Several biochemical tests are useful in the evaluation and management of patients with hepatic dysfunction. These tests can be used to (1) detect the presence of liver disease, (2) distinguish among different types of liver disorders, (3) gauge the extent of known liver damage, and (4) follow the response to treatment.
Liver tests have shortcomings. They can be normal in patients with serious liver disease and abnormal in patients with diseases that do not affect the liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest a general category of liver disease, such as hepatocellular or cholestatic, which then further directs the evaluation.
The liver carries out thousands of biochemical functions, most of which cannot be easily measured by blood tests. Laboratory tests measure only a limited number of these functions. In fact, many tests, such as the aminotransferases or alkaline phosphatase, do not measure liver function at all. Rather, they detect liver cell damage or interference with bile flow. Thus, no one test enables the clinician to accurately assess the liver's total functional capacity.
To increase both the sensitivity and the specificity of laboratory tests in the detection of liver disease, it is best to use them as a battery. Tests usually employed in clinical practice include the bilirubin, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. When more than one of these tests provide abnormal findings or the findings are persistently abnormal on serial determinations, the probability of liver disease is high. When all test results are normal, the probability of missing occult liver disease is low.
When evaluating patients with liver disorders, it is helpful to group these tests into general categories. The classification we have found most useful is given below.
Tests Based on Detoxification and Excretory Functions
(See also Chap. 42) Bilirubin, a breakdown product of the porphyrin ring of heme-containing proteins, is found in the blood in two fractions—conjugated and unconjugated. The unconjugated fraction, also termed the indirect fraction, is insoluble in water and is bound to albumin in the blood. The conjugated (direct) bilirubin fraction is water soluble and can therefore be excreted by the kidney. When measured by modifications of the original van den Bergh method, normal values of total serum bilirubin are reported between 1 and 1.5 mg/dL with 95% of a normal population falling between 0.2 and 0.9 mg/dL. If the direct-acting fraction is less than 15% of the total, the bilirubin can be considered to all be indirect. The most frequently reported upper limit of normal for conjugated bilirubin is 0.3 mg/dL.
Elevation of the unconjugated fraction of bilirubin is rarely due to liver disease. An isolated elevation of unconjugated bilirubin is seen primarily in hemolytic disorders and in a number of genetic conditions such as Crigler-Najjar and Gilbert's syndromes (Chap. 42). Isolated unconjugated hyperbilirubinemia (bilirubin elevated but <15% direct) should prompt a workup for hemolysis (Fig. 302-1). In the absence of hemolysis, an isolated, unconjugated hyperbilirubinemia in an otherwise healthy patient can be attributed to Gilbert's syndrome, and no further evaluation is required.
Algorithm for the evaluation of chronically abnormal liver tests. ERCP, endoscopic retrograde cholangiopancreatography; CT, computed tomography; AMA, antimitochondrial antibody; ANA, antinuclear antibody; SPEP, serum protein electrophoresis; TIBC, total iron-binding capacity; GGT, α glutamyl transpeptidase; W/U, work up.
In contrast, conjugated hyperbilirubinemia almost always implies liver or biliary tract disease. The rate-limiting step in bilirubin metabolism is not conjugation of bilirubin, but rather the transport of conjugated bilirubin into the bile canaliculi. Thus, elevation of the conjugated fraction may be seen in any type of liver disease. In most liver diseases, both conjugated and unconjugated fractions of the bilirubin tend to be elevated. Except in the presence of a purely unconjugated hyperbilirubinemia, fractionation of the bilirubin is rarely helpful in determining the cause of jaundice.
While the degree of elevation of the serum bilirubin has not been critically assessed as a prognostic marker, it important in a number of conditions. In viral hepatitis, the higher the serum bilirubin, the greater the hepatocellular damage. Total serum bilirubin correlates with poor outcomes in alcoholic hepatitis. It is also a critical component of the Model for Endstage Liver Disease (MELD) score, a tool used to estimate survival of patients with end-stage liver disease. An elevated total serum bilirubin in patients with drug-induced liver disease indicates more severe injury.
Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the kidney. Therefore, any bilirubin found in the urine is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease. A urine dipstick test can theoretically give the same information as fractionation of the serum bilirubin. This test is almost 100% accurate. Phenothiazines may give a false-positive reading with the Ictotest tablet. In patients recovering from jaundice, the urine bilirubin clears prior to the serum bilirubin.
Ammonia is produced in the body during normal protein metabolism and by intestinal bacteria, primarily those in the colon. The liver plays a role in the detoxification of ammonia by converting it to urea, which is excreted by the kidneys. Striated muscle also plays a role in detoxification of ammonia, which is combined with glutamic acid to form glutamine. Patients with advanced liver disease typically have significant muscle wasting, which likely contributes to hyperammonemia in these patients. Some physicians use the blood ammonia for detecting encephalopathy or for monitoring hepatic synthetic function, although its use for either of these indications has problems. There is very poor correlation between either the presence or the severity of acute encephalopathy and elevation of blood ammonia; it ...