Lanthanum Carbonate Opacities—A Systematic Review

Background: Lanthanum carbonate is a phosphate binder used in advanced kidney disease. Its radiopaque appearance has been described in many case studies and case series. Misinterpretation of this phenomenon leads to unnecessary diagnostic tests and procedures. The objectives of this study were to summarize the literature on lanthanum carbonate opacities and present a visual overview. Methods: A systematic search was conducted using MEDLINE, Embase, and Web of Science. We included all types of studies, including case reports/studies, describing radiological findings of lanthanum carbonate opacities in patients with chronic kidney disease. No filter for time was set. Results: A total of 36 articles were eligible for data extraction, and 33 articles were included in the narrative synthesis. Lanthanum carbonate opacities were most commonly reported in the intestines (26 studies, 73%), stomach (8 studies, 21%), and the aerodigestive tract (2 studies, 6%). The opacities in the intestine were most frequently described as multiple, scattered radiopaque densities, compared with the aerodigestive tract, where the opacities were described as a single, round foreign body. Suspicion of contrast medium or foreign bodies was the most common differential diagnosis. LC opacities in patients with CKD are commonly misinterpreted as foreign bodies or suspect contrast media. Conclusions: CKD patients treated with LC may have opacities throughout the digestive tract that can vary in appearance. Stopping LC treatment or changing to an alternative phosphate binder prior to planned image studies can avoid diagnostic confusion. If this is not an option, knowledge of the presentation of LC opacities is important.


Introduction
Phosphate retention exacerbates renal osteodystrophy and increases the risk of soft tissue and vascular calcification and death [1]. Therefore, medical treatment includes phosphate binders [2]. Phosphate binders are used to control hyperphosphatemia [3]. They can be divided into calcium-containing phosphate binders such as calcium carbonate and calcium acetate. In cases of increased calcium levels, calcium-free phosphate binders, including the most widely used calcium-free phosphate binders sevelamer and lanthanum carbonate (LC), are used.
LC Lanthanum carbonate was introduced in 2005 in the United States, and in 2009 in Japan, under the brand name Fosrenol™ [4,5]. LC is available as a chewable tablet or oral powder [6]. It disassociates in the upper gastrointestinal tract to lanthanum ions (La 3+ ), forming insoluble lanthanum phosphate complexes that pass through the GI tract almost unabsorbed [6,7]. The absorbed part is excreted in bile [7]. The appearance of LC-associated opacities' was first described in 2006, suggesting that the opacities were related to calcium-phosphate accumulation [8]. However, it has since become clear that The narrative synthesis consisted of 30 [8][9][10][11][12][13] single case reports, 1 case series [4], and 2 cohort studies [41,42]. The case series included 9 patients, and the cohort studies included 126 and 169 patients.
Therefore, the review consists of reports from a total of 334 patients. The studies were from 14 different countries, with Japan being the most common [4,24,28,31,32,41]. Among the included papers, 13 studies reported dispensing LC in tablet form, but the remaining articles did not specify the dispensation form. The duration of LC treatment ranged from days [12] to 6 years [31]; 19 articles did not specify duration treatment.
Characteristics of included studies can be found in Table 1.

Quality of Included Studies
All but three articles passed the quality assessment. Both of the cohort studies were included and the case series article as well. The quality assessment is displayed in Table 2. Table 2. Overview quality assessment on all studies.

Yes No Unclear
Does the case/the case series mirror the whole experience of the investigator? 3 0 33 Was the exposure adequately ascertained? 20 16 0 Was the outcome adequately ascertained 35 0 1 Were alternative causes ruled out? 14 12 10 Was the case/case series described with sufficient details? 33 0 3

Author Year
Image Study Modality (CT, X-ray, etc.)       Beam-hardening artifacts on computed tomography images are shown, which were caused by lanthanum carbonate hydrate in a patient on dialysis. Reprinted with permission from ref. [24]. Copyright Japanese Journal of Radiology 2010. Lanthanum carbonate has a radiopaque appearance on the plain abdominal radiography. Reprinted with permission from ref. [27]. Copyright 2016 Revista Española Enfermedades.

Location of Opacities
(CT) image with strong artifacts caused by tablets in the ascending and transverse colon is observed. Lanthanum carbonate has a radiopaque appearance on the plain abdominal radiography. Reprinted with permission from ref. [27]. Copyright 2016 Revista Española Enfermedades.
Beam-hardening artifacts on computed tomography images are shown, which were caused by lanthanum carbonate hydrate in a patient on dialysis. Reprinted with permission from ref. [24]. Copyright Japanese Journal of Radiology 2010.  Beam-hardening artifacts on computed tomography images are shown, which were caused by lanthanum carbonate hydrate in a patient on dialysis. Reprinted with permission from ref. [24]. Copyright Japanese Journal of Radiology 2010.

Discussion
Our review highlights that LC opacities can be seen throughout the gastrointestinal (GI) tract and even in the upper airways. In general X-ray, ultrasound and CT can be affected by LC opacities, but also other image modalities such as dual-emission X-ray absorptiometry (DEXA) scanning [29,30,42] and transesophageal echocardiography [28]. The heterogeneous differential diagnoses can lead to many misinterpretations (Table 4). Table 4. Differential diagnosis of lanthanum carbonate opacities.

Differential Diagnosis
Small metal objects such as small coins [20,35] Contrast [25,27,30,[34][35][36][37][38][39] Sclerosing peritonitis [10] Tuberculosis [10] Lead ingestion [10] Intestinal bleeding [11,12] Phlebosclerotic colitis [11] We did not find any examples of in vivo MRI studies regarding the effect of LC. However, one magnetic resonance imaging (MRI) study performed an in vitro trial with LC in plastic bottles filled with distilled water or edible agar. The study determined that ground LC tablets had no contrast enhancement effect on T1-weighted images; on T2weighted images, it did not affect the signal intensity of the solvent. However, unground LC tablets may be visualized as filling defects on MRIs [43].

Fosrenol Administration
Some case reports described the cause of the LC opacities as whole tablets contributing to hoarseness, dysphagia, and fecaloma [4,20,22]. Furthermore, a differential diagnosis of foreign bodies results in suspicion of perforation, obstruction, intussusception, fistula formation, abdominal abscess formation, and death, and therefore, is a medically urgent situation [44]. Patients with chronic kidney disease must be encouraged to chew or crush the LC tablets, switch to Fosrenol powder, or use an alternative phosphate binder. A few studies suggest that LC should be used with caution in diverticulitis patients, as diverticulitis flare-ups may occur if the tablets are not appropriately chewed [4,18]. In particular, 1000 mg LC tablets may cause a problem for the older population, as they are 2.2 cm in diameter [20].
Radio-opacity is not exclusively linked to LC. Other drugs such as chloral hydrate, heavy metals, iodides, phenothiazines, enteric-coated pills, and solvents could also be considered if radiographic opacities are seen in imaging [45].

Could LC Opacities Have a Hidden Consequence?
Other studies have described the LC deposition in the gastric mucosa during endoscopy examinations as whitish lesions [46]. Shitomi et al. named the phenomenon "gastric lanthanosis" and described the pathology as reflective bright white spots by gastroscopy and eosinophilic histiocytes [41]. Another study described a high-density layer around the entire circumference of the stomach wall. These authors reported reddish-brown deposits phagocytized by macrophages histologically, and X-ray spectroscopy confirmed the presence of lanthanum in the specimen. Iwamuro et al. argued that lanthanum deposition might cause gastric erosions, ulcers, and epigastric discomfort [47]. However, a recent review described the progression and outcome of gastric lanthanosis as unknown [46]. the authors of this review propose an investigation of the clinical importance of gastric lanthanosis as a potential future research field.
The strength of this study lies in the fact that, to our knowledge, this is the first systematic review regarding LC opacities in image studies of chronic kidney disease patients. Our review gives a good overview of the consequences of differential diagnosis of LC opacities.
Nevertheless, our study also has weaknesses. Our review consists almost exclusively of case studies. Due to this feature, we were unable to determine the extent of the problem with LC opacities among patients taking LC. However, producing a visual overview of LC opacities does not require studies with a specific design. Future research might focus on the frequency of LC opacities and the most common locations, as well as the long-term effects of gastric lanthanosis.

Conclusions
Our review shows that LC opacities can vary in appearance and have been observed throughout the digestive tract of patients with chronic kidney disease. Unfortunately, the misinterpretation of these radiological opacities results in many different differential diagnoses. Therefore, we recommend that patients treated with LC should switch to an alternative phosphate binder several days prior to image testing, to avoid misinterpretation. In addition, radiologists and clinicians ordering imaging should be familiar with the effect of LC treatment on imaging, to avoid unnecessary diagnostic tests. Other tasks include making sure patients receiving LC are able to chew the tablets and, alternatively, considering a change to LC powder or an alternative phosphate binder. Further studies regarding the long-term effects of gastric lanthanosis could yield important insights. Institutional Review Board Statement: Since this study was a systematic review, no ethical approval was required.

Informed Consent Statement: Not applicable.
Data Availability Statement: Links to the different studies included in the review are listed in Table 3.