Accumulation of advanced glycation endproducts in patients with systemic amyloidosis.

Amyloidosis is a protein folding disease characterized by deposition of protein
fibrils with a β-sheet structure. This structure is responsible for its
insolubility and resistance to proteolysis. Is systemic amyloidosis deposition
of amyloid in (vital) organs leads to organ dysfunction and, if untreated,
eventually leads to death.
Different types of amyloidosis can be distinguished depending on the type of
precursor protein of the amyloid fibril. The three most common types of
systemic amyloidosis are: AA, AL and ATTR amyloidosis.
In AA amyloidosis the precursor protein is serum Amyloid A protein (SAA), an
acute phase reactant. This type of amyloidosis is seen in patients with chronic
inflammatory diseases. In AL amyloidosis the precursor protein is a kappa or
lambda immunoglobulin light chain. The underlying plasma cell dyscrasia is
often very low grade and usually lacks the malignant sheets of immature plasma
cells as seen in multiple myeloma. ATTR amyloidosis is an autosomal dominant
hereditary disease caused by various point mutations of transthyretin (TTR),
whereas in old age a senile type of ATTR amyloidosis is caused by deposition of
wild-type TTR. Transthyretin is almost exclusively produced by the liver and
functions as transport protein of thyroid hormone and retinol binding protein.
Advanced glycation end products (AGEs) are proteins or lipids that become
non-enzymatically glycated by exposure to sugars under influence of oxidative
stress. Increased accumulation of AGEs is seen in patients with diabetes
mellitus, patients with renal insufficiency and patients with (chronic)
inflammation. AGE have several harmful effects. First, cross-linking of AGEs
with proteins in the extracellular matrix results in a decrease of tissue
elasticity. Second, AGE-modification may alter protein structure and function.
Third, AGEs may modulate the function of cells by interaction with and
activation of the receptor for AGEs (RAGE).
Several studies have shown the presence of AGEs in amyloid depositions in
patients with ATTR amyloidosis. Recent studies demonstrated that fibrinogen
from ATTR patients displays an impaired chaperone capacity, due to differential
glycation by methylglyoxal. Glycation of fibrogen thus affects its ability to
suppress protein aggregation and amyloid deposition.
Based on these findings it can be hypothesized that AGEs are involved in the
pathophysiology of systemic amyloidosis in several ways.

To explore whether:
1. Accumulation of AGEs is increased in systemische amyloïdose.
2. AGE accumulation is related to the degree of AGE deposition.
3. AGE accumulation is related to inflammation, renal function en glycemic
status in patients with amyloidosis.

1. AGE accumulation will be studied cross-sectionally in patients with AL and
ATTR amyloidosis and healthy age- and sex-matched controls.
Tissue AGEs accumulation can be assessed as skin autofluorescence, following
the principles of the AGE-reader, which is a validated and non-invasive
technique.

2. Skin autofluorescence will be related to the amyloid load in fat tissue
(semi-quantitative scored Congo red-stained abdominal fat smears) and extent of
amyloid deposition as assessed using 123I-gelabelde serum amyloïd P component
(SAP) scintigraphy.
Abdominal fat smears and SAP scintigraphy are obtained as part of standard
clinical care.

3. Skin autofluorescence will be related to levels of C-reactive protein as
measure of inflammation, creatinine as measure of renal function, and HbA1c as
measure of glycemic status.

Patient burden related to participation in this study exists of measurement of
skin autofluorescence using the AGE-reader which takes approximately 10
minutes. This technique is non-invasive, painless and safe. Measurement of skin
autofluorescence will be combined with a routine outpatient clinic visit.
Data of patients and controls will be coded. Results of individual patient will
not be reported to their physician or medical specialists. The result of
AGE-measurement is not disclosed to the patient as AGE-measurement has not yet
been validated in patients with amyloidosis and that there are no consequences
attached to the outcome.
In addition to the routine blood tests the HbA1c-level will be determined. For
this purpose, it is not necessary to draw extra blood. If the patient appears
to have diabetes this will be communicated with the patient and his or her
physician.
The results of this study can provide insight into the pathophysiology of
systemic amyloidosis.