Metabolic Syndrome Consequent to Endocrine Disorders. Группа авторов

An excess level of glucocorticoid is also associated with the visceral obesity and fatty liver [83].

      The study from the USA analyzed prevalence of the MetS and NAFLD in adult (predominantly male) hypopituitary patients [3]. Although the study was controlled for obesity, hypopituitary patients exhibited significantly higher prevalence of hypertension (88 vs. 78%), hypertriglyceridemia (80 vs. 70%), and MetS (90 vs. 71%) [3]. Interestingly, patients with hypopituitarism had significantly higher elevations in serum aminotranspherase levels and hyperbilirubinemia as well as higher INR and hypoalbuminemia consistent with the increased prevalence of liver dysfunction in NAFLD and MetS [3]. High prevalence of abnormal liver function in hypopituitary patients may be strongly affected by endocrine deficiency and its metabolic consequences (insulin resistance, visceral fat accumulation), rather than obesity determined by BMI value [3].

      In a Japanese study, prevalence of NAFLD was significantly increased by 6.4-fold in 66 GHD hypopituitary patients compared with the control group [81]. In GHD group serum aminotransferase levels, CRP, and parameters of insulin resistance (IRI and HOMA-IR) were significantly higher than in controls [81]. In GHD patients with NAFLD(+) BMI, visceral fat area, fasting IRI, and HOMA-IR were significantly higher than that in NAFLD(–) GHD patients [81]. HDL cholesterol was lower, while triglycerides and fibrotic marker for the liver type IV collagen were significantly elevated compared to NAFLD(–) GHD group [81]. In 16 (21%) patients with NAFLD, liver biopsy found that 14 had characteristics of NASH [81]. One year of GHRT resulted in significantly decreased aminotranspherase levels and fibrotic markers while, based on histological analysis, steatosis and fibrosis scores in these patients significantly improved [81].

      Interestingly gender difference in the prevalence of fatty liver disease (it is much more common in men) was abolished by hypopituitarism and GHD [82]. Fatty liver disease was more common in patients with more severe hypopituitarism, obesity, and MetS and etiology of craniopharyngeoma and non-functioning adenoma compared to other etiologies of hypopituitarism [81].

      Impact of Other Hormone Deficiencies on MetS in Patients with Hypopituitarism

      GC and Metabolic Phenotype

The association between excess GC and MetS phenotype is well recognized in patients with Cushing’s syndrome. In GHD, as in obesity, there is an increased local 11-β hydroxysteroid dehydrogenase type 1 activity in the adipose tissue resulting in increased cortisol exposure [86].

      Thus GHRT suppresses 11-β hydroxysteroid dehydrogenase type 1 activity thereby unmasking low adrenal reserve, leading to overt central hypocorticism which has to be replaced [86].

Recommended daily doses used for replacement of secondary adrenal insufficiency were reduced, during the last 10 years, as daily cortisol production rate was confirmed to be substantially lower than previously thought (9–11 mg/m², corresponding to 15–19 mg/day) [88].

Hypopituitary patients on GC replacement were more insulin resistant when they received HC than without HC. When HC dose was reduced from 20–30 mg to 10–15 mg/day, in 11 hypopituitary patients, body weight, total and abdominal fat mass, total cholesterol, and triglycerides decreased after 6–12 months [89]. Significant HC dose-response relationship was demonstrated, in more than 2,000 patients, for waist circumference, serum triglyceride concentration, total and LDL cholesterol, and BMI [18]. Hypopituitary ACTH-deficient patients receiving HC doses of <20 mg/day had similar metabolic profile to those who were ACTH sufficient [18]. The study clearly indicated that lower doses of HC (≤20 mg/day) are advocated for replacement therapy of secondary adrenal insufficiency and that doses above 20 mg/day are associated with increased mortality [17, 19].

Survey of the European Registry for Adrenal Insufficiency (EU AIR) revealed that the most common regime for dosing HC 15–20 mg/day, in patients with secondary adrenal insufficiency, was twice daily (47.8%) and thrice daily (30.1%) [90]. New once daily formulations aim to deliver cortisol in a more physiological fashion and improve metabolic profile and compliance of patients with hypopituitarism and secondary adrenal insufficiency [91].

It is important to remember that the reported risk of death from infectious diseases was 1.6-fold higher in patients with ACTH deficiency compared to ACTH sufficient patients with hypopituitarism [13]. Adrenal crisis and hyponatremia were also associated with an increased standardized mortality ratio for hypopituitary patients [13]. Important interactions with thyroxin, GH, and sex steroids should not be ignored since they can induce cortisol clearance and increase the risk for adrenal crisis [20].

The aim of daily GC replacement is to deliver sufficient cortisol for day to day activity in unstressed condition. However increased doses are needed during stressful conditions (surgery, trauma, acute illness). The aim of chronic GC replacement is to avoid under- and over-replacement in order to avoid adverse cardiometabolic risk and increased mortality as stated in the current guidelines and recommendations [87, 93].

      Thyroxin and Metabolic Phenotype

Untreated mild or poorly replaced central hypothyroidism (CH) may potentially contribute to adverse cardiometabolic risk. In CH bioactivity of TSH is reduced due to abnormal glycosilation, TSH half-life is longer and thyroid hormones may be within the lower normal range [94]. Patients with untreated GHD may have higher T4 levels since GH replacement increases and GC reduces T4–T3 conversion [93–95]. Estrogen treatment increases thyroid binding globulin and patients may need higher doses of T4 replacement. Recommendations for adequate T4 replacement in CH are based on few reports that suggest direct dosing by weight using mean dose of 1.6 µg/kg targeting TSH below 0.1 mU/L and FT4 in mid to high normal reference range [87]. Patients with CH on empirical T4 doses 1 µg/kg had worse outcome in terms of BMI, total, LDL, and HDL cholesterol than patients on doses 1.6