The Dangers Of Gadolinium and GBCAs

Mybiohack.com

I have visited ERs and hospitals during my adventure to regain my health and have had my fair share of scans.

If you’ve ever had an MRI with contrast before, then there’s a likelihood that you have some levels of the lanthanide element gadolinium stored in your body and/or brain. R

In this post, we will discuss the epigenetic effects of gadolinium and some experimental ways to remove it from the body.

Contents:

1. Basics Of Gadolinium

2. Downsides Of Gadolinium

3. Gadolinium Levels And Testing

4. Ways To Remove And Protect Against Gadolinium

5. Gadolinium-Based Contrast Agent Alternatives

6. What Makes Gadolinium Exposure Worse?

7. Mechanism Of Action

8. More Research

Gadolinium (Gd) is a lanthanide chemical element, and highly toxic, so it must be bound to a chelated medium (which we call gadolinium-based contrast agents or GBCA), to reduce its harmful effects. R

GBCAs allowed up to see the body light up during scans and has been a huge advance in medical scans.

Unfortunately, no revolutionary technology goes without it’s downsides.

Gd in GBCAs was originally believed to be excreted by the body, but unfortunately we have discovered that Gd may accumulate in tissue, since GBCAs stability may deposit free Gd (Gd3+) into tissue. R

Lanthanides toxicology have been well known and Gd3+ is no exception.

1. Accumulates In The Body And Brain

Repeated exposure to Gd has shown to accumulate in the body and brain and increase the risk of gd-related toxicity by increasing inflammation in the tissue it is in. R

This has been shown to independent of kidney function or impairment. R

Gd has been found to accumulate in the:

• Bone – Bone tissue samples from those who underwent hip surgery found out Gd concentrations in bone did not change after 8 years after original exposure. R R

• Brain – Especially in the cerebellum, dentate nucleus and globus pallidus R R R R R

• Eye R

• Heart R

• Kidneys R

• Liver R

• Lungs R

• Pancreas R

• Skeletal Muscle R

• Skin R

• Vessel Wall R

2. Causes Excitotoxicity And Brain Damage

Gd mimics calcium (Ca2+) in the body and may block voltage-gated calcium channels, therefore inhibiting Ca2+ -dependent processes such as:

• Blood coagulation R

• Contraction of smooth R

• Hormone regulation R

• Skeletal and cardiac muscle R

• Transmission of nerve impulses R

Gd may also lower brain-derived neurotrophic factor (BDNF) expression. R

Gd can easily (slowly) pass through and/or disrupt the blood-brain barrier (BBB). R R R

Use of GBCAs may get into the brain easier with a disrupted BBB (such as after a Traumatic Brain Injury). R R

Gd in the brain may worsen verbal fluency. R

3. Destroys Cells And Mitochondria

Gd stresses the endoplasmic reticulum (ER) of cells and may cause proteopathy. R

It also may directly induce cell death (necrosis and apoptosis). R

Gd may cause mitochondria to die (too much oxidative stress). R R R

4. Neurotoxic To The Nervous System

Gd may be neurotoxic to the nervous system. R

For example, in a case study, Gd has shown to cause encephalopathy. R

In animal models, Gd has shown to cause myoclonus, ataxia, tremor, and corpus callosum damage and hemorrhage. R

Long-term oral administration of lanthanides has shown to affect learning and memory, swimming and walking abilities, and touch response behavior in rats. R

5. Activates The Immune System

Although rare, GBCAs can cause acute allergic reactions via non-IgE-mediated mast cell degranulation and complement activation. R

GBCA exposure activates toll-like receptor (TLR) 4 and TLR7-mediated gene expression, resulting in increased production of many cytokines (such as IL-6), chemokines, and growth factors (ie TGF-b1). R R

Gadolinium is also a potent inhibitor of the mononuclear phagocyte system (MPS) and GdCl3 is widely used to kill Kupffer cells in animal models. R

6. Impairs Kidney Function

Gd may cause renal failure or toxicity. R R

For example, a 56-year-old woman with normal kidney function had 2 consecutive vascular imaging procedures with GBCA and a few days later, the patient developed acute renal failure and acute tubular necrosis. R

Nephrogenic systemic fibrosis (NSF) is a major complication from Gd exposure and may possibly be worse in those with lower Klotho expression. R R

7. Inflames The Pancreas

Gd has shown to cause acute pancreatitis. R

For example, Gd-induced recurrent acute pancreatitis was reported in a 58-year-old woman administered gadobenate dimeglumine for MRI. R

8. May Be Toxic To The Liver

In humans, Gd has shown to induce hepatotoxicity (vacuolar degeneration, disorganized hepatic cords). R

It can also increase TG, LDL, and VLDL levels while reducing HDL levels. R

9. Alters Blood Homeostasis

Gd may be hematoxic, as it has shown to reduce WBC count in animals. R

Gadolinium also blocks the ability for blood cells to hydrolyze ATP. R

It make the heart more susceptible to phenylephrine (via stimulation of angiotensin II AT1 receptors). R

It also reduces nitric oxide (NO) bioavailability. R

10. Inflames The Skin

In animal models exposed to Gd, their skin had more scarring and swelling. R

Gd3+ has a proliferative effect on fibroblasts in vitro  and may promote their migration. R

11. Alters Bone Turnover

Gd exposure may be correlated with osteoperosis (as Gd can substitute for calcium in the bone hydroxyapatite structure). R

Total Gd3+ concentration has been shown to be significantly lower in patients with osteoporotic fractures exposed to GBCAs than in osteoarthritic patients. R

12. May Play A Role In Cancer

Insoluble deposits containing Gd3+ have been found in brain tumors following contrast-enhanced MRI. R

13. Induces Reproductive And Transgenerational Problems

If Gd is anything like it’s relative lanthanide, samarium, then Gd may cause reproductive toxicity in men. R

Pregnancy can lead to mobilization of Gd from bone through the placenta into the fetus. R R R R R

This may increase the risk of a broad set of rheumatological, inflammatory or infiltrative skin conditions, and for stillbirth or neonatal death. R R

14. Alters Thyroid Function

Gd can alter thyroid hormones by binding to thyroid hormone receptors (THR) in the brain. R

THs (especially T3 and T4) play important roles in brain development, including the development of the cerebellum. R R

Gd can directly induce cell death to these THR neurons. R

Having no Gd levels is good and repeated exposure can increase retention in the body.

Testing the bone may be the best way to get accurate levels (without looking at brain tissue). R

Testing in the hair or blood can also performed (get hair test done here).

Remove:

• Activated Carbon (from guava or avocado) R

• Deferasirox (iron chelator, not strong) R

• Deferiprone (iron chelator, not strong) – decreased the release of catalytic iron by cells treated with Gd R

• Deferoxamine (iron chelator) – doubled urinary excretion of gadolinium R

• Diethylenetriaminepentaacetic acid (DTPA) – stronger affinity to Gd than EDTA R

• EDTA – weak affinity to Gd R

• 1,2-HOPO SAMMS – has high affinity, rapid removal rate, and large sorption capacity for both free and chelated Gd R

Protect:

• Corticosteroids – may help prevent mast cell degranulation during GBCA administration R

• Daclizumab – may reduce lesion damage from Gd on T1 and T2 in MS patients R

• Imatinib – decreased gd-induced dermal hypercellularity R

• MAP-kinase antagonists R

• Milk Thistle – prevents contrast-induced renal dysfunction R

• Mitoxantrone (Novantrone) – may reduce lesion damage from Gd on T1 and T2 in MS patients R

• N-acetylcysteine (NAC) – blocks neurotoxic effects of Gd on ER stress/proteopathy as well as metabolic injury from Gd R R

• NSC23766 (Rac inhibitor) – reduced migration of skin cells R

• PI3K antagonists R

• Resveratrol – prevents contrast induce dysfunction (via activation of SIRT1-PGC-1α-FoxO1) R

• Tempol – reduces oxidation by Gd in skin R

• T3 – may protect against low levels of Gd R

Extremely small-sized iron oxide NPs (ESIONs) exhibit fewer adverse effects than the MnO NPs and the clinically used GDI GBCAs. R

High levels of phosphate, erythropoietin (EPO) and/or iron may make Gd exposure worse. R

Low renal function can also make Gd exposure a higher risk. R

Zinc may also make GBCA’s less stable (in vitro). R R

Glycosaminoglycans (N-acetylgalactosamine + galactose), possibly. R

Simple:

• Increases ACE R

• Increases αSMA R

• Increases ATF4 R

• Increases ATF6 R

• Increases Beta-galactosidase R

• Increases C/EBP R

• Increases Caspase-3 R

• Increases CaSR R

• Increases CXCL11 R

• Increases Cyt-c R R

• Increases Fibronectin R

• Increases Glycine R

• Increases GPC R

• Increases Granulocytes R

• Increases GSSG R

• Increases hPAP R

• Increases Hyaluronan R

• Increases IFN-alpha R

• Increases IFNγ R

• Increases IL-4 R

• Increases IL-6 R R

• Increases IL-13 R

• Increases KIM-1 R

• Increases Lactate R R

• Increases LDL R

• Increases Lymphocytes R

• Increases MCP-1 R

• Increases MCP-3 R

• Increases MIP1β R

• Increases MIP-2 R

• Increases MMP-1 R

• Increases NGAL R

• Increases Osteopontin R

• Increases PC R

• Increases PDGF R

• Increases ROS R R

• Increases SCF R

• Increases TGFβ R R

• Increases TIMP-1 R

• Increases TLR-4 R

• Increases TLR-7 R

• Increases TMAO R

• Increases TNF-a R R

• Increases VEGF R

• Increases VLDL R

• Increases XBP1 R

• Increases XCL10 R

• Reduces Acetate R

• Reduces Acetoacetate R

• Reduces ADP R

• Reduces Alanine R

• Reduces alpha-Glucose R

• Reduces Allantoin R

• Reduces ANG-II-AT1 R

• Reduces ATP R

• Reduces Betaine R

• Reduces Ca2+-Mg2+-ATPase R

• Reduces CCN2 R

• Reduces CCN3 R

• Reduces Choline R

• Reduces Citrate R

• Reduces EH R

• Reduces Glutamine R

• Reduces GST R

• Reduces HDL R

• Reduces Glutamate R

• Reduces Histidine R

• Reduces Isoleucine R

• Reduces Leucine R

• Reduces Myo-inositol R

• Reduces NAG R

• Reduces NO R

• Reduces Succinate R

• Reduces TMA R

• Reduces Threonine R

• Reduces Tyrosine R

• Reduces Valine R

• Reduces WBC R

Advanced:

• Gd agents (GBACs) consist of a central paramagnetic Gd3+ chelated to a ligand to prevent direct toxicity by free Gd3+. R

• Low-stability GBACs may gradually dissociate, leading to the formation of insoluble Gd3+ salts and/or soluble Gd3+ (bound to proteins, peptides or glycosaminoglycans [GAG]). R

• Free Gd3+ is a toxic lanthanide heavy metal with a size similar to that of Ca2+. R

• This similarity can lead to competitive inhibition of biological processes requiring Ca2+ and cause toxicity. R

• Lanthanide ions such as Gd3+ can bind to Ca2+ binding enzymes and affect voltagegated calcium channels, and therefore, lead to adverse biological effects. R

• Lanthanides are more soluble in serum than in water. R

• Gadolinium also inhibits the activity of Ca2+-Mg2+-ATPase, glutathione S-transferases (GST), epoxide hydrolase (EH), and certain dehydrogenases and kinases. R

• Gd3+ can induce allosteric activation of the G-protein-coupled calcium-sensing receptor (CaSR). R

• The maximum number of unpaired electrons is 7, in Gd3+, with a magnetic moment of 7.94 B.M., but the largest magnetic moments, at 10.4–10.7 B.M., are exhibited by Dy3+ and Ho3+. R

• However, in Gd3+ all the electrons have parallel spin and this property is important for the use of gadolinium complexes as contrast reagent in MRI scans. R

• Dechelation leading to the release of free Gd3+ may lead to the release of chemokines and subsequent attraction of CD34 + fibrocytes followed by the development of fibrosis. R

• EPO can increase the expression of the profibrotic chemokine monocyte-chemotactic protein-1 (MCP-1). R

• In the thyroid, disruption of intracellular Ca2+ homeostasis by blocking calcium channels with Gd-DTPA-BMA may alter CaMKIV activity, leading to alteration of TR-mediated transcription. R

• Gd may cause T1 shortening in the cerebral cortex. R

• Gd binds highly to phosphate. R

• The current FDA and EMA-approved GBCAs are gadobenate (MultiHance), gadobutrol (Gadavist), gadodiamide (Omniscan), gadopentetate (Magnevist), gadoterate (Dotarem), gadoteridol (ProHance), gadoversetamide (OptiMARK), gadoxetate (Eovist), and gadofosveset (Ablavar, US only). R

• Gd3+ concentration was significantly higher (180-fold) in rats skin that received gadodiamide than in those treated with gadoteric acid. R

• Gd shows no evidence to by ototoxic (toxic to hearing). R

• Gd may have benefits at preventing colon polyps. R

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