The Liver, Bile, and the Brain Adrenal (HPA) Axis – Dr Fiona McCulloch

We often associate the adrenals and their secretion of with stress and sleep, as well as their impact on blood sugar regulation.Most don’t realize that there’s a powerful connection between the liver and adrenal function, as well.

Read on to discover how having a “sluggish” liver can disrupt this important function in our bodies.

The HPA Axis and Response toEnvironment

Ultimately, the brain processes what’s going on in our environment through a part known as the hypothalamus which activates the pituitary to send a signal down to the adrenal glads, which sit on top of the kidneys. Those then release the hormone cortisol to help us deal with the stress.Cortisol is generally known as the “stress hormone”, and understandably so.It’s definitely released in times of stress to help with our metabolism, as well as with the transcription of genes that help us release energy.

This important regulatory pathway is known as the HPA Axis (HPA stands for Hypothalamic-Pituitary-Adrenal).

The HPA Axis and Circadian Rhythm

Corticosteroids are also released in daily circadian rhythms. These regulate the balance of our immune, metabolic, and cardiovascular systems. Cortisol is involved in many complex physiological processes, depending on day/night cycles as well as fasting/feeding cycles.

Feedback loops—Enough is Enough

Cortisol works through negative feedback loops. Once enough cortisol is secreted, it becomes a signal to the brain, reducing any further production at the end of the circadian cycle, or at the end of the physiological stressor it was made to help us manage.

As a result, abnormally increased cortisol production can disrupt our natural feedback loops, resulting in less (or altered) adrenal function over time.

Liver and the HPA Axis

We often think of the liver as the “detoxification organ”, and it definitely is.

That said, most people don’t realize that of one of the liver’sbiggest roles is controlling the rate of energy distribution throughout the body.

When the brain sends stress stimuli down to the adrenal glands, cortisol is produced. Cortisol causes the liver to release glucose. It does this in order to provide energy for the body’s increased needs during stress or in cases of hypoglycemia.

Blocked Bile Flow affects The HPA Axis

Interestingly, it has also been found that blockages in bile flow—often common in women—are associated with dysfunction of the HPA axis. [1]

Related post:Thyroid Hormone Testing and Women’s Cycles

Nausea from Sluggish Liver

What is Bile?

The liver synthesizes bile acids and which are transported to the intestine through the biliary system (i.e. the gallbladder).

Bile contains bile acids, phospholipids, and cholesterol. It also contains aqueous components such as electrolytes , bilirubin, amino acids, enzymes, proteins and peptides like glutathione mixed in specific ratios

The biliary system is also an excretory route for toxic metabolites and other molecules that would otherwise become harmful if accumulated in the body (bilirubin, cholesterol).

The Genetics of Bile

Certain people seem to have transporter protein mutations, which cause them to have difficulty metabolizing and regulating their bile acids[2].

Manygenes regulating bile production or metabolism are affected by hormones, or bychangesin hormones.This may be why some people are far more prone to gallbladder attacks, to biliary issues in and around pregnancy, and to gallbladder thickening or sludge.

What Exactly is a “Sluggish Liver or Gallbladder”?

Also known as cholestasis, this is characterized by reduced bile flow into the intestine from the gallbladder and liver.

Toxic bile componentsaccumulate in the liver, and poor bile excretion and/or composition causes manyintestinal effects. These include fat malabsorption, diarrhea, malabsorption of fat-soluble vitamins, and disrupted intestinal signalling, which is typically performed by bile acids.

Bile Acids and Cholestasis

The Liver, Cholesterol and Cortisol

As we discussed in the pregnenolone steal article, cholesterol is needed for the first step in synthesizing hormones.

First, the liver controls the level of cholesterol in the blood. This mean that ultimately, your liver determines the availability of the cholesterol backbone for your hormones.

Studies have found that low HDL (good cholesterol) levels are common in patients with liver conditions[3] It has even been proposed that HDL could be used as an indicator of liver function.

Interestingly, there is evidence that HDL is actually the preferred type of cholesterol that the adrenals use for cortisol production[4]. In ill patients, low HDL is associated with impaired production of cortisol when stimulated by ACTH (meaning the brain is less able to trigger cortisol on demand, when HDL cholesterol is low[5).

Liver Bile Acids and the Brain

Bile acids actually directly affect the hypothalamus in the brain, and its communication with the adrenals: the HPA Axis.

In a healthy liver, bile acids are secreted into the gallbladder and excreted through the intestines.

Most of the bile acids are then recycled back from the intestine to the liver. It’s a cycle that keeps things moving along, excreting toxins on a regular basis and taking back in essential compounds.

In a “sluggish liver or gallbladder” , however, bile acids remain in the liver for too long.

These bile acids can then escape into the blood and pass through the blood-brain barrier. They do this by disrupting endothelial tight junctions in the brain, allowing them to enter into neurons[7].

Bile acids have been found to activate cortisol receptors in the brain and suppress the natural production of cortisol in response to both stress and circadian rhythm[8].

The subsequent lack of cortisol in the liver then further alters bile acid homeostasis. This creates more issues with bile acids in the systemic circulation, and thus the cycle continues.

How to Determine if Cholestasis, or Blocked Bile Flow May Be an Issue:

Risk Factors for Cholestasis

  • Polycystic Ovary Syndrome
  • Pregnancy
  • Birth Control Pills
  • Post-Partum
  • Viral hepatitis
  • Antibiotics including amoxicillin and clavulinate

Symptoms and Signs:

  • Difficulty digesting fats
  • Nausea or heaviness after eating
  • Abdominal pain, particularly after eating fatty foods
  • Fatty liver (NAFLD) commonly found in prediabetes and insulin resistance
  • History of gallbladder attacks or gallstones
  • Itchy skin
  • fatigue

In more severe cases:

  • light-colored stools
  • dark-colored urine
  • yellowish tint to skin or the whites of the eyes
  • Intense itching of the palms and soles in pregnancy

Testing (Blood)

  • Bilirubin
  • ALT
  • GGT
  • Lipid (Cholesterol) panel
  • Hs-crp
  • Ultrasound (often negative) – more involved imaging may be required if obstruction is suspected.

At-Home Maintenance and Prevention:

  1. High-fibre diet rich in plants and vegetables.
  2. Non-GMO lecithin. Lecithin can help to emulsify bile salts and is now available from sunflower which is often preferred over soy.
  3. Drinking lemon water each morning can help to move the biliary system
  4. Bitters prior to meals: consuming bitter flavours such as dandelion can help promote digestion and biliary function.
  5. Castor oil packs: regular use of these can help promote optimal biliary flow.


If cholestasis is an issue along with other hormonal conditions—such as thyroid, PCOS, serious fatigue or prediabetes—see a licensed licensed naturopathic doctor or physician with an interest in liver function.

There are options that can help promote optimal bile flow, particularly during periods of hormonal change, such as postpartum or in perimenopause.

Article References:

  1. Swain MG, Patchev V, Vergalla J, Chrousos G, Jones EASuppression of hypothalamic-pituitary-adrenal axis responsiveness to stress in a rat model of acute cholestasisJ Clin Invest1993;91:1903-8.
  2. Manka, P., Olliges, V., Bechmann, L. P., Schlattjan, M., Jochum, C., Treckmann, J. W., … Canbay, A.Low Levels of Blood Lipids Are Associated with Etiology and Lethal Outcome in Acute Liver FailurePLoS ONE2014;9(7):e102351.
  3. Yaguchi H, Tsutsumi K, Shimono K, Omura M, Sasano H, Nishikawa T.Involvement of high density lipoprotein as substrate cholesterol for steroidogenesis by bovine adrenal fasciculo-reticularis cellsLife Sci1998;62:1387-95.10.1016/S0024-3205(98)00077-0
  4. Marik, P. E.The hepatoadrenal syndrome: a common yet unrecognized clinical conditionCriticalCare Medicine33;6:1254-1259.
  5. Swain MGFatigue in liver disease: pathophysiology and clinical managementCan J Gastroenterol2006;20:181-8.10.1155/2006/624832
  6. Quinn M, McMillin M, Galindo C, Frampton G, Pae HY, DeMorrow SBile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanismsDig Liver Dis2014;46:527-34.
  7. McMillin M, Frampton G, Quinn M, Divan A, Grant S, Patel N, et al.Suppression of the HPA axis during cholestasis can be attributed to hypothalamic bile acid signalingMol Endocrinol2015;29:1720-30.10.1210/me.2015-1087

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