Endocrine Functions Of The Liver

The liver is an amazing organ and plays a role in some very critical metabolic pathways including being involved in direct hormone production, hormone metabolism, detoxification, and processing and redistribution of metabolic fuels. The liver participates in different pathways with other endocrine organs, including the pituitary, pancreas, gut, thyroid, adrenal glands, and bone. Diseases that affect the liver lead to a range of symptoms and problems, including hypogonadism, osteoporosis, effects on glucose metabolism and growth hormone (GH), and controversial effects on cortisol.

The liver is highly vascular and has a lot of blood supply, and so is well-positioned to provide and receive  signals from our pancreas (which sits just under the left rib) and even our gut hormones. It also receives blood and serves as an important organ in how we process drugs and medications. Despite only representing 2.5% of the body weight, the liver receives up to 25% of the total cardiac output from the heart when we are at rest.

It also receives a unique double afferent blood flow from the hepatic artery and partially deoxygenated portal vein, with around 75% of the blood flow from the latter.

The portal vein, in turn, receives blood from the stomach, small and large intestines, pancreas, spleen, and gallbladder, with direct physiological implications on the regulation of metabolism by endocrine liver functions.

Direct hormone production

Did you know the liver has a role in making hormones?

The liver directly synthesizes multiple hormones, including 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF-1), and angiotensinogen. 

For example let's look at Vitamin D: 

The liver is the main site of 25-hydroxylation of vitamin D to 25-hydroxyvitamin D (calcidiol), the main storage form of vitamin D.

Vitamin D is a secosteroid hormone well known for its role in calcium and bone homeostasis, with pleiotropic effects on cellular proliferation, differentiation, and immunomodulation.

25-hydroxyvitamin D (calcidiol) then undergoes 1-alpha-hydroxylation in the kidney to the activated form 1,25-dihydroxyvitamin D (calcitriol), which provides the active hormonal effects of vitamin D.

The hydroxylation of vitamin D to produce calcidiol is mainly carried out in the liver by multiple cytochrome P450 mixed-function oxidases (CYPs) located in the mitochondria, endoplasmic reticulum (ER), and microsomes, though studies also show presence of these CYPs in extrahepatic tissues.

Hormone metabolism

The liver is involved in the metabolism of multiple endocrine hormones, including thyroid hormones, glucagon-like peptide-1, and steroid hormones, with roles in both activation and inactivation of the hormones.

Thyroid hormone: Hepatic metabolism has roles in both activation and inactivation of thyroid hormones. The biologic activity of thyroid hormone is mainly mediated through the active thyroid hormone T3. The thyroid only secretes 20% of the daily T3 requirement, with the remainder 80% converted from T4 by peripheral selenium-containing deiodinase enzymes (DIO), of which three primary deiodinases (type 1, 2, and 3) have been identified.

The liver expresses DIO1, along with the kidney and thyroid, which converts T4 to T3, though with less kinetic efficiency compared to DIO2, which is expressed by brown adipose tissue and the pituitary. Subsequently, the thyroid hormone is metabolised by conjugation with sulfate or glucuronic acid, which occurs prominently in the liver.

Sex hormones: 

The liver is the main site for metabolic conversion of estrogens, progesterone, and androgens to their metabolites via CYPs, which are abundantly expressed in the liver. In particular, as part of the first phase of metabolism, estrogens undergo hydroxylation by numerous CYPs, including 2-hydroxylation to 2-hydroxyestradiol and 4-hydroxylation to 4-hydroxestradiol, which represent 80% and 20% of biotransformation of estradiol in the liver, respectively.