CASE STUDIES IN LABORATORY MEDICINE

Chapter numbers refers to Basic Pathology by Kumar, Cotran, Robbins. 6th edition

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A 4-year-old child has a serum AP of 1150 U/L (normal pediatric value, 115-340 U/L), a serum phosphate of 5.0 mg/dL (normal pediatric value, 3.6-5.6 mg/dL), and a serum (-glutamyltransferase (GGT) of 30 U/L (normal, 6-37 U/L). After the clotted blood was spun down in the test tube, the serum was visibly hemolyzed owing to difficulty in obtaining the specimen. The physical examination of the child is unremarkable except for a few different-colored bruises on the right thigh and buttocks.

Questions

1. Why is the normal range of AP higher in children than in adults?

2. What is the significance of a hemolyzed serum sample and the elevated serum AP?

3. What is the most likely cause of the elevated AP?

Case Discussion

The normal range for serum AP is three to five times higher in children than in adults owing to increased osteoblastic activity in active bone growth.

A hemolyzed serum sample does not significantly alter the alkaline phosphatase activity; however, it would falsely increase the serum potassium, serum lactate dehydrogenase, and serum aspartate transaminase (AST; SGOT) because these analytes are located within red blood cells.

Since the serum GGT is normal, the serum AP is not of liver origin (Chapter 16). Recall that serum AP and GGT are indices of cholestasis (blockage to bile flow) in liver disease, hence both should be elevated if the AP is of liver origin. The different-colored bruises on the thigh and buttocks indicate the possibility of child abuse, and the elevated AP over normal for age is due to healing of a bone fracture or fractures. A bone survey should be obtained to document this possibility.

Case 2: A Medical Student with an Isolated Elevation of Serum Alanine Aminotransferase (ALT; SGPT)

A 27-year-old medical student complains of excessive fatigue and a poor appetite over the last few months. He has some vague right upper quadrant pain on deep palpation; however, the liver is not enlarged on physical examination. A biochemical profile reveals a serum ALT of 125 U/L (normal, 8-20 U/L) and a normal serum aspartate aminotransferase (AST; SGOT), total bilirubin, AP, and GGT.

Questions

1. What is the significance of an isolated elevation in transaminase in this medical student?

2. What tests, if any, would you order to further evaluate this patient?

Case Discussion

One problem with an isolated elevation in a laboratory test is whether it represents a true- or a false-positive result, the latter being more likely owing to the low prevalence of disease in ambulatory patients. Although most clinicians repeat the test when there is doubt about its validity, an alternative is to calculate what the reference interval of the test would be using 3 rather than 2 standard deviations (SD) from the mean of the test. Recall that the reference intervals for the majority of laboratory tests are based on 2 SD from the mean of the test. The mean of the serum ALT is 14 U/L (normal, 8-20 U/ L), hence 2 SD is 6 U/L and 1 SD is 3 U/L. Since 3 SD encompasses 99% of the normal population, the upper limit of the ALT reference interval for 3 SD is 23 U/L (14 + 9). Hence, the patient has a medically significant elevation of ALT rather than a false-positive result.

The transaminases, ALT and AST, are liver cell necrosis indices that are released into the circulation with diffuse liver cell injury (Chapter 16). Furthermore, with the exception of alcoholic hepatitis, ALT is invariably higher than AST and is also more specific for liver cell injury than AST, which is also present in high concentration in muscle and RBCs. Hence, the patient must have a resolving hepatitis, in which the AST would be expected to return to normal before the ALT. This possibility can be documented with hepatitis serologic testing, i.e., anti-HAV lgM and lgG, HBsAg, anti-HBc lgM, and anti-HCV antibodies. It is likely that the patient has resolving hepatitis A, unless there is a history of needle puncture or intimate contact with a person having active disease.

Case 3: A Pregnant Woman with Hypertension, Proteinuria, and Pitting Edema

A 29-year-old woman in her 33rd week of pregnancy is noted to have a 5-lb (2.5 kg) weight gain in 1 week, dependent pitting edema in her feet, a blood pressure of 142/92 mm Hg on three separate readings, and a urine dipstick test demonstrating 2+ proteinuria (sulfosalicylic acid [SSA] method 2+). No casts or RBCs are noted in the urine sediment examination. Important laboratory test results are as follows:

Serum BUN = 18 mg/dL Serum creatinine = 1.2 mg/dL

(normal, 7-18 mg/dL) (normal, 0.6-1.2 mg/dL)

Serum uric acid = 6.5 mg/dL Serum AST = 100 U/L

(normal, 3.0-8.2 mg/dL) (normal, 8-20 U/L)

Serum ALT = 150 U/L Serum AP = 150 U/L

(normal, 8-20 U/L) (normal, 20-70 U/L)

Serum GGT = 37 U/L Serum total bilirubin = normal

(normal, 6-37 U/L)

Questions

1. Are the serum blood urea nitrogen (BUN), creatinine, and uric acid levels really "normal" in this patient?

2. What is the significance of the elevated liver function tests?

Case Discussion

The patient has a classic presentation of pre-eclampsia, which most commonly occurs in the third trimester. Recall that in pregnancy, the plasma volume is increased greater than the increase in RBC mass. This is responsible for a slight drop in the Hb concentration; an increase in the creatinine clearance; and increased clearance of urea, creatinine, and uric acid. Hence, in pregnancy, a serum BUN > 10 mg/dL, a serum creatinine > 1.0 mg/dL, and a uric acid > 5 mg/dL is abnormal even though the values are all in the "normal" range for an adult.

The renal disease associated with pre-eclampsia ("endotheliosis"; Chapter 14) is associated with a reduction in the creatinine clearance and an increase in serum BUN, creatinine, and uric acid, since they are not filtered and cleared from the plasma as in a normal pregnancy. The elevated serum AP is normal for pregnancy and is of placental origin. In this case, it should not be construed as indicating cholestatic liver disease, since the GGT is normal (see discussion of case 1). Elevation of the transaminases may occur in preeclampsia owing to mild periportal (zone I) necrosis of hepatocytes (Chapter 16). Diffuse liver cell disease or cholestasis must be present for the total bilirubin to be elevated.

A positive dipstick for protein is always confirmed by an SSA precipitation test. The dipstick protein detects albumin but not globulins, while the SSA detects both albumin and globulins. Hence, the equal results in both tests (2+) indicate that albumin is mainly being lost in the urine. Proteinuria in preeclampsia may sometimes be in the nephrotic range (> 3.5 g/24 h), in which case there would be fatty casts in the urine and more advanced pitting edema owing to hypoalbuminemia and the loss in plasma oncotic pressure.

An asymptomatic 65-year-old woman on a routine physical examination is noted to have the following abnormalities in her biochemical profile:

Serum calcium = 11.3 mg/dL Serum phosphorous = 2.9 mg/dL

(normal, 8.4-10.2 mg/dL) (normal, 3.0-4.5 mg/dL)

Serum sodium = 140 mEq/L Serum potassium = 4.0 mEq/L

(normal, 135-147 mEq/L) (normal, 3.5-5.0 mEq/L)

Serum chloride = 112 mEq/L Serum bicarbonate = 16 mEq/L

(normal, 95-105 mEq/L) (normal, 22-28 mEq/L)

Questions

1. What is the differential diagnosis for hypercalcemia?

2. Is there a simple test that can help differentiate the cause of her hypercalcemia?

3. What additional test should be ordered to confirm your diagnosis?

Case Discussion

Hypercalcemia in an ambulatory setting is most commonly due to primary hyperparathyroidism (HPTH), whereas in the hospital, it is most commonly secondary to malignancy with either metastasis to the bone marrow or the secretion of a parathormone-like peptide (Chapter 20). Other diseases account for < 25% of all cases of hypercalcemia, hence the differential is primarily between HPTHand cancer-induced hypercalcemia. Since this patient is asymptomatic and ambulatory, primary HPTH is more likely. Recall that parathormone (PTH) normally increases the distal reabsorption of calcium and inhibits the proximal reabsorption of phosphate and bicarbonate. Hence, an excess of PTH secreted by a parathyroid adenoma (most common cause) will produce hypercalcemia, hypophosphatemia, and metabolic acidosis of the normal anion gap type. The anion gap (AG) is equal to the serum sodium minus the sum of the serum chloride and bicarbonate (Chapter 4). In this patient, the AG is 12 mEq/L (140 - [112 + 16]), which is normal (12 mEq/L + 4). The reason for the normal AG is that for every loss of bicarbonate of 1 mEq/L in the urine, there is an equal gain in chloride ions to counterbalance the loss in negative charges, hence the AG remains unchanged.

Another useful test is the chloride/phosphate ratio (Chapter 20), which if > 33 is associated with primary HPTH rather than malignancy-induced or another cause of hypercalcemia. The patient's ratio is 39. When hypercalcemia is due to something other than primary HPTH, the hypercalcemia suppresses the patient's own PTH, hence there is no normal AG metabolic acidosis and the chloride/ phosphate ratio is < 33 (generally < 29).

The serum PTH level should be determined in this patient; it will be elevated in primary HPTH and depressed in any other cause of hypercalcemia.

A 35-year-old type I insulin-dependent diabetic has had the flu for the past week. He now presents with hypotension, dry mucous membranes, and poor skin turgor. The patient is tachypneic, and his breath has a fruity odor. He has the following pertinent laboratory findings:

Serum albumin = 6.0 g/dL Serum calcium = 9.0 mg/dL

(normal, 3.5-5.5 g/dL) (normal, 8.4-10.2 mg/dL)

Serum phosphorous = 5 Serum BUN = 60 mg/dL

mg/dL (normal, 3.04.5) (normal, 7-18 mg/dL)

Serum creatinine = 2 mg/dL Serum glucose = 800 mg/dL

(normal, 0.6-1.2 mg/dL) (normal, 70-110 mg/dL)

Serum sodium = 132 mEq/L Serum potassium = 6.0 mEq/L

(normal, 135-147 mEq/L) (normal, 3.5-5.0 mEq/L)

Serum chloride = 92 mEq/L Serum bicarbonate = 17 mEq/L

(normal, 95-105 mEq/L) (normal, 22-28 mEq/L)

Urinalysis: Dipstick urine for glucose and ketones is strongly positive; the dipstick protein is 1 + (SSA 1+).

Questions:

1. What physical signs and laboratory tests indicate the patient's volume status?

2. What acid-base abnormalities are present?

3. Why does the patient have hyperkalemia?

4. What is the corrected serum sodium?

5. Is renal disease present in this patient?

Case Discussion

The patient is volume depleted. His blood pressure is low owing to a mixed hypotonic loss of fluid in his urine (more water than salt) from osmotic diuresis induced by glucosuria. Poor skin turgor and dry mucous membranes also indicate the loss of salt and water from the interstitial space within the extracellular fluid compartment (ECF; Chapter 4). The serum albumin is elevated owing to hemo concentration of albumin secondary to a reduction in plasma volume. The serum BUN and creatinine are disproportionately elevated, and the BUN/creatinine ratio is 30/1 (normal, 10/1; Chapter 14). Recall that urea is filtered and reabsorbed in the proximal tubule, the latter being dependent on the glomerular filtration rate (GFR). The lower the GFR, the greater the amount of urea reabsorption. Creatinine is filtered by the kidney and neither reabsorbed nor secreted. Therefore, when hypovolemia is present and the GFR is reduced, the serum BUN increases as more urea is reabsorbed in the proximal tubules, and the creatinine increases only slightly from the reduction in clearance of the analyte from plasma. This condition is called prerenal azotemia.

The patient has an increased anion gap metabolic acidosis secondary to an increase in keto acids (acetoacetic [AcAc], (-hydroxybutyrate [(-OHB]; Chapter 20). This situation is the result of poor glucose control when the patient was sick with the flu. A lack of insulin results in the release of glucagon and other counterregulatory hormones (cortisol, catecholamines). Glucagon increases glycogenolysis and gluconeogenesis, hence the increase in blood glucose. It also stimulates hormone-sensitive lipase in the adipose, causing the release of free fatty acids and glycerol (which is converted to glycerol 3-phosphate in the liver and used as a substrate for gluconeogenesis). Fatty acids undergo (-oxidation in the mitochondria, leading to an increase in acetyl-CoA, which is converted in the liver to ketone bodies (acetone [fruity odor of breath], AcAc, and (-OHB). Acetone and AcAc (not (-OHB) are detected in the plasma and urine with a nitroprusside reaction. Keto acids are responsible for the patient's increased AG metabolic acidosis. The AG in this patient is 23 mEq/L (132 - [92 + 17] = 23).

Hyperkalemia is due to the metabolic acidosis and the buffering of excess hydrogen ions by cells in exchange for potassium in order to maintain electroneutrality. This transcellular shift of potassium underscores the importance of how pH alters serum potassium and obscures the patient's true total body potassium status. Once the patient is treated with insulin, the potassium will drop dramatically, often into hypokalemic range, as it enters muscle and adipose along with the glucose. Hypokalemia is common in this setting owing to the loss of potassium along with sodium and water in the urine secondary to osmotic diuresis.

The serum sodium is always lower in the presence of hyperglycemia, since glucose establishes an osmotic gradient favoring the movement of water out of the intracellular fluid compartment (ICF) into the ECF, where it dilutes the sodium (Chapter 4). The correction for sodium for the dilutional effect of glucose is as follows: corrected serum sodium = measured serum sodium + (serum glucose/100 x 1.6), which in this case is 145 mEq/L (132 + [800/100] x 1.6). The reason the patient's serum sodium is at the upper limit of the normal range for sodium when the dilutional effect of glucose is eliminated is that osmotic diuresis produces a hypotonic loss of fluid, which over time produces hypernatremia (( serum Na ( ( TBNa/ ( ( TBW). Note: The measured rather than the corrected serum sodium is utilized when calculating the AG in the presence of metabolic acidosis.)

The patient has proteinuria, which may indicate the presence of diabetic glomerulosclerosis (Chapter 14). Captopril, an angiotensin-converting enzyme inhibitor, is useful in this situation, since it blocks the vasoconstrictor effect of angiotensin II on the efferent arteriole, hence reducing the pressure on the glomerular capillaries. Diabetic nephropathy may be associated with the nephrotic syndrome owing to the increased permeability of the glomerular capillaries to protein from nonenzymatic glycosylation of their basement membranes.

Case 6: A Patient with Rheumatoid Arthritis and an Elevated Total Protein

A 62-year-old woman with rheumatoid arthritis presents with a history of increased pain and stiffness in her hands and generalized fatigue. She has increased the dose of NSAIDs over the last few months without relief of pain. Physical examination reveals swelling and tenderness of the second and third metacarpophalangeal joints in both hands, pale palmar creases, and pale conjunctiva. Her stool guaiac is positive. She has the following pertinent laboratory data:

Serum total protein = 8.5 g/dL Serum albumin = 3.0 g/dL

(normal, 6.0-7.8 g/dL) (normal, 3.5-5.5 g/dL)

Serum globulins = 5.5 g/dL Serum Iron = 40 (g/dL

(normal, 2.3-5.5 g/dL) (normal, 50-170 (g/dL

Serum ferritin = 50 ng/mL

(normal, 10-120 ng/mL)

CBC: Hb = 7.0 g/dL (normal, 12.0-16.0 g/dL); rouleaux are present as are a mild normocytic anemia and an absolute monocytosis.

Questions

1. Has iron deficiency been ruled out in this patient?

2. Why is the total protein increased and serum albumin decreased?

3. What is the significance of an absolute monocytosis?

Case Discussion

Because the patient has a chronic disease and a positive stool guaiac, both anemia of chronic disease (ACD) and iron deficiency may be present. The serum iron is decreased in both of these anemias, so it cannot differentiate the two when both are present (Chapter 12). ACD is characterized by iron blockade in macrophages (serum ferritin is increased), whereas iron deficiency is associated with absent iron stores (low serum ferritin). The serum ferritin represents a small circulating fraction of the iron stores; however, it is also located in the hepatocyte., In inflammation, interleukin-1 (IL-1) released from macrophages stimulates the synthesis and release of acute-phase reactants from the liver, one of which is ferritin (Chapter 3). Hence, in inflammation, the serum ferritin may be increased even though the ferritin stores in the bone marrow are depleted. A bone marrow examination would be required to document whether the iron stores are adequate; however, this is a painful, expensive procedure. Since the NSAIDs are likely responsible for the positive stool guaiac (they produce gastric erosions), they should be discontinued and the patient followed to see whether the stool guaiac becomes negative. If not, further workup of the GI tract would be indicated to document the source of the bleeding.

The total proteins are the sum of the serum albumin and the globulins, the latter representing (1-globulins ((1~antitrypsin), (2-globulins ((2-macroglobulin, haptoglobin), (-globulins (complement, transferrin, (-lipoproteins), and (-globulins (IgG, IgA, IgM, IgD, and IgE; Chapter 3). The total protein and serum albumin are directly measured, and the globulins are calculated by subtracting albumin from the total protein. In general, an elevated total protein is due to an increase in globulins. The increase in globulins is primarily secondary to an increase in (-globulins, particularly IgG. IgG is not only the most abundant (-globulin but also the one most often increased in chronic inflammation owing to increased synthesis by many different clones of plasma cells. Since the patient has rheumatoid arthritis, a chronic disease, she most likely has an increase in IgG causing the increase in total protein. Serum protein electrophoresis would demonstrate a polyclonal gammopathy (Chapter 3) with a diffuse elevation of (-globulins due to their synthesis by many different clones of plasma cells. Hypoalbuminemia is present in the patient owing to reduced synthesis of albumin by the hepatocytes as a way to conserve amino acids for synthesis of acute-phase reactants. Transferrin synthesis is also decreased.

Absolute monocytosis is expected in patients with chronic disease. Just as neutrophils are the key inflammatory cells in acute inflammation, monocytes and macrophages share the same notoriety in chronic inflammation. They contain growth factors and have phagocytic properties that are important in the healing process.

A 70-year-old man has an intermittent history of constipation and diarrhea and a weight loss of 20 pounds over the last 3 months. He states that he has a dragging sensation in his right upper abdomen. Pertinent past history includes the transfusion of 5 units of blood 10 years ago after his spleen was ruptured in a car accident. Positive physical findings include a slightly enlarged, nontender liver, an anal fissure, and a diffusely enlarged, nontender prostate gland. His stool

guaiac is positive. Pertinent laboratory findings are listed below:

Serum AP = 125 U/L Serum GGT = 100 U/L

(normal, 20-70) (normal, 6-37)

Serum LDH = 250 U/L Serum AST, ALT, and total bilirubin are normal

Serum iron = 40 (g/dL Serum ferritin = 280 ng/mL

(normal, 65-175 (g/dL) (normal, 20-250 ng/mL)

CBC: mild normocytic anemia; corrected reticulocyte count is 2%.

Prostate-specific antigen (PSA) = 6 ng/mL (normal, < 4 ng/mL)

Questions

1. What is the significance of the liver function test abnormalities?

2. What is the significance of the elevated PSA?

3. Does the patient require a workup of the gastrointestinal tract to explain the positive stool guaiac?

Case Discussion

The liver function tests (LFTs) are characteristic of focal disease because of the absence of transaminase elevation (transaminases are markers of cell necrosis in diffuse injury) and the normal total bilirubin levels. Therefore, it is unlikely that the patient has liver disease resulting from his previous transfusions (since hepatitis C is the most common cause of posttransfusion hepatitis). Unlike the transaminases, which are released with cell injury, both AP and GGT are synthesized when there is compression of the bile ducts by an extrinsic mass. The history of alternating constipation and diarrhea, a positive stool guaiac, hepatomegaly, and weight loss suggests colon cancer with metastatic disease to the liver, which would produce the LFT findings noted in this case. An increase in serum LDH is frequently associated with an underlying malignancy, since it is a nonspecific enzyme marker of malignancy.

The elevated PSA is most likely secondary to benign prostatic hyperplasia, since the gland is diffusely enlarged and the PSA is < 10 ng/mL (Chapter 18). With PSA levels this low, most clinicians would follow the patient with PSA levels rather than submit him to a transrectal ultrasound examination and potential transrectal biopsy. The elevated serum AP is of liver, not bone, origin (prostate cancer is osteoblastic) owing to the increase in serum GGT.

A positive stool guaiac should always be evaluated even if it appears that an anal fissure or hemorrhoids are the most likely source of the bleeding (Chapter 15). Since the patient is over 50 years of age, colon cancer must be ruled out as the cause of a positive stool guaiac. This underscores why annual stool guaiacs are recommended in all patients > 50 years of age. In this case, the patient had a rectosigmoid adenocarcinoma with a "napkin ring" configuration that was responsible for the constipation and diarrhea. Imaging studies confirmed the presence of metastasis to the liver.

A 42-year-old executive complains of fatigue and some recent alterations in mental status, such as forgetting appointments. He traveled outside the United States 2 months ago on a business meeting. He has vague right upper quadrant pain on deep palpation and borderline enlargement of the liver. Important laboratory findings are listed below:

Serum AST = 120 U/L Serum ALT = 80 U/L

(normal, 8-20 U/L) (normal, 8-20 U/L)

Serum AP = 68 U/L Serum GGT = 170U/L

(normal, 2-70 U/L) (normal, 6-37 U/L)

Serum total bilirubin = normal Serum glucose = 60 mg/dL

Serum uric acid = 9.8 mg/dL (normal, 70-110 mg/dL)

(normal, 3.0-8.2 mg/dL) CBC and urinalysis results are normal.

Questions

1. What is the clinical significance of the abnormal liver function tests?

2. Why does the patient have hypoglycemia?

3. Does the patient have gout?

Case Discussion

The transaminases are markers of cell necrosis, and in most cases, the serum ALT is higher than the AST. However, this patient's serum AST is higher than the serum ALT, and his serum GGT is disproportionately elevated over the serum AP. This enzyme relationship is characteristic of alcohol-related liver disease (Chapter 16). Alcohol is a mitochondrial poison, and AST is primarily located in the mitochondria, hence it is preferentially elevated over the ALT. Alcohol also stimulates the cytochrome P-450 system, increasing the synthesis of GGT rather than of AP. Thus, the patient has alcohol-related liver disease rather than a viral hepatitis secondary to HAV (most common cause of traveler's hepatitis).

Alcohol intake also explains the patient's hypoglycemia and memory problems. In the metabolism of alcohol, NADH is increased, which results in the reversal of all the normal NAD:NADH reactions, one of which is pyruvate to lactate. Since pyruvate is an intermediate in gluconeogenesis, its conversion to lactate reduces its concentration, so fasting hypoglycemia may occur. Recall that the brain requires glucose for fuel; therefore, fasting hypoglycemia results in mental status abnormalities (neuroglycopenia) in these patients (Chapter 20).

Hyperuricemia is not a criterion for the diagnosis of gout. The presence of monosodium urate crystals in the synovial fluid must be documented to diagnose gout. Furthermore, hyperuricemia is not always present even in acute attacks of gout. Hyperuricemia in this patient is likely due to the increase in lactic acid and (-OHB competing with uric acid for excretion in the proximal tubule. The synthesis of (-OHB is increased in alcoholism owing to the increase in acetyl-CoA as the end product of alcohol metabolism and its conversion into ketone bodies by the liver. The increase in NADH drives the reaction from acetoacetic acid to (-OHB. Hence, people with alcoholism commonly have two causes for Increased AG metabolic acidosis: lactic acidosis and (-OHB ketoacidosis. Approximately 20% of patients with hyperuricemia will develop gout (Chapter 21).

A 30-year-old man with a long history of intravenous drug abuse and chronic hepatitis B presents with jaundice. Physical examination reveals a malnourished man with ascites, dependent pitting edema, spider anglomata, female secondary sex characteristics, and bilateral gynecomastia. Rectal examination reveals yellow-brown stool and a negative stool gualac. External hemorrhoids are present. The patient has poor concentration, but no asterixis is present. He has the following biochemical profile:

Total protein 8.3 g,d/L Serum albumin 2.5 g/dL

(normal, 6.O-7.8 g/dL) (normal, 3.5.-5.5 g/dL)

Serum globulins 5.8 g/dL Serum calcium 6.5 mg/dL

(normal, 2.3-3.5 g/dL) (normal, 8.4-10.2 mg/dL)

Serum phosphorous 2.5 mg/dL Serum BUN 6 mg/dL

(normal, 3.0-4.5 mg/dL) (normal, 7-18 mg/dL)

Serum creatinine 0.9 mg/dL Serum sodium 131 mEq/L

(normal, 0.6-1.2 mg/dL) (normal, 135-147 mEq/L)

Serum potassIum 3.0 mEqIL Serum chloride 91 mEq/L

(normal, 3.5-5.0 mEq/L) (normal, 95-105 mEq/L)

Serum bicarbonate 20 mEq/L Serum total bilirubin 6.0 mg/dL

(normal, 22-28 mEq/L) (normal, 0.1-1.0 mg/dL)

Serum AST 200 U/L Serum ALT 350 U/L

(normal, 8-20 U/L) (normal, 8-20 U/L)

Serum AP 180 U/L Serum GGT 100 U/L

(normal, 20-70 U/L) (normal, 6-37 U/L)

Serum LDH 300 U/L Urinalysis: positive for bilirubin

(normal, 45-90 U/L)

CBC: macrocytic anemia with hypersegmented neutrophils, mild neutropenia, and mild thrombocytopenla

Coagulation: prothrombin time (PT) is prolonged and does not correct with intramuscul& vitamin K.

Questions

1. What is the clinical significance of his abnormal liver function tests, hypoalbuminemia, and prolonged prothrombin time that does not correct with intramuscular vitamin K?

2. What is your interpretation of the electrolyte abnormalities in this patient?

3. What is the clinical significance of hypocalcemia in this patient?

4. Why does he have a low serum BUN?

5. What is the most likely cause of the macrocytic anemia?

Case Discussion

The liver function tests exhibit findings consistent with chronic end-stage liver disease secondary, most likely, to chronic hepatitis B. The transaminases are moderately elevated, and ALT is higher than AST. In acute hepatitis, the transaminases would be higher owing to the presence of more liver tissue; however, in chronic hepatitis, the loss of hepatocytes and replacement by fibrosis results in less of an increase. Hypoalbuminemia and a prolonged prothrombin time (PT) are markers of increased severity of liver disease, since both depend on the ability of the liver to synthesize proteins (albumin and coagulation factors). Inability to correct the PT with vitamin K documents that the liver is unable to synthesize the precursor vitamin K-dependent factors II, VII, IX, and X for (-carboxylation by vitamin K into functional coagulation factors (Chapter 4).

The electrolytes reveal hyponatremia, hypokalemia, and a mild increased AG metabolic acidosis (AG = 20; 131 - [91 + 20]). Since the patient has ascites and dependent pitting edema, the TBNa must be increased; therefore, in order for there to be hyponatremia, there must be a hypotonic gain of fluid: ( serum Na ( ( TBNa/ ( ( TBW. This finding is expected owing to reduced venous return to the right heart (fluid is in the interstitial space) with a subsequent drop in the cardiac output. This decreases the effective arterial blood volume, which initiates the release of ADH, aldosterone (activation of the renin-angiotensin-aldosterone system), and increased renal reabsorption of a hypotonic fluid containing a little more water than salt (in the same proportions as depicted in the serum sodium relationship above). Hence, when the hypotonic fluid reabsorbed by the kidneys encounters the reduced oncotic pressure (hypoalbuminemia) in the capillary and venular system, it is driven into the interstitial space by Starling's forces without restoring the cardiac output (Chapter 4). In addition, some of the fluid contributes to the formation of ascitic fluid. The increased AG metabolic acidosis may be secondary to ketoacidosis from starvation and lactic acidosis from liver disease.

The total serum calcium represents the calcium that is bound to albumin (40%), other anions (13%), and free (ionized calcium; 47%). A low ionized calcium may result in tetany. Therefore, in the presence of hypoalbuminemia, the most common cause 9f hypocalcemia, the total calcium is decreased while the ionized calcium is normal, so tetany is not present. The serum calcium must be corrected according to the following formula: corrected serum calcium = serum calcium - serum albumin + 4. The correction in this patient is 8 mg/dL ([6.5 - 2.5] + 4 = 8), which is decreased. Hypocalcemia is partly due to hypoalbuminemia and to hypovitaminosis D secondary to his liver disease. The liver is responsible for the first hydroxylation step in vitamin D metabolism after its reabsorption from the small bowel. Hypocalcemia is a stimulus for secondary hyperparathyroidism, which likely is present in this patient as well.

Because of the decrease in cardiac output (see above), the reduction in the glomerular filtration rate would be expected to increase the reabsorption of urea in the proximal tubule (see case 5), leading to prerenal azotemia. However, owing to location of the urea cycle in the liver, the presence of liver disease seriously hampers the normal function of disposing of ammonia in the urea cycle. Hence, in chronic liver disease, the serum BUN is low while the ammonia level is increased (Chapter 16).

The macrocytic anemia with hypersegmented neutrophils in this patient is more likely secondary to folate rather than to B12 deficiency owing to the 3- to 4-month supply of folate in the liver versus the 6- to 9-year supply of B12 (Chapter 12). This is easily verified by measurement of serum folate, RBC folate, and B12. The elevated serum LDH is most likely secondary to destruction of the macrocytic RBCs (which contain increased LDH1 isoenzyme) in the bone marrow by macrophages (ineffective erythropoiesis).

Case 10: A Smoker with Mental Alterations

A 59-year-old smoker has a recent onset of mental alterations including loss of memory. His physical examination reveals scattered sibilant rhonchi that clear with coughing. The skin turgor is normal, and the mucous membranes are moist. His biochemical profile reveals the following:

Serum BUN = 6 mg/dL Serum uric acid = 3.0 mg/dL

(normal, 7-18 mg/dL) (normal, 3.0-8.2 mg/dL)

Serum sodium 110 mEq/L Serum potassium = 4.0 mEq/L

(normal, 135-147 mEq/L) (normal, 3.5-5.0 mEq/L)

Serum chloride 79 mEq/L Serum bicarbonate = 20 mEqIL

(normal, 95-l05 mEq/L) (normal, 22-28 mEq/L)

Random urine sodium = 80 mEq/L

(normal, <20 mEq/L)

Chest x-ray: centrally located mass in the left hilar area

CT scan of the brain: no focal lesions

Questions

1. Why does the patient have hyponatremia?

2. What would be a nonpharmacologic treatment for the hyponatremia?

Case Discussion

The patient has severe hyponatremia in the presence of normal skin turgor, hence the TBNa must be normal (Chapter 5). Therefore, the hyponatremia must be secondary to a gain of pure water: ( serum Na ( TBNa/ ( ( TBW. With a history of smoking and a centrally located mass in the lungs, the patient most likely has the inappropriate ADH syndrome (SiADH) secondary to secretion of ADH by a small-cell carcinoma of the lung. The increase in reabsorption of free water in the kidneys by ADH produces a dilutional hyponatremia favoring the movement of water into the ICF compartment by osmosis. Cerebral edema would explain the patient's mental alterations. Eventually, the plasma volume increases, which increases the cardiac output and the effective arterial blood volume. Unfortunately, ADH cannot be suppressed. However, there is no stimulus for activation of the renin-angiotensin-aldosterone system, and the proximal tubules of the kidneys are unable to reabsorb salt owing to the increase in peritubular capillary hydrostatic pressure (Chapter 4). Hence, the random urine sodium is increased. Since ADH is present (it should be suppressed when the EABV is increased), the free water is being reabsorbed rather than eliminated, so urine concentration rather than dilution is occurring in the patient. This explains why the urine osmolality is often higher than the plasma osmolality in SiADH.

A nonpharmacologic method of managing SiADH is water restriction without restriction of salt intake, since the TBNa is normal in these patients.

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