagnosis in patients with hypernatremia are assessment of the volume status, urine osmolality, is depicted in Fig. 30.7. The most important parameters and urine sodium concentration.

Fig. 30.7 Diagnostic P approach to hyper- Na Volume status ECV deficit natremia.

UNa < 20 mmol/L, UNa >20 mmol/L, UOsm> 800 mOsm/L UOsm< 800 mOsm/L

Renal water loss Extrarenal • osmotic diuresis ( ) water loss (osmotic and loop • skin diuretics) • gastrointestinal • interstitial nephropathies • post obstruction

ECV excess

UNa >20 mmol/L, UOsm >800 mOsm/L

Excess of salt intake • iatrogenic (hypertonic infusions) • NaCl tablets • hypertonic dialysis Mineralocorticoid excess

Euvolemia (ECV slightly )

UOsm > 800mOsm/L UOsm < 800 mOsm/L

Hypodipsia Diabetes insipidus (DI) • no access to free water • central DI (CDI) versus nephrogenic DI • CNS disease affecting thirst center (NDI): differential diagnosis with thirst test

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