Fecal occult blood

Fecal occult blood (FOB) refers to blood in the feces that is not visibly apparent (unlike other types of blood in stool such as melena or hematochezia). A fecal occult blood test (FOBT) checks for hidden (occult) blood in the stool (feces). Newer tests look for globin, DNA, or other blood factors including transferrin, while conventional stool guaiac tests look for heme.

Medical uses

Fecal occult blood testing (FOBT), as its name implies, aims to detect subtle blood loss in the gastrointestinal tract, anywhere from the mouth to the colon. Positive tests ("positive stool") may result from either upper gastrointestinal bleeding or lower gastrointestinal bleeding and warrant further investigation for peptic ulcers or a malignancy (such as colorectal cancer or gastric cancer). The test does not directly detect colon cancer but is often used in clinical screening for that disease, but it can also be used to look for active occult blood loss in anemia or when there are gastrointestinal symptoms.

The stool guaiac test for hidden (occult) blood in the stool can be done at home or in the doctor's office, or can be performed on samples submitted to a clinical laboratory. Testing kits are available at pharmacies in some countries without a prescription, or a health professional may order a testing kit for use at home. If a home fecal occult blood test detects blood in the stool it is recommended to see a health professional to arrange further testing.

Source of bleeding

Gastrointestinal bleeding has many potential sources, and positive results usually result in further testing for the bleeding site, usually looking for lower gastrointestinal bleeding before upper gastrointestinal bleeding causes unless there are other clinical clues. Colonoscopy is usually preferred to computerized tomographic colonography.

An estimated 1â€"5% of large tested populations have a positive fecal occult blood test. Of those, about 2â€"10% have cancer, while 20â€"30% have adenomas.

A positive test can result from upper gastrointestinal bleeding or lower gastrointestinal bleeding. The common causes are:

• 2â€"10%: cancer (colorectal cancer, gastric cancer)
• 20â€"30% adenoma or polyps
• Bleeding peptic ulcer
• Angiodysplasia of the colon
• Sickle cell anemia

In the event of a positive fecal occult blood test, the next step in the workup is a form of visualization of the gastrointestinal tract by one of several means:

1. Sigmoidoscopy, an examination of the rectum and lower colon with a lighted instrument to look for abnormalities, such as polyps.
2. Colonoscopy, a more thorough examination of the rectum and entire colon.
3. Virtual colonoscopy
4. Endoscopy refers to upper gastrointestinal endoscopy. It is sometimes performed with chromoendoscopy, a method that assists the endoscopist by enhancing the visual difference between cancerous and normal tissue, either by marking the abnormally increased DNA content (toluidine blue) or failing to stain the tumor, possibly due to decreased surface glycogen on tumor cells(Lugol). Infrared fluorescent endoscopy and ultrasonic endoscopy can interrogate vascular abnormalities such as esophageal varices.
5. Double contrast barium enema: a series of x-rays of the colon and rectum.

Stool color

Although red or black stools can be an indication of bleeding, a dark or black color can be due to black licorice, blueberries, iron supplements, lead, Pepto-bismol, and a red color can come from natural or artificial coloring such as red gelatin, popsicles, Kool-Aid, and large amounts of beets.

Colorectal cancer screening

Screening methods for colon cancer depend on detecting either precancerous changes such as certain kinds of polyps or on finding early and thus more treatable cancer. The extent to which screening procedures reduce the incidence of gastrointestinal cancer or mortality depends on the rate of precancerous and cancerous disease in that population. gFOBT and flexible sigmoidoscopy screening have each shown benefit in randomized clinical trials. Evidence for other colon cancer screening tools such as iFOBT or colonoscopy is substantial and guidelines have been issued by several advisory groups but does not include randomized studies.

The American College of Gastroenterology has recommended the abandoning of gFOBT testing as a colorectal cancer screening tool, in favor of the fecal immunochemical test. Though the FIT test is preferred, even the guaiac FOB testing of average risk populations may have been sufficient to reduce the mortality associated with colon cancer by about 25%. With this lower efficacy, it was not always cost effective to screen a large population with gFOBT.

If colon cancer is suspected in an individual (such as in someone with an unexplained anemia) fecal occult blood tests may not be clinically helpful. If a doctor suspects colon cancer, more rigorous investigation is necessary, whether or not the test is positive.

The 2009 recommendations of the American College of Gastroenterology (ACG) suggest that colon cancer screening modalities that are also directly preventive by removing precursor lesions should be given precedence, and prefer a colonoscopy every 10 years in average-risk individuals, beginning at age 50. The ACG suggests that cancer detection tests such as any type of FOB are an alternative that is less preferred and which should be offered to patients who decline colonoscopy or another cancer prevention test. However, two other recent guidelines, from the US Multisociety Task Force (MSTF) and the US Preventive Services Task Force (USPSTF) while permitting immediate colonoscopy as an option, did not categorize it as preferred. The ACG and MSTF also included CT colonography every five years, and fecal DNA testing as considerations. All three recommendation panels recommended replacing any older low-sensitivity, guaiac-based fecal occult blood testing (gFOBT) with either newer high-sensitivity guaiac-based fecal occult blood testing (hs gFOBT) or fecal immunochemical testing (FIT). MSTF looked at six studies that compared high sensitivity gFOBT (Hemoccult SENSA) to FIT, and concluded that there were no clear difference in overall performance between these methods.

In 2006, the Australian Government introduced the National Bowel Cancer Program and has been updated many times with targeted screening will be done of all Australians aged over 50 to 74 by 2017â€"2018. Cancer Council Australia recommended that FOBT should be done every two years. Gradually government fund disbursement made some people are not yet eligible for the national program and should pay for a FOBT by themself.

In colon cancer screening, using only one sample of feces collected by a doctor performing a digital rectal examination is discouraged.

Iron deficiency anemia

An extensive literature has examined the clinical value of FOBT in iron deficiency anemia.

Gastrointestinal disease and medications

Conditions such as ulcerative colitis or certain types of relapsing infectious diarrhea can vary in severity over time, and FOBT may assist in assessing the severity of the disease. Medications associated with gastrointestinal bleeding such as Bortezomib are sometimes monitored by FOBT.

Alcoholism

Several aspects of FOBT in alcoholism warrant further discussion.

Testing secretions for occult blood

The use of tests for occult blood in disorders of the mouth, nasal passages, esophagus, lungs and stomach, while analogous to fecal testing, is often discouraged, due to technical considerations including poorly characterized test performance characteristics such as sensitivity, specificity, and analytical interference. However, chemical confirmation that coloration is due to blood rather than coffee, beets, medications, or food additives can be of significant clinical assistance.

A related concept to colon cancer screening by FOBT, based on most neoplasms affecting the surface epithelium and losing small amounts of blood but no visible blood loss, is screening in populations at high risk for esophageal or gastric cancers by testing for blood by swallowing a small capsule that is recovered after 3 to 5 minutes by gentle retrieval by means of an attached nylon thread.

Regulatory impact

Regulations from the Joint Commission may have unintentionally decreased digital rectal examination and FOBT in hospital settings such as Emergency Departments.

Marathon runners

Gastrointestinal (GI) complaints and low intensity GI bleeding frequently occur in marathon runners. Strenuous exercise, particularly in elite athlete runners and less frequently in other exercise activities, can cause acute incapacitating gastrointestinal symptoms including heartburn, nausea, vomiting, abdominal pain, diarrhea and gastrointestinal bleeding. Approximately one third of endurance runners experience transient but exercise limiting symptoms, and repetitive gastrointestinal bleeding occasionally causes iron deficiency and anaemia. Runners can sometimes experience significant symptoms including hematemesis. Exercise is associated with extensive changes in gastrointestinal (GI) tract physiology, including diversion of blood flow from the GI tract to muscle and lungs, decreased GI absorption and small intestinal motility, increased colonic transit, neuroimmunoendocrine changes in hormones and peptides such as vasoactive intestinal peptide, secretin and peptide-histidine-methionine. Substantial changes occur in stress hormones including cortisol, in circulating concentrations and metabolic behavior of various leucocytes, and in immunoglobulin levels and major histocompatibility complex expression. Symptoms can be exacerbated by dehydration or by pre-exercise ingestion of certain foods and hypertonic liquids, and lessened by adequate training.

Ingestion of 800 mg of cimetidine 2 hr before running a marathon did not significantly affect the frequency of gastrointestinal symptoms or occult gastrointestinal bleeding. Conversely, 800 mg of cimetidine 1 hr before the start and again at 50 miles of a 100-mile running race substantially decreased GI symptoms and postrace guaiac test positivity but did not affect race performance.

Nomenclature

In 2007 the nomenclature of overt, obscure and occult bleeding was clarified.

The different methods of testing for "fecal occult blood" as broadly considered actually test for particular components of blood or for aberrantly expressed cellular markers from the intestinal mucosa.

Methodology

There are four methods in clinical use for testing for occult blood in feces. These look at different properties, such as antibodies, heme, globin, or porphyrins in blood, or at DNA from cellular material such as from lesions of the intestinal mucosa.

• Fecal immunochemical testing (FIT), and immunochemical fecal occult blood test (iFOBT). FIT products utilize specific antibodies to detect globin. FIT screening is more effective in terms of health outcomes and cost compared with guaiac FOBT. According to the guidelines of the American College of Gastroenterology, "Annual fecal immunochemical testing is the preferred colorectal cancer detection test."

FIT testing has replaced most gFOBT tests as the colon cancer screening test of choice. This methodology can be adapted for automated test reading and to report quantitative results, which are potential factors in design of a widescale screening strategy. The number of fecal samples submitted for FIT may affect the clinical sensitivity and specificity of the methodology.[8] High sensitivity gFOBT tests such as Hemoccult SENSA remains an accepted option;[8] and may retain a role in monitoring gastrointestinal conditions such as ulcerative colitis; however the FIT test is preferred in recent guidelines.

• Stool guaiac test for fecal occult blood (gFOBT): â€" The stool guaiac test involves smearing some feces onto some absorbent paper that has been treated with a chemical. Hydrogen peroxide is then dropped onto the paper; if trace amounts of blood are present, the paper will change color in one or two seconds. This method works as the heme component in hemoglobin has a peroxidase-like effect, rapidly breaking down hydrogen peroxide. In some settings such as gastric or proximal upper intestinal bleeding the guaiac method may be more sensitive than tests detecting globin because globin is broken down in the upper intestine to a greater extent than is heme. There are various commercially available gFOBT tests which have been categorized as being of low or high sensitivity, and only high sensitivity tests remain an acceptable alternative to FIT testing, which is now the best-practices recommendation in colon cancer screening. Optimal clinical performance of the stool guaiac test depends on preparatory dietary adjustment.

• Fecal porphyrin quantification: â€" HemoQuant, unlike gFOBT and FIT, permits precise quantification of hemoglobin, and is analytically validated with gastric juice and urine, as well as stool samples. The heme moiety of intact hemoglobin is chemically converted by oxalic acid and ferrous oxalate or ferrous sulfate to protoporphyrin, and the porphyrin content of both the original sample and of the sample after hemoglobin conversion to porphyrin is quantified by comparative fluorescence against a reference standard; the specificity for hemoglobin is increased by subtracting the fluorescence of a sample blank prepared with citric acid to correct for the potential confounding effect of existing non-specific substances. Precise quantification measurement has been very useful in many clinical research applications.

• Fecal DNA test[1]: â€" The PreGen-Plus test extracts human DNA from the stool sample and tests it for alterations that have been associated with cancer. The test looks at 23 individual DNA alterations, including 21 specific point alterations in the APC, KRAS and p53 genes, as well as testing BAT26, a gene involved in microsatellite instability (MSI). and a proprietary DNA Integrity Assay (DIA).

Additional methods of looking for occult blood are being explored, including transferrin dipstick and stool cytology.

Test performance

Reference standards

The estimates for test performance characteristics are based on comparison with a variety of reference methods including 51-chromium studies, analytical recovery studies in spiked stool samples, analytical recovery after ingestion of autologous blood, rarer studies of carefully quantified blood instilled at bowel surgery as well as other research approaches. Additionally, clinical studies look at variety of additional factors.

Gastrointestinal blood loss in health

In healthy people about 0.5 to 1.5 ml of blood escapes blood vessels into the stool each day. Significant amounts of blood can be lost without producing visible blood in the stool, estimated as 200 ml in the stomach, 100 ml in the duodenum, and lesser amounts in the lower intestine. Tests for occult blood identify lesser blood loss.

Clinical sensitivity and specificity

Fecal Immunochemical Testing (FIT) picks up as little as 0.3 ml of blood in the stool; yet this test threshold doesn't cause undue false positives from normal upper intestinal blood leakage because it does not detect occult blood from the stomach and upper small intestine. Thus the FIT test is much more specific for bleeding from the colon or lower gastrointestinal tract than alternatives. The detection rate of the test decreases if the time from sample collection to laboratory processing is delayed; processing the sample in under five days from collection is recommended.

Stool guaiac test for fecal occult blood (gFOBT) sensitivity varies depending on the site of bleeding. Moderately sensitive gFOBT can pick up a daily blood loss of about 10 ml (about two teaspoonfuls), and higher sensitivity gFOBT can pick up lesser amounts, requires at least 2 ml. to become positive. The sensitivity of a single stool guaiac test to pick up bleeding has been quoted at 10 to 30%, but if a standard three tests are done as recommended the sensitivity rises to 92%. Reduced patient compliance with the collection of three samples hampers the usefulness of this test. Further discussion of sensitivity and specificity issues that relate particularly to the guaiac method is found in the stool guaiac test article.

Fecal porphyrin quantification by HemoQuant can be false positive due to exogenous blood and various porphyrins. HemoQuant is the most sensitive test for upper gastrointestinal bleeding and therefore may be most appropriate fecal occult blood test to use in the evaluation of iron deficiency Advised to stop red meat and aspirin for three days prior to specimen collection False positives can occur with myoglobin, catalase, or protohemes and in certain types of porphyria.

The DNA based PreGen-Plus was four times more sensitive than fecal blood testing, including detection of early stage disease, when treatment is most effective. Sensitivity increased to 51.6% compared to 12.9%. Additional clinical trials of the PreGen-Plus method are underway to more fully characterize its clinical performance. Expanding the range of DNA testing by looking at additional known genetic markers, such as CTNNB1, or by analyzing epigenetically methylated genes such as MLH1 which is very common in serrated polyps with microsatellite instability (MSI) and in proximal colon tumours that have poorer differentiation, does not appear to appreciably increase the sensitivity of the method because CTNNB1 mutations are infrequent in sporadic colorectal cancer, and because BAT26 alterations and lack of MLH1 expression show a high degree of overlap.

References

FIT by Pinnacle BioLabs FAQ sheet

External links

• More information on the Pinnacle BioLabs Fecal Immunochemical test
• FOBT Overview at Mayo Clinic
• Overview at Cleveland Clinic
• ColonCancerCheck including fact sheets in 24 languages at Ontario Ministry of Health and Long-Term Care
• Colorectal Cancer Screening -- Curr Opin Gastroenterol. 2010 PMID 20664346