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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Ophthalmology Volume 100, Number 10, October 1993

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.

References

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2. Billewicz WZ, Chapman RS, Crooks J, et al. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med 1969;38:255-66.

3. Fries PD, Char DH. Hyperthyroidism and hypothyroidism. In: Gold DH, Weingeist TA, eds. The Eye in Systemic Dis­ease. Philadelphia: JB Lippincott, 1990;chap. 29.

4. Eden S, Sundbeck G, Lindstedt G, et al. Screening for thy­roid disease in the elderly. Serum concentrations of thyro­tropin and 3,5,3'-triiodothyronine in a representative pop­ulation of 79-year-old women and men. Compr Gerontol [A] 1988;2:40-5.

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13. Stone RA. Systemic diseases associated with elevated intra­ocular pressure and secondary glaucoma. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Vol. 2. St. Louis: C V Mosby, 1989;chap. 63.

14. Hertel G. Einiges tiber den Augendruck und Glaukom. Klin Monatsbl Augenheilkd 1920;64:390-2.

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16. Gorman CA. Extrathyroid manifestations of Graves' disease. In: Ingbar SH, Braverman LE, eds. Werner's The Thyroid: A Fundamental and Ginical Text, 5th ed. Philadelphia: JB Lippincott, 1986; chap. 44.

17. Stein R, Romano A, Treister G, Bartov E. Effect of sub­conjunctival injection of hyaluronidase on outflow resistance in normal and in open-angle glaucomatous patients. Metab Pediatr Syst Ophthalmol 1982;6:169-74.

18. B{miny EH, Scotchbrook S. Influence of testicular hyal­uronidase on the resistance to flow through the angle of the anterior chamber. Acta Physiol Scand 1954;30:240-8.

19. Barany EH. Physiologic and pharmacologic factors influ­encing the resistance to aqueous outflow. In: Newell FW, ed. Glaucoma: Transactions of the First Conference. New York: Josiah Macy Jr Fndn, 1956;153.

20. Pedler C. The relationship of hyaluronidase to aqueous out­flow resistance. Trans Ophthalmol Soc U K 1956;76:51-63.

21. Lieb WA, SHirk N. Interrelationship of ascorbic acid and facility of outflow: steroid hormones as possible regulating mechanisms of intraocular pressure. In: Paterson G, Miller SJH, Paterson GD, eds. Drug Mechanisms in Glaucoma: The Gilston Glaucoma Symposium. London: J & A Chur­chill, 1966; 105-36.

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22. The 1983 Report of the National Advisory Eye Council. Vision Research: A National Plan, 1983-1987. Vol. I. [Washington, DC]: U.S. Dept. of Health and Human Ser­vices, 1983;12-13.

23. Croxson MS, Ibbertson HK. Subclinical hypothyroidism. N Z Med J 1980;91:89-91 .

24. Ridgway EC, Cooper DS, Walker H, et al. Peripheral re­sponses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1981 ;53: 1238-42.

25. Bell GM, Todd WTA, Forfar JC, et al. End-organ responses

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to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol 1985;22:83-9.

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28. Althaus BU, Staub JJ, Ryft-De Leche A, et al. LDL/HDL­changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol 1988;28: 157-63.