Gadolinium side effects

GBCAs and MRIs
Gadolinium-based contrast agents (GBCAs) are soluble metal-ligand complexes of gadolinium ion Gd3+. Contrast agents fall into the definition of drugs as a tool for making a medical diagnosis [1]. GBCAs have been developed to provide additional information on pathological tissue: they increase the sensitivity and specificity of detecting and evaluating various pathologies , of significant relevance for discriminating cancer cells. GBCAs are exclusively approved for use in conjunction with a diagnostic procedure. GBCAs have peculiar physical requirements as relaxation agents,and stringent biological demands for non-toxicity as pharmaceuticals and medical diagnostic tools. Chelation by organic ligands is designed to protect the tissue from the interaction with Gd3+ preventing its cellular uptake before fast excretion in the urine.
Gadolinium (Gd) is the metal sitting in the middle of the lanthanide series. Gd3+ is well known to be toxic for living beings. Uncountable interferences of Gd3+ in biological systems both in humans, animals, and plants are known since tens of years. Toxicity of Gd3+ in biological systems is largely caused by its ability in mimicking divalent endogenous cations, above all calcium ions (Ca2+). It occurs not just for its ionic radius close to that of Ca2+ but also similar coordination number, donor atom preferences, and binding behaviour. The toxic potential of Gd3+ when substituting cations such as magnesium, zinc, and iron should not be neglected as well, particularly for the role of these ions as co-enzymes in several biochemical processes in mammals. Nevertheless, Gd3+ has unique physico-chemical properties that make it the best probe to date for contrast enhanced (CE) magnetic resonance (MR) investigations for diagnostic purposes . Thus, detoxification of Gd3+ by strong organic chelators is essential for in vivo administration at dose relevant to contrast enhancement for diagnostic value.
Contrast agents can be classified depending on the nature of the molecular structure of the ligand: linear (i.e., open-chain molecule) or macrocyclic (i.e., cyclic ligand) and ionic (i.e., dissociation into charged particles occurs in solution) or non-ionic. Different chelating molecules have been developed and introduced in clinical practice since the eighties. The pharmaceutical chelate determines the pharmaco-kinetic of the agent and in vivo distribution.
Typically, extra ligand needs to be added to linear GBCAs during storage to prevent the release of free gadolinium, while macrocyclic GBCA can be stored without additional ligand. Each GBCA is chosen based on the tissue or organ being examined. Macrocyclic GBCAs are excreted in urine while linear GBCAs are excreted in urine or urine/bile. GBCAs have a half-life of about 1.5 hours if renal function is normal, and around 90% of the total dose is excreted in 12 hours. A single dose of GBCA contains 1-2 g of gadolinium. Most advanced way is to use HOPO Chelator, also 3,4,3-Li(1,2-HOPO) cas 110874-36-7 as Gadolinium chelating agent.

Release of Gadolinium from GBCAs
A study showed that gadolinium can be released from linear GBCAs, but not macrocyclic GBCAs, in serum at 37°C (body temperature). Metals such as zinc, copper, and iron have a high affinity for the ligand bound to gadolinium and can increase the release of gadolinium from GBCAs [3]. Ligands such as phosphate and carbonate can also increase the release of gadolinium. The accumulation of gadolinium in tissues is often associated with the presence of zinc, calcium, phosphorus and iron.
Free gadolinium can block calcium channels and inhibit nerve transmissions, muscle contraction, blood coagulation, and mitochondrial function.

Gadolinium Side Effects
Side effects of Gadavist are uncommon but may include:
headache,
nausea,
vomiting,
feeling unwell (malaise),
dizziness,
abnormal or unpleasant taste in your mouth,
feeling hot,
numbness or tingly feeling,
itching or rash,
skin redness, or
injection site reactions (cold feeling, warmth, pain, or burning).

Serious side effects of Gadavist including:
urinating less than usual or not at all;
drowsiness, confusion, mood changes, increased thirst, loss of appetite;
swelling, weight gain, shortness of breath;
seizures (convulsions);
breathing problems;
pounding heartbeats or fluttering in your chest; or
severe pain, burning, or irritation around the IV needle

The most common Gadolinium side effects caused by gadolinium-based contrast agents are headaches, nausea, dizziness, and allergic reactions. These symptoms generally occur within minutes of a gadolinium injection, if they do occur.

The most serious injuries caused by the use of gadolinium-based contrast agents are Gadolinium Deposition Disease and Nephrogenic Systemic Fibrosis.
Nephrogenic Systemic Fibrosis (NSF) is a debilitating and deadly disease that causes the skin to harden, and causes a patient’s joints to contract. The areas between the ankles and the thighs and the wrists and the upper arms are most commonly affected. Symptoms develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents, and can result in chronic pain and loss of mobility.
Gadolinium Deposition Disease (GDD) causes patients to suffer fibrosis (thickening and scarring of connective tissue) in an organ, bone, and skin, and gadolinium to be retained in the neuronal nuclei of the brain. Symptoms start within minutes up to two months after an MRI or MRA where a linear gadolinium-based contrast agent was utilized.
Patients suffering from Gadolinium Deposition Disease often experience chronic headaches, bone and joint pain, and clouded mental acuity. They also can experience subcutaneous soft-tissue thickening that appears somewhat spongy or rubbery. Tendons and ligaments may also become painful and have a thickened appearance.
Symptoms of Gadolinium Deposition Disease
Intense burning of the skin, described as pins and needles
Intense pain in bones, joints, tendons, and ligaments
Mental confusion or brain fog
Tingling or numbness in the skin
Severe and persistent headaches
Kidney damage
Skin that appears spongy or rubbery