Discussion
To reduce hyperphosphatemia in dialysis dependent patients there are
different oral phosphate binders available. As compared with other
phosphate binders, Lanthanum carbonate does not show an increased risk
for all-cause mortality or malignancy while maintaining a similar effect
of reducing serum phosphate levels. However, 17.8% of patients showed
gastrointestinal symptoms that required hospitalization. Unspecific
gastrointestinal symptoms, like emesis, are the most common adverse
effects. The oral bioavailability is 0.001% and is mostly eliminated
through the gastrointestinal tract where it forms insoluble complexes
with ingested phosphate. Since 2015 numerous case reports and a few
studies showed an association with lanthanum carbonate intake and
lanthanum phosphate deposition especially in the gastric mucosa.
Nevertheless, the accumulation mechanism is not entirely understood.
Lanthanum carbonate is soluble at resting gastric pH-levels which could
be a way of penetrating the gastric mucosa. Chronic kidney disease
patients also have a disruption of the epithelial tight junctions in the
gastrointestinal tract which leads to a higher permeability for
substances like lanthanum. Lanthanum carbonate is radiopaque. In
abdominal CT, a high-density linear appearance (HD-LA), can be found in
60% - 79%, and is seen as a correlate for gastric lanthanum
depositions. Yabuki et al. suggest using the HD-LA as a screening
criterion. Whereas Namie et al. described a continuing HD-LA in CT after
8 months of discontinuation, our patient didn’t show radiopaque objects
in an abdominal radiograph, but radiographs may not be as sensitive to
slight lanthanum depositions as a CT might be. Further studies are
needed to investigate if abdominal radiographs and CTs can be used as a
screening method. Endoscopically the depositions appear as whitish
mucosal lesions that vary in shape and size. Although Shitomi et al.
found that those distinctive endoscopic observations might be difficult
to detect in a case with slight depositions. This is why Iwamuro et al.
suggest taking biopsies also in cases without an endoscopic correlate
because they found lanthanum depositions by histology in endoscopically
normal mucosa.
The histologic correlate to the whitish discoloration are histiocytes
containing brownish foreign bodies in the lamina propria. In an early
stage of deposition, the macrophages are arranged singly or in small
clusters, whereas in later stages they diffusely infiltrate the mucosa.
The macrophages in our specimen showed a diffuse infiltration pattern,
which fits with a later stage accumulation. Nakamura et al. suggest that
M2-polarised macrophages play a crucial role for the clearance of
lanthanum. Lanthanum is likely to be resistible to intracellular
digestion, so histiocytic activation with following tissue damage is
conceivable. The endoscopic features show a significant relationship
with the degree of histiocytic infiltration. Hattori et al. found that
the histiocytic infiltration is specific for lanthanum deposition. The
daily dose of lanthanum carbonate positively correlates with lanthanum
deposition in the mucosa. Various histopathological changes are
described with lanthanum depositions. Most often metaplastic changes,
regenerative changes, foveolar hyperplasia, and chromic or active
inflammation are described. Nishida et al. found no association between
the range of atrophic changes and lanthanum depositions. Our patient
also showed no atrophic changes in the mucosa, which would be concordant
with Nishidas observations. Haratake et al. and Valika et al. found that
preformed ulcers as well as underlying pathologies induced by NSARs
aggravate the entry of lanthanum.As those mucosal changes are often
described with a helicobacter pylori positive gastritis, several authors
looked for a relationship between helicobacter infection and lanthanum
deposition. Namie et al. suggest that a helicobacter pylori infection
may aggravate lanthanum entry through the compromised mucosal barrier.
Shitomi et al. did not find helicobacter pylori infection in patients
with a lanthanosis and propose that a helicobacter infection might
prevent accumulation of lanthanum in the mucosa through a higher pH and
a disturbed histiocytic infiltration in the setting of an inflammation.
Iwamuro et al. suggest that the gastric body is predominantly affected
by lanthanum deposition, which was also true for our patient, because of
the prolonged contact time of lanthanum with the mucosa.
Another reason why it is important that endoscopist should know about
gastric lanthanosis is that it can endoscopically imitate early gastric
cancer. Yabuki et al. even described squamous cell carcinoma associated
with lanthanum deposition in a rat model. They also found that other
mucosal lesions such as chronic inflammation and intestinal metaplasia
were more frequent in mucosa with lanthanum depositions. So, they
conclude that lanthanum could indirectly induce metaplasia. Tabushi et
al. described the first case of early gastric cancer in association with
gastric lanthanosis. Shitomie et al. and Takatsuna et al. described
gastric cancer in gastric lanthanosis patients, but they found less or
any lanthanum depositions in the neoplasia itself. They suggest that the
neoplastic mucosa has a malfunctioning absorption mechanism which leads
to lesser lanthanum deposition in that area. With this in mind it is
crucial to know how those depositions develop over time and if they are
reversible. Lanthanum depositions seem to gradually expand over time,
while taking lanthanum carbonate, in humans as well as in a rat model.
Whilst Rothenberg et al. observed a reduction in symptoms and
histological findings after cessation of lanthanum carbonate, Awad et
al. found only a reduction of symptoms. Namie et al. and Hoda et al.
described persisting depositions after cessation. Hoda et al. reported
one patient that received a kidney transplant and discontinued lanthanum
carbonate. What this patient has in common with our patient is the
discontinuation of lanthanum carbonate due to kidney transplant and
continuing lanthanum deposition in the gastric mucosa. We found no other
cases in the literature that described a long cessation of lanthanum
carbonate with lanthanum deposits. A limitation of our case report is
that we have no preceding endoscopies or biopsies, so we do not know how
the lanthanum deposition changed over time. We think that the
immunosuppressants our patient takes could be involved in the long
duration of the deposition. As Tacrolimus and Mycophenolat inhibit
mainly lymphocytes, but also macrophage immune response one could
postulate that this leads to a prolonged clearance of lanthanum. But
neither the accumulation-, nor the clearance mechanism are understood,
so we can only speculate at this moment.