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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1562_Библиотеки_им_академика_М_И_Перельмана.pdf
In: Hernias ISBN: 978-1-62948-441-9
Editor: Mark A. Suckow © 2014 Nova Science Publishers, Inc.
Chapter 1
THE INHERITABILITY AND GENETIC
ASPECTS OF GROIN HERNIAS
Jakob Burcharth
*
and Jacob Rosenberg
Center for Perioperative Optimization, Department of Surgery,
Herlev Hospital, Herlev, Denmark
ABSTRACT
Through evolution, the anatomy of the human groin has become vulnerable for
protrusions of intra-abdominal content. A patent processus vaginalis (PPV) or failure of
the fascia transversalis to contain the abdominal contents leads to groin herniation.
Development of the processus vaginalis is related to calcitonin gene-related peptide,
however the process of obliteration of the processus vaginalis has still not been clarified
in detail. Delayed closure of the processus vaginalis leads to indirect inguinal hernias in
children, as well as in adults.
The reason why groin hernias develop is still unknown. Several known risk factors
such as male gender, PPV, increased intra-abdominal pressure, and collagen-based
diseases may predispose to the development of groin hernias. Positive family history has
been shown to pose a significant risk factor for the development of primary and recurrent
groin hernias. Consensus regarding a possible inheritance pattern has not yet been
established; however multifactorial inheritance, autosomal dominant inheritance, as well
as polygenic inheritance have all been suggested. The strongest relation of groin hernia
with inheritance has been shown between related females with increased risks of up to 17
times the normal. Inheritance has been shown between siblings and from parents to
children. Inheritance of groin hernias should be divided between inguinal and femoral
hernias; and inguinal hernias should be considered with respect to subtype (direct and
indirect), since great epidemiologic and etiologic differences exist between these hernia
types.
A variety of diseases and syndromes have been linked to the presence of groin
hernias, e.g. abdominal aortic aneurysms, prolapsed disc and urogenital prolapse. The
genetic aspects of these diseases and syndromes as well as the genetic aspects of
microfibril diseases (e. g., Marfan Syndrome, Loeys disease), elastin diseases (e. g.,
*
Corresponding author: Jakob Burcharth, M.D., Dept. of Surgery, Herlev Hospital, Herlev Ringvej 75, DK-2730
Email: jakobburcharth@gmail.com.
Jakob Burcharth and Jacob Rosenberg
2
Williams syndrome, Cutis Laxa, Costello syndrome, Menkes disease), collagen based
diseases (e. g., Ehlers Danlos, osteogenesis imperfecta) and disorders of sexual
differentiation (e. g., androgen insensitivity syndrome, persistent Mullerian syndrome),
could direct the search toward an area of genetic interest.
The perspectives of the unraveling of groin hernias as inheritable and a possible part
of a group of diseases is the possibility of personalized medicine. Thus, the operative
approach may be individualized depending on the quality of the patient’s collagen.
Furthermore, persons at increased risk could be monitored preoperatively to avoid
complications and postoperatively to discover potential recurrences or contralateral groin
hernias.
Keywords: Groin hernia, inguinal hernia, femoral hernia, inheritance, genetic, risk factor,
connective tissue, embryology
INTRODUCTION
Groin hernia surgery is one of the most commonly performed general surgical procedures
in both children and adults worldwide and affects all races [Everhart, 2008; Sanders et al.,
2008; Burcharth et al., 2013b]. A groin hernia is defined as a protrusion of a portion of an
organ or abdominal content through an abdominal opening in the groin area, where a hernia
sac covers the abdominal content. Groin hernias can be classified in several different ways
[Nyhus, 1993; Zollinger, 2004]. One of these classifications divides groin hernias into
inguinal hernias and femoral hernias, where inguinal hernias further are subdivided into
indirect inguinal hernias (IIH) (also known as lateral hernias) and direct inguinal hernias
(DIH) (also known as medial hernias) according to the hernia’s relation to the inferior
epigastric vessels (i.e. lateral or medial to the vessels) [Zollinger, 2004]. It has long been
known that the different groin hernia types and subtypes occur with different prevalence in
different ages, however the specific age and gender specific prevalences have just recently
become available in large scale studies [Burcharth et al., 2013b].
Inguinal hernias are numerically and percentage-wise more common in males than
females in all ages, and occurrence has peaks at the age of 0 to 5 years and at around 75 to 80
years of age [Burcharth et al., 2013b]. In contrast, femoral hernias are numerically and
percentage-wise more common in females than males throughout life and the prevalence rises
continuously with age [Burcharth et al., 2013b]. However, despite the fact that femoral
hernias are more common in females compared with males, females still develop around four
times more inguinal hernias then femoral hernias numerically [Primatesta and Goldacre,
1996; Burcharth et al., 2013b]. Furthermore, the type and subtype of hernia differs with age.
In childhood and adolescence, the vast majority of groin hernias are inguinal hernias
[Burcharth et al., 2013b], and almost all inguinal hernias in childhood and adolescence are
IIH [Ein et al., 2006]. Among adults, inguinal hernias constitute approximately 95 % (60%
IIH and 40% DIH of primary groin hernia operations, respectively) and femoral hernias 5%
of groin hernias [Burcharth et al., 2013a].
Anatomically, an IIH protrudes through the internal inguinal ring within the cremaster
fascia and extends down the spermatic chord for varying distances. The hernia sac may be
contained within the inguinal canal or it may exit from the external ring to descend onward
towards the level of the testicle, thus forming a scrotal hernia. A DIH protrudes through the
The Inheritability and Genetic Aspects of Groin Hernias
3
posterior wall of the inguinal canal medially to the inferior epigastric vessels thereby
penetrating or stretching the fascia transversalis. A femoral hernia protrudes through medially
towards the femoral vein and into the femoral canal deep to the inguinal ligament [Weber and
Tracy, 1993].
Due to large number of groin hernia operations performed worldwide yearly, groin
hernias constitute a significant socioeconomic problem [Kingsworth and LeBlanc, 2003;
Rutkow, 2003]. It is estimated that well over 25% of all American males are expected to have
an inguinal hernia at some point in their lifetime [Ruhll and Everhart, 2007] and more than 7
% of all males have been operated for a groin hernia before the age of 31 years [Burcharth
and Rosenberg, 2013]. The pathogenesis of inguinal and femoral hernias is still unknown, and
there exists a need for fully identifying relevant risk factors as a means to reduce risk of
developing groin hernias, as well as complications such as incarcerations and strangulations
of the hernia. Several patterns have been discovered in terms of age and gender based
prevalence, and several other risk factors have been proposed. One of the strongest risk
factors is the presence of a ´positive family history´ of groin hernia (defined as the presence
of a close related first degree family member either operated for a groin hernia or diagnosed
with a groin hernia). Conceivably, in the future individualized treatment might be based on a
factual risk score.
EVOLUTIONARY ASPECTS OF GROIN HERNIA DEVELOPMENT
AND CONGENITAL INGUINAL HERNIAS
Anatomy and Evolutionary Aspects of Groin Hernias
Over time, the anatomical area around the human groin has become particularly
vulnerable to protrusions of intra-abdominal content. Groin hernias arise in the anatomical
space outlined between the internal oblique muscle and the transverse abdominal muscles on
the upper edge and the superior pubic ramus on the lower edge. This area contains all nerves,
muscles, tendons and blood vessels passing from the abdomen to the lower limbs. Quite
arbitrarily, this anatomical space is divided by the inguinal ligament and by the fascia
transversalis, which forms the posterior wall. In the case of failure or weakness of the
structures located in this anatomical area, a groin herniation may occur.
Adoption by humans of upright posture and changing from quadrupedal to bipedal
locomotion was in almost every evolutionary sense positive. However, in terms of groin
anatomy and risk of developing groin hernias, it was not without consequences [McArdle,
1997]. As man evolved, the back wall of the inguinal canal came to consist of a relatively
weak and structurally unsupported thin fascia transversalis. The change from quadrupedal to
bipedal locomotion meant that the groin area opened up and became stretched, thus reducing
the otherwise effective mechanical effect of the muscular shutter mechanism of the groin, and
making this area further prone to herniation [Abrahamson, 1998]. Other species have similar
groin construction as humans, however the groin structures are not stretched and the inguinal
canal points upwards, away from gravitational effect in contrast to the human inguinal canal
that point downwards. This means, that in animals, the abdominal content is directed forward
and downward away from the inguinal region and on to the anterior wall of the abdomen
Jakob Burcharth and Jacob Rosenberg
4
[McArdle, 1997]. Upright posture means that the gravitational stress points directly onto the
internal ring of the inguinal canal, which could be the anatomical reason for groin hernia
development [Abrahamson, 1998]. However, although groin hernias are very common, the
anatomical composition and development cannot solely explain the development of groin
hernias, as a much greater prevalence would be expected.
Embryologic Aspect of Groin Hernias
In the human embryo, the testes originate along the urogenital tract in the
retroperitoneum and migrate during the second trimester of pregnancy to the internal inguinal
ring, where they arrive after around 6 months of gestation. The development of the processus
vaginalis (PV) is most likely caused by a complex interaction between several factors during
the prenatal period, and is believed to be controlled by the calcitonin gene-related peptide
released from the genitofemoral nerve under the influence of fetal androgen hormones.
During the third month of gestation, the PV extends down towards the scrotum and follows
chorda tuberculum (which lies from the retroperitoneum to the scrotum). In the seventh
month of gestation, the testicle descends into the scrotum where the PV covers the testicle and
the sac (tunica vaginalis).
At the time of birth, the portion of PV between the testicle and the abdominal cavity at
the internal inguinal ring obliterates, leaving a peritoneal cavity separate from the tunica
vaginalis, which surrounds the testis. The mechanisms leading to obliteration are still
unknown [Skandalakis et al., 1993; Clarnette and Hutson, 1996]. The process of obliteration
of the PV is similar in female fetuses, however the PV and round ligament descend into the
labia majora instead of the scrotum. Even though the details of the obliteration are not fully
clarified, it is known that smooth muscle cells surrounding the PV play an important role in
the obliteration process [Hosgor et al., 2004a]. In instances where the PV does not obliterate
or only partially obliterates a patent processus vaginalis (PPV) results, and it is considered a
main risk factor for IIH development in children and adults. The right testicle will normally
descend slightly later than the left testicle, which could be the reason why a higher number of
right-sided hernias is seen, since the right PV obliterates later than the left [Nataraja and
Mohaomed, 2011]. The final obliteration of the PV normally occurs within the first two years
of life [Tam, 1990]. Autopsies of newborns have shown that up to 94% of newborns had a
PPV [Weber and Tracy, 1993]. It is important to bear in mind that not all PPV develop into a
groin hernia. What exactly that leads a PPV to become a groin hernia is unknown, however it
is clear that a PPV only has the potential to become a hernia when it is large enough to
contain abdominal viscera.
Complete failure of PV obliteration leaves an opening from the peritoneum to tunica
vaginalis which has the possibility of developing into a hydrocele or a groin hernia. A
hydrocele is defined as a collection of fluid surrounding the testicle between the layers of
tunica vaginalis. A hydrocele of the spermatic cord occurs when the fluid-filled remnant of
the PV is separated from the tunica vaginalis. Hydrocele is common in boys. Several different
outcomes can result from a non-obliterated PV: 1) If only the distal end of the PV obliterates,
a shorter hernia sac will be the result; 2) if there is an incomplete proximal obliteration with
the mid-canal remaining patent, a hydrocele of the cord may occur; and 3) if the PV does not
obliterate at all, a PPV will be created possibly leading to an IIH.
The Inheritability and Genetic Aspects of Groin Hernias
5
Presence of a PPV does not necessarily indicate that a hernia is present or that a hernia
will develop in the future. However, delayed obliteration of the PV is considered one of the
main reasons for the development of IIH in infants and adults. The adult scrotal IIH is
anatomically identical with that of an infant [Van Wessem et al., 2003]. It has been shown
that a remarkably large proportion of adults have occult PPV, even into late adulthood,
without having clinical signs or symptoms of a groin hernia [Van Wessem et al., 2003].
Occult PPV is more common in males than females (21% versus 8%, respectively) [Van
Wessem et al., 2003], and the presence of a PPV has been identified as a risk factor for
development of an IIH [Clarnette and Hutson, 1996].
One of the most important risk factors for development of groin hernia in children is
prematurity. This may be due to the fact that obliteration occurs at an earlier stage when
children are born prematurely. In general, it is understood that the earlier the birth, the higher
the risk of developing inguinal hernia. It has been shown in several studies that the
cumulative risk of inguinal hernia development in normal term births is around 1% in boys
and about 0.1% in girls; however in pre-mature infants the cumulative risk is about 7% in
boys and about 1% in girls [Boocock and Todd, 1985; Peevy et al., 1986; Powell et al., 1986].
Most congenital inguinal hernias are right-sided, whereas left-sided inguinal hernias in
children pose a significant risk factor for metachronous contralateral inguinal hernia as found
on an evaluation of 22,104 patients (p<0.001) [Ron et al., 2007; Nataraja and Mahomed,
2011]. This finding implies that the laterality of the inguinal hernia in childhood could arise
from different etiologies in terms of right-sided hernia forming as a result of a developmental
defect and left-sided hernias occurring as a result of a more generalized defect.
GENERAL RISK FACTORS FOR DEVELOPMENT OF GROIN HERNIAS
Patient Demographics as Risk Factors for Development of Groin Hernias
The specific pathogenesis underlying development of groin hernias (inguinal hernias and
femoral hernias) is still unknown. Several patient-related demographic factors have been
proposed as risk factors for development of groin hernias. For example, old age has been
found to be a significant risk factor for the development of groin hernias (inguinal hernias and
femoral hernias) [Primatesta and Goldacre, 1996; Ruhl and Everhart, 2007; Burcharth et al.,
2013]. The main hypothesis regarding old age as a risk factor is that the connective tissue in
the groin region weakens with advancing age.
Male gender has been found to represent a significant risk factor for the development of
inguinal hernia in both childhood and adulthood [Phillips et al., 2004; Burcharth et al., 2013].
One study found that males had an overall increased relative risk (RR) of developing inguinal
hernias of 7.5 (CI 95% 6.2-9.2) compared with females [Ruhl and Everhart, 2007]. In
contrast, female gender has been shown to be a risk factor for development of femoral hernias
in all ages from childhood to old age compared with males [Dabbas et al., 2011; Burcharth et
al., 2013]. Among females, it has furthermore been shown using multivariate adjusted
analyses, that height under 158 cm was protective against inguinal hernia development,
whereas chronic cough and the presence of an umbilical hernia were significant risk factors
Jakob Burcharth and Jacob Rosenberg
6
for the occurrence of inguinal hernia with RR of 2.8 (1.3-6.0) and 3.2 (1.2-8.7), respectively
[Ruhl and Everhart, 2007].
Previously it was believed that overweight patients had a higher risk of groin hernia
development; however, data from large population-based studies have documented that
overweight and obesity actually may protect against inguinal hernia development.
Overweight, defined as a body mass index (BMI) from 25-30, has been documented to lower
the relative risk of developing inguinal hernia to 0.79 compared with individuals having a
BMI less than 25 [Abramson et al., 1978; Abramson et al., 1981; Liem et al., 1997]. These
findings were confirmed by a nationwide Swedish register-based study, which found that the
risk of developing an inguinal hernia among obese patients (BMI>30) was even lower than
for the overweight patients with a RR 0.51 [Rosemar et al., 2008].
Hernia Related Conditions
High intra-abdominal pressure that arises during coughing, lifting, and straining has been
suggested as a factor in development of groin herniation. However, the inguinal canal has a
complex anatomical and physiological “shutter mechanism” that normally counteracts high
intra-abdominal pressure. When the internal oblique muscles and transversus abdominis
muscles contract, their lower fibers will shorten and straighten. As a result, the fibers descend
and come to approximate with the inguinal ligament, thereby covering the fascia transversalis.
This is desirable due to the thin structure of the fascia transversalis. Contraction of the
transversus abdominis muscle also pulls up the muscular crurae of the internal inguinal ring,
causing the ring to close like a sphincter around the spermatic cord. At the same time the
external oblique muscle contracts, its aponeurosis which forms the anterior wall of the
inguinal canal becomes tense and presses on the internal inguinal ring and on the weak
posterior wall of the inguinal canal, thus reinforcing them by exerting counter-pressure
against the intra-abdominal forces pushing outward. The inguinal ligament is furthermore
pulled upward by the same contraction to become convex cranially [Abrahamson, 1998].
When intra-abdominal pressure arises passively (and not actively) these mechanisms are
not activated, and the groin area is much more exposed for herniation of the intra-abdominal
content. Clinical conditions such as ascites, hepatic cirrhosis, ventriculo-peritoneal shunts,
polycystic kidney disease, and patients receiving peritoneal dialysis have all been associated
with development of groin hernia [Brown et al., 1983; Belghiti et al., 1990; Grosfeld et al.,
1991; Tsai et al., 1996; Morris-Stiff et al., 1997]. Other diseases that have been significantly
linked as risk factors for inguinal hernia development include varicose veins [Abramson et
al., 1981], hemorrhoids [Abramson et al., 1978] and hiatal hernia [De Luca et al., 2004].
Inguinal hernias have been documented to be a risk factor for the development of abdominal
aortic aneurysms [Antoniou et al., 2011a]. Furthermore, a significant link has also been
shown between stress urinary incontinence following operation for inguinal hernia in females
[Tokk et al., 2004]. All of these diseases have been suggested to have their origins in
connective tissue disorders.
Studies have failed to find an association for constipation, chronic cough (in males),
alcohol consumption, height (in males), or education level with the risk for groin herniation
[Ruhl and Everhart, 2007]. In contrast, chronic obstructive pulmonary disease (COPD) has
The Inheritability and Genetic Aspects of Groin Hernias
7
been shown to be a risk factor for development of DIH in males with an odds ratio of 2.04
(1.04-4.00) [Lau et al., 2007].
Connective Tissue Composition
The idea that defective connective tissue composition, locally in the groin or
systemically, could be a risk factor for inguinal hernia development, was primarily inspired
by consideration of the genetic connective tissue diseases Ehlers-Danlos syndrome (EDS)
[Pyeritz, 2000], Marfans syndrome [Dean, 2007] and osteogenesis imperfacta [Falvo et al.,
1974].
Altered collagen composition has profound effects on tissue elasticity and resistance to
tensile strength. The main tensile strength and structural integrity arise from the collagen
type-I/III ratio. Collagen type-I represents the strong rigid part of collagen due to the many
cross-links, and collagen type-III represents the elastic component due to fewer cross-links.
Type-III collagen is more flexible than type-I collagen suggesting that the relative
composition of collagen types determines the elastic properties of tissue [Lynen et al., 2006].
Studies investigating the collagen composition of patients with inguinal hernias, have
generally focused on one of two points: 1) differences in collagen amount and composition
between patients operated for an inguinal hernia compared to a control group without hernia;
and 2) the difference in the collagen amount and composition between patients operated for
an IIH compared with patients operated for a DIH.
A significantly lower collagen type-I/III ratio and pro-collagen type-I/III ratio was found
between patients operated for inguinal hernias and a control group [Friedman et al., 1993'
Rosch et al., 2002]. Furthermore, the amount of collagen type-I and type-IV in the hernia sac,
rectus sheath and peritoneum were significantly lower in hernia patients compared with a
control group [Ozdogan et al., 2006; Oǧuzkurt et al., 2007; Casanova et al., 2009]. The
differences in collagen composition between patients operated for inguinal hernia and control
groups did not apply to children, where no differences in collagen type I/III were seen
[Hosgor et al., 2004b]. The amount of elastin in linea alba was found to be higher in patients
with inguinal hernias compared with a control group [Fachinelli et al., 2011]. Further, it has
been demonstrated that the changes in collagen occur both on the affected (herniated) side
and on the opposite (non-herniated) side, indicating a systemic change in some component of
connective tissue metabolism [Pans et al., 2001].
Between the different subtypes of inguinal hernia (DIH, IIH), the collagen level of the
fascia transversalis was generally lower for patients with DIH than those with IIH [Wagh et
al., 1974; Rodrigues et al., 2002]. Furthermore, the collagen type-I/III ratio decreased in the
skin and hernia sac in patients with DIH compared to those with IIH [Klinge et al., 1999a;
Klinge et al., 1999b]. It is believed that these changes in fascia transversalis may be due to an
increase of the collagen type-III, instead of a decrease in collagen type-I [Meyer et al., 2007].
Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase
(TIMP) are connective tissue modulating enzymes that regulate the extracellular matrix
(ECM) with regard to degradation of the elements in the ECM [Burcharth and Rosenberg,
2008]. Several different MMP’s have been proposed as influential for development of
inguinal hernia. A study investigating MMP-1 and MMP-13 in the blood of patients with
primary inguinal hernia did not find that these MMP’s played a role in the development of
Jakob Burcharth and Jacob Rosenberg
8
primary inguinal hernia [Rosch et al., 2002]. However, it has been shown that tissue levels of
MMP-2 and MMP-9 were significantly higher in patients with inguinal hernia than in patients
from the control group, and that TIMP-1 and TIMP-2 were significantly lower in the patients
with hernias compared with a control group [Abci et al., 2005; Smigielski et al., 2009;
Antoniou et al., 2011b]. Additional studies showed that differences in MMP-2 levels existed
not only for patients with inguinal hernia vs. controls, but also were altered in patients with
DIH compared to those with IIH [Bellón et al., 1997; Bellón et al., 2001; Smigielski et al.,
2011]. This suggests dysregulation between patients with inguinal hernias compared to a
control group, and dysregulation between patients with DIH compared with IIH. MMP-2
serum levels were higher in patients with inguinal hernias than in a control group, especially
in young men with DIH [Smigielski et al., 2009].
In order to function properly, the MMP’s, TIMP’s and connective tissue relevant
enzymes (e. g., lysyl oxidase) require the trace elements, copper and zinc. One study found
that, although the circulating levels of copper and zinc were identical between patients with
inguinal hernia and controls, copper and zinc levels were significantly lower in the tissue
local to the hernia [Ozdemir et al., 2011]. With respect to inguinal hernia subtype, serum and
tissue levels of copper were lower in patients with DIH than in those with IIH [Kayaoglu et
al., 2005], with consequently lower levels of lysyl oxidase activity in patients with DIH
compared to those patients with IIH and controls [Pascual et al., 2009].
Habits and External Factors
It has been speculated that a single strenuous event could serve as a risk factor for
development of inguinal hernia [Palumbo et al., 1963; Edgar, 1979; Kang et al., 1999]. In
contrast, other authors have argued against that position [Fisher, 1982; Pathak and Poston,
2006], thus the effect of a strenuous event on inguinal hernia development is undecided.
Sündstrom et al [2010] proposed the idea that anti-retroviral therapy (combination
therapy against HIV infection) could be a risk factor for development of groin hernia. The
HIV combination therapy consists of three drug classes: nucleoside reverse transcriptase
inhibitors (NRTi), protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors
(NNRTIs). Several commonly recognized side-effects related to this treatment include altered
body fat distribution and metabolic changes (i. e., hyperlipidemia, hyperglycaemia) [Carr et
al., 2000]. Interestingly, patients receiving combination anti-retroviral therapy had a higher
risk of developing inguinal hernia with a RR of 4.4 (1.1-16.1) [Sündstrom et al., 2010]. The
authors of that study suggested that the increased risk may be due to the protease inhibitor
component of the treatment.
The chemicals in cigarette smoke have been demonstrated to significantly alter the
collagen composition in the body through the release of elastases and collagenases into the
blood [Cannon and Read, 1981]. As a result, smoking has been proposed as a risk factor for
inguinal hernia development [Cannon and Read, 1981]. Further, smoking is recognized to
greatly increase the risk of recurrence after surgical repair of inguinal hernia [Sorensen et al.,
2002]. In contrast, others have found by multivariate analysis that current smokers actually
have lower risk of being operated for a groin hernia [Ruhl and Everhart, 2007; Rosemar et al.,
2008].
The Inheritability and Genetic Aspects of Groin Hernias
9
High levels of physical and recreational activity have been suggested as risk factors for
development of groin hernias [Flich et al., 1992; Carbonell et al., 1993]. However, other
studies found no impact of physical activity on the risk of developing a groin hernia [Lau et
al., 2007]. Liem et al [1997] found that a high level of physical activity had a protective effect
against development of inguinal hernia in women.
In summary, the well-documented patient related risk factors for developing groin hernias
are male gender (risk factor for inguinal hernia development), female gender (risk factor for
femoral hernia development), and old age. Chronic cough and the presence of other
abdominal hernias have only been documented as a risk factor for groin herniation in females.
It has been shown that a high body mass index (BMI) (overweight or obesity) is protective
against development of groin herniation.
With regard to hernia-related clinical issues, a significant association has been
documented between groin hernias and COPD (in males), ascites, hepatic cirrhosis,
ventriculoperitoneal shunt, polycystic kidney disease, varicose veins, hemorrhoids, hiatal
hernia, abdominal aortic aneurysm, stress urinary incontinence (in females), and patients
receiving peritoneal dialysis. The collagen I/III ratio and the pro-collagen I/III ratio in
connective tissue have been shown to be important factors in inguinal hernia development
and in differentiating the inguinal hernia subtypes. The degradation of the connective tissue,
as measured by levels of MMP-2,9 and TIMP-1 and TIMP-2 as well as copper- and zinc-
dependent enzymes, greatly increases the risk of groin hernia development. Finally, external
factors such as combination antiretroviral therapy for HIV increase the risk of inguinal hernia
development. Surprisingly, the available evidence suggests cigarette smoking to have a
protective effect against groin hernia development.
THE HERITABLE ASPECTS OF GROIN HERNIAS
The inherited aspects of groin hernia development exist as supplementary risk factors to
those mentioned in the previous section. As early as 1936, a positive family history (defined
as closely related, first-degree family members who have either been operated for, or
diagnosed with, a groin hernia) has been proposed as a risk factor for development and
recurrence of groin hernia [West, 1936]. In general, this has received very little attention,
probably due to the complexity of the study designs required to show such a potential
correlation. The studies that address the possible heritable aspects of groin hernia can be
divided into those evaluating the effect of a positive family history of groin hernia, studies on
twins with groin hernia, and studies evaluating specific inheritance patterns [Burcharth et al.,
2013c].
The Influence of A Positive Family History of Groin Hernia
A number of studies have evaluated the effect of a positive family history of development
of groin hernias [Akin et al., 1997; Liem et al., 1997; Junge et al., 2006; Lau et al., 2007;
Jansen et al., 2009; Ashindoitiang et al., 2012]. All of these studies found that a positive
family history of groin hernia represented a significant risk factor for development of a groin
Jakob Burcharth and Jacob Rosenberg
10
hernia (Table 1). A large interview-based prevalence study with over 20,000 persons found
that 20.6% of all persons diagnosed with a groin hernia had a positive family history of groin
hernia [Akin et al., 1997]. In other studies evaluating the risk of developing groin hernia, risk
ratios differed slightly between genders, with males having an increased risk ratio of 8.73
(4.95-15.4) [Lau et al., 2007] and adult females having an increased risk ratio of 4.3 (1.9-9.7)
[Liem et al., 1997]. Furthermore, a positive family history of groin hernia carried an increased
risk of overall recurrence after operation [Junge et al., 2006] and earlier recurrence following
operation [Jansen et al., 2009]. Thus, a positive family history is a very potent risk factor for
development of groin hernia. All of the studies evaluating positive family history evaluated
inguinal hernias and none of the studies included femoral hernias.
Twins with Groin Hernias
Two studies have evaluated the occurrence of groin hernia in twins however the study
conclusions are not in agreement. One study found that both twins were significantly more
prone to develop groin hernias if they were monozygotic instead of dizygotic, probably due to
a higher degree of concordance [Marshall et al., 1962]. The other study did not find this
difference [Bakwin, 1971] and therefore did not conclude that a relationship existed. The
obvious conclusion, however, is that when the occurrence is not 100% in monozygotic twins,
then the genetic mechanism of groin hernia development is not simple, e.g. a single genetic
defect with 100% penetrance. Thus, the inheritance pattern is most likely complex and
possibly also affected by external factors.
Inheritance Patterns of Groin Hernias
Several large clinical trials have tried to map the inheritance patterns of inguinal hernias
[Sawaguchi et al., 1975; Czeizel and Gárdonyi, 1979; Gong et al., 1994; Jones et al., 1998].
No studies on inheritance of femoral hernias exist. The database and clinical studies related to
inguinal hernias did not reach similar conclusions regarding the inheritance pattern. However,
all studies agreed that any potential inheritance pattern is complex and most likely polygenic
and multifactorial. One study found that polygenic inheritance with a threshold was the most
likely explanation to the groin hernia inheritance patterns [Sawaguchi et al., 1975]. Other of
the studies suggested that the inheritance pattern was multifactorial with a threshold [Czeizel
and Gárdonyi, 1979; Jones et al., 1998]. Only one study suggested that the inheritance pattern
was autosomal dominant with reduced penetrance [Gong et al., 1994].
One study evaluating children and their siblings found that sisters of females with groin
hernia had the highest risk of developing groin hernias with a relative risk ratio of 17.8 [Jones
et al., 1998]. This was confirmed by Czeizel and Gárdonyi, [1979] who found that the risk
was highest between sisters versus brothers or brother and sister, however with a slightly
lower risk ratio of 7.1. Furthermore, that study showed that the effect not only was
pronounced from daughter to daughter, but also from mother to daughter [Sawaguchi et al.,
1975; Czeizel and Gárdonyi, 1979]. It was also noted that a significant correlation existed
between bilateral groin hernias in children and groin hernia in the mother [Sawaguchi et al.,
1975].