Pathophysiology
Components of Liver Function Test
Hepatocellular Labs
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Aminotransferase includes AST and ALT. They are markers of hepatocellular injury. They participate in gluconeogenesis by catalyzing the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid, respectively. AST is present as cytosolic and mitochondrial isoenzymes and is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and red cells. It is not as sensitive or specific for the liver as ALT and elevation in AST may be seen as secondary to nonhepatic causes as well. AST activity in neonates and infants is approximately twice that in adults, but these decline to adult levels by approximately six months.[7]
ALT is a cytosolic enzyme that is found in high concentrations in the liver. The half-life of ALT is approximately 47 ± 10 hours. ALT is usually higher than AST in most types of liver disease in which the activity of both enzymes is predominantly from the hepatocyte cytosol. Hepatocellular injury and not necessarily cell death triggers the release of these enzymes into circulation. Both AST and ALT values are higher in normal males than females.[8]They also correlate with obesity with a normal reference range higher in those with higher body mass index.[9]
Cholestasis Labs
Alkaline phosphatase is part of a family of zinc metalloenzymes that are highly concentrated in the microvilli of the bile canaliculus as well as several other tissues (e.g., bone, intestines, and placenta).[1] There are four isozymes: placental ALP or hPLALP (human placental ALP), germ cell ALP (GCALP or PLALP-like), intestinal ALP (IALP), and tissue-nonspecific ALP (TNALP). Of these four, PLALP and GCALP are the most heat stable at 65 C, and the bone ALP component of TnALP is the least. In healthy, non-smoking individuals, the PLALP and GCALP represent less than 1% of total ALP activity in the serum.[10]
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A condition that can result in significantly increased plasma ALP is benign transient hyperphosphatasemia. Originally described in infants, transient hyperphosphatasemia can also occur in adults and during pregnancy. There is a marked rise in ALP, often to several thousand IU/L, which usually indicates significant pathology. It is, however, a benign condition with a return to normal of the ALP in 6 to 8 weeks. Transient hyperphosphatasaemia is associated with concurrent infections in over 60% of cases, particularly GIT infections. There is a characteristic pattern on polyacrylamide gel electrophoresis, with the normal pattern of isoenzymes being accompanied by variant forms that react with neuraminidase. It is believed to be due to changes in carbohydrate side chains causing failure of recognition by receptors and reduced clearance, thus prolonging half-life.[11]
Glycoprotein gamma-glutamyltransferase (GGT) is located on membranes of cells with high secretory or absorptive activities. Its primary function is to catalyze the transfer of a gamma-glutamyl group from peptides to other amino acids. It is also abundant in many other sources of the body (kidney, pancreas, intestine, prostate, testicles, spleen, heart, and brain) but is more specific for biliary disease when compared to alkaline phosphatase because it is not present in bone. Serum GGT shows electrophoretic mobility and lectin-affinity reaction identical to the liver enzyme but different from GGT from the kidney, urine, and pancreas.GGT levels are reported to be increased by an average of 12-fold in obstructive liver disease compared to ALP, which increased only 3-fold, so GGT is slightly more sensitive than ALP in this regard.GGT activity level in children may be a reliable index of bile duct damage. It is a useful indicator in separating the two forms of idiopathic cholestasis, with or without bile duct involvement. In infants diagnosed with biliary atresia and managed surgically, the GGT levels stay high in the blood if the infant is breastfed. This is due to the high level of GGT in human breast milk for at least four weeks postpartum.[12]
There is a relationship between plasma GGT activity and weight, with values being 50% higher in individuals with a BMI greater than 30 kg/m2. This is believed to be due to fat deposition in the liver (steatosis) in obese subjects. Steatosis with a raised plasma GGT also occurs in diabetes mellitus, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. Any liver disease that results in fibrosis and/or cirrhosis, such as alcoholic cirrhosis, PBC, PSC, hemochromatosis, α1-antitrypsin deficiency, and Wilson disease, will cause a raised plasma GGT. Space-occupying lesions, including malignancy (HCC or metastases secondary to malignancy elsewhere in the body), and granulomatous disease, for example, sarcoidosis and TB, are also associated with a raised plasma GGT.5′-Nucleotidase (5′NT) is associated with the canalicular and sinusoidal plasma membranes. Its function is undefined. 5′NT is also found in the intestine, brain, heart, blood vessels, and endocrine pancreas. Serum levels of 5′NT are unaffected by sex or race, but age affects the level; values are lowest in children and increase gradually, reaching a plateau at approximately age 50 years. As with GGT, the primary role of the serum 5′NT level is to identify the organ source of an isolated serum alkaline phosphatase elevation. The 5′NT level is not increased in bone disease but primarily in hepatobiliary disease. LDH is commonly included in biochemical liver panels but has poor diagnostic specificity for liver disease. Markedly increased LDH levels are observed in hepatocellular necrosis, shock liver, lymphoma, or hemolysis associated with liver disease.[13]
Bilirubin is the end product of heme catabolism, with 80% derived from hemoglobin. Unconjugated bilirubin is transported to the liver loosely bound to albumin. Bilirubin is water-insoluble and cannot be excreted in the urine. Bilirubin that is conjugated is water-soluble and appears in the urine. It is conjugated in the liver to bilirubin glucuronide and subsequently secreted into bile and the gut, respectively.[14]
Synthetic Function Tests
Albumin is synthesized by the hepatic parenchymal cells at a rate dependent on colloidal osmotic pressure and dietary protein intake. The rate of albumin synthesis is also subject to feedback regulation determined by the plasma albumin concentration. Maintenance of plasma albumin concentrations can be achieved with only 10% of normal hepatocyte mass. The half-life of albumin is 21 days. Traces of albumin can be found in almost all extracellular body fluids. Little is lost from the body by excretion.[15] It is catabolized in various tissues, which are taken up by cells by pinocytosis. Its constituent amino acids are released by intracellular proteolysis and returned to the body pool. With any liver disease, there is a fall in serum albumin, reflecting decreased synthesis. If liver function is normal and serum albumin is low, this may reflect poor protein intake (malnutrition) or protein loss (nephrotic syndrome, malabsorption, or protein-losing enteropathy).[16]
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Prothrombin time (PT) measures the rate of conversion of prothrombin to thrombin. Except for factor VIII, all other coagulation factors are synthesized by the liver. Prothrombin time requires factors II, V, VII, and X, and, as these are made in the liver, the liver’s function is crucial in coagulation. Suppose the synthetic function of the liver is normal and prothrombin time is delayed. This may indicate treatment with warfarin, consumptive coagulopathy (eg, disseminated intravascular coagulopathy), or vitamin K deficiency.[17]
Serological Tests
Liver-related autoantibodies are crucial for correctly diagnosing and classifying autoimmune liver diseases, namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA, and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.[18]PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents in at least two variants; first, the classical primary sclerosing cholangitis (PSC) mostly affects adult men wherein the only (and non-specific) reactivity is an atypical perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH.[19]
Secondary Biochemical Liver Tests
Alpha-fetoprotein (AFP) measurements are used as a tumor marker for the detection and monitoring of primary hepatocellular malignancies, such as hepatoblastoma and HCC. Hepatoblasts produce alpha-fetoprotein, which is why it is raised in the regenerating liver, particularly in chronic viral hepatitis.[20]
Carbohydrate deficient transferrin is a high-specificity test for detecting excess alcohol intake as a cause of liver damage. The carbohydrate antigen CA19-9 is useful in monitoring the activity of the autoimmune disease PSC, which often progresses to a tumor of the bile ducts or cholangiocarcinoma.[21] Measurement of serum ferritin can be useful in identifying hemochromatosis, but ferritin is a positive acute phase reactant, so it is raised in many illnesses as well as being released from damaged hepatocytes in acute hepatic failure.[22]
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