Endocrinologic dysfunction

LCH exhibits a predilection for the hypothalamo-pituitary (HP) region leading to permanent posterior and/or anterior pituitary hormonal deficiencies in a subset of patients.

Diabetes insipidus (DI)

Diabetes Insipidus (DI) is the most common disease-related consequence that can predate the diagnosis or develop anytime during the course of the disease [Kaltsas et al 2000; Prosch et al 2004]. DI is found in up to 30% of patients [Arico et al 2003], but may reach to 40% in patients with multisystem disease or 94% in the presence of other pituitary deficiencies [Kaltsas et al 2000; Makras et al 2007]. Polyuria and polydipsia, and/or structural abnormalities of the HP region dictate investigations to confirm DI.

Anterior pituitary hormonal deficiencies

Anterior pituitary dysfunction (APD) is found in up to 20% of patients, almost always with DI [Kaltsas et al 2000; Amato et al 2006]. Although APD is not invariably associated with abnormal HP imaging it is almost always encountered in patients with MS LCH who have DI and HP pathology on MR imaging [Makras et al 2006]. Growth hormone deficiency (GHD) is the most frequent disease-related APD found in up to 50% of patients with DI [Makras et al 2007]. In adults there are no specific GHD-related symptoms that can suggest the diagnosis [Donadieu et al 2004c].

Gonadotropin deficiency is the second most common deficiency, presenting with menstrual disturbances in women and decreased libido in men [Makras et al 2007]. ACTH deficiency may be partial or complete and present either with non-specific symptoms or as acute adrenal insufficiency following stressful events. TSH deficiency is almost always associated with panhypopituitarism and may present with subtle symptoms or obvious signs of hypothyroidism. Moderately elevated prolactin levels attributed to pituitary stalk infiltration can cause galactorrhoea in females and gonadotropin deficiency in all patients. Established endocrine deficiencies almost never recover over time, although apparent HP abnormal imaging may often regress either in response to treatment or as a result of the “natural course” of the disease [Makras et al 2006].

Hypothalamic involvement

Hypothalamic involvement is less frequent than pituitary involvement and leads to not only pituitary dysfunction, but neuropsychiatric and behavioral disorders, disturbances of thermo-regulation and sleeping pattern, and autonomic and metabolic abnormalities. The most frequent consequence is severe obesity due to increased appetite. Hypothalamic-related adipsia may seriously complicate the management of diabetes insipidus.

Metabolic abnormalities

One study involving 14 adult patients and 42 controls has shown that adults with LCH are at high risk of developing abnormalities of carbohydrate metabolism (diabetes mellitus, impaired glucose tolerance) and lipid metabolism leading to increased insulin resistance even in the absence of obesity [Alexandraki et al 2008].

Bone metabolism

Adults with LCH may present with a lower than expected bone mineral density at any age especially during periods of active disease [Makras et al 2012].

Other endocrine tissue involvement

The thyroid gland may occasionally be involved in the disease process while fine needle aspiration or even histological specimens may be mistaken with thyroid carcinoma. Unlike the lower genital tract, ovaries are quite rarely involved, mostly in the context of disseminated disease. Adrenal infiltration has been described in autopsy series although without any obvious clinical findings. Pancreatic involvement is also extremely rare, although there are reports of glucose metabolism abnormalities secondary to pancreatic and/or hepatic infiltration and dysfunction.

Investigation of hormonal deficiencies

A plasma osmolality in the range of 280- 295mOsmol/Kg in combination with an urine to plasma osmolality ratio > 2:1 exclude apparent DI, whereas a water deprivation test is usually required to reveal cases of partial DI. An early morning serum cortisol level ≥ 500 nmol/l (18 μg/dl) virtually excludes ACTH deficiency, whereas a cortisol level < 100 nmol/l (3.6 μg/dl) is suggestive of ACTH deficiency. For intermediate serum cortisol values an insulin tolerance test (ITT), if not contra-indicated, can access the adequacy of hypothalamic (HP)-adrenal axis as well as GH reserve. Although an insulin-like growth factor I (IGF-I) level below the age-adjusted normal range may be suggestive of growth hormone deficiency (GHD), it is not as reliable as the GH response to the ITT or other dynamic tests. Low basal gonadal steroids along with low gonadotropin levels in the presence of a relevant clinical setting are suggestive of hypogonadotropin hypogonadism. Occasionally in young females with menstrual disturbances and low oestradiol levels, failure of gonadotropin levels to rise in response to clomiphene stimulation is required to confirm the diagnosis. Finally, lack of TSH elevation in the presence of a low serum T4 level is indicative of TSH deficiency in the absence of the non-thyroidal illness syndrome.

Recommendation

Evaluation of TSH, free T4 and morning urine osmolality is recommended in all patients, further procedures (water deprivation test, plasma osmolality, serum cortisol, insulin like growth factor I, gonadal steroids and gonadotropin serum levels) to detect partial diabetes insipidus or anterior pituitary deficiencies should be performed when clinical symptoms are present (Grade D2 *).

* Grades of recommendation see here.