Alpha-1-antitrypsin deficiency in a diverticular disease population

The incidence of diverticular disease (DD) is increasing worldwide and
is becoming a significant burden on national healthcare systems.1
Diverticulosis is the most common pathological finding in routine colonoscopy.
It comprises both diverticulitis and diverticular hemorrhage. Obesity, smoking,
and various inheritable disorders raise an individual*s risk of
diverticulosis5. The underlying pathophysiological mechanism that causes the
formation of colonic diverticula is not clear. The dominant theory is based on
fibre deficiency, which was set in 19712. This theory states that fibre
deficiency results in decreased intestinal contents and smaller size of the
lumen. Since the colonic muscles are contracting continuously in order to
transmit and expel the stool, an increased intraluminal pressure is formed.
This increased pressure leads to the formation of diverticula at the weakest
anatomical locations in the wall. These predestined weak spots in the colonic
wall are formed due to the entering of terminal branches of the colonic
arteries and are called vasa recta.

However, within the last decade, a new hypothesis has emerged, which
may be helpful in understanding the etiology of diverticulosis. This hypothesis
is based on the fact that diverticulosis is an age-related disorder, since
ageing eventually leads to the altering of colonic epithelia, colonic mucosal
flora and microbial environment3. Ageing induces a declining colonic wall
mechanical strength, which can be partly attributed to changes in collagen
structure. Wess et al preformed a study to investigate how the collagen
structure changes in colonic diverticulosis.4 The results indicated that
colonic collagen from subjects affected by colonic diverticulosis had a higher
number of cross-links than subjects with unaffected colonic tissue. This
illustrates that the structural changes to tissue collagen affected by colonic
diverticulosis have a greater impact than the changes that occur as part of the
natural ageing process. Consequently, colonic diverticulosis could be the
result of an exaggerated and premature ageing process and intrinsic changes in
collagen structure.

Alpha-1-antitrypsin (A1AT) is a protease inhibitor of the proteolytic
enzyme elastase and also of the proteases trypsin, chymotrypsin, and thrombin.
It is part of a larger family of structurally unique serine protease
inhibitors, referred to as serpins, which have also been implicated in the
pathogenesis of neurodegenerative diseases, angioedema, and coagulation
abnormalities, collectively called *serpinopathies*.6,7 It is assumed that
there are at least 116 million carriers (PiMS and PiMZ) and 3.4 million
deficiency allele combinations (PiSS, PiSZ, and PiZZ) worldwide. Furthermore,
A1AT-deficiency is one of the most common hereditary disorders in the world and
is not only a disease among Europeans, yet, is one that affects individuals
from all racial subgroups worldwide.8

A large part of the A1AT-deficiency population eventually develops
severe pulmonary pathology. Sometimes a lung transplantation is necessary to
improve long-term survival.9 In the field of lung transplant surgery, the
correlation between A1AT-deficiency and gastro-intestinal complications has
been highlighted. Gastrointestinal complications after lung transplantation
have been reported with incidence rates ranging from 3% to 51%, but the
underlying mechanisms are poorly understood.10,11,12 Elective abdominal
operations are relatively safe in properly prepared lung transplant recipients.
However, laparotomy for urgent surgical conditions, such as bowel resections
and a subtotal pancreatectomy, are associated with increased morbidity and
mortality rates. This is partly caused by the seriousness of acute abdominal
conditions and the operation, but also by the status of the lung transplant as
manifested by previous rejection episodes, perioperative steroid dosages and
FEV1 values.13 Bredahl et al discovered that A1AT-deficiency is the only
significant risk factor identified for gastrointestinal complications that
required laparotomy within three months after lung transplantation.10 Recently
Tanash investigated cause-specific mortality in individuals with severe A1AT
deficiency in comparison with the general population in Sweden. They discovered
PiZZ individuals had an increased mortality due to respiratory and hepatic
disease, diverticulitis, and pulmonary embolism was markedly increased compared
with the age- and sex-matched Swedish population. We think this finding
supports our hypothesis that A1AT could have a direct relation with developing
diverticula. 14

The ALADDIN-study aims to determine additional causes for developing
diverticulosis with respect to the already poorly understood causes. An
interesting hypothesis is that connective tissue diseases, in particular
deviations in the A1AT protein contribute to the development of
diverticulosis. Once there is a better understanding of the relation between
A1AT and the prevalence of diverticulosis, it will be possible to investigate
alternative treatment approaches for this global health issue. For example, a
screening program for patients who are in need of lung transplantation could be
evaluated since A1AT deficiency is common in this population. Moreover,
preventive screening could be an option in these specific groups to identify
early abdominal problems, focusing on diverticulosis and its complication
diverticulitis, cholecystolithiasis and gastric/duodenal ulcers. Once it is
clear that these patients have a higher risk on serious abdominal problems, a
more aggressive approach could be used.

This study aims to investigate whether deviations in A1AT contributes
to the development of diverticula. Better understanding of the association
between A1AT and diverticula could possibly contribute to changes in the
treatment of diverticulitis. After an extensive literature review, we have
concluded that a link between A1AT and the presence of diverticula has never
been explored before. However, there is a lot of circumstantial evidence that
there is a link between these pathologies.

Primary Objective:
To determine the prevalence of A1AT-pathology by genotype analysis of patients
with DD and comparing this to a population without DD.

Secondary Objective:
To determine whether the population with A1AT pathology develops more often an
episode of diverticulitis, whether it leads to more hospital admissions and to
more diverticulitis related surgeries compared to the population without A1AT
pathology.

Patients with abdominal pain, who visit the ER from 2017 till 2019 or are
admitted in hospital and develop abdominal pain and have to undergo an
abdominal CT scan will be analysed. The flowchart in Figure 1 summarizes the
process of inclusion and exclusion. The research group will consist of patients
diagnosed with diverticula, whereas the control group will consist of patients
who have no diverticula or only a few of them. A patient is eligible for the
research group if an abdominal CT scan reveals several diverticula whereas a
patient is eligible for the control group if an abdominal CT scan shows no
diverticula or only a few of them. . 16,17,18,19,20,21

During the visit in which the patient undergoes an abdominal CT scan, each
eligible patient will be asked if he or she wants to receive any information
with regards to this study. The conversation will take place after the CT scan.
If they do want to receive information, the patient information folder will be
provided. After receiving the necessary information, the patient will reflect
whether he or she wants to participate in this study. After this period, the
individual will be asked whether he or she wants to participate. If they do
want to be part of the study, informed consent will be obtained.

After the selection procedure, blood samples will be collected in order to
determine the concentration of A1AT in serum. We will also perform genotype
analysis to determine specific phenotypic variations. Genotype analysis uses
allele-specific amplification that allows the variants to be identified, such
as S or Z. Although the optimum formula for A1AT deficiency testing has not
been formulated, serum level measurement combined with genotype analysis is
often used in clinical setting.

Once all data is collected patients with diverticula will be compared to
patients without diverticula(or only a few diverticula). Furthermore,
evaluation on the development and severity of diverticulitis in both groups
will be performed by closely monitoring them during and after their hospital
visit or hospital admission. We will also gain additional information from the
questionnaires and patient records about previous hospital admissions as a
result of diverticulitis.

The design of this study is a multi centre prospective case-controlled study.

The patients who will participate in our research will have to undergo a
venepuncture procedure, which will result in 3 blood samples. During the same
visit they will be asked to fill out a questionnaire to provide additional
information.