Hepatic Function Tests as Aids in the Diagnosis and Evaluation of the Surgical Patient

Hepatic Function Tests as Aids in the Diagnosis and Evaluation of the Surgical Patient WILLIAM C. SHOEMAKER, M.D. *

The liver is, perhaps, one of the most difficult organs to evaluate functionally, to manipulate therapeutically, and to diagnose accurately. Although tests of hepatic function abound, their abundance may obscure their potential usefulness and at times may fail to inspire much confidence in the mind of the practicing clinician. In contrast to the gallbladder, which has as its only function the concentration and storage of bile, the liver has a total of 508 known functions, each of which theoretically could be framed into a test. Actually, there are an unlimited number of possible hepatic tests, since each of an estimated 100,000 different kinds of enzymes in the liver cell effects a specific metabolic reaction. Many of these hepatic actions are important, if not vital, functions, the absence of which may lead to a clinically manifest disorder. So protean in nature and so legion in number are hepatic functions, that a really thorough evaluation of the hepatic functional capacities may stagger the imagination. More difficult to understand than the number of hepatic tests, is their lack of correlation with liver disease processes. Normal hepatic tests have been observed in the face of a liver almost completely displaced by carcinoma. The experimental counterpart of this, namely, normal hepatic tests after removal of 80 per cent of the organ, has also been observed. Thus, evaluation of hepatic disease by measurement of biochemical function is complicated both by the large hepatic reserve which is normally present and the remarkable capacity of hepatic cells for regeneration. But subtle and elusive though its functions are, the liver is a vital organ, and its From the Department of Surgical Research, Division of Surgery, Hektoen Institute for Medical Research, Cook County Hospital, Chicago, Illinois Supported in part by Grants from the United States Public Health Service, by the Charles H. and Rachel M. Schwab Memorial Foundation and by a Public Health Service Career Award (1-K6-HE6305) * Director, Department of Surgical Research, Michael Reese Hospital, Chicago, Illinois

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absence is not compatible with life. Evaluation and diagnosis must rest upon an understanding of the normal functional relationships and pathophysiologic factors involved in hepatic disease processes.

NORMAL HEPATIC FUNCTIONAL INTERRELATIONSHIPS

The liver has long been considered the central organ of metabolism. It regulates many, if not most, of the concentrations of plasma constituents, removes metabolic end-products, clears bilirubin and other hemochromogens resulting from red cell destruction, detoxifies and conjugates abnormally occurring poisons, provides a constant source of glucose to meet energy requirements of the peripheral tissues, synthesizes all of the plasma albumin, fibrinogen and prothrombin as well as 80 per cent of the plasma globulins, controls and regulates fat transport, exerts considerable control on the circulating hormonal concentrations by inactivating or metabolizing them, and secretes the bile acids as well as other substances necessary to digestion. Further, the liver is a major site of glycogen storage as well as the site of storage of fat-soluble vitamins. In essence, the liver is the major organ regulating or controlling body metabolism. The liver not only performs biochemical work of its own, but it also is metabolically and functionally interrelated to the remainder of the body. For example, the liver makes glucose to supply the energy needs of the muscle mass, and removes the organic acids resulting from incomplete oxidation of this glucose (Cori cycle). Further, under certain physiologic conditions, the liver removes free fatty acids released by the fat depots, esterifies cholesteryl and glyceryl to form cholesterol esters and neutral fat. Under other conditions, the liver releases fatty acids to supply nutritional requirements of the peripheral tissues. In these respects the liver's metabolic actions must be viewed in relation to the demands of the peripheral tissues.

MEASUREMENT OF HEPATIC FUNCTION

Basically, most laboratory tests of hepatic function are: (1) measurements of the concentration of normal constituents of plasma, urine and feces; (2) the identification of abnormally occurring substances in plasma, , urine or feces; (3) measurements of the capacity of the liver to remove test doses of foreign dyes or abnormal substances; and (4) measurements of the capacity of the liver to clear a "load" of a substance normally occurring in the plasma and normally removed by the liver (tolerance tests). These hepatic function tests are measurements which may reflect alteration in the rate of important biochemical reactions. Abnormal chemical concentrations in the plasma may reflect increased physiologic require-

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ments of the peripheral tissues or inability of the liver to meet the normal or abnormal demands of the periphery, or a combination of both. These organ interrelationships may be expressed in terms of rate reactions of specific functions, for example, low plasma albumin may represent an increased rate of peripheral utilization, an increased rate of loss through the urine, as in nephrosis, or a decreased rate of synthesis by the liver. Many disease processes also may be expressed in terms of altered rates of certain key biochemical reactions. Accumulation of bilirubin in the plasma, which becomes manifest in jaundice, occurs when the rate of bilirubin formation exceeds the maximum rates of clearance by the liver. Hepatic function tests find their greatest usefulness in the differential diagnosis of the jaundiced patient and in the patient with upper gastro~ intestinal hemorrhage, in the preoperative evaluation of the patient with severe liver disease (as, for example, in the cirrhotic patient on whom a portacaval shunt is contemplated) and in the postoperative management of such a patient.

BILIRUBIN METABOLISM Laboratory confirmation of a clinical diagnosis in the icteric patient is based in part on an understanding of normal and pathological bilirubin metabolism. According to current concepts, following destruction of red cells, hemoglobin is broken down to free bilirubin by the reticuloendothelial system of liver, spleen and bone marrow. Under normal conditions, hemo~ globin and bilirubin are produced at the rate of approximately 6 grams and 220 mg. per day, respectively. The free, water~insoluble, indirect van den Bergh~reacting bilirubin is transported, loosely attached to plasma proteins, to the polygonal hepatic cells in an average of 90 minutes. Accord~ ing to present views, free bilirubin is conjugated with glucuronic acid by the enzyme, bilirubin transferase, in the hepatic polygonal cell to form principally bilirubin diglucuronide. Conjugated bilirubin is water~soluble and couples with the diazo reagent to give a direct (one-minute) van den Bergh reaction. The conjugated bilirubin, then, is excreted by the liver cells via the intrahepatic bile canaliculi and extrahepatic bile ducts into the duodenum where it may be converted by bacterial action into a group of substances referred to as urobilinogen. The latter may be partly absorbed by the gut into the systemic circulation and later excreted in the urine. Abnormal rates of the metabolism or transport of hemoglobin break~ down products at any step outlined above may give rise to an accumulation of bilirubin in the plasma and clinical icterus. In simplest terms, with increased rates of red cell destruction, hemolytic icterus occurs. With hepatic cellular damage, a metabolic block from diffuse damage to all functions of the polygonal cell results in failure of conjugation of free bilirubin to bilirubin glucuronide and the accumulation of free, indirect

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van den Bergh-reacting bilirubin in the plasma (hepatocellular jaundice). Obstructive jaundice occurs when there is anatomic or physiologic block in the biliary tract; the rate of excretion is slowed or halted resulting in a backing up of conjugated bilirubin into the plasma.

DIFFERENTIAL DIAGNOSIS OF JAUNDICE

Hemolytic jaundice is produced by an excessive rate of red cell breakdown which in turn results in excessive rates of bilirubin presentation to the liver. When the liver's capacity to metabolize and excrete the excessive rates of bilirubin production is exceeded, hemolytic or prehepatic jaundice appears. In instances in which the bone marrow is maximally stimulated, 45 grams of hemoglobin and 1500 mg. of bilirubin may be produced per day; that is, there is a seven-fold increase over normal values. Several laboratory aids may help to localize the block at this particular step. There is increased plasma or bilirubin levels (80 per cent or more indirect van den Bergh), absence of bilirubin in the urine, and increased urinary and fecal urobilinogen. With extensive damage to the hepatic polygonal cells, hepatocellular or medical jaundice may occur because of (1) decreased bilirubin transferase activity, (2) impaired conjugation of bilirubin due to diffuse and generalized impairment of the functional capacity of hepatic cells, and (3) failure of the hepatic cell to excrete normally the conjugated bilirubin into the bile canaliculi so that this pigment regurgitates into the blood. Hepatocellular jaundice gives rise to abnormalities of hepatic function which may include: increased serum bilirubin, decreased albumin concentration, increased globulin, reversal of the A/G ratio, alterations in the plasma protein electrophoretic pattern, increased prothrombin time, positive flocculation tests (cephalin cholesterol, thymol turbidity), decreased choline esterase, increased transaminase activity (GOT, GPT), and decreased cholesterol ester concentration when measured quantitatively and as a percentage of the total cholesterol. If the disease process is limited to an obstruction of the extrahepatic biliary system, a pure form of obstructive jaundice (if such can exist) would occur without alteration of hepatocellular function. Under these circumstances, there would be a bile stasis pattern of function testselevated serum bilirubin, elevated icterus index, elevated alkaline phosphatase, elevated total cholesterol concentration and increased percentage of cholesterol esters-without appreciable evidence of hepatocellular damage. If the obstruction were complete, the urine would be bile-stained, the stools acholic and the concentration of both fecal and urinary urobilinogen nil. These tests do not distinguish between extrahepatic biliary tract obstruction (such as common duct stone) and intrahepatic or hepatocanalicular jaundice.

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By and large, what is desired from the clinical point of view is the differentiation of obstructive or "surgical jaundice," defined as those surgically correctable lesions which obstruct the biliary tree (as tumors, calculi and strictures), from "medical jaundice," defined as those diseases affecting the liver cells per se (as viral hepatitis, cirrhosis, drug hepatitis). This differentiation is based on abnormalities of tests measuring hepatocellular function along with normal findings in tests for cholestasis in medical jaundice and vice versa in surgical jaundice. These designations, however, are not as clear-cut as one would like to suppose; obstruction of the common duct is a surgically correctable lesion, but obstruction at the level of the intrahepatic bile canaliculi is not. Other exceptions to the above classification are those types of liver disease which may have both a significant obstructive component and abnormal liver function tests indicative of polygonal cell damage; e.g., cholangiolytic hepatitis, primary biliary cirrhosis and some forms of drug hepatitis. Moreover, low grade cholangitis occurring because of common duct obstruction may produce parenchymal disease. Long-standing (three to six weeks) common duct obstruction usually leads to hepatocellular abnormalities manifest in impaired hepatocellular function tests. Hemolytic and hepatocellular processes also may be interrelated; portal cirrhosis may be associated with an increased red cell destruction, and transfusion of old blood may add to the jaundice in patients with impaired hepatic function. Further, hemolytic disorders may predispose to the deposition of gallstones and biliary obstruction. Impaired bilirubin conjugation resulting from the congenital absence of the enzyme, bilirubin transferase, may produce the so-called "Gilbert's syndrome," a disease which is characterized by a chronic, familial mild jaundice without other evidence of hepatocellular or hemolytic disease.

TESTS OF HEPATIC FUNCTION (See also Table 1)

Liver function tests are used to measure abnormalities of bilirubin metabolism and other hepatic capacities in order to differentiate between obstructive and hepatocellular jaundice. A few well-tried tests will make this distinction to the extent that such is possible. Increasing the number of hepatic function tests which merely estimate the extent of damage of a larger number of specific functions of the polygonal cell will not give additional substantial information on the pathophysiologic mechanisms of the icterus. A brief resume of the relevance of some of the major hepatic tests to differential diagnosis of the jaundiced patient follows. 1. Elevation of serum bilirubin over 0.8 mg.flOO ml. is abnormal. Usually 30 to 70 per cent of the total bilirubin is in the conjugated form. In theory, less than 40 per cent conjugated suggests hepatocellular jaundice;

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Table 1.

SHOEMAKER

Summary oj Expected Alterations in Hepatic Tests

HF~MOLYTIC

JAUNDICE

Serum

C.

HEPATOCELLULAR

CIRRHOSIS

JAUNDICE

JAUNDICE

COMPL}<~TE

PARTIAL

WITHOUT

OBSTRUCTION

OBSTRUCTION

++ to ++++ ++ to ++++ 0 to +

++ or +++

++++

0

++

Oor +

+++

o

+ to +++ ++++

++++ +++

++ or +++ ++ to ++++ ++ to ++++ +to++ Oto+++ 0

Bile acids Stools Albumin

N N or dark N or low

++ N or light Very low

Gamma

N

globulin Prothrombin

+++

Nor + N Low ++

N

Low with no re- N or lew spom~e to vi taminK

N N

+++ +++

N

++ to +++

N

Low

N

Low

N or low

Phosphatase

N

Transaminase

N

N or + but low N to + with severe failure +to+++ Nto++

Choline

N

Low

bilirubin Urinary bilirubin BSP Urinary urobilinogen

Thymol Cephalin flocculation Zinc sulfate turbidity Total cholesterol Cholesterol

++ N or light N or low Nor +

++++ Clay colored

N

N or low

N or low

Nor +

++to+++ Oto+ ++ Oto +

o to +

++

o to +

o to +

N or low

Nto ++

++to +++

N or low

N or low

++ or +++

++++

N or low N

N or low N

Oto +

esters

Low

esterase Part,ial and complete biliary tract obstruction in this table are assumed to represent primarily pure

cases of obstruction with little or no hepatocellular dysfunction. "N" represents normal; +, ++, +++. ++++ represent various degrees of elevation over normal values; "low" represents values below normal.

over 80 per cent indicates hemolytic or obstructive jaundice. In practice, differentiation between direct (one-minute) and indirect (30-minute) bilirubin is rarely of diagnostic value except in hemolytic jaundice where free or indirect bilirubin predominates. Elevated bilirubin levels which are stable and unremitting in the presence of complete obstruction suggest tumor of the pancreas. Intermittent jaundice indicated by fluctuating total bilirubin concentrations suggests movement of a common duct stone or necrosis of an ampullary tumor. 2. The absence from the urine of urobilinogen, which is comprised of a group of colorless pigment precursors (as mesobilirubinogen and stercobilinogen) and the oxidized, colored form, urobilin, indicates that there has been complete obstruction of the biliary tract. An anatomical block occurring at this site prevents excretion of bilirubin with its various metabolites, the subsequent changes to urobilinogen in the gut, the reabsorption of the latter into the circulation (enterohepatic recirculation) and eventual excretion in the urine. Increased urinary urobilinogen indicates that some bilirubin has been delivered into the gut, but that the rate of excretion of reabsorbed pigment

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by the kidney exceeds that of the liver and, thus, implies hepatic dysfunction. Hemolytic jaundice is suggested by very high urinary and fecal urobilinogen levels, usually given as over 1: 100 dilution, or 3 Ehrlich units. The daily urinary output must also be considered, since large differences in the rate of urine output will obviously influence the concentration of the pigment in a given sample. 3. Excessive amounts of bile acids which are partly reabsorbed from the gut are normally cleared by the liver and re-excreted by enterohepatic circulation, but with hepatocellular dysfunction, they !nay be excreted in the urine. In hepatocellular jaundice, the rate of bile acid synthesis and the reabsorption from the gut is decreased. This however, is more than offset by impaired rates of hepatic removal, which leads to increased serum levels and increased urinary output rates. In hemolytic jaundice, bile acid levels in blood and urine are nor!nal, since hepatic clearance rates are not impaired. In obstructive jaundice, regurgitation also leads to increased levels in both serum and urine. With complete biliary obstruction, the highest values are seen. With mild jaundice in the subsiding phase, and in Gilbert's disease, bile !nay not be present in the urine. 4. Stools are nor!nal or light colored in hepatocellular jaundice, and acholic in complete biliary tract obstruction. 5. Albumin levels are decreased, gamIna globulin and other globulin fractions are increased, A/G ratio is reversed, protein electrophoretic patterns are altered, and other proteins (as prothrombin, fibrinogen and choline esterase) produced by the liver cells are decreased with hepatocellular jaundice. 6. Hypoprothrombinemia with restoration of prothrombin levels after parenteral administration of vitamin K occurs if the cause of the hypoprothrombinemia is faulty absorption due to lack of bile salts in the gut. Failure of a significant response (15 per cent in 24 to 48 hours) to 10 mg. parenteral, synthetic vitamin K administration indicates severe hepatocellular damage. 7. Thymol turbidity over 6 Maclagen units, cephalin-cholesterol flocculation tests 3 to 4 plus, and zinc sulfate turbidity over 16 units suggest hepatic cellular disease. In general, the thymol test !nay be more positive in viral hepatitis and the cephalin in cirrhosis. Thymol test of nor!nal or low values (4 units or less) argues against viral hepatitis. On occasion nor!nal values, however, may be seen in drug hepatitis, homologous serum hepatitis and cirrhosis. These tests are based on a fine precipitate usually comprised of gamma globulins. They also depend on concentrations other than gamma globulins which may affect the stability of the suspensions; albumin and alpha globulin improve stability, whereas beta and gamIna globulins, lipoproteins and serum lipids increase turbidity or flocculation. 8. Total plasma cholesterol is normally from 150 to 250 mg.j100 mI.; about two-thirds of the total cholesterol is attached to a fatty acid (choles-

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terol ester). The liver normally esterifies the free cholesterol to the ester form and also clears the ester form from the plasma; thus it may both manufacture and clear cholesterol esters. With hepatocellular damage there may be impaired rates of production of free cholesterol, esterification to cholesterol esters and removal or excretion of the total cholesterol. The usual pattern in hepatitis and cirrhosis is for a decreased total cholesterol (100 to 150 mg./100 ml.) and a decreased ester form (33 per cent or less). In biliary tract obstruction there is a decreased or absent excretion of bile acids with a subsequent backing up of the cholesterol precursor. In biliary obstruction, with relatively adequate hepatocellular function, there is a rise in total cholesterol, and a decrease in the percentage of the esterified form but not in the absolute level. A low ratio of esterified to total cholesterol when the absolute levels are high suggests an obstructive process. 9. Elevated alkaline phosphatase activity above 12 Bodansky units suggests an intra- or extrahepatic biliary obstruction. This increased activity may be explained as an increased rate of enzyme production by the liver or by a decreased rate of hepatic excretion of phosphatase of extrahepatic origin. However, increased enzyme activity also depends on the complex interactions of cofactors, activators and inhibitors. When the plasma activity of this enzyme which presumably arises from the bone, gut and liver is below 5 units, a hepatocellular process is suspected Pure obstruction gives rise to high alkaline phosphatase activity, but, when there is concomitant parenchymal damage, the enzyme activity may not be appreciably elevated. Elevated levels also may be encountered in carcinoma of the liver, either primary or metastatic. 10. Increased plasma transaminase activity (GOT and GPT) presumably occurs from a leaking of these enzymes out of the damaged hepatic cell. This is in contrast with the appearance of the enzyme alkaline phosphatase (vide supra) in which case serum activity is elevated in obstructive jaundice as a result of decreased rates of hepatic removal or increased hepatic release. Values over 400 units suggest hepatocellular jaundice and values under 300 units suggest an intra- or extrahepatic biliary obstruction. High values may occur in obstruction accompanied by cholangitis, or polygonal cell damage. 11. The bromsulphalein (BSP) retention test measures the percentage of dye remaining in the circulation 45 minutes after intravenous administration of a test dose. The dye not remaining in the circulation presumably has been removed in large part by the liver. The rate of removal of this artificial dye is a reflection of the hepatic capacity to remove bilirubin, since both are thought to be metabolized by the same pathways. The test is valid only when the patient is lying in bed in a nearly basal state, since the additional demands produced by exertion or ambulation may materially affect the delicate balance between peripheral demands and hepatic capacities. The BSP test is not usually performed in clinical icterus since this

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and other dyes (as indocyanine green and rose bengal) are thought to be excreted by the same pathways as bilirubin. The observation of BSP retention does not shed more light on the problem of differential diagnosis than is already furnished by the existence of bilirubinemia. BSP, which is a most sensitive measurement of liver cell function, finds its main usefulness in screening for liver damage, establishing drug toxicity, in following the course of the disease and in the differential diagnosis of upper gastrointestinal bleeding. It is used when bilirubin levels are between 0 and 1 mg./lOO ml.

OTHER LABORATORY AIDS IN THE DIAGNOSIS OF JAUNDICE 1. White cell counts under 5000 suggest liver disease, drug hepatitis or an inflammatory process associated with portal cirrhosis. White cell counts over 15,000 suggest cholangitis as the cause of the jaundice. 2. Differential white cell counts may suggest infectious mononucleosis or, if eosinophilia is present, drug hepatitis. 3. Red cell counts may suggest hemolytic disorders, anemias, etc. . 4. Occult blood in the feces may point to neoplasia in the pancreas, ampulla, etc., or suggest blood dyscrasias. 5. X-rays may elucidate esophageal varices, calcification in the region of the pancreas, filling deformities in the stomach or duodenum, apparent hepatic masses, spleen size and, in cases of mild jaundice, gallbladder and common duct visualization. Serum amylase, serum lipase and other tests of pancreatic function may be used to rule out associated pancreatic disease. 6. A beneficial effect after ACTH or hydrocortisone (the hydrocortisone test) may confirm the impression of viral hepatitis. 7. Percutaneous liver biopsy may provide histologic diagnosis when there is disagreement between the clinical and laboratory findings or when there is reasonable doubt as to the correct diagnosis. When hepatic tumor is suspected, negative results should be viewed with caution, since biopsies may not be representative of the liver as a whole. Serial biopsies at intervals of two weeks or more may be used to follow the efficacy of treatment.

EVALUATION OF HEPATIC INSUFFICIENCY The hepatic function tests have their greatest usefulness in the evaluation of hepatic insufficiency. Serial measurements of a few key tests may provide valuable information as to the progress of the disease state, once the diagnosis has been established. In addition, these tests may be helpful in pre- and postoperative management of hepatic insufficiency as well as in the establishment of "operability" in the elective case. The hepatic

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function tests are used in the cirrhotic patient in whom esophageal varices have suggested the need of a portacaval shunt. The following criteria have been used as optimal conditions for the elective portacaval shunt: 1. Albumin over 3.0 gm./lOO ml. 2. BSP less than 25 per cent retention 3. Prothrombin greater than 50 per cent of normal 4. Bilirubin levels below 2 mg./lOO ml. 5. Cholesterol esters 33 per cent or more of total cholesterol 6. Flocculation tests 1-!- or less It is realized that many patients requiring emergency shunt procedures will not fulfill these requirements; these criteria, therefore, are to be viewed as relative, rather than absolute.

OTHER USES OF HEPATIC FUNCTION TESTS

The diagnosis of massive upper gastrointestinal bleeding may rest between esophageal varices and bleeding peptic ulcer. Although the bromsulphalein test is often elevated in both conditions, 25 per cent retention strongly indicates hepatic cirrhosis with varices. A history of alcoholism, clinical findings of liver stigmata, and x-ray studies may substantiate the diagnosis. Hepatic function tests are used for screening nonjaundiced patients suspected of having hepatic injury. This problem also arises with exposure to industrial poisons, overdosage or untoward reactions from drugs, and in the patient suspected of a preicteric viral hepatitis. Bromsulphalein retention tests, serum bilirubin, flocculation tests, urinary urobilinogen, hippuric acid, and galatose clearance tests are most frequently used in these instances. Successful relief of extrahepatic obstruction is indicated by the reduction of serum bilirubin and the appearance of urobilinogen in the urine. There may be some delay in the return of the alkaline phosphatase to normal levels. Serial hepatic function tests at intervals of several days have been used to follow the course of the disease and to give forewarning of imminent hepatic failure. Ominous signs include a sudden decrease in the plasma total cholesterol, a decrease of esterified cholesterol to 33 per cent of the total cholesterol, a rapid rise in serum bilirubin, a prothrombin time of less than 20 per cent with no significant response to parenteral vitamin K administration, a marked decrease in the serum cholinesterase and a rise in nonprotein nitrogen and aminoaciduria. In very severe cases of hepatic insufficiency, low blood urea nitrogen and nonprotein nitrogen have been associated with increased levels of blood amino acids. Under these conditions the rate of hepatic uptake of amino acids and the rate of hepatic synthesis of urea are decreased. In the less severe cases, however, there is

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more commonly an elevation of blood urea, which may have been augmented by renal impairment.

SUMMARY

Interpretation of hepatic tests is obfuscated by the fact that hepatic metabolism is so inextricably interrelated with that of other organs. Furthermore, each of the numerous, presently available hepatic tests measures a specific function rather than a specific, etiologic agent. A brief review was made of normal and abnormal bilirubin metabolism as well as other metabolic abnormalities in terms of the rates of the various reactions. In this context, evaluation of hepatic function tests in the differential diagnosis of jaundice, upper gastrointestinal hemorrhage, and pre- and postoperative management of the patient with liver disease was discussed. 629 South Wood Street, Chicago, Illinois 60615