Antimitochondrial antibodies (AMA)
The mitochondria create energy for the cells in your body to use. They’re critical to the normal functioning of all cells.
Antimitochondrial antibodies (AMAs) are an example of an autoimmune response that occurs when the body turns against its own cells, tissues, and organs. When this happens, the immune system attacks the body as though it were an infection.
The AMAs can attack the mitochondria, and the test looks for elevated levels of these antibodies in your blood. The test is most often used to detect an autoimmune condition known original known as primary biliary cholangitis, now known as primary biliary cholangitis (PBC).
The condition known as PBC destroys the mitochondria in the small bile ducts of the liver. Damaged bile ducts affect the liver’s ability to get rid of toxins. This can cause scarring, or cirrhosis of the liver.
Other tests may be ordered to diagnose PBC include the following:
• Smooth muscle antibodies (SMA)
• Antinuclear antibodies (ANA)
• Alkaline phosphatase (ALP)
• IgM level
• Prothrombin time (PT)
• C-reactive protein (CRP)
These tests often help detect PBC, distinguishing it from other autoimmune conditions causing liver damage, and may be useful predictors of the need for a liver transplant.
Tests Useful for Routine Evaluation of Liver Disease
Bilirubin: Hyperbilirubinemia results from increased bilirubin production, decreased liver uptake and/or conjugation, or decreased biliary excretion (see Jaundice, Chapter 65 JAUNDICE). Defects in bilirubin production, hepatic uptake, or conjugation cause unconjugated (or free) bilirubin in serum to increase; the last elevates conjugated bilirubin in serum and allows bile to appear in urine. Serum bilirubin measurements are based on the van den Bergh reaction: a direct reaction gives conjugated bilirubin; the addition of methanol allows a complete reaction, which measures total bilirubin (conjugated plus unconjugated), while the difference represents unconjugated bilirubin (an indirect value).
Serum bilirubin may not be a particularly sensitive index of liver disease or prognosis, but it is established and necessary. Total bilirubin is normally < 17 µmol/L (1 mg/dL). The only value of fractionating bilirubin into the total and direct-reacting components is to determine unconjugated hyperbilirubinemia (present when the unconjugated fraction is > 15% of total bilirubin). This is usually required only when finding an isolated bilirubin elevation (with other conventional liver tests normal) or for neonatal jaundice. Estimation of the reserve bilirubin binding capacity of serum is important in managing neonatal jaundice and preventing kernicterus (see Metabolic Problems in the Newborn, Chapter 189 DISTURBANCES IN NEWBORNS AND INFANTS). Sophisticated techniques can separate the conjugates of bilirubin but add nothing of clinical value.
Urine bilirubin (normally absent) can be detected at the bedside with a commercial urine test strip. In unconjugated hyperbilirubinemia, bilirubinuria is also absent; its presence confirms that any raised plasma levels are from conjugated (direct-reacting) hyperbilirubinemia. An early sign of hepatobiliary disease can be bilirubinuria, which develops in acute viral hepatitis even before jaundice appears. It may be absent, however, under other circumstances despite increased serum bilirubin. False-negatives occur with prolonged storage of the urine specimen, which may oxidize bilirubin, ascorbic acid (from vitamin C ingestion), or nitrate in the urine (from a UTI).
Urobilinogen is normally present in trace amounts (17 µmol/L) in the urine and also can be assessed by commercial test strips. This intestinal metabolite of bilirubin becomes elevated from hemolysis (excess pigment formation) or mildly impaired hepatic uptake and excretion (ie, when the enterohepatic circulation of this pigment exceeds the liver’s capacity to clear and excrete it). Failure of bilirubin excretion into the small intestine reduces urobilinogen formation so that the urine may test falsely low or absent. Thus urobilinogen, though sensitive for mild liver disease, is too nonspecific and difficult to interpret.
Alkaline phosphatases are a group of isoenzymes with a common capacity to hydrolyze organic phosphatase ester bonds in an alkaline medium, generating an organic radical and an inorganic phosphate. Their biologic function is unknown. Alkaline phosphatase in serum normally comes from the liver and bone and, during pregnancy, from the placenta. It is also present in some tumors (eg, bronchogenic carcinoma). Bone growth in children causes an age-dependent rise in normal values, particularly in infants of < 2 yr. Thereafter, alkaline phosphatase activity declines, reaching normal adult levels after a spurt during adolescent growth. It is slightly increased in older people. During pregnancy, serum levels rise two- to fourfold by the 9th mo and then return to normal by 21 days postpartum.
Alkaline phosphatase increases markedly in diseases that impair bile formation (cholestasis) and to a lesser extent in hepatocellular disease. Values in cholestasis, whether from intrahepatic causes (primary biliary cholangitis, drug-induced liver disease, liver transplantation rejection) or graft-vs.-host (GVH) disease, will be similarly elevated and less distinguishable from extrahepatic causes (duct obstruction from stricture, stone, or tumor), all rising some fourfold. In hepatocellular disease (eg, various forms of hepatitis, cirrhosis, infiltrative disorders), levels tend to be lower with some overlap. Isolated elevations (other liver tests are normal) occur in granulomatous or focal liver disease (eg, abscess, neoplastic infiltration, or partial bile duct obstruction). In some extrahepatic malignancies without liver metastasis, the cause is obscure: bronchogenic carcinoma may produce its own alkaline phosphatase; hypernephroma in 15% of cases induces a nonspecific hepatitis as the presumed origin of the enzyme elevation. For Hodgkin’s lymphoma, the cause of the isolated alkaline phosphatase elevation is unknown. Generally an isolated alkaline phosphatase elevation found in an otherwise asymptomatic adult, particularly if elderly, is not worth investigating.
Techniques using heat inactivation or electrophoresis can distinguish bone vs. liver origin for alkaline phosphatase, but using another serum enzyme provides a simpler discrimination: 5′-nucleotidase is a group of phosphatases that differ biochemically from alkaline phosphatase; they catalyze the hydrolysis of nucleotides (eg, adenosine 5′-phosphate) to release the inorganic phosphate from the 5′ position and are restricted to the plasma membranes of the liver cell. This enzyme increases in hepatobiliary, but not bone, diseases. In practice, it is useful to assess the anicteric patient. Values are low in childhood, rise gradually during adolescence, and plateau after age 50 yr. 5′-Nucleotidase is normally elevated in some women during the last trimester of pregnancy. Because of its specificity for liver disease, 5′-nucleotidase offers some advantage over alkaline phosphatase, but neither can differentiate obstructive from hepatocellular disease. They may or may not rise and fall in parallel.
Gamma-Glutamyl transpeptidase (or gamma-glutamyl transferase –GGT) is an enzyme (present in the liver, pancreas, and kidney) that transfers the gamma-glutamyl group from one peptide to another peptide or to an L-amino acid. Levels of GGT are elevated in hepatobiliary and pancreatic diseases that obstruct the common duct but are normal in pregnancy and bone disease. GGT levels parallel those of alkaline phosphatase and 5′-nucleotidase in cholestatic conditions. Because it is not physiologically elevated in pregnancy or childhood, GGT has a role here in detecting hepatobiliary disease. Drugs and alcohol ingestion, which induce microsomal enzymes, also elevate GGT; alone, it is a poor marker for alcoholic liver disease. Combined with transaminases, the detection of alcohol abuse becomes more secure. The extreme sensitivity (greater than alkaline phosphatase) of this enzyme limits its usefulness, but the test is replacing 5′-nucleotidase to detect hepatobiliary disease as the cause of an isolated rise in alkaline phosphatase.
Transaminases: Aspartate transaminase (AST –formerly SGOT) is present in the heart, skeletal muscle, brain, and kidney as well as the liver. AST levels also increase in MI, heart failure, muscle injury, CNS disease, and other nonhepatic disorders. Despite some nonspecificity, high levels indicate liver cell injury. Values of > 500 IU/L (> 400 u./mL) suggest acute viral or toxic hepatitis. Such high values also occur in marked heart failure (ischemic hepatitis) and even with common duct stones. The magnitude of the elevation has no prognostic value and does not correlate with the degree of liver damage. AST is reliable and part of routine screening for liver disease. Serial testing provides good monitoring: A fall to normal indicates recovery unless associated with the end stages of massive hepatic necrosis.
The alanine transaminase (ALT –formerly SGPT) is found primarily in liver cells and therefore has greater specificity for liver disease, but it offers little other advantage. In most liver diseases, the AST increase is less than that of ALT (AST/ALT ratio < 1), except in alcohol-related liver injury where the ratio frequently is > 2. (The basis for this is the greater need of pyridoxal 5′-phosphate as a cofactor for ALT; this cofactor is deficient in the alcoholic, limiting the rise of ALT.) Many exceptions limit the practicality of the ratio. However, a ratio > 3 with an inordinate increase in GGT (> 2 times the alkaline phosphatase) is highly suggestive.
Lactic dehydrogenase: LDH commonly included in automated analysis, is insensitive as an indicator of hepatocellular injury but is better as a marker for hemolysis or MI. It might be quite high with malignancies involving the liver.
Tests Useful in Special Circumstances of Liver Disease
Serum proteins: The liver synthesizes most proteins in serum: alpha- and beta-globulins, albumin, and clotting factors (but not gamma globulin, which is produced by B lymphocytes). Hepatocytes also make specific proteins: alpha1-antitrypsin (AAT, which is absent in AAT deficiency), ceruloplasmin (reduced in Wilson’s disease), and transferrin and ferritin (saturated with iron and greatly increased, respectively, in hemochromatosis). These and some other serum proteins increase in response to tissue injury (eg, inflammation); such acute phase reaction may produce a spuriously normal or elevated value.
Serum albumin the main determinant of plasma oncotic pressure, transports numerous substances (eg, unconjugated bilirubin). Its serum concentration is determined by the relative rates of its synthesis and degradation or loss, by its distribution between the intra- and extravascular beds, and by plasma volume. In adults, the liver normally synthesizes 10 to 15 gm (0.2 mmol)/day, which represents about 3% of the total body pool of albumin. Its biologic half-life is about 20 days, meaning that serum levels will not reflect hepatocellular function in acute liver disease. Serum albumin (and its synthesis) is decreased in chronic liver disease (eg, cirrhosis, ascites) because of the increased volume of distribution. Alcoholism and malnutrition also depress albumin synthesis. Hypoalbuminemia also results from excess albumin loss from the kidney (nephrotic syndrome), gut (protein-losing gastroenteropathies), and skin (burns).
Prothrombin time (PT) involves the interactions of fibrinogen, prothrombin, and factors V, VII, and X, which the liver synthesizes. Vitamin K is necessary for prothrombin and factors VII and X production in an active form. Vitamin K deficiencies result from either inadequate intake or malabsorption (since it is fat-soluble, vitamin K requires bile salts for intestinal absorption and would therefore be deficient in cholestasis). Malabsorption of vitamin K as a cause of a prolonged PT can be shown by giving it parenterally (eg, 10 mg s.c.) and finding a significant improvement 24 to 48 h later when the PT is repeated.
PT is relatively insensitive for detecting mild hepatocellular dysfunction. However, because the biologic half-lives of the clotting factors involved are short (hours to a few days), the PT has a high prognostic value in acute liver injury. In acute viral or toxic hepatitis, an abnormal PT prolonged > 5 sec above control is an early indicator of fulminant hepatic failure.
Serum Igs rise in most cases of chronic liver disease when the reticuloendothelial system is defective or bypassed by vascular shunts. The inability to clear portal venous blood of transient bacteremias from normal colonic flora results in chronic antigenic stimulation of the extrahepatic lymphoid tissue and hypergammaglobulinemia. Serum globulin levels rise slightly in acute hepatitis and more markedly in chronic active hepatitis, particularly that of the autoimmune variety. The pattern of Ig increase adds little: IgM is quite elevated in primary biliary cholangitis (PBC), IgA in alcoholic liver disease, and IgG in chronic active hepatitis.
Specific proteins may be diagnostic. Viral antigens (Ags) and antibodies (Abs) are associated with specific causes of hepatitis (see Acute Viral Hepatitis, Chapter 69 ACUTE VIRAL HEPATITIS and Infectious Mononucleosis, Chapter 205 EATING DISORDERS).
Mitochondrial Abs are positive, usually in high titers in > 97% of patients with PBC. These heterogeneous Abs are also present in 30% of patients with “autoimmune” chronic active hepatitis (HBsAg negative) and in some cases of connective tissue disease. They are absent in mechanical obstruction of the biliary system and primary sclerosing cholangitis; hence they have important diagnostic value, particularly when liver histopathology is equivocal.
Other Abs occur in autoimmune chronic active hepatitis: Smooth muscle Ab (SMAb) particularly directed against actin is found in 70% and double-stranded antinuclear Abs (ANAbs) are positive in high titers. Some patients exhibit another auto-Ab, antiliver-kidney -microsome Ab (LKM-1 Ab), which appears to define a subgroup of patients with chronic active hepatitis. None is diagnostic, and none reveals the pathogenesis of the disease process.
Alpha-Fetoprotein (AFP) synthesized by the fetal liver, is normally elevated in the mother and newborn. By 1 yr of age, infants achieve normal adult values (< 20 ng/mL). Marked elevations develop in primary hepatocellular carcinoma: AFP is a useful screening test, since few other conditions cause > 400 ng/mL. These include embryonic teratocarcinomas, hepatoblastomas, infrequent hepatic metastases from the GI tract, and perhaps some cholangiocarcinomas. In fulminant hepatitis, AFP can be > 1000 ng/mL; lesser elevations (100 to 400 ng/mL) occur in acute and chronic hepatitis (these values may represent hepatic regeneration).