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Updated: 03/13/08 01:44 PM |
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| HOME | HEAL | EDUCATE | RESEARCH | DIRECTORY | OUTREACH |
Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
Download Chapter ♦ Download Lecture Slides & Notes
Download Chapter ♦ Download Lecture Slides & Notes
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K. Other Commonly Used Tests of Hepatobiliary Dysfunction
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1. Intracellular and Canalicular Enzymes
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Following hepatocyte injury, intracellular and canalicular enzymes leak from hepatocytes into plasma. These enzymes vary in their degree of specificity for liver injury as compared with injury to other body organs, in their sensitivity for detecting hepatocellular injury and in the timing and degree of their elevation following hepatocellular injury.
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a. Aminotransferases (Figure 17)
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Aminotransferases in serum (AST and ALT) reflect hepatocyte injury
AST is also released by injured red blood cells and myocytes |
Elevations of serum aminotransferases - aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - are the most useful indicators of hepatocellular injury, ranging from increased plasma membrane permeability to severe hepatocellular necrosis. As the largest organ, the liver has the highest concentrations of AST and ALT; as a result, serum levels of these enzymes are elevated to some extent in almost all hepatobiliary diseases. The highest levels (above 1,000 U) are seen in severe viral hepatitis, drug- or toxin-induced hepatitis, and ischemic hepatic necrosis, usually with ALT > AST. This ratio may be reversed in severe liver injury. Elevations are usually less marked in cholestasis and in alcoholic liver disease, with ALT usually < AST, due to impaired synthesis of ALT. ALT <. In addition to liver, low levels of ALT are present in the kidney, while AST is also found in erythrocytes and myocytes. Thus, elevation of AST >> ALT is usual in hemolysis, myocardial infarction or skeletal muscle diseases. Although aminotransferase levels may reflect the extent of hepatic necrosis, they do not correlate with eventual outcome.
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Figure 17 Serum Alkaline Phosphatase in Hepatobiliary Diseases Ranges of serum alkaline phosphatase (horizontal axis) are expressed as a percent of the upper limit of normal. The vertical dashed line represents 3X the upper limit of normal, usually taken as the diagnostic discriminator between hepatocellular diseases (lower values) and cholestatic disorders (higher values). Note that, for each type of disease, a proportion of the values lie on the inappropriate side of the discriminatory cutoff. ©American Gastroenterological Assn., Undergraduate Teaching Project, Unit 21, Slide 105. Milner-Fenwick, Timonium, MD, 1989. Based on Zimmerman HJ, West M, Am J Gastroenterol 1963;40:387-404. Reproduced with permission. |
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b. Alkaline phosphatases
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Multiple sources of plasma alkaline phosphatase
Alk. phosphatase >3X normal suggests cholestasis |
Alkaline phosphatases are isoenzymes produced in the liver, small intestine, kidney, placenta, and bone. All of these tissues contribute to the normal plasma level. These enzymes, including those synthesized in the hepatocytes and cholangiocytes, are secreted into bile. In both hepatocellular injury and biliary obstruction, plasma concentrations usually rise, but are generally much higher in cholestasis of any cause (Figure 17). This is due to both induction of alkaline phosphatase synthesis in hepatocytes by retained bile salts, as well as the diminished ability to secrete the enzyme into the bile.
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c. Transpeptidases
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| GGT helps to pinpoint bile ducts or liver as source of increased alkaline phosphatase |
Gamma-glutamyl transpeptidase (GGT) is localized to hepatocytes and cholangiocytes, but is a more sensitive indicator of biliary tract disease than hepatocellular disease. Its primary usefulness is limited to the exclusion of bone disease as the source of an elevated serum alkaline phosphatase level (GGT is not found in bone).
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d. 5'-Nucleotidase
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5’-Nucleotidase also helps to pinpoint bile ducts or liver as source of increased alkaline phosphatase |
a. 5'-Nucleotidase
This group of enzymes catalyzes the release of inorganic phosphate from nucleotides. Although present in the cytoplasm of many organs, in the liver they are present primarily within the microsomes. It is thought that only hepatobiliary tissue can release these nucleotidases into the circulation. The plasma concentration is unaffected by bone diseases. Plasma concentrations rise in all types of hepatobiliary disease, but are highest in cholestatic conditions where the degree of elevation parallels, but is lower than, that of alkaline phosphatase. Due to this lower sensitivity, an elevation of the serum 5'-nucleotidase level is mainly useful to indicate that the liver and/or bile ducts are the source of an elevated serum alkaline phosphatase. A normal level, however, does not exclude the liver as the source of the increased alkaline phosphatase.
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2. Tests Measuring Synthetic Function of Hepatocytes
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The liver is the only source of many proteins and lipoproteins found in the body (including most coagulation factors and albumin). The concentration of certain plasma proteins may be taken as an indirect measure of their synthesis rate in the liver.
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a. Plasma prothrombin time (PT)
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The short t½ (hours) of these clotting factors allows PT increase rapidly in acute liver disease |
Only the hepatocytes synthesize coagulation factors 1 (fibrinogen), 2 (prothrombin or PT), 5, 7, 9, and 10. The PT measures blood clotting as regulated by these factors and is prolonged when factors 1, 2, 5, 7, 9, and 10 are deficient (either singly or in combination). All of these factors have very short half-lives (e.g., factor 7, 1/2 day).
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Poor synthesis of clotting factors vs. malabsorption of. Vitamin K |
A prolonged PT may result from impaired hepatic synthesis of clotting factors in acute or chronic liver injury, or to malabsorption of Vitamin K. This vitamin is an essential cofactor for the synthesis of clotting factors 2, 7, 9, and 10. Being lipid-soluble, vitamin K requires the presence of bile salts in the upper intestine for efficient absorption. Thus, in chronic cholestatic conditions, impaired bile salt secretion leads to Vitamin K deficiency. By contrast, in cirrhosis, synthesis of the clotting factors is impaired, despite an adequate supply of Vitamin K. A single 10 mg dose of parenteral Vitamin K will correct the elevated PT if poor oral intake or absorption of Vitamin K is the cause, whereas the PT does not respond to Vitamin K in hepatocellular diseases.
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b. Serum (plasma) albumin
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| Plasma albumin is synthesized only by hepatocytes. |
Albumin, quantitatively the major plasma protein synthesized by the liver, is a useful indicator of total functional hepatocyte mass. Its concentration, normally 3.5 to 6.0 g/dL, is the composite result of hepatic synthesis rate, catabolism (including external loss), and equilibration with extravascular fluids (see diagram below).
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Figure 18 Albumin Synthesis and Catabolism |
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| Long half-life of albumin means level falls slowly with onset of liver injury |
Albumin is synthesized only by hepatocytes and has a relatively long half-life -- 14-21 days. Thus, a decreased synthetic rate will not be reflected by a decline in plasma (serum) albumin concentration for 2-3 weeks. Serum albumin levels, therefore, are often normal in acute liver disease but low levels are the best marker and index of the severity of chronic liver disease.
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| Increased albumin catabolism or urinary loss may contribute to a low serum albumin level |
Albumin is catabolized mainly in the reticuloendothelial system (including liver). Thus, in fulminant liver failure, severe stress, sepsis, multiple organ failure, or acute alcoholic hepatitis, release of various cytokines may accelerate albumin catabolism, causing an acute decrease in the serum albumin concentration over a period of several hours to days. The normal losses across the gut wall may be increased 2-3-fold with portal hypertension or inflammatory bowel disease, and even more with protein-losing enteropathies, including sprue. The normally small losses of albumin in the urine may increase considerably with the nephrotic syndrome.
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c. Plasma lipoproteins and cholesterol
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Serum lipoproteins and cholesterol usually elevated in cholestasis and alcoholic liver disease, low in most hepatocellular diseases. |
Most plasma lipoproteins are synthesized in the liver. LDL released from peripheral fat stores is taken up by the liver through specific receptors. In viral hepatitis, all plasma lipoproteins are usually decreased, mainly due to decreased synthesis. By contrast, in alcoholic liver disease, metabolic effects of alcohol stimulate synthesis and impair hepatic uptake of LDL, so LDL levels are often elevated, whereas HDL levels are low. In cholestasis, LDL levels increase progressively with the duration of disease, whereas HDL levels are normal early, but fall as synthesis is impaired with persistent obstruction. In hepatocellular disease, cholesterol levels are low due to impaired synthesis. In cholestasis, plasma cholesterol levels can be elevated due to retained bile salts inhibiting the conversion of cholesterol to bile salts.
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3. Tests of Globulin Synthesis
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a. Immunoglobulins (γ-globulins)
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Gamma globulins high in autoimmune hepatitis |
Most diffuse hepatic injuries induce an intrahepatic inflammatory reaction which includes infiltration by varying numbers of lymphocytes and plasma cells. The associated increase in synthesis of immunoglobulins is reflected by an increase in their plasma concentrations. In general, the immunoglobulins are increased in a non-specific manner in many different types of chronic liver disease and thus have limited diagnostic value. In certain conditions, however, some fractions are characteristically more markedly elevated (i.e., IgG in chronic autoimmune hepatitis or IgM in primary biliary cirrhosis). The normal adult range for total γ-globulins is 0.7 to 1.5 g/dL (paper electrophoresis).
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b. Total globulins and albumin/globulin (A/G) Ratio |
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| Albumin/globulin ratio below 1.0 usually indicates liver disease |
The less abundant α- and β-globulins are largely lipoproteins. Changes in lipoprotein levels may thus modify the changes in total globulins that tend to be dominated by the γ-globulins. Total globulin levels in serum are normally 2.5-3.5 g/dL, and thus lower than the normal albumin level. In chronic liver disease, the Albumin/Globulin (A/G) ratio often is lower than 1.0, and an A/G ratio less than 1.0 should strongly suggest liver disease.
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4. General Usefulness of “Liver Function Tests” (LFT’s).
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| Use "liver function tests" selectively for specific purposes |
Liver laboratory tests are often called "liver function tests" (LFTs), but the aminotransferases are in fact markers of hepatobiliary damage, NOT liver function. AST and/or ALT are intermittently mildly elevated in normal subjects, probably due to incidental exposures to environmental toxins, alcohol, or medications. By contrast, some other tests are poorly sensitive for assessing the degree of hepatic injury or amount of hepatic functional reserve. Although hundreds of different tests have been devised, a physician does best if he/she employs only a few for specific purposes. The clinical situations wherein LFTs are most helpful are the: a) differential diagnosis of jaundice; b) detection of hepatic dysfunction in the non-jaundiced patient; c) rough measure of the degree of hepatic dysfunction in a patient with known liver disease; and d) assessment of the progression of known hepatic illness under serial observation.
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Next Section (L): Hepatobiliary Defects in Bile Salt Metabolism & Secretion » |
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