Articles on Medical Diseases and Conditions

Category: Liver and Biliary Tract Tests

Liver and Biliary Tract Tests

  • Acute Hepatitis Virus Hepatitis

    Hepatitis virus B will be used as a model here. After an incubation period, acute viral hepatitis most often begins with some combination of GI tract symptoms, fever, chills, and malaise, lasting 4-7 days. During this phase there is no clinical jaundice. Leukopenia with a relative lymphocytosis is common, and there may be a few atypical lymphocytes. Hemoglobin values and platelet counts usually are normal. Liver function tests reflect acute hepatocellular damage, with AST and ALT values more than 10 times the upper reference limit and usually more than 20 times the upper limit. ALP is usually elevated; values typically are less than 3 times the upper reference limit, but some patients may have elevation even higher than 5 times the upper limit. Lactic dehydrogenase (LDH) is usually less than 3 times normal. Serum bilirubin values begin climbing toward the end of this initial phase. The next development is visible jaundice; during this period, clinical symptoms tend to subside. The serum bilirubin level continues to rise for a time, then slowly falls. Both conjugated and unconjugated fractions are increased. The ALP level often begins to fall shortly after clinical icterus begins. The AST level begins to decrease about 1-2 weeks after it reaches its peak. A convalescent phase eventually ensues, with return of all test values to normal, beginning with the ALP. Some patients continue to manifest a low-grade hepatitis (chronic persistent or chronic active), reflected by variable and intermittent AST abnormalities (usually mild or moderate in degree) with or without ALP elevation. The majority of patients (75%-80%) never develop jaundice during viral hepatitis; this condition is known as “anicteric hepatitis.” In such situations, function tests reveal mild to moderate acute hepatocellular damage with a minimal obstructive component.

    The textbook picture of AST more than 20 times (especially when over 25 times) the upper reference range limit (see the box), an ALT level greater than or equal to AST; with ALP mildly elevated and GGT mildly or moderately elevated, is strongly suggestive of hepatitis virus hepatitis. Other liver disorders that may be associated with an AST level over 20 times the upper reference limit include a small minority of patients with drug-induced liver injury (especially acetaminophen overdose), active alcoholic cirrhosis, a few cases (2%) of infectious mononucleosis, and some cases of severe liver passive congestion, as well as a few patients with early “atypical” extrahepatic obstruction. In addition, there are nonhepatic etiologies for markedly elevated AST, such as acute myocardial infarct and severe skeletal muscle injury. The patient may not be seen until the early convalescent phase, or the patient may have a mild anicteric episode. If so, the AST level may have decreased to less than 20 times the upper reference limit, and the differential diagnosis includes a wide variety of conditions, such as subsiding hepatitis, chronic hepatitis, alcoholic and active cirrhosis, infectious mononucleosis or cytomegalovirus infection, liver congestion, drug-induced liver dysfunction, liver space-occupying lesions, and severe fatty liver.

    Chronic hepatitis is usually associated with AST values less than 20 times the upper reference limit and usually less than 10 times the upper limit. However, one study reported that about 15% of persons with the category of chronic hepatitis known as “chronic active hepatitis” had AST values at some time greater than 20 times the upper reference limit.

  • Liver Biopsy

    This procedure has been greatly simplified, and its morbidity and mortality markedly reduced, by the introduction of small-caliber biopsy needles such as the Menghini. Nevertheless, there is a small but definite risk. Relative contraindications to biopsy include a PT in the anticoagulant range or a platelet count less than 50,000/mm3. Liver biopsy is especially useful in the following circumstances:

    1. To differentiate among the many etiologies of liver function test abnormality when the clinical picture and laboratory test pattern are not diagnostic. This most often happens when the AST level is less than 10 or 20 times the upper reference limit and the ALP level is less than 3 times the upper limit. In cases of possible obstructive jaundice, extrahepatic obstruction should be ruled out first by some modality such as ultrasound.
    2. To prove the diagnosis of metastatic or primary hepatic carcinoma in a patient who would otherwise be operable or who does not have a known primary lesion (in a patient with an inoperable known primary lesion, such a procedure would be academic).
    3. In hepatomegaly of unknown origin whose etiology cannot be determined otherwise.
    4. In a relatively few selected patients who have systemic diseases affecting the liver, such as miliary tuberculosis, in whom the diagnosis cannot be established by other means.

    A discussion of liver biopsy should be concluded with a few words of caution. Two disadvantages are soon recognized by anyone who deals with a large number of liver specimens. First, the procedure is a needle biopsy, which means that a very small fragment of tissue, often partially destroyed, is taken in a random sample manner from a large organ. Localized disease is easily missed. Detection rate of liver metastases is about 50%-70% with blind biopsy and about 85% (range, 67%-96%) using ultrasound guidance. Second, many diseases produce nonspecific changes that may be spotty, may be healing, or may be minimal. Even with an autopsy specimen it may be difficult to make a definite diagnosis in many situations, including the etiology of many cases of cirrhosis. The pathologist should be supplied with the pertinent history, physical findings, and laboratory data; sometimes these have as much value for interpretation of the microscopic findings as the histologic changes themselves.

    In summary, liver biopsy is often indicated in difficult cases but do not expect it to be infallible or even invariably helpful. The best time for biopsy is as early as possible after onset of symptoms. The longer that biopsy is delayed, the more chance that diagnostic features of the acute phase have disappeared or are obscured by transition to healing.

  • Endoscopic Retrograde Choledochopancreatography

    Endoscopic retrograde choledochopancreatography entails passing a special endoscopic tube system into the duodenum, entering the pancreatic duct or the common bile duct with the end of a cannula, and injecting x-ray contrast material. The procedure is used predominantly for diagnosis of pancreatic disease, but it may occasionally be helpful in equivocal cases of biliary tract obstruction. Cannulating the common bile duct is not easy, and best results are obtained by very experienced endoscopists.

  • Percutaneous Transhepatic Cholangiography

    Percutaneous transhepatic cholangiography consists of inserting a cannula into one of the intrahepatic bile ducts through a long biopsy needle and injecting x-ray contrast material directly into the duct. This procedure outlines the biliary duct system and both confirms biliary tract obstruction by demonstrating a dilated duct system and pinpoints the location of the obstruction. The technique is not easy and requires considerable experience; more than 25% of attempts fail (most often in patients with intrahepatic obstruction due to liver cell damage). There is a definite risk (although very small) of producing bile peritonitis, which occasionally has been fatal. Preparation for surgical intervention should be made in advance in case this complication does develop.

  • Computerized Tomography and Ultrasound

    Ultrasound has been reported to detect metastatic liver tumor in approximately 85%-90% of patients (literature range, 63%-96%, with some of the lower figures being earlier ones). Computerized tomography (CT) has a sensitivity of 90%-95%. Radionuclide scans detect a few more patients with diffuse liver abnormality than CT or ultrasound. However, CT and ultrasound can differentiate cysts from solid lesions in the liver, which both look the same on radionuclide scanning. CT can also detect abnormalities outside the liver as incidental findings to a liver study. Ribs may interfere with ultrasound examination of the liver dome area, and gas in the hepatic flexure of the colon can interfere in the lower area of the liver. Magnetic resonance imaging (MRI) has about the same detection rate as CT but is much more expensive and at times has some problems with liver motion due to relatively slow scan speed.

    CT and ultrasound are important aids in differentiating extrahepatic from intrahepatic biliary tract obstruction through visualization of the diameter of the intrahepatic and common bile ducts. In complete extrahepatic obstruction, after a few days the common bile duct becomes dilated; in most cases the intrahepatic ducts eventually also become dilated. In intrahepatic obstruction the common bile duct is not dilated. Ultrasound has asensitivity of about 93% (literature range, 77%-100%), and CT is reported to have a sensitivity of about 94% (literature range, 85%-98%). There have also been considerable advances in the ability of ultrasound and CT to demonstrate the approximate location of obstruction in the biliary system as well as making an overall diagnosis of obstruction. Gas in the intestine may interfere with ultrasound in a few cases.

    In general, most investigators believe that ultrasound is the procedure of choice in possible biliary tract obstruction; those few cases that are equivocal or technically inadequate with ultrasound can be studied by CT or some other technique such as percutaneous transhepatic cholangiography.

  • Radionuclide Liver Scan

    If a radioactive colloidal preparation is injected intravenously, it is picked up by the reticuloendothelial system. The Kupffer cells of the liver take up most of the radioactive material in normal circumstances, with a small amount being deposited in the spleen and bone marrow. If a sensitive radioactive counting device is placed over the liver, a two-dimensional image or map can be obtained of the distribution of radioactivity. A similar procedure can be done with thyroid and kidney using radioactive material that these organs normally take up (e.g., iodine in the case of the thyroid). Certain diseases may be suggested on liver scan if the proper circumstances are present:

    1. Space-occupying lesions, such as tumor or abscess, are often visualized as discrete filling defects if they are more than 2 cm in diameter.
    2. Cirrhosis typically has a diffusely nonuniform appearance accompanied by splenomegaly, but the cirrhotic process usually must be well established before scan abnormality (other than hepatomegaly) is seen. The most typical picture is obtained in far-advanced cases, but the scan appearance may differ somewhat even in these patients.
    3. Fatty liver has an isotope distribution like that of cirrhosis, but only if severe.
    4. Liver scanning may be useful to differentiate abdominal masses from an enlarged liver.

    Undoubtedly, more sensitive equipment will become available and, perhaps, better radioactive isotopes. At present, useful as the liver scan may be, it is often difficult to distinguish among cirrhosis, fatty liver, and disseminated metastatic carcinoma with nodules less than 2 cm in diameter. Liver scan is reported to detect metastatic carcinoma in 80%-85% of patients tested (literature range, 57%-97%) and to suggest a false positive diagnosis in 5%-10% of patients without cancer. The majority of these false positive studies are in patients with cirrhosis, hepatic cysts, hemangiomas, or a prominent porta hepatis.

  • Alpha Fetoprotein Test (AFP)

    Fetal liver produces an alpha-1 globulin called “alpha fetoprotein” (AFP), which becomes the dominant fetal serum protein in the first trimester, reaching a peak at 12 weeks, then declining to 1% of the peak at birth. By age 1 year, a much greater decrease has occurred. Primary liver cell carcinomas (hepatomas) were found to produce a similar protein; therefore, a test for hepatoma could be devised using antibodies against AFP antigen. Original techniques, such as immunodiffusion, were relatively insensitive and could not detect normal quantities of AFP in adult serum. Extensive studies using immunodiffusion in several countries revealed that 30%-40% of European hepatoma patients who were white had positive test results, whereas the rate among Chinese and African Americans with hepatoma was 60%-75%. Men seemed to have a higher positive rate than women. Besides hepatoma, embryonal cell carcinoma and teratomas of the testes had an appreciable positivity rate. Reports of false positive results with other conditions included several cases of gastric carcinoma with liver metastases and a few cases of pregnancy in the second trimester. Subsequently, when much more sensitive radioimmunoassay techniques were devised, small quantities of AFP were detected in normal adult individuals. RIA and EIA have increased the abnormality rate in hepatoma somewhat, especially in European patients, whereas elevations accompanying other conditions are also more frequent. For example, according to one report, AFP levels were increased in approximately 75% of hepatoma cases, 75% of embryonal carcinomas or teratomas of the testes, 20% of pancreatic or gastric carcinomas, and 5% of colon and lung carcinomas. Others have found AFP elevations by immunoassay methods in 90% or more of hepatomas (literature range, 69%-100%) and in 0%-5% of various nonneoplastic liver diseases. The most frequent nonneoplastic elevations occurred in conditions associated with active necrosis of liver cells, such as hepatitis and active alcoholic cirrhosis. An AFP level of 500 ng/ml was suggested by several investigators as a cutoff point in differentiating hepatoma from nonneoplastic liver disease. Almost all of the nonneoplastic disease (except some cases of hepatitis virus hepatitis) were less than 500 ng/ml, whereas 50% or more patients with hepatoma had values higher than this.

  • Cell Component Autoantibodies

    Antibodies that react against specific structures in cells can be demonstrated by immunofluorescent technique. Antimitochondrial antibodies are found in 80%-100% of biliary cirrhosis patients and may aid in the diagnosis of this uncommon disease. False positive results have been reported in some patients with drug-induced cholestasis and chronic active hepatitis, as well as in a relatively small number of patients with extrahepatic obstruction, acute infectious hepatitis, rheumatoid arthritis, and other conditions. There are subgroups of antimitochondrial antibodies; the M-2 subgroup is claimed to be specific for primary biliary cirrhosis. However, it is very difficult to obtain testing for M-2 alone. Anti-smooth muscle antibodies were reported in 45%-70% of patients with chronic active (“lupoid”) hepatitis but have also been found in biliary cirrhosis and, less frequently, in other liver diseases (except alcoholic cirrhosis). An immunofluorescence expert is needed to set up and interpret these procedures. Liver biopsy is still needed.

  • Blood Ammonia

    One function of the liver is the synthesis of urea from various sources of ammonia, most of which come from protein-splitting bacteria in the GI tract. In cirrhosis, there is extensive liver cell destruction and fibrous tissue replacement of areas between nodules of irregularly regenerating liver cells. This architectural distortion also distorts the hepatic venous blood supply and leads to shunting into the systemic venous system, a phenomenon often manifested by esophageal varices. Thus, two conditions should exist for normal liver breakdown of ammonia: (1) enough functioning liver cells must be present and (2) enough ammonia must reach these liver cells. With normal hepatic blood flow, blood ammonia elevation occurs only in severe liver failure. With altered blood flow in cirrhosis, less severe decompensation is needed to produce elevated blood ammonia levels. Nevertheless, the blood ammonia is not directly dependent on the severity of cirrhosis but only on the presence of hepatic failure.

    Hepatic failure produces a syndrome known as “prehepatic coma” (hepatic encephalopathy), which progresses to actual hepatic coma. Clinical symptoms of prehepatic coma include mental disturbances of various types, characteristic changes on the electroencephalogram, and a peculiar flapping intention tremor of the distal extremities. However, each element of this triad may be produced by other causes, and one or more may be lacking in some patients. The ensuing hepatic coma may also be simulated by the hyponatremia or hypokalemia that cirrhotic patients often manifest or by GI bleeding, among other causes. Cerebrospinal fluid glutamate levels are currently the most reliable indicator of hepatic encephalopathy. However, this requires spinal fluid, and in addition, the test is often not available except in large medical centers or reference laboratories. Of more readily available laboratory tests, the blood ammonia level shows the best correlation with hepatic encephalopathy or coma. However, the blood ammonia level is not elevated in all of these patients, so that a normal blood ammonia level does not rule out the diagnosis. Arterial ammonia levels are more reliable than venous ones since venous ammonia may increase to variable degree compared to arterial values. RBCs contain about 3 times the ammonium content of plasma, so that hemolysis may affect results. Muscular exertion can increase venous ammonia. Plasma is preferred to serum since ammonia can be generated during clotting. Patient cigarette smoking within 1 hour of venipuncture may produce significant elevation of ammonia. One investigator reported transient ammonia elevation at 0.5-3 hours and again at 3.5-6 hours after a meal containing protein in some normal persons, with the effect being magnified in persons with liver disease.

    Blood ammonia has been proposed as an aid in the differential diagnosis of massive upper GI tract bleeding, since elevated values suggest severe liver disease and thus esophageal varices as the cause of the bleeding. However, since cirrhotics may also have acute gastritis or peptic ulcer, this use of the blood ammonia level has not been widely accepted. At present, the blood ammonia is used mainly as an aid in diagnosis of hepatic encephalopathy or coma, since elevated values suggest liver failure as the cause of the symptoms. Otherwise, ammonia determination is not a useful liver function test, since elevations usually do not occur until hepatic failure.

  • Serum Proteins

    Serum albumin levels decrease to variable degrees in many severe acute and chronic disorders. Albumin is synthesized in the liver, so most acute or chronic destructive liver diseases of at least moderate severity also result in decreased serum albumin levels. In addition, there may be other serum protein changes. In cirrhosis of moderate to severe degree, there is a decreased albumin level and usually a “diffuse” (“polyclonal”) gamma-globulin elevation, sometimes fairly marked. About 50% of patients with well-established cirrhosis have a characteristic serum protein electrophoretic pattern with gamma-globulin elevation that incorporates the beta area (so-called beta-gamma bridging). However, about 35% of cirrhotic patients show only various degrees of gamma elevation without any beta bridging, and about 10% have normal gamma levels. Hepatitis may also be associated with moderate elevation of the gamma globulins. Biliary obstruction eventually causes elevated beta-globulin levels, since beta globulins carry cholesterol.