The incidence of occult hypothyroidism, following treatment of laryngeal carcinoma is high. Nevertheless, the development of such hypothyroidism may remain unnoticed unless thyroid function testing is carried out. Although no generally accepted guidelines are available, it is suggested that thyroid function should be tested every six months in the first few years after treatment for laryngeal carcinoma and then yearly thereafter. Substitution therapy may improve some symptoms, but most symptoms are non-specific and are also associated with general cancer treatments. However, substitution therapy of subclinical hypothyroidism is controversial: there is a growing body of evidence that supports a permissive role for thyroid hormone in the growth of certain solid tumours so thyroid hormone replacement therapy may not be indicated in patients with subclinical hypothyroidism and current cancer. In patients who have been treated for laryngeal cancer, it is therefore important to screen for hypothyroidism because of the high incidence of the condition, its potential impact on health-related quality of life, the low burden of substitution therapy in addition to the fact that the actual testing itself is easy.
by Dr Remco de Bree, Dr A. M. Lo Galbo, Dr P. Lips and Dr C. R. Leemans


Laryngeal carcinoma is the most common form of head and neck cancer. When treating patients for laryngeal cancer, the goal is not only to cure but also to preserve function. Early laryngeal cancer can usually be managed successfully with either radiotherapy or surgery. Advanced laryngeal carcinoma is traditionally treated by surgery and radiotherapy. However, carefully selected advanced lesions are initially treated by irradiation, with surgery reserved for salvage treatment. With the emphasis on preservation of organ and function, regimes using altered fractionation schedules of radiation and the combination of chemotherapy and radiation have emerged. As a consequence, most of these patients are initially treated with radiotherapy with or without chemotherapy. Laryngectomy is mainly used for very large lesions or recurrences after initial organ preservation treatment [1].

Hypothyroidism can be a sequela after treatment of head and neck cancer, especially laryngeal carcinoma [2]. Several pathophysiological mechanisms may account for the development of hypothyroidism resulting from the treatment of laryngeal and hypopharyngeal cancer. A part or all of the thyroid gland may be resected for oncological reasons or the vascular supply of the thyroid may be injured during surgery [3]. Radiation has also been shown to induce fibrosis within the capsule of the thyroid gland, which may result in decreased thyroid function [4]. Moreover, from the Chernobyl nuclear accident it is known that radiation exposure is associated with an increased incidence of circulating antithyroid antibodies, which may theoretically induce hypofunction of the thyroid and indeed, a relation between hypothyroidism and circulating antithyroid antibodies has been found [5,6]. However, it is not clear if radiation induces development of these antibodies or patients with circulating antithyroid antibodies predispose for development of hypothyroidism after radiotherapy. [3,7-9]

Incidence and symptoms of hypothyroidism
As reported in different studies, the incidence of hypothyroidism in patients treated for laryngeal cancer varies depending on site, stage, treatment and time after treatment. The incidence ranges between 10% and 78%, whereas the incidence in the general population has been reported to be 2% (<65 years) to 5% (>65 years) [10,11].

Thyroid dysfunction may cause various physical, psychological and psychiatric problems and disturbances. Physical problems consist in weight gain, feeling cold, dry skin, constipation, lack of energy and fatigue [12,13]. Several studies show subclinical hypothyroidism as a risk factor of heart failure and atherosclerosis [14-16]. The main psychological symptoms include anxiety, dysphoria, emotional lability, insomnia and deterioration in cognitive functions [17]. As a result of changes in serotonergic and noradrenergic receptors psychiatric disorders such as psychotic disorders, depressive disorders and rapid cycling bipolar disorder can be seen [17].

Given the slow development and relatively non-specific nature of the symptomatology, it is possible that a considerable number of patients have a non-diagnosed hypothyroidism. Symptoms such as weight gain, cold intolerance, constipation, dry skin and fatigue are frequently wrongly attributed to the tumour or its intensive treatment. Lo Galbo et al found that in patients treated for laryngeal cancer, weight gain and cold intolerance were associated with (subclinical) hypothyroidism, whereas fatigue and constipation were not [7]. Since however fatigue, is a common general symptom after cancer treatment it may not be specific enough for the prediction of hypothyroidism. On the contrary, head and neck cancer patients more often suffer from weight loss than weight gain. Thus, weight gain may be more specific for hypothyroidism in these patients. For these reasons, the development of hypothyroidism may remain unnoticed if thyroid function testing is not carried out. Lo Galbo et al found that the  prevalence of occult hypothyroidism following treatment for laryngeal carcinoma was 28% (44 of 156 patients): subclinical hypothyroidism in 18.6% and clinical hypothyroidism in 9.6% of cases [7]. The development of thyroid dysfunction is thought to be delayed until some time after completion of treatment. Although hypothyroidism is most frequently diagnosed within the first 2 years, it may develop many years after treatment [18]. In a retrospective study of the follow-up of patients who had undergone laryngectomy and radiotherapy, Ho et al found that 20% of the patients developed hypothyroidism within 3 years, 39% within 6 years and 93% within 10 years [19].

The development of hypothyroidism may remain unnoticed if thyroid function testing is not carried out. The diagnosis of hypothyroidism can be easily made from laboratory determination of the levels of thyroid stimulating hormone (TSH) and free T4 (FT4). Hypothyroidism is defined as overt (clinical) if TSH is increased and FT4 decreased whereas it is classified as subclinical if the TSH is increased and FT4 is normal. Reference values may differ between laboratories but usually lie in the range of 0.3-4.5 mU/L for TSH and 11.0-24.0 pmol/L for FT4. Anti-thyroid antibodies, e.g. thyroid peroxidase antibody (anti-TPO) and thyroglobulin antibody (anti-Tg), may precede the development of hypothyroidism. There are no generally accepted guidelines regarding thyroid function testing during regular follow-up [10,20]. Several studies report that hypothyroidism almost always develops within five years after treatment, with the majority of cases occurring within the first two years [11,21,22]. Garcia-Serra et al recommend that thyroid function should be tested every six months in the first few post-treatment years and then yearly thereafter [21]. Tell et al even recommend life-long thyroid hormone screening as well as thyroid auto-antibody screening after radiotherapy to the neck [8]. Ozawa et al and Nishiyama et al found that hypothyroidism not only occurred in the late phase but also in the subacute phase (within 12 months) [4], [22]. Occult hypothyroidism before treatment may become clinically apparent by radiotherapy. Ozawa and Nishiyama suggest that all patients should be screened before they are treated by radiotherapy. Because of the increased risk of wound-healing problems, preoperative assessment of thyroid function is encouraged in patients who have undergone radiotherapy before salvage surgery. In addition, patients who have undergone radiotherapy of laryngeal carcinoma should be informed about the signs and symptoms of hypothyroidism.

Treatment
In patients with clinical hypothyroidism substitution therapy with thyroxin is considered to be safe and cheap. Unfortunately, most of the symptoms mentioned above and associated with diagnosed hypothyroidism are not specific for hypothyroidism but are often generally encountered after cancer treatment so substitution therapy will not always improve these symptoms.

Treatment of subclinical hypothyroidism is controversial. Gulseren et al found significant improvements in  anxiety, depression and fatigue both in clinical and subclinical hypothyroidism [17].
However, Jaeschke et al found a lack of symptom response in subclinical hypothyroidism and suggested that patients’ symptoms were nonspecific and may not have been  caused by the (subclinical) hypothyroidism [12,13]. It was discovered by Walsch et al that small changes in thyroxin dosage, introduced  with the aim of achieving serum TSH concentrations in the lower reference range, did not change well-being or quality of life [16]. Razvi et al state that substitution
treatment of subclinical hypothyroidism leads to a significant improvement of cardiovascular risk factors and tiredness [14]. Because substitution therapy requires lifelong medication with associated potential problems of labelling, multi-drug therapy and thyroid hormone-induced osteoporosis, Jaeschke et al suggest just watchful waiting for subclinical hypothyroidism [12,13]. On the other hand, it has been reported recently by Nelson et al that in head and neck cancer patients there is an association between the development of hypothyroidism and improved survival [23]. In a retrospective study they found that patients who develop secondary hypothyroidism after treatment have an increased overall survival rate and increased recurrence-free survival compared with patients who did not become hypothyroid. However, in an analysis which standardised the timing of the length of survival on the basis of the detection of hypothyroidism, it was found that, although the general trend of increased survival and increased recurrence-free survival in hypothyroid patients was preserved, the relationship was statistically not significant [23]. Nevertheless it is possible to speculate that an increased duration of hypothyroidism may lead to an improved outcome. This may be caused by the role of thyroid hormone in controlling the cell cycle, in both normal and neoplastic cells. Therefore, theoretically, the maintenance of patients at a clinically tolerable level of hypothyroidism may actually have a beneficial effect in regard to their neoplastic disease [23]. It is therefore advised that thyroid hormone replacement therapy may not be indicated in patients with subclinical hypothyroidism who are asymptomatic and have a mildly elevated TSH. This may be especially relevant for individuals with a prior or current cancer diagnosis in view of the growing body of evidence that supports a permissive role for thyroid hormone in the growth of certain solid tumours [24]. For this reason only patients with TSH levels of 10 mU/L or higher should received substitution therapy.

In conclusion, it is important to screen for hypothyroidism in patients who have been treated for laryngeal cancer because of the high incidence of the condition, its potential impact on health-related quality of life, the low burden of substitution therapy in addition to the fact that the actual testing itself is easy to carry out.

References
1. Bree R de, Leemans CR. New developments for optimal management of head and neck cancer. Onkologie 2004; 27: 339-342.
2. Smolarz K et al. Hypothyroidism after therapy for larynx and pharynx carcinoma. Thyroid 2000; 10:  425-429.
3. Aimoni C et al. Thyroid function studies in patients with cancer of the larynx: preliminary evaluation. Otolaryngol Head Neck Surg 2003; 129: 733-738.
4. Ozawa H et al. Hypothyroidism after radiotherapy for patients with head and neck cancer. Am J Otolaryngol 2007; 28:46-9.
5. Farahati J et al. Inverse association between age at the time of radiation exposure and extent of disease in cases of radiation-induced childhood thyroid
carcinoma in Belarus. Cancer 2000; 88: 1470-1476.
6. Pacini F et al. Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occuring thyroid carcinoma in Italy and France. J Clin Endocrinol Metab 1997; 82: 3563-3569.
7. Lo Galbo AM et al. The prevalence of hypothyroidism after treatment for laryngeal and hypopharyngeal carcinomas: are autoantibodies of influence? Acta Otolaryngol 2007, 127: 312-317.
8. Tell R et al. Long-term incidence of hypothyroidism after radiotherapy in patients with head-and-neck cancer. Int J Rad Oncol Biol Phys 2004; 60 :395-400.
9. Sinard RJ et al. Hypothyroidism after treatment for nonthyroid head and neck cancer. Arch Otolaryngol Head Neck Surg 2000; 126: 652-657.
10. Leon X et al. Hypothyroidism in patients treated with total laryngectomy. A multivariate study. Eur Arch Otorhinolrayngol 2002; 259:193-196
11. Mercado G et al. Hypothyroidism: a frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 2001; 92: 2892-2897.
12. Jaeschke R et al. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med 1996; 11: 744-749.
13. Jaeschke R et al. Spectrum of quality of life impairment in hypothyroidism. Qual of Life Res 1994; 3: 323-327.
14. Razvi S et al. The beneficial effects of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab 2007; 92: 1715-1723.
15. Rodondi N et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005; 165: 2460-2466.
16. Walsh JP et al. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab 2006; 91: 2624-2630.
17. Gulseren S et al. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch of Med Research 2006; 37: 133-139.
18. Gal RL et al. Risk factors associated with hypothyroidism after laryngectomy. Otolaryngol Head Neck Surg 2000; 123: 211-217.
19. Ho AC et al. Thyroid dysfunction in laryngectomees 10 years after treatment. Head Neck 2008; 30: 336-40.
20. Lo Galbo AM et al. Detecting hypothyroidism after treatment for laryngeal or hypopharyngeal carcinomas: a nationwide survey in The Netherlands. Eur Arch Otorhinolaryngol, 2009: 266: 713-718.
21. Garcia-Serra A et al. Thyroid function should be monitored following radiotherapy to the low neck. Am J Clin Oncol 2005; 28: 255-258.
22. Nishiyama K et al. A prospective analysis of subacute thyroid dysfunction after neck irradiation. Int J Radiat Oncol Biol Phys 1996; 34: 439-444.
23.Nelson M et al. Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2006; 132: 1041-1046.
24.  Hercbergs A, Davis P. Hypothyroidism in the patient with cancer: how much thyroid supplementation is “safe”? Arch Otolaryngol Head Neck Surg 2006; 133: 625-626.

The authors
Remco de Bree1, Annalisa M. Lo Galbo1, Paul Lips2 and C. René Leemans1
1 Department of Otolaryngology / Head and Neck Surgery,
2 Department of Endocrinology,VU University Medical Center, Amsterdam, The Netherlands.

Correspondence to:
Remco de Bree, MD, PhD
Department of Otolaryngology/Head and Neck Surgery
VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam PO Box 7057, 1007 MB Amsterdam, The Netherlands
Tel: +31-20-4443689
Fax: +31-20-4443688
e-mail: r.bree@vumc.nl

Hypothyroidism in women associated with liver cancer

Women with a history of hypothyroidism face a significantly higher risk of developing liver cancer, according to a new study in the May 2009 issue of Hepatology.
Hypothyroidism is the most common thyroid disorder among U.S. adults, affecting between 8 and 12 percent of the U.S. population, and more women than men. The condition can cause hyperlipidaemia and weight gain and may play a role in the development of nonalcoholic steatohepatitis which can progress to more severe liver disease. Studies have also suggested a clinical association between hypothyroidism and hepatitis C, which is contributing to the rising rate of liver cancer in the US.
Researchers, led by Manal Hassan of Anderson Cancer Center at the University of Texas, designed a case-control study to better understand the association between hypothyroidism and the development of liver cancer. They included 420 patients with the condition and 1,104 healthy controls. Demographic data and information were gathered from each subject about liver cancer risk factors, such as smoking, alcohol consumption and family cancer history. The participants were also asked about their history of thyroid conditions and obesity. They were also tested for hepatitis B and C. Women with a history of hypothyroidism had twice the risk of liver cancer. Women who had a prior history of hypothyroidism for more than 10 years had a threefold higher risk of liver cancer compared to women without a history of thyroid disorders. Adjusting for obesity did not change the association.
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