Laboratory tests and diagnostic procedures in evaluation of liver disease

REVIEWS

Laboratory Tests and Diagnostic Procedures in Evaluation of Liver Disease

SANJIV CHOPRA, M.D.

West Roxbury, Massachusetts

PATRICK H. GRIFFIN, M.D.

Boston, Massachusetts

From the Division of Gastroenterology, Depart- ment of Medicine, West Roxbury Veterans Ad- ministration Medical Center, West Roxbury, Massachusetts, Brigham and Women’s Hospital, Boston, Massachusetts, and Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Sanjiv Chopra, Department of Medicine, West Roxbury Veterans Administration Medical Center, 1400 VFW Park- way, West Roxbury, Massachusetts 02132. Manuscript accepted September 11, 1984.

Evaluation of liver disease can be a difficult and imposing problem for general internists and noninternists alike. Physicians are often faced with a confusing array of what are commonly referred to as “liver function tests”; indeed, with the advent of and commonplace use of automated serum testing batteries, these findings are in- creasingly frequent in asymptomatic persons. Abnormalities in liver function are occasionally discovered incidentally when the testing battery is performed without suggestion of liver disease. There are numerous examples of algorithms and flow diagrams designed with an aim toward aiding clinicians in completion of an adequate diagnostic evaluation when faced with a particular set of abnormalities on “liver function tests.” However, a clearer understanding of these tests and others, which are in a broader sense tests of liver function, might be of greater value than such a systemattc and regimented approach to the evaluation of liver disease.

An ideal liver function test would be one sensitive enough to detect minimal liver disease, specific in pointing to a particular derangement in liver function, and capable of reflecting the severity of the underlying pathophysiologic problem. No such laboratory test exists. As such, the term “liver function tests” generally refers to a group of serologic tests that evaluate different aspects of liver function [l-4], and one that is best utilized in concert with the total clinical context and in conjunction with serial determinations to ascertain the course or ev- olution of the hepatic disorder. In addition, certain stool and urine tests, radionuclide imaging, contrast cholangiography, and histologic assessment (liver biopsy) are often utilized to delineate the nature of the liver disease and as such may be viewed in a broad context as tests of liver function.

SERUM TRANSAMINASES

Serum glutamic oxaloacetic transaminase, also referred to as as- partate aminotransferase, and serum glutamic pyruvic transaminase, also calied alanine aminotransferase, are commonly employed to ascertain liver function. Striking elevations (in the thousands) in the serum levels of glutamic oxaloacetic transaminase, a mitochondrial enzyme, and glutamic pyruvic transaminase, a cystosolic enzyme, are encountered in acute viral hepatitis, acute drug- or toxin-induced liver damage, and ischemic hepatitis [3,4]. The height of the elevation does not, however, correlate with extent of liver cell necrosis evident on liver biopsy and therefore has no predictive prognostic value. Rapidly decreasing transaminase levels together with a rising bilirubin level and prolongation of the prothrombin time portend a very poor

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DIAGNOSTIC APPROACHES IN LIVER DISEASE-CHOPRA and GRIFFIN

prognosis. In all these conditions, the transaminase levels usually return to normal over several weeks to months with resolution of the primary hepatic disorder: the exception is ischemic hepatitis, wherein the transaminase levels often return to normal within days as the hypotension or left ventricular failure is corrected or alleviated.

The transaminase elevations are mild to modest in alcoholic hepatitis. Characteristically, the glutamic oxaloacetic transaminase level is much higher than the gtutamic pyruvic transaminase level (glutamic oxaloacetic transaminase to glutamic pyruvic transaminase ratio greater than 2: 1, which is very suggestive of alcoholic hepatitis and cirrhosis) and elevations greater than 500 IU in either transaminase level are distinctly unusual [ 51.

In patients with extrahepatic obstruction, both transaminase levels are almost invariably less than 1,000 IU. Persistent elevations above this level would be distinctly rare for uncomplicated extrahepatic obstruction.

Significant elevations of transaminase levels have been noted in a few normal, healthy subjects while consuming a diet of conventional foods containing 25 to 30 percent of total calories as sucrose [6]. False- positive elevations in glutamic oxaloacetic transaminase levels have been reported in patients receiving erythromycin estolate [7] or para-aminosalicylic acid and during diabetic ketoacidosis, when the glutamic oxaloacetic transaminase level has been determined by calorimetric assay. The opposite, that is, falsely lowered (sometimes absent) glutamic oxaloacetic transaminase values, has been observed in azotemic patients [8]. This phenomenon is most marked when the SMA 12/60 autoanalyzer is used. Glutamic oxaloacetic transaminase activity increases significantly after hemodialysis, but the inhibitor does not appear to be urea per se.

Although elevations in transaminase levels may be the first laboratory signal of liver disease (preicteric phase) or the only signal (anicteric hepatitis) to a physician, it is important to remember that significant liver damage may be present in a patient with normal levels of transaminases. Specifically, transaminase levels are often normal in patients with hemochromatosis, patients receiving methotrexate, or following jejuneileal bypass operations, despite advanced liver disease. Contrari- wise, “unexplained” (normal liver biopsy results) elevations of both transaminase levels may have their basis in a primary muscle disorder. Although alcohol dehydrogenase is present in large amounts in the liver only and ornithine transcarbamylase is apparently located only in liver tissue, serum assays for these enzymes have not been shown to be more advantageous than tests for the transaminases and are therefore not routinely performed in the clinical laboratory.

ALKALINE PHOSPHATASE

Serum alkaline phosphatase activity may originate from liver, bone, intestine, or placenta. On rare occasions, patients with a variety of malignant tumors may have elevations in the serum alkaline phosphatase level that are not caused by liver or bony metastases. This isoenzyme, referred to as Regan isoenzyme, is bioche- mically and immunologically indistinguishable from placental alkaline phosphatase, and in addition to being present in serum, can also be present in tumor tissue or in malignant effusion fluids [9].

In normal children with active bone growth, influx of enzyme from osteoid tissue may result in a threefold elevation above normal in alkaline phosphatase values. In the third trimester of pregnancy, the serum level may double as a consequence of the contribution of placental alkaline phosphatase, making interpretation of results of this test difficult during the latter stage of pregnancy. Also, persons over the age of 50 years may normally have one and a half times normal values. Subjects with blood groups 0 and B, who are ABH se- cretors and Lewis antigen-positive, may have a significant amount of intestinal alkaline phosphatase in their serum, especially after ingestion of a fatty meal [lo]. Thus, unlike other enzymes in the serum, the activity of alkaline phosphatase can be noticeably affected by eating; hence, it is recommended that alkaline phosphatase activity be assayed in the fasting state.

Very high levels of serum alkaline phosphatase are found in patients with osteoblastic bone disorders or with cholestatic-both intrahepatic and extrahepatic-disease. In patients with jaundice, separation of intrahepatic cholestasis (e.g., primary biliary cirrhosis, granulomas in the liver, etc.) from extrahepatic obstruction (e.g., stone, stricture, “silent” malignancy) is not possible on the basis of the height of the serum alkaline phosphatase level [ Ill.

Although an elevation of the serum alkaline phosphatase level may be the first clue to hepatobiliary disease, the alkaline phosphatase level is normal on rare occasions despite extensive metastatic hepatic deposits or complete bile duct obstruction.

Patients with stage I or II Hodgkin’s disease, hyper- nephroma, congestive heart failure, myeloid metaplasia, peritonitis, diabetes, subacute thyroiditis [ 121, or uncomplicated gastric ulcer have been reported to have mild elevations in serum alkaline phosphatase levels that are of probable liver origin in the absence of overt liver involvement. Recently, twofold to fourfold elevations in serum alkaline phosphatase levels were reported in several members of a family [ 131. No bone or hepatic disorder was present in this family, who demonstrated the enzyme elevation in a pattern suggesting autosomal dominant inheritance. In this context, the elevation of the serum alkaline phospha-

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tase level may be no more specific than that of an elevated sedimentation rate, and the routine use of automated biochemical tests has indeed increased awareness of this phenomenon.

The most reliable method of determining the tissue origin of an elevated alkaline phosphatase level is polyacrylamide gel electrophoresis. Since this is not routinely available in most clinical laboratories and since methods using urea denaturation or heat inactivation are quite unreliable, it is common practice to measure serum 5’-nucleotidase, gamma glutamyl transpeptidase, or leucine aminopeptidase when dealing with an iso- lated or disproportionately elevated serum alkaline phosphatase level. In such instances, elevations of the levels of any of these three enzymes generally imply that the source of the elevated alkaline phosphatase level is hepatobiliary and not bony. Leucine aminopeptidase and 5’-nucleotidase levels may increase in normal pregnancy, whereas gamma glutamyl transpeptidase levels do not. However, commonly used drugs such as barbiturates, phenytoin, and alcohol may cause induction of hepatic microsomal gamma glutamyl transpeptidase; therefore, an elevated serum level of this enzyme does not necessarily imply frank liver cell injury. A disproportionately elevated serum gamma glutamyl transpeptidase level for several days often follows moderate alcohol ingestion. This finding is used by many physicians to detect alcohol abuse in patients who underestimate or deny the ingestion of alcohol.

SERUM LACTATE DEHYDROGENASE

Serum lactate dehydrogenase activity may arise from myocardium, liver, skeletal muscle, brain or kidney tissue, and red blood cells [ 141. Therefore, an elevated serum lactate dehydrogenase value is a nonspecific finding. The hepatic origin (lactate dehydrogenase 5) of serum lactate dehydrogenase can be verified by isoenzyme determination. Increased lactate dehydrogenase levels are seen in patients with a variety of hepatobiliary disorders including acute viral or drug hepatitis, congestive heart failure, cirrhosis, and extrahepatic obstruction. Striking elevations in serum lactate dehydrogenase and alkaline phosphatase levels are highly suggestive of metastatic disease to the liver.

SERUM BILIRUBIN

Most clinical laboratories use spectrophotometry to measure serum bilirubin. The normal value for total bilirubin is less than 1 mg/dl. Two fractions-a conjugated or direct fraction (normally less than 0.25 mg/dl) and an unconjugated or indirect fraction-are obtained fairly routinely. It is useful to classify hyperbilirubinemia into conjugated and unconjugated categories. Patients are considered to have conjugated hyperbilirubinemia if greater than 50 percent of the elevated total bilirubin


level is conjugated, and categorized as having unconjugated hyperbilirubinemia if greater than 80 percent of the total bilirubin level is unconjugated or indirect- reacting. Mild unconjugated hyperbilirubinemia (total bilirubin level less than 5 mg/dl) is seen in Gilbert’s disease, uncomplicated hemolytic disorders, and congestive heart failure. Mild conjugated hyperbilirubinemia is a constant finding in the Dubin-Johnson and Rotor syndromes. Conjugated hyperbilirubinemia of varying intensity is seen in a variety of liver disorders including acute viral, drug-induced, and toxin-induced hepatitis, shock liver, and metastatic disease to the liver. Even in fulminant hepatitis, the liver is capable of conjugating the bilirubin.

The height of the serum bilirubin level has no discriminative value in distinguishing intrahepatic cholestasis from extrahepatic obstruction. Indeed, fairly marked elevations in total serum bilirubin levels have been reported in patients with non-biliary tract sepsis [ 15,161. Although patients with fulminant hepatitis may be anicteric, the level of serum bilirubin is of prognostic import in certain conditions such as alcoholic hepatitis, primary biliary cirrhosis, and halothane hepatitis. In primary biliary cirrhosis, persistent elevations of greater than 2.0 mg/dl in the serum total bilirubin level usually occur late in the course of the disease and imply a poor prognosis [ 171. Bilirubin levels greater than 10 mg/dl have been associated with a 60 percent mortality in patients with halothane hepatitis [ 181. Recently, with the use of alkaline methanolysis and high-performance liquid chromatography [ 191, it has been shown that all of the serum bilirubin in normal subjects and patients with Gilbert’s disease is unconjugated. It has been suggested that the detection of any conjugated bilirubin using this assay is indicative of hepatobiliary disease and would be of value in patients without overt jaundice.

URINE BILIRUBIN

The presence of bilirubin in the urine implies that it is direct bilirubin that is present, as indirect bilirubin is tightly bound to albumin and hence not filtered by the normal kidney. This inexpensive and sensitive test serves several functions: a positive result can rapidly confirm clinically suspected hyperbilirubinemia; it implies hepatobiliary disease and excludes hemolysis; and it may provide an early clue to the presence of hepatobiliary dysfunction, as presence of urine bilirubin often antedates overt icterus.

URINE UROBILINOGEN

Urobilinogen results from the breakdown of conjugated bilirubin by intestinal bacteria. Normal excretion in stool averages 100 mg per day. About 10 to 20 percent is absorbed into the portal circulation, from where most of it undergoes entero-hepatic circulation. A small



amount, usually less than 2 mg per day, is excreted in the urine. Although urinary estimation is dependent upon several factors including urine pH, rate of urine pro- duction, timing of collection (there is a diurnal variation), and method employed, complete absence of urinary urobilinogen implies absence of bilirubin in the intestine and strongly suggests complete bile duct obstruction. Increased urinary urobilinogen suggests hemolysis of hepatic dysfunction. Elevated levels might be expected in spontaneous or surgical portosystemic shunts.

FECAL UROBILINOGEN

Fecal urobilinogen estimations are arduous and require several days’ collection of stool. Increased values almost always signify overproduction of bile pigments as occurs in hemolytic disorders or in shunt hyperbilirubinemia.

coagulation wherein factor VIII levels are generally decreased. Vitamin Kdependent factors include factors II, VII, IX, and X. A prolongation of the prothrombin time beyond four seconds that of control despite vitamin K administration (5 to 10 mg parenteral vitamin K; prothrombin time measurement repeated 24 hours later) signifies fairly advanced liver disease [21]. The prognostic significance of a markedly elevated prothrombin time is exemplified by the 100 percent mortality reported in a study of patients with halothane hepatitis who had a prothrombin time greater than 20 seconds [22]. Other clinically relevant aspects of abnormalities in coagulation include the necessity to correct these factor deficiencies in patients with significant bleeding and the fact that certain procedures such as liver biopsy are contraindicated in patients with a significant coagulopathy.

SERUM ALBUMIN AND GLOBULIN ALPHA FETOPROTEIN

Albumin is synthesized exclusively by hepatic paren- chymal cells and has a serum half-life of about 20 days. Decreased levels in the serum can occur as a consequence of decreased synthesis or excessive losses. The former occurs in patients with malnutrition or significant liver disease [20]. Hypoalbuminemia secondary to excessive loss of albumin is seen in patients with nephrotic syndrome or protein-losing enteropathy.

A fall in the serum albumin level and a rise in levels of globulins, primarily gamma globulins, are freqently seen in patients with chronic hepatitis or cirrhosis. El- evations in IgA levels are common in alcoholic cirrhosis, and elevations in IgG levels are common in chronic active hepatitis. Elevations in IgM levels are frequently seen in primary biliary cirrhosis; of the immunoglobulins, only an elevation of the IgM fraction on immunoelec- trophoresis has any significant specificity.

Alpha fetoprotein is a unique alpha-l-globulin normally synthesized in large amounts by embryonic liver cells and in trace amounts by fetal yolk sac cells and the fetal gastrointestinal tract. High serum concentrations (greater than 500 rig/ml by radioimmunoassay) are present in 70 percent of patients with primary hepatocellular carcinoma in the United States [23]. Concen- trations of this protein fall dramatically in patients in whom partial curative hepatectomy is carried out. Serial determinations aid in monitoring the response to therapy or detecting early recurrence.

Diminished levels of alpha-l-globulins due to defi- cient alpha-l-antitrypsin activity can be associated with chronic active hepatitis and cirrhosis in children and adults.

Patients with yolk sac tumors with germ cell elements may also have high concentrations of alpha fetoprotein. Modest elevations may be seen occasionally with other tumors, notably gastrointestinal malignancies metastatic to the liver. Levels up to 500 rig/ml are seen during pregnancy. High levels indicate multiple pregnancy, significant fetal neural tube defects, fetal distress, or fetal death.

SERUM FERRITIN

COAGULATION FACTORS

All the clotting factors are synthesized by the liver, with the exception of factor VIII, which is synthesized by reticuloendothelial cells and vascular endothelial cells. The half-life of these coagulation factors is short, ranging from six hours for factor VII to five days for fi- brinogen. Therefore, acute liver injury often results in a prolongation of the prothrombin time, which is dependent upon the activity of factors II, V, VII, and X. Factor VIII levels may be normal or increased in severe hepatic injury; hence, assessment of factor VIII levels may help distinguish the coagulopathy of liver disease from that secondary to disseminated intravascular

Serum ferritin levels accurately reflect hepatic and total-body iron stores. Serum ferritin levels are low in iron deficiency and elevated in iron overload disorders such as genetic idiopathic hemochromatosis. Occa- sionally, normal levels of serum ferritin may be found in patients with precirrhotic hemochromatosis. Serum ferritin levels may be elevated in the absence of iron overload in patients with hepatocellular necrosis, Hodgkin’s disease, lymphoma, lymphocytic leukemia, rheumatoid arthritis, uremia, or hyperthyroidism. Mea- surement of serum iron concentration, percent trans- ferrin saturation, and serum ferritin level is the screening regimen currently recommended for idiopathic genetic hemochromatosis [ 241.


ANTIMITOCHONDRIAL ANTIBODY

This autoantibody can be detected in the serum by a variety of methods including immunofluorescence, double immunodiffusion, complement fixation, radioimmunoassay, and enzyme-linked immunoassay. Mi- tochondrial antibodies are found in 0.8 to 1.6 percent of the general population, 6 percent of patients with cryptogenic cirrhosis, 10 percent of patients with chronic active hepatitis, and 85 to 90 percent of patients with primary biliary cirrhosis [25]. Antimitochondrial antibodies are also found in a significant number of asymptomatic relatives of patients with primary biliary cirrhosis and chronic active hepatitis. Although the antibody titer has no discriminative value in distinguishing patients with primary biliary cirrhosis from patients with a variety of other hepatobiliary disorders or autoimmune conditions, recent studies suggest that the mitochondrial antibodies seen in disorders other than primary biliary cirrhosis can be differentiated from those that appear to be specific for primary biliary cirrhosis on the basis of characteristic immunofluorescent patterns that they mediate in rat and human tissues or the effects of trypsin pretreatment of such tissue sec- tions on immunofluorescent staining [26,27]. Mito- chondrial antibodies directed against a purported specific primary biliary cirrhosis antigen are believed to have high diagnostic relevance, and it has been stated that when such antibodies are not detected in the serum, a diagnosis of primary biliary cirrhosis should be made with caution and only after a careful period of clinical follow-up [28]. Mitochondrial antibodies appear to play no part in the pathogenesis of primary biliary cirrhosis and provide no useful prognostic insight in this disorder.

SERUM CERULOPLASMIN

Ceruloplasmin, a blue copper-containing glycoprotein, is an acute-phase reactant. Ninety-five percent of patients with Wilson’s disease have serum ceruloplasmin concentrations below 20 mg/dl. Ten percent of het- erozygotes have low ceruloplasmin levels but remain healthy. Low concentrations may also be seen in patients with fulminant hepatitis unrelated to Wilson’s disease, nephrotic syndrome, and protein-losing enteropathy.

BILE ACIDS

Serum levels of bile acids can be measured by sensitive chromatography techniques and radioimmunoassays [29]. Measurements can be made in the fasting state, two hours postprandially, and following intravenous isotopic administration (bile acid tolerance test). The cost of the test and the need for appropriate facilities


in the laboratory limit the usefulness of these tests, which currently appear to be not significantly superior to more routine and readily available tests. In addition, an abnormal test result does not discriminate between hepatocellular and cholestatic liver disease.

SULFOBROMOPHTHALEIN SODIUM

When injected intravenously, sulfobromophthalein sodium is fairly rapidly and exclusively cleared by the liver. Five milligrams per kilogram of body weight are injected intravenously, and serum determinations are made at 30 and 45 minutes. Normal subjects retain less than 10 percent at 30 minutes and less than 5 percent at 45 minutes. The test is a measure of hepatic excretory function and is dependent upon hepatic blood flow. In the Dubin-Johnson syndrome, an initial fall is followed by a characteristic secondary rise at 45 to 90 minutes, as the conjugated sulfobromophthalein sodium cannot be excreted at the canalicular level and “regurgitates” into the bloodstream [30]. Local extravasation of sulfobromophthalein sodium dye at the injection site is painful. On rare occasions, a severe systemic reaction (possibly fatal) can occur. Because of these reasons, this test has been largely abandoned in general clinical use.

BLOOD AMMONIA

Ammonia arises from bacterial degradation of nitrog- enous contents (dietary protein, blood) in the intestine. Although the blood and cerebrospinal fluid ammonia levels are elevated in most patients with hepatic coma, there is a poor correlation between blood ammonia level and the degree of hepatic encephalopathy [31]. The correlation is better with arterial ammonia as compared with venous ammonia, which may be increased by muscular exercise, seizure activity, or even clenching the fist. Serial values of arterial ammonia are occasionally helpful in following individual patients. Elevations in arterial blood ammonia levels have also been recognized in patients with portosystemic shunting or inborn disorders of urea metabolism, and in patients following ureteroileostomy. Blood ammonia measurements are of limited utility in the evaluation of most patients with known hepatobiliary disease. Its greatest usefulness may be in evaluating patients with coma or altered mental status of unclear cause. In such patients, an elevated arterial ammonia concentration would suggest hepatocellular dysfunction as an important contributing factor.

SERUM LIPIDS AND LIPOPROTEINS

Patients with cholestatic disorders (both intrahepatic and extrahepatic) frequently have an elevation in the concentration of serum phospholipids and unesterified



cholesterol. Skin xanthomas commonly appear if the total serum cholesterol level exceeds 450 mg/dl for longer than three months. The major component of unesterified cholesterol is an abnormal low-density lipoprotein designated lipoprotein X [32]. Contrary to earlier claims, quantitation of serum lipoprotein X levels is not helpful in distinguishing intrahepatic cholestasis from extrahepatic obstruction. Patients with cirrhosis or malignant biliary obstruction who are malnourished may have low total serum cholesterol levels.

BREATH TESTS

Several radiolabeled compounds have been used to assess hepatic function in humans. Most studies have employed 14C aminopyrine. The test is inexpensive and entails minimal radioactive exposure to patients (generally, less than 0.5 @i per test) but should not be performed in children or pregnant women. Studies in humans suggest that the aminopyrine test (‘4C02-a metabolic product of the methyl group of aminopyrine-is measured) is an indirect measure of mixed- function oxidase mass [33]. Although not yet widely available, breath tests may emerge as excellent noninvasive screening tests for detecting liver disease or prove useful in the periodic follow-up of patients in whom liver biopsy is contraindicated.

HEPATIC SCINTISCANNING

Technetium-99m sulfur colloid is taken up selectively by the reticuloendothelial cells and is used commonly in clinical practice. In many centers, scanning is routinely performed prior to percutaneous needle biopsy of the liver. It often provides useful information regarding the size and shape of the liver, although on occasion virtually no hepatic uptake of colloid is present in patients with severe or far-advanced liver disease. Het- erogeneous uptake of colloid by the liver with “shift” of colloid to the spleen and vertebral bone marrow is characteristic but not specific for cirrhosis of the liver. Focal defects of the liver are seen in many conditions, including hepatic cysts, hemangiomas, abscesses, tumors, amyloidosis and “regenerative” cirrhotic nodules, and peliosis hepatis. Lesions smaller than 2 cm in size and present deep within the hepatic paren- chyma may escape detection on liver scanning [34].

Hepatic scintiscanning may aid in the distinction between focal nodular hyperplasia and hepatic adenoma, as scanning usually shows normal findings in the former condition, whereas a cold defect is usually present in patients with a hepatic adenoma. Avid uptake by an enlarged caudate lobe is characteristic of Budd- Chiari syndrome. In this condition, there is occlusion of the major right and left hepatic veins. The caudate lobe has a separate arterial supply and venous drainage and

hence characteristically undergoes compensatory hypertrophy [35].

Hepatic scintiscanning is also useful in the evaluation of hepatic or splenic trauma and in the detection of remnant or accessory splenic tissue in patients who have undergone splenectomy.

HEPATOBILIARY SCANNING

Agents being used with increasing frequency for biliary scanning are technetium-99m-labeled acetanilide iminodiacetic acid derivatives (dimethyl, paraisopropyl, and diisopropyl iminodiacetic acids) [36]. These agents are rapidly taken up by functioning hepatocytes and excreted into the bile. These radiopharmaceuticals are superior to Rose-Bengal as biliary scanners. In a broad sense, they evaluate hepatic excretory function and the patency of the biliary tree. Adequate visualization is often obtained in patients with serum bilirubin levels between 5 and 10 mg/dl. Nonvisualization of the gallbladder within two hours with good visualization of the common bile duct is highly suggestive of cystic duct obstruction or calculous cholecystitis. Caution in interpretation must be exercised in those patients with concomitant hepatocellular dysfunction who exhibit poor hepatic uptake and concentration of the isotope. Dimethyl iminodiacetic acid scanning is thus most useful in excluding cystic duct obstruction and acute cholecystitis if the gallbladder is clearly visualized. Dimethyl iminodiacetic acid scanning has been used to demonstrate the gallbladder as the site of the defect observed on the inferior border of the liver on technetium-99m sulfur colloid scanning. Dimethyl iminodiacetic acid can also be used to diagnose choledochal cysts and demonstrate biliary leaks or assess the patency of biliary- enteric shunts.

ANGIOGRAPHY

Selective celiac, superior mesenteric, and hepatic angiography is employed in the evaluation of selected patients with liver disease. Enlargement of the hepatic arteries, neovascularity, arteriovenous shunting, and portal vein thrombosis are frequently encountered in patients with primary hepatocellular carcinoma. How- ever, differentiation from other primary hepatic lesions such as focal nodular hyperplasia or angiosarcoma and from vascular metastatic tumors such as hyperne- phroma, carcinoid, and choriocarcinoma is not always possible. Angiography may be useful in defining the extent of tumor and delineating the anatomic vascular supply in preparation for hepatic lobectomy. Angiog- raphy is routinely performed prior to elective shunt surgery for patients with variceal bleeding in order to define anatomy.


ULTRASONOGRAPHY

Ultrasound examination of the abdomen is a useful test in the evaluation of liver disease [37]. It is available in most hospitals, is inexpensive, and entails no radiation exposure to patients. Thus, it is particularly applicable in the evaluation of liver and biliary tract disease in children and pregnant women. Marked obesity and excessive intestinal gas can be limiting factors in ob- taining good resolution of the images.

Ultrasound examination of the liver will often identify mass lesions 1 to 2 cm in size in the hepatic paren- chyma and do this independent of hepatic function. The nature of defects seen on technetium-99m sulfur colloid scanning-solid or cystic-can readily be ascertained and it can facilitate guided aspiration of cysts or biopsy specimens of lesions. Ultrasonography is an appropriate procedure for detecting gallstones and confirming the presence of ascites; study in the fasting state is important. It is often used as the first test in the evaluation of patients with cholestatic jaundice. Dilated bile ducts can be readily seen on ultrasound examination in patients with mechanical extrahepatic biliary tract obstruction [38]. Dilation of the bile ducts may not be evident if the obstruction is incomplete or intermittent or if it has been present for a short duration. Serial ultrasound examinations may provide valuable information in these circumstances. The common bile duct is frequently dilated following cholecystectomy. There- fore, an enlarged duct in this situation does not necessarily signify ongoing biliary tract obstruction [39].

COMPUTED TOMOGRAPHIC SCANNING

This modality is useful in detecting mass lesions (cysts, tumors, abscesses) within the liver, and computed tomographic scanning with contrast enhancement can often accurately predict the nature of the lesion iden- tified. It has an advantage over ultrasound in obese patients and those with excessive gas, but its wide- spread use is limited by the high cost; an additional consideration is radiation exposure to patients. In patients with cholestatic jaundice, computed tomographic scanning can distinguish intrahepatic cholestasis from mechanical extrahepatic obstruction with an accuracy rate of 90 percent. Computed tomographic scanning after intravenous injection of iodinated contrast material has been reported to demonstrate hypertrophy of the caudate lobe, stagnation of contrast material at the periphery of the liver, narrowing of the inferior vena cava in its intrahepatic section, and failure of opacifi- cation of the major hepatic veins in patients with Budd-Chiari syndrome [40]. This constellation of findings appears to be specific for Budd-Chiari syndrome, although further confirmatory experience is necessary


before this diagnosis can be confidently made in the absence of liver biopsy or venography.

Recently, hepatic computed tomography has been used to evaluate iron overload in the liver. It appears to be moderately sensitive and highly specific for this purpose. Dual-energy computed tomography, although technically more difficult, may provide a very accurate, relatively noninvasive method of measuring hepatic iron concentration in patients with precirrhotic idiopathic hemochromatosis [41].

Computed tomographic scanning can also be useful in assessing liver fat content [42]. Monoenergetic computed tomographic scanning has been shown to accurately (good agreement with histologic and chemical liver fat determination) predict liver fat content in patients with alcoholic liver disease.

PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY

Percutaneous transhepatic cholangiography using a “skinny” Chiba needle is performed in most institutions by skilled radiologists. The success rate with multiple passes approaches 90 to 95 percent in patients with extrahepatic biliary tract obstruction and 70 percent in patients with intrahepatic cholestasis and normal-sized bile ducts [43]. It is considered by many to be the procedure of choice for demonstrating the site and possible nature of the lesion in patients with cholestatic jaundice in whom an ultrasound examination reveals dilated intrahepatic bile ducts [44]. Likewise, percutaneous transhepatic cholangiography is preferred over endoscopic retrograde cholangiopancreatography in patients with surgically distorted gastroduodenal anatomy such as following hemigastrectomy and Billroth II anasto- mosis [45]. Marked ascites and irreversible coagulopathy are contraindications to this procedure. Serious complications occur in about 5 percent of patients and include cholangitis, hemorrhage, bile peritonitis, pneumothorax, and drug reaction, and are responsible for a 0.5 percent attendant mortality.

ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY

This procedure is usually performed by a gastroenter- ologist and has a success rate of 80 to 90 percent in skilled hands. Recent pancreatitis is a contraindication to this procedure. Serious complications occur in about 5 percent of patients and include pancreatitis, instru- mental injury, cholangitis, sepsis, and aspiration pneumonia. Endoscopic retrograde cholangiopancreatography would appear to be the procedure of choice if periampullary carcinoma, common duct stones, or postcholecystectomy biliary tract disease is



strongly suspected on clinical grounds [46]. In patients with common duct stones, endoscopic papillotomy may provide definitive therapeutic benefit.

Since the reported success rate and incidence of serious complications are similar with percutaneous transhepatic cholangiography and endoscopic retrograde cholangiopancreatography, the choice between the two is often dictated by the skills of the persons performing these tests and often has to be made on a case-by-case basis [47].

NEEDLE BIOPSY OF THE LIVER

Percutaneous needle biopsy of the liver is a commonly utilized and safe procedure that can be performed at the bedside. It often provides precise and accurate tissue diagnosis without resorting to general anesthesia and laparotomy, and most agree that it can be performed as an outpatient procedure provided facilities are available for short-term observation and hospitalization should the need arise [48]. Accepted indications for liver biopsy include hepatocellular disease of uncertain cause, unexplained hepatomegaly and/or splenomeg- aly, hepatic filling defects demonstrated by radionuclide scanning, ultrasound examination, or computed tomographic scanning, chronic hepatitis, fever of unknown origin, and staging of malignant lymphoma. Liver biopsy is often helpful in the evaluation of patients with clinically suspected alcoholic liver disease to confirm the diagnosis and ascertain the severity of damage to the liver and in the evaluation of patients with portal hypertension. Liver biopsy is the single best “liver function test” (the gold standard) in documenting hemochromatosis, Wilson’s disease, certain varieties of glycogen storage disease, and type I Crigler-Najjar syndrome. Liver biopsy is not particularly helpful in distinguishing intrahepatic from extrahepatic obstruction. Although liver biopsy is not apparently associated with an excessive risk of complications in patients with extrahepatic obstruction [49], the pathognomonic features of extrahepatic obstruction-a bile infarct with feathery degeneration of surrounding hepatocytes-are not invariably present. Additionally, it provides no information regarding the site or nature of the obstructing lesion. With the advent of imaging modalities to visualize the extrahepatic biliary tree, needle biopsy of the liver is rarely performed today when extrahepatic obstruction is suspected.

Contraindications for percutaneous needle biopsy of the liver include uncooperative or comatose patients, hydatid cyst disease, hemangioma or angiosarcoma of the liver, right pleural disease or local infection at the proposed biopsy site, and significant coagulopathy. Arbitrarily employed contraindications include a prolongation of the prothrombin time greater than four seconds over control, a partial thromboplastin time

greater than 15 seconds over control, and a platelet count less than 75,000/mm3. A bleeding time should be obtained in patients with borderline clotting abnormalities or uremia, and in those taking antiplatelet drugs. In patients with a severe coagulopathy, the transvenous (transjugular) approach may be used [50,51]. In this technique, a catheter is placed in the jugular vein and manipulated into a hepatic vein. If bleeding occurs, it occurs within the vascular system itself. Amyloidosis is not a contraindication unless the liver is very mas- sively enlarged or there is an associated bleeding ten- dency. Tense ascites and severe anemia are relative contraindications. Complications are numerous but rare and the overall mortality rate is less than 0.02 percent. The incidence of complications appears to increase significantly if multiple passes (greater than four using the transthoracic route) are employed. The most common untoward effect is pain at the biopsy site or right shoulder, occurring in less than 5 percent of patients. Moderate to severe pain with or without hypotension usually manifests within the first three hours of the procedure. Serious bleeding occurs in less than 0.3 percent of patients, although asymptomatic subcapsular or intrahepatic hematomas are probably considerably more common [52,53]. Extremely rare serious se- quelae include pneumothorax, hemothorax, hemobilia, arteriovenous fistula formation, and perforation of colon or gallbladder. If suspicion for highly vascular tumors such as carcinoid is high, angiography or nuclear medicine flow scanning should be performed before percutaneous biopsy. Suspected hepatoma is not a contraindication to biopsy. Liver biopsy in unsuspected echinococcal cyst disease can be followed by dis- semination of daughter scoleces or fatal anaphy- laxis.

PERITONEOSCOPY AND LAPAROTOMY

Peritoneoscopy may be performed using local anesthesia and mild sedation. It permits adequate visualization of the anterior surface of the liver, gallbladder, and stomach as well as parts of the small intestine and colon [ 541. It has proved useful in the diagnosis by direct visual inspection and directed needle biopsy of a variety of hepatic disorders including cirrhosis, hepatomegaly, hepatic malignancy, and portal hypertension. Peritoneoscopy has helped in determining the cause of ascites and in the staging of Hodgkin’s disease. Con- traindications include tense ascites, an uncooperative patient, marked obesity, surgical abdominal scars, and severe coagulopathy. Serious complications occur in 1 to 2 percent of patients and include air embolism, subcutaneous emphysema, ascites leak, bowel perforation, and hemorrhage. The overall mortality rate is approximately 0.03 percent.



Laparotomy is now seldom performed for the express purpose of diagnosing hepatobiliary disease. On occasion, however, it is necessary to undertake this procedure to obtain biopsy and culture material and perform operative cholangiography.

The increasing availability of and familiarity with the vast array of both noninvasive (e.g., ultrasonography, computed tomographic scanning, dimethyl iminodiacetic acid scanning, etc.) and invasive (e.g., skinny

needle transhepatic cholangiography, endoscopic retrograde cholangiopancreatography, angiography, liver biopsy, etc.) hepatic tests have resulted in the in- frequent use of peritoneoscopy and laparotomy for the evaluation of hepatobiliary disease.

ACKNOWLEDGMENT

We are grateful for the secretarial assistance of Ms. Sandra Petkus.

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Laboratory tests and diagnostic procedures in evaluation of liver disease

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