TSH elevation associated with pregnancy problems

Preconception TSH and pregnancy outcomesTSH (thyroid stimulating hormone) when elevated even within the ‘normal’ range at preconception, can result in adverse pregnancy outcomes. Further evidence for this was presented in a studyrecently published in Clinical Endocrinology, that examines whether subclinical hypothyroidism (SCH) has negative effects on pregnancy.

“Subclinical hypothyroidism (SCH), defined as elevated TSH and normal free T4 (fT4) levels, with an incidence of 2–13·7%, is the most common thyroid disorder during pregnancy. SCH has also been associated with adverse foeto-maternal outcomes…”

Thyroid hormone levels before pregnancy

Adverse effects of SCH during the first trimester and after have been documented in earlier studies, but there has been much less data for preconception thyroid hormone levels.

“To the best of our knowledge, this study was the first large-scale study to investigate the association between maternal TSH levels within the 6 months before conception and the risk of adverse pregnancy outcomes in a population at low risk. The second aim was to determine whether the first-trimester specific reference range or nonpregnant reference range for TSH should be applied during preconception evaluation.”

This was a large study, with 248,501 pairs of volunteer couples recruited from a free National Pre-pregnancy Checkups Project from 2010 to 2012 in China, out of which 184,611 women who later became pregnant were examined by measuring maternal thyroid stimulating hormone within 6 months before conception.

“Participants were grouped according to TSH: 0·48–2·49 mIU/l (n = 133 232, 72%), 2·50–4·28 mIU/l (n = 44 239, 24%) and 4·29–10·0 mIU/l (n = 7140, 4%). Multivariable logistic regression models were used to study the association between TSH and pregnancy outcomes.”

Preconception TSH elevation increases risk of adverse pregnancy outcomes

Even when within what is often still considered the normal non-pregnant range, thyroid stimulating hormone elevation predicted pregnancy problems.

“The overall incidence of adverse pregnancy outcomes was 28·6%. Compared with TSH 0·48–2·50 mIU/l, TSH 2·50–4·29 mIU/l was associated with spontaneous abortion [aOR: 1·10,], preterm birth (aOR: 1·09) and operative vaginal delivery (aOR: 1·15, 95% CI: 1·09–1·21), while TSH 4·29–10 mIU/l was correlated with spontaneous abortion (aOR: 1·15), stillbirth (aOR: 1·58), preterm birth (aOR: 1·20), caesarean section (aOR: 1·15) and large for gestational age (LGA) infants (aOR: 1·12).”

The authors discuss the implication of these odds ratios that are small yet significant.

“The present study involving 194 154 subjects demonstrated that preconception high TSH was associated with a small but significant increased risk of overall adverse pregnancy outcomes, including spontaneous abortion, preterm birth and LGA infants, regardless of whether we used first-trimester-specific upper limit (2·50 mIU/l) or nonpregnant reference upper limit (4·29 mIU/l). Our data support that women planning a pregnancy within 6 months should be regarded as ‘pregnant status’ and that closer observation may be required once TSH levels exceed 2·50 mIU/l, rather than the nonpregnant reference upper limit.”

Clinicians should also bear in mind:

Borderline TSH elevation has been shown to portend deleterious impacts on various pregnancy outcomes. In the present study, we found that the higher the preconception TSH, the higher the incidence of adverse pregnancy outcomes. This was concordant with other studies, although they measured TSH during pregnancy, rather than before conception. Thyroid hormones themselves directly affect foetal development and utero-placental maturation; hence, maternal hypothyroidism can influence pregnancy outcomes, especially in early gestation.”

Regarding case management, the authors conclude:

“…preconception high TSH levels were associated with a small but significant increased risk of overall adverse events, including preterm birth, CS delivery and LGA infants, even within normal nonpregnant range. TSH <2·5 mIU/l is more suitable for the assessment of women planning a pregnancy in China, but one should not make a hasty decision to initiate treatment at this point without repeating TSH measurement and checking TPO antibody status. Prospective randomized controlled trials examining the role of levothyroxine supplement in mildly hypothyroid prepregnant women are warranted in the future.”

See also Subclinical hypothyroidism in pregnancy.

Subclinical hypothyroidism in pregnancy

BMJ 349.7978Subclinical hypothyroidism, poor thyroid effect with thyroxine (T4) in the ‘normal’ range and thyrotropin (TSH) within ‘normal’ according to reference ranges of many labs, is a vital issue for both mother and baby. A ‘state of the art review‘ just published in BMJ (British Medical Journal) offers practitioners important reminders guidelines for subclinical hypothyroidism in pregnancy, a common and vital problem. The authors note:

“Subclinical hypothyroidism is associated with multiple adverse outcomes in the mother and fetus, including spontaneous abortion, pre-eclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased IQ in the offspring.”

Defining subclinical hypothyroidism

These values of TSH (thyrotropin) are not often flagged as out of range by clinical laboratories:

“Subclinical hypothyroidism is defined as raised thyrotropin combined with a normal serum free thyroxine level. The normal range of thyrotropin varies according to geographic region and ethnic background…These discrepancies are probably the result of different daily intakes of iodine, varying prevalence of thyroid autoimmunity, genetic background, and environmental factors... In the absence of local normative data, the recommended upper limit of thyrotropin in the first trimester of pregnancy is 2.5 mIU/L, and 3.0 mIU/L in the second and third trimester.”

Special physiology of pregnancy

Pregnancy puts weighty demands on thyroid physiology:

“Pregnancy is a stress test for the thyroid. The thyroid gland must produce 50% more thyroid hormone for euthyroidism to be maintained and to provide enough thyroid hormone for the developing fetus. Simultaneously, the physiological changes that accompany pregnancy result in marked alterations in the normal range of thyroid function. Specifically, human chorionic gonadotropin, which peaks in the first trimester, crossreacts with the thyrotropin receptor, resulting in an upper limit of normal of thyrotropin of 2.5 mIU/L during the first trimester.

Causes of subclinical hypothyroidism

As noted in many reports here, by far the most common cause of hypothyroidism in developed countries is autoimmune thyroiditis (Hashimoto’s disease). The authors articulate a number of key points for clinicians to bear in mind:

“The leading cause of hypothyroidism in developing countries is severe iodine deficiency, whereas in developed countries it is autoimmune thyroiditis. Thyroid autoantibodies are detected in about half of pregnant women with subclinical hypothyroidism and in more than 80% with overt hypothyroidism. Antibodies directed against thyroid peroxidase (TPO-Ab) should therefore be measured in patients with subclinical hypothyroidism to establish a diagnosis of autoimmune thyroid disease.”

Personally I have found in practice that antibodies to thyroglobulin (TG-Ab) can crop up and should be measured as well:

“Although only positive TPO-Ab tests have been shown to be significantly associated with hypothyroidism, antibodies to thyroglobulin (TG-Ab) should also be measured. In a study of 992 unselected women who consulted a tertiary referral center for infertility, the overall prevalence of autoimmune thyroid disease was 16%. Of these women, 8% had both antibodies, 5% had TG-Ab only, and 4% had TPO-Ab only. Women with isolated TG-Ab had significantly higher serum thyrotropin concentrations than those without autoimmune thyroid disease…If thyrotropin concentrations are raised, TPO-Ab should be measured to establish a diagnosis of autoimmune thyroid disease. If TPO-Ab are present, the measurement of TG-Ab should be considered.”

Antibodies can be suppressed and might not show up when first measured

It is of great importance for clinicians to be aware that the results of any medical test involving antibodies may be obscured by any one of a number of factors that can suppress antibody expression. This includes pregnancy:

“Finally, it is important to realize that because the immune system is suppressed during pregnancy, thyroid antibody titers decrease on average by 60% in the second half of pregnancy. Consequently, in some women with autoimmune thyroid disease, thyroid antibody test will be negative during pregnancy but positive postpartum because the immunosuppression of pregnancy yields to an immunologic rebound during the first six months postpartum.”

Iodine deficiency during pregnancy

Although autoimmune thyroiditis accounts for most cases of hypothyroid in developed controls in general, there is a greater need for iodine during pregnancy that more easily result in deficiency.

During pregnancy, the iodine requirement increases by about 50% because the woman needs to produce more thyroid hormone, renal loss of iodine is exacerbated by the increased glomerular filtration rate, and the fetus needs to produce thyroid hormone during the second half of pregnancy. The contribution of iodine deficiency to thyroid insufficiency depends on the severity of iodine deficiency, and inadequate iodine intake is seen in both developing and developed countries.In 2011, nearly 45% of Europeans, including pregnant women and those of child bearing age, were estimated to be iodine deficient…The National Health and Nutrition Examination Survey (NHANES) has documented a marked decrease in the median urinary iodine concentration over the past three decades, with the current value for pregnant women being 125 μg/L, indicating that pregnant women in the US are probably mildly iodine deficient.”

There are serious consequences of maternal iodine sufficiency for fetal brain development:

“The Avon Longitudinal Study of Parents and Children confirmed the central role that maternal iodine status plays in the development of childhood cognition…The results showed that after adjustment for confounders, children of women with an iodine to creatinine ratio less than 150 μg/g were more likely to have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than children of mothers with ratios 150 μg/g or more. Moreover, when the less than 150 μg/g group was subdivided, scores worsened progressively in the less than 150 μg/g, 50-150 μg/g, and less than 50 μg/g subgroups.”

Clinical Note: Care must be taken in prescribing iodine supplementation because inappropriate amounts can trigger autoimmune thryoiditis in those who are vulnerable. See earlier posts on the accepted method for determining iodine deficiency (24 hour urine collection) and other studies pertinent to supplementation by typing ‘iodine’ in the search box above.

Screening for subclinical hypothyroidism in pregnancy

The authors support a rational approach to screening:

“Current evidence on subclinical hypothyroidism does not support universal screening. However, the incidence and impact of overt hypothyroidism and the ability of treatment to prevent associated adverse events is sufficient to justify universal screening for thyroid disease. In support of this position, a cost effective analysis showed that universal screening with the goal of identifying and treating overt hypothyroidism is cost effective. Because universal screening would also identify patients with subclinical hypothyroidism, these patients should be treated as indicated in current guidelines unless ongoing and future studies prove otherwise.”

Clinicians sharing patient care should note:

“…obstetricians and gynecologists provide the majority of pregnancy related care. Studies have reported that some obstetricians have limited knowledge about the association between thyroid disease and pregnancy.”

Treatment for subclinical hypothyroidism in pregnancy

Far too many women and their children currently still fall though the medical cracks. It should be remembered that subclinical hypothyroidism in the first trimester can worsen as the pregnancy progresses. The authors advance the following guidelines:

Subclinical hypothyroidism has been associated with multiple adverse maternal, fetal, and neonatal outcomes, and a preliminary intervention trial suggests that treatment is beneficial. On the basis of current evidence, we believe it is reasonable to recommend treating women with new onset subclinical hypothyroidism during pregnancy. Levothyroxine therapy during pregnancy is inexpensive and has been shown to be safe…Irrespective of the prepregnancy thyrotropin value, all patients should be instructed to have thyrotropin measured as soon as pregnancy is confirmed.”

Treatment algorithm for levothyroxine before pregnancyThe authors conclude with some important points:

“The past two decades have seen major advances in our understanding of the physiological changes that occur in the thyroid during pregnancy and the impact of subclinical hypothyroidism on adverse maternal and fetal outcomes. The normal upper range of thyrotropin is 2.5 mIU/L in the first trimester of pregnancy and 3.0 mIU/L in the second and third trimesters. Hypothyroidism is present in 2-15% of pregnant women. It is mainly caused by iodine deficiency in developing countries and autoimmune thyroid disease in developed countries. Subclinical hypothyroidism has been associated with multiple negative outcomes, including pregnancy loss, preterm delivery, gestational diabetes, and impaired neurologic development in the offspring. Women on levothyroxine before conception require careful management to ensure that the euthyroid state is maintained throughout pregnancy. “

Histamine intolerance

American Journal of Clinical NutritionHistamine intolerance (HI), which may present with a multitude of potential symptoms, occurs when the capacity to degrade histamine falls short. It can contribute numerous diverse conditions including IBS and inflammatory bowel diseases, asthma, postural orthostatic tachycardia syndrome (POTS), complications of pregnancy, drug hypersensitivity, headache, cardiac arrhythmia, blood pressure dysregulation, and intestinal permeability (by means of which it contributes to autoimmunity). Suspicion of HI should be high if relevant symptoms persist after antibody mediated food allergies are avoided or ruled out. A paper published in The American Journal of Clinical Nutrition expands on key points of histamine intolerance, a phenomenon that may be far more widespread than generally recognized.

“Histamine belongs to the biogenic amines and is synthesized by…mast cells, basophils, platelets, histaminergic neurons, and enterochromaffine cells, where it is stored intracellularly in vesicles and released on stimulation. Histamine is a potent mediator of numerous biologic reactions.”

Histamine intolerance widely unrecognized in clinical practice:

Because of the multifaceted symptoms, the existence of histamine intolerance is frequently underestimated, or its symptoms are misinterpreted. Clinical symptoms and their provocation by certain foods and beverages appear similar in different diseases, such as food allergy and intolerance of sulfites, histamine, or other biogenic amines (eg, tyramine). Therefore, the differentiation of the causal agent in adverse reactions to food, alcohol, and drugs is a difficult challenge.”

There are numerous ways to incite the release of histamine…

“Besides the well-known triggering of degranulation of mast cells by crosslinking of the FcεRI receptor by specific allergens, several other nonimmunologic stimuli, such as neuropeptides, complement factors (ie, C3a and C5a), cytokines, hyperosmolarity, lipoproteins, adenosine, superoxidases, hypoxia, chemical and physical factors (eg, extreme temperatures, traumas), or alcohol and certain food and drugs, may activate mast cells.”

In other words, stimuli as diverse as temperature, dehydration and mechanical trauma to Histamine and histamine intolerancelipoproteins, oxidative stress, reduced oxygen saturation, various signalling molecules and alcohol of any kind, not to mention food and drugs, can trigger the release of histamine from mast cells. The vast range of potential symptoms is congruent with its mechanisms of action:

“It causes smooth muscle cell contraction, vasodilatation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, and it stimulates gastric acid secretion and nociceptive nerve fibers. In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, day-night rhythm, and the regulation of histamine- and polyamine-induced cell proliferation and angiogenesis in tumor models and intestinal ischemia.”

Histamine intolerance occurs when the capacity to degrade histamine is insufficient.

“Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. The main enzyme for metabolism of ingested histamine is diamine oxidase (DAO). An impaired histamine degradation based on a reduced DAO activity and the resulting excess of histamine may cause numerous symptoms mimicking an allergic reaction….In histamine-sensitive patients with reduced DAO activity, symptoms occur even after the ingestion of the small amounts of histamine that are well tolerated by healthy persons. Symptoms can be manifest via…actions of histamine in multiple organs, such as the gastrointestinum, lung, skin, cardiovascular system, and brain, according to the expression of histamine receptors.”

Patients with chronic headaches should be investigated for histamine intolerance:

Headache can be induced dose-dependently by histamine in healthy persons as well as in patients with migraine….In migraine patients, plasma histamine concentrations have been shown to be elevated both during headache attacks and during symptom-free periods. An increase in the number of brain mast cells is associated with pathologic conditions such as migraine, cluster headache, and multiple sclerosis. Many migraine patients have histamine intolerance evidenced by reduced DAO activity.”

It can play a major role in gastrointestinal disorders:

“…gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished DAO activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease, ulcerative colitis, allergic enteropathy, food allergy, and colorectal neoplasmas. In the colonic mucosa of patients with food allergy, a concomitant reduced HNMT and an impaired total histamine degradation capacity (THDC) have been found, so that the enzymes cannot compensate each other. Therefore, an impaired histamine metabolism has been suggested to play a role in the pathogenesis of these diseases.”

Chronic nasal congestion and asthma are considerations:

“During or immediately after the ingestion of histamine-rich food or alcohol, rhinorrea or nasal obstruction may occur in patients with histamine intolerance; in extreme cases, asthma attacks also may occur. Reduced HNMT activity has been shown for patients with food allergy and asthma bronchiale.”

Dysmenorrhea, estrogen dominance and menstrual headache should be evaluated for histamine intolerance:

“In the female genital tract, histamine is mainly produced by mast cells, endothelial cells, and epithelial cells in the uterus and ovaries. Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea. Besides the conctractile action of histamine, these symptoms may be explained by the interplay of histamine and hormones. Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol via H1R; meanwhile, only a moderate effect on progesterone synthesis was observed. The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandine F2α stimulated by estradiol and attenuated by progesterone. Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations. And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations. In pregnancy, DAO is produced at very high concentrations by the placenta, and its concentration may become 500 times that when the woman is not pregnant. This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy.”

Why might someone develop histamine intolerance?

“Histamine intolerance can develop through both increased availability of histamine and impaired histamine degradation. Underlying conditions for increased availability may be an endogenous histamine overproduction caused by allergies, mastocytosis, bacterias, gastrointestinal bleeding, or increased exogenous ingestion of histidine or histamine by food or alcohol. Other biogenic amines, such as putrescine, may also be involved in displacing histamine from its mucosal mucine linkage, which results in an increase of free absorbable histamine in circulation. However, the main cause of histamine intolerance is an impaired enzymatic histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT. Gastrointestinal diseases with altered enterocytes also may cause decreased production of DAO. Yet another cause can be competitive inhibition of histamine degradation of DAO by other biogenic amines, alcohol, or drugs…DAO inhibits the transepithelial permeation of exogenous histamine, and impaired DAO activity results in increased enteral histamine uptake with consequent increased plasma histamine concentrations and corresponding symptoms. Increased amounts of histamine metabolites may also inhibit HNMT, the second enzyme metabolizing histamine.”

There is evidence for genetic in some patients but the role of chronic inflammation appears to take center stage:

“Recently, a potential genetic background of a reduced histamine metabolism has also been investigated… Various single-nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy, gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma. No significant difference in the distribution of the investigated HNMT alleles could be shown between patients with gastrointestinal diseases and control subjects, but a functional relevant polymorphism of the HNMT gene (chromosome 2q22) has been described for white asthma patients. Conversely, this association could not be observed in Japanese, German pediatric, and East Indian populations. Thus, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, but the high interindividual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance.”

Regarding the amount of histamine consumed:

In contrast to an IgE–mediated food allergy, in which the ingestion of even a small amount of the allergen elicits symptoms, in histamine intolerance, the cumulative amount of histamine is crucial. Besides variations in the amount of histamine in food according to storage and maturation, the quantity consumed, the presence of other biogenic amines, and the additional intake of alcohol or DAO-blocking drugs are pivotal factors in the tolerance of the ingested food.”

See Foods rich in histamine and Foods with suggested histamine-releasing capabilities. Regarding alcohol in general and wine in particular:

Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of DAO. The relation between the ingestion of wine, an increase in plasma histamine, and the occurrence of sneezing, flushing, headache, asthma attacks, and other anaphylactoid reactions and a reduction of symptoms by antihistamines has been shown in various studies.”

Sulfite sensitivity can be mistaken for histamine intolerance:

“Sulfites may be contained in wine, but they are also contained in foods that are poor in histamine, such as fruit juice, frozen vegetables, and lettuce. Thus, in patients reporting intolerance to wine, a careful history of reactions to other foods rich in histamine or sulfites should be taken.”

And the reaction to wine is not necessarily determined by the amount of histamine present:

“In DBPC wine tests with healthy persons and in patients with chronic urticaria and wine intolerance, the histamine content did not influence wine tolerance. In the latter group, an increase in plasma histamine could be shown, paradoxically, after ingestion of the histamine-poor wine.”

Clinicians attempting to diagnose histamine intolerance should bear in mind that it can be tricky to judge it by foods consumed:

“…the amount of histamine in natural food varies pronouncedly according to storage and maturation.”

See also Drugs releasing histamine or inhibiting diamine oxidase. Regarding laboratory assessment of histamine intolerance:

“In a patient with clinical suspicion of histamine intolerance (ie, ≥2 typical symptoms), improvement of symptoms by histamine-free diet or antihistamines, DAO may be determined in serum or tissue biopsy… Furthermore, the total histamine degradation capacity [by DAO] can be measured… Serum DAO concentrations showed no significant daily variations and no significant sex differences…. Histamine intolerance is presumably highly likely in patients with DAO activity <3 U/mL, likely (but less likely) in patients with DAO activity <10 U/mL, and improbable in patients with DAO activity ≥10 U/mL.”

The authors conclude:

“In patients with typical symptoms of histamine intolerance that are triggered by histamine-rich food and alcohol, with intolerance of drugs that liberate histamine or block DAO, and with a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered. A histamine-free diet, if necessary, supported by antihistamines or the substitution of DAO, leads to an improvement of symptoms…”


Neurogastroenterology & MotilityIt should be clear that histamine intolerance can be a cause of IBS (irritable bowel syndrome), as evidenced by a study published in the journal Neurogastroenterology & Motility in which the authors observed the effects of histamine release on bowel ANS (autonomic nervous system) function:

“We hypothesized that blockade of histamine H1 receptors affects ANS responses differently between IBS subjects and controls.”

They subjected twelve individuals with IBS and the same number of matched controls to irritation of the bowel by either chlorphenamine or the same amount of saline (sham), and with stimulated their rectums with electrical currents of 0 mA (for the sham) or 30 mA. They quantified autonomic nervous system function with heart rate variability (HRV) and mean arterial pressure (MAP), and measured plasma catecholamines and histamine. They also recorded subjective perceived stress during this mildly barbarous trial. Blocking histamine receptors with chlorphenamine made a big difference:

“Mean arterial pressure showed significant effects of diagnosis and drug × diagnosis interaction. The MAP significantly increased after chlorphenamine administration in IBS subjects, but not in controls. Heart rate revealed a significant drug effect, which decreased after chlorphenamine administration in controls, but not in IBS subjects. Perceived stress significantly increased by rectal stimulation and a significant stimulus × diagnosis interaction was revealed, indicating greater reduction in IBS subjects by chlorphenamine.”

They concluded that histamine plays a significant role in gut autonomic dysregulation of IBS patients:

“Sympathetic vasomotor tone in IBS subjects differentially responded on administration of a histamine H1 antagonist to that of controls. These findings suggest an increased histaminergic activity in IBS subjects.”


GastroenterologyThe authors of a study published in Gastroenterology also correlated the effect of the release of mast cell mediators (histamine) proximal to nerve fibers in gut mucosa on pain in IBS:

“We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients.”

They quantified pain in IBS patients, identified colonic mucosal mast cells and measured their tryptase and histamine release. They also assessed intestinal nerve to mast cell distance with electron microscopy…

“Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls. There was a 150% increase in the number of degranulating mast cells. Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase and histamine. Mast cells located within 5 μm of nerve fibers were 7.14 ± 3.87/field vs. 2.27 ± 1.63/field in IBS vs. controls. Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort.”

In other words, mast cells releasing histamine close to nerve cells in the colon correlated with IBS pain.


Hypertension Vol 45 Issue 2Clinicians should also be aware that histamine release due to mast cell activation (MCA) can cause Postural Orthostatic Tachycardia Syndrome (POTS; also called Postural Tachycardia Syndrome) as described by a fascinating paper published in the journal Hypertension.

Postural tachycardia syndrome (POTS) is a disabling condition…characterized by symptoms of fatigue, tachycardia, shortness of breath, and even syncope on standing. The etiology is not clear, but 2 possibilities have been proposed previously. In the neuropathic variant, the primary defect is thought to be a partial autonomic denervation that compromises lower limbs with exaggerated orthostatic venous pooling, and perhaps the kidneys with low levels of plasma renin activity. Patients with the hyperadrenergic variant are thought to have centrally driven sympathetic activationA circulating vasodilator could produce reflex sympathetic activation, presenting clinically as “hyperadrenergic” POTS. In our evaluation of patients with POTS, some described flushing episodes associated with orthostatic intolerance. On the basis of this observation, also reported by others, we hypothesized that activated mast cells may provide a source of circulating vasodilators in a subset of patients with hyperadrenergic POTS. If true, histamine and other mast cell mediators could play an important role in the pathogenesis of this syndrome.”

The authors describe the phenomenon of mast cell activation (MCA):

“In 1991, Roberts and Oates described the clinical syndrome of idiopathic mast cell activation (MCA). In this condition, there is no evidence of mast cell proliferation, but patients are disabled by episodic MCA, documented by accumulation of mediators in plasma or urine. Patients with this syndrome typically present episodes or “attacks” of flushing accompanied by palpitations, lightheadedness, dizziness, shortness of breath, occasional nausea and diarrhea, headache, and syncope. Here we describe patients disabled by persistent orthostatic intolerance and evidence of MCA. These patients often present with a typical hyperadrenergic variant of POTS and biochemical evidence of MCA.”

Their data confirmed the role of histamine in POTS:Mechanisms underlying association between MCA and hyperadrenergic POTS

MCA+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. In addition, patients were disabled by orthostatic intolerance and a characteristic hyperadrenergic response to posture, with orthostatic tachycardia (from 79±4 to 114±6 bpm), increased systolic blood pressure on standing (from 117±5 to 126±7 mm Hg versus no change in POTS controls), increased systolic blood pressure at the end of phase II of the Valsalva maneuver (157±12 versus 117±9 in normal controls and 119±7 mm Hg in POTS), and an exaggerated phase IV blood pressure overshoot (50±10 versus 17±3 mm Hg in normal controls)… Episodes of MCA were documented in these patients by elevated levels of urinary methylhistamine taken immediately after a spontaneous event… The symptoms described during these spells are probably induced by acute release of mast cell mediators such as histamine and PGD2. Patients with isolated MCA are symptomatic only during episodes, whereas our group of patients also experienced chronic fatigue and orthostatic intolerance in between episodes, eventually leading to a disabling condition.”

Clinicians managing POTS should note the authors’ conclusion:

“We report a novel syndrome of chronic hyperadrenergic orthostatic intolerance associated with episodes of MCA… A correct diagnosis is important because the presence of MCA mandates a different approach in the treatment of these patients. β-Blockers, a commonly used therapeutic option in POTS patients, should be used with caution, if at all, because of the risk of triggering MCA. These patients can be treated with H1/H2 histamine antagonist and central sympatholytics.”


Annals of DermatologyRegarding atopic dermatitis (AD) and histamine intolerance, a typical case is described by the authors of a paper published in Annals of Dermatology. Their findings compel them to conclude:

In cases of AD showing negative results on allergy tests and worsening of AD skin lesions after intake of certain types of food, it would be reasonable to consider histamine intolerance. Therefore, a low-histamine diet and a histamine-free diet could be helpful for such cases.”


Inflammatory Bowel Diseases Vol 17 Issue 2From a realistic clinical perspective the histamine-degrading enzyme DAO (diamine oxidase) takes center stage. In illuminating research published in the journal Inflammatory Bowel Diseases the authors investigated the measurement of serum DAO activity in inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and its correspondence to intestinal permeability was published in the journal Inflammatory Bowel Diseases. The authors note:

“The intestinal mucosa serves as a major anatomic and functional barrier to potentially harmful intraluminal components such as bacteria and several antigens. The intestinal barrier is formed by epithelial cells and the junctional complex, including the tight junction (TJ) complex. Alterations of the composition of TJs was reported for both Crohn’s disease (CD) and ulcerative colitis (UC)… In addition, the impaired permeability may represent the early onset of inflammatory bowel disease (IBD) because increased intestinal epithelial permeability precedes clinical relapse in patients with asymptomatic CD… These data suggest that small intestinal permeability plays a critical role in the disease onset of IBD and an examination of small intestinal permeability would be useful for diagnosing IBD and predicting disease relapse.”

Regarding intestinal permeability and diamine oxidase activity:

Diamine oxidase (DAO) is an enzyme that catalyzes the oxidation of diamines such as histamine, putrescine, and cadaverine. In humans and rodents, DAO is specifically located at the apical end of mature villous cells with high activity and its activity reflects the integrity and maturity of the small intestinal mucosa. Several studies of humans and animals revealed that DAO activity in serum inversely correlates with intestinal permeability of small intestine… We measured serum DAO activity levels in patients with IBD and evaluated the clinical significance of DAO in IBD.”

Their results show a strong correlation of DAO activity and IBD regardless of whether the condition is in an acute symptomatic or latent phase, and whether or not CRP or white blood cells are elevated:

Serum DAO activity in patients with CD was significantly lower than that in control subjects. In addition, serum DAO activity in patients with UC was significantly lower than that in control subjects. There were no significant differences between patients with active CD and inactive CD ( or in patients with active UC and inactive UC. Furthermore, the disease phenotype of CD and UC was not associated with serum DAO activity. Serum DAO activity was not significantly correlated with CRP or WBC.”

And a great insight into the pathogenesis of ulcerative colitis (UC) emerges:

“This study first demonstrates that serum DAO activity is significantly lower in patients with CD and UC regardless of the level of disease activity. Of note, in patients with UC in whom small intestinal inflammation was not involved, serum DAO activity was significantly lower than that in healthy controls. These findings strongly indicate that small intestinal permeability is strongly involved in the pathophysiology of not only CD but also UC.”

The authors conclude:

“In conclusion, measurement of serum DAO activity can be an easy and convenient modality for evaluating small intestinal permeability. Reduced serum DAO activity in patients with IBD suggests the importance of mucosal permeability of the small intestine as a pathogenic factor and its measurement together with serology, clinical factors, and genetics might be useful for predicting the disease onset of IBD.”


Human Reproduction Update Vol 14 Issue 5Histamine intolerance and diamine oxidase activity are also very relevant in pregnancy. In a paper published in Human Reproduction Update the authors note:

The balance between histamine and the histamine-degrading enzyme DAO seems to be crucial for an uncomplicated course of pregnancy. Reduced or precipitously falling DAO activities have been found in high-risk pregnancies, whereas maternal plasma enzyme titres within the normal range have been mostly associated with a favourable fetal prognosis. DAO at the feto–maternal interface has therefore been supposed to act as a metabolic barrier to prevent excessive entry of bioactive histamine from the placenta into the maternal or fetal circulation.”

Effects of histamine and diamine oxidase activities on pregnancyThey undertook a detailed and extensive review of the voluminous literature on histamine and pregnancy, finding…

“Without the protective action of an increased DAO activity, an excess of histamine exerts pathological effects on the course of pregnancy. The presence of the HRs [histamine receptors] at the feto–maternal interface also support the view that prolonged exposure of feto–maternal interface tissues to high levels of histamine might have fundamental roles in the pathogenesis of pre-eclampsia…Persistently low or falling DAO plasma curves have been shown in various pregnancies complications such as toxaemia, diabetes, anaemia, threatened and missed abortion compared with normal pregnancies, especially during the last trimester. Fetal organic and skeletal abnormalities as far as spontaneous abortion after DAO inhibition with aminoguanidine observed in pregnant rats stress the impact of a sufficient histamine degradation during pregnancy.”

On the therapeutic side practitioners can consider DAO support as an option when low DAO activity is determined:

“Moreover, a substitution of DAO might present a therapeutical option for patients with high-risk pregnancy or women with yet-to be identified genetically predetermined defects in DAO activity in the future.”


Wiener klinische Wochenschrift Vol 125 Iss 9-10Regarding the laboratory diagnosis of histamine intolerance, the authors of a paper recently published in Wiener klinische Wochenschrift (Viennese Clinical Weekly—The Central European Journal of Medicine) examine the usefulness of serum diamine oxidase activity, noting…

“Histamine intolerance (HIT) is characterized by an imbalance between histamine intake and the capacity for histamine degradation. The main enzyme for metabolizing ingested histamine is diamine oxidase (DAO). Determining DAO activity in serum may be useful in diagnosing HIT.”

They assessed 316 subjects with clinically suspected HIT and 55 healthy controls for serum DAO activity over three and a half years. Twenty of those with highly reduced DAO activity went on a histamine-free diet for six to twelve months and their DAO activity was determined again. The serum DAO activity had high clinical significance:

We found that DAO activity was significantly lower in patients than in healthy control subjects. Furthermore, 54 patients had highly reduced serum DAO activity (< 40 HDU/ml). Their main symptoms involved the skin, gastrointestinal tract, respiratory system, and eyes. In all the 20 patients with highly reduced DAO activity, the main clinical symptoms typical of histamine intolerance disappeared after they adopted a histamine-free diet. Furthermore, the serum DAO activity values measured increased significantly.

Their conclusion of their study is a straightforward endorsement of serum DAO activity for evaluating HI (HIT):

“Our results suggest that determining DAO activity in serum is a useful tool in diagnosing HIT. Furthermore, our results showed the benefit of a histamine-free diet because after the diet the majority of symptoms disappeared and the serum DAO activity significantly increased.”


Pediatric ResearchSerum DAO activity applies just as well to case management of pediatric gastroenteritis as evidenced by a study in the journal Pediatric Research. According to these findings, DAO activity also reflected number of functioning enterocytes (intestinal cells):

“Patients with severe gastroenteritis tended to have lower DAO activity values than patients with moderate gastroenteritis. Our results support the hypothesis that serum DAO activity is a marker of the total mass of functional enterocytes, the decrease of which during gastroenteritis is reflected in a decrease of serum DAO activity values.”


PLOS ONEInterestingly, diamine oxidase is also involved in hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in particular and drug hypersensitivity in general, a widespread clinical problem. The authors of study published in PLOS One state:

“Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions… Unpredictable adverse drug reactions related to NSAIDs are common in clinical practice… It is intriguing that chemically unrelated NSAIDs and NSAIDs with different pharmacological mechanisms cause cross-hypersensitivityHistamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs.”

They analyzed single nucleotide polymorophisms (SNPs) relevant to histamine metabolism and DAO in 442 subjects with NSAID hypersensitivity and 414 healthy matched controls. Their data did indeed show a correspondence between DAO capacity and hypersensitivity to NSAIDs:

The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR = 1.7 with a gene-dose effect. The association was replicated in two populations from different geographic areas.”

The authors summarize the great clinical significance of their data:

“In conclusion, the findings described in this study indicate that a detrimental mutation in the DAO gene is related to a clinical development of hypersensitivity to NSAIDs. These findings agree with the general model in which mutations in genes encoding histamine-metabolizing enzymes may increase the risk, or modify the clinical presentation, of allergic diseases in which histamine plays an important role. This finding could guide future research in the area of drug hypersensitivity as it points to a common mechanism which may affect the clinical presentation of hypersensitivity reactions, regardless of drug-specific triggering mechanisms.”


Allergy Vol 66 Issue 7Similar findings were reported in a paper published in the journal Allergy. Here the authors discriminated between the presence of SNPs that impair DAO activity and the actual phenotypic expression of histamine intolerance.

“Histamine intolerance (HIT) is associated with an excess of histamine because of an impaired function of the histamine-degrading enzyme diamine oxidase (DAO)… Diamine oxidase serum activity was significantly associated with seven SNPs within the DAO gene… Diamine oxidase variants were not associated with the HIT phenotype per se, only with DAO activity alone and the subgroup of HIT patients displaying a reduced DAO activity.”

Clinical note: This is a good example for the preference of a functional test (in this case serum DAO activity) over a genetic test in clinical case management. As in so many other conditions, the genes may be there but how are they being expressed? The authors conclude:

DAO gene variants strongly influence DAO expression and activity but alone are not sufficient to fully effectuate the potentially associated disease state of HIT, suggesting an interplay of genetic and environmental factors.”


Inflammation ResearchCould daily variations in serum diamine oxidase confound the attempt to measure and manage histamine intolerance? Happily, this was investigated by research published in the journal Inflammation Research.

“Histamine in food has been shown to induce intolerance reactions mimicking food allergy. These reactions seem to be due to impaired histamine metabolism caused by reduced diamine oxidase activity. To validate routine serum diamine oxidase assessment, daily variations of diamine oxidase were evaluated.”

Examining diamine oxidase activity every two hours from 9 am to 5 pm, the authors found…

Serum diamine oxidase levels showed no significant daily variations and no significant sex differences. Antihistamines had no influence on diamine oxidase activity except for cimetidine, which caused 25% inhibition at the highest dose tested and diphenhydramine, which caused 19% increase of enzyme activity.”


Clinical summary: Histamine intolerance is a widespread phenomenon that can mimic allergy. It plays a role in many diverse conditions including IBS and inflammatory bowel diseases, asthma, postural orthostatic tachycardia syndrome (POTS), complications of pregnancy, drug hypersensitivity, headache, cardiac arrhythmia, blood pressure dysregulation, and intestinal permeability (by means of which it contributes to autoimmunity). Suspicion should be raised if relevant symptoms persist after antibody mediated food intolerance is out of the picture. It can be objectively evaluated with serum DAO activity. HI can be ameliorated by supplementation with DAO. Practitioners need to be astute in its diagnosis and management.

Tune back in for a forthcoming post on histamine intolerance and wine.


ECNPUpdate: Medscape Medical News reports from the 26th European College of Neuropsychopharmacology (ECNP) Congress in Barcelona, Spain that Antihistamine May Decrease Schizophrenia Symptoms. Quoting the authors of the study just presented:

Histamine has received relatively little attention in clinical studies of psychiatric disorders even though it has important functions as a regulator of several key neurotransmitters…Our results suggest that a H2 [histamine] receptor antagonist has antipsychotic properties and may provide a new potential pharmacological approach to the treatment of patients with schizophrenia who have not responded well enough to presently available treatments.”

The use of any non-aspirin NSAIDs during pregnancy increases the risk of spontaneous abortion

Summary: any type of non-aspirin NSAID must be used only with great caution during pregnancy because they may significantly increase the risk of spontaneous abortion.

Research recently published in the Canadian Medical Association Journal alerts practitioners and pregnant women to the risk for spontaneous abortions caused by the gestational use of any non-aspirin non-steroidal anti-inflammatory drug (NSAID). The authors state:

“We aimed to quantify the association between having a spontaneous abortion and types and dosages of nonaspirin NSAIDs in a cohort of pregnant women.”

They examined data for 4705 women who had a spontaneous abortion compared to ten times as many matched controls, and correlated associations between different types and dosages of non-aspirin NSAIDs with having the spontaneous abortion. Their data raises some serious alarm:

“Adjusting for potential confounders, the use of nonaspirin NSAIDs during pregnancy was significantly associated with the risk of spontaneous abortion (odds ratio [OR] 2.43). Specifically, use of diclofenac (OR 3.09), naproxen (OR 2.64), celecoxib (OR 2.21), ibuprofen (OR 2.19) and rofecoxib (OR 1.83) alone, and combinations thereof (OR 2.64), were all associated with increased risk of spontaneous abortion. No dose–response effect was seen.”

In other words, there as an overall 243% increase in the risk for spontaneous abortion. The increase was over 300% for diclofenac (Voltaren®) and more than 200% for ibuprofen. The authors express the gravity of their concern supported by the data in their conclusion:

Gestational exposure to any type or dosage of nonaspirin NSAIDs may increase the risk of spontaneous abortion. These drugs should be used with caution during pregnancy.”

Female reproductive disorders and gluten sensitivity

Minverva GinecologicaAs the authors of this paper published in the journal Minerva Ginecologica state:

“In the past coeliac disease, or intolerance to gluten, has been considered a rare disease in infancy, whose most important signs were chronic diarrhea with malabsorption and reduced growth. However, besides this classical form, there are a number of other clinical and subclinical forms which may appear even in the adult life and without any overt intestinal sign.”

The authors defined their objective:

“The aim of the present paper is to describe and evaluate the effects of coeliac disease on female reproduction. Such effects include delayed menarche, amenorrhea, infertility and early menopause.”

In addition, they noted that…

“Epidemiological studies show that besides reduced fertility, affected women are at higher risk of reproductive problems such as pregnancy loss, low birthweight of offspring and reduced duration of breastfeedingthe possible prevention or treatment of the reproductive effects is only the lifelong maintenance of a gluten-free diet.”

Journal of Reproductive MedicineAnother paper published in the Journal of Reproductive Medicine reports on a case that highlights the link between gluten sensitivity and amenorrhea. The authors’ conclusion:

“Celiac disease should be considered in patients presenting with malnutrition and primary amenorrhea.”

This was followed by a much more extensive study published recently in the same journal. The authors summarize an extensive body of literature on the subject:

“In women, this disease (celiac, gluten sensitivity) may have implications on menstrual and reproductive health. The symptom complex includes delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction. These women benefit from early diagnosis and treatment. Therefore, celiac disease should be considered and screening tests performed on women presenting with menstrual and reproductive problems and treated accordingly.”

They offer an exhortation to doctors in their conclusion:

“Evidence in the literature suggests that celiac disease should be suspected in females with menstrual abnormalities, infertility and adverse pregnancy outcome. All health care providers should be aware of these diverse manifestations of the disease. Treating the disease has a benefit and may lead to prevention of symptoms and improvement in the quality of life…It is challenging to identify women with silent celiac disease and treat them with a gluten-free diet and nutrient supplements, which may lead to prevention of menstrual and other reproductive dysfunction.”

Gynecologic and Obstetric InvestigationAnother paper published in the journal Gynecologic and Obstetric Investigation focuses on the impact of gluten sensitivity on the reproductive cycle, fertility, pregnancy, and menopause. The authors explain that…

“Celiac disease (gluten-sensitive enteropathy) may manifest clinically with an array of nongastrointestinal symptoms among which are: dermatitis herpetiformis; dementia; depression; various neurological symptoms; osteoporosis; osteomalacia; dental enamel defects, and anemia of various types. Important data have accumulated in recent years regarding the association between celiac disease, fertility and pregnancy. Many primary care obstetricians and gynecologists and perinatologists are not aware of these important relationships.”

What does the scientific evidence establish?

“Review of the literature reveals that patients with untreated celiac disease sustain a significantly delayed menarche, earlier menopause, and an increased prevalence of secondary amenorrhea. Patients with untreated celiac disease incur higher miscarriage rates, increased fetal growth restriction, and lower birth weights.”

Clinical GastroenterologyAn interesting paper that dramatically shows the difference between adhering and not adhering to a gluten free diet for female reproductive health was published in the Journal of Clinical Gastroenterology:

“This study shows a broad analysis of gynaecological and obstetrical disturbances in patients with celiac disease in relation to their nutritional status and adherence to a gluten-free diet.”

In their investigation the authors analyzed data on adults and children/adolescents with gluten sensitivity, taking into consideration nutritional status and gluten-free diet adherence, and compared them to adults and adolescents with irritable bowel syndrome (not due to gluten) as a control group. What did the data show?

“…adult celiac patients, irrespective of the nutritional status…presented delayed menarche, secondary amenorrhea, a higher percentage of spontaneous abortions, anemia and hypoalbuminemia…After treatment, patients presented with normal pregnancies and one patient presented spontaneous abortion. The adolescents who were not adherent to gluten-free diet presented delayed menarche and secondary amenorrhea.”

They state what should by now be obvious in their conclusion:

“Therefore, celiac disease should be included in the screening of reproductive disorders.”

Important: gluten sensitivity without celiac manifestations (1) must be treated the same way as celiac disease and (2) cannot be diagnosed by the usual celiac tests for tissue transglutaminase antibodies, etc. Antibody levels, including anti-gliadin (gluten) antibodies, can fluctuate for a number of reasons resulting in false negatives. The gluten gene sensitivity test can be relied on for a dependable result. This post could go on at great length but the message is clear: for female reproductive disorders gluten sensitivity must be considered as a possible contributing cause.

Men: you are not immune. I am finding gluten sensitivity to be a common cause of low testosterone levels (hypogonadia).