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An Association between Hypothyroidism and Primary Open,angle Glaucoma
Kevin D. Smith, FRCS(C), Bryan P. Arthurs, FRCS(C), Nabil Saheb, FRCS(C)
Purpose: To test the hypothesis that there is an association between hypothyroidism and primary open-angle glaucoma.
Methods: The study was conducted in a case-control fashion. Sixty-four patients with primary open-angle glaucoma were evaluated for hypothyroidism by history and by undergoing a thyroid-stimulating hormone immunoradiometric assay. Sixty-four control subjects from the general eye clinic were evaluated in the same manner. Patients found to have elevated thyroid-stimulating hormone immunoradiometric assay were evaluated by an endocrinologist for hypothyroidism.
Results: Of the primary open-angle glaucoma group, 23.4% had hypothyroidism. A diagnosis was made previously in 12.5% patients, and 10.9% were newly diagnosed. Of the control subjects, 4.7% had hypothyroidism. A diagnosis had been made previously in 1.6% of the control subjects, and 3.1 % were newly diagnosed. The difference between the two groups was found to be statistically significant.
Conclusion: A statistically significant association between hypothyroidism and primary open-angle glaucoma is demonstrated. There is a large group (10.9%) of patients with primary open-angle glaucoma with undiagnosed hypothyroidism. Ophthalmology 1993; 1 00: 1580-1584
Hypothyroidism is a common endocrine disorder characterized by low levels of thyroid hormones and the effects thereof on various body tissues and functions. The two most common causes of hypothyroidism are Hashimoto's thyroiditis and radioiodide therapy for hyperthyroidism. The female:male ratio is 5: 1. Symptoms of hypothyroidism include cold intolerance; coarse dry skin; hoarse voice; constipation; apathy; a generalized slowing, including speech; arthralgias; fatigue; headaches; and weight gain. Myxoedema develops secondary to the accumulation of hydrophillic mucopolysaccharides in the ground sub-
Originally received: August 19, 1992. Revision accepted: March 12, 1993.
From the Department of Ophthalmology, McGill University, Montreal, Canada.
Presented at The McGill 15th Annual Clinical and Scientific Day, May 30, 1992.
Reprint requests to Kevin D. Smith, FRCS(C), Department of Ophthalmology, National Defense Medical Center, 1745 Alta Vista Dr, Ottawa, Ontario KIA OK6.
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stance of the dermis, as well as other tissues, leading to thickening of the facial features and doughy induration of the skin. ',2 Ocular findings in hypothyroidism include chemosis, periorbital edema, blepharoptosis, and nyctalopia.3
Hypothyroidism can be a difficult diagnosis to make because the classic symptoms can often be found in the normal elderly population.4,5 The diagnosis of hypothyroidism is based on clinical findings, presence of thyroid antibodies, low values of the thyroid hormones, thyroxine (T4) and triiodothyroxine (T3), and elevation of thyroidstimulating hormone. Thyroid-stimulating hormone becomes abnormally elevated before the thyroid hormones becoming abnormally low and has been demonstrated to be an excellent screening test for hypothyroidism. '
Bilous and Tunbridge6 recently have summarized the literature on the epidemiology of hypothyroidism and state that hypothyroidism can be found in 5% of the population, 1 % percent as previously diagnosed and 4% newly diagnosed with elevated thyroid-stimulating hormone.
Recently, Smith et al7 reported a patient who had poorly controlled primary open-angle glaucoma which
Smith et al . Hypothyroidism and Primary Open,angle Glaucoma
Table 1. Grades of Hypothyroidism
Grade 1: Overt Grade 2: Mild Grade 3: Subclinical Grade 4
Clinical features Diagnosis not in doubt Minor nonspecific symptoms Asymptomatic and Asymptomatic and and signs that respond to clinically euthyroid clinically thyroxine replacement euthyroid
Serum TSH Markedly elevated Elevated Minor elevation Normal T~ Low May be normal Normal Normal T3 Low normal or low Normal Normal Normal
TRH test Abnormal TSH Abnormal TSH response Abnormal TSH Normal response response
Thyroid antibodies Usually positive Usually positive Often positive Positive
TSH = thyroid-stimulating hormone; TRH = thyrotropin-releasing hormone.
Adapted from Evered et al.9
reversed on diagnosis and treatment of hypothyroidism. The same authors8 then studied patients who were newly diagnosed with hypothyroidism using tonography and tonometry. They found poor facility of outflow. This normalized with treatment of the hypothyroidism alone. There was a concomitant improvement in intraocular pressure.
These recent findings have led to our interest in the relationship between hypothyroidism and glaucoma. A clinical study was designed to test the hypothesis that there is an association between hypothyroidism and primary open-angle glaucoma.
Materials and Methods
The study was organized in a case-control fashion. The case group consisted of consecutive patients presenting to the glaucoma clinic at the Montreal General Hospital. Each patient fulfilled the criteria for primary open-angle glaucoma: a history of elevated intraocular pressure greater than 21 mmHg with associated disc damage confirmed by visual fields. Each had open angles and no other secondary cause of open-angle glaucoma. Patients younger than 40 years of age and patients with any other cause of glaucoma were excluded.
For a control group, consecutive patients presenting to the general eye clinic were recruited. Patients younger than 40 years of age and patients with glaucoma were excluded. This group was chosen as a control because it represents an ambulatory elderly population similar to the case group.
Patients were evaluated for history of thyroid disease, and they were asked whether they were taking any medication for hypothyroidism. After giving informed consent, patients underwent a blood test, the thyroid-stimulating hormone immunoradiometric assay (ventrex-coated tube radioimmunoassay high-sensitivity thyroid-stimulating hormone).
This test is a highly sensitive and precise assay for thyroid-stimulating hormone. The sensitivity is 0.013 mIU /
ml and is defined as the minimum concentration of thyroid-stimulating hormone which can be statistically distinguished from the OmIU/ml calibrator in the assay. Specificity using cross-reactivity studies is greater than 99.999%. It is a two-site immunoradiometric assay commonly referred to as a "sandwich" assay. The system uses a solid-phase coupled monoclonal antibody (antibodycoated tube) and a radiolabeled polyclonal antibody. The sample to be assayed is incubated simultaneously with the radiolabeled antibody in solution. During this incubation, the antigen binds to the immobilized antibody, whereas the radiolabeled antibody reacts with the antigen. The tube is decanted and washed, and the radioactivity of the labeled antibody bound to the antigen on the tube is measured in a gamma counter. Calibrators of known thyroid-stimulating hormone concentration are run concurrently with samples being assayed, and a calibration curve is constructed. The unknown thyroid-stimulating hormone concentration in each sample is calculated from this curve.
If the thyroid-stimulating hormone immunoradiometric assay was elevated, the patient was referred to an endocrinologist for assessment. The endocrinologist was not aware if the patient was from the case or control group. If the patient was found to have hypothyroidism, the degree of the disease was classified by the endocrinologist according to Evered et al9 (see Table 1).
Results
The case group included 64 patients with primary openangle glaucoma, 34 females and 30 males. The average age was 72 years. The control group included 64 patients, 33 females and 31 males. The average age was 70 years.
In the primary open-angle glaucoma group, a total of 23.4% (n = IS) of patients were found to be hypothyroid. A diagnosis had been made previously in 12.5% (n = 8) of patients, and these patients were receiving treatment. A total of 10.9% (n = 7) of patients were newly diagnosed with an elevated thyroid-stimulating hormone level. Fol-
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low-up was done by an endocrinologist. Of the newly diagnosed patients with hypothyroidism, three had overt hypothyroidism, three had mild hypothyroidism, and one had subclinical hypothyroidism.
In the control group, a total of 4.7% (n = 3) of patients were found to have hypothyroidism. A diagnosis had been made previously in 1.6% (n = 1) of patients, and this patient was receiving treatment. A diagnosis of an elevated thyroid-stimulating hormone was made in 3.1 % (n = 2) of patients. Follow-up was done by an endocrinologist. Of these patients, one had mild hypothyroidism and one had subclinical hypothyroidism.
Fisher's exact test (two-tailed) was used for statistical analysis. When comparing the proportion (23.4%) of individuals with hypothyroidism in the primary open-angle glaucoma group with the proportion (4.7%) of individuals with hypothyroidism in the control group, the difference was found to be statistically significant (P < 0.004).
When comparing the proportion (12.5%) of individuals with previously diagnosed hypothyroidism in the primary open-angle glaucoma group with the proportion (1.6%) of individuals with previously diagnosed hypothyroidism in the control group, the difference was found to be statistically significant (P < 0.03).
When comparing the proportion (10.9%) of individuals with newly diagnosed hypothyroidism in the primary open-angle glaucoma group with the proportion (3.1 %) of individuals with newly diagnosed hypothyroidism in the control group, the difference between the groups was found not to be statistically significant (P = 0.16). Larger numbers would be needed to show significance.
Discussion
This clinical study demonstrates that there is an association between hypothyroidism and primary open-angle glaucoma. This association is statistically significant, and the control group is consistent with other populationbased studies.6 This study is the first of its kind where a group of patients with primary open-angle glaucoma was tested using thyroid-stimulating hormone.
The literature is sparse and inconclusive as to a relationship between hypothyroidism and primary open-angle glaucoma. McLenachan and DavieslO in 1965 are the only authors who have addressed this issue in a similar fashion to this article. The authors reviewed the illnesses of 100 patients with open-angle glaucoma and assessed them for hypothyroidism on a clinical and biochemical basis. Tests used were radio-iodine uptake, agglutination of thyroglobulin-coated tanned erythrocytes, serum cholesterol, and electrocardiography. One hundred patients with closed-angle glaucoma were used for control.
The study was appropriately criticized by Cheng and Perkinsll in 1967 because no details of criteria for diagnosing thyroid disease were given. The thyroid tests used in that study are now outdated and inaccurate compared with modern evaluation with thyroid-stimulating hormone. A further criticism is that 38% ofMcLenachan and
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Davies' open-angle group were deemed open-angle glaucoma because of elevated intraocular pressure alone. Remarkably, McLenachan and Davies found 25% of their patients with open-angle glaucoma to be "subthyroid," a finding close to this study's 23.4%.
Cheng et alii went on to study 13 patients with hypothyroidism, most of whom were already receiving treatment for hypothyroidism, and found normal mean intraocular pressure. Thus, they concluded there was no association between hypothyroidism and primary openangle glaucoma.
An article by Krupin et al l2 in 1977 often is used to suggest there is no association between hypothyroidism and glaucoma. 13 The authors investigated the response of thyroid-stimulating hormone and thyroid hormones before and after administration of oral dexamethasone in patients with primary open-angle glaucoma and in patients who demonstrated an elevated intraocular pressure to topical corticosteroid. They showed no difference in thyroid-stimulating hormone suppression between the two groups and concluded that primary open-angle glaucoma was not associated with an increased prevalence oflow thyroid function values. Krupin et al alluded to the thyroid function response to dexamethasone suppression not thyroid function in general. Any comment on an association between hypothyroidism and glaucoma was impossible because patients with any history of physical or laboratory evidence of thyroid disease were excluded from the study. The issue ofa relationship between hypothyroidism and glaucoma remains unresolved according to StoneY
We already have mentioned a case report and a tonographic study which seem to suggest not only an association between hypothyroidism and primary open-angle glaucoma but possibly a cause and effect. The only other case report in the literature showing a response of glaucoma to treatment of hypothyroidism is that in Hertel'sl4 study in 1920, which reported a reduction in intraocular pressure in two patients with hypothyroidism after treatment with Thyreoidin. Another tonographic study also has been done. Pestereva,15 in 1988, examined newly diagnosed patients with hypothyroidism using tonography, and also showed poor facility of outflow.
In the hypothyroid state, enzyme activity is slowed down so that enzyme products are produced and degraded at altered rates. Specifically in hypothyroidism, in the absence of a significant net increase in other connective tissue mucopolysaccharides, there is a 150% increase in hyaluronic acid within the tissues. This is due to decreased degradation of hyaluronic acid compared with its production. This accumulation of hyaluronic acid leads to the accumulation of sodium, water, and protein in many body tissues such as skin, intestinal tract, heart, and skeletal muscle. Many signs of hypothyroidism result such as weight gain, constipation, shortness of breath, hoarse voice, doughy induration of the skin, periorbital edema, blepharoptosis, etc. This buildup of hyaluronic acid in the tissues has been shown to be reversed with treatment of the hypothyroidism. 16
Smith et al . Hypothyroidism and Primary Open-angle Glaucoma
Stein et al l7 examined the effect of subconjunctival injection of hyaluronidase on living human normal eyes and in patients with primary open-angle glaucoma. They found that outflow resistance decreased in 15% of normal eyes and in 48% of primary open-angle eyes. The authors postulated that hyaluronic acid plays a role in the pathogenesis of primary open-angle glaucoma. Either it accumulates in greater amounts in glaucoma or it is found in a normal amount in a trabecular meshwork with fewer or smaller outflow channels. Other studies using hyaluronidase to perfuse postmortem animal or human eyes lend their support. 18-21
We propose that in the untreated hypothyroid state hyaluronic acid accumulates excessively in the trabecular meshwork and/or aqueous, causing an obstruction to facility of outflow. This would lead to open-angle glaucoma in a patient with a normal or borderline trabecular meshwork, or it would exacerbate a glaucoma with an already compromised trabecular meshwork. In addition, the glaucomatous result could reverse with treatment of the hypothyroidism.
Another implication of this study is that there is a large group of patients with primary open-angle glaucoma with undiagnosed hypothyroidism (10.9%). If, as estimates would suggest,22 there are 2 million people in North America with primary open-angle glaucoma, then this study suggests there are 218,000 (10.9%) patients with primary open-angle glaucoma who have undiagnosed hypothyroidism. Even those patients with subclinical hypothyroidism could reach successful outcomes because early treatment helps improve quality of life and cardiac performance and prevents atherosclerosis and progression to overt hypothyroidism.23-28
In summary, this clinical study demonstrates a strong association between hypothyroidism and primary openangle glaucoma. We propose that in the hypothyroid state, hyaluronic acid accumulates in the trabecular meshwork and/or aqueous, causing an obstruction to facility of outflow. This accumulation would reverse with treatment of the hypothyroidism. We note there is a large group of patients with primary open-angle glaucoma with undiagnosed hypothyroidism.
Further research is recommended with regard to the epidemiologic implications of this study and the pathophysiology of the proposed mechanism. In addition, the occurrence of untreated hypothyroidism underlying poorly controlled or newly diagnosed primary open-angle glaucoma needs to be identified and then the glaucoma should be followed to assess the response to thyroid treatment.
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