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Cholestasis indices

  1. Gastroepato
  2. Gastroenterology
  3. Cholestasis indices
  4. Cirrhosis
  5. Stasis liver, etiopathogenesis
  6. Stasi liver
  7. The patient with liver disease

Notes by dr. Claudio Italiano

They are laboratory parameters that allow the hepatologist to be aware of the proper functioning of the biliary function of the liver and, above all, of the excretion of bile from the biliary tract.
It's very important to know the values ​​of the cholestasis indices to immediately understand if there is a block in the outflow of bile from the liver to the choledochus and therefore require further instrumental investigations

The main indices are listed below:

- γGT
- LDH
- ALP
- 5'-NT
- Bilirubin
- bile acids

Gamma-glutamyl transpeptidase

The gamma-glutamyl hepatic transpeptidase (GGT) derives from hepatocytes and from the biliary epithelium, but like ALP, GGT is found in numerous extrahepatic tissues including the kidney, spleen, pancreas, heart, lung and brain. However, GGT is not found to be appreciable in the bone and therefore is useful for confirming the hepatic origin of a high ALP. The normal serum GGT level is significantly higher in children than in adults. Both recurrent benign intrahepatic cholestasis and Byler's disease, rare cholestatic hepatopathies that often begin in childhood, are characterized by an increase in serum ALP in the absence of GGT increase.

Therefore, serum GGT should be measured in all children with cholestatic liver disease. GGT is also a microsomal enzyme and is therefore induced by alcohol and some drugs such as most anticonvulsants and warfarin. In fact it has been reported that a GGT / ALP ratio above 2.5 is indicative of alcohol abuse. However, more than a third of regular alcohol users (> 80 g / day) have normal plasma GGT levels and the enzyme often does not increase when alcohol is used. Therefore the value of GGT for assessing a suspected alcohol intake is limited.

Jaundice patient with percutaneous
drainage of the hepatic tree

Lactic dehydrogenase

Lactic dehydrogenase (LDH) has a large tissue distribution; increased levels of LDH are observed, in addition to acute and chronic liver disease, in case of skeletal muscle damage or ischemia heart disease, hemolysis, stroke and renal infarction. Because of this non-specificity, the dosage of LDHs rarely adds useful information to those obtained from transaminase values ​​alone. Uncommon situations in which serum LDH levels may be diagnostically useful include the massive but transient increase in the characteristic LDH of ischemic hepatitis and the persistent increase in LDH, associated with increased levels of alkaline phosphatase, which suggests a malignant infiltration of the hepatic parenchyma (see hepatocellular carcinoma).

Alkaline phosphatase

Alkaline phosphatase (ALP) comprises a group of enzymes present in various tissues including the liver, bone, intestine, kidneys, placenta, leukocytes and various neoplasms. The physiological roles of the different ALP enzymes are not clear, but their production tends to increase in tissues undergoing metabolic stimulation. Therefore the serum activity of ALP during adolescence is up to three times higher than that of adults for rapid bone growth; ALP also increases in late pregnancy due to placental growth and metabolism. Bone and liver are the major source of serum ALP, although people with blood group 0 or B may have an increased serum ALP secondary to an intestinal production, especially after a fatty meal. This possibility provides the rationale for carrying out the determinations of fasting ALP. Patients with chronic renal failure may also have increases in intestinal ALP isoforms; moreover, serum ALP levels can rarely be increased on a genetic basis in the absence of a clear liver disease. Hepatic ALP is normally present in the apical (for example, canalicular) domain of the hepatocyte plasma membrane and in the luminal domain of the bile ducts epithelium. In the context of liver disease, the increase in ALP results more from an increase in the synthesis and release of the enzyme in the serum than from an altered biliary secretion. Bile acids, retained in cholestatic hepatic diseases, can solubilize the plasma membrane of the hepatocyte and facilitate the release of ALP. Since the increase in serum ALP is secondary to the synthesis of a new enzyme, ALP does not increase one or two days after an acute biliary obstruction. Furthermore, as the half-life of serum ALP is about 1 week, serum level may remain elevated for several days after resolution of a biliary obstruction. Levels of ALP up to 3 times normal values ​​are not very specific and are observed in different liver diseases. Significant increases in ALP are observed above all in infiltrated hepatic diseases (for example, primary or metastatic tumors) or in biliary obstructions; both intrahepatic (for example, primary biliary cirrhosis, CBP) and extrahepatic. The increase in serum ALP with hepatic infiltration is probably secondary to the compression of the small intrahepatic bile ducts. It is important to underline that in the focal obstruction of the intrahepatic ducts secondary to a tumor the levels of ALP can be elevated, while the levels of serum bilirubin are characteristically normal. Although sensitive, serum ALP may occasionally be normal despite the presence of a large hepatic metastasis or rarely despite documented obstruction of the main ducts. The value of ALP can not be used to distinguish with certainty an intra- and extrahepatic ductal obstruction or a hepatic infiltration. For example, overlapping levels may be present in hepatic metastases located in strategic areas, obstructive coledocolitiasis and CBP. The level of ALP can rarely be increased during a tumor pathology without recognizable hepatic or bone involvement. This so-called "Regan isoenzyme" is biochemically distinct from hepatic ALP and has been identified in association with several types of cancer (for example, lung neoplasms). Another explanation for increasing serum ALP in a cancer patient is the presence of nonspecific hepatitis reported in association with Hodgkin's disease and renal cell carcinoma without clear hepatic involvement. The increase in ALP is commonly seen in neonatal hepatopathy from various causes.

5'-Nucleotidase

The 5'-nucleotidase (5'-NT) is present in numerous tissues including the liver, the myocardium, the brain, the blood vessels and the pancreas. Despite this large tissue distribution, significant increases in plasma 5'-NT levels are observed almost exclusively in hepatopathies. In the liver this enzyme is localized in both sinusoidal hepatocytes and in the canalicular plasma membranes. The enzyme has a sensitivity overlapping that of ALP in identifying a biliary obstruction, a hepatic infiltration or a picture of cholestasis but it can show different kinetics from both ALP and GGT, as it increases many days after the experimental ligation of the bile duct. Therefore 5'-NT may occasionally be normal in the presence of acute increases of the other two enzymes and may be less useful than GGT as a test to confirm the hepatic origin of increased ALP levels.

Bilirubin

Bilirubin is an organic anion derived mainly from the catabolism of hemoglobin. The metabolism, the measurement of bilirubin and the diagnostic approach to the patient are described in detail in another chapter and in this section will be discussed only briefly. Serum bilirubin consists of two main forms, a water soluble, conjugate, defined as a "direct" fraction and a fat soluble, non-conjugated, termed "indirect" fraction. Plasma bilirubin normally has a concentration of less than 1 mg / dl (18 μmol/l). The serum bilirubin level is represented in normal conditions almost entirely from unconjugated bilirubin, when measured with sensitive techniques, and reflects a balance between the rates of production and hepatobiliary excretion. The production of bilirubin is accelerated in case of hemolysis, ineffective erythropoiesis, reabsorption of a hematoma or, rarely, muscle damage; in all these cases an unconjugated hyperbilirubinemia is observed. In case of alteration of the biliary excretion, as observed in the pathologies of the hepatic parenchyma or in the obstruction of the biliary tree, an increase in conjugated bilirubin occurs characteristically. The bilirubin in the urine is always in the conjugated form and is therefore indicative of hepatobiliary pathology, since the non-conjugated form is bound to the albumin and is not filtered by the normal glomeruli.

Direct hyperbilirubinemia

Unconjugated hyperbilirubinemia (e.g., indirect bilirubin fraction greater than 85% of total plasma bilirubin) results from both an increased production of bilirubin and from congenital or acquired defects of hepatic uptake and conjugation. The diagnosis of haemolysis is based on a careful medical history (for example, history of anemia, recent blood transfusions, drug intake) and on simple screening tests (for example, complete blood count, a peripheral blood smear, reticulocytes, LDH and haptoglobin). If these screening tests suggest the diagnosis of hemolysis, the specific cause can be investigated through more specialized investigations (for example, the Coombs test, glucose-6-phosphate dehydrogenase assay [G6PD], electrophoresis of the hemoglobin). It is important to note that, in the presence of normal liver function, chronic hemolysis may not occur with a persistent increase in plasma bilirubin at concentrations above 5 mg / dl.

Conjugated bilirubinemia

Conjugated hyperbilirubinemia (e.g., direct bilirubin fraction greater than 50% of total plasma bilirubin) occurs as a result of congenital or acquired hepatic excretion, limiting the speed of bilirubin metabolism, and the resulting bilirubin reflux conjugated from hepatocytes in plasma. Although the measurement of the conjugated fraction is not reliable in distinguishing biliary obstruction from parenchymal liver disease, the magnitude of bilirubin increase may be useful for prognostic purposes in alcoholic hepatitis, primary biliary cirrhosis, and fulminant hepatic failure. Since conjugated bilirubin is cleared by the kidney, bilirubin plasma concentrations rarely exceed 30 mg / dl in the absence of hemolysis or renal failure.
A fraction of circulating conjugated bilirubin detected in a long-term cholestasis (delta fraction) is closely linked to albumin and therefore does not appear in urine but reacts directly with the reacting diazo used for the measurement of bilirubin. This phenomenon may explain the occasional paradox of the patient with a pathology of the hepatic parenchyma which presents a modest increase in direct bilirubin levels but mild or completely absent bilirubinuria, such as the tendency of bilirubinuria to disappear before hyperbilirubinemia in patients with hepatopathy in the resolution phase. This may also contribute to the tendency of hyperbilirubinemia to resolve more slowly than other biochemical indices of liver injury.

Bile acids

Bile acids are organic anions synthesized from cholesterol exclusively in the liver. Although several studies suggest that measurement of bile acid plasma concentration represents a sensitive index of hepatic pathology, there is little evidence that their determination offers any further advantage over conventional biochemical tests for early detection of liver disease. Furthermore, the usefulness of measurement of plasma bile acids in determining the prognosis in case of acute or chronic liver disease is uncertain and therefore their measurement is not widespread.

cfr index of hepatology