Abnormalities in Collagen Composition May Contribute To The Pathogenesis of Hemorrhoids: Morphometric Analysis
Abnormalities in Collagen Composition May Contribute To The Pathogenesis of Hemorrhoids: Morphometric Analysis
Abnormalities in Collagen Composition May Contribute To The Pathogenesis of Hemorrhoids: Morphometric Analysis
DOI 10.1007/s10151-014-1238-5
ORIGINAL ARTICLE
Received: 14 September 2014 / Accepted: 29 September 2014 / Published online: 9 November 2014
The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract
Purpose While hemorrhoidal disease is common, its etiology remains unclear. It has been postulated that disturbances in collagen lead to reduced connective tissue
stability, and in turn to the development of hemorrhoidal
disease. We aimed to compare the quality and quantity of
collagen in patients with hemorrhoidal disease versus
normal controls.
Methods Specimens from 57 patients with grade III or IV
internal hemorrhoids undergoing hemorrhoidectomy
between 2006 and 2011 were evaluated. Samples from 20
human cadavers without hemorrhoidal disease served as
controls. Quality of collagen was analyzed by collagen I/III
ratio, and quantity of collagen was determined by collagen/
protein ratio. The study group was subdivided into gender
and age subgroups.
Results The male:female ratios in the study and control
groups were 30:27 and 10:10, respectively. Median age
was significantly less in the study group [46.9 years (range
2069)] compared to the control group [76 years (range
4690)] with P \ 0.05. Tissues from patients in the study
group had significantly lower collagen I/III ratio as compared to the control group (4.4 1.1 vs. 5.5 0.6;
P \ 0.0001). Nevertheless, despite a trend toward lower
collagen/protein ratio in the study group, it did not reach
statistical significance (57 42.4 vs. 73 32.5 g/mg;
Y. Y. Nasseri K. M. Van Groningen M. Berho
M. C. Osborne S. Wollman E. G. Weiss S. D. Wexner (&)
Department of Colorectal Surgery, Cleveland Clinic Florida,
2950 Cleveland Clinic Blvd., Weston, FL 33331, USA
e-mail: [email protected]
E. Krott
Klinik fur Allgemein-, Visceral-und Transplantationschirurgie,
Universitatsklinikum Aachen, Aachen, Germany
Introduction
Hemorrhoids have been described as far back as the preChristian era [1]. In 1830, de Montegre [2] assembled an
early literature review of 78 articles on hemorrhoids published between 1582 and 1817. His manuscript remarked
how little was known about the overall prevalence and risk
factors of hemorrhoidal disease; not much changed during
the past 200 years. Although most colorectal surgeons
recognize that hemorrhoids are common, they are unaware
of their true prevalence. Previous studies have reported
rates ranging from 4.4 [3] to 86 % in the general population [4].
Hemorrhoidal disease is defined as the symptomatic
enlargement and distal displacement of the normal anal
cushions [5]. The main theory regarding the pathophysiology of hemorrhoidal disease suggest that they are the
result of abnormal dilation of veins of the internal hemorrhoidal venous plexus, abnormal distention of the arteriovenous anastomosis, and prolapse of the cushions and
the surrounding connective tissue. Numerous factors have
been linked with hemorrhoidal disease including inadequate fiber intake, prolonged lavatory sitting, constipation,
diarrhea, and pregnancy. Family history of hemorrhoidal
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Methods
Patients
Patients with grade III or IV internal hemorrhoids who
underwent standard hemorrhoidectomies between 2006 and
2011 were identified. Specimens from these patients were
collected and fixed in 10 % formalin and immediately
embedded in paraffin for later analysis. The study group
was further subdivided into one of two genders and one of
three age groups (20, 40, and 60 s).
The control group was made up of 20 human cadavers
without hemorrhoidal disease. In review of the past medical histories of these cadavers, hemorrhoidal disease was
never listed as a condition they had. All 20 cadavers died of
natural causes and were made available from the Institute
of Anatomy of the RWTH Aachen, Germany. The cadavers
were analyzed immediately after their arrival at the institute, and the anal and deep rectal skin and submucosa were
resected by traditional hemorrhoidectomy. Specimens from
the 20 controls were collected and fixed in 10 % formalin
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85
M:F
ratio
Mean age in
years (range)
Collagen
I/III ratio
P value
(collagen I/III)
Study (n = 57)
30:27
Control (n = 20)
10:10
46.9 (2069)
4.4 1.1
P \ 0.001
76 (469)
5.5 0.6
Collagen/protein
ratio (g/mg)
P value
(collagen/
protein)
57 42.4
0.167
73 32.5
Collagen
I/III ratio
P value
(collagen
I/III)
Collagen/
protein
ratio (g/mg)
P value
(collagen/
protein)
50.8 32.6
0.258
Gender
Results
The mean age of the study group was 46.9 (2069), which
was significantly lower than the mean age of the control
group 76 (4690) years with P \ 0.05. The male:female
ratios for the study and control groups were 30:27 and
10:10, respectively.
Collagen type I/III ratio
The mean collagen I/III ratio was significantly lower in
patients with hemorrhoidal disease as compared to the
control group (4.4 1.1 vs. 5.5 0.6; P \ 0.001;
Table 1). See Figs. 1 and 2 for representative comparative
collagen I/III ratio slides. Within the study group, there was
no significant difference in the collagen I/III ratio between
men and women (4.4 1.2 vs. 4.3 1.0; P = 0.612) and
Male (n = 30)
Female
(n = 27)
4.3 1.0
64 50.9
Age
20 s (n = 17)
40 s (n = 18)
4.8 1.2
46.3 23.6
65 62.8
60 s (n = 22)
4.1 1.0
59.7 34.4
0.314
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86
Discussion
Collagen is the major insoluble fibrous protein in the
extracellular matrix and connective tissue and is the single
most abundant protein in the animal kingdom. While there
are at least 16 types of collagen, 8090 % of the collagen
in the body consists of types I, II, and III [10]. Type I
collagen fibers have immense tensile strength and can
withstand enormous forces, while type III collagen are
thinner and more immature [10, 11]. The strength and
quality of connective tissue is primarily determined by the
amount and ratio of collagens Type I and III. Decreased
Type I to III collagen ratio translates into decreased amount
of cross-linking and hence, reduced mechanical stability of
connective tissue.
Our data clearly indicated a decrease in Type I/III collagen ratio in patients with hemorrhoidal disease as compared to normal controls. This finding may link reduced
mechanical stability and tensile strength in extracellular
matrix with development of hemorrhoidal disease. Our
study further demonstrated a lower trend in the collagen/
protein ratio in patients with hemorrhoidal disease,
although this did not reach statistical difference as was seen
in the Willis et al. [9] study. This difference can be
attributed to difference in the power of the two studies.
Although hemorrhoidal disease has been associated with
older age, we failed to demonstrate any difference in
quality or quantity of hemorrhoids among different age
groups within the study group. This finding may be due to
either the small number of patients in each age group or to
the fact that only patients with known hemorrhoidal disease
were compared. Perhaps there is a true degradation in
collagen with age in the general population, but due
to genetic/hereditary factors, patients with hemorrhoidal
disease are subject to earlier and more rapid tissue
degradation.
The previously held belief that connective tissue disease
directly correlates with hernias and genitourinary prolapse
may also hold true with hemorrhoidal disease [12, 13]. As
mentioned in the study by Willis et al., we too believe that
hemorrhoidal turnover and degradation is likely the
sequelae of genetic, metabolic, and environmental
components.
One of the limitations of our study is the relatively small
number of control patients. One must bear in mind that it is
difficult to find hemorrhoidal tissue from live surgical
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None.
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