Imaging in Drug Side Effects

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Current Medical Imaging Reviews, 2015, 11, 23-37 23

Imaging in Drug Side Effects

Sandra Baleato-González1,*, Roberto García-Figueiras

1, María Ageitos Casais

1, Amadeo Arango

Díaz1, Iván Sanz-Falque

1 and Joan C. Vilanova

2

1Department of Radiology, Hospital Clinico Universitario, Choupana s/n 15706 Santiago De

Compostela, Spain; 2Department of Radiology, Clínica Girona and Hospital Santa Caterina,

Lorenzana 36, Girona, 17002 Spain

Abstract: Drug side effects are common in clinical practice and its diagnosis and radiologic manifes-

tations are not always evident or known. Adverse effects may cause medical complications and nega-

tively affect prognosis and outcome of patients. In this setting, an early diagnosis might have relevant

clinical and therapeutic implications. Different studies have shown that adverse drug reactions related

hospital admissions comprise up to 10% of the total number of hospitalizations and are an important

cause of morbidity and mortality in adults. Most adverse drugs reactions have no distinctive radiologi-

cal features. However, certain iatrogenic disorders have distinctive imaging characteristics that allow their recognition.

We illustrate the imaging findings of drugs side effects and review those complications that radiologists may diagnose.

Keywords: Drugs, Side effects, Medical Imaging.

INTRODUCTION

Adverse drugs reactions are an important cause of mor-

bidity and mortality in adults [1]. Different studies have

shown that drug toxicity related hospital admissions com-

prise up to 10% of the total number of hospitalizations and

may involve any body organ. Most drug-induced toxicities

have no distinctive radiological features on imaging. How-

ever, certain iatrogenic disorders have characteristic imaging

findings that allow their recognition. This paper will review

the radiological manifestations of the most notable complica-

tions induced by drugs “from head to toe” using different

imaging techniques.

1. NERVOUS SYSTEM

Nervous system (NS) toxicity is a significant source of

morbidity in the treatment of patients [2-5]. Neurotoxicity

may appear during treatment or being a late effect of therapy.

In this setting, treatment-related NS toxicities need to be

distinguished from complications related to the underlying

disease. Main pathologic entities associated to NS toxicity

include encephalopathy, vascular complications, meningitis,

mielopathy, neuropathies, and hypothalamo-hipophyseal

involvement.

1a. Intracraneal Drug-induced Anomalies

Encephalopathy. There are many different classes of

agents that can result in a drug-induced encephalopathy [2-

7]. Clinical presentation is variable. Acute encephalopathy

develops within a few hours to days after therapy administra-

tion and presents with altered behaviour, disorientation, con-

fusion, and agitation. Symptoms generally resolve spontane-

ously. Metronidazole is one of the therapeutic agents that

*Address correspondence to this author at the Department of Radiology,

Hospital Clinico Universitario, Choupana s/n 15706 Santiago De Compos-

tela, Spain; E-mail: [email protected]

have associated to the development of acute encephalopathy.

In these patients, MRI shows bilateral and symmetric in-

volvement of the dentate nuclei in the cerebellum [3, 6-7].

The lesions show increased signal intensity on T2-weighted

images, which are reversible after discontinuation of the

drug. Acute disseminated encephalomyelitis (ADEM) is an

immune mediated disease of the brain that usually occurs

following a viral infection or vaccination [8]. As it involves

autoimmune demyelization, ADEM is similar to multiple

sclerosis (Fig. 1).

Fig. (1). Acute disseminated encephalomyelitis (ADEM). A 72-

year-old-male patient with neurologic deficits following influenza

vaccination. ADEM was suspected. Axial T2- weighted (a) and

FLAIR (b) images showed large multifocal, hyperintense and bilat-

eral white matter lesions with enhancement after contrast admini-

stration on axial (c) and coronal (d) contrast-enhanced T1-weighted

images.

1875-6603/15 $58.00+.00 ©2015 Bentham Science Publishers

24 Current Medical Imaging Reviews, 2015, Vol. 11, No. 1 Baleato-González et al.

Subacute encephalopathy is rare and may develop days to

weeks after administration of a drug [6]. Typical MRI find-

ings show symmetrical areas of the white matter with in-

creased signal on DWI and decreased ADC. These MRI

findings have been interpreted as cytotoxic edema [9].

Chronic encephalopathy usually starts to develop with a

prolonged latency (months to years). It is most frequently

irreversible and sometimes even progressive. Recently, Pro-

gressive multifocal leukoencephalopathy has been linked to

methotrexate, rituximab, natalizumab (which was used to

treat multiple slecrosis), efalizumab (an anti-psoriasis drug),

and interferon [5-6]. Other potentially implicated agents are

fluorouracil, topotecan, cisplatin, cytarabine, carmustine, and

thiotepa [4-6]. MRI depicts symmetric periventricular white

matter abnormalities, which can be accompanied by ven-

tricular dilatation and cortical atrophy in severe cases. Cere-

bral atrophy has been mainly observed in valproic-acid en-

cephalopathy.

Cerebrovascular disease. Vascular pathology (including

arterial occlusion, venous thrombosis, and hemorrhage) has

been associated with the administration of different drugs [4-

5, 10-11]. Women taking hormone replacement therapy or

oral contraceptives or patients under androgens or antiangio-

genic treatment have an increased risk of ischemic stroke or

intracranial venous thrombosis. Patients on anticoagulation

therapy show an increased risk for intracraneal hemorrhage.

Beside this, antiangiogenic drugs and imatinib have also

been reported to increase the risk of bleeding. In oncologic

patients, the risk of hemorrhage with antiangiogenic therapy

does appear to vary somewhat with underlying tumor type

[4]. Many other antineoplastic agents, such as cisplatin,

bleomycin, etoposide, vinblastine, methotrexate, cytarabine,

tamoxifen, asparaginase, cyclophosphamide, have been re-

lated to cerebrovascular or diseases in literature.

Posterior reversible encephalopathy syndrome (PRES) is

a specific type of acute encephalopathy caused by vasogenic

edema that results from breakdown in cerebral vascular

autoregulation [7, 12-13]. PRES is characterized by head-

ache, confusion, visual disturbances, seizures, and transient

changes on neuroimaging in the parieto-occipital lobes.

PRES has been associated to the use of cytotoxic and immu-

nosuppressive drugs such as tacrolimus, cyclosporine, and

cisplatin. MRI findings include symmetrical posterior cor-

tico-subcortical lesions, which are hyperintense on FLAIR

and T2-weighted sequences and shows an increase of appar-

ent diffusion coefficient ADC values [5, 7, 12-13] (Fig. 2).

Meningitis. Drug-induced aseptic meningitis cannot be

distinguished from meningitis caused by other agents, and

diagnosis is, therefore, made by exclusion and based on

close association between drug administration and onset of

symptoms [14]. Aseptic meningitis is a typical complication

of nonsteroidal anti-inflammatory drugs, antibiotics, intrave-

nous immunoglobulins, and intrathecal therapy. When per-

formed, neuroimaging was normal in the majority of pa-

tients, however different imaging findings have been occa-

sionally reported, including diffuse meningeal contrast en-

hancement (probably reflecting a blood-brain barrier break-

down) and bilateral supratentorial white matter T2-signal

abnormalities without gadolinium enhancement and with

complete resolution along time [14].

Hypothalamo-hipophyseal System Involvement.

Ipilimumab is an immunotherapeutic agent with clinical ac-

tivity in the treatment of metastatic melanoma and renal cell

carcinoma. Immune-related adverse events such as hypo-

physitis have been reported [15]. MR imaging features of

hypophysitis are non-specific and include by diffuse en-

largement of the pituitary gland with loss of normal posterior

pituitary signal intensity.

1b. Extracraneal Involvement

Mielopathy. As it was mentioned, vaccines may induce

an acute encefalomielitis (ADEM) [8]. During the acute

phase patients have local enlargement of the cord and areas

of increased signal on long TR/TE MR sequences. Other

drugs such as the antibiotic clioquinol, nitrous oxide (an in-

haled anesthetic) or anti-TB medication exposure have been

also related to myelopathy.

Neuropathy. Drug-induced neuropathy is a frequent

complication [2-5]. Imaging findings are usually scarce.

Fig. (2). Posterior reversible encephalopathy syndrome (PRES). A 45-year-old-male treated with tacrolimus. A MRI examination was

performed for evaluating the presence of ataxia. MRI confirmed an isolated lesion on the cerebellum with no supratentorial involvement

compatible with PRES. Axial fluid-attenuated inversion-recovery sequence (FLAIR) image of brain (a) revealed a hyperintense lesion on the

left cerebellum. DWI acquired with a “b” factor of 1000 s/mm2 (b) and corresponding ADC map (c) demonstrated high signal intensity on

DWI and ADC secondary to vasogenic edema.

Imaging in Drug Side Effects Current Medical Imaging Reviews, 2015, Vol. 11, No. 1 25

However, in the case of ascending polyradiculoneuropathy

after intrathecal methotrexate therapy [5, 16], MR may de-

pict lumbosacral ventral root enhancement that shows a dis-

tribution that correlates with the affected area.

2. THORAX

2a. Lung

Drug induced lung injury, an increasingly common cause

of both acute and chronic lung disease, is caused by numer-

ous drugs including certain antibiotics [17-20]. Clinical di-

agnosis is often difficult to establish and is frequently only

suggested after the exclusion of infection, radiation pneu-

monitis, or recurrence of the underlying disease. However,

early diagnosis is essential because cessation of therapy and

treatment of the drug-induced lung injury can often decrease

morbidity and mortality. Lung high-resolution computed

tomography (HRCT) is more sensitive than chest radiogra-

phy for defining the radiographic abnormalities, but present

different limitations: HRCT pattern is rarely specific for a

drug etiology, the radiographic pattern of involvement did

not always correspond to the underlying histological findings

and it is of limited value in determining prognosis. A list of

drugs that cause pulmonary toxicity is available on the Web-

site pneumotox.com online [21].

Nonspecific Interstitial Pneumonia (NSIP). NSIP can

be associated with toxic effects of drugs. Amiodarone,

methotrexate, and carmustine are the most commonly en-

countered. At HRCT, NSIP shows a lower lobe predominant

process with patchy areas of ground-glass opacity and vary-

ing degrees of reticular abnormality, traction bronchiectasis

and consolidation. Although not specific, these findings

should suggest the diagnosis of NSIP in the presence of con-

sistent clinical and histologic finding [22].

Usual Interstitial Pneumonitis (UIP). HRCT features of

UIP are predominantly basal and peripheral reticular areas

with honeycombing and traction bronchiectasis. Cytotoxic

chemotherapeutic agents, such as bleomycin and metho-

trexate, are the most common reported drugs induced UIP

[22]. New generations of antineoplastic agents as gemcit-

abine, taxanes and especially drugs acting on the mTOR

pathway, also produces pulmonary toxicity [23-26]. The role

of drugs taken concomitantly may be important. Hazardous

associations have been reported that can increase the risk of

lung toxicity. Coadministration of cisplatin and bleomycin

increases the risk of bleomycin-induced interstitial lung dis-

ease. The Combined therapies of docetaxel and irradiation

(Fig. 3) for non-small-cell lung cancer (NSCLC) or do-

cexatel and other chemotherapeutic agents is very toxic and

must be taken into account when planning are treatment

strategies for NSCLC [27].

Hypersensitivity Lung Disease. Several drugs can result

in a hypersensitivity reaction in the lungs, for instance cy-

clophosphamide, sulfonamides or nonsteroidal anti-inflam-

matory drugs. The HRCT appearance is similar to that seen

in hypersensitivity pneumonitis secondary to other causes.

Bilateral patchy ground-glass opacities are the most common

finding. However, intralobular interstitial thickening is ob-

served in antineoplastic agent–induced pneumonitis and cen-

trilobular opacities in antibiotic-induced pneumonitis [28].

Bronchiolitis Obliterans. The most common drugs as-

sociated at this entity are sulfasalazine and penicillamine.

HRCT findings include hyperinflation, decreased vascular-

ity, bronchiectasis, bronchial wall thickening, mosaic perfu-

sion, and air trapping on expiratory images [18].

Bronchiolitis Obliterans with Organizing Pneumonia

(BOOP). BOOP is a chronic process consisting in inflamma-

Fig. (3). Usual interstitial pneumonitis (UIP). A 56-year-old man with non-small cell lung cancer treated with a combination of docetaxel

and radiation therapy. Following radiotherapy, the patient presented dyspnea. Thoracic CT was performed. Basal CT images (a-c) and 5

months after treatment (d-f) showed the appearance of typical radiologic changes suggesting UIP, including ground-glass opacities, basal and

peripheral reticular pattern with honeycombing, and traction bronchiectasis.


tory infiltration and fibrosis that predominantly involves the

distal airways. Several medications have been associated

with the development of the BOOP lesion. HRCT usually

shows scattered areas of ground-glass opacities or consolida-

tions with air bronchogram that are often peripheral in distri-

bution. There are no associated bronchiectasis or honey-

combing [29,30].

Pulmonary Hemorrhage. Diffuse pulmonary hemor-

rhage is an uncommon complication of drug therapy. Af-

fected patients can present with acute respiratory distress.

HRCT usually shows scattered or diffuse ground-glass

opacities and consolidations. The drugs most commonly as-

sociated are anticoagulants, amphotericin B, high-dose cy-

clophosphamide, mitomycin, cytarabine, and penicillamine

[17].

Eosinophilic Pneumonia (EP). This pathology is a reac-

tive inflammatory pulmonary process with multiple etiolo-

gies [31]. Drug-induced EP may be considered as a possible

hypersensitivity reaction and it is characterized by the accu-

mulation of eosinophils and macrophages in the alveoli; the

alveolar septa are thickened and infiltrated by eosinophils,

lymphocytes, and plasma cells [32]. A definitive diagnosis of

EP is made when there is evidence of a parenchymal patchy

infiltrate on a HRCT that typically have a peripheral and

upper lobe distribution, peripheral blood eosinophilia, and

increased eosinophils in either lung biopsy tissue or bron-

choalveolar lavage fluid (usually >25%). CT may be helpful

as a 'road map' for a potential biopsy or to give a better view

of the location of the opacities, but it is not necessary to con-

firm a diagnosis [17]

Pulmonary Edema with or Without Diffuse Alveolar

Damage. A non-cardiogenic pulmonary edema, which mani-

fests as acute respiratory distress, may occur with a variety

of drugs most commonly with cytotoxic agents, such as

bleomycin, cytosine arabinoside (Ara-C), methotrexate, and

cyclophosphamide [17-19]. Diffuse alveolar damage, a more

severe form of non-cardiogenic pulmonary edema, occurs

when injury results in necrosis of alveolar endothelial cells

and type II pneumocytes (Fig. 4). DAD is divided into an

acute exudative phase and a late reparative or proliferative

phase. The exudative phase is characterized by alveolar and

interstitial edema and hyaline membranes, is most prominent

in the first week after lung injury. HRCT shows patchy or

diffuse bilateral ground-glass opacities or lung consolida-

tions with a predominance of these findings in the dependent

regions of the lungs. The reparative phase, which is charac-

terized by proliferation of type II pneumocytes and intersti-

tial fibrosis, typically occurs after 1 or 2 weeks.

2b. Pleural Disease

Drug-induced pleural disease is uncommon and mani-

fests as pleural effusions, pleuritis and/or pleural thickening

[33,34]. It may occur as an isolated disorder, associated to

parenchymal disease or in the context of a systemic reaction.

Pleural effusions represent the most common manifestation.

However, hemothorax in anticoagulated patients and pleural

fibrosis with the use of methysergide have been reported.

Ergotamine, ergonovine maleate, bromocriptine, amiodar-

one, and pergolide can produce similar fibrotic response

[35].

2c. Mediastinum

Mediastinal adenopathy may be a complication of

drugs that induce hypersensitivity reactions. Classic associ-

ated drugs are anticonvulsants, particularly phenytoin, and

carbamazepine [36-37].

2d. Cardiac Involvement

The mechanisms of cardiac toxicity are not completely

understood for many drugs. Multiple morphologic and func-

tional imaging techniques can be used to detect and evaluate

the drug-induced cardiac dysfunction, including echocardi-

Fig. (4). Diffuse alveolar damage (DAD). A 66-year-old-female treated with methotrexate presented in the emergency room with progres-

sive shortness of breath and cough. Lung HRCT images (a-c) showed diffuse ground-glass opacities and normal heart size. These findings

may suggest DAD. Seven days later, a new CT scan (d-f) evidenced ground-glass opacities and interstitial fibrosis, which correspond to the

reparative phase of DAD.


ography, magnetic resonance imaging, and radionuclide im-

aging.

Myocardium. Myocardial dysfunction has been reported

for different drugs, such as cytotoxic and cytostatic drugs

(eg, anti-HER2 agents) used to treat cancer, antipsychotic

drugs, and antifungal drugs. Some of them can cause poten-

tially permanent or irreversible dysfunction (eg, doxorubi-

cin), whereas others may cause potentially reversible cardiac

toxic effects [38].

Besides, clinicians have become attentive to drug-

induced myocardial infarction following reports that some

selective cyclooxygenasa (COX) inhibitors increase the risk

of this event. However, the most frequently reported drugs

associated to myocardial infarction were the antimigraine

drug sumatriptan, the calcium antagonist nifedipin, and nico-

tine [39].

Valvular Disease. Different drugs have a potential of

causing valvular heart problems, including cabergoline (used

to manage prolactinomas), ergotamine, and methysergide

[36]. These drugs increase serotonin levels in the blood and

secondary may cause thickening and fibrosis of the valve.

Pericarditis. Pericardial reactions to drugs are rare.

However, several medications and toxic substances can in-

duce pericarditis, tamponade, adhesions, fibrosis, or constric-

tion [40].

2e. Pulmonary Vascular Disease

Vascular system can be involved at different levels caus-

ing different clinical anomalies such as pulmonary embolism

or pulmonary hypertension.

Pulmonary Embolism. Oral contraceptives or hormone

therapy are well-known cause of pulmonary embolism (PE)

[17]. CT pulmonar angiography is the standard test of choice

for the diagnosis of direct and indirect findings of acute PE.

The direct findings of PE include a filling defect that oc-

cludes a contrast-enhanced pulmonary vessel, while indirect

signs are seen in the lung parenchyma with peripheral

wedge-shaped areas of consolidation,

Pulmonary Hypertension. Drugs that have been associ-

ated with the onset of pulmonary hypertension include am-

phetamines, chemotherapeutic drugs, or tryptophan. Imaging

findings of pulmonary hypertension include a main pulmo-

nary artery diameter of greater than 29 mm and right atrial

and ventricular enlargement [41].

3. ABDOMEN AND PELVIS

Cross-sectional imaging of drug side effects in the abdo-

men and pelvis is a complex endeavour due to the multiple

organ systems and the broad differential diagnoses to be

considered [42-43].

3a. Hepatic Complications

Liver is one of the most frequent organs involved in drug

side effects. More than 1200 drugs have been related to he-

patic complications [44] and drug toxicity is the leading

cause of acute liver failure in the United States [45]. Drug-

induced liver changes may consist in hepatitis, architectural

distorsion, deposition diseases, vascular anomalies, or tumor

induction.

Toxic Hepatitis. Different therapies may cause a toxic

hepatitis. Antibiotics are a commonly implicated cause of

drug-induced hepatotoxicity with amoxicilin-clavulanic acid

being the most common [46-47]. Imaging findings are usu-

ally nonspecific and include hepatomegaly, gallbladder wall

thickening, and periportal low attenuation on CT. On MR

imaging, T1 and T2 relaxation times of the liver are in-

creased. High signal intensity, corresponding to lymphedema

or inflammation, can often be noted in the periportal region.

Hepatomegaly is a frequent and nonspecific finding. How-

ever, hepatomegaly with associated splenomegaly and lymph

node enlargement has been described with the use of hydan-

toin (an anticonvulsant therapy) [48].

Alteration of Liver Architecture. Liver contour

changes following chemotherapy in patients with liver me-

tastases have been described. Chemotherapy causes areas of

retracted tumor tissue and scarring and a regenerative phe-

nomenon in the liver parenchyma. This entity is referred to

as pseudocirrhosis because it resembles macronodular cir-

rhosis [49,50]. Common imaging findings include capsular

retraction, volume loss, caudate hypertrophy, and portal hy-

pertension and can be observed within a few weeks or

months after therapy (Fig. 5). However, unlike cirrhosis, at

Fig. (5). Pseudocirrhosis. A 46-year-old female with breast cancer and hepatic metastasis. Abdominal CT images showed a metastatic le-

sion in a liver, which showed normal morphology and contour. The patient began with chemotherapy treatment. Six months later, the liver

showed imaging findings that mimicked cirrhosis (pseudocirrhosis).


pathology patients do not have bridging portal fibrosis, but

can manifest nodular regenerative hyperplasia [51].

Deposition Disease of the Liver. Different substances

may accumulate in liver as a consequence of drugs admini-

stration. Hepatic steatosis is due to the abnormal accumula-

tion of lipids, particularly triglycerides within hepatocytes.

Fatty liver may be associated with exogenous steroids and

several drugs such as amiodarone, methotrexate, 5 fluoracil,

tamoxifen, NSAIDs, or metoprolol [52]. On ultrasound (US),

liver with fatty changes demonstrates increased echogenicity

and attenuation. Unenhanced CT scan shows hepatic attenua-

tion lower than the spleen, while liver signal drops out in

fatty liver in out-of-phase gradient-echo T1-weighted MR

imaging. Amiodarone and and its metabolite, desethylamio-

darone, are likely to accumulate in the liver parenchyma.

These compounds contain two atoms of iodine, thus the ac-

cumulation of amiodarone and desethylamiodarone leads to

increased iodine content within the liver. Furthermore, the

levels of amiodarone correlate with liver CT density and CT

density of the liver may normalize after cessation of amio-

darone administration [53].

Vascular Liver Anomalies. Sinusoidal obstruction syn-

drome (SOS or veno-occlusive disease) is a unique form of

hepatic venous obstruction resulting from occlusion of the

small hepatic venules and intrahepatic veins [54]. The basic

mechanism of this entity is an injury of the endothelium of

the hepatic venules caused by direct destruction or as a con-

sequence of inflammation leading to edema and necrosis of

the wall of the venule. The resultant venous outflow obstruc-

tion leads to sinusoidal dilatation, congestion, hepatocellular

necrosis, and can result in centrilobular fibrosis. SOS usually

presents within 2 to 4 weeks following the exposure to the

medication. Imaging findings resemble those of Budd-Chiari

syndrome with hepatomegaly and ascites but the major he-

patic veins appear patent (Fig. 6). SOS is almost always seen

in association with chemotherapy conditioning regimens for

bone marrow transplantation, particularly those containing

cyclophosphamide or busulfan.

Liver Tumors Induced by Drugs. Hepatocellular ade-

noma (HCA) is a benign liver neoplasm strongly associated

with oral contraceptive use and androgen steroid therapy.

HCA may have characteristic findings on CT and MRI

[55,56]. These include the presence of a single mass or mul-

tiple masses that contain fatty or hemorrhagic areas that usu-

ally show hypervascular to the liver on the hepatic arterial

phase [56]. Besides, FNH appears to be a late complication

of an iatrogenic vascular disease in children with a history of

malignancy treated with chemotherapy [57-58] (Fig. 7).

3b. Biliary and Pancreatic Complications

Many drugs may affect biliary tree and pancreas causing

gallstones, biliary strictures or acute pancreatitis.

Lithiasis. Ceftriaxone, a parenteral third generation

cephalosporin, is widely used for the treatment of a variety

of bacterial infections in both adults and children. Pseu-

dolithiasis or gallbladder precipitates is a complication de-

Fig. (6). Sinusoidal obstructive syndrome (SOS). A 26-year-old-woman treated with contraceptive oral pills. MR imaging showed a patchy

pattern due to a presence of hypointensity bands on axial T1-weighted image (a) and hyperintensity on short tau inversion recovery (STIR)-

weighted image secondary to SOS or “Budd-Chiari like syndrome”. (b) Equilibrium phase enhanced gradient-echo T1-weighted image fol-

lowing the administration of gadolinium chelates demonstrated complete permeability of suprahepatic veins (arrow) and a delayed homoge-

neous enhancement of liver parenchyma.

Fig. (7). Focal nodular hyperplasia (FNH) after chemotherapy. A 3-year-old-child diagnosed with orbital rhabdomyosarcoma (white

arrow) and treated with chemotherapy agents (vincristine and ifosfamide). 6 year after, a follow-up ultrasound demonstrated a solid, hypo-

echoic, highly vascular mass situated in the left lobe of the liver. Axial-T2 weighted MR image demonstrated the lesion with a slight hyper-

signal suggestive of FHN (black arrow).


veloped in 43% of the children treated for serious infections

with ceftriaxone. These precitates resolved completely with

the cessation of therapy [59]. On US, the concretions seen in

ceftriaxone pseudolithiasis are indistinguishable from typical

gallstones. They are brightly echogenic with true shadowing

posteriorly. Other drugs such as furosemide or octreotide can

also cause gallstones.

Biliary Strictures. There are many drugs that are associ-

ated with biliary stricture on literature. However, imaging

findings in these cases are also unspecific and other causes

of biliary stricture must be rule out.

Acute pancreatitis. Drugs are considered a relatively

rare cause of acute pancreatitis. However up to 200 drugs

have been associated to pancreatitis [60]. The true incidence

of drug-associated pancreatitis (DAP) is not accurately

known and estimated around 2% of all cases with acute pan-

creatitis [61,62]. The diagnosis of drug-induced pancreatitis

is difficult to establish, mainly due to the absence of a cause-

specific diagnostic test [63]. Therefore, it is usually based on

the following criteria: 1) Acute pancreatitis occurs during the

administration of a drug, 2) all the other common causes are

excluded, 3) symptoms of acute pancreatitis disappear after

drug withdrawal, and 4) symptoms recur after a rechallenge

of the suspected drug. Unfortunately, drug-induced pan-

creatitis has no distinguishing clinical or imaging features. However, the prognosis of drug-induced pancreatitis is gen-

erally excellent.

3c. Esophagogastrointestinal Complications

Motility Disorders. The motor disorders of the gastroin-

testinal tract may be secondary to drugs. The motor activity

of the small intestine is less likely to be affected by drugs

than is the colon. The reduction of bowel motility may be

severe enough that it can cause paralytic ileus or pseudo-

obstruction. Imaging techniques show prominent colonic

dilatation without distal obstructing lesion [64]. Cathartic

colon is a differentiated functional colonic anomaly that oc-

curs with chronic use of stimulant laxatives. This entity

causes an atonic and redundant colon.

Hyperplasia. Chronic use of proton-pump inhibitors can

cause gastric fold thickening secondary to parietal cell hy-

pertrophy and hyperplasia [65].

Ulceration and Perforation. Nonsteroidal anti-

inflammatory drugs (NSAIDs) are among the most com-

monly prescribed drugs worldwide. Although NSAIDs are

effective, their use is associated with a broad spectrum of

adverse reactions. GI side effects are the most common and

range from dyspepsia, heartburn, and abdominal discomfort

to more serious life-threatening complications such as peptic

ulcer disease and perforation. The most common NSAID-

associated GI complications are peptic ulcer disease and en-

teropathy [66]. Mucosal damage is seen in 30-50% of pa-

tients taking NSAIDs users, but most lesions are of little

clinical significance and disappear or reduce in number with

continued use, probably because of mucosal adaptation.

Only 15 to 30% users have endoscopically confirmed ulcers,

with the gastric antrum being most frequently affected. Per-

foration may also complicate the administration of many

chemotherapy agents and target therapies [67-69]. Recently,

GI perforation has been reported with bevacizumab, a mono-

clonal antibody against vascular endothelial growth factor,

with perforation reported in 1.5 to 2% of patients treated for

metastatic colorectal cancer [70]. The pathogenesis of bowel

perforation is unknown, but suggested mechanisms include

ischemia with thrombosis of intestinal mesenteric vessels

(Fig. 8).

Ischemia. Before attributing gastrointestinal ischemia to

a medication, it is necessary to exclude other risk factors for

Fig. (8). Bowel Perforation secondary to bevacizumab. A 45-year-old man with bowel perforation induced by bevacizumab. Abdominal

CT shows a large pneumoperitoneum (long arrow) and portal venous gas (short arrow).


ischemia. Bowel ischemia (mainly colitis) has been reported

with the use of therapeutic agents such as digitalis, diuretics,

ergotamine, hormonal therapy, -interferon, dopamine,

methysergide, or NSAIDs [70]. Imaging findings of ische-

mia are similar regardless of the primary cause. The most

common CT finding in bowel ischemia is bowel wall thick-

ening, although it is nonspecific. The thickened bowel wall

sometimes shows the target sign, alternating layers of high

and low attenuation within the thickened bowel wall secon-

dary to submucosal edema or hemorrhage. However, the

bowel wall is thinned when the involved bowel segment be-

comes gangrenous [71-72].

Inflammation. Neutropenic enterocolitis is characterized

by fever and right lower quadrant pain in neutropenic pa-

tients. It is seen in children and adults with hematologic ma-

lignancies, with anaplastic anemia, and after myelosuppres-

sive therapy for solid malignancies and it is one of the few

oncological emergencies [43, 73]. Diagnosis criteria include

neutropenia (neutrophil count less than 1 cell/μl), tempera-

ture greater than 38.3 ºC and evidence for colitis. This entity

is most likely to occur early after commencement of chemo-

therapy. CT is the modality of choice for the diagnosis. Sug-

gestive features include colonic mural thickening with low–

density areas representing edema and/or necrosis, pericolic

inflammation with fat stranding, ascitis, and pneumatosis

intestinalis and free air in the presence of underlying mural

necrosis and perforation. Although the right colon is most

frequently involved, a condition specifically referred to as

typhlitis, any segment of the colon or small bowel may be

involved in enterocolitis.

Gastrointestinal Hemorrhage. Both, intravenous hepar-

ins and oral agents, such as warfarin, may induce hemor-

rhage as a major complication [74]. It is reported in up to 4%

of treated patients. The commonest sites of anticoagulant-

related hematomas (ACH) are the soft tissues, the gastroin-

testinal tract, and the urinary tract. Gastrointestinal bleeding

can be intraluminal, intramural, retroperitoneal, extraperito-

neal, or into solid abdominal organs. Endoscopic techniques

are currently considered the first-line diagnostic and thera-

peutic procedures of choice for both upper and lower gastro-

intestinal bleeding and CT angiography is used in assessing

patients with an acute abdomen. The CT angiographic diag-

nosis of active gastrointestinal bleeding is made when hyper-

attenuating extravasated contrast material is seen within the

bowel lumen [75].

Bowel Edema. Angiotensin converting enzyme inhibi-

tors (ACEIs) are widely used to treat patients with hyperten-

sion and refractory cardiac failure. Angioedema induced by

ACEIs is present in 0.1-0.7% of treated patients. In rare

cases, it can involve visceral organs such as the bowel [76].

The mechanism of action by which ACEIs cause angioe-

dema is not fully understood, although bradykinin seems to

be involved. It is most common in females, suggesting a pos-

sible sex-linked or hormonal etiology. Symptoms typically

present within 24-48 hours of initiation of therapy and re-

solve within 24-48 hours after discontinuing the ACEIs. Im-

aging findings include a long-segment involvement of small

bowel, with a tendency to affect the jejunum. The affected

bowel loops typically show the target sign produced by al-

ternating enhancement of the mucosa, relatively hypodense

submucosa (related to edema), and enhancing serosa [77]

(Fig. 9).

Infection. In recent years there has been a marked in-

crease in the incidence of pseudomembranous colitis (PMC)

Fig. (9). Bowel angioedema secondary to angiotensin converting enzyme inhibitors (ACEIs). A 53-year-old presented in emergency

room with complaints of abdominal pain. Abdominal CT showed edema of the small bowel (arrow) and moderate ascitis secondary to treat-

ment to ACEIs.


mainly due to the increase in the use of prophylactic and

broad-spectrum antibiotics [78]. This condition results from

replacement of “normal” gut flora and colonization by Clos-tridium difficile produces both a cytotoxin and enterotoxin,

resulting in colonic inflammation, diarrhea, and characteris-

tic pseudomembranous exudates. Clinical findings may be

absent or range from mild self–limiting diarrhea to fulminant

colitis requiring colectomy. CT manifestations of PMC in-

clude mural thickening, low- attenuation mural thickening

corresponding to mucosal and submucosal oedema, “the ac-

cordion sign”, the “target sign” (intense mucosal enhance-

ment occurring due to mucosal hyperaemia and yuxtaposed

to low attenuation mural edema), mural enhancement, colo-

nic dilatation, pericolonic stranding and ascites [71, 73, 78].

The degree of wall thickening is generally greater than in

other inflammatory or infectious forms of colitis (often

>10mm) and is classically diffuse in distribution.

3d. Kidney

In its key role as the primary eliminator of exogenous

drugs and toxins, the kidney is vulnerable to developing

various forms of injury. Mechanisms of injury are varied and

all renal structures may be affected [79].

Inflammation. NSAIDS and antibiotics probably ac-

count for a significant proportion of cases of tubulointersti-

tial nephritis. Renal ultrasonography may demonstrate kid-

neys that are normal to enlarge in size, with increased corti-

cal echogenicity, but there are nonspecific ultrasonographic

findings [80]. Lithium is a drug prescribed for the treatment

of bipolar disorders that may cause a chronic nephritis with

characteristic tubular microcysts [81-83] (Fig. 10).

Ischemia. Renal papillary necrosis is characterized by

coagulative necrosis of the renal medullary pyramids and

papillae secondary to the development of ischemia. One of

the most common and most preventable etiologic factors is

the use of analgesics, including phenacetin and the COX

inhibitors.

Calculi. A number of medications used to treat a variety

of conditions may induce the formation of calculi. Drug-

induced calculi represent 1-2% of all renal calculi. These

medications may lead to metabolic abnormalities that facili-

tate the formation of stones. The use of furosemide is well

recognized as a predisposing factor of nephrocalcinosis in

infants [84]. Urinary calculi can also be induced by medica-

tions when the drugs crystallize and become the primary

component of the stones. In this case, urinary supersaturation

of the agent may promote formation of the calculi. Drugs

that induce calculi via this process include magnesium tris-

ilicate, ciprofloxacin, sulfa medications, ephedrine, triam-

terene, and indinavir [85]. CT was thought to identify all

urinary calculi but it cannot reliably confirm the presence of

indinavir calculi [86].

Tumor lysis syndrome is an oncologic emergency seen in

patients with tumor of high proliferative rate such as acute

leukemia and Burkitt’s lymphoma [42, 43, 50]. In these pa-

tients, initiation of therapy causes massive cell destruction.

This results in hyperuricemia that produces precipitation of

uric acid with secondary urinary tract obstruction and acute

renal failure.

3e. Bladder

Inflammation. Bladder is vulnerable to the adverse ef-

fects of drugs because of the excretion of drug metabolites in

the urine. Cyclophosphamide and tiaprofenic acid can cause

chemical cystitis, and should be withdrawn if a patient de-

velops irritative symptoms or haematuria. Hemorrhagic cys-

titis results from damage to the bladder transitional epithe-

lium and wall blood vessels. Cyclophosphamide is the most

Fig. (10). Lithium nephropathy. A 54-year-old man with bipolar disorder and long-term lithium therapy. Abdominal CT shows multiple

and bilateral microcysts in both the cortex and medulla secondary to a chronic tubulointerstitial nephropathy.


common cause of hemorrhagic cystitis [42,43,50,87]. Ac-

rolein (a metabolic product of cyclophosphamide) causes

sloughing, thinning, and inflammation of the urothelium.

Although, the bladder is the organ most susceptible to dis-

ease because of prolonged surface contact with the inciting

agent in urine, the entire urothelial surface is at risk. Focal or

diffuse thickening and hypervascularity of the bladder wall

can be detected on imaging techniques [42, 43, 87]. The

most common finding in the upper tracts is hydronephrosis

caused by reflux or obstruction (Fig. 11). Urothelial thicken-

ing, perinephric fluid collections or hemorrhagic pyelitis

have been also reported.

Neurogenic Alterations. Neurogenic bladder has been

described in patients receiving different therapies as a result

of peripheral neurotoxicity. MRI spine evaluation should be

performed to exclude medullary causes of bladder dysfunc-

tion.

3f. Uterus

Tamoxifen is a nonsteroidal antiestrogen agent that is

used for the treatment of breast cancer and to prevent breast

cancer in some high-risk populations. Tamoxifen may, how-

ever, cause adverse effects at the uterine level, including

polyps, endometrial hyperplasia, endometrial carcinoma,

leiomyomas, and adenomyosis [42, 88]. Endocervical mi-

croglandular hyperplasia is also a usual finding in oral con-

traceptive pills users [42].

3g. Ovary

Ovarian hyperstimulation syndrome (OHSS) is an iatro-

genic complication of ovarian stimulation with infertility

treatments. This syndrome is characterized by ovarian en-

largement due to multiple ovarian cysts and an acute fluid

shift into the extravascular space that produces ascites

[42,89].

3h. Retroperitoneum

Inflammation. Retroperitoneal fibrosis is mainly an

idiopathic process, however methysergide, methyldopa, or

ergot alkaloids may cause this entity [90]. Imaging tech-

niques may demonstrate a soft tissue mas around aorta and

inferior vena cava that is isodense to surrounding muscle. CT

and MRI allow the evaluation of retroperitoneal fibrosis lo-

cation, extent, and effect on adjacent organs and vascular

structures.

4. MUSCULOSKELETAL SYSTEM

Drug-induced musculoskeletal disorders can vary greatly

from those that are asymptomatic to severe and even life-

threatening conditions. Musculoskeletal abnormalities can

involve the bones, the joints, or soft tissues.

4a. Bone Abnormalities

It has been established that drugs may interfere with bone

metabolism by acting on the maturation, mineralization or

morphology. Main drug-induced bone anomalies are osteo-

malacia, osteoporosis, and osteonecrosis.

Osteomalacia (OM). OM is a metabolic bone disease

characterized by a defect of bone mineralization. OM can be

secondary to several causes. Among these, an important role

may be attributed to some drugs, usually anticonvulsants

(phenobarbital, phenytoin, and carbamazepine) and drugs

containing a high concentration of aluminium [91-93]. OM

presents with a wide variety of clinical, biochemical and

radiographic manifestations mimicking other musculoskele-

tal disorders, including osteoporosis [94,95]. Characteristic

pseudofractures (also named Looser's zones) are only present

in some patients.

Osteoporosis is the result of bone loss due to an imbal-

ance in bone turnover in which bone resorption exceeds bone

formation. Drug-induced osteoporosis is common and has a

significant impact on the prognosis of patients suffering from

chronic debilitating diseases. Glucocorticoids are the drugs

causing osteoporotic fractures most frequently, but osteopo-

rosis with fractures is observed also in patients treated with

aromatase inhibitors for breast cancer, in men receiving anti-

androgen therapy for prostate cancer, in postmenopausal

women treated with high doses of thyroxine, and in patients

treated with thiazolinediones for diabetes mellitus [96,97].

Radiographic features of corticosteroid-induced osteoporosis

are usually indistinguishable from those of primary osteopo-

rosis. Insufficiency fractures can involve any bone, most

frequently thoracic and lumbar vertebrae, sacrum or long

bones [91]. Conventional radiography allows qualitative and

semiquantitative evaluation of osteoporosis, while dual-

energy x-ray absorptiometry and quantitative CT have been

developed to quantify bone mineral content and assess bone

loss.

Osteonecrosis. Steroids and bisphosphonates have been

associated to osteonecrosis in hips and jaw, respectively. The

exact mechanisms of corticosteroid-induced osteonecrosis

Fig. (11). Hemorrhagic cystitis. A 6-year-old child treated with cyclophosphamide that presented hematuria. CT showed diffusely thick-

ened bladder wall with multiple hyperdense foci (black arrow on c) compatible with hemorrhagic cistitis. Hydronephrosis and hemorrhagic

pyelitis (black arrow on a) were visible at a higher level.


remain unknown but the disease develops in 8%–10% of all

corticosteroid users. Bisphosphonates are standard treatment

of patients with bone metastases but are associated to os-

teonecrosis of the jaw (ONJ). The estimated prevalence of

intravenous bisphosphonate-associated ONJ in cancer pa-

tients is as high as 6%–10% [98]. CT is the modality of

choice to diagnosis this entity showing sclerosis with bone

fragmentation and areas of lysis (Fig. 12).

4b. Muscle Disorders

Myopathy. The combination of skeletal muscle weak-

ness, tenderness and pain with the possibility of the plasma

creatinine kinase elevation suggests the presence of myopa-

thy. Muscle toxicity is a well-known side effect associated

with the use of statins and high dose of glucocorticoids. D-

penicillamine, antiretroviral therapy with zidovudine, and

misuse of androgenic hormone derivatives by bodybuilders

has been also reported in association to myopathy [99]. Im-

aging features are nonspecific, showing diffuse edema and

inflammation in acute cases and atrophy with fatty infiltra-

tion in chronic myositis [100]. Drug-induced myopathy is a

dignosis of exclusion without specific clinical signs or sero-

logic, neurophysiologic, or histologic characteristics [101].

Rhabdomyolysis. Destruction of skeletal muscle cells is

a clinical condition of potential life threatening. The inci-

dence of rhabdomyolysis with statin therapy is approxi-

mately 0.04%–0.2% and is dose dependent [102]. Rhabdo-

myolysis has been recently reported for sunitinib, a tyrosine

kinase inhibitor used in renal cancer patients [103]. There are

not characteristic imaging findings of rhabdomyolysis. MRI

may show hyperintensity areas on T2-weighted images sug-

gesting muscle edema.

4c. Joints

Tendon Rupture and Tendinitis. These are well recog-

nized but rare complications of treatment with fluoroqui-

nolones (FQs). FQs tendinopathy occurs more commonly in

tendons under high stress, mainly involving the Achilles

tendon (Fig. 13), although any tendon can be affected. The

exact mechanism is unknown [104].

4d. Soft Tissues

Fat necrosis. Subcutaneous and intramuscular injections

can cause fat necrosis, which will also calcify. Soft tissue

calcifications are one of the most common radiologic mani-

festations and are often seen in the gluteal region.

HIV-associated lipodystrophy. Long-term therapy with

antiretroviral therapy produces lipodystrophy. This is a com-

plex syndrome characterized by changes in regional fat mass,

Fig. (12). Bisphosphonate-associated osteonecrosis of the jaw. Axial and coronal CT scans showing cortical bone loss on the right side of

the mandible (arrow) in a 60-year-old man diagnosed with mieloma multiple and treated with zoledronic acid.


dyslipidemia, and insulin resistance. Adipose tissue redistri-

bution is characterized by loss of peripheral subcutaneous

adipose tissue (face, limbs, buttocks), visceral fat accumula-

tion, and lipomatosis, especially in the dorsocervical area

(“buffalo hump”) (Fig. 14) [105, 106].

5. VASCULAR SYSTEM

Venous thrombosis. Deep vein thrombosis (DVT) is a

common vascular disorder. A thrombus either arises sponta-

neously or is caused by clinical conditions including surgery,

trauma, or prolonged bed rest (107). DVT might be induced

by drugs, being a common vascular side effect of antineo-

plastic therapy, oral contraceptive users, corticoids, and

COX inhibitors [11].

Vasculitis. Drug-induced vasculitis is the most common

form of vasculitis. The differential diagnosis between drug-

induced and idiopathic vasculitic conditions may be difficult,

however imaging techniques play a pivotal role in the diag-

nosis of large vessel vasculitis and in demonstrating internal

organ involvement [108].

CONCLUSION

Drugs are associated with significant complications in

different organs. Awareness of these complications can help

the radiologist to detect these at early stages, which helps in

the appropriate management and results in better outcome.

CONFLICT OF INTEREST

The authors confirm that this article content has no con-

flict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Received: September 08, 2014 Revised: November 04, 2014 Accepted: November 15, 2015

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