Elevated alkaline phosphatase and bilirubin in colorectal cancer patient

Patient History

The patient's medical history involved a resected colorectal carcinoma at the age of 60, with no evidence of metastatic disease. Liver function was normal at the time of surgery. Three years later, the female patient was found to have serum bilirubin levels of 20 ?mol/L. The serum levels for aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were 23 U/L and 820 U/L, respectively.

Interpretation of the Laboratory Tests

High serum levels of ALP can indicate the presence of disease in the liver, bone, intestinal tract, and/or parathyroid, but the most common use for this assay is to detect disease of the hepatobiliary tract (Tietz, 1999, p 676). This is because the liver will respond to any obstruction in the biliary tree by producing more ALP, and these levels can be especially high if the blockage is extrahepatic (> 3 times the upper limit of the normal range). The normal range for women between the ages of 61 and 65 is 50-130 U/L, which is the age of the patient at the time of the most recent test. The patient's serum ALP levels are therefore 6-fold higher than the upper limit of the normal range. This level of ALP is consistent with a number of diseases and conditions, including extrahepatic obstructions like stones or a tumor of the pancreas head, or osteogenic bone cancer. The patient's ALP levels are not consistent with Paget's disease, because this condition tends to produce serum levels reaching 10 to 25 times the normal upper limit (Tietz, 1999, p. 677). The presence of disease affecting hepatocytes is unlikely given how high the ALP levels are, but this possibility can't be eliminated using this test alone. The sources of serum ALP can also be discriminated to some extent through laboratory testing, because different ALP isoenzymes are produced by the liver, bone, and placenta. This test can help discriminate between liver or bone diseases, including malignancies, or ectopic expression of the placental form (Regan isoenzyme) by other malignancies.

Assuming the bilirubin assay results are for total bilirubin, then the patients serum levels are slightly elevated (17%). The upper limit of the normal range for adult females is 17.1 ?mol/L (Tietz, 1999, p. 1170), so a serum level of 20 ?mol/L in an adult female would represent mild hyperbilirubinemia insufficient to cause the symptoms of jaundice (Tietz, 1999, p. 1158). The evaluation of total bilirubin serum levels is normally performed to assess liver function, but can also be used to evaluate diseases and treatments affecting the various stages of bilirubin production, metabolism, and excretion. In healthy individuals, bilirubin is extracted from senescent red blood cells by the liver, where it is conjugated with glucuronic acid for excretion in the bile (Tietz, 1999, p. 1135). Hemolysis or ineffective erythropoiesis represent prehepatic causes of hyperbilirubinemia, producing unconjugated bilirubin, otherwise any number of intrahepatic or post-hepatic diseases and conditions that affect liver or biliary function can elevate conjugated bilirubin serum levels as well (Jones, 2001). Together with the high serum levels of ALP, the mild hyperbilirubinemia could indicate a problem with the hepatobiliary system, but is otherwise not very useful diagnostically.

The patient's serum levels of AST (23 U/L) are well within the normal range for this enzyme (8-43 U/L; Jones, 2005). This test is typically used to assess liver function and represents one of two markers that can indicate the presence of liver disease. The other enzyme frequently used to assess liver function is alanine aminotransferase (ALT), which is a more specific and longer lasting marker for diseases affecting the cellular integrity of hepatocytes. In mild hepatocellular disease, the cytosolic forms of ALT and AST are released and the ALT/AST ratio is typically close to, or above, unity (Tietz, 1999, p. 653). If the liver disease is severe enough to cause hepatocyte necrosis, then the ALT/AST ratio is depressed due to the additional release of the mitochondrial isoenzyme of AST. Both AST and ALT can become elevated before clinical signs or symptoms of disease have manifested, and are therefore a preferred method for assessing hepatocyte health. In contrast to ALT, which is specific to hepatocytes, AST is also stored at high concentrations in the heart, skeletal muscle, and kidneys, and is therefore less liver-specific than ALT. The fact that the patient's AST levels are within the normal range for adults, diseases resulting in elevated serum AST levels can be eliminated as possible sources of elevated ALP levels and mild hyperbilirubinemia. Hepatocytes are therefore unlikely to be affected in this patient by whatever is causing these symptoms.

Additional Tests

Additional tests are required to obtain a definitive diagnosis. First, the possibility of drug toxicity or a history of alcoholism affecting liver function should be assessed (Walmsley, Watkinson, and Cain, 1999, p. 151). If these factors are eliminated then the most instructive laboratory tests would be serum levels for ?-glutamyl transferase (GGT) or 5'-nucleotidase (NTP), because these biliary tract enzymes can help to discriminate between several possible sources of elevated ALP (Tietz, 1999, p. 1168).

GGT

GGT is present in all tissues except muscle, but at particularly high concentrations in the kidney (Tietz, 1999, p. 687). Despite the wide distribution throughout the body and being concentrated in the kidneys, elevated serum levels are almost always diagnostic of any form of liver disease. In cases of hepatic or posthepatic biliary obstruction the serum levels may rise 5- to 30-fold above the normal range, and is therefore more sensitive than ALP and NTP, and more specific than ALP.

NTP

Although NTP is present in many different tissues throughout the body, it is generally considered to be specific for hepatobiliary disease. In contrast to ALP though, NTP is only slightly elevated by some cases of bone malignancy, but always tracks with ALP when the hepatobiliary system is affected (Tietz, 1999, p. 685). If NPT levels in this patient were found to be similar to ALP levels, then it would be diagnostic for hepatobiliary disease.

If the GGT or NTP serum levels turn out to be significantly elevated, then the cancer history of the patient should trigger an ultrasound and/or CT scan of the biliary tree in an effort to locate any tumor masses that could be obstructing bile flow (Tietz, 1999, p. 1168). Screening for hepatitis should also be performed, because chemotherapy can sometimes trigger reactivation of the virus (Kusumoto, Tanaka, Mizokami, and Ueda, 2009).

Should the above tests for GGT or NTP turn out to be negative, then this would suggest the source of ALP is not the hepatobiliary system, but a bone or other malignancy (Tietz, 1999, p. 1168). In this situation, determining the ALP isoenzyme responsible for the elevated serum levels would be diagnostically useful. This test would help discriminate between liver, bone, and ectopic ALP production by malignancies. Given the gender of the patient and history of cancer, screening for breast cancer is also warranted.

Other tests that should be run given the age of the patient include determination of plasma calcium, phosphate, and vitamin D levels, and running parathyroid hormone studies (Walmsley, Watkinson, and Cain, 1999, pp. 157-158). Blood calcium and phosphate levels could be indicative of bone involvement. Vitamin D deficiency often results in elevated serum ALP levels, and is typically one of the first symptoms detected. Secondary hyperparathyroidism can also cause elevated serum levels of ALP.