Achalasia and thyroid disease

Abstract

AIM: To investigate some possible etiologies of achalasia by screening patients with achalasia for some autoimmune diseases such as thyroid disease.

METHODS: We examined 30 known cases of achalasia (20 females, 10 males). Their age ranged 15-70 years. All of them were referred to our institute for treatment. Their sera were evaluated to detect some possible associations with rheumatoid disease, thyroid disease, inflammatory process, anemia, etc.

RESULTS: Seven out of 30 patients (23%) had thyroid disease including four patients with hypothyroidism (13.3%), two patients with hyperthyroidism (6.6%), and one had only thyroid nodule but was in euthyroid state (3.3%). Two of these hypothyroid patients had no related clinical symptoms (subclinical) and two had clinical manifestations of hypothyroidism. There were no correlations between the intensity of thyroid diseases and the severity of achalasia symptoms.

CONCLUSION: The etiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. Thyroid disease presents concomitantly with achalasia in about one fourth of our patients who may have a common etiology.

Key Words: Achalasia; Thyroid disease; Hypothyroidism; Esophageal motility; Etiology

INTRODUCTION

Achalasia is a common and well characterized primary motility disorder of the esophageal body and lower esophageal sphincter (LES), causing impaired progressive peristalsis in the esophageal body, incomplete relaxation of LES during swallowing, and sometimes increased abnormal relaxation of the LES pressure. Previous studies evaluating esophagomyotomy and esophageal resection specimens have shown that the presence of myenteric inflammation is a consistent and early pathologic change in patients with achalasia[1,2]. The disorder is observed in both genders primarily in the fifth and sixth decades of life, although achalasia can present at any age[3,4]. The cause of the degeneration of neurons in achalasia is not known. The observations that achalasia is associated with HLA-DQw1 and that affected patients often have circulating antibodies to enteric neurons suggest that achalasia may be an autoimmune disorder[5-7]. Nonspecific degeneration of smooth muscle cells and a loss of small nerve fibers have been reported[8-10]. Another controversial issue is the role of inflammatory infiltrates in the pathogenesis of the disease. A study has suggested that complement activation is involved in the autoimmune pathogenesis of achalasia[11]. Achalasia is associated with extra esophageal autonomic nervous dysfunction that involves cardiovascular and papillary function as well as regulation of mesenteric arterial blood flow[12]. Some investigators have proposed that achalasia may result from chronic infections with herpes zoster or measles viruses, but modern studies have not confirmed an association between achalasia and any recognized viral disease[13,14]. However, a recent study also showed that there is no association between the most common viruses and achalasia[14]. As myenteric neurons synthesizing nitric oxide are responsible for the inhibitory component of esophageal peristalsis and LES relaxation, it is considered likely that these neurons are involved in this disease[15,16].

Since there is no consistent single abnormality in achalasia, this study was designed to evaluate the relationship between achalasia and some of the commonest autoimmune diseases.

MATERIALS AND METHODS

Patients

All 42 newly diagnosed patients referred between 2001 and 2005 to our research center (Poursina Hakim Research Institution, Gastroenterology Division, Isfahan, Iran) were examined prospectively and enrolled in the study. Poursina Hakim Institution is a reference tertiary care center that services a population of about 4 000 000 individuals in the central area of Iran. Of the 42 enrolled cases in the study based on clinical and radiological findings, 6 patients with pseudoachalasia but without endoscopic features of achalasia were excluded due to non-compliance (one case) or some other reasons such as loss of follow-up due to changing their address or phone number, immigration to other provinces and admission by other physicians far from our institution. Finally 30 cases were included. Their symptoms, laboratory results, and historical and functional data were recorded. Achalasia was defined by clinical criteria, namely prolonged (more than 1 year) intermittent or progressive dysphagia to liquids and solids in addition to some other minor symptoms such as regurgitation, chest pain and nocturnal cough plus barium swallow with a typical beak like appearance. We obtained posterior-anterior chest x ray radiographies at 1, 5, and 20 min after a single barium meal to assess barium column and measure its heights and widths as well as the delay time of esophageal clearance (timed barium swallow). Upper gastrointestinal endoscopy was done to confirm the diagnosis and to rule out secondary achalasia (such as esophageal tumors of cardia and fundus, submucosal tumor of distal esophagus, peptic stricture and other mucosal or infiltrative lesions of the esophagus or gastric cardia). Endoscopic findings suggestive of achalasia may be seen and are very helpful if endoscopy is done carefully by experts in this field. Some of the suggestive criteria for achalasia are as following: esophageal dilation, esophageal dysmotility or aperistalsis in response to air insufflations, abnormal LES opening and high pressure LES during scope passage. Manometery although very helpful especially in early stages of the disease, was not available in our province at the time of the study, so it was not done for most of them.

Exclusion criteria included those found to have an underlying malignancy during the study, any types of generalized neuropathies, diabetes mellitus, non-compliance or unwillingness of patients to continue the study, and finally those lost to follow up by any reason.

The patients’ history was taken using a structured questionnaire. We interviewed, examined and completed a questionnaire designed to detect possibility of connective tissue and autoimmune diseases, other gastrointestinal motility disorders, diabetes mellitus, use of immunosuppressive medications, chronic viral illnesses, thyroid problems, usage of a regular immunosuppressive medication and also habits and addictions for all patients. Informed consent was obtained from all patients. None of the patients underwent surgical therapy.

Laboratory methods

After diagnosis of achalasia, all patients were screened for a set of selected autoimmune disease and other markers as shown in Table 1. Serum factors were evaluated by biochemical techniques. A double check of laboratory tests was conducted by a second laboratory to assure validity of abnormal results. Equivocal laboratory results were rechecked by a reference laboratory.

Table 1 Test and methods used in this study.

Test title	Kit	Manufacturedcountry
Anti nuclear anti body (ANA)	Biostems	Spain
Antineutrophil cytoplasm antibody (c-ANCA)	Binding site	England
Calcium	Man	Iran
Phosphorus	Man	Iran
Alkaline phosphatase	Man	Iran
Thyroid stimulating hormone(TSH)	Isfahan pharmacology faculty	Iran
T3 Resin uptake	kavoshiar	Iran
T3, T4	Isfahan pharmacology faculty	Iran
Albumin	Man	Iran
Globulin	Man	Iran
Rapid plasmin reagin (RPR)	Anison	Iran
Urine analysis	Combi	Germany
Complete blood count	-	Germany

All tests except for urine analysis were performed on blood or serum samples.

Symptoms

Clinical data regarding symptoms of dysphagia, regurgitation, and chest pain, nocturnal cough and pyrosis were collected by means of a validated questionnaire. Dysphagia was described as difficulty in swallowing, and regurgitation as the sensation of stomach contents going up the esophagus. The frequency of each symptom was graded on a scale ranging from 0 to 5 (0 = none, 1 = once per month or less, 2 = once per week up to three to four times a month, 3 = two to four times per week, 4 = once per day, 5 = several times per day). This scoring system is similar, but with some modifications, to that used by Eckardt et al[17] and modified by Vaezi et al[18].

Statistical analysis

For comparison between patients with achalasia and normal population, Student’s t-test assuming equal variance was used. In addition, we analyzed the symptoms using the non-parametric Mann-Whitney test, because the data were not normally distributed.

RESULTS

Of the 42 newly suspected achalasia patients referred to our institution, 36 (11 men and 25 women) fulfilled the participating criteria in the study, but only 30 (20 females, 10 males) finished the study. The remaining six patients were statistically similar by age and gender to the 30 cases and they had no unusual reason for their loss of follow-up.

Thyroid disease

Of the 30 patients, 7 had thyroid disease (23.7%), 4 had hypothyroidism (13.3%), 2 had hyperthyroidism (6.7%) and one (3.3%) had only a thyroid nodule in euthyroid state. Two of these hypothyroidism patients had no related clinical symptoms (subclinical) and two had clinical manifestations of hypothyroidism. Both patients with subclinical hypothyroidism were diagnosed in our screening. One patient experienced hypothyroid shock after balloon dilation therapy (cool skin, hypothermia, hypotension and bradicardia not responsive to volume expansion and intravenous atropine injection). She had clinical symptoms of hypothyroidism which was not detected before balloon dilation therapy. The results of laboratory tests are listed in Table 2.

Table 2 Average score of all patients and those suffering from thyroid disease respectively (mean ± SD).

	Patients withhypothyroidism	Patients with benignthyroid diseases1	Patients withoutthyroid problems	Mean score ofall patients
Age	39.5 ± 14.3 a	35.8b± 11.9b	38.5 ± 18.1	37.9 ± 16.7
Dysphagia	5c	4.5 ± 1.1d	4.8 ± 0.45	4.8 ± 0.66
Regurgitation	5e	4.7 ± 0.75f	3.5 ± 1.9	3.8 ± 1.8
Nocturnal cough	2.5 ± 2.8 g	2.5 ± 2.5h	2.5 ± 2.2	2.5 ± 2.2
Chest discomfort	3.75 ± 1.5 i	2.2 ± 2.1 j	1.86 ± 2.7	1.96 ± 2
Weight loss	0.5 ± 0.5k	0.4 ± 0.5l	0.65 ± 4.08	0.6 ± 0.49

Scoring system: 0 = none; 1 = once per month or less; 2 = three to four times a month; 3 = two to four times per week; 4 = once per day; 5 = several times per day,

¹Composed of thyroid nodules, hypothyroidism and hyperthyroidism. No significant differences between groups were found by independent t-test, Mann-Witney test and chi-square test. P values of differences between thyroid disease groups and other patients with achalasia: ^a: 0.7;

^b: 0.7;

^c: 0.5;

^d: 0.6;

^e: 0.09;

^f: 0.1; ^g: 1;

^h: 0.97; ^I: 0.08;

^j: 0.57;

^k: 0.6;

^l: 0.3. (the first and second columns were compared with the third column).

Patients’ ethnicity

There were 21 (70%) Fars (the major Persian ethnicity), 7 Bakhtiari, an Iranian tribe, living in west of Isfahan Province) (23%), one Gilaki (another group of Iranians originating from northern Iran) (3.3%), and one patient was Turkish inhabitant in the central area of Iran (3.3. 0%).

Age and symptoms

The median age of onset of symptoms was 37 years (range 15-80 years). The mean age of patients with thyroid disease and other patients with achalasia was 35.8 and 38.5 years (P: 0.9). All patients complained of dysphagia to both liquids and solids. Regurgitation, weight loss, chest discomfort and heartburn were reported in 28 (93.3%), 18 (60%), 15 (50%) and 8 (26.6%) patients, respectively.

The symptoms of patients were compared (Table  2). Correlations between the intensity of thyroid disease and the severity of achalasia symptoms were statistically insignificant by Mann-Whitney test.

Prevalence and incidence of achalasia

In 2002 -2005, 42 cases of suspected achalasia were identified in or referred to our center. Of these, 19 were residents of Isfahan during the period of the study. The population of Isfahan was about 4 million in 2006. The overall ethnic- and gender-specific incidences of achalasia in our cases are shown in Table 3. No strong history of rheumatic disease or neuropathy in patients and their family was detected in our study.

Table 3 Overall and specific ethnicity and gender of all patients and those suffering from thyroid disease respectively.

	Hypothyroid patients		Benign thyroid diseases1		Without thyroid problems		Total
	n	%	n	%	n	%	n	%
Number	4	13.3	7	23.7	23	76.6	30	100
Gender	♂1 ♀3	♂25 ♀75	♂2 ♀5	♂28 ♀72	♂8 ♀15	♂34 ♀66	♂10 ♀20	♂33 ♀67
Ethnicity2	F: 3	F: 75	F: 5	F: 71	F: 16	F: 69	F: 21	F: 70
	B: 1	B: 25	B: 2	B: 28	B: 5	B: 21	B: 7	B: 23

¹Composed of thyroid nodules, hypothyroidism and hyperthyroidism.

²Composed of the most common ethnicity in patients, F: Fars; B: Bakhtiari.

Serological study

All serum samples were evaluated with sensitive tests for autoimmune diseases but we did not find any positive test except for 2 positive anti nuclear antibody tests (6.6%). Evaluation for vasculitis, some electrolyte disturbances, and anemia did not show any important finding (Table 4).

Table 4 Final result of laboratory evaluation in all patients.

Test	Normal (%)	Abnormal (%)
Thyroid function tests	80	20
Calcium and phosphorus	100	-
Alkaline phosphatase	100	-
Albumin	100	-
Globulin	100	-
ANA	93.4	6.6
C_ANCA	100	-
RPR (VDRL)	100	-
Complete Blood Count	100	-
Urine analysis	100	-

All tests except for urine analysis were performed on blood or serum samples.

DISCUSSION

Although achalasia is a historically recognized clinical entity, its fundamental pathophysiology remains poorly understood. Primary achalasia accounts for the majority of cases. The etiology of primary achalasia is not entirely clear and probably multidimensional[19] including genetic predisposition (supported by the concordance for the disease in monozygotic twins[20] and associations with some HLA loci[7]), inflammation (myopathy of the smooth muscle cells[21], neuropathy[22,23] and inflammatory changes in esophageal specimens[24]), infections (virus[14], Chagas’ disease, poliomyelitis[25,26], varicella zoster virus[27] and Helicobacter[28]), ischemia, toxicity and autoimmune disease[19]. Some other diseases postulate these etiologies such as concomitant appearance of achalasia and Guillain-Barré syndrome [29], Parkinson’s disease[30], triple A syndrome[31], etc.

There are some reports about thyroid and esophageal problems in animals[32] but we have not found any reports about such problems in humans in English articles. Although it has been reported that there is a correlation between achalasia and autoimmune diseases, this is the first cross sectional study evaluating the relative prevalence of these problems (rheumatic disease, thyroid disease, inflammatory disease, etc) in a consecutive series of patients affected by achalasia which led us to a few interesting points. First, the results of serological tests obtained from this study confirmed some literature data that predict a potential autoimmune etiology of achalasia. Second, an association was found between thyroid problems and achalasia. Third, the frequency of thyroid disease was higher in patients with achalasia than in normal population.

It was reported that the prevalence of hypothyroidism is 4.6% (0.3% clinical and 4.3% subclinical) in the United States of America[33]. Whickham showed that the prevalence of spontaneous hypothyroidism in community is 1.5% in females and less than 0.1% in males [34]. These prevalence rates are similar to those reported in Finland[35], Japan[36], and in another US survey[37-39]. Heydarian and Azizi reported that the prevalence of hyperthyroidism, overt and subclinical hypothyroidism is 0.45%, 0.35% and 2.2% in Iran, respectively[40]. The prevalence of hypothyroidism and benign thyroid diseases (hypothyroidism, hyperthyroidism and thyroid nodules) in our patients was significantly higher than that reported in latter study (P value and confidence interval for each group were 0.025 and 0.000, 1.3-43.4 and 2.9-76.5 respectively).

The mean age of our patients is one -two decades lower than reported in other studies[3,4]. It may have a role in these findings. We found about a 5-fold rise in the prevalence of thyroid dysfunction in this study. Since our center is the only center offering balloon dilation therapy in Isfahan, we can assume that the overall population with achalasia in this area is very similar to that registered in our center and therefore these data are repeatable in our future study, but they may not be generalized in all cases of achalasia in other societies. Hence we suggest a similar study in all centers working in this subject. We should direct our future studies to find the possible genetic and environmental risk factors for earlier disease in this geographic area.

The reason why there is such a relatively strong association between these diseases can be explained by the literature describing most thyroid problems as probable autoimmune diseases[41-44]. Autoimmune etiology of achalasia is also supported by the presence of circulating autoantibodies against the myenteric plexus and inflammatory T-cell infiltrates in the myenteric plexus, as well as the increased prevalence of HLA class II antigens. Possibly the initiating event may be an unknown environmental insult due to a viral infection resulting in inflammation of the myenteric plexus in susceptible patients. Not all affected individuals develop achalasia[45]. However, autommunity at least has a concomitant or susceptible role in pathogenesis.

Is there a symptomatic mimicry between achalasia and thyroid diseases? There is some evidence in animal model that a mega esophagus may occur in hypothyroidism which is a criterion of achalasia[32]. We had one clinical hypothyroid patient and one clinical hyperthyroid patient detected before balloon dilation therapy. We treated these two patients with levothyroxine and methimazole respectively for 6 mo after achievement of euthyroid state. No clinical or radiological improvements were obtained in symptomatology and radiological findings of achalasia after treatment, suggesting that what we found is actually a true association rather than a symptomatic mimicry or a transient neurological dysfunction. We also found a 6% positive ANA in this series which is similar to that in general population[46]. These findings may give some stronger evidence for certain autoimmune bases of achalasia. However, more and larger groups are necessary and a larger spectrum of autoimmune markers must be tested to make it possible to establish the utility of the issue in the early diagnosis of achalasia and identification of different etiologic mechanisms, which would allow us to think about novel outline of management since the existing treatments are only partially palliative.

We also found a hypothyroid shock after balloon dilation therapy which was fortunately well managed because we were alert to the problem. Therefore we recommend clinical evaluation of thyroid disease for all patients and thyroid function test for suspicious cases to control thyroid function before any invasive therapy. Clinical severity was statistically similar in both groups of patients with normal and abnormal thyroid function tests. Therefore we cannot predict the possibility of thyroid disease on the basis of severity indexes.

In conclusion, achalasia may be associated with thyroid diseases (hypothyroidism, hyperthyroidism and thyroid nodules), and this association should be kept in mind when a new case of achalasia is diagnosed. More accurate and extensive immunopathological studies should be performed to assess the possibility of a common immunopathogenesis or a cause and effect relationship in these diseases.

ACKNOWLEDGMENTS

The authors thank Ziba Farajzadegan MD, Hamid Tavakoli MD, Mehran Haghighi MD, Abbas Esmaeili MD, Peyman Adibi MD, Ali Akbar Vosughi MD, Mandana Soleymani MS, and other Poursina Hakim colleagues for their superb assistance in executing, coordinating and analyzing this project.