ORIGINAL ARTICLE nLeadership
Gadolinium Deposition Disease: A New
Risk Management Threat
H. Benjamin Harvey, MD, JD
, Vrushab Gowda, BS
, Glen Cheng, MD, JD
Gadolinium-based contrast agents (GBCAs) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30%
of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety
proﬁle and attendant medicolegal liability associated with GBCAs changed in 2016 with the description of gadolinium deposition
disease (GDD). Despite being unproven scientiﬁcally, a groundswell of GDD-related litigation and personal injury advertising targeting
potential GDD patients has occurred. In this article, we describe what GDD is, why GDD has created medicolegal risk, and how this
risk might be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the
period of purported GDD development. As such, based on the currently available data, the authors recommend the preferential use of
gadoteridol as the default GBCA for MRI imaging.
Key Words: Gadolinium, gadolinium deposition disease, lawsuit, liability, risk management
J Am Coll Radiol 2019;-:---. Copyright ª2019 American College of Radiology. This is an open access article under the CC BY-NC-ND
Contrast agents further enhance the diagnostic power of
MRIs and have found particular application in angiography
and oncologic imaging. Structurally, they consist of a linear
or macrocyclic carrier ligand chelated to a paramagnetic
metal ion, which serves to reduce T1 relaxation time and
facilitate visualization of perfused structures. These com-
pounds most commonly contain gadolinium(III) as the
active material, although iron oxide–and manganese-based
agents are also employed . Gadolinium-based contrast
agents (GBCAs) have enjoyed wide use since their intro-
duction some 30 years ago, with some 450 million doses
administered worldwide to date . They are generally well
tolerated and associated with lower rates of adverse events
than iodinated contrast agents .
Despite their ubiquity, GBCAs are not without their
risks. Alongside hypersensitivity reactions, acute nephro-
toxicity, and transient encephalopathy, nephrogenic sys-
temic ﬁbrosis (NSF) has been identiﬁed as a potentially
debilitating process associated with GBCA exposure . A
newly proposed pathology joined this complement in
2016: gadolinium deposition disease (GDD) .
Although shrouded in controversy as to its
pathophysiologic mechanism, modiﬁable risk factors, and
even existence as a disease in its own right, GDD has
grown salient in the public eye—a fact not lost on
personal injury attorneys.
The increasing risk exposure created by the advent of
GDD bears far-reaching implications for health systems,
referring physicians, and radiologists. This article surveys the
landscape facing these stakeholders by answering three
questions: What is GDD? Why does GDD create medico-
legal risk? How can this risk be mitigated?
FROM DEPOSITION TO DISEASE:
CORRELATION OR CAUSATION?
It has long been known that GBCA administration leaves
behind residual gadolinium. Studies have demonstrated its
uptake in various tissues, including bone, kidney, and the
brain, even in patients with an intact blood-brain barrier,
Harvard Medical School, Boston, Massachusetts.
Massachusetts General Hospital Department of Radiology, Boston,
Massachusetts General Hospital Institute for Technology Assessment,
Harvard Law School, Cambridge, Massachusetts.
Harvard T.H. Chan School of Public Health, Environmental and Occu-
pational Medicine and Epidemiology.
Corresponding author and reprints: H. Benjamin Harvey, MD, JD,
Department of Radiology, Massachusetts General Hospital, Institute for
Technology Assessment, 175 Cambridge Street, Suite 200, Boston,
MA 02114; e-mail: email@example.com.
The authors state that they have no conﬂict of interest related to the ma-
terial discussed in this article.
Copyright ª2019 American College of Radiology. This is an open accessarticle under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1546-1440/19/$36.00 nhttps://doi.org/10.1016/j.jacr.2019.11.009 1
preserved renal function, and normal hepatic clearance [6-
8]. Interestingly, gadolinium preferentially deposits within
the brain in the dentate nuclei and globi pallidi, perhaps
conveyed to these structures through the recently
discovered glymphatic system [9,10]. Although both linear
and macrocyclic GBCAs alike collect within the brain,
linear agents (eg, gadopentetate, gadobenate, gadodiamide,
gadoxetate) are particularly prone to deposition [11,12].
Researchers have only recently suggested a potential
pathological consequence to this deposition in patients
with normal renal function.
In 2016, Semelka et al ﬁrst described a constellation of
self-reported symptoms in patients with normal renal
function who had received GBCAs . 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
GDD is still only a proposed disease process with no
clear proof of its true existence. Nonetheless, theories con-
cerning the pathophysiological basis of this proposed disease
continue to be ﬂoated. Some have postulated that gadolin-
ium competitively inhibits calcium channels, thereby
interfering with proper neurologic function [16,17]. Others
suggest that GDD symptomatology may causally depend on
impaired heavy metal metabolism, itself a consequence of
heredity . Similar to other heavy metal toxicities,
chelation treatment has been proposed for GDD.
However, in the absence of a proven disease process, there
is no clear evidence to support chelation treatment at this
GDD, although still unproven, has nonetheless resulted
in an impressive regulatory and industry response. Shortly
following the initial description of GDD, the ACR and the
American Society of Neuroradiology issued a position
statement concerning the use of GBCAs, calling for pro-
viders to consider “multiple factors . . . when selecting a
GBCA, including diagnostic efﬁcacy, relaxivity, rate of
adverse reactions, dosing/concentration, and propensity to
deposit in more sensitive organs such as the brain”. The
US FDA convened the Medical Imaging Drugs Advisory
Committee in May and September 2017, which yielded a
692-page transcript of meeting minutes. This panel
concluded with “fair uniformity that there is no evidence of
a causal relationship between the symptoms and signs in
patients with normal renal function and the retention of
gadolinium”. Despite this statement, the FDA took the
remarkable step of requiring imaging centers to distribute
patient Medication Guides to better apprise patients of
GBCA-associated risks prior to administration . The
European Medicines Agency went one step further by
restricting the use of certain linear GBCAs, all the while
concluding that “there is currently no evidence that
gadolinium deposition in the brain has caused any harm
to patients”. The glaring discordance between these
regulatory actions and the regulatory-convened scientiﬁc
panel statements of “no causality”is confusing for medical
practitioners, patients, and likely for juries. Laypeople can
easily misconstrue an overabundance of caution as
SYSTEMS-LEVEL SIGNIFICANCE: THE
ELEPHANT IN THE COURTROOM
Unlike NSF, GDD is marked by a signiﬁcantly larger risk
footprint. The limited epidemiological understanding of this
proposed disease process does not permit a ﬁne resolution of
population-level data at present. However, a recent study
has described a high prevalence of ‘GDD-like’symptom-
atology among patients receiving a GBCA. For instance, a
recent article from Parillo et al suggests that 13% of patients
who received the macrocyclic GBCA gadoterate meglumine
experienced ‘GDD-like’symptoms within the ﬁrst 24 hours
after administration . While not demonstrating causation,
the numbers are nonetheless alarming. Approximately 39
million MRI scans are performed in the United States each
year and as many as 12 million of these patients require
GBCA administration. Thus, if GDD liability were to
materialize, a pool of potential plaintiffs growing by over 1
million per annum is sufﬁciently large for institutional
actors to take heed. As such, large health systems are
increasingly making enterprise-level formulary switches pri-
marily to mitigate this risk exposure.
In the wake of NSF, personal injury attorneys are no
stranger to GBCA-based lawsuits. A simple web search will
show that many personal injury attorneys are already active
in the GDD space. Based on case characteristics alone, it is
likely that GDD cases will only proliferate over time .
There is a vast pool of potential plaintiffs, bearing low
costs of capture and still lower barriers to entry. Because
GDD clinical diagnostic criteria are largely subjective,
their existence is difﬁcult to disprove . Nonspeciﬁc and
transient constitutional, neurologic, and dermatologic
2Journal of the American College of Radiology
Volume -nNumber -nMonth 2019
features post-GBCA administration that extend beyond the
formal GDD diagnostic criteria may represent confounding
sources of symptomatology leading to an overdiagnosis of
‘GDD’post hoc . And ﬁnally, the emergence of these
symptoms is dispersed over 2 months, which limits
Notwithstanding the absence of a proven pathologic
mechanism of GDD, many courts have had to wrestle with
the viability of these claims. In multiple cases against
manufacturers, courts have repeatedly dismissed GDD-
based claims, citing amongst other issues inadequate evi-
dence of general causation between GBCAs and GDD
symptomatology . This has led may other plaintiffs to
withdraw their claims voluntarily . However, several
cases continue to work their way through the court
systems. With a growing corpus of GDD-related medical
literature, the concern arises that the new literature on
GDD, even if ﬂawed methodologically, could in aggregate
sufﬁce to pass the Daubert standard for expert testimony
, . In turn, this would allow greater amounts
of expert testimony and technical evidence supporting
GDD-based claims into personal injury proceedings,
thereby increasing the viability of said claims.
The breadth of risk management exposure to physicians
and health systems remains uncertain. It is unclear if and
how far a GDD case against physicians or health systems
could proceed given that GBCA administration remains the
standard of care. Yet it remains plausible that GDD-based
claims against providers could have life if case theories assert
negligence in the choice of GBCA, i.e., choosing a GBCA
that results in greater brain gadolinium deposition than
necessary. ACR and ASNR opinions afﬁrming the general
safety of these agents are unlikely to be dispositive in such
litigation. For instance, a review of cerebral palsy suits shows
that the American College of Obstetrics and Gynecology
professional opinion has not historically been accorded
decisive weight .
RISK MANAGEMENT STRATEGIES: REDUCING
BRAIN RETENTION DURING THE EARLY
Multiple varieties of GBCAs exist, each with differing risk
proﬁles.Thus,bychoosingtheright GBCA, radiologists
and referrers likely can reduce their risk exposure.
Experience from NSF lawsuits shows that litigation has
often been mitigated through the use of class II agents and
judicious estimated glomerular ﬁltration rate precautions.
Although the ACR has yet to articulate speciﬁcpractice
recommendations, this article advocates adoption of a
similar approach to GBCA selection to mitigate the risk
To begin, macrocyclic GBCAs should be used over
linear agents whenever appropriate because it is well estab-
lished that the latter more avidly deposits within tissues such
as the brain and kidneys. Moreover, signiﬁcant differences
between GBCAs also exist within the macrocyclic class of
GBCAs. Among macrocyclics, gadoteridol offers signiﬁcant
advantages over its peers from a risk management perspec-
tive, with animal studies demonstrating signiﬁcantly lower
retention and more efﬁcient clearance in cerebral, cerebellar,
and renal tissue during the period of purported GDD
development [30,31]. These ﬁndings have been replicated in
recent well-conducted conﬁrmatory studies and afﬁrmed by
Hani Abujudeh, author of the textbook Quality and Safety
in Radiology and one of the ﬁrst radiologists to describe NSF
[12,32,33]. In a recent review article, Dr Abujudeh noted
that “an increasing number of health systems [are
switching] to gadoteridol given its markedly lower levels of
gadolinium retention in the brain and kidneys”. The
risk management beneﬁts of gadoteridol have also been
extolled by attorney and risk management expert Dr
Nicholas Argy .
From a practical standpoint, a data-driven strategy of
risk mitigation grounded in the well-conducted studies
described above is likely to be simultaneously palatable,
attractive, and straightforward to both patients and potential
juries. Thus, based on the current data, we endorse a
strategy for risk mitigation based on the use of gadoteridol as
the default GBCA for MRI imaging. Such an approach aims
to minimize gadolinium retention in the brain during the
GDD-sensitive time window of the ﬁrst 2 months post-
administration. However, this approach should not be
construed as a bright-line rule. Providers should not hesitate
to use other GBCAs, including linear agents, when clinically
advisable, such as with hepatic or tumor imaging. Given the
lack of clear evidence of GDD, it seems unnecessary and
even premature to implement an informed consent process
at this time. As an alternative, shared decision making tools
could prove both helpful to patients and reduce the risk of
possible GDD-related litigation down the road .
One perverse reality of this risk management issue is that
the radiologists and referring physicians who are exposed to
GDD-related liability are often not the individuals tasked
with making the GBCA decision. To compound this
problem, institutional GBCA decisions often factor in
ﬁnancial considerations (i.e., cost-to-charge ratio). However,
exposing patients to more gadolinium for a ﬁnancial gain is
unlikely to be well received by a jury if evidence for GDD
starts to mount. As such, physicians should communicate to
the pharmacy staff, clinical administrators, and risk man-
agers who make the enterprise-level formulary decisions the
importance of considering GDD-related liability when
selecting a GBCA. Moreover, whatever the GBCA choice,
Journal of the American College of Radiology 3
Leadership nHarvey, Gowda, Cheng nGadolinium Deposition Disease
health systems should be able to offer an evidence-based
defense of their GBCA selection that goes beyond a dollar
Although the science of GDD is uncertain at best, health
care providers would nonetheless be well advised to proac-
tively guard against GDD and its attendant liability. The
beneﬁts of a risk mitigation strategy could be substantial—
including averting costly and disruptive litigation. Based on
the current data and regulatory statements, this article ad-
vocates for a risk mitigation strategy focused on reducing
brain gadolinium retention during the period of purported
GDD development in the ﬁrst two months after GBCA
administration. As such, the authors recommend the use of
gadoteridol as the default GBCA for MRI imaging, with
other GBCAs, including linear agents, reserved for when
clinically advisable. Caution in GBCA choice now could pay
high dividends by avoiding costly GDD claims down the
-Increasing risk exposure created by the advent of
GDD bears far-reaching implications for health sys-
tems, referring physicians, and radiologists.
-GDD, although still unproven, has nonetheless
resulted in an impressive regulatory and industry
-Unlike NSF, GDD is marked by a signiﬁcantly larger
-The preferred risk mitigation strategy is focused on
appropriate usage of GBCAs and on reducing brain
gadolinium retention during the GDD-sensitive
period of the ﬁrst 2 months when GBCAs are needed.
-The authors, in agreement with other risk manage-
ment experts, recommend the use of gadoteridol as the
default GBCA for MRI imaging.
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