Iron deficiency anemia

Transcription

1 Iron deficiency anemia

2 Global Burden of Anemia KASSEBAUM et al BLOOD, ٣٠ JANUARY ٢٠١۴ x VOLUME ١٢٣, NUMBER ۵

3 KASSEBAUM et al BLOOD, ٣٠ JANUARY ٢٠١۴ x VOLUME ١٢٣, NUMBER ۵

4 KASSEBAUM et al BLOOD, ٣٠ JANUARY ٢٠١۴ x VOLUME ١٢٣, NUMBER ۵

5 Iron Distribution Adult male has ~۴g total body iron stores Andrews NEJM, ٢٣ DEC ١٩٩٩ x VOLUME ٣۴١, Number ٢۶

6 Iron Absorption Food sources supply: ١٠-٢۵ mg / day Absorbed in the brush border of the upper small intestine Enhanced by gastric acid Inhibited by systemic inflammation Most dietary iron is nonheme form, <۵% bioavailability < ١٠% dietary iron is heme form, >٢۵% bioavailability

7 Iron absorption from food Rice Spinach Black beans Corn Lettuce Wheat Soy beans Ferritin Veal liver Fish muscle Hemoglobin Veal muscle Non-heme iron Heme iron ٠ ۵ ١٠ ١۵ ٢٠ ٢۵ Iron Absorption (% of dose)

8 Transferrin plasma iron transporter protein. Carries less than ١% of total body iron Ferritin intracellular storage of iron Hemosiderin long term iron storage pool

9 Iron Losses Iron is closely conserved in humans <٠.٠۵% of iron is lost per day normally ١. Very small amounts in urine, bile and sweat ٢. Cells shed from skin, intestinal and urinary tracts ٣. Menstrual blood loss ۴. Pregnancy and lactation Humans have NO other physiologic means to excrete excess iron

10 Pathogenesis of Iron Deficiency Blood loss Occult or overt GI losses, traumatic or surgical losses Failure to meet increased requirements Rapid growth in infancy and adolescence Menstruation, pregnancy Inadequate iron absorption Diet low in heme iron Gastrointestinal disease or surgery Excessive cow s milk intake in infants

11 Andrews NEJM, ٢٣ DEC ١٩٩٩ x VOLUME ٣۴١, Number ٢۶

12 Features of Iron Deficiency Anemia Depends on the degree and the rate of development of anemia Symptoms common to all anemias: pallor, fatigability, weakness, dizziness, irritability

13 Other features of IDA Pagophagia - craving ice Pica - craving of nonfood substances e.g., dirt, clay, laundry starch Glossitis - smooth tongue Restless Legs angular stomatitis - cracking of corners of mouth Koilonychia - thin, brittle, spoon-shaped fingernails

14 Tests for Iron Deficiency Peripheral blood smear Red cell indices (MCV, MCH) Serum ferritin Serum iron / transferrin = iron saturation Bone marrow iron stain (Prussian blue)

15 Sequential Changes in IDA NORMAL DEPLETED IRON STORES IRON DEFICIENCY IRON DEFICIENCY ANEMIA FERRITIN IRON SATURATION MCV & Hb & Hct

16 Differential for low serum ferritin ١. Iron Deficiency ٢. Iron Deficiency

17 Differential Diagnosis of IDA Thalassemia trait (low MCV, normal RDW) Imbalance of globin chain production

18 IDA vs. Inflammation IDA Inflammation Ferritin Serum Iron Transferrin sat Marrow Iron No

19 SEARCH FOR SOURCE OF BLOOD AND IRON LOSS Once the diagnosis of anemia due to iron deficiency is established, attempts must be made to identify the cause. Several of the common causes, such as colonic and uterine cancer, have ominous prognoses unless discovered and treated promptly. Celiac disease should be considered in all patients, especially those with a history of iron deficiency anemia unresponsive to oral iron therapy. The search for sources of blood loss starts with the patient's history, which in women is directed to menses,pregnancy, delivery, lactation, and, in both men and women, to sources of overt or occult blood loss.

20 Examples include : History of gastric or duodenal ulcer disease, H pylori infection, sprue, esophageal varices Family history of a bleeding disorder (eg, von Willebrand disease, hereditary hemorrhagic telangiectasia) Family history of colonic malignancy (eg, hereditary non-polyposis colon cancer) Multiple blood donations Chronic intravascular hemolysis with hemoglobinuria (eg, paroxysmal nocturnal hemoglobinuria, defective prosthetic heart valve) Marathon running

21 DIAGNOSIS OF IRON DEFICIENCY The serum or plasma ferritin has replaced assessment of bone marrow iron stores as the gold standard for the diagnosis of iron deficiency in most patients The normal ferritin concentration ranges from ۴٠ to ٢٠٠ ng/ml (mcg/l). Virtually all patients with serum ferritin concentrations less than ١٠ to ١۵ng/mL are iron deficient, with a sensitivity of ۵٩ percent and a specificity of ٩٩ percent Given the low sensitivity of a ferritin level <١۵ ng/ml for diagnosing iron deficiency, a higher ferritin cutoff level for suspecting iron deficiency is more appropriate.

22 Provided that an anemic patient does not have an accompanying infectious or inflammatory disease, a cutoff limit of ۴١ ng/ml for serum ferritin provides improved diagnostic efficiency, with a sensitivity and specificity of ٩٨ percent.

23 Suspecting the diagnosis Iron deficiency should be suspected in patients with hypochromic, microcytic anemia. Suggested tests include, in addition to the complete blood count, red blood cell indices, and examination of the peripheral blood smear: Serum iron and total iron binding capacity (transferrin) Serum ferritin Stool specimens for presence of occult blood

24 INTRODUCTION AND DEFINITIONS In ٢٠٠٧, the American Gastroenterological Association proposed the following nomenclature to standardize terms used to describe chronic gastrointestinal (GI) blood loss : Occult bleeding refers to the initial presentation of a positive fecal occult blood test (FOBT) result and/or iron-deficiency anemia (IDA) when there is no evidence of visible blood loss to the patient or physician. Obscure bleeding is defined as bleeding from the GI tract that persists or recurs without an obvious etiology after upper endoscopy, colonoscopy, and radiologic evaluation of the small bowel (such as by small bowel follow-through or enteroclysis). Obscure bleeding is subdivided into overt or occult, depending upon the presence or absence of clinically evident bleeding.

25 The major cause of iron deficiency in developed countries is blood loss. In men the blood loss is most commonly from the GI tract; in women, menstrual blood loss must also be considered

26 CAUSES OF OCCULT GI BLEEDING differential diagnosis for occult gastrointestinal (GI) bleeding is broad. Some of the more common causes include colon cancer esophagitis peptic ulcers gastritis inflammatory bowel disease vascular ectasias portal hypertensive gastropathy diverticula, celiac disease gastric antral vascular ectasias.

27 However, less common causes such as gastroesophageal cancers, hemosuccus pancreaticus, hemobilia, aortoenteric fistulas, endometriosis, and infections also need to be considered.. In addition, hemorrhoids can rarely lead to a positive fecal occult blood test. While overt bleeding from hemorrhoids can result in anemia, anemia in the setting of occult GI bleeding should not be attributed to hemorrhoids

28 Non-gastrointestinal sources of blood loss such as hemoptysis and epistaxis can also cause a positive fecal occult blood test The medical history and physical examination can help focus the differential diagnosis. As examples, colon cancer is more likely in patients older than ۵٠ years, while angiodysplasias are more common in patients with renal failure. The presence of oral telangiectasias may signal the presence of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) mucocutaneous pigmentation may be due to Peutz-Jeghers syndrome where hamartomatous polyps may ulcerate and cause occult GI bleeding.

29 TESTING FOR OCCULT BLOOD The best method (digital examination versus a patient-submitted stool sample) for obtaining stool for testing is controversial. Digital examination of the rectum can cause local trauma and some suggest that stool obtained during rectal examination should not be tested because of possible false positives. However, most studies have shown similar rates of detection of significant lesions regardless of how the stool samples were obtained

30 Guaiac based fecal occult blood test This test identifies hemoglobin by the presence of a peroxidase reaction that turns guaiac-impregnated paper blue. A positive test is more likely with more blood in the GI tract. For the Hemoccult II test, fecal blood loss of ١٠ ml per day (١٠ mg per gram of stool) is required for the test to be positive ۵٠ percent of the time, although the test can be positive with levels of less than ١ mg per gram of stool..

31 While dietary factors may influence the test results, studies have shown that a restrictive diet may not be needed. False positive results can be seen with ingestion of red meat and dietary peroxidases (found in turnips and radishes). Vitamin C can lead to false negative results. By contrast, oral iron supplements do not result in a false positive result. A major problem with guaiac based fecal occult blood testing is the high rate of false positive results.

32 Immunochemical tests Other tests for occult blood include immunologic assays for intact human hemoglobin, which may detect as little as ٠.٣ mg per gram of stool (HemeSelect, FECA, I-FOBT, and Hemoccult ICT) These tests react only to human hemoglobin and do not detect upper GI bleeding, since hemoglobin is digested in the small bowel. These tests are more specific than guaiac tests, and appear to be equal to or more sensitive than Hemoccult II (guaiac based) when used for colorectal cancer screening.

33 EVALUATION OF A POSITIVE FECAL OCCULT BLOOD TEST General approach The following approach is consistent with the ٢٠٠٧ American Gastroenterological Association guidelines on obscure gastrointestinal (GI) bleeding. The evaluation of a patient with a positive fecal occult blood test depends upon whether iron deficiency anemia is present. Without iron deficiency anemia A patient with a positive fecal occult blood test and no anemia should undergo a colonoscopy. If the patient also has upper gastrointestinal symptoms, an upper endoscopy should also be performed. Further testing in these patients is not recommended.

34 With iron deficiency anemia A patient with a positive fecal occult blood test and iron deficiency anemia should undergo upper endoscopy and colonoscopy. Since there is often uncertainty as to whether a positive finding on one endoscopic examination represents the true cause of bleeding, both examinations are recommended in the majority of cases. Patients without a lesion identified on standard endoscopic evaluation (assuming the examination was adequate) should have a small bowel examination. We agree with the AGA guideline that, when available, the small bowel examination of choice in the majority of patients is wireless capsule endoscopy

35 If the initial evaluation with upper endoscopy, colonoscopy, and capsule endoscopy is unrevealing, alternative non-gi sources for the patient s iron deficiency should be considered. If the suspicion for a GI source of blood loss remains high, additional testing is indicated

36 Diagnostic tests Upper endoscopy Important lesions in the upper digestive tract are frequently detected in patients who test positive for fecal occult blood or have iron deficiency anemia. While the presence of symptoms referable to the upper gastrointestinal tract has been associated with the detection of corresponding findings, even in patients without symptoms, the prevalence of lesions in the upper gastrointestinal tract is greater than or equal to that of colonic lesions A number of studies have evaluated the yield of performing upper endoscopy or small bowel examination in patients who have a positive test for occult blood, iron deficiency anemia, or both. As examples, upper GI sources of bleeding were found in ٣۶ to ۵۶ percent of patients with iron deficiency anemia, and in ١٣ to ٢٨ percent of patients with positive fecal occult blood tests without iron deficiency anemia. The proportion of patients with both upper and lower GI lesions ranged from ۵ to ١٧ percen

37 Colonoscopy Because of the high prevalence of colorectal cancer and adenomatous polyps in developed countries, most patients should undergo colonoscopy. Colonoscopy is the preferred modality because it can detect a wide range of lesions, including polyps, cancers, and angiodysplasias. Colonoscopy also permits therapeutic intervention. Radiographic studies (including barium enemas and CT colonography, also called "virtual colonoscopy") do not offer the option of biopsy or polypectomy. However, they may have a role in selected patients.

38 Small bowel evaluation If complete endoscopy and colonoscopy with adequate visualization do not reveal the source of the bleed, additional evaluation is recommended. While an upper GI series with a small bowel followthrough and/or enteroclysis was traditionally the next test performed, where available, CT enterography, magnetic resonance (MR) enterography and wireless capsule endoscopy have largely replaced these modalities. An upper GI with small bowel follow-through involves ingestion of a barium solution with subsequent radiologic imaging of the small intestine. However, small bowel erosions, ulcerations, and angiodysplasias can be missed with this test. Enteroclysis is performed by passing a tube into the proximal small bowel and injecting barium, methylcellulose, and air, followed by radiographic imaging. This is felt to be superior to standard small bowel follow-through testing, but the yield has been less than ٢٠ percent in many studies. In addition, the test is extremely uncomfortable for patients and has been largely replaced by CT enterography

39 CT enterography involves ingestion of a neutral contrast agent to distend the small bowel, followed by CT imaging of the abdomen. Using neutral contrast allows for better evaluation of the wall of the small bowel, which is difficult to see when standard barium solutions are used. MR enterography is an alternative to CT enterography. It has the advantage of not using ionizing radiation, which allows for sequential imaging of the small bowel. Like CT enterography, a neutral contrast agent (often polyethylene glycol) is used to distend the small bowel.

40 With increasing availability of and experience with wireless capsule endoscopy (WCE), many gastroenterologists will omit radiographic imaging, opting instead to proceed directly with WCE for small bowel evaluation. Capsule endoscopy is equally or more sensitive than other methods for the diagnosis of small bowel sources of blood loss Other methods available for evaluating the small bowel include push enteroscopy, deep small bowel enteroscopy, and intraoperative enteroscopy.

41 EVALUATION OF ISOLATED IRON DEFICIENCY ANEMIA Patients with unexplained iron deficiency anemia but a negative fecal occult blood test should be evaluated for a GI source of blood loss. This is particularly important in men and postmenopausal women. In patients with isolated iron deficiency anemia, a diagnosis of celiac disease should be considered and serologic evaluation with IgA and anti-tissue transglutaminase antibody should be performed. If patients have symptoms suggesting either an upper or lower GI source, it is reasonable to start the evaluation with an upper endoscopy or colonoscopy, respectively.

42 For patients who are asymptomatic, a colonoscopy is usually the first test obtained. In patients with profound anemia, it is reasonable to start the evaluation with both an upper endoscopy and a colonoscopy Patients who do not have a lesion identified during colonoscopy that explains the anemia should undergo an upper endoscopy, and vice versa. If both upper endoscopy and colonoscopy are negative additional testing, such as wireless capsule endoscopy should be pursued

43 SPECIAL SITUATIONS Patients with a known risk factor for gastrointestinal blood loss A positive fecal occult blood test should not be attributed to gastrointestinal lesions that are infrequently associated with occult bleeding (eg, esophageal varices and colonic diverticula). It is rare for esophagogastric varices to cause occult GI bleeding, with the possible exception of those that have been treated with endoscopic sclerosis or banding. Similarly, most patients with bleeding colonic diverticular disease present with overt, rather than occult, bleeding.

44 Thus, in a patient with known esophagogastric varices or colonic diverticula, a positive test for occult blood or otherwise unexplained iron deficiency anemia should not preclude a diagnostic evaluation. Colonic diverticula commonly occur in the age bracket with the highest incidence of colon cancer, and colon cancer is far more likely to bleed in an occult manner.

45 Aspirin, antiplatelet agents, and warfarin Data are conflicting regarding the effect of antiplatelet agents and anticoagulants on fecal occult blood testing, and, if possible, these agents should be discontinued prior to fecal occult blood testing. However, it should not be assumed that a positive test in a patient on one of these agents is a false-positive. In one study, the use of aspirin, nonsteroidal antiinflammatory agents, clopidogrel, or warfarin was associated with lower positive predictive values of fecal occult blood testing for advanced colorectal neoplasia compared with patients not taking these agents (٢١, ١٩, ٧, and ٢٠ percent, respectively, versus ٣١ percent) In a second study, the use of low-dose aspirin was associated with an increased sensitivity for detecting advanced colorectal neoplasms with only a slight decrease in specificity

46 Alcohol abuse The presence of fecal occult blood should not be attributed to alcohol ingestion alone unless coexistent pathology has been excluded. In a study of ١٠٠٠ patients hospitalized for alcohol detoxification, ٢٢ patients (٢.٢ percent) without overt gastrointestinal bleeding tested positive for occult blood. The subsequent endoscopic evaluation found that ٢۴ percent of these individuals had peptic ulcer disease, ٣٢ percent had premalignant colonic neoplasia, and all had upper GI mucosal inflammation.

47 Premenopausal women The optimal approach to premenopausal women with iron deficiency anemia is uncertain. In one series, a clinically important lesion was detected in ٢٣ of ١٨۶ premenopausal women (١٢ percent) who underwent endoscopy. The most common source of bleeding was in the upper gastrointestinal tract, including peptic ulcer disease (٣ percent) and gastric cancer (٣ percent). On multivariable analysis, independent predictors of a significant finding on endoscopy included a positive fecal occult blood test, hemoglobin <١٠ g/dl, and abdominal symptoms.

48 Another study of ١٨٧ premenopausal women found an exclusive and possible gastrointestinal cause for iron deficiency anemia in ٢٧ and ٣۵ percent of patients, respectively. While the high prevalence of positive findings in these studies may have reflected referral bias, endoscopic evaluation should be obtained in premenopausal women who have a positive test for fecal occult blood, anemia out of proportion to menstrual blood loss, abdominal symptoms, or a family history of gastrointestinal malignancy, particularly in those older than ۴٠ years of age.

49 NTRODUCTION In ٢٠٠٧, the American Gastroenterological Association proposed the following nomenclature to standardize terms used to describe chronic gastrointestinal blood loss : Occult bleeding refers to the initial presentation of a positive fecal occult blood test (FOBT) result and/or iron-deficiency anemia (IDA) when there is no evidence of visible blood loss to the patient or clinician. Obscure bleeding is defined as bleeding from the gastrointestinal (GI) tract that persists or recurs without an obvious etiology after upper endoscopy, colonoscopy, and radiologic evaluation of the small bowel (such as by small bowel follow-through or enteroclysis). Obscure bleeding is subdivided into overt or occult, depending upon the presence or absence of clinically evident bleeding.

50 ETIOLOGY Obscure gastrointestinal bleeding accounts for approximately ۵ percent of patients with gastrointestinal bleeding In approximately ٧۵ percent of these patients, the source is in the small bowel. The remainder of cases are due to missed lesions in either the upper or lower gastrointestinal tract. There are multiple potential causes of obscure gastrointestinal (GI) bleeding

51 Patients younger than ۴٠ may be more likely to have inflammatory bowel disease, a Meckel's diverticulum, Dieulafoy's lesion, or a small bowel tumor (eg, gastrointestinal stromal cell tumor, lymphoma, carcinoid, adenocarcinoma, or polyp). Older patients may be more likely to have bleeding from vascular lesions, erosions, or ulcers related to non-steroidal antiinflammatory drugs.

52 EVALUATION The evaluation of obscure GI bleeding consists of a judicious search for the cause of bleeding, which should be guided by the clinical history, physical findings, and the results of previous evaluation. Several options are available for subsequent testing. An approach to diagnosis is presented below. History and physical examination There are several elements from the medical history and physical examination that can provide clues about the cause of bleeding and help define the aggressiveness with which a bleeding site should be sought: Skin, nail, and mucosal changes may suggest the presence of several disorders associated with gastrointestinal bleeding or iron deficiency anemia including:

53 Recurrent hematemesis indicates bleeding above the ligament of Treitz and usually proximal to the second portion of the duodenum (ie, upper GI bleeding), while recurrent passage of bright red blood per rectum suggests a lower GI cause. Melena can originate from bleeding anywhere from the nose to the right colon. As a result, the presence of melena has little localization value. A review of over-the-counter medications may reveal inadvertent use of nonsteroidal anti-inflammatory agents. A family history of cancer occurring at an early age, particularly colorectal or endometrial, may suggest the presence of hereditary nonpolyposis colorectal cancer.

54 Telangiectasias of the lips or oropharynx, which may reflect hereditary hemorrhagic telangiectasia. Dermatitis herpetiformis, which may reflect celiac disease. Miscellaneous conditions with cutaneous and gastrointestinal manifestations (eg, Kaposi's sarcoma, Peutz-Jeghers syndrome, tylosis, pseudoxanthoma elasticum, Ehlers-Danlos syndrome, blue rubber bleb nevus syndrome, Henoch-Schönlein purpura, neurofibromatosis, malignant atrophic papulosis, Klippel-Trenaunay- Weber syndrome, Heyde's syndrome).

55 Repeat upper endoscopy and colonoscopy Lesions within reach of a standard upper endoscope or colonoscope may be missed for a variety of reasons; thus, a repeat examination may be warranted. Repeat examinations probably have their greatest value in patients with obscure GI bleeding and iron deficiency anemia or overt bleeding with melena or maroon blood per rectum. Lesions that are commonly missed in the upper gastrointestinal tract include Cameron's ulcers or erosions in a hiatus hernia, peptic ulcers, and vascular ectasias.

56 An aortoenteric fistula should be considered in patients with a history of an abdominal aortic aneurysm repair. Biopsies of the duodenum should be obtained in patients in whom celiac disease is suspected based upon serologic testing

57 Angioectasia may be missed on the medial aspect of the second part of the duodenum. Thus, consideration should be given to using a side viewing endoscope at the time of repeat endoscopy. The use of a side viewing scope may also be helpful in detecting hemobilia, a rare but significant cause of obscure bleeding. Some authorities recommend that the repeat procedures (both upper endoscopy and colonoscopy) be performed by an endoscopist other than the one who performed the original

58 Hemorrhoidal bleeding can lead to obscure bleeding, anemia, and a transfusion requirement in a small subset of patients Because hemorrhoidal bleeding is minor in most patients, hemorrhoids are uncommonly recognized as being an important source of more serious blood loss. A sigmoidoscopy (without a bowel preparation) on the day of bleeding can help point to hemorrhoids as the cause of obscure bleeding if blood is seen in the distal rectum but not more proximally. Such patients should be referred to a colorectal surgeon for further evaluation and treatment.

59 Lesions missed on upper endoscopy and colonoscopy are sometimes detected when the patient is referred for capsule endoscopy.

60 Classic disease The classic definition of celiac disease or gluten-sensitive enteropathy includes the following three features: villous atrophy symptoms of malabsorption such as steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency resolution of the mucosal lesions and symptoms upon withdrawal of gluten-containing foods, usually within a few weeks to months. Patients with classic disease present with diarrhea, weight loss, or malabsorption, and possess antibodies against gliadin and especially tissue transglutaminase. The severity of histologic changes in the small bowel does not necessarily correlate with the severity of clinical manifestations

61 Atypical celiac disease Patients with atypical disease exhibit only minor gastrointestinal complaints. They can display anemia, dental enamel defects, osteoporosis, arthritis, increased transaminases, neurological symptoms, or infertility. However, most of these patients show severe mucosal damage and possess the celiac specific antibody pattern.

62 Asymptomatic (silent) celiac disease Patients are often recognized incidentally based upon screenings for antibodies against gliadin or tissue transglutaminase. Although these patients very often display the characteristic architectural remodelling of the intestinal mucosa seen in celiac disease (ie, crypt hyperplasia and villous atrophy), they do not show clinical symptoms. Often minor symptoms (eg, fatigue) are only realized after introduction of a gluten free diet.

63 Latent celiac disease There are some patients who have normal jejunal mucosa and minor symptoms or no symptoms at one or more time points while on a normal, gluten-containing diet. Two variants of what has been called latent celiac disease have been identified: Celiac disease was present before, usually in childhood; the patient recovered completely with a gluten-free diet, remaining "silent" even when a normal diet was reintroduced. About ٢٠ percent of such patients continue to have latent disease (asymptomatic with normal villous architecture) into adulthood, while the others re-develop variable degrees of villous atrophy. Latency may be transient and thus regular follow up of such patients is warranted.

64 CLINICAL MANIFESTATIONS

65 Gastrointestinal manifestations Patients may present with classic signs, including diarrhea with bulky, foul-smelling, floating stools due to steatorrhea and flatulence. These symptoms are paralleled by the consequences of malabsorption, such as growth failure in children, weight loss, severe anemia, neurologic disorders from deficiencies of B vitamins, and osteopenia from deficiency of vitamin D and calcium.

66 subclinical disease The development and widespread availability of serologic screening has led to the understanding that celiac disease can exist in a very mild form and may go largely undetected, since most patients have mild and unspecific symptoms, such as fatigue, borderline iron deficiency, or otherwise unexplained elevations in serum aminotransferases, or no symptoms at all. Some patients are identified because of the physician's increased awareness. Those without any specific complaints may be diagnosed during screening programs or during endoscopy performed for other reasons. Thus, celiac disease may represent a continuum with variable degrees of severity.

67 Establishing the diagnosis of subclinical celiac disease is of potential importance for four reasons: the danger of malignancy, the presence of unsuspected nutritional deficiencies, the association with low-birth weight infants in affected mothers, the occurrence of autoimmune disorders.

68 Some studies have found that the prevalence of autoimmune diseases (eg, Type ١ diabetes mellitus, collagen vascular disease, autoimmune thyroiditis) is related to the duration of undetected celiac disease, and may reach more than ٣٠ percent of patients diagnosed after age ٢٠ years. However, this is likely to be related to common genetic predispositions, and the relationship between the duration of gluten exposure and the risk of autoimmune disorders remains unsettled

69 Numerous autoimmune conditions are frequently associated with celiac disease including dermatitis herpetiformis, type ١ diabetes mellitus, and autoimmune thyroiditis. Patients with celiac disease should therefore be screened for these conditions. Serological screening for celiac disease is indicated in patients with autoimmune conditions associated with celiac disease and in first degree relatives of patients with celiac disease

70 IgA deficiency is more common in celiac disease (٢ to ۵ percent) than in the general population (<٠.۵ percent). The IgA EMA and IgA ttg serology tests will be falsely negative in untreated celiac disease in patients with IgA deficiency. As a result, total serum IgA can be measured in addition to IgA EMA or IgA ttg especially when there is heightened clinical suspicion for celiac disease and IgA markers are negative.

71 If total IgA levels are abnormally low, an IgG-based assay should be used to test for celiac disease. The IgG antigliadin assay has been traditionally used in this circumstance but is not ideal since it yields frequent false positive results. Thus, serum IgG ttg or IgG DGP tests are preferable. Negative results upon testing for HLA DQ٢ or DQ٨ can also help exclude the diagnosis in this setting..

72 In addition to serologic markers, the diagnosis usually requires a small bowel biopsy, which can be obtained during upper endoscopy. Exceptions are patients with compatible serologic findings and biopsy-proven dermatitis herpetiformis in whom the diagnosis can be established without a small bowel biopsy

73 A few controversies remain regarding confirmation of the diagnosis. Some authorities recommend that a repeat small intestinal biopsy should be obtained ۶ to ٢۴ months after beginning a gluten-free diet to demonstrate histologic improvement. Some also recommended a repeat small bowel biopsy (after gluten rechallenge) following a gluten-free diet. We do not believe that these approaches are generally required unless the diagnosis remains uncertain based upon the serologic profile, histology and clinical response

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