Clinical and Interpretive

A liver profile consists of albumin, total bilirubin, direct bilirubin, indirect bilirubin (calculation), alkaline phosphatase, ALT, AST, and total protein and is useful in assessing hepatic function.

Alanine aminotransferase (ALT) is present primarily in liver cells. In viral hepatitis and other forms of liver disease associated with hepatic necrosis, serum ALT is elevated even before the clinical signs and symptoms of the disease appear. Although serum levels of both aspartate aminotransferase (AST) and ALT become elevated whenever disease processes affect liver cell integrity, ALT is a more liver-specific enzyme. Serum elevations of ALT are rarely observed in conditions other than parenchymal liver disease. Moreover, the elevation of ALT activity persists longer than does AST activity. Values are typically at least ten times above the normal range. Levels may reach values as high as one hundred times the upper reference limit, although twenty to fifty-fold elevations are most frequently encountered. In infectious hepatitis and other inflammatory conditions affecting the liver, ALT is characteristically as high as or higher than aspartate aminotransferase (AST), and the ALT/AST ratio, which normally and in other condition is <1, becomes greater than unity. ALT levels are usually elevated before clinical signs and symptoms of disease appear.

Aspartate aminotransferase (AST) is found in high concentrations in liver, heart, skeletal muscle and kidney. AST is present in both cytoplasm and mitochondria of cells. In cases involving mild tissue injury, the predominant form of AST is that from the cytoplasm. Severe tissue damage results in more of the mitochondrial enzyme being released. High levels of AST can be found in cases such as myocardial infarction, acute liver cell damage, viral hepatitis and carbon tetrachloride poisoning. Slight to moderate elevation of AST is seen in muscular dystrophy, dermatomyositis, acute pancreatitis and crushed muscle injuries. Elevated aspartate aminotransferase (AST) values are seen in parenchymal liver diseases characterized by a destruction of hepatocytes, with values typically at least 10 times above the normal range. Levels may reach values as high as one hundred times the upper reference limit, although twenty to fifty-fold elevations are most frequently encountered. AST levels are usually elevated before clinical signs and symptoms of disease appear. Five- to 10-fold elevations of both AST and ALT occur in patients with primary or metastatic carcinoma of the liver, with AST usually being higher than ALT, but levels are often normal in the early stages of malignant infiltration of the liver. Elevations of ALT activity persist longer than do those of AST activity. Elevated AST values may also be seen in disorders affecting the heart, skeletal muscle and kidney.

Plasma or serum levels of albumin are frequently used to assess nutritional status. Albumin is a carbohydrate-free protein, which constitutes 55% to 65% of total plasma protein. It maintains oncotic plasma pressure, is involved in the transport and storage of a wide variety of ligands, and is a source of endogenous amino acids. Albumin binds and solubilizes various compounds, including bilirubin, calcium, long-chain fatty acids, toxic heavy metal ions, and numerous pharmaceuticals. Hypoalbuminemia is caused by several factors: impaired synthesis due either to liver disease (primary) or due to diminished protein intake (secondary); increased catabolism as a result of tissue damage and inflammation; malabsorption of amino acids; and increased renal excretion (eg, nephrotic syndrome). Hyperalbuminemia is of little diagnostic significance except in the case of dehydration. When plasma or serum albumin values fall below 2.0 g/dL, edema is usually present.

Bilirubin is one of the most commonly used tests to assess liver function. Approximately 85% of the total bilirubin produced is derived from the heme moiety of hemoglobin, while the remaining 15% is produced from RBC precursors destroyed in the bone marrow and from the catabolism of other heme-containing proteins. After production in peripheral tissues, bilirubin is rapidly taken up by hepatocytes where it is conjugated with glucuronic acid to produce bilirubin mono- and diglucuronide, which are then excreted in the bile. A number of inherited and acquired diseases affect one or more of the steps involved in the production, uptake, storage, metabolism, and excretion of bilirubin. Bilirubinemia is frequently a direct result of these disturbances. The most commonly occurring form of unconjugated hyperbilirubinemia is that seen in newborns and referred to as physiological jaundice. The increased production of bilirubin, that accompanies the premature breakdown of erythrocytes and ineffective erythropoiesis, results in hyperbilirubinemia in the absence of any liver abnormality. The rare genetic disorders, Crigler-Najjar syndromes Type I and Type II, are caused by a low or absent activity of bilirubin UDP-glucuronyl-transferase. In Type I, the enzyme activity is totally absent, the excretion rate of bilirubin is greatly reduced and the serum concentration of unconjugated bilirubin is greatly increased. Patients with this disease may die in infancy owing to the development of kernicterus. In hepatobiliary diseases of various causes, bilirubin uptake, storage, and excretion are impaired to varying degrees. Thus, both conjugated and unconjugated bilirubin are retained and a wide range of abnormal serum concentrations of each form of bilirubin may be observed. Both conjugated and unconjugated bilirubins are increased in hepatitis and space-occupying lesions of the liver; and obstructive lesions such as carcinoma of the head of the pancreas, common bile duct, or ampulla of Vater. The level of bilirubinemia that results in kernicterus in a given infant is unknown. In preterm infants, the risk of a handicap increases by 30% for each 2.9 mg/dL increase of maximal total bilirubin concentration. While central nervous system damage is rare when total serum bilirubin (TSB) is <20 mg/dL, premature infants may be affected at lower levels. The decision to institute therapy is based on a number of factors including TSB, age, clinical history, physical examination, and coexisting conditions. Phototherapy typically is discontinued when TSB level reaches 14 to 15 mg/dL. Physiologic jaundice should resolve in 5 to 10 days in full-term infants and by 14 days in preterm infants. When any portion of the biliary tree becomes blocked, bilirubin levels will increase. Specimens should be protected from light and analyzed as soon as possible. Grossly hemolyzed specimens should be rejected because hemoglobin inhibits the diazo reaction and falsely decreased results may be seen. Compounds that compete for binding sites on serum albumin contribute to lower serum bilirubin levels (eg, penicillin, sulfisoxazole, acetylsalicylic acid). Direct bilirubin is a measurement of conjugated bilirubin. Jaundice can occur as a result of problems at each step in the metabolic pathway. Disorders may be classified as those due to: increased bilirubin production (eg, hemolysis and ineffective erythropoiesis), decreased bilirubin excretion (eg, obstruction and hepatitis), and abnormal bilirubin metabolism (eg, hereditary and neonatal jaundice). Inherited disorders in which direct bilirubinemia occurs include Dubin-Johson syndrome and Rotor Syndrome. Jaundice of the newborn where direct bilirubin is elevated includes idiopathic neonatal hepatitis and biliary atresia. The most commonly occurring form of jaundice of the newborn, physiological jaundice, results in unconjugated (indirect) hyperbilirubinemia. In hepatobiliary diseases of various causes, bilirubin uptake, storage and excretion are impaired to varying degrees. Thus both conjugated and unconjugated bilirubin is retained and a wide range of abnormal serum concentrations of each form of bilirubin may be observed. Both conjugated and unconjugated bilirubin are increased in hepatocellular diseases, such as hepatitis and space-occupying lesions of the liver; and obstructive lesions such as carcinoma of the head of the pancreas, common bile duct, or ampulla of Vater. Direct bilirubin levels must be assessed in conjunction with total and indirect levels and the clinical setting. Specimens should be protected from light and analyzed as soon as possible; grossly hemolyzed specimens should be rejected because hemoglobin inhibits the diazo reaction and falsely low results may be seen.

Alkaline phosphatase (ALP) is present in a number of tissues including liver, bone, intestine, and placenta. Serum ALP is of interest in the diagnosis of 2 main groups of conditions-hepatobiliary disease and bone disease associated with increased osteoblastic activity. A rise in ALP activity occurs with all forms of cholestasis, particularly with obstructive jaundice. The response of the liver to any form of biliary tree obstruction is to synthesize more ALP. The main site of new enzyme synthesis is the hepatocytes adjacent to the biliary canaliculi. ALP also is elevated in disorders of the skeletal system that involve osteoblast hyperactivity and bone remodeling, such as Paget’s disease, hyperparathyroidism, rickets and osteomalacia, fractures, and malignant tumors. A considerable rise in alkaline phosphatase activity caused by increased osteoblast activity following accelerated bone growth is sometimes seen in children and juveniles. The elevation in alkaline phosphatase (ALP) tends to be more marked (more than 3 fold) in extrahepatic biliary obstruction (eg, by stone or by cancer of the head of the pancreas) than in intrahepatic obstruction, and is greater the more complete the obstruction. Serum enzyme activities may reach 10 to 12 times the upper limit of normal, returning to normal on surgical removal of the obstruction. The ALP response to cholestatic liver disease is similar to the response of gamma-glutamyltransferase (GGT), but more blunted. If both GGT and ALP are elevated, a liver source of the ALP is likely. Among bone diseases, the highest level of ALP activity is encountered in Paget disease as a result of the action of the osteoblastic cells as they try to rebuild bone that is being resorbed by the uncontrolled activity of osteoclasts. Values from 10 to 25 times the upper limit of the reference interval are not unusual. Only moderate rises are observed in osteomalacia, while levels are generally normal in osteoporosis. In rickets, levels 2 to 4 times normal may be observed. Primary and secondary hyperparathyroidism are associated with slight to moderate elevations of ALP; the existence and degree of elevation reflects the presence and extent of skeletal involvement. Very high enzyme levels are present in patients with osteogenic bone cancer. A considerable rise in ALP is seen in children following accelerated bone growth. In addition, an increase of 2 to 3 times normal may be observed in women in the third trimester of pregnancy, although the interval is very wide and levels may not exceed the upper limit of the reference interval in some cases. The additional enzyme is of placental origin.

Plasma proteins are synthesized predominantly in the liver; immunoglobulins are synthesized by mononuclear cells of lymph nodes, spleen and bone marrow. The 2 general causes of alterations of serum total protein are a change in the volume of plasma water and a change in the concentration of one or more of the specific proteins in the plasma. Of the individual serum proteins, albumin is present in such high concentrations that low levels of this protein alone may cause hypoproteinemia. Hemoconcentration (decrease in the volume of plasma water) results in relative hyperproteinemia; hemodilution results in relative hypoproteinemia. In both situations, concentrations of all the individual plasma proteins are affected to the same degree. Hyperproteinemia may be seen in dehydration due to inadequate water intake or to excessive water loss (eg, severe vomiting, diarrhea, Addison’s disease and diabetic acidosis) or as a result of increased production of proteins. Increased polyclonal protein production is seen in reactive, inflammatory processes; increased monoclonal protein production is seen in some hematopoeitic neoplasms (eg, multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of undetermined significance). Mild hyperproteinemia may be caused by an increase in the concentration of specific proteins normally present in relatively low concentration, eg, increases in acute phase reactants and polyclonalimmunoglobulins produced in inflammatory states, late-stage liver disease, and infections. Moderate-to-marked hyperproteinemia may also be due to multiple myeloma and other malignant paraproteinemias, although normal total protein levels do not rule out these disorders. A serum protein electrophoresis should be performed to evaluate the cause of the elevated serum total protein. Hypoproteinemia may be due to decreased production (eg, hypogammaglobulinemia) or increased protein loss (eg, nephrotic syndrome, protein-losing enteropathy). A serum protein electrophoresis should be performed to evaluate the cause of the decreased serum total protein. If a nephrotic pattern is identified, urine protein electrophoresis should also be performed. The total protein concentration is 0.4 to 0.8 mg/dL lower when the specimen is collected from a patient in the recumbent position.