Herxheimer Reactions - What Exactly Are They ?

*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.

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“Herx” Reactions

Perhaps one of the most common terms aside from a ‘crash’ in the world of chronic illness. In this article i will explore the technical aspects of what happens during a specific type of reaction that occur during detoxification protocols and what to do to help avoid them.

“The liver vigilently protects a chaperone called MPRP2 (ABCC2), that escorts toxins from Phase 2 conjugation into the bile. When MRP2 is overloaded, a series of events happens resulting in a “Herx” reaction.”

The Basic Process Of Detox / Herxing

• During detoxification stimulation toxins are pushed out of tissues into the blood, which makes its way to the liver.

• Phase 1 (CYP450 genes) make the toxin water soluble, and in this process can create toxic / oxidative radicals.

• The water soluable toxin then makes its way into Phase 2 detoxification - conjugation - using one or more of the following Phase 2 pathways - Methylation, Sulfation, Glucuronidation, Amino Acid Conjugation, Glutathione Conjugation, Acetylation. Pon1 and NQO1 can also play a role, primarily for pesticides/herbicides, and volatile organic compounds (e.g. benzene) respectively.

• Once the toxin has been conjugation it is escorted into the bile by a chaperone called MRP2 (ABBC2). Be leery of genetic mutations on this gene. If MRP2 gets overloaded by too high of an out flow from Phase 2 conjugation, the liver seconds it to protect it, to make more of MRP2 is a very costly process. When MRP2 gets seconded, toxin intermediates (billirubin, xenobioitcs, etc) can accumulate.

• Once MRP2 gets seconded and cordoned off, the liver shuts the valve that exits to the gallbladder, called the Bile Salt Export Pump (BSEP / ABCB11). Once this valve shuts, the bile and toxins are shunted out another door of the liver back into the blood.

• Once the bile and toxins hit the blood - the cascade of symptoms can start - neurological (toxins hit brain), lower back ache (toxins hit kidney), and skin rashes (Bile acids come out through the skin).

Things to Watch Out For…..

Aside from going slow, what can be done ? For starters inspecting your genetics, especially at MRP2 and BSEP will be helpful. MRP2 can be supported by a number of compounds to help protect it, start with Milk Thistle.

How To Protect mrp2

1. Anti-oxidants like Milk Thistle, Glutathione, NAC, etc

2. Stimulate NrF2 which activates MRP2 - Schisandra, astaxanthin, curcumin, milk thistle, etc

3. Stimulate PXR which activates MRP2 - Schisandra, Resveratrol, Luteolin, Quercetin, Milk Thistle

4. Slow down phase 1 and phase 2 detoxification - milk thistle can help slow down the most commonly used phase 2 pathway - glucuronidation.

Increase bile flow

1. TUDCA

2. Artichoke

3. Dandelion

4. Bitter herbs - gentian, andrographis

lipid membrane repair for canalicular membranes

1. Phosphatidylcholine

2. NT Factor Lipids

3. Tocotrienols

lowering inflammatory cytokines (tnfa, etc) that inhibit mrp2

1. Boswellia

2. Omega 3’s

3. Curcumin, Resveratrol, etc

how to support bile salt export pump (bsep/abcb11)

1. Support transcriptional activation of BSEP via FXR, PXR, and LXR.

   • FXR - Reishi, soluable fiber, tudca

   • PXR - Resveratrol, Schisandra

2. Activate NrF2 - Astaxanthin, Curcumin, Milk Thistle

3. Support Bile Flow

4. ATP Support - Coq10, PQQ, Acetyl Carnitine, B1, B2, B3

5. Control Inflammatory Cytokines (TNFA, etc) that downregulate BSEP

6. Avoid estrogen dominance - DIM can help here

7. Support parasympathetic branch of nervous system

In general, assessing genetic weaknesses in your system can provide clues where the issue is - which can inform potential solutions. MRP2 relies heavily on NrF2 and PXR activation and to a lesser extent PPAR alpha, while BSEP relies heavily on FXR activation. Knowing if these transcriptional factors are genetically compromised can inform potential strategies as well.

If one has been nutrient deficient for quite a while, then its very plausible that there is a significant stock pile of toxins that has accumulated in the tissues. As such, when these basic nutrients are replenished this can cuase toxins to be mobilized out of tissues and into the liver. Basic cofactors for phase 1 cyp450 genes are : NAD/B3, FAD/B2, Heme, and oxygen. Some of the basic cofactors for phase 2 conjugation include: NAD/B3, FAD/B2, Magnesium, Glutathione, Iron Sulfur Clusters, Heme, Glycine, Carnitine, B9/Folate, B6, and Sulfate. Assessing genetics across CYP450 genes can be informative too - so you understand which herbs and toxins may be more difficult to process. The same can be done for phase 2 conjugation pathways - to inform what herbs may be more supportive to the compromised pathways, and which herbs to potentially avoid.

I hope this article sheds some light on the mechanics and technical details of Herx reactions - and provides some clues and the motivation for diving deeper to understand where you may have some issues that can be addressed to limit Herx like reactions in the future.

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