Consent
statement
Written informed consent was obtained from the patient to publish this
report in accordance with the journal’s patient consent policy.
Conflict of interest
statement
Felix Harpain reports a grant and lecture fee from Takeda, outside the
submitted work. Elisabeth Hütterer and Anton Stift report lecture fees
from Takeda, outside the submitted work. Clara Luhn, Hermine Agis,
Ingrid Simonitsch-Klupp and Christopher Dawoud have indicated they have
no conflict of interests to disclose.
Case Report
Corresponding Author: Felix Harpain, MD
Department of General Surgery, Division of Visceral Surgery, Medical
University of Vienna, Austria
Währinger Gürtel 18-20, 1090 Vienna, Austria.
Phone: 43-1-40400-69400
E-mail:
felix.harpain@meduniwien.ac.at
Keywords: amyloidosis, intestinal failure, glucagon-like
peptide-2, teduglutide, enteral autonomy
Total numbers of Figures and Tables: 2 Figures, 0 Tables, 0
Supplementary Figures and 0 Supplementary Tables.
Word count: excluding abstract, acknowledgements, tables,
figure legends and references: 2286
Word count abstract : 230
ABSTRACT
Amyloidosis is a heterogeneous disease characterized by tissue
deposition of abnormally-folded fibrillary proteins that can manifest
itself by a wide variety of symptoms depending on the affected organs.
GI involvement among amyloidosis patients is common. Its clinical
manifestation often presents with nonspecific symptoms such as weight
loss, diarrhea and malabsorption. With no specific treatment existing
for GI amyloidosis, therapy focuses on impeding amyloid deposition as
well as managing the patients’ symptoms with supportive measures. Here
we present an AL-amyloidosis patient with GI involvement and intestinal
failure who was successfully treated with the GLP-2 analogue
teduglutide. Over the course of treatment with teduglutide, the patient
was able to achieve independence from parenteral nutrition and
experienced a significant improvement in quality of life as stool
frequency and consistency improved, urinary output was stabilized and
body weight as well as body composition improved over the course of
teduglutide therapy. With no longer being exposed to the burden and
associated risks of parenteral nutrition, we were able to reduce the
potential morbidity and mortality rate as well as to improve the
patient‘s overall quality of life. Intestinal tissue biopsy workup
revealed a histopathological correlate for the clinical response;
Congo-Red-positive intestinal depositions almost completely disappeared
within six months of teduglutide therapy. Implementing intestinotrophic
GLP-2 analogue teduglutide may enrich the spectrum of treatment options
for amyloidosis patients with intestinal failure who are dependent on
parenteral support.
BACKGROUND
Amyloidosis is a chronic progressive disease in which misfolded,
insoluble as well as digestion-resistant proteins accumulate in various
tissues causing severe structural and functional organ damage (1, 2). As
the body is unable to eliminate these accumulating proteins, they
permanently disrupt the enzyme function and cell metabolism and thereby
impair the function of the organs where they have accumulated. The
deposition of these insoluble fibrillary proteins, called amyloids, may
affect any tissue or organ. However, the heart, kidneys, liver, nervous
system and gastrointestinal tract are most often affected. (3, 4)
Several subforms of amyloidosis may be classified based on the involved
amyloidogenic protein, the associated clinical syndromes, and the extent
of organ system involvement (3).
Within generalized amyloidosis, the gastrointestinal (GI) tract is often
affected by amyloids primarily deposited in the small intestine (5). The
misfolded proteins mostly appear in the muscularis mucosae and stromal
tissue affecting the vasculature, nerves and nervous plexuses close by
leading to impaired intrinsic peristalsis and absorption (6, 7). Typical
symptoms are constipation, alternating constipation and diarrhea,
chronic diarrhea, abdominal pain, and malabsorption leading to severe
weight loss since enteral nutrient and fluid supply can no longer
sufficiently be utilized (7-9). In addition, GI tract involvement also
significantly affects the overall survival in amyloidosis patients: Lim
et al. observed in a prospective cohort study of AL-amyloidosis patients
a 15.84 months survival in patients without GI involvement and 7.95
months with GI involvement. (10)
Intestinal failure (IF), as the worst consequence of malabsorption, is
not only associated with increased morbidity and mortality but also
associated with poor quality of life (QoL) (11, 12).
IF in short bowel syndrome (SBS) patients is caused by surgical bowel
resection resulting in patients being unable to meet nutritional needs
for enteral autonomy and are therefore dependent on parental support
(PS) (13).
A significant impact in treating IF was achieved with the glucagon-like
peptide-2 (GLP-2) analogue teduglutide (14). GLP-2 is secreted from the
enteroendocrine L-cells of the terminal ileum and colon and was
discovered and described as a key factor in intestinal rehabilitation
and growth (15). GLP-2 stimulates the growth of the intestinal mucosa
through stimulation of crypt cell proliferation and inhibition of
enterocyte apoptosis (16, 17). Additionally, GLP-2 impedes gastric
emptying and acid secretion, stimulates intestinal blood flow and
increases the intestinal barrier function (15). The drug is approved for
patients suffering from SBS with chronic IF and enhances the intestinal
absorption of fluids and nutrients and, therefore, can reduce the
patients’ need for parenteral support (PS) (18).
To the best of the authors‘ knowledge, this case report is first to
present the use of teduglutide in treating AL-amyloidosis-associated IF.
CASE REPORT
In this case report we present a 45-year-old male patient with
AL-amyloidosis with renal and enteric involvement (iFLC (involved free
light chain) 103.2 mg/l, dFLC (difference free Light chain) 71.1mg/l,
kappa/lambda ratio 0.31). The patient was first presented to our
hospital after the initial diagnosis of renal AL-amyloidosis of the
kidneys was made and transferred with suspicion of gastrointestinal
involvement.
The patient presented to an outside hospital with progressive edema of
the lower extremities, shortness of breath, massive diarrhea and body
weight loss of unknown origin. A nephrotic range proteinuria (Palladini
Stage II (19) with a protein/creatinine ratio 24530mg/g,
albumin/creatinine ratio 22696mg/g, eGFR of >50mL/min per
1.73 m2) prompted a kidney biopsy with the
histopathologic workup clearly revealing an AL-amyloidosis with
glomerular deposition of lambda light chains. After having already lost
ten kilograms within six months the patient was introduced to our
clinical department of hematology and hemostaseology and treated
interdisciplinary with our IF unit (see Figure 1 for body weight
course).
The patient suffered from massive diarrhea (8-12 bowel movements per
day, Bristol stool scale 6-7 (20)), malabsorption, fecal incontinence,
leg edema, hypotonic blood pressure and disorientation due to his
physical weakness. A bone marrow biopsy showed approximately 20%
atypical plasma cells with an aberrant immunophenotype
(CD20+/Cyclin-D1+/CD117+/Lambda+) as well as vascular AL-amyloidosis. An
initial colonoscopy with random intestinal biopsies histologically
confirmed GI involvement by AL-amyloidosis (see Figure 2). In addition
to the nephrotic syndrome that led to an extreme protein loss, the
severe diarrhea increased the patient’s protein deficiency. Furthermore,
the diagnostic workup revealed no cardiac involvement by amyloidosis,
staging the patient at Mayo 2012 stage 0 (Troponin T 0.014ng/dl, proBNP
223 pg/ml, dFLC 71.1mg/l) (21).
Symptomatic therapy in terms of antidiarrheal and antisecretory agents
and daily albumin infusions was performed. Additionally, the patient
received tight-meshed counselling through our SBS unit dietary program.
Unfortunately, however, a satisfying improvement of the overall medical
condition could not be achieved by it.
The underlying plasma cell dyscrasia was treated with the monoclonal
antibody daratumumab and the proteasome inhibitor bortezomib: The
patient received an induction therapy consisting of three cycles of
daratumumab and dexamethasone and nine cycles of daratumumab, bortezomib
and dexamethasone followed by a maintenance therapy of daratumumab and
dexamethasone. With that treatment, the patient revealed a good
hematologic response (iFLC of 31.7mg/l, dFLC of 7.9mg/l). Nevertheless,
in terms of organ therapy response, we observed a disease progression:
although an improvement of the protein/creatinine ratio and
albumin/creatinine ratio with 4459mg/g and 3380mg/g, respectively, could
be achieved, renal function deteriorated with an over 25% increase of
serum creatinine after nine cycles of therapy (from 1.12 to 2.51 mg/dl
with a concomitant decrease of the glomerular filtration rate from 63.63
to 28.07 ml/min per 1.73 m2) (22). We waived periodic
24 h urine protein measurements as those were biased anyway by the
massive volume losses caused by the diarrhea.
In addition, the patient continued to be severely malnourished, with a
body mass index of 19kg/m2 and laboratory tests
revealing his malnourishment. He continued to suffer from severe
diarrhea resulting in energy and fluid loss subsequently making him
dependent on PS. He was started on a parenteral nutrition (PN)
(900kcal/day) and intravenous fluids with additional water-soluble and
fat-soluble vitamins, trace elements and albumin (20g) on a daily basis
(see Figure 2 for the course of PS). With the PS, the excessive weight
loss of the patient (now already over 30 kg in 4 months) could be
stopped. Although he was able to maintain his weight with the offered
PS, gaining body weight was not possible and his general physical
weakness was obvious.
Considering the patient’s course and the prognosis of the disease and
his poor QoL, which was severely affected by the diarrhea, the need for
PS, and his risk of central line-associated bloodstream infections
(CLABSI) and sepsis, the option of off-label treatment with teduglutide
was discussed within an interdisciplinary team. The possibility of
achieving enteral autonomy through teduglutide therapy and adjusting him
to an optimal diet without the disadvantages of PS was presented to the
patient who agreed to a therapy attempt with teduglutide.
At the beginning of the treatment, the patient received an adjusted dose
of teduglutide due to his renal function impairment. Nevertheless, the
patient showed an excellent response and tolerance to teduglutide so
that the dose could be increased to the full, body weight-adjusted dose
with improvement of the renal function after three months.
Throughout treatment with teduglutide, the patient’s dependency on PN
was eliminated (see Figure 1). The patient’s leg edema also regressed
and his physical condition improved due to his body weight gain. In
addition, we also observed a symptomatic response as his daily bowel
movements were reduced down to two to four per day (with an improved
stool consistency, Bristol stool scale 4-5) with a stable daily urine
output of around 1000 ml per day (see Figure 1 for urine output over
time). The excellent clinical course under teduglutide therapy prompted
a follow-up colonoscopy. Analysis of small and large bowel tissue
biopsies revealed an almost complete disappearance of the Congo-Red
positive material as a potential histopathological correlate to the good
clinical response (see Figure 2).
DISCUSSION
This case report presents an AL-amyloidosis patient with severe enteric
involvement leading to intestinal failure who was treated with the GLP-2
analogue teduglutide and thereby was able to discontinue PN and
simultaneously achieve a good nutritional status. Histological workup
revealed that intestinal amyloid deposits nearly disappeared after six
months of teduglutide therapy.
Amyloidosis is a poor prognosis disease and is known to manifest itself
in a wide array of symptoms depending on the involved organ with most
patients having several organ systems involved at presentation (4). The
GI tract is often affected in patients with amyloidosis and denotes a
significant risk factor for poor prognosis as it nearly halves the
median survival compared to amyloidosis patients with an unaffected
intestine (7, 10, 23).
GI involvement also played a dominant role in the course of the disease
in the here presented case. Unable to be sufficiently alleviated by
symptomatic therapy in terms of antidiarrheal and antisecretory agents
and daily albumin infusions the general health status worsened over the
initial course of therapy. Although the amyloidosis-specific therapy
achieved a good hematologic, organ response (GI and renal) was poor.
With decreasing physical strength and malnourishment and a significant
body weight loss, PS was an unavoidable measure in the course of
treatment leading to a stabilization of the health status. However, with
PS it was not possible to sufficiently improve the patients’ symptoms
and enable a significant body weight gain. Furthermore, due to PS the
patient was now also exposed to new risks such as CLABSI, central
thrombosis, and intestinal failure-associated liver disease (IFALD) (24,
25). Up to 70% of PN-associated deaths are attributable to the
infection of the central venous catheter exposing this patient
population to a significant health risk (26-28). Besides the well-known
metabolic issues and infectious risks associated with PS, patients also
need to face psychological problems such as depression and anxiety due
to their inability of having normal oral intake, long “hook up” times
to PS restricting their mobility on day time and overnight infusions
deteriorating sleeping habits (29).
The synopsis of the clinical findings led to the experimental approach
of treating the patient with the intestinotrophic growth factor
teduglutide, which is currently approved and specifically indicated for
the treatment of SBS patients with IF (SBS-IF) (18). The patients‘
AL-amyloidosis with intestinal involvement showed great similarities to
the clinical manifestation of SBS-IF. Therefore, treatment with
teduglutide presented a great opportunity to achieve an improved
nutritional status without exposing the patient to the risks of PS. By
activating the GLP-2 receptor, teduglutide is able to induce enterocyte
proliferation in the crypts and hindering enterocyte apoptosis at the
top of the villi, thereby causing intestinal mucosal growth and
subsequently enhancing intestinal absorptive capacity (16, 17). The
results of the pivotal prospective randomized-controlled STEPS trial and
the open-label extensions revealed that around 20 percent of patients on
teduglutide were able to completely discontinue PS (18, 30-32).
Nevertheless, subsequent retrospective cohort analyses, unbound to any
study weaning protocols revealed much higher enteral autonomy rates
(33-36). Especially, the experience at our institution of SBS-IF
patients under teduglutide therapy showed a much-improved outcome, with
over 90% of patients achieving enteral autonomy and thereby complete
independence from PS (37). The experiences with teduglutide at our
institution, the similarity of the clinical manifestation of the
patient‘s AL-amyloidosis-associated IF to SBS-IF patients and the
general good tolerability of teduglutide (38) supported the here
presented new treatment approach with teduglutide. Three months into the
treatment with teduglutide as well as being closely supervised and
supported by a multidisciplinary team within our institution, the
patient was able to fully discontinue PN, reduce intravenous fluid
intake while at the same time improving urinary output and gaining body
weight. After the discontinuation of PN, the patient continued gaining
weight, finally reaching a body weight of 65kg and a total weight gain
of 10 kg.
Another interesting finding of this case report is the histopathological
workup of the intestinal biopsies revealing a potential explanation for
the excellent clinical outcome. The patient received a colonoscopy at
the initial presentation at our institution where the pathological
workup in terms of a positive Congo-Red staining of the biopsy specimens
confirmed the diagnosis of intestinal involvement of the AL-amyloidosis.
After six months of teduglutide treatment with an excellent clinical
response to the teduglutide therapy, another colonoscopy with intestinal
biopsies was performed. Histopathological analysis revealed a near total
disappearance of the Congo-Red positive stained material with only
remnant positive staining in single fibers of the lamina propria of the
small bowel and a complete disappearance in the large bowel. As the
Congo-Red staining is highly specific for the amyloid deposits, this
would mean intestinal regeneration from the amyloidosis.
Nevertheless, an explanation for the observed phenomena is yet to be
awaited and needs further research. The intestinal amyloid deposits are
usually observed in the stromal compartment and subsequently hinder
intestinal function, while current knowledge of the functional principle
of the GLP-2/GLP-2R axis involves the mucosal crypt-villus axis as
activation induces crypt cell proliferation and exerts anti-apoptotic
actions of the enterocytes at the tip of the villi (16, 17). Although
the effector tissue is the intestinal mucosal epithelium, the actual
GLP-2R seems to be located in non-epithelial cells such as subepithelial
myofibroblasts, enteric neurons and the enteroendocrine L-cells with
growth factors such as keratinocyte growth factor, insulin-like growth
factor 1, and ErbB subfamily of ligands transducing the intestinotrophic
actions (39-41). The stromal location of the GLP-2R location may hold
the key to the unknown mechanism of amyloid clearance under teduglutide
therapy in the here presented case.
CONCLUSION
This case report describes a new treatment approach of an amyloidosis
patient with IF who was successfully treated with the GLP-2 analogue
teduglutide. The treat-to-target goal of enteral autonomy in such
patients seems to be of utmost importance as it eases the patients of
PS-associated morbidity and mortality while enabling improved body
weight and composition as well as QoL.
FIGURE LEGENDS
Figure 1 Clinical response to teduglutide therapy.
Left y-axis depicting parenteral support volume in milliliter [ml],
right y-axis body weight in kilogram [kg].
i.v. intravenous ; PN parenteral nutrition ; PSparenteral support ; TED teduglutide .
Figure 2 Congo-Red staining before (A) and after six
months (B) of teduglutide therapy.
Panel A depicting Congo-Red staining of small and large bowel
biopsies showing conspicuous deposition of intensely stained homogeneous
amorphous fibrillary material in the lamina propria (LP) (focal green
autofluorescence was noted in polarized light, not shown). PanelB revealed Congo-Red staining of both small- and large bowel
biopsies after treatment, demonstrating only single fibers (small bowel)
with weak specific red staining within the LP; the biopsy of the large
bowel showed no Congo-Red positive depositions.
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