Interpreting and Correlating Abnormal Laboratory Values The major purpose of performing analyte determinations in the clinical laboratory

is to aid in the diagnosis and management of patients with disease and individuals in health assessment. In this regard, the clinical pathologist/Clinical Biochemist/Clinical Microbiologist are often called upon as a consultant to explain abnormal laboratory values, especially those that do not seem to correlate with one another, and to recommend or even to order laboratory tests that may lead to the correct diagnosis in the work-up of patients for particular medical problems. For evaluation of test results, the laboratory computer is an invaluable aid. Virtually all such systems perform daily checks for patient values that lie significantly outside of their established reference intervals or that have undergone large changes over a 24-hour period. These are often reported as failed delta checks. Thus patients with significantly abnormal laboratory findings can be identified. Fundamental Principles in Interpretation of Values Before embarking on a discussion of specific conditions giving rise to abnormal values, certain precepts should always be followed, encapsulated as follows: Never rely on a single (out-of-reference range) value to make a diagnosis. It is vital to establish a trend in values. A single sodium value of, for example, 130 mEq/L does not necessarily indicate hyponatremia. This single abnormal value may be spurious and may reflect such factors as improper phlebotomy technique, laboratory variability, etc. Rather, a series of low sodium values in successive serum samples from a given patient does indicate this condition. Thus it is vital to follow trends in particular values. Osler's Rule. Especially if the patient is under the age of 60 years, try to attribute all abnormal laboratory findings to a single cause. Only if there is no possible way to correlate all abnormal findings should the possibility of multiple diagnoses be entertained.

Abnormalities in Clinical Chemistry:

Glucose Abnormalities

The normal reference interval for fasting serum glucose is generally between 70-110 mg/dL. As described in Chapter 16 , the two basic abnormalities that occur with serum glucose levels are hyperglycemia, almost always associated with diabetes mellitus, and hypoglycemia due to iatrogenic (overdose with insulin in the diabetic patient) or to other underlying causes (such as reactive hypoglycemia due to hypersensitivity to insulin, insulinoma, etc.). To establish hyperglycemia, it is vital to determine whether the patient has (1) a fasting serum glucose level greater than or equal to 126 mg/dL, or (2) a serum glucose level greater than or equal to 200 mg/dL and classic symptoms of diabetes, or (3) a 2-hour postload plasma glucose concentration greater than or equal to 200 mg/dL during an oral glucose tolerance test. Any one of the above findings is diagnostic, if it can be confirmed by repeat testing on a subsequent day. In the glucose tolerance test, described in Chapter 16 , after giving the patient, who has not eaten for 12 hours

overnight, a well-defined amount of glucose orally, the blood and urine glucose levels are followed. Normally, serum glucose levels rise and then fall within about a 2-hour period. If the glucose levels remain elevated, however, the diagnosis of diabetes mellitus may again be made. Also, if glucose is detected in the urine at any point, evidence for this condition is also obtained, although absence of urinary glucose does not in any way rule out diabetes mellitus. High levels of serum glucose also result in the glycosylation of hemoglobin. Glycosylated hemoglobin levels change slowly over time and therefore constitute a stable and reliable indicator of serum glucose levels over the past 2-3 months. Glycosylated hemoglobin levels that are greater than 7% are considered to be indicative of diabetes mellitus, and efficacy of treatment is gauged by whether this serum level is reduced to less than 7. Of all of the methods for diagnosing and especially for monitoring treatment of diabetes mellitus, measurement of glycosylated hemoglobin levels is perhaps the most accurate and should be measured in conjunction with blood glucose determinations.
Other Abnormal Laboratory Findings in Diabetes Mellitus

As discussed in the electrolyte section above, under the influence of insulin, whenever glucose is transported into the cell, it is accompanied by potassium. In diabetes, in the absence of insulin, blood glucose is elevated as is potassium. Due to increased metabolism of fats, there is a buildup of acetoacetic acid, leading to a metabolic acidosis. In diabetes where the blood glucose becomes exceptionally elevated, i.e., > 300 mg/dL, serum osmolality becomes dangerously high and can cause nonketotic, hyperosmolar coma. In this condition, red (and white) cell water flows from the cells into the vascular volume, tending to dilute analytes such as sodium. Thus the nonketotic, hyperosmolar coma patient may have a hyperosmolar serum, hyperglycemia, hyperkalemia and hyponatremia. In ketotic states, the patient will have, additionally, a metabolic acidosis and a large anion gap. In hypoglycemia, serum glucose levels of < 60 mg/dL on a series of random fasting serum specimens strongly indicate this condition. Glucose tolerance tests show that after an initial sharp rise of serum glucose levels, there is an abnormally rapid drop to levels substantially below 60 mg/dL. If hypoglycemia is suspected, it is advisable to give the patient a 5-hour glucose tolerance test because the hypoglycemic dip often is not seen until after 3 hours. Glucose tolerance tests on patients with suspected hypoglycemia should be performed with great caution because the procedure can induce severe reactive hypoglycemia causing loss of consciousness and even shock.

Interpreting and Correlating Abnormal Laboratory Values Electrolyte Abnormalities Hyponatremia The four most common causes of hyponatremia are given in Table 1, together with a fifth, rare, cause, Bartter's syndrome. A sixth, metabolic cause, diabetes mellitus, is also presented in this table. In all forms of hyponatremia, the chloride ion concentration is also generally low since chloride is the chief counter-ion for sodium. Table 1. Common Causes of Hyponatremia and Electrolyte Patterns in Serum and Urine with Normal Renal Function[*]
Cause 1. Overhydration 2. Diuretics 3. SIADH** 4. Adrenal failure 5. Bartter's syndrome Serum Na Low Low Low Low Low Urine Na (UNa) Urine osmolality Low Low High Mildly elevated Low Normal Low Low High Normal Low Normal Serum K Normal low Low Normal low High Low High or High High High Normal 24-Hour UNa or Low High

6. Diabetic *** hyperosmolarity Low

* **

All Na and K values are concentrations except for 24-hour UNa, which is the total number of milliequivalents of Na excreted in 24 hours in the urine. Secretion of inappropriate levels of antidiuretic hormone.

*** In this condition, serum glucose is markedly elevated.

Basic Principle

All confirmed serum sodium abnormalities must be followed up with urinalysis on the patient who should be fluid restricted. This urinalysis should include the urine sodium and urine osmolality. For conditions 1 and 2 in Table 1 , the serum sodium tends to correct over a 24-hour period when the patient is fluid restricted.
Overhydration.

In this condition, the most common cause of which is the consumption of large amounts of water or hypotonic fluids due to such causes as psychogenic polydipsia, serum sodium is reduced

below 135 mEq/L. Since the consumed water is excreted by the kidneys, the urine is also dilute in this ion. In fact, the osmolality of urine will be low, i.e., < 300 mOsm . Often accompanying hyponatremia in overhydration are low values of the hematocrit and low values of BUN, discussed subsequently. This triad of findings strongly suggests overhydration as the cause. Urinalysis in the fluid-restricted patient will reveal urinary sodiums of < 25 mEq/L and low osmolalities. The potassium may also be low although it often remains within the reference range. Since mainly water is excreted in urine in this condition, the total 24-hour sodium excretion will be low (cause no. 1 in Table 1 ).
Use and/or Abuse of Diuretics.

Loop diuretics block the chloride pump in the loop of Henle, thereby blocking the formation of the ion gradients via the countercurrent multiplier, necessary for water conservation. Thus water is lost. Also, because sodium is no longer retained because it follows chloride in the loop, it also is depleted from serum. The 24-hour sodium excretion is high, unlike in over-hydration (entry 2 in Table 1). The pattern resembles overhydration (dilute serum and urine) except that loop diuretics cause severe potassium depletion unless the diuretic is combined with a potassiumsparing diuretic like triamterene. Combined hyponatremia and hypokalemia with a high urinary sodium and potassium 24-hour excretion point to diuretic use. Of course, a history will generally also reveal use of diuretics.
Syndrome of Inappropriate ADH (SIADH) Secretion

(entry 3, Table 1 ). In this condition, secondary to head trauma, seizures, other CNS diseases, and neoplastic conditions especially lung, breast and ovarian cancers, that secrete ADH-like hormones, the serum sodium is depressed due to the excess retention of water in the collecting ducts. This results in depletion of water in the renal tubules, thereby concentrating the urine. Therefore, while the serum is dilute in sodium (hypotonic), the urine is concentrated to levels > 40 mEq/L, and the urine osmolality exceeds 300 mOsm while the serum osmolality < 280 mOsm. This pattern clearly is diagnostic of SIADH.
Aldosterone Deficit

(entry 4, Table 1 ). This condition is secondary to Addison's disease and AIDS-related hypoadrenalism. Without aldosterone, the Na+K+ and Na+H+ exchange in the distal convoluted tubules and collecting ducts does not occur. Therefore, serum sodium concentration is reduced while serum potassium concentration increases, and there is a mild metabolic acidosis. Urinary sodium increases but not to the high levels seen in SIADH, and the osmolality of urine is also not so elevated as in SIADH.
Bartter's Syndrome

(entry 5, Table 1 ). This condition resembles diuretic use except that the hyponatremia is not corrected with fluid restriction. The cause of this rare condition is unknown, but sodium chloride gradients cannot form in the loop of Henle. This results in retention of chloride ion that is not available for the countercurrent mechanism. Thus the ion gradients that normally form in the

loop of Henle cannot exist. In this condition, there is a persistent hyponatremia, hypokalemia and a high 24-hour sodium and potassium excretion.
Diabetic Hyperosmolar State.

In patients with diabetes mellitus, if they are in a hyperosmolar state, i.e., where the serum glucose is markedly elevated, say around 700 mg/dL, the hyperosmolality of serum causes efflux of cellular water, with a consequent osmotic dilution of serum sodium. Roughly, for each 100 mg/dL increase in serum glucose, there is a 1.6 mEq/L decrease in the serum Na + concentration. Since transport of glucose into cells is accompanied by concurrent transport of potassium into cells, low insulin levels also cause high serum potassium. So, the net effect of diabetic hyperosmolar states is a low serum sodium and a high serum potassium. This resembles hypoaldosteronism (cause 4 in Table 1 ), but the presence of abnormally high glucose levels signals the possibility of diabetes mellitus as the cause.
Pseudohyponatremia

This condition is usually caused by the presence of excess lipids in serum. No sodium ions are dissolved in lipids, which can take up a considerable volume of serum. If the absolute amount of sodium in a given volume of serum is determined, as is performed when using such methods of sodium determination as flame photometry, this value is divided by the sample volume to get the concentration. But part of this volume is lipid that has no sodium. So a falsely low value of sodium can be obtained. This artifact is eliminated by the use of ion-selective electrodes that directly determine the concentration of sodium and do not depend upon knowledge of the volume of serum.
Hypernatremia

Table 2 summarizes the three basic causes of hypernatremia. Note that each cause is the counterpart of a cause for hyponatremia. These causes are summarized as follows. Table 2-- Common Causes of Hypernatremia and Electrolyte Patterns in Serum and Urine with Normal Renal Function[*] Cause Serum Urine Na Urine Serum 24-Hour Na (UNa) osmolality K UNa 1. Dehydration 2. Diabetes insipidus 3. Cushing's syndrome disease High High or High High Low Low High Low Normal Normal Normal Low Varies Low Low

* All Na and K values are concentrations except for 24-hour UNa, which is the total number of milliequivalents of Na excreted in 24 hours in the urine.

Dehydration.

This can be caused by excess renal loss with high positive free water clearance (i.e., loss of water in excess of NaCl), excess sweating and low water intake. The serum sodium is elevated, as is the hematocrit (possibly masking a true anemia), and the urine sodium is also high due to increased renal excretion of NaCl.
Diabetes insipidus (DI).

DI may be central (neurogenic) (i.e., due to decreased vasopressin secretion) or nephrogenic (i.e., due to decreased renal response). Functionally, this condition is the reverse of SIADH, i.e., water retention in the tubules is not adequate. While this condition is not completely understood, and may be multifactorial, current research suggests that either mutation and/or changes in protein expression of water channel molecules (renal aquaporins) and/or the vasopressin V2 renal collecting tubule cell receptor may play a role in both pathological water loss, such as in nephrogenic DI, and pathological water retention, such as in SIADH. The pattern is elevated serum sodium but dilute urinary sodium due to the functionally inadequate levels of ADH.
Hyperaldosteronism.

This condition may result from adrenal hyperplasia, Cushing's syndrome and Cushing's disease. The levels of circulating aldosterone are inappropriately high, causing excessive reabsorption of Na and excretion of K+ and H+ ions. The patient will be hypernatremic and hypokalemic and exhibit a mild metabolic alkalosis.
Hypokalemia

Many of the causes of hypokalemia overlap with those of hyponatremia including overhydration; use of loop diuretics; SIADH; and Bartter's syndrome, as discussed above. In addition to these causes overlapping with those of hyponatremia, there are the following states that lead uniquely to hypokalemia. 1. 2. Infusion of insulin to diabetics. This results in rather large influxes of potassium into cells, lowering it in serum. Alkalosis. Red blood cells are themselves excellent buffers. They are capable of exchanging potassium for hydrogen ions. Thus, in acidosis, H+ ions enter red cells in exchange for K+ ions. Conversely, in alkalosis, H+ ions leave red cells (to neutralize excess base) while K+ ions enter the red cells. Vomiting. The major loss is both H+ and K+ from the stomach.

3.

Hyperkalemia

Among the major causes are those that also cause hypernatremia, e.g., dehydration and diabetes insipidus, and, additionally, the following: acidosis and diabetes mellitus (as discussed above); and hemolysis. Any kind of cell damage, such as rhabdomyolysis, and especially hemolysis of erythrocytes, can cause hyperkalemia. In hemolysis, all of the intracellular K+ is extruded into plasma. Another analyte that is concentrated in red cells that rises with K+ in hemolysis is lactate dehydrogenase (LD). Concomitant elevations of potassium and LD in serum should be taken as

indications of hemolysis either artifactually after a blood sample has been taken from the patient or, less commonly, hemolysis from an underlying hemolytic condition.