Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate

    Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate Shinichi Ban MD, PhD, Syunji Suzuki MD, Kenji Kubota MD, PhD, Susumu Ohshima PhD, Hideaki Satoh MD, PhD, Hiroki Imada MD, Yoshihiko Ueda MD, PhD PII: DOI: Reference:

S1092-9134(16)30184-8 doi: 10.1016/j.anndiagpath.2016.10.001 YADPA 51118

To appear in:

Annals of Diagnostic Pathology

Please cite this article as: Ban Shinichi, Suzuki Syunji, Kubota Kenji, Ohshima Susumu, Satoh Hideaki, Imada Hiroki, Ueda Yoshihiko, Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate, Annals of Diagnostic Pathology (2016), doi: 10.1016/j.anndiagpath.2016.10.001

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Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate

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Running title: Gastric mucosal status and lanthanum deposition

of Pathology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan Department of bPathology and cNephrology, Saiseikai Kawaguchi General Hospital, Kawaguchi, Japan dDivision of Morphological Science, Biomedical Research Center, Saitama Medical University, Moroyama, Iruma, Saitama, Japan

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aDepartment

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Hideaki Satoh, MD, PhD b Hiroki Imada, MD a,b Yoshihiko Ueda, MD, PhD a

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Shinichi Ban, MD, PhD a,b,* Syunji Suzuki, MD c Kenji Kubota, MD, PhD c Susumu Ohshima, PhD d

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Correspondence author: Shinichi Ban, MD, PhD Department of Pathology Dokkyo Medical University Koshigaya Hospital 2-1-50 Minami-Koshigaya, Koshigaya Saitama 343-8555, Japan phone +81-48-965-4959; fax +81-48-965-5476 E-mail： [email protected] The authors declare that they have no conflicts of interest.

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Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate

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Running title: Gastric mucosal status and lanthanum deposition

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Shinichi Ban Syunji Suzuki Kenji Kubota Susumu Ohshima

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Hideaki Satoh Hiroki Imada Yoshihiko Ueda

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The authors declare that they have no conflicts of interest.

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Abstract

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Lanthanum carbonate is a popular chemical which is administered for

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patients with end-stage kidney disease to reduce the absorption of phosphate, and lanthanum deposition in the gastrododenal mucosa has recently been

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reported. The aim of this study was to assess whether any histologic changes of the gastric mucosa are related to the deposition of lanthanum. 24 patients

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who revealed the histology of lanthanum deposition on gastroduodenal biopsy between 2011 and 2014 were included in the study, and their clinical records and gastroduodenal biopsies obtained from 2011 to 2015 were reviewed, adding the review of gastroduodenal biopsies before 2011 if

dispersive

X-ray

spectroscopy

(SEM-EDX)

was

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microscopy–energy

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possible. Analysis of the deposited materials by scanning electron

performed for a representative gastric biopsy. All patients were diagnosed as

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renal insufficiency due to chronic kidney disease and treated with dialysis for more than five years, with confirmation of lanthanum carbonate use for

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22 patients. Out of 121 gastric biopsies and 10 duodenal ones between 2011 and 2015, 86 gastric biopsies (71.1%) and 3 duodenal biopsies (30%), respectively, revealed histology consistent with lanthanum deposition, which was confirmed by SEM-EDX analysis for a representative case. The deposition tended to occur in the gastric mucosa with regenerative change, intestinal metaplasia, or foveolar hyperplasia (p<0.05). Such mucosal changes were observed in about half of the gastric biopsy samples obtained prior to 2010, in which no lanthanum deposition was identified irrespective of the gastric mucosal status. Although direct association between

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lanthanum deposition and clinical symptoms is not clear, the evaluation of

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the gastric mucosal status (prior to administration) seems to be important to

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predict lanthanum deposition when lanthanum carbonate is administered

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for patients with chronic kidney disease treated with dialysis.

Keywords: lanthanum carbonate; chronic kidney disease; dialysis; gastric

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mucosa; biopsy

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1. Introduction

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Lanthanum carbonate is now a popular chemical which is administered

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for patients with end-stage kidney disease to reduce the absorption of phosphate and keep optimum phosphate levels. After an oral intake, it binds

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phosphate to form a complex insoluble in water, which are reportedly excreted mostly in stool with extremely low levels of absorption and no

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evidence of systemic adverse effects [1,2]. However, several recent publications have revealed lanthanum deposition in the gastric and duodenal mucosae of patients treated with lanthanum carbonate [3-7], and we have also not a little encountered such cases in the recent four years.

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Here, we assessed whether any histologic changes of the gastric mucosa are

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related to the deposition of lanthanum, which had not been fully clarified in

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the previous reports.

2. Materials and methods

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In routine practice at Department of Pathology, Saiseikai General Hospital, Kawaguchi, Japan, from 2011 to 2014, we encountered 24 patients whose gastroduodenal mucosal biopsies showed foreign body-laden macrophage accumulation, which was later revealed to be consistent with the histology of lanthanum deposition [3-7]. For the 24 patients, we reviewed the clinical records and histology (H&E-stained slides) of the gastrodeuodenal mucosal biopsy specimens obtained between 2011 and 2015. Besides, we added the review of the gastroduodenal biopsy specimens of the same patients obtained before 2011

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if possible. For a formalin-fixed paraffin-embedded section of a gastric biopsy

scanning

electron microscopy–energy

dispersive

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materials by

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of a representative case, we performed element analysis of the deposited

spectroscopy (SEM-EDX).

X-ray

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This study was approved by Ethics Committee of Saiseikai General

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Hospital.

3. Results

The 24 patients included 13 men and 11 women with ages ranging from 45 to 90 years (65.3 years in average) at the time of the last gastroduodenal

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endoscopy with biopsy. All patients were diagnosed as renal insufficiency due

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to chronic kidney disease and treated with dialysis for more than five years. The history of oral intake of lanthanum carbonate was confirmed for 22

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patients. The gastroduodenal endoscopy was performed mostly for regular surveillance of neoplasms, especially gastric cancer, without gastrointestinal

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complaints, including follow-up after endoscopic resection of gastroduodenal neoplasms. One gastroduodenal endoscopy was performed for searching the cause of anemia, and the other for a complaint of nausea after meal. The endoscopic biopsies were obtained from sites with various findings including small polyps or polypoid lesions, erosion or slightly depressed lesions, mucosal irregularity with reddish and/or whitish in color, scar after endoscopic tumor resection, and non-remarkable mucosa for H. pylori check-up. The total number of biopsy obtained between 2011 and 2015 was 131

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including 121 gastric biopsies and 10 duodenal ones. Histological findings

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consistent with lanthanum deposition was observed in 86 gastric biopsies

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(71.1%) and 3 duodenal biopsies (30%). The deposited materials were phagocytosed by macrophages in the lamina propria, which showed

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amphophilic and/or yellowish-brown fine granules, and amphophilic and/or brownish rods or curly strings (Fig. 1A). The SEM-EDX analysis of the

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representative gastric biopsy revealed both lanthanum and phosphorus were major components of the deposited materials (Fig. 2). The degree of lanthanum deposition could be graded semiquantitatively by evaluating H&E-stained slides of each biopsy as follows (Figs. 1B-D): Grade 0, no

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deposition; Grade 1, deposition in a very limited area of the biopsied tissue;

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Grade 2, deposition in less than half of the area or in multifocal limited areas of the biopsied tissue; Grade 3, deposition in more than half of the area of the

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biopsied tissue.

The gastric mucosa on biopsy obtained between 2011 and 2015 showed

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various histologic findings including chronic active gastritis, intestinal metaplasia, regenerative change, foveolar hyperplasia, fundic gland polyp, and intramucosal neoplasms, and lanthanum deposition in each gastric mucosal alteration was observed in various degrees (Table 1). When the histologic status of the non-neoplastic gastric mucosa was divided into two groups, one with at least one of the features including regenerative change, intestinal metaplasia, and foveolar hyperplasia (91 biopsies, 79.1%), and the other without such changes (24 biopsies, 20.9%), and correlated with two groups of the deposition grade divided into Grade 0/1 and Grade 2/3, a

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significant correlation was achieved on Fisher’s exact test (p<0.05),

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suggesting the tendency of lanthanum deposition in higher degrees in the

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gastric mucosa with regenerative change, intestinal metaplasia, and/or foveolar hyperplasia (Figs. 1B-D). The 5 out of 10 duodenal biopsies

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including the three with lanthanum deposition were obtained from the duodenal bulbus, all of which showed regenerative change, hyperplastic

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change with foveolar metaplasia, or ectopic gastric mucosa. 22 gastric biopsies and one duodenal biopsy obtained between 2006 and 2010 were available for review, and in just two gastric mucosal tissues each biopsied from different patient in 2010, Grade 3 and Grade 1 lanthanum

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deposition was observed in intestinalized and hyperplastic mucosa,

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respectively. 10 out of 22 gastric biopsies (45.5%) showed regenerative change, or intestinal metaplasia, or foveolar hyperplasia.

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Information about details of lanthanum carbonate intake could be obtained for 17 patients (Table 2). The shortest time interval between the

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start of lanthanum carbonate intake and the first biopsy sample with the deposition was four months, and for three patients, the time interval was within one year whereas the most frequent time interval was more than one year and within two years. The time interval did not seem to correlate with the amount of lanthanum carbonate used.

4. Discussion We first encountered a gastric biopsy sample with findings consistent with lanthanum deposition in 2011. In the present review of biopsies obtained

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before 2011, lanthanum deposition was identified in only two gastric biopsy

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samples obtained in 2010, and never seen in ones obtained prior to 2010.

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This finding is reasonable because lanthanum carbonate was introduced in Japan in 2009. Taken together the results of our review, lanthanum

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deposition in early-onset cases could appear around one year after the start of oral intake irrespective of the used amount, although others would take

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longer intervals until the appearance of the deposition. This finding is consistent with previous reports, in which the intervals between the start of oral intake and the appearance of the deposition are variable [3-7], being the shortest intervals of 9 months and 7 months [4,6].

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It was reported in humans that little amount of lanthanum is absorbed

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from the gut into the systemic circulation after oral intake [1]. Actually, an increase in plasma lanthanum levels and lanthanum concentrations in bone

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biopsy samples was reportedly relatively low in patients receiving lanthanum carbonate [8]. Thus, lanthanum deposition in the gastroduodenal

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mucosa does not seem to originate from the lanthanum circulating in the blood. Although lanthanum deposition in a regional lymph node of the stomach and in a mesenteric lymph node was reported [6,9], the plasma lanthanum concentration was not high in the former case, and lanthanum was not detected in other tissues except the lymph node in the latter case (an autopsy case), being a lymphatic route suggested for both the cases. Besides, no lanthanum deposition was identified in the colorectal biopsy or EMR specimens of the same patients as the present review series (data not shown).

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Therefore, in humans, it is reasonable to perceive that lanthanum

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deposition in the gastroduodenal mucosa in patients with oral intake of

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lanthanum carbonate occurs directly through the gastroduodenal epithelium, which could partly be attributed to disruption of the gastrointestinal

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epithelium resulting in increased permeability in patients with chronic kidney disease [10]. However, in the present review, the chemical tended to

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deposit in the gastric mucosa showing regenerative change, intestinal metaplasia, and/or foveolar hyperplasia, suggesting the relationship between the deposition favored sites and the underlying mucosal pathology. This is supported by the fact that in previously reported cases, the gastric mucosa lanthanum

deposition

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with

showed

intestinal

metaplasia

[3,5,6],

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regenerative change [4], and reactive foveolar hyperplasia [7] in descriptions and/or figures. Besides, with no reference to chronic kidney diseases and/or

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dialysis, it was reported that permeability of lanthanum nitrate was increased in intestinalized gastric epithelium with compared to normal

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gastric epithelium [11]. The gastric mucosal changes described above do not seem to be secondarily caused by lanthanum deposition because half of the gastric biopsy samples obtained before 2011, most of which were free from lanthanum deposition, already showed similar mucosal findings. However, the possibility is also to be considered that lanthanum deposition would become a factor which promotes gastric mucosal changes described above. The lanthanum deposition was not directly associated with clinical symptoms in the present review cases, and its clinical significance is unclear. However, some cases with disappearance of digestive symptoms or

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gastrointestinal bleeding after cessation of treatment with lanthanum

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carbonate have been reported [5,7]. As discussed above, the chance of

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lanthanum deposition is likely related to the status of gastric mucosa. The evaluation of the gastric mucosal status (prior to administration) seems to be

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important to predict lanthanum deposition when lanthanum carbonate is

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administered for patients with chronic kidney disease treated with dialysis.

Acknowledgements

We wish to acknowledge Ms Noriko Murai, Biomedical Research Center, Saitama Medical University, for her technical assistance of scanning

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electron microscopy–energy dispersive X-ray spectroscopy.

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References

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[1] Pennick M, Dennis K, Damment SJ. Absolute bioavailability and disposition of lanthanum in healthy human subjects administered

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lanthanum carbonate. J Clin Pharmacol 2006;46:738-46. [2] Damment SJ. Pharmacology of the phosphate binder, lanthanum

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carbonate. Ren Fail 2011;33:217-24.

[3] Makino M, Kawaguchi K, Shimojo H, Nakamura H, Nagasawa M, Kodama R. Extensive lanthanum deposition in the gastric mucosa: the first histopathological report. Pathol Int 2015;65:33-7.

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[4] Haratake J, Yasunaga C, Ootani A, Shimajiri S, Matsuyama A, Hisaoka

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M. Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate. Am J Surg Pathol

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2015;39:767-71. [5] Rothenberg

ME,

Araya

H,

Longacre

TA,

Pasricha

PJ.

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Lanthanum-Induced Gastrointestinal Histiocytosis. ACG Case Rep J 2015;2:187-9. [6] Tonooka A, Uda S, Tanaka H, Yao A, Uekusa T. Possibility of lanthanum absorption in the stomach. Clin Kidney J 2015;8:572-5. [7] Valika AK, Jain D, Jaffe PE, Moeckel G, Brewster UC. A Nodular Foreign Body Reaction in a Dialysis Patient Receiving Long-term Treatment With Lanthanum Carbonate. Am J Kidney Dis 2016;67:128-32. [8] Spasovski GB, Sikole A, Gelev S, Masin-Spasovska J, Freemont T, Webster I, Gill M, Jones C, De Broe ME, D'Haese PC. Evolution of bone

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and plasma concentration of lanthanum in dialysis patients before,

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during 1 year of treatment with lanthanum carbonate and after 2 years of

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follow-up. Nephrol Dial Transplant 2006;21:2217-24.

[9] Davis RL, Abraham JL. Lanthanum deposition in a dialysis patient.

[10]

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Nephrol Dial Transplant 2009;24:3247-50.

Vaziri ND, Yuan J, Nazertehrani S, Ni Z, Liu S. Chronic kidney

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disease causes disruption of gastric and small intestinal epithelial tight junction. Am J Nephrol 2013;38:99-103. [11]

Ji R, Zuo XL, Yu T, Gu XM, Li Z, Zhou CJ, Li YQ. Mucosal barrier

defects in gastric intestinal metaplasia: in vivo evaluation by confocal

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endomicroscopy. Gastrointest Endosc. 2012;75:980-7.

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Table 1. Histopathologic findings of gastrododuodenal biopsies and grade of lanthanum

Non-remarkable gastric mucosa

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Chronic active gastritis

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Chronic active gastritis with intestinal metaplasia Intestinalized gastric mucosa Regenerative intestinalized

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Regenerative gastric mucosa

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Regenerative hyperplastic gastric mucosa

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Hyperplastic gastric mucosa (foveolar hyperplasia)

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Duodenal mucosa*

Intramucosal neoplasm**

●●

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gastric mucosa

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Fundic gland polyp

1

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0

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Grade

Histological findings

3

●●●●● ●

●

● ●● ●●●●●

●

●●●●

●●●●●

●●●●●

●●●●●

●

●

●●●●

●●●

●●●

●●●●

●●●●

●●●●●

●

2

●●●●●

●●●

●●●●●

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deposition in 2011 - 2015

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Gastroduodenal mucosae show mild to moderate chronic inflammatory cell infiltration except for biopsies with chronic active gastritis *Including 5 biopsies from the bulbus and 4 ones from the non-bulbus areas, the former showing regenerative or hyperplastic change often with foveolar metaplasia. Lanthanum deposition is observed just in the biopsies from the bulbus. **6 neoplastic biopsies of the stomach and 1 neoplastic biopsy of the duodenal 2 nd portion, including 2 gastric biopsies with lanthanum deposition.

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Table 2. Duration until lanthanum deposition and its amount

Average amount of

intake and the first biopsy

Patients

with lanthanum deposition

No.

≤ 1 year

lanthanum carbonate per day (mg)

3*

1 year < ≤ 2 years

10

> 2 years

4**

1,100 1,500

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667

**longest interval 4 years 2 months

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*shortest interval 4 months

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carbonate

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lanthanum

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Interval between start of

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High-power histological appearance of lanthanum deposition in a

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Fig. 1

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Figure legends

biopsied gastric mucosa (A), and histological alterations of the gastric

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mucosa with various grades of lanthanum deposition: Grade 1 deposition in the mucosa with foveolar hyperplasia (B), Grade 2 deposition in the mucosa

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showing regenerative change (C), and Grade 3 deposition in regenerative intestinalized mucosa (D). original magnification: A ×400, B-D ×100.

Scanning electron microscopy–energy dispersive X-ray spectroscopy

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Fig. 2

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analysis of a gastric biopsy with peaks of lanthanum (La) and phosphorus

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(P).

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Highlights

Lanthanum deposition depends on the histologic changes of the gastric

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mucosa.

They include regenerative change, intestinal metaplasia, or foveolar

Evaluation of the gastric mucosal status is important at lanthanum

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carbonate use.

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hyperplasia.