Summary of special issue on gadolinium bioeffects and toxicity with a look to the future
Introduction
The family of gadolinium-related disorders in humans has at their core two essential factors: [1] the presence of gadolinium, and [2] the host response.
What seems correct, at this time, is that gadolinium disorders align in four general categories: [1] an acute response, acute allergic reactions, mediated by acute allergic elements, generally polypeptides, and some combination of antibodies, chemokines, cytokines, and other mediators of acute allergic responses; [2] a subacute/chronic response, cell-mediated reactions, Nephrogenic Systemic Fibrosis (NSF), with CD 34 + fibrocytes and other myeloid cells being major elements; [3] storage condition, gadolinium storage condition (GSC), in which the gadolinium lies primarily inert within the body, bound to a couple of molecules: either its formulated ligand, or phosphates, carbonates, aminoglycans, and likely other compounds, emphasizing inert for the time-being, with the long term consequences as still unknown [4]; and gadolinium deposition disease (GDD) that appears to combine acute and subacute components of the host immune response.
Far from being unique to gadolinium, family of disorders is likely a very common pattern of disease for the majority of injurious processes that can affect humans, where deterministic type disease is common and predictable, since they represent known and predictable effects to many cells in the body in all individuals because of their intrinsic damaging nature; and what is termed stochastic effects, which are relatively uncommon and are considered random and unpredictable. The concept of random and unpredictable is likely incorrect, as in reality these effects are almost certainly grounded in presumably gene-based immune-system-mediated responses, which varies between individuals, for which we have not yet identified the immune mechanisms, nor have recognized the genetic basis for them. There likely is no such thing as stochastic effects, from the perspective of random, but these are effects that some individuals will experience because their responses differ from the bulk of the population, and the genetic basis for these responses have not yet been elucidated. For imagers, the classic comparison would be the effects from medical radiation in which deterministic effects are dose dependent and predictable, since all individuals will experience them, which includes skin reddening and epilation and cataract induction; and the stochastic effect of cancer-induction, that only some subjects will experience.
As with many other disease states that are based on accumulation, the storage state of accumulating the substance is vastly more common than the disease state; where what determines the disease state is the elicitation of a host response. A good comparison is non-alcoholic fatty liver disease (NAFLD), the storage state, and non-alcoholic steatohepatitis (NASH), the disease state [1]. Not unlike the proportional relationship between GSC and GDD, NAFLD is much more common than NASH.
Section snippets
Exploding myths
- 1.
“Free” gadolinium ions (Gd+3). The description of gadolinium as “free” is incorrect; gadolinium released from its manufactured ligand should be described as unchelated, dechelated or dissociated. Gadolinium is never free; it is always in some form of bond to some other molecule/chemical. Gadolinium released in vivo from its ligand is often rapidly bound to native host molecules, and exists in vivo in a number of various chemical entities [2], including: precipitated oxides, hydroxides,
Facing facts
- 1.
Gadolinium deposition disease (GDD) is a real entity. In this issue, our group presents a survey of patients who suffer with this condition (12). At the present time NSF has been well accepted for one decade. GSC has been published on for at least 12 years, but the recent spate of publications on brain deposition over the last two years has made this entity irrefutable. In this issue, articles by Maravilla et al. [14], Kanda et al. [15] and Radbruch [16] extensively review the experience with
Future directions
- 1.
Generalization of treatment for gadolinium toxicity. One of the exciting possibilities of refining the scientific investigation for the causes of, and treatments for gadolinium diseases, is that this will likely shed light on a greater array of other disorders. Gadolinium exposure, type of agent and dose are generally determinable, and the number of subjects who have received gadolinium number in the tens of millions, so the potential data base is large, and hence statistically meaningful data
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Cited by (10)
Gadolinium Deposition Disease: A New Risk Management Threat
2020, Journal of the American College of RadiologyCitation Excerpt :Suggesting causation from correlation, the authors postulated this symptomatology to represent GDD and went on to propose diagnostic criteria for this newly proposed disease. To meet the diagnostic criterion for GDD, a patient must exhibit at least three of the following five broad symptom clusters within a period of hours to 2 months post-GBCA administration: (1) peripheral neuropathic pain in either a “glove and stocking” or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain [5,13]. Furthermore, it was proposed that GDD may clinically manifest after the initial infusion of GBCA or after multiple administrations in a dose-dependent manner [14,15].
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