James Neuberger Queen Elizabeth Hospital, Birmingham, UK The term “liver function test” (LFT) has become established in health care, but the term is misleading as the blood analytes measured may not accurately reflect the extent or nature of liver disease (Box 1.1). Although a more appropriate term is “liver blood tests,” this term is not used in this chapter, as the old term of LFTs has become enshrined in medical use. In addition, other commonly measured analytes give useful guidance on the presence and extent of liver disease (such as full blood count, prothrombin count). The term “normal range” has also become established, although it is preferable to use the term “reference range.” This range should ideally be determined for each laboratory and each piece of equipment. Factors that may affect the reference range include the selection of healthy people for determination of the reference range and the patient population; other factors that may affect the reference range include sex, age, and ethnic factors, time of day or season when samples are collected, variation in venipuncture technique, preparation, storage, and analysis of samples. The reference range should be established by testing at least 120 samples (although many regulatory bodies suggest a higher number) and clear outliers are usually excluded. The reference range may be determined by one of two approaches: Whichever approach is adopted, the implication is that, for healthy individuals, around 5% samples will have values lying outside the reference range. In some cases, such as blood sugar or triglycerides, the reference range is determined more by consensus than the process outlined above. When abnormal tests are reported, further investigations should be undertaken, the nature and extent will depend on the clinical situation. A guide to further management of abnormal liver tests is given in Box 1.2. This will help to define the presence (if any) of liver disease, the extent of liver damage, and the cause of the abnormal liver tests and, where appropriate, the response to treatment. A clinician needs to understand the several tests available to assess liver function and causes of liver disease and the limitation of these tests. Analytes measured in the battery of LFTs include: Interpretation of liver tests must always be made in the clinical context, and the extent, pattern of liver abnormality, and time course must be considered. For example, a falling high value for ALT may indicate improvement in the extent of hepatitis, but in the case of severe hepatitis, a return to normal values may indicate a failing liver (ALT predominantly coming from hepatocytes). Conversely, a serum ALT in the normal range may be misleading: cirrhosis may be present in the presence of an established cirrhosis and serum ALT in the upper part of the normal range is associated with an increased risk of death. Decreased circulating concentrations of albumin may be the result of either decreased production or increased loss. Levels are normally lower in the second and third trimesters of pregnancy because of increased plasma volume. Liver disease: the liver synthetizes about 12–15 g albumin daily. Its long half‐life (around 21 days) means that low levels from liver disease is not a robust marker of acute liver disease. In advanced liver disease from any cause, low albumin is a consequence of both decreased synthesis and increased catabolism. In those with ascites, loss of albumin to the ascites may contribute to the low serum albumin. Nutritional deficiency: the synthesis of albumin is dependent on the availability of amino acids (especially tryptophane), iron, and zinc, so nutritional causes may be associated with low serum albumin. Renal loss: normal loss of albumin through the kidney is normally very low but may increase with fever or exercise. Glomerular disease will lead to increased loss of albumin and may result in nephrotic syndrome. Gut loss: Protein‐losing enteropathy is characterized by loss of proteins including albumin via the gastrointestinal tract that exceeds synthesis. Protein loss through the gut may be due to mucosal disease without erosion (such as celiac disease), gut disease with mucosal erosions (such as Crohn’s disease) or increased lymphatic pressure (such as lymphangiectasis). Extravascular loss: albumin may leak from the vascular to extravascular compartments. For example, in burns, there is increased vascular permeability which, combined with an acute phase response, leads to inhibition of protein synthesis, with a resulting low serum albumin. Similar mechanisms account for low albumin levels in sepsis which is also associated with increased catabolism of albumin. Multifactorial causes of low albumin: low serum albumin may be seen in a variety of conditions which are associated with a combination of decreased albumin synthesis (which may be induced by inflammatory cytokines switching protein production from albumin to acute phase proteins), leakage from the vascular compartment, and increased catabolism. This may be seen in critical illnesses, for example. In advanced cardiac failure low serum albumin is also due to combinations of poor intake, poor adsorption, decreased synthesis, leakage form vascular compartments, and increased catabolism. Analbuminemia (with concentration of < 1 g/l) is a very rare cause of low albumin levels. High levels of albumin are uncommon and are not related to liver disease. Causes include some respiratory disorders such as tuberculosis, dehydration, vitamin A deficiency, excess corticosteroids, and some leukemias. Samples not processed immediately can also give artificial high concentrations of albumin. The enzymes AST and ALT catalyze the transfer of the α‐amino groups of alanine and aspartate to the α‐keto‐group of ketoglutaric acid, forming pyruvic and oxaloacetic acid, respectively. Whereas ALT is located primarily in the hepatocytes, AST is more widely distributed, including skeletal and cardiac muscle, red and white blood cells, brain, pancreas, and kidney. Within the hepatocyte, ALT is located primarily in the cytosol, whereas AST is located in the mitochondria (80%) and, to a lesser degree, in the cytosol. The reference ranges will vary between laboratories but the upper limit of normal is higher in males than females and should be considered in the light of body weight. In most cases of liver damage, both AST and ALT are elevated. Very high levels (> 500 iu/l) are seen in fulminant hepatic failure, ischemic hepatitis, acute Budd–Chiari syndrome, hepatic necrosis from drugs or hepatic artery ligation. Historically, there was much emphasis placed on the ratio of AST to ALT. In general, serum ALT levels are higher than serum AST in liver diseases, while AST is greater in some cases of alcohol‐related injury, steatosis, myopathy, ischemic hepatitis, hemolysis, thyroid disease, after strenuous exercise, and sepsis. In some instances, this increase is due to AST from non‐hepatic sources (such as muscle) or hepatic mitochondrial damage leading to a rise in mitochondrial AST (mAST). Although the ratio of AST to mAST may be helpful in defining liver causes of raised transaminases, mAST is rarely measured in clinical practice. Rarely, AST may bind to immunoglobulin A, leading to elevated measured levels; this is seen occasionally in association with liver malignancy. Low levels of ALT and AST may be seen in patients on long‐term hemodialysis, and this may be due, in part, to pyridoxine deficiency. In those in the very advanced stage of fulminant hepatic failure, serum transaminase activity falls; this may be a sign of necrotic liver rather than improvement in liver function. Alkaline phosphatases (ALPs) are in a family of enzymes that hydrolyze phosphate esters. There are several isoenzymes which differ in distribution and substrate. Isoenzymes are found in the liver, bone, intestine, placenta, leukocytes, and kidney. Within the liver, where are two isoenzymes, the ALP is distributed in sinusoidal and canalicular membranes, as well as the cytosol. There are several different approaches to the measurement of ALP and laboratory values and normal ranges vary according to methodology. The normal range of ALP is dependent on: Elevated levels of ALP are seen in association with: Raised levels of ALP are seen in most forms of liver disease and include: Other causes such as infection, cirrhosis, hepatitis where elevated ALP is less marked than transaminase levels. Mild elevations in ALP are seen not infrequently in non‐alcohol‐related fatty liver disease (NAFLD; 10% of patients may have isolated mild ALP rises). Occasionally there is a familial increase in ALP. It is usually possible to determine whether the raised ALP is due to hepatic or non‐hepatic causes by analyzing the isoenzymes, most rely on GGT (see below) as, in general, rises in liver and biliary ALP is mirrored by rises in GGT. Low levels of ALP are uncommon but may be seen in Wilson’s disease, hypothyroidism and iodine deficiency, pernicious anemia, zinc deficiency, achondroplasia, and hypophosphatasia. GGT catalyzes the transfer of peptide γ‐glutamyl groups to other amino acids, as well as being involved in the metabolism of some glutathione conjugates of drugs, and is also associated with oxidative stress. There are several isoenzymes. The enzyme is widely distributed in membranes including liver, biliary tree and gall bladder, spleen, pancreas, kidney, heart, and lung. Within the liver, GGT is distributed throughout the liver and in the biliary tree but is concentrated in the biliary epithelial cells in the small bile ductules. There is a correlation between higher levels of GGT with heart disease, stroke, and type 2 diabetes. The reference range is dependent on: Levels of GGT are elevated in several scenarios: Bilirubin is derived primarily from the degradation of hemoglobin. The metabolism of bilirubin and the various mechanisms of hyperbilirubinemia are shown in Figure 1.1. Figure 1.1 Metabolism of bilirubin and causes of jaundice. The normal range of bilirubin is affected by sex and is higher in men than women. Usually, the laboratories measure total serum bilirubin, although assessment of conjugated and unconjugated bilirubin will help to determine whether there is increased production or decreased excretion. As shown in Figure 1.1, unconjugated bilirubin is not water soluble (it is transported in plasma conjugated primarily to albumin) and therefore it is not seen in the urine in increased amounts. Causes for elevated levels of serum bilirubin can be seen in Box 1.3. Thus, unless there is a clear cause for the high serum bilirubin, it is helpful to measure direct and total bilirubin to distinguish the “pre‐hepatic” causes of hyperbilirubinemia from hepatic and biliary causes. A clinical rule of thumb is that unconjugated hyperbilirubinemia is not associated with dark urine, but the clinical assessment of both clinical jaundice and bilirubinuria are unreliable. Hemolysis is associated with increased unconjugated bilirubin, a reticulocytosis, and low haptoglobin (a protein that binds free bilirubin). Gilbert’s syndrome is a very common and innocent explanation for elevated total bilirubin, with near normal direct bilirubin values. It is an autosomal recessive condition related to variations in the UGT1A1 gene, which codes for uridine diphosphate glucuronosyltransferase, an enzyme involved in bilirubin conjugation. Thus, the person has higher levels of unconjugated serum bilirubin which may lead to mild jaundice (without dark urine), and levels are greater at times of physical or emotional stress. No treatment or routine follow‐up is required. The diagnosis is made on the basis of a raised unconjugated serum bilirubin and no signs of hemolysis. The diagnosis can, if necessary, be confirmed by mutation analysis of the gene involved, but generally this is not relevant practically. Other mutations may lead to the Crigler–Najjar syndrome, which presents in the newborn. Enzyme levels are much lower than those seen in Gilbert’s syndrome. High levels of unconjugated bilirubin may lead to neurological damage in the child and therefore active management by specialists may be indicated.
1
Liver Tests
Introduction
The Reference Range
The Standard Liver Function Tests
Albumin
Decreased Production of Albumin
Increased Loss of Albumin
Aspartate and Alanine Amino Transferase
Alkaline Phosphatase
Liver Causes of Raised Alkaline Phosphatase
Gamma‐Glutamyl Transferase
Bilirubin
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