Alkaline phosphatase biliary obstruction

The Group II (biliary tract) enzymes are abnormal usually when the serum bilirubin concentration is also abnormal. Most commonly used is alkaline phosphatase which is a highly sensitive indicator of biliary tract obstruction, perhaps because the enzyme is synthesized as an induced response to obstruction of even small bile ducts. Most techniques used to identify the origin of an elevated serum alkaline phosphatase are not very useful from a clinical viewpoint (23). The simultaneous measurement of GMT activity has been found to be useful in differentiating between the hepatic and bony origin of alkaline phosphatase. An increased GMT activity in a patient with an increased ALP activity is a good indication that there is biliary biliary tract disease (62,63). 

Alkaline phosphatase levels and GGT are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines in condition such as primary biliary cirrhosis, sclerosing cholangitis, drug-induced cholestasis, gallstone disease, and autoimmune cholestatic liver disease. 

Alkaline phosphatase (ALP) Liver kidney, bone, placenta, intestine, biliary epithelia 30-300 lU/L (higher in children due to increased bone growth) Raised levels may indicate biliary inflammation/ obstruction, malignant infiltration, cirrhosis, bone destruction, Paget s disease... 

A 63-year-old man, who had taken amiloride and alfuzosin for 9 months for hypertension and benign prostatic hyperplasia, became jaundiced. His aspartate transaminase was 3013IU/1, alanine transaminase 2711 IU/1, alkaline phosphatase 500 IU/1, and total bilirubin 415 pmol/l. Viral causes, autoimmune hepatitis, and biliary obstruction were excluded. After withdrawal of alfuzosin, his liver function tests gradually returned to normal within 6 months. 

Measurement of serum y-GT activity has clinical significance. The enzyme is present in all tissues, but the highest level is in the kidney however, the serum enzyme originates primarily from the hepatobiliary system. Elevated levels of serum y-GT are found in the following disorders intra- and posthepatic biliary obstruction (elevated serum y-GT indicates cholestasis, as do leucine aminopeptidase, 5 -nucleotidase, and alkaline phosphatase) primary or disseminated neoplasms some pancreatic cancers, especially when associated with hepatobiliary obstruction alcohol-induced liver disease (serum y-GT may be exquisitely sensitive to alcohol-induced liver injury) and some prostatic carcinomas (serum from normal males has 50% higher activity than that of females). Increased activity is also found in patients receiving phenobarbital or phenytoin, possibly due to induction of y-GT in liver cells by these drugs. 

In Ghosh and Nath s experiments with paper electrophoresis (barbitone buffer, pH 8.6), rachitic serum showed an alkaline phosphatase mobility close to the mobility of jS-globulin (Nil). Sera from infective hepatitis and obstructive biliary cirrhosis, however, showed maximum alkaline phosphatase activity in the 2-globulin zone (G5). 

C2. Carlsten, A., Edlund, Y., and Thulesius, 0., Bilirubin, alkaline phosphatase and transaminases in blood and lymph during biliary obstruction in the cat. Ada Physiol. Scand. 63, 58-67 (1961). 

Sebesta, D. G., Bradshaw, F. J., and Prockop, D. J., Source of the elevated serum alkaline phosphatase activity in biliary obstruction Studies using isolated liver perfusion. Gastroenterology 47, 166-170 (1964). 

The liver can be involved in CF. Biliary cirrhosis secondary to bile duct obstruction occurs in as many as 18% of patients, whereas fatty infiltration occurs in about 30% of patients in a pattern unrelated to nutritional status. Bile ducts may be obstructed by inspissated mucus, which may lead to focal or multilobar cirrhosis. Such hepatic involvement can occur at any age but is more common with advancing age and can lead to portal hypertension, esophageal varices, and hypersplenism. The most common laboratory abnormality associated with hepatic involvement is elevated serum hepatic isoenzymes (gamma-glutamyltranspeptidase, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase)." ... 

Space occupying lesions of the liver, partial biliary obstruction and hepatotoxic drugs, may raise serum alkaline phosphatase in the presence of normal serum bilirubin (see Fig. 11). 

The association between hyperphosphatasemia and hepatobiliary disorders was first reported in 1930 (R24) and until the late 1960s, this association was explained in terms of the excretion theory. According to this theory, skeletal alkaline phosphatase is normally excreted by the liver and failure of this excretory process, as in biliary obstruction, results in serum alkaline phosphatase elevation (G28). 

The excretion theory is now thoroughly discounted and there is considerable evidence to suggest that in hepatobiliary disease, the eirculating alkaline phosphatase comes from the liver and/or the bile passages (H15a, K7, P19, R21, S24). It now appears established that biliary obstruction leads to increased synthesis of alkaline phosphatase in the hepatobiliary system (K6) and that the newly synthesized enzyme then reaches the blood via canalicular-sinusoidal connections (R23). 

Enzymatic estimations are only moderately helpful in distinguishing the various hepatic disorders from each other. The belief that high serum alkaline phosphatase activities are indicative of biliary obstruction while normal or only moderately elevated activities occur in association with hepatocellular damage is now known to be an oversimplification. There is considerable overlap between values in obstructive and nonobstructive hepatic disease (Fig. 10), so that serum alkaline phosphatase elevation or nonelevation in the differential diagnosis of hepatobiliary disease is useful only in a statistical sense (H14). 

Fig. 10. Serum alkaline phosphatase values (King-Armstrong units/deciliter) in 49 patients with documented bile duct obstruction (solid circles) and in 49 patients with hepatic cirrhosis or hepatitis (open circles). Note the si ficant overlap between the groups. Note also that the highest value in biliary obstruction was Iras than ten times the upper limit of normal. From Hill and Zieve (H14) with permission.

Intrahepatic and Extrahepatic Sepsis. Bacterial infection of the liver, with microscopic or macroscopic abscess formation, results in hyperbilirubinemia and a rise in serum alkaline phosphatase (B53). Hyperphosphatasemia is greater in patients with microabscesses, particularly in cases of biliary tract obstruction, than in patients with macroscopic abscesses, who show only modest serum alkaline phosphatase elevation (R32). 

Marked elevation of serum alkaline phosphatase in an alcoholic patient usually denotes the presence of biliary tract obstruction or space occupying lesions within the liver. However, in a few patients, alcoholic hepatitis and cirrhosis may be present, with marked hyperphosphatasemia due to intrahepatic cholestasis (PIO). 

Obstruction of the biliary passages, whether intrinsic or extrinsic, causes serum alkaline phosphatase elevation. The degree of elevation is very variable (Bll, S12). In most instances, values are greater than 3 times the upper reference limit, but they rarely exceed 10 times the upper reference limit (see Fig. 10). 

Cholestasis in the absence of demonstrable mechanical biliary obstruction is usually referred to as intrahepatic cholestasis, a term which implies that there is microscopic obstruction within the liver itself (P21). The condition occurs after the administration of various drugs, (see Table 10), in the presence of some infectious disorders (see Section 7.4), and during the last months of pregnancy. Mean serum alkaline phosphatase values in women with clinically overt cholestasis of pregnancy are higher than in matched controls (R13), although individual patients may have values appropriate to the last trimester of pregnancy (H2, R13). In some patients with intrahepatic cholestasis, no cause is identifiable (R35, S58). Serum alkaline phosphatase values in idiopathic cholestasis may be 7 times the upper reference limit (S75). 

Patients with this disorder frequently develop h)q)erbilirubinemia and hyperphosphatasemia during exacerbations. As each individual attack subsides, serum bilirubin concentrations return to normal at times when serum alkaline phosphatase values are still elevated. This sequence of events parallels that seen in most patients with extrahepatic biliary obstruction. 

Gullick (G27) studied 100 patients with carcinoma of the pancreas. Fifteen of 18 icteric patients had elevated serum alkaline phosphatase values, but there was no correlation between the severity of the hyperbilirubinemia and that of the hyperphosphatasemia. Among nonicteric patients, serum alkaline phosphatase elevation was usually associated with hepatic metastases (G27). The majority of patients with carcinoma of the pancreas without biliary obstruction have normal serum alkaline phosphatase activities (K32). 

The activity of alkaline phosphatase in serum is elevated above normal in a variety of different bone diseases, as well as biliary obstruction and some other liver diseases. Measurement of alkaline phosphatase activity in serum can thus give useful information about these conditions. It is especially useful for diagnosis of preclinical rickets and osteomalacia (section 11.3.4). 

Hepatobiliary conditions Alkaline phosphatase is found in cells lining the bile canaliculi and is normally excreted in the bile. If the biliary flow is obstructed, the enzyme is regurgitated back into the bloodstream. Its presence in grossly elevated amounts in the serum therefore suggests cholestasis rather than liver cell damage. Large increases in serum alkaline phosphatase activity are therefore found in extra-hepatic biliary obstruction whereas more moderate increases are found in a whole variety of other liver conditions such as hepatitis, cirrhosis and hepatic carcinomas. 

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