Uncle Buck, a 50 year old health conscious guy, goes in for his annual checkup including glucose, TSH, total cholesterol, CBC, and a fecal occult blood test. The results were all normal, except for a positive FOBT. The risk for colon cancer polyps begins at age 50, and the diagnostic yield increases with age. A positive FOBT indicates blood in the stool, however, the traditional guaiac reaction used in the lab for Uncle Buck's case has some interferences associated with it. A colonoscopy for Uncle Buck was the follow-up test to the FOBT to detect polyps in the intestine. However, Uncle Buck's colonoscopy results were negative, along with detecting still another positive FOBT before he leaves the physician's office that same day. Colorectal lesions are usually revealed in a colonoscopy; however, miss rates of adenomas do occur if the screening is done too rapidly, or if screening is done consecutively.
The early stages of colon cancer can be also be missed on a colonoscopy if the disease has not progressed to a detectable level. However, Uncle Buck's case is most likely not colon cancer, but rather a discrepancy with the screening methods.
The FOBT has traditionally been performed using guaiac-based methods that detect the peroxidase activity of heme in blood and other peroxidases (3). Guaiac gum is saturated on a piece of filter paper. If heme oxidase is present, after hydrogen peroxide has been added to oxidize peroxidases present in heme, there is a color change observed. If a blue color does not emerge within 1 minute after hydrogen peroxide is added, the test is negative (3). Technical expertise is needed to carry out this complex test, so that an accurate result is generated. Only experienced personnel should carry out G-FOBT. Guaiac-based FOBT has a lower sensitivity and thus limited diagnostic performance for detecting colon cancer. The G-FOBT is used only for blood in stool, not in urine (3). Thus, several interferences could result from using this method in the case of Uncle Buck's laboratory results. False positives are strongly correlated with diet before the test, so peroxidase sources are restricted 72 hours before the test. Some examples of peroxidase sources are red meat (beef, lamb, and liver), cantaloupe, lightly cooked or uncooked turnips, horseradish, radishes, broccoli, cauliflower, spinach, tomato, parsnips, bananas, and vitamin C-rich fruit (3). Drugs, such as, steroids, nonsteroidal anti-inflammatory agents, and aspirin also cause false positives since these medications may result in gastrointestinal blood loss (4). The rate of false-positives is about 30%. The G-FOBT is designed to detect a blood loss of 20 mL/day and a normal intestine has a blood loss of up to 2.0 mL/day (4). Sensitivity of guaiac tests is usually between 50-70% and specificity is generally over 95%, increasing to 98-99% when dietary restrictions are followed. Despite the lower sensitivity, G-FOBT is effective enough to reduce CRC mortality by 33% in U.S. cases (3). The G-FOBT test is too selective for contents in fecal blood, causing false-positives.
The immunochemical FOBT (iFOBT) detects only intact human globin protein. With the use of either monoclonal or polyclonal antibodies, labeled antibody attaches to the intact globin antigen and results in a positive test result. This test is specific for bleeding in the lower GI tract because the globin protein cannot remain intact after passing through the upper GI tract (3). The sensitivity is higher for I-FOBT because of higher detection rates for advanced adenomas and cancer. The detection rate is 2.5 times more for advanced adenomas and cancer and 2.2 times more for cancers were detected with I-FOBT in comparison with G-FOBT (2). In current studies, the sensitivity of I-FOBT has been reported to be roughly 60% for CRC, which is substantially higher than G-FOBT. This test is also semi-quantitative, which allows more cut-off or threshold values to be continually modified (2). IFOBT also has no dietary restrictions because it is specific for human blood. There is a slight difference in specificity for both tests; however, it is significant to cause high volumes of false positive results. The difference is estimated in one study, as 0.2%, with I-FOBT in favor (2).
In addition, colonoscopies are considered the "gold standard" for colorectal screening, as it has been shown to reduce the CRC incidence by 76-90% in recent cohort studies (7). The test is not advanced enough, as there is an approximately 24% miss rate for adenomas by tandem colonoscopies. For adenomas smaller than 5 mm, the miss rate is 15-25% (7). On average, colonoscopies detect polyps of 10 mm or more in average risk individuals (6). At least 20-30% of the average risk population (asymptomatic, age 50 and above), carry adenomatous polyps. The majority of these are <10 mm (6). The controversy is that if these small adenomas actually progress to colon cancer. Uncle Buck could have a small adenoma that has not progressed to colon cancer and thus is non- detectable in the colonoscopy. Also, recent studies suggested a strong correlation with the colonoscopic withdrawal times during the screening procedure and adenoma detection rates. Focusing on small adenoma detection needs to be implemented as this will indefinitely improve colorectal mortality and incidence (7).
Enzyme Immunoassay (EIA) is used for the detection of human hemoglobin (1). The hemoglobin is reacted with a specific anti-human hemoglobin antibody and attached to the solid phase. The antigen-antibody complex reacts, and the enzyme activity bound to the solid phase is then instrumentally measured by color intensity. The absorbance is directly related to the amount of hemoglobin (antigen) in the sample (1). The amount of hemoglobin is directly correlated to diet and the anaerobic flora of the intestine (5). In fecal samples, however, hemoglobin degrades with time (1). This results in loss of antigenicity which results in falsely reduced values. Uncle Buck's values could be lower than normal, possibly producing false negative results. However, no polyps were found in the colonoscopy, which would suggest heme components in fecal matter.
Possibilities of other diseases that produce a positive FOBT result are iron deficiency anemia, inflammatory bowel disease, bleeding from the upper gastrointestinal tract, colonic angiodysplasias, and hemorrhoids because these conditions are associated with chronic blood loss (4). Uncle Buck's fluctuating results is most likely from invalid results from the G-FOBT test because it is too selective for the contents in fecal blood, causing false-positives. If Uncle Buck's test was a false positive result, it is hard to pinpoint the cause because of lower specificity. Although a small adenoma could have been missed in his colonoscopy, he has no signs or symptoms of colon cancer and his CBC did not indicate an abnormal blood picture. A follow-up colonoscopy in the next 2-3 months will confirm whether adenomas are developing to a detectable level (3).
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