Management of Dyslipidemia in Endocrine Diseases

A 47 year old woman presents to clinic to establish care. She has recently moved to your region. She was diagnosed with autoimmune adrenal insufficiency at age 12, and takes glucocorticoid replacement therapy. She currently takes 20 mg every morning and 5 to 10 mg in the afternoon. She tells you that her previous endocrinologist kept attempting to reduce her hydrocortisone dose, but every time she decreased the dose she suffered severe fatigue and would go back up to this dose. She states she was trained in sick day management, and doubles the dose for 2–4 days each time she has nausea, vomiting, fever or severe fatigue. She estimates that she doubles her dose at least 5 times each year. At age 22 she presented with Graves’ disease, was treated with radioactive iodine ablation, and subsequently became hypothyroid treated with levothyroxine. Her current dose is 150 mcg daily. She was diagnosed with endometriosis in her teens. She had one pregnancy complicated by pre-eclampsia at age 32, and had hysterectomy and oophorectomy at age 37. She took estrogen for 2–3 years afterwards, but then discontinued it as she didn’t see the need. She has struggled with her weight for years, but has recently put on about 10 lbs (4.5 kg) with the stress of the move, and her current weight is 216 lbs (98.2 kg). She reports her height as 5’6” (1.67 m); and her BMI is 34.9 kg/m2. She has long standing depression controlled with citalopram 40 mg daily. She has never smoked. Her current medications are: Hydrocortisone, 25–30 mg daily Levothyroxine 150 mcg daily Multivitamin, one daily Citalopram, 40 mg daily. Her current medications are: Hydrocortisone, 25–30 mg daily Levothyroxine 150 mcg daily Multivitamin, one daily Citalopram, 40 mg daily. Her blood pressure is 132/74 mmHg. Her pulse is 82 beats per minute. Her examination is notable for generalized obesity with numerous pale striae on her abdomen. Her thyroid is not palpable. The remainder of the exam is normal. Fasting labs: Metabolic panel normal, with fasting glucose 97 mg/dl and eGFR > 60 ml/min/m2 Hemogram: normal TSH 6.9 mIU/ml (normal range 0.5–5.0 mIU/ml) Free T4 0.6 ng/dl (normal range 0.8–1.8 ng/dl) Total cholesterol 234 mg/dl LDL cholesterol 148 mg/dl HDL cholesterol 32 mg/dl Triglycerides 268 mg/dl The ASCVD risk calculator estimates her 10 year risk as 2.8%. Fasting labs: Metabolic panel normal, with fasting glucose 97 mg/dl and eGFR > 60 ml/min/m2 Hemogram: normal TSH 6.9 mIU/ml (normal range 0.5–5.0 mIU/ml) Free T4 0.6 ng/dl (normal range 0.8–1.8 ng/dl) Total cholesterol 234 mg/dl LDL cholesterol 148 mg/dl HDL cholesterol 32 mg/dl Triglycerides 268 mg/dl The ASCVD risk calculator estimates her 10 year risk as 2.8%.

Beyond the topics raised by the case vignette, the Endocrine Society addressed several other endocrine diagnoses that affect lipid levels and CVD risk. These are summarized below.

In the setting of growth hormone deficiency, elevations in total cholesterol and LDL-c are common seen, while TG and HDL-c changes are variable 78 – 80 . Conversely, in growth hormone excess, such as seen in acromegaly, increased TG is commonly observed with variable effects on cholesterol and LDL-c levels 81 , 82 . Growth hormone inhibits hepatic lipase and lipoprotein lipase activity 81 , 83 and can increase hepatic LDL-R expression and decrease PCSK9 expression 84 , 85 .

Numerous endocrine disorders affect lipid levels, and thus may confer risk for CVD. As the current CVD risk calculators that are widely used to guide lipid lowering therapy decisions do not consider endocrine co-morbidities, CVD risk may be under-estimated, and thus lipid lowering therapy may be under-utilized in these populations. Consideration of the additional impact of endocrine diseases when assessing individuals for dyslipidemia, CVD risk, and lipid lowering therapy is urged.

Does the ASCVD risk calculator 10 year risk estimate reassure you? Are there any other factors you need to consider?

On the surface, this patient appears to have several endocrine issues that need to be addressed, but cardiovascular risk does not appear to be one. She is obese, has premature menopause, inadequately treated hypothyroidism, and over-treated adrenal insufficiency. Managing these chronic conditions is important, and would likely be addressed by most endocrinologists. However, the 10 year CVD risk estimate may seem reassuring, and it would not be surprising if most providers did not consider CVD risk reduction and lipid lowering therapy as high priorities. The recent guidelines published by the endocrine society suggest that her endocrine co-morbidities may impact her cardiovascular risk, and should be considered 2 . In the following sections we will address these (and others) one by one.

The majority of lipid management guidelines recommend assessment of lipid levels and cardiovascular risk factors within an individual, then based on estimated cardiovascular disease (CVD) risk, suggest lipid lowering therapy and/or lipid goals 1 . Overall, this approach works well. However, one of the limitations is that the cardiovascular risk factors typically included in risk calculators and guidelines are somewhat limited: smoking, hypertension, diabetes, age, sex, and race, are the typical factors. In some, but not all, guidelines additional factors such as family history of premature CVD events, chronic inflammatory disorders, chronic kidney disease, and premature menopause (age < 40 years) are often also noted as risk enhancing factors. However, these factors are fairly difficult to turn into a quantitative risk, and thus often not included in risk calculators, and may be overlooked by providers. Most endocrine disorders are chronic in nature, and thus even a relatively minor effect to increase risk for CVD can lead to a significant impact when duration of exposure is considered. While robust therapies exist for many endocrine disorders (whether it be suppression of excess hormone amounts, or replacement of hormone deficiencies), the therapies do not perfectly restore normal physiology. Thus, individuals with endocrine disorders are at potential increased CVD risk, and maximizing strategies to reduce that risk are needed. The Endocrine Society recently published a guideline explicitly assessing the lipid profile and CVD risk and thus indications for lipid lowering therapy in individuals with endocrine diseases 2 . This new guideline suggests that some endocrine diseases, including hyperthyroidism, hypothyroidism, Cushing disease, chronic glucocorticoid therapy with doses above physiological needs, obesity, postmenopausal hormone replacement therapy use, and premature menopause should be included in the list of risk enhancing factors. This article will review various endocrine conditions that can impact lipid levels and/or CVD risk.

Hypopituitarism, of which growth hormone deficiency is the most common hormone abnormality, is associated with increased premature mortality, including increased risk of CVD 86 – 88 . Growth hormone deficiency itself may affect the myocardial and endothelial tissue, cardiac performance and coronary calcification, though the direct mechanisms linking growth hormone deficiency and CVD are not fully understood. Although long term growth hormone therapy improves the dyslipidemia in growth hormone deficiency 89 – 91 it is not clear that growth hormone therapy can decrease mortality 92 .