**2.5 TSH deficiency**

142 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

The hypothalamic-pituitary-adrenal axis appears to be the most radioresistant in patients irradiated for non-pituitary disorders. Clinically apparent ACTH deficiency occurs in only about 3% of patients receiving a total radiation dose to the h-p axis of 40-50 Gy (Constine et al., 1993; Livesey et al., 1990). In contrast, the frequency of ACTH deficiency in patients treated with intensive irradiation for NPC is significantly higher. Samman et al (Samaan et al., 1987) reported a frequency of 4% in the first 4 years after irradiation and a cumulative frequency of 20% after 15 years, while Lam et al (Lam et al., 1991) reported a cumulative frequency of 30.7% after 5 years. Differences in radiation schedules and diagnostic criteria may explain the higher frequency in the latter study (Lam et al., 1991). In most reported cases, however, ACTH deficiency was partial and only a few patients needed regular hydrocortisone replacement because of symptoms of hypocortisolism (Lam et al., 1991;

From a clinical perspective, significant as opposed to subtle abnormalities in ACTH secretion, are unlikely to be missed by the ITT, which remains the "gold standard". If the ITT is contraindicated, alternative tests like Glucagon and Synacthen may be considered. Measurements of 9 am cortisol may be adequate; a level in excess of 300 nmol/l almost always excludes significant ACTH deficiency. However, during periods of acute stress or acute illness, a level in excess of 500 nmol/l is required to confirm normality of the ACTHadrenal axis. Patients with lower levels or those who are symptomatic should be considered for a stimulation test. As ACTH deficiency is a slowly evolving abnormality, it is very unusual to have a normal synacthen test in the context of a clinically significant ACTH

It is to be noted that increased oestrogen levels due to HRT, use of contraceptive pill (OCP) or pregnancy may raise cortisol binding globulin (CBG) resulting in spurious elevation of circulating total cortisol levels by as much as 3 folds or more. Under these circumstances, an apparently normal random cortisol level may occur in the presence of a significant cortisol deficiency. Any assessment of cortisol levels should only be done after withdrawing any oestrogen containing medications for at least 4 weeks. If the patient was on the oral contraceptive pill (OCP) appropriate advice about mechanical contraception should be provided. If the patient is not willing to stop oestrogen replacement therapy or if pregnant, a stimulation test may be needed. The normality of the ACTH-adrenal axis is then determined by a normal cortisol increment rather than by the normality of the absolute basal or

Adrenal dysfunction with reduction in spontaneous and/or stimulated cortisol secretion is an important diagnosis to make. Missing a diagnosis of this nature may put patients at risk of acute adrenal crisis during periods of acute stress. Although regular hydrocortisone replacement therapy may not be necessary in asymptomatic patients with partial ACTH deficiency, oral or intravenous hydrocortisone replacement therapy may become necessary during situations that can lead to acute adrenal crisis due to failure of the ACTH-adrenal axis to meet the increased demands for cortisol. Such patients should be properly informed about the emergency use of hydrocortisone during severe stress, acute illness, surgery, and trauma. Patients should also be advised to have a steroid medi-alert bracelet for emergency

**2.4 ACTH deficiency** 

Samaan et al., 1987; Samaan et al., 1982).

stimulated cortisol levels.

situations.

deficiency that normally results in secondary adrenal atrophy.

Like the ACTH axis, the hypothalamic-pituitary-thyroid axis appears to be the least vulnerable to radiation damage and the latter is highly dose-dependent (Constine et al., 1993; Lam et al., 1991; Littley et al., 1989a). With radiation doses of less than 50 Gy, the frequency of TSH deficiency remains as low as 3-6%, such as that found in survivors of non-pituitary brain tumours (Livesey et al., 1990; Oberfield et al., 1992). Patients irradiated during adulthood for non-pituitary brain tumours were reported to have 9% rate of secondary hypothyroidism (Agha et al., 2005). A higher incidence of overt secondary hypothyroidism is noted in patients with pituitary tumours (Littley et al., 1989a), but more frequently following intensive irradiation schedules utilizing doses in excess of 50 Gy, typically used for head and neck tumours including NPC (Chen et al., 1989; Constine et al., 1993; Lam et al., 1991; Pai et al., 2001; Samaan et al., 1987). For example Lam et al (Lam et al., 1991) reported a cumulative incidence of secondary hypothyroidism of 14.9% after 5 years of follow up. The exact incidence of TSH deficiency may be under-estimated in NPC patients due to the high frequency of coexisting primary thyroid dysfunction causing TSH elevation.

Annual testing of thyroid function is indicated in patients irradiated for NPC who are particularly at much greater risk of primary hypothyroidism due to radiation-induced damage of the thyroid gland. The diagnosis of frank central hypothyroidism is straightforward - subnormal T4 level with normal or low basal TSH concentration. Given the wide range of normal free T4 levels, a significant decline in free T4 levels over time with normal or low normal TSH levels may signify a diagnosis of evolving central hypothyroidism or a mixed (primary and secondary) hypothyroidism even before free T4 levels drop below the lower normal limit. This should be highly suspected in the presence of gonadotrophin and/or ACTH deficiency or if there is history of thyroidal irradiation and it may warrant a therapeutic trial with thyroxin in the presence of a supportive clinical picture.

Thyroxine replacement therapy may precipitate symptomatic acute adrenal insufficiency in an otherwise asymptomatic individual with unrecognised ACTH deficiency. It is mandatory that reduced cortisol production be ruled out with certainty before starting thyroxine therapy. If cortisol deficiency coexists, it should be treated first before intruding thyroxine therapy. It is also important to continue to assess the ACTH-adrenal axis at regular intervals after commencing thyroxine replacement therapy.

With the difficulty in diagnosing evolving central hypothyroidism by a single test, it has been claimed that the presence of a hypothalamic TSH response to a TRH test and/or diminished nocturnal TSH surge despite a normal free T4 level may imply a diagnosis of socalled "hidden" central hypothyroidism in a substantial proportion of irradiated children (Rose et al., 1999). In a recent study by the author et al (Darzy & Shalet, 2005), however, it was demonstrated that, like in some normal individuals, the loss of nocturnal TSH surge

Endocrine Complications Following Radiotherapy

high dose radiotherapy to the neck.

higher chance of thyroid dysfunction in the long-term.

thyroid surgery in addition to radiotherapy (Wu et al., 2010).

hypothyroidism that may warrant a trial of thyroxine replacement therapy.

levels is worth considering with a proper assessment of the response.

and Chemotherapy for Nasopharyngeal Carcinoma 145

microvascular and macrovasular damage resulting in thyroid tissue hypoxemia and nutrient-poor environment leading to reduced synthetic and secretory capacity, and radiation-induced fibrosis that may prevent compensatory hypertrophy of the gland (Miller & Agrawal, 2009). The development of thyroid antibodies after radiotherapy may predict a

Subtle thyroid dysfunction occurs soon after radiotherapy for NPC; Chen et al (Chen et al., 1989) have demonstrated increased peak TSH responses to TRH stimulation a month after radiotherapy and more so after 15-18 months of radiotherapy. More severe degrees of thyroid dysfunction with increased TSH and reduced free T4 tend to occur in the long term. However, hypothyroidism may occasionally develop as early as 6 weeks after completion of

A cumulative incidence of increased TSH of 18% and 45% was reported in 166 patients treated for NPC in the first 4 years and after 15 years of follow up, respectively (Samaan et al., 1987). In a prospective study of 408 patients who had received radiation therapy for NPC; the estimated incidences for clinical hypothyroidism were 5.3%, 9.0%, and 19.1% and for sub-clinical hypothyroidism were 9.7%, 15.7%, and 20.5% at 3, 5 and 10 years after radiotherapy, respectively (Wu et al., 2010). This study has also showed that clinical hypothyroidism occurred more frequently in younger patients, female sex and following conformal radiotherapy. Some reports have also suggested a higher incidence of radiationinduced hypothyroidism in the younger age group treated for Hodgkin's disease (Shalet et al., 1977) or for NPC (Zubizarreta et al., 2000), while other reports did not (Daoud et al., 2003; Kupeli et al., 2006). These rates of radiation-induced hypothyroidism are significantly higher than the reported rates of 0.3-1.3% in the general population (Wu et al., 2010). Much higher rated of hypothyroidism are seen in other head and neck tumours that involved

The diagnosis of primary hypothyroidism is straight forward. Frank (clinical) hypothyroidism is associated with increased TSH and subnormal free T4. Sub-clinical cases are characterised by increased TSH but apparently normal free T4. The presence of radiation-induced hypothalamic-pituitary damage with TSH deficiency may compound the biochemical picture and interpretation of the thyroid functions tests. Significant reduction in free T4 levels, albeit in the normal range, may be seen in the presence of normal or slightly elevated TSH levels. Under these circumstances a trend showing a progressive decline in free T4 levels despite a stable/mild increase in TSH levels following radiotherapy supports the diagnosis of central hypothyroidism or a combined primary and secondary

It is recommended that all patients have a thyroid function test at baseline and every 6-12 months after radiotherapy. Symptoms and signs of hypothyroidism should be explored during any consultation. The symptoms of overt hypothyroidism include weight gain or difficulty loosing weight, intolerance to cold, dry skin, hair loss, constipation, menorrhagia or intermenstrual spotting, decrease physical activity, lethargy, easy fatigability, muscle cramps, and slow mentation. The signs include periorbital oedema, loss of eyebrows, cool and dry skin, a prolonged relaxation phase of deep tendon reflexes, and pleural or pericardial effusions. If the biochemical diagnosis is uncertain, a trial of thyroxine replacement therapy in those with "sub-clinical" hypothyroidism with "normal" free T4

seen in about 20% of euthyroid adult cancer survivors did not reflect a genuine loss of diurnal rhythm, but simply occurred as a result of a physiological shift in the timing of the peak TSH (acrophase) and/or the nadir TSH levels potentially leading to an erroneous diagnosis of "hidden" central hypothyroidism. Therefore, serial thyroid testing to demonstrate a decline in T4 levels provides the only means for diagnosing "hidden" central hypothyroidism.
