Латентная целиакия - еще одна причина повторного невынашивания (недавние публикации)

[Dr.Vad]

The prevalence of positive antibodies for subclinical celiac disease (CD) in RPL versus controls (taking patients with at least two positive tests) was 3.51% versus 0.0% (P < 0.04). The condition of all these patients is silent from the gastrointestinal viewpoint, however this condition can be the cause of an unfavorable outcome of pregnancy.

The CD is an autoimmune disorder associated with the production of an autoantibody against transglutaminase which is present in human tissue. Early expression of anti-endomysium is observed in the cultured small intestinal mucosa of patients with celiac disease exposed to gliadin.

Women with undiagnosed celiac disease seem to have an 8.9-fold relative risk of multiple abortions and low birth weight babies compared with treated patients.

A gluten free diet resulted in a 9.18-fold reduction in the abortion rate and a reduction in the prevalence of low birth weight babies from 29.4% to zero. In another study, 15% of 68 women with untreated CD had miscarriages compared with 6% of controls, but after a gluten free diet, the miscarriage rate was similar in patients and controls.

Autoantibodies in Argentine women with recurrent pregnancy loss RPL.
Bustos D, Moret A, Tambutti M, Gogorza S, Testa R, Ascione A, Prigoshin N.
Am J Reprod Immunol. 2006 Mar;55(3):201-7.

-------------

Celiac disease (CD) is a permanent intolerance to gluten characterized by destructions of the small intestinal villi and malabsorption. The gluten-free diet (GFD) results in healing of the mucosa, resolution of the malabsorpitive states, and reversal of great part of CD effects. Among the extradigestive complications associated with CD, unexplained infertility has been reported since the 70's. The prevalence of CD among women with unexplained infertility is 2.5-3.5%, higher, although not always significantly, than control population. To date, it is widely accepted that untreated CD represents a risk for abortion, low birth weight babies and short-breast feeding period. These features can be corrected by GFD. Some discrepancies could stem from the heterogeneity of the studies. In conclusion, each woman with unexplained infertility should be screened for CD.

Minerva Med. 2007 Jun;98(3):217-9.
Women and celiac disease: association with unexplained infertility.
Pellicano R, Astegiano M, Bruno M, Fagoonee S, Rizzetto M.

--------------

A case-control study about the effect of GFD on pregnancy was conducted from 1995 to 2006. A cohort of 13 women (mean age 32 years, range 22-38 years) affected by CD with recurrent miscarriages was observed. In all of them several causes of miscarriage (gynecological, endocrine, hematological, etc.) were excluded. All patients were started on a gluten-free diet and were reassessed throughout a long-term follow-up period to evaluate the outcome of pregnancy. RESULTS: Six of 13 became pregnant (46.15%) as follows: 1 patient (7.69%) 1 year after GFD was started, 3 patients (23.07%) 2 years after GFD was started, 1 patient (7.69%) after 3 years, and finally 1 (7.69%) 4 years after GFD was started. Moreover, two patients (16.66%) had multiple pregnancies (one had had two childbirths and another had undergone three births within a 7-year follow-up period under GFD).

Effect of gluten-free diet on pregnancy outcome in celiac disease patients with recurrent miscarriages.
Tursi A, Giorgetti G, Brandimarte G, Elisei W.
Dig Dis Sci. 2008 Nov;53(11):2925-8.

[Dr.Vad]

CLINICAL PRESENTATIONS

The clinical presentation of CD varies greatly, ranging from asymptomatic to severely malnourished patients. The most common clinical manifestations of CD include abdominal cramping pain with moderate to severe abdominal distension, frequently associated with relapsing or permanent dyspepsia, presence of gastro-esophageal reflux (GERD) and recurrent episodes of altered bowel habits (diarrhea and/or constipation), weight loss, bone disease, anemia and weakness.

While diarrhea was almost considered a persistent symptom, this is not the case in adults, and up to 50% of patients predominantly have constipation, which on many occasions becomes refractory to all types of therapy. It should be noted, that up to 30% of celiac patients have increased body mass index (BMI) and obvious obesity at diagnosis.

CD is sometimes divided into clinical subtypes. The terms “symptomatic or classic” apply to cases that meet the typical features described above. By contrast, in the “atypical forms” of the disease, the gastrointestinal symptoms may be absent or less pronounced, and in this case the extra-intestinal features predominate, such as chronic iron deficiency anemia, osteoporosis, short stature or failure to thrive, infertility and increased number of abortions.

Since atypical presentations are found more frequently in later decades, CD is now considered to be a multisystemic disorder, rather than a sole gastrointestinal process.

Risk groups and associated disorders

• First degree relatives
• Down´s and turner´s syndromes
• IgA selective deficiency
• Endocrine diseases
o Type 1 diabetes mellitus
o Autoimmune thyroid diseases
o Alopecia areata
• Neurologic diseases
o Cerebellar ataxia
o Epilepsy
o Peripheral neuropathy
o Multiple sclerosis
• Liver diseases
o Primary biliary cirrhosis
o Autoimmune hepatitis
o Autoimmune cholangitis
o Idiopathic hypertransaminasemia
• Rheumatologic diseases
o Rheumatoid arthritis
o Sjögren´s syndrome
• Heart diseases
o Idiopathic dilated cardiomyopathy
o Autoimmune myocarditis
• Cutaneous diseases
o Dermatitis herpetiformis
o Psoriasis
o Vitiligo
• Others
o Iron-deficiency anemia
o Osteoporosis
o Increased risk of fractures
o Infertility
o Amenorrhea
o Dental enamel defects
o Depression and anxiety
o Chronic asthenia

SEROLOGICAL TESTS

Among the serological tests needed to diagnose CD, the measurement of anti-gliadin IgA antibodies (AGA), has completely fallen into disuse and probably justifiably abandoned, as its sensitivity and specificity is very low (around 50%). In 1997, tissue transglutaminase 2 (tTG) was established by Dieterich et al to be the auto-antigen for anti-endomysial antibodies and since then, is preferred for clinical use, because it show good sensitivity, greater than 90%, and a high specificity, around 95%, although it displays small variations between the different commercial kits employed.

The presence of these antibodies correlates with the degree of villous atrophy and various studies have clearly shown that the sensitivity of testing tTG is decreased in patients with normal duodenal biopsies or with mild histological changes.

Measurement of tTG antibodies of the IgA isotype is usually determined in the clinical practice. Nevertheless, IgA deficiency occurs in 1.7%-2.6% of CD patients, which represents 10-15 times increase, over that in the general population. If IgA deficiency is found, measuring the IgG class tTG is recommended. Diagnosis of CD based solely on serologic markers is not accepted and the identification of the characteristics changes at the duodenal mucosa is required before starting on a GFD.

(World J Gastroenterol 2006 November 7;12(41):6585-6593)

[Dr.Vad]

It has been shown that women with diagnosed coeliac disease more frequently experience recurrent spontaneous miscarriage, delayed menarche, early menopause, amenorrhoea and vaginal discharge. Fertility problems are also more common in both men and women with coeliac disease. Screening for coeliac disease should be part of the diagnostic scheme of women with unexplained infertility, because treatment of this disease is suggested to be a major predictor for favourable pregnancy outcome. In about 25% of patients suffering from coeliac disease hyperprolactinaemia is diagnosed, which may be one of the causes of impotence and loss of libido.

The importance of nutrition on reproduction is well established. It has been suggested that the reproductive disorders in coeliac disease patients are due to the nutritional deficiencies as a consequence of malabsorption.

Zinc is an essential trace element, which is required for DNA synthesis, cell division, protein synthesis and immune response. Approximately 300 enzymes are dependent on zinc for their activities. Zinc finger proteins are important for the transcription of steroid receptors.

Zinc deficiency is characterized by skin lesions, hair loss and failure to thrive. Maternal zinc deficiency has been associated with impaired synthesis/secretion of FSH and LH. Abnormal ovarian development, obstetrical disorders, such as spontaneous abortion, congenital malformations, still birth, pre-eclampsia and intra uterine growth retardation have been associated with a primary zinc deficiency, which may lead to secondary endocrine derangements. The importance of zinc and its deficiency as possible factor for male subfertility has been suggested by Wong et al. The zinc content is high in the adult testis and the prostate has a higher concentration of zinc than any other organ of the body. An increase of semen pH is correlated to zinc concentration decrement in the seminal fluid. Abnormalities in spermatozoal function and fertilising capacity appear to be related to major changes in the seminalplasma levels of zinc and other trace elements. Moreover, it has been shown that zinc deficiency impairs angiotensin converting enzyme (ACE) activity, which may lead to depletion of testosterone and inhibition of spermatogenesis. In men suffering from coeliac disease gonadal dysfunction is believed to be due to the reduced conversion of testosterone to dihydrotestosterone caused by low levels of the zinc dependent 5-alpha-reductase enzyme. This leads to a derangement of the hypothalamic-pituitary axis. The most striking endocrine findings in untreated coeliac disease patients are the increased plasma testosterone and free testosterone index, the reduced concentration of the active testosterone derivative dihydrotestosterone and the raised serum luteinising hormone level, which is a pattern indicative of androgen resistance. Investigation of the zinc status in coeliac disease patients might, therefore, be valuable in preconceptional counseling.

A selenium deficiency is often diagnosed in coeliac disease patients. Selenium is an important trace element in the reproduction process as well. Selenium deficiency in women is associated with subfertility and spontaneous abortion. The selenium requirements of a pregnant woman and lactating mother are increased as a result of the selenium transport to the fetus via the placenta or to the new born infant via breast milk. The concentration of selenium during pregnancy seems not to have an effect on the weight of the baby or length of pregnancy. Selenium is involved in spermatogenesis as well and a deficiency results in subfertility. The content of selenium increases in male gonads during pubertal maturation. Selenium is localised in the mitochondrial capsule protein (MCP) of the mid-piece of the spermatozoa.

Mild to severe anaemia in coeliac disease patients is mainly caused by an iron and/or folate deficiency. During pregnancy the requirement of both elements is enhanced. Therefore, coeliac disease patients in particular could be at an increased risk of developing iron and folate deficiency during pregnancy. Both deficiencies have been associated with an increased maternal and fetal morbidity and mortality due to the insufficient oxygen-carrying capacity of the blood. Additional folic acid supply has been demonstrated to be an important factor in the prevention of neural tube defects and possibly orofacial schisis and recurrent spontaneous abortion.

Coeliac disease and reproductive disorders: a neglected association.
Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP.
Eur J Obstet Gynecol Reprod Biol. 2001 Jun;96(2):146-9