Differential Diagnosis

Acute Potassium Disorders

July 15, 2017 Cardiology, Clinical Skills, Critical Care, Differential Diagnosis, EKG/ECG No comments , , , , ,

Disorders of potassium homeostasis are common in hospitalized patients and may be associated with severe adverse clinical outcomes, including death. Prevention and proper treatment of hyper- and hypokalemia depend on an understanding of the underlying physiology.

The total body potassium content of a 70-kg adult is about 3500 mmol (136.5 g), of which only 2% (about 70 mmol / 2.73 g) is extracellular. It is not surprising that the extracellular potassium concentration is tightly regulated. In fact, two separate and cooperative systems participate in potassium homeostasis. One system regulates external potassium balance: the total body parity of potassium elimination with potassium intake. The other system regulates internal potassium balance: the distribution of potassium between the intracellular and extracellular fluid compartments. This latter system provides a short-term defense against changes in the plasma potassium concentration that might otherwise result from total body potassium losses or gains.

Disorders of Potassium Homeostasis

Disorders of potassium homeostasis may be conveniently divided according to the duration of the disturbance: acute (<48 hours’ duration) or chronic.

Acute Hyperkalemia

Excessive potassium intake. Given an acute potassium load, a normal individual will excrete about 50% in the urine and transport about 90% of the remainder into cells over 4 to 6 hours. It is possible to overwhelm this adaptive mechanism such that if too much potassium is taken in too quickly, significant hyperkalemia will result. Such events are almost always iatrogenic. One’s ability to tolerate a potassium load declines with disordered internal balance and impaired renal potassium excretory capacity. In such circumstances, an otherwise tolerable increase in potassium intake may cause clinically significant hyperkalemia: Doses of oral potassium supplements as small as 30 to 45 mmol have resulted in severe hyperkalemia in patients with impaired external or internal potassium homeostasis.

KCl, used as a supplement, is the drug most commonly implicated in acute hyperkalemia. Banked blood represents a trivial potassium load under most circumstances, because a unit of fresh banked blood, either whole or packed cells, contains only 7 mmol (273 mg) of potassium. Thus, severe hyperkalemia would result only from massive transfusion of compatible blood. However, the potassium concentration in banked blood does increase substantially as the blood ages.

Patients undergoing open heart surgery are exposed to cardioplegic, solutions containing KCl typically at about 16 mmol/L, which may lead to clinically significant hyperkalemia in the postoperative period, especially in patients with diabetes mellitus with or without renal failure.

Abnormal potassium distribution. Acute hyperkalemia may result from sudden redistribution of intracellular potassium to the extracellular space. If only 2% of intracellular potassium were to leak unopposed from cells, serum potassium level would immediately double. Fortunately, such dramatic circumstances are rarely encountered. Nevertheless, smaller degrees of potassium redistribution commonly result in clinically significant hyperkalemia.

Among the most impressive syndromes associated with acute hyperkalemia are those involving rapid cell lysis. The tumor lysis syndrome results from treatment of chemosensitive bulky tumors with release of intracellular contents, including potassium, into the ECF. Extreme hyperkalemia even causing sudden death has featured prominently in some series of patients. Most of such patients were in renal failure from acute uric acid nephropathy, thus impairing their ability to excrete the potassium load. Rhabdomylosis, either traumatic or nontraumatic, may result in sudden massive influx of potassium to the extracellular space. Other circumstances that may result in redistributive hyperkalemia include severe extensive burns, hemolytic transfusion reactions, and mesenteric ischemia or infarction.

Pharmacologic agents. Two drugs may rarely cause acute hyperkalemia by redistribution: digitalis glycosides and succinylcholine. Massive digitalis overdose has been associated with extreme hyperkalemia. Succinylcholine depolarizes the motor end plate and in normal individuals causes a trivial amount of potassium leak from muscle, resulting in an increase in serum potassium level by about 0.5 mmol/L. In patients with neuromuscular disorders, muscle damage, or prolonged immobilization, however, muscle depolarization may be more widespread, causing severe hyperkalemia. Prolonged use of nondepolarizing non depolarizing neuromuscular blockers in critically ill patients may predispose to succinylcholine-induced hyperkalemia.

Hyperkalemic periodic paralysis. This rare syndrome of episodic hyperkalemia and paralysis is caused by a mutation of the skeletal muscle sodium channel, inherited in an autosomal dominant pattern. Attacks may be precipitated by exercise, fasting, exposure to cold, and potassium administration, and prevented by frequent carbohydrate snacks. Attacks are usually brief and treatment consists of carbohydrate ingestion. Severe attacks may require intravenous glucose infusion.

Acute renal failure. Hyperkalemia accompanies acute renal failure in 30% to 50% of cases. It is seen most commonly in oliguric renal failure. Contributing factors include tissue destruction and increased catabolism.

Pseudohyperkalemia. It refers to a measured potassium level that is higher than that circulating in the patient’s blood. It has a number of possible causes. First, it may be caused by efflux of potassium out of blood cells in the test tube after phlebotomy. This may be seen in a serum specimen in cases of thrombocytosis or leukocytosis, when the clot causes cell lysis in vitro. These days, many clinical laboratories measure electrolytes in plasma (unclotted) specimens. Even under these conditions, extreme leukocytosis may cause pseudohyperkalemia if the specimen is chilled for a long time before the plasma is separated, leading to passive potassium leak from cells. Hemolysis during specimen collection with false raise [K+] or plasma potassium concentration by liberating intraerythrocyte to potassium. Second, if the patient’s arm is exercised by fist clenching with a tourniquet in place before the specimen is drawn, the sampled blood potassium concentration will rise significantly as a result of local muscle release of intracellular potassium.

Acute Hypokalemia

Treatment of diabetic ketoacidosis. It is well recognized that patients presenting in DKA are always severely depleted in total body potassium as a result of glucose-driven osmotic diuresis, poor nutrition, and vomiting during the development of DKA. Paradoxically, most patients in DKA have a normal serum potassium level upon admission. Insulin deficiency and hyperglycemia appear to account for the preservation of a normal [K+] despite severe total body potassium depletion. Once therapy for DKA is instituted, however, [K+] typically plummets as potassium is rapidly taken up by cells. Potassium replacement at rates up to 120 mmol (4.68 g) per hour have been reported, with total potassium supplementation of 600 to 800 mmol (23.5 to 31.2 g) within the first 24 hours of treatment. Hypokalemia in this setting may lead to respiratory arrest.

Refeeding. A situation analogous to DKA arises during aggressive refeeding after prolonged starvation or with aggressive “hyperalimentation” of chronically ill patients. The glucose-stimulated hyperinsulinemia and tissue anabolism shift potassium into cells, rapidly depleting extracellular potassium.

Pharmacologic agents. Specific beta2-adrenergic receptor agonists may cause electrophysiologically significant hypokalemia, especially when given to patients who are potassium depleted from the use of diuretic drugs. Epinephrine, given intravenously in a dose about 5% of that recommended for cardiac resuscitation, cause a fall in [K+] by about 1 mmol/L. A rare cause of severe hypokalemia is poisoning with soluble barium salts such as chloride, carbonate, hydroxide, and sulfide. Soluble barium salts are used in pesticides and some depilatories, which may be ingested accidentally or intentionally. Thiopentone, a barbiturate used to induce coma for refractory intracranial hypertension, is associated with redistributive hypokalemia in the majority of treated patients within 12 hours of initiating therapy.

Hypokalemic periodic paralysis. Three forms of this rare syndrome have been described: familial, sporadic, and thyrotoxic. All have in common attacks of muscle weakness accompanied by acute hypokalemia caused by cellular potassium uptake.

Pseudohypokalemia. Severe leukocytosis may cause spuriously low plasma potassium concentrations if blood cells are left in contact with the plasma for a long time at room temperature or higher. This phenomenon results from ongoing cell metabolism in vitro with glucose and potassium uptake. Unexpected hypokalemia and hypoglycemia in the setting of leukocytosis should alert the clinician to this phenomenon.


Potassium exchange between ECF and ICF: insulin, epinephrine, and [H+]

Potassium renal secretion: [K+], dietary intake of potassium, AngII, aldosterone, tubular sodium delivered to principal cells (at distal nephron).

EKG Changes of Potassium Disturbances



Hyperkalemia produces a progressive evaluation of changes in the EKG that can culminate in ventricular fibrillation and death. The presence of electrocardiographic changes is a better measure of clinically significant potassium toxicity than the serum potassium level. As the potassium begins to rise, the T waves across the entire 12-lead EKG begin to peak. This effect can easily be confused with the peaked T waves of an acute myocardial infarction. One difference is that the changes in an infarction are confined to those leads overlying the area of the infarct, whereas in hyperkalemia, the changes are diffuse. With a further increase in the serum potassium, the PR interval becomes prolonged, and the P wave gradually flattens and then disappears. Ultimately, the QRS complex widens until it merges with the T wave, forming a sine wave pattern. Ventricular fibrillation may eventually develop.

It is important to note that whereas these changes frequently do occur in the order described as the serum potassium rises, they do not always do so. Progression to ventricular fibrillation can occur with devastating suddenness. Any change in the EKG due to hyperkalemia mandates immediate clinical attention.


With hypokalemia, the EKG may again be a better measure of serious toxicity than the serum potassium level. Three changes can be seen, occurring in no particular order, including: ST-segment depression, flattening of the T wave with prolongation of the QT interval, and appearance of a U wave. The term U wave is given to a wave appearing after T wave in the cardiac cycle. It is usually has the same axis as the T wave and is often best seen in the anterior leads. Its precise physiologic meaning is not fully understood. Although U waves are the most characteristic feature of hypokalemia, they are not in and of themselves diagnostic. Other conditions can produce prominent U waves, and U waves can sometimes be seen in patients with normal hearts and normal serum potassium levels. Rarely, severe hypokalemia can cause ST-segment elevation. Whenever you see ST-segment elevation or depression on an EKG, you first instinct should always be to suspect some form of cardiac ischemia, but always keep hypokalemia in your differential diagnosis.

Evaluation of Chronic Heart Failure

July 12, 2017 Cardiology, Critical Care, Differential Diagnosis, Laboratory Medicine No comments , , , ,

Table 28-3 and 28-4, taken from the European Society of Cardiology heart failure guideline, recommend a routine assessment to establish the diagnosis and likely cause of heart failure. Once the diagnosis of heart failure has been made, the first step in evaluating heart failure is to determine the severity and type of cardiac dysfunction, by measuring ejection fraction through two-dimensional echocardiography and/or radionuclide ventriculography. Measurement of ejection fraction is the gold standard for differentiating between the two forms of heart failure, systolic and diastolic, and is particularly important given that the approaches to therapy for each syndrome differ somewhat. The history and physical examination should include assessment of symptoms, functional capacity, and fluid retention.


Functional capacity is measured through history taking or preferably an exercise test. Analysis of expired air during exercise offers a precise measure of the patient’s physical limitations. However, this test is uncommonly performed outside of cardiac transplant centers. The NYHA has classified heart failure into four functional classes that may be determined by history taking. The NYHA functional classification should not be confused with the stages of heart failure described in the American College of Cardiology/American Heart Association heart failure guideline. The NYHA classification describes functional limitation and is applicable to stage B through stage D patients, whereas the staging system describes disease progression somewhat independently of functional status.

Assessment of fluid retention through measurement of jugular venous pressure, auscultation of the lungs, and examination for peripheral edema is central to the physical examination of heart failure patients.

Given the limitation of physical signs and symptoms in evaluating heart failure clinical status, a number of noninvasive and invasive tools are under development for the assessment of heart failure. One such tool that has proven useful in determining the diagnosis and prognosis of heart failure is the measurement of plasma B-type natriuretic peptide (BNP) levels. Multiple studies demonstrate the utility of BNP measurement in the diagnosis of heart failure. The diagnostic accuracy of BNP at a cutoff of 100 pg/mL was 83.4 percent. The negative predictive value of BNP was excellent. At levels less than 50 pg/mL, the negative predictive value of the assay was 96%.


Based largely on the findings of the BNP Multinational Study, clinicians were advised that a plasma BNP concentration below 100 pg/mL made the diagnosis of congestive heart failure unlikely, while a level above 500 pg/mL made it highly likely. For BNP levels between 100 pg/mL and 500 pg/mL, the use of clinical judgement and additional testing were encouraged.

Additionally, plasma BNP is useful in predicting prognosis in heart failure patients. However, serial measurement of plasma BNP as a guide to heart failure management has not yet been proven useful in the management of acute or chronic heart failure.

The Differential Diagnosis of Abnormal Serum Uric Acid Concentration

June 28, 2017 Differential Diagnosis, Laboratory Medicine No comments , , ,

Reference range: 4.0-8.5 mg/dL or 237-506 mmol/L for males >17 years old; 2.7-7.3 mg/dL or 161-434 mmol/L for females >17 years old

Uric acid is the metabolic end-product of the purine bases of DNA. In humans, uric acid is not metabolized further and is eliminated unchanged by renal excretion (the net result of filtration, secretion, and reabsorption). It is completely filtered at the renal glomerulus and is almost completely reabsorbed. Most excreted uric acid (80% to 86%) is the result of active tubular secretion at the distal end of the proximal convoluted tubule.

As urine becomes more alkaline, more uric acid is excreted because the percentage of ionized uric acid molecules increases. Conversely, reabsorption of uric acid within the proximal tubule is enhanced and uric acid excretion is suppressed as urine becomes more acidic.

When serum uric acid exceeds the upper limit of the reference range, the biochemical diagnosis of hyperuricemia can be made. Hyperuricemia can result from an overproduction of purines and/or reduced renal clearance of uric acid. When specific factors affecting the normal disposition of uric acid cannot be identified, the problem is diagnosed as primary hyperuricemia. When specific factors can be identified, the problem is referred to as secondary hyperuricemia.

As the serum urate concentration increases above the upper limit of the reference range, the risk of developing clinical signs and symptoms of gouty arthritis, renal stones, uric acid nephropathy, and subcutaneous tophaceous deposits increases. However, many hyperuricemic patients are asymptomatic. If a patient is hyperuricemic, it is important to determine if there are potential causes of false laboratory test elevation and contributing extrinsic factors.

Exogenous Causes

Medications via 1) decreased renal excretion resulting from drug-induced renal dysfunction; 2) decreased renal excretion resulting from drug competition with uric acid for secretion within the kidney tubules; and 3) rapid destruction of large numbers of cells from anti-neoplastic therapy.

Diet. High-protein weight-reduction programs can greatly increase the amount of ingested purines and subsequent uric acid production.

Endogenous Causes

Endogenous causes of hyperuricemia include diseases, abnormal physiological conditions that may or may not be disease related, and genetic abnormalities. Diseases include 1) renal diseases (e.g., renal failure); 2) disorders associated with increased destruction of nucleoproteins; and 3) endocrine abnormalities (e.g., hypothyroidism, hypoparathyroidism, pseudohypoparathyroidism, nephrogenic diabetes insidious, and Addison disease).

Predisposing abnormal physiological conditions include shock, hypoxia, lactic acidosis, diabetic ketoacidosis, alcoholic ketosis, and strenuous muscular exercise.

Genetic abnormalities include Lesch-Nyhan syndrome, gout with partial absence of the enzyme hypoxanthine guanine phosphoribosyltransferase, increased phosphoribosyl pyrophosphate P-ribose-PP synthetase, and glycogen storage disease type I.

Clinical Skills – Cluster the Clinical Findings

April 18, 2017 Clinical Skills, Differential Diagnosis, History Taking No comments

It is often challenging to decide whether clinical data fit into one problem or several problems. If there is relatively long list of symptoms and signs, and an equally long list of potential explanations, one approach is to tease out separate clusters of observations and analyze one cluster at a time. Several clinical characteristics may help.

Patient age: The patient’s age may help; younger adults are more likely to have a single disease, whereas older adults tend to have multiple diseases.

Timing of symptoms: The timing of symptoms is often useful. For example, an episode of pharyngitis 6 weeks ago is probably unrelated to the fever, chills, pleuritic chest pain, and cough that prompted an office visit today. To use timing effectively, you need to know the natural history of various diseases and conditions.

Involvement of different body systems: Involvement of the different body systems may help group clinical data. If symptoms and signs occur in a single system, one disease may explain them. Problems in different, apparently unrelated, systems often require more than one explanation. Again, knowledge of disease patterns is necessary.

Multisystem conditions: With experience, you will become increasingly adept at recognizing multi system conditions and building plausible explanations that link manifestations that are seemingly unrelated. To explain cough, hemoptysis, and weight loss in a 60-year-old plumber who has smoked cigarettes for 40 years, you would rank lung cancer high in your differential diagnosis. You might support your diagnosis with your observation of the patient’s cyanotic nailbeds. With experience and continued reading, you will recognize that his other symptoms and signs fall under the same diagnosis. Dysphagia would reflect extension of the cancer to the esophagus, pupillary asymmetry would suggest pressure on the cervical sympathetic chain, and jaundice could result from metastases to the liver. Related risk factors should be explored promptly.

Key questions: You can also ask a series of key questions that may steer your thinking in one direction and allow you to temporarily ignore the others. For example, you may ask what produces and relieves the patient’s chest pain. If the answer is exercise and rest, you can focus on the cardiovascular and musculoskeletal systems and set the gastrointestinal (GI) system aside. If the pain is more epigastric, burning, and occurs only after meals, you can logically focus on the GI tract. A series of discriminating questions helps you analyze the clinical data and reach logical explanations.

The Physical Examination – Heart

August 25, 2016 Cardiology, Clinical Skills, Differential Diagnosis No comments , , , , , , ,

The Splitting of Heart Sounds

While these events are occurring on the left side of the heart, similar changes are occuring on the right side, which involves the right atrium, tricuspid valve, RV, pulmonic valve, and pulmonary arteries. Right ventricular and pulmonary arterial pressures are significantly lower than corresponding pressures on the left side. Note that right-sided cardiac events usually occur slightly later than those on the left. Instead of a hearing a single heart sound for S2, you may hear two discernible components, the first from left-sided aortic valve closure, or A2, and the second from right-sided closure of the pulmonic valve, or P2.

The second heart sound, S2, and its two compnents, A2 and P2, are caused primarily by closure of the aortic and pulmonic valves, respectively. During inspiration, the right heart filling time is increased, which increases right ventricular stroke volume and the duration of right ventricular ejection compared with the neighboring left ventricle. This delays the closure of the pulmonic valve, P2, splitting S2 into its two audible components. During expiration, these two components fuse into a single sound, S2.

Of the two components of the S2, A2 is normally louder, reflecting the high pressure in the aorta. It is heard throughout the precordium. In contrast, P2 is relatively soft, reflecting the lower pressure in the pulmonary artery.

S1 also has two components, an earlier mitral and a later tricuspid sound. The mitral sound – the principal component of S1 – is much louder, again reflecting the higher pressures on the left side of the heart. It can be heard throughout the precordium and is loudest at the cardiac apex. Splitting of S1 does not vary with respiration.


Auscultation of heart sounds and murmurs is a pre-eminent skill that leads directly to important clinical diagnoses. The ACC and the AHA has deemed cardiac auscultation as "the most widely used method of screening for valvular heart disease." Review the six auscultatory areas in Figure 9-41, with the follwing caveats: 1) many authorities discourage designations such as "aortic area," because murmurs may be loudest in other areas, and 2) these areas do not apply to patients with cardiac dilatation or hypertrophy, anomalies of the great vessels, or dextrocardia.Screen Shot 2016-08-25 at 6.57.34 PM

Throughout your examination, take your time at each of the six auscultatory areas. Concentrate on each of the events in the cardiac cycle, listening carefully to S1, then S2, then other sounds and murmurs occurring in systole and diastole.

Known Your Stethoscope

It is important to understand the uses of both the diaphragm and the bell.

The diaphragm. The diaphragm is better for picking up the relatively high-pitched sounds of S1 and S2, the murmurs of aortic and mitral regurgitation, and pericardial friction rubs. Listen throughout the precordium with the diaphragm, pressing it firmly against the chest.

The bell. The bell is more sensitive to the low-pitched sounds of S3 and S4 and the murmur of mitral stenosis. Apply the bell lightly, with just enough pressure to produce an air seal with its full rim. Use the bell at the apex, then move medially along the lower sternal border. Resting the heel of your hand on the chest like a fulcrum may help you to maintain light pressure.

Identifying Systole and Diastole

To facilitate the correct identification of systole and diastole, as you auscultate the chest, palpate the right carotid artery in the lower third of the neck with your left index and middle fingers – S1 falls just before the carotid upstroke and S2 follows the carotid upstroke.

Identifying Heart Murmurs


First decide if you are hearing a systolic murmur, falling between S1 and S2, or a diastolic murmur, falling between S2 and S1. Palpating the carotid pulse as you listen can help you with timing. Murmurs that coincide with the carotid upstroke are systolic.

Location of Maximal Intensity

This is determined by the site where the murmur originates. Find the location by exploring the area where you hear the murmur. Describe where you hear it best in terms of the intercostal space and its proximity to the sternum, the apex, or its measured distance from the midclavicular, midsternal, or one of the axillary lines.

Radiation for Transmission from the Point of Maximal Intensity

This reflects not only the site of origin but also the intensity of the murmur, the direction of blood flow, and bone conduction in the thorax. Explore the area around a murmur and determine where else you can hear it.


This is usually graded on a six point and expressed as a fraction. The numerator describes the intensity of the murmur whereever it is loudest; the denominator indicates the scale you are using. Intensity is influenced by the thickness of the chest wall and the presence of intervening tissue.

Screen Shot 2016-08-25 at 7.57.09 PMPitch

This is categorized as high, medium, or low.


This is described in terms such as blowing, harsh, rumbling, and musical.