Society has gained a heightened awareness of celiac disease (CD) in recent years, particularly among adults (Reilly & Green, 2012). Although knowledge has focused on how CD is associated with gastrointestinal (GI) symptoms, recent research is unveiling the effects of CD on other systems of the body. Not only are gastroenterologists the ones most likely diagnosing CD, but primary care providers and obstetricians/gynecologists are also suspecting and detecting more cases among their patients. Once thought to be more of a childhood diagnosis, CD signs and symptoms presenting themselves in adulthood are increasingly prevalent among those in young and middle adulthood. Estimates suggest about 1% of the U.S. population has CD (Reilly & Green, 2012). Bast, Leffler, Murray, and Pietzak (2010) state that approximately 3 million Americans likely have CD, but only 150,000 are diagnosed. The purpose of this article is to highlight the pathophysiology of CD with a specific focus on the female reproductive system, discuss the need for comprehensive screening and the diagnostics used for CD, and describe management of CD effects, including the integration of a gluten-free diet (GFD).
Celiac disease is an immune-mediated sensitivity triggered by the ingestion of foods containing gluten. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a branch of the National Institutes of Health, when a person with CD ingests gluten (a protein found in wheat, barley, and rye), his or her immune system responds by damaging the villi of the small intestine (NIDDK, 2008). This can result in problems associated with malabsorption of nutrients, along with other symptoms, the causes of which are not 100% understood (Bast et al., 2010; NIDDK, 2008).
Although many autoimmune disorders have a genetic predisposition associated with their presence, CD also has an environmental trigger (gluten). The detrimental response is a function of innate and adaptive immune systems responding to the introduction of gluten. Predisposition has been linked to the genes that encode inherited human leukocyte antigen (HLA), specifically the alleles known as HLA-DQ2 and HLA-DQ8. Human leukocyte antigens are found in most cells, particularly white blood cells (McCabe et al., 2012), which guard the body by identifying other cells as self or non-self. In people with CD, the HLA-DQ2 and HLA-DQ8 alleles identify gluten as an invasive foreign body that produces antibodies (immunoglobulins) that inflame the small intestines in an attempt to protect the body. Ninety-five percent of patients with CD express the HLA-DQ2 allele and the remaining patients test positive for the HLA-DQ8 allele (McCabe et al., 2012). The discussion becomes complicated because these alleles exist in 33% of the general population, so having either allele is not sufficient for a CD diagnosis (McCabe et al., 2012). Essentially, the presence of either allele is useful for exclusion of suspected CD but cannot exclusively confirm the diagnosis.
The exact pathophysiological mechanisms of CD involve several concepts and interacting processes. It is important to understand that gliadin is a glycoprotein extract from gluten believed to be toxic to the intestinal lining among those with CD (NIDDK, 2008). In general, the gluten molecule is hydrophobic and resistant to normal protein digestion by peptidases due to its high amount of proline residues, thereby allowing a long peptide chain to remain after digestion (NIDDK, 2008). This is a problem with CD because this long peptide chain (the toxic fraction of gliadin) gets under the epithelial cells that line the intestinal villi and triggers an immune response and inflammation, as well as causing the overexpression of IL-15 (interleukin 15) in the intestine (NIDDK, 2008). In addition, gliadin peptides have been shown to upregulate both the stress molecule MIC-A (major histocompatibility complex class I-related chain A) on the surface of enterocytes and the NKG2D (activating natural killer cell receptors) on the infiltrating intraepithelial lymphocytes (NIDDK, 2008). This promotes a lymphocyte-mediated cytotoxic response and is likely the cause of villous atrophy (NIDDK, 2008).
With the innate immune responses, tissue transglutaminase (tTG) links ingested gliadin and causes specific degradation of glutamine into glutamic acid, allowing the gliadin peptides to be more efficiently presented to gliadin-reactive CD4 T cells and generate an immune response (NIDDK, 2008). Gliadin becomes even more toxic for those who are already sensitive. The presentation is what stimulates the production of immunoglobulin IgA and IgG antibodies against tTG. Without tTG, gliadin is less immunogenic and may not stimulate T cells as effectively. Therefore, there is a combination of activities by the innate and adaptive immune systems in the generation of gliadin-reactive T cells, a cytotoxic response, and autoantibody formation (NIDDK, 2008).
The intestinal villous atrophy is caused by accelerated epithelial cell shedding. To compensate for this loss, epithelial cell production increases, causing hypertrophy of the crypts of Lieberkuhn (McCance, Huether, Brashers, & Rote, 2010). The increased cell production is not sufficient to keep up with the cell loss. The villi shorten and atrophy, and their newly produced surface cells are not mature enough to sustain absorptive functions. Microvilli and the brush border disappear, leaving patches of bald mucosa, which leads to severe malabsorption. Damage to the mucosal cells causes inflammation and edema, and can have secondary effects that exacerbate malabsorption, specifically in the duodenum and jejunum (McCance et al., 2010).
Clinical Manifestations of CD
Presentation of CD may be clinically overt or silent, with no symptoms to note, which is why many people remain undiagnosed throughout most of their lives. Children may present with failure to thrive, diarrhea, steatorrhea, abdominal distention, and malnutrition (McCance et al., 2010). Adults suffer from diarrhea, constipation, flatulence, bloating, belching, abdominal pain, and vomiting, which may progress, resulting in fatigue, malnutrition, and weight loss. In addition, because of intestinal villous damage and the associated malabsorption, vitamin deficiencies and iron-deficiency anemia do occur. Less typical presentations can be seen as alterations in the skin, cardiovascular, central nervous, reproductive, and musculoskeletal systems. More specifically, CD can lead to dermatitis herpetiformis (DH), cardiomyopathy, seizures, depression, miscarriage, infertility, delayed puberty, osteoporosis, short stature, dental anomalies, and arthritis (Bast et al., 2010).
Not all people will experience GI symptoms, however. One highly referenced study by Zugna, Richiardi, Akre, Stephansson, and Ludvigsson (2010) included 11,495 women with diagnosed CD. Results indicated that 79% of the patients with villous atrophy, the gold standard for diagnosis, reported GI symptoms but 95% with villous atrophy had CD, as seen by multiple diagnostic markers, including serum laboratory values.
Dermatitis herpetiformis, a pruritic, blistering skin rash of the elbows, knees, and buttocks, affects 15%-25% of CD patients (Rodrigo, 2006). Most people with DH have no digestive symptoms associated with CD (McCabe et al., 2012).
Histological changes of the intestinal villi cause nutritional deficiencies and inflammation, which can lead to secretion of water and electrolytes, followed by watery diarrhea. Carbohydrates, amino acids, dipeptides, water-soluble vitamins, bile salts, and cations are also not absorbed from the intestinal lumen (McCance et al., 2010). Potassium loss leads to muscle weakness, whereas magnesium and calcium malabsorption can cause seizures or tetany. Furthermore, unabsorbed fatty acids combine with calcium and secondary hyperparathyroidism increases phosphorus excretion, resulting in bone reabsorption (McCance et al., 2010).
Without diagnosis and intervention, more serious complications can include ulcerative jejunitis/ileitis; small intestine bacterial overgrowth; lymphocytic colitis; and adenocarcinoma of the small intestine, pharynx, and esophagus (Bast et al., 2010). Celiac disease may even prove to be fatal when complicated by cancers such as enteropathy-associated T-cell lymphoma, which is a rare, high-grade, non-Hodgkin's lymphoma of the upper small intestine.
Implications for Female Reproduction
The literature review provides a global perspective on evidence of reproductive-related consequences linked to CD. Women with reproductive problems or pregnancy complications may have no specific symptoms, but infertility or other problems such as delayed menarche, amenorrhea, and early menopause, may be the first manifestation of a problem attributable to CD (Ozgor & Selimoglu, 2010). Untreated CD can include increased prevalence of secondary amenorrhea or adverse pregnancy events including spontaneous abortions and fetal growth restrictions (Martinelli, Fortunato, Tafuri, Germinario, & Prato, 2010).
Some studies (Kolho, Tiitinen, Tulppala, Unkila Kallio, & Savilahti, 1999; Tiboni, Grazia de vita, Faricelli, Giampietro, & Liberati, 2005) indicate CD may account for a significant percentage of unexplained infertility or subfertility. Choi et al. (2011) identified 2.1% of the 188 women in the infertile group to have CD, which was not significantly different for the incidence of infertility in the general population. However, it did find a 5.9% significant increase in CD prevalence among participants with unexplained infertility. Another study conducted by Khoshbaten et al. (2011) with 200 women discovered an increased prevalence of CD autoantibodies with unexplained infertility (8%) when compared with participants in a control group who were reproductively healthy (3.5%). This implies the likelihood of CD in infertile patients was 2.39 times greater than in the control group of women (Khoshbaten et al., 2011). Seungdamrong and McGovern (2007) concluded that CD affects 4%–8% of women with unexplained infertility.
Shortened Fertility Span and Amenorrhea
Significant differences in the reproductive life span of women with untreated CD, such as having a shorter fertile life span, have also been detected (Santonicola et al., 2011; Shamaly, Mahameed, Sharony, & Shamir, 2004). Shamaly et al. (2004) noticed delayed menarche and earlier menopause among Iranian women. Other findings such as women with CD having later onset of menarche, earlier menopause, and shorter fertile life spans were found when compared with the control group (Santonicola et al., 2011). This study also found that women with CD experienced worse hot flashes, muscle/joint problems, and irritability than women in the control group. Treating the CD with a GFD significantly decreased the muscle/joint problems, although no statistical significance was noted (Santonicola et al., 2011).
Menstrual irregularities were noted in multiple international studies among women with CD (Kotze, 2004; Martinelli et al., 2010). Martinelli et al. (2010) compared 62 celiac women with 186 healthy women and found menstrual irregularities were more prevalent among celiac women, with a frequency of 19.4% of the celiac women experiencing amenorrhea compared with just 2.2% of the healthy controls. About 70% of women with menstrual cycle disorders received their CD diagnosis after the onset of menstrual irregularities, which may suggest that had the CD been treated, the irregularities may never have occurred (Martinelli et al., 2010). Kotze (2004) found similar results of delayed menarche and increased secondary amenorrhea in 28% of the 76 CD women compared with none of the 84 women in the control group.
Adverse Pregnancy Outcomes
Additional findings have included an increased risk for adverse outcomes such as miscarriages and preterm births in pregnancy among CD women. Santonicola et al. (2011) found among women with untreated CD, 85% experienced pregnancies with less-than-ideal outcomes compared with just 32% of participants in the control group. Martinelli et al. (2010) supported these findings, showing celiac women brought their pregnancies to term only 78% of the time and experienced spontaneous abortions in 22% of their pregnancies, compared with healthy women who brought their pregnancies to term 88% of the time and experienced spontaneous abortions only 12% of the time. The average length of gestation for celiac women was 38.5 weeks, whereas it was 40.5 for healthy women (Martinelli et al., 2010). Of the full-term pregnancies, gestational disorders were reported for 65% of celiac women versus 31% of the healthy women (Martinelli et al., 2010). A significant correlation between CD and threatened abortion, gestational hypertension, placental abruption, severe anemia, uterine hyperkinesia, and intrauterine growth restriction was also found (Martinelli et al., 2010). Kotze (2004) also showed an increased proportion of pregnancies ending in spontaneous abortion, seen in 35.5% of the subjects.
Although the exact mechanism causing these adverse outcomes is unknown, researchers are investigating and postulating explanations. Fifty women of reproductive age with biopsy-confirmed CD who had not yet been treated were compared with 11 healthy women regarding their sera, tissue makeup, and pregnancy outcomes (Sóñora et al., 2011). It is known that antibodies to tTG are present in the serum of celiac patients, and it is also known that tTG exists in the endometrial tissue of women and may even play a role in helping implantation of an embryo (Sóñora et al., 2011). A significant correlation between a history of gynecological and/or obstetric complications and the capability of sera to modify in vitro transamidating activity was found. In addition, sera from the group of women with prior gynecological/obstetric disorders significantly induced higher inhibition of tTG activity than those of healthy donors or celiac women without these complaints (Sóñora et al., 2011). More specifically, maximal inhibition of tTG was seen in women with previous miscarriages and alterations of menstrual cycle.
Tissue transglutaminase is widely expressed in early and term placenta with strong enzymatic activity at the syncytiotrophoblast microvillous membrane, the primary interface between maternal and fetal tissue where it is exposed to maternal circulating antibodies (Sóñora et al., 2011). In the study, placental tTG was recognized by positive tTG-IgA sera from nonpregnant donors that then inhibited its enzymatic activity in situ. Impairment of tTG function in the uterus and at the embryo–maternal interface could affect these gynecological/obstetric disorders, possibly explaining the link between CD and the complications (Sóñora et al., 2011).
When considering the complications of intrauterine growth restriction, low birth weight, preterm delivery, and cesarean delivery, infants of mothers with CD who were diagnosed and treated prior to conception had no increased risk of adverse effects compared with the general population (Seungdamrong & McGovern, 2007). For most women, the complications can be easily resolved with strict adherence to a GFD and iron and folate supplementation, especially during the reproductive years (Seungdamrong & McGovern, 2007).
Among the celiac women studied by Kotze (2004), 84.2% suffered from iron-deficiency anemia and 48.7% suffered from hypoalbuminemia as determined by ferritin, total proteins, and albumin levels. The proportion of celiac women with anemia was related to the amount of malnutrition as determined by a specific algorithm. In those with moderate and severe malnutrition (as seen by a weight loss of 20%–30% and >30%, respectively), all of the women had iron-deficiency anemia (Kotze, 2004). As previously stated, malnutrition can play a significant role in CD and, as seen in this study, cause iron-deficiency anemia.
Shamaly et al. (2004) noted GI complaints and iron-deficiency anemia to be more common in infertile women with CD than in infertile women without CD. This suggests that CD is not always silent in infertile women with CD. It also suggests that due to malabsorption seen in CD, infertile women with iron-deficiency anemia should be worked up for the disease. Inflammation of and damage to the gastric mucosa can lead to malabsorption and nutritional deficiencies, which may be an additional presentation of CD among some patients.
Hershko and Patz (2008) outlined the association of iron-deficiency anemia with CD as one of the most common extraintestinal manifestations of CD. Although folate and cobalamin deficiencies are known complications of CD, the most common nutritional anemia associated with CD is iron-deficiency anemia. Villous atrophy of the intestinal mucosa is an important cause of abnormal iron absorption, as seen in the laboratory values suggesting iron-deficiency anemia in most anemic patients with CD. Additional supporting evidence includes the failure to increase a patient's serum iron following oral iron loading and refractoriness to oral iron treatment. It was reported that up to 46% of patients with subclinical CD have iron-deficiency anemia, whereas 5.2% of those with iron-deficiency anemia have CD (Hershko & Patz, 2008).
Management of CD Patients by Primary Care Providers
Several components are required to diagnose CD. Physical examination, serological testing, intestinal biopsy, and response to a GFD are needed to definitively diagnose CD. Serological markers may be unreliable when considered independently, which is why multiple sequential blood tests are typically done in addition to other diagnostics. The serum test for tTG antibody (tTG-IgA) is a first-line marker due to high sensitivity (90%–96%) and specificity (>95%) reported with CD (Quest Diagnostics, 2012). In conjunction with this test, a total serum IgA is conducted (Quest Diagnostics, 2012). If tTG-IgA is positive, the EMA-IgA may be performed. If IgA is negative, and there is strong clinical suspicion for CD, IgG is then obtained, because 2%–10% of patients with CD may have selective IgA deficiency (Quest Diagnostics, 2012), meaning this negative IgA can represent a false-negative result. For those with a known IgA deficiency, testing IgG anti-tTG antibodies is preferred (Fasano & Catassi, 2012). With the possibility of false-negatives and false-positives, it is important to consider clinical presentation and suspicion, as well as genotyping.
Because levels of anti-tTG and EMA tend to decrease in the absence of gluten ingestion, these markers are useful to monitor adherence to a GFD. Testing frequencies of every 6 months after starting the GFD and every 1 year in asymptomatic individuals are recommended by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Quest Diagnostics, 2012). Testing can be performed at any time in individuals with persistent or recurrent symptoms (McCance et al., 2010).
Genotyping can also be a useful tool in determining the presence of, or susceptibility to, CD. Because of its genetic predisposition, serological screening is recommended for all first-degree relatives of CD patients (Fasano & Castassi, 2012). Testing for HLA-DQ2 and HLA-DQ8 may be useful in these instances, because one of these is present in approximately 97% of celiac-positive patients (Fasano & Castassi, 2012). With its high negative predictive value, the disease would be unlikely to develop in anyone who tests negative for both HLA-DQ2 and HLA-DQ8 (Fasano & Castassi, 2012). A few cases of CD have been discovered in people not carrying these gene pairs, but this is a rare finding. An important element to note is that the presence of the genes does not confirm the presence of disease because most relatives of individuals with CD (60%–70%) carry this genotype but are not affected by CD. Although the test is positive in 96%–99% of CD patients, it is also positive in 30%–40% of the general population (Bast et al., 2010). This testing is helpful in patients in whom securing a diagnosis is difficult due to equivocal small bowel biopsy findings, a positive antibody with a normal biopsy, and/or IgA deficiency (Bast et al., 2010). In addition, HLA genotyping is recommended in patients who have self-started on a GFD because tTG testing may show negative findings.
Although serological testing can be a starting point for diagnosing CD, positive results are usually followed by an intestinal biopsy, long considered the gold standard in celiac diagnosis. The biopsy aims to find histological changes of the small bowel mucosa, which may be difficult because those changes may not be continuous throughout the intestine. Instead, patchy changes are likely, so it is recommended to obtain four to six biopsy samples from the second part of the duodenum (Hershko & Patz, 2008). These samples should be obtained prior to the patient adopting a GFD because histological changes can be reversed with the GFD (Hershko & Patz, 2008).
Diagnosing DH can be done through blood tests and a skin biopsy. If the antibody tests are positive and the skin biopsy has the typical findings of DH, patients do not need to have an intestinal biopsy. Both the skin disease and the intestinal disease respond to a GFD and recur if gluten is added back into the diet. The rash symptoms can be controlled with antibiotics such as dapsone (generic-only). Because dapsone does not treat the intestinal condition, people with DH must maintain a GFD (NIDDK, 2008).
Total elimination of gluten from the diet is the only treatment that is effective for CD. Medications and surgical procedures are not treatment options, so the GFD is the prescribed treatment. With gluten being the trigger for intestinal inflammation, eliminating gluten from the body will eliminate the inflammation and allow healing. A newly diagnosed patient will typically be referred to a nutritionist in order to assess current eating habits and ways to modify them, as well as support groups and networks to help cope with what can be a drastic change in one's life.
No amount of gluten, no matter how small, is acceptable in a GFD. Even in small amounts, the gluten can trigger inflammation and damage the intestinal villi, causing associated symptoms and nutrient malabsorption. Most patients who follow a strictly GFD will begin to notice symptom improvement in several weeks, but it may take up to 2 years for the intestine to fully heal in adults (National Foundation for Celiac Awareness [NFCA], 2011).
To eliminate gluten from one's diet, a person must not eat foods containing wheat, barley, or rye. Other, less obvious sources of gluten include malt (in most beers), bulgur, bran, couscous, orzo, matzo, kamut, panko, faro, and spelt. Hidden sources of gluten include deli meats, gravies and sauces, bouillons, dairy substitutes, licorice, soy sauce, salad dressings, communion wafers, chapstick, and toothpaste. In addition, some people with CD have been known to have sensitivity to oats. Although oats in their natural form do not contain gluten, an estimated 1%–5% of celiac patients react to oats in their pure form. In addition, many mills processing oats process wheat, increasing the chances of cross contamination. It is recommended that people with CD pay careful attention to the oats they consume, ensuring they are “certified gluten-free” and from gluten-free facilities (NFCA, 2011).
Eliminating gluten from one's diet means that most breads, pastas, and baked goods are off-limits. Gluten-free foods are becoming more available in larger grocery retailers, in addition to specialty food stores. Scrutinizing food labels must be done when shopping, but the consumer must be aware that simply because wheat is not listed among the ingredients does not guarantee the absence of gluten in the product. “Gluten-free” labels help the consumer identify celiac-friendly products. Learning what foods are acceptable for consumption, and using possible substitutes, is key. Some examples of foods not containing gluten include potato, rice, quinoa, nuts and nut flours, amaranth, tapioca, corn, beans, and buckwheat. Many of these are available in flours, which should substitute for the commonly used all-purpose flour (NFCA, 2011). Adapting to a GFD may be more difficult for some people than others, potentially causing psychological effects, the extent of which may depend on a person's age or social habits.
Not only will a new celiac patient require ample education and guidance but also the person's family and friends will need to be educated. A celiac patient may face risks when living with other gluten-eating people. Educating housemates on the potential for cross contamination of gluten and strategies to prevent it are crucial. Some medications also contain gluten as a binder but the specific type of starch is not required on medication labels (NFCA, 2011). For that reason, it is best to speak with a pharmacist to ascertain which drugs are safe to consume.
Effectiveness of the GFD on Female Reproductive Problems
The impact of the GFD on gynecological and obstetric problems did have significant results, showing increased secondary amenorrhea in those who were noncompliant with following the GFD versus those who were compliant. These results, although significant, only assessed a total of 18 women (8 were GFD compliant, 10 were not) because participants were excluded if they were menopausal, had no active sex life, or were using contraceptive methods (Kotze, 2004). Similarly, Choi et al. (2011) showed that the infertile patients who were positive for CD were able to conceive within 1 year of starting a GFD.
Additional notable results include the efficacy of following a GFD as treatment of CD. As described by Ozgor and Selimoglu (2010), some of the earliest research regarding reproduction and CD, dating back to 1970, showed improved pregnancy outcomes once women with CD were put on a strict GFD. This review also highlighted interesting data from several studies in the 1990s reporting concurrent results that delayed menarche and early menopause were more common in women with untreated CD than those who were following a GFD. Those untreated celiac women were also more likely to experience secondary amenorrhea than those with treated CD or without CD entirely (Ozgor & Selimgolu, 2010).
More recent studies include work from Santonicola et al. (2011), who discovered that women following a GFD for at least 10 years before menopause were able to delay menopause, postponing it from affecting them at the earlier age range seen in many CD women. This lengthened the fertile life span to an average of 36.3 years, as opposed to the 35 years seen with untreated CD. The previously mentioned study by Zugna et al. (2010) found that women had decreased fertility 0–2 years prior to their time of diagnosis of CD, but had similar fertility to the healthy women following diagnosis and the initiation of a GFD. This implies that this timing of 0–2 years may be when CD is most active in women, causing them to get tested for CD. In addition, it suggests that following a GFD allows a woman's fertility to return to that of a healthy woman. Nenna, Mennini, Petrarca, and Bonamico (2011) agreed that the malabsorption of vitamins and nutrients associated with CD, as well as the increased activation of the immune system, improves greatly once a GFD is followed. The immediate effect of a GFD in patients may suggest a major role of selective nutrient defects (such as folate, zinc, antioxidants, and micronutrients) for the metabolism of carrier or receptor proteins for sex hormones. In addition, Nenna et al. (2011) recommended that malabsorption of vitamin B12 may cause hyperhomocysteinemia, and thereby increase the likelihood of thrombosis, which can lead to infertility. Fertility can be restored by histological, clinical, and pathological remission (Nenna et al., 2011).
Ciacci et al. (1996) provided interesting results when analyzing the effect of a GFD on pregnancy outcomes. They examined 12 women with CD after 1 year of following a GFD compared with celiac women who were untreated. All outcomes were better in the group of women following the GFD, including the average number of pregnancies per woman, which was 2.5 in the women following the GFD versus 1.08 in untreated women. The average number of spontaneous abortions per woman was 0.08 versus 1.08 in untreated women (Ciacci et al, 1996). The prevalence of spontaneous abortion was 43.3% for the untreated group compared with 7.7% for the treated group of CD women. There were no low-birth-weight babies born to women in the GFD group, whereas there was 29.4% of low-birth-weight babies in the untreated group (Ciacci et al., 1996). Clearly, these numbers show GFD to be beneficial in the reproductive health of a pregnant celiac woman.
Guidelines for Management of Women
Considering the research and implications, there are few obvious negative consequences to CD testing. The cost is far less than the health problems associated with undiagnosed and untreated CD. These thoughts coincide with those stated by Rostom et al. (2004). Therefore, the following guidelines are recommended for diagnosis and treatment of women who may have CD. Those who should have serological testing done include the following:
- Any person who has a family member with CD, regardless of symptoms present, because there is a 10%–15% increased chance of having CD if a family member also has this disease (Fasano & Catassi, 2012). This may require practitioners to address this question in an initial review of family history or on a preliminary medical history form.
- Patients with autoimmune disorders including Type 1 diabetes mellitus, thyroid disorders, Down's syndrome, or Turner's syndrome, because these disorders can also increase the chances of having CD (Fasano & Catassi, 2012).
- Any woman who complains of the common CD symptoms, including diarrhea and abdominal pain, particularly if pain worsens after eating gluten-containing foods.
- Women presenting with DH.
- Women known to have vitamin deficiencies, particularly iron-deficiency anemia.
Serological testing should include total IgA and tTG-IgA testing, with or without EMA. If tTG-IgA and the total IgA are low, the patient should have IgG testing done because it is likely there is an IgA deficiency. Should results indicate CD as a possibility, the patient should be referred to a gastroenterologist and have an intestinal biopsy. If that shows villous damage, the patient should then be “prescribed” a GFD and referred to a nutritionist for guidance.
Considering that not every test for CD confirms the diagnosis independently of other tests, should a strong clinical suspicion exist without suggestive blood values, a biopsy is still recommended. On the contrary, should blood work be highly suggestive of the disease and clinical suspicion present, but intestinal villi are normal, following a GFD is still recommended (Table 1).
TABLE 1. -
Case Study Depicting a Woman With Celiac Disease With Infertility Problems
|A 35-year-old woman had been attempting to conceive for the last 8 years. She initially presented to this fertility practice when she was 32 years old, after having already tried hormonal therapy for 4 years at another practice in the state, including several cycles of clomiphene citrate hormonal therapy, the first in 2007. Upon initial consultation, she was Gravida 1, Para 0, and had experienced one miscarriage at 8 weeks of conception. She had previous use of various triphasic oral contraceptive pills—for a total of 8 years before she began trying to conceive naturally.
|The patient had normal Papanicolaou tests to date, no history of dysmenorrhea or menorrhagia, and no history of sexually transmitted infections. Other notable history included being positive for the methylene tetrahydrofolate reductase (MTHFR) mutation (homozygous with normal homocysteine) and a history of chronic Lyme disease (diagnosed in 1990). Routine screening for new patients at this practice included blood tests (CBC count, a chemistry panel, estrogen and progesterone levels, and a thyroid panel), diagnostic ultrasonograms of fallopian tubes and uterus, and analysis of semen from her husband. All of the results were normal for the patient. Because of the patient's positive MTHFR mutation, she was at increased risk for blood clots due to her risk for homocysteinemia. As a precaution, her homocysteine levels were checked every 3 months and continued to remain normal. The patient was also referred to a hematologist/oncologist to assess the risk associated with fertility treatments, pregnancy, and the MTHFR gene. She was cleared by the practitioner to proceed with treatments.
|The patient was also referred to a rheumatologist for clearance because of her previously diagnosed Lyme disease. Results from blood work done by the rheumatologist included a negative ANA titer and rheumatoid factor, as well as low positive abnormal autoantibodies to gliadin, although the patient reported no overt evidence of disease resembling celiac disease.
|In June 2011, the patient underwent her first round of IVF, after retrieving fresh eggs and fertilizing them with her husband's sperm. Two embryos were used and additional embryos were cryopreserved for possible future use. Her hCG levels rose appropriately at first, but her ultrasound at 8 weeks showed no gestational sac along with the patient reporting heavy bleeding 1 day prior. This suggested a spontaneous abortion had occurred, confirmed with another ultrasound 1 week later.
|In October 2011, the patient underwent another round of IVF with fresh egg retrieval, fertilization, and return of two embryos to the patient. Again, the patient's hCG levels rose appropriately and ultrasound findings were optimistic. At 8 weeks, a gestational sac, fetal pole, and healthy fetal heartbeat were detected. However, 1 week later, the heartbeat was weak and difficult to detect, suggesting a nonviable fetus. Seven days later, an ultrasound showed no retained products of conception.
|Another consultation was held, counseling the patient on other possible options, including proceeding again with a fresh cycle, adjusting the hormonal therapies, proceeding with frozen embryos, or even using a donor egg. Given her previously positive test for gliadin autoantibodies, it was also suggested she try a gluten-free diet and see a gastroenterologist. The patient denied gastrointestinal symptoms and felt as though embracing a gluten-free diet might be too difficult. In addition, the patient was referred to the Antenatal Testing Unit to discuss other potential sources of difficulty or risk. It was suggested that she see a gastroenterologist to investigate celiac disease further.
|In October 2012, the patient began hormone treatment again to prepare for a frozen embryo transfer. Routine blood work was conducted to assess for readiness of transfer by looking at the patient's estrogen and progesterone levels. However, despite oral estrogen for several months, the patient's blood estrogen levels never rose as anticipated. This suggested a potential problem of absorption. Again, it was recommended that she see a gastroenterologist, whom she saw in early 2013. Although the gastroenterologist saw nothing to definitely diagnose the patient with celiac disease (based on blood work), he suggested that a gluten-free diet may help with fertility efforts. Doing so would not be to her detriment but, instead, could only help her situation. Because her blood levels were not convincing for celiac disease, no intestinal biopsy was performed.
|In May 2013, the patient attempted fertility treatment again, after 4 months of following a gluten-free diet. She did state that it was difficult, but her energy level had improved. This time, the patient was started on transdermal estrogen patches, rather than oral estrogen, because this might be more effective, given she had shown poor gastrointestinal absorption. Her levels rose and, in June 2013, she had five of her previously cryopreserved embryos transferred to her uterus. She responded well, showing appropriate levels of hCG increase and the presence of a gestational sac. At 8 weeks, the fetal heartbeat was strong and the patient was referred to continue care with her obstetrician. She was due to have her first child in March 2014.
|Although it was unsure if the patient had success due to a gluten-free diet or the transdermal estrogen regimen, it was likely a combination of the two. Had the patient embraced a gluten-free diet earlier, she might have had success conceiving years ago, perhaps without fertility treatment at all. Although her blood levels were not conclusive of celiac disease, the delays in referring to a gastroenterologist or suggesting a gluten-free diet were substantial, particularly in this situation. Because the patient had tested positive for gliadin antibodies, in addition to difficulty conceiving naturally, a further workup should have been conducted at the initial visit. Additional celiac blood work should have been done immediately, as well as referral to a gastroenterologist and a nutritionist. Had those steps taken place, the couple might even have two children by now.
Note. CBC = complete blood cell; hCG = human chorionic gonadotropin; IVF = in vitro fertilization.
With CD impacting 3 million Americans and the statistical evidence indicating drastic underdiagnosis of CD, action is warranted to ensure those with CD be identified and treated. Not only can a person suffer from GI symptoms, but also the implications for a woman's reproductive health are significant. These include menstrual irregularities, difficulty achieving and maintaining a healthy pregnancy, and increased menopausal symptoms. With treatment as straightforward as following a GFD, symptoms can be eliminated and the reproductive consequences improved.
The overarching obstacle with treating CD is identifying that a person has it in the first place. Because many practitioners do not routinely screen for CD, many patients are never diagnosed. For that reason, it is necessary to increase the frequency of celiac screening with practitioners following guidelines of who to screen. Because of an increased prevalence among certain populations, including women with suspected fertility challenges, initial testing for CD with simple blood tests can be the start of improved CD diagnosis.
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