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373916155JessicaBrorsdotter MarieEriksson
373916155JessicaBrorsdotter MarieEriksson
Abstract
The aims of the present study were to investigate the radiographic alveolar bone loss in
patients with severe liver disease and to evaluate the method used for assessing alveolar
bone loss in panoramic radiographs. In this study a total of 66 consecutive patients with
various liver diseases referred to the Hospital dentistry clinic at Huddinge hospital for
an evaluation of their dental status prior to a prospective liver transplantation were
included. The subjects were divided into two groups. Patients awaiting liver
transplantation, those who received a new liver and survived and those not accepted for
transplantation were considered to be a uniform group, the survivors (S). The other
group included patients that died prior to or shortly after liver transplantation, the
diseased (D). In each OPG all available teeth were registered, but measurements were
only made on the distal surfaces of the canines and on the mesial and distal surfaces of
all premolars and molars. The proximal bone loss was calculated as part of the root
length in percentage. If one or more of the chosen fixed reference points could not be
determined the tooth was excluded. The reason for exclusion was noted for each surface.
The main reasons for non-readability were an overlap of teeth (65%), inability to
distinguish the apex of the tooth (22%) or the cementoenamel junction (15%). There
was no significant difference in radiographic alveolar bone loss between survivors (S)
and diseased patients (D). The alveolar bone loss was however significantly worse in
smokers and previous smokers compared to non-smokers, which indicate that the
method of assessing alveolar bone loss in panoramic images used in this study is
justifiable.
Introduction
Oral epithelium
The oral epithelium that faces the oral cavity is nonkeratinized lining mucosa and keratinized
masticatory mucosa (1). Masticatory mucosa is a keratinized stratified, squamous epithelium
(2), which consists of four layers:
• Stratum basale, basal layer of cuboidal cells along the basal lamina (3), possess ability
of mitotic cell division (2)
• stratum spinosum, a cell layer which has cytoplasmic spines (2) and where
Langerhans cells are found, cells which are involved in antigen processing (3)
• stratum granulosum, the cells become more flattened, keratin is synthesized and
keratohyaliln granules may be seen (3)
• stratum corneum, these cells are shed from the epithelial surface (2), keratins may be
found extracellulary here and contribute to the protective function of the epithelium
(3). However it should be added that the oral epithelium might be orthokeratinized or
parakeratinized in humans (2).
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In contrast to the masticatory mucosa the lining mucosa has no stratum corneum (2). The
lining mucosa is composed of stratum basale, stratum spinosum and the third superficial
layer, stratum superficiale (1).
As oral epithelium faces the oral cavity, the oral sulcular epithelium faces the tooth without
being in contact with the tooth surface (2). The oral sulcular epithelium is structurally similar
to the oral epithelium while the junctional epithelium differs (2). Both the oral sulcular
epithelium and the oral epithelium exhibit rete pegs towards the connective tissue (2), the rete
pegs increase the epithelium area for contact with vascular supply and nerves (1). Junctional
epithelium only shows rete pegs when inflamed (2).
The junctional epithelium provides contact between the gingiva and the tooth in the
cervical area (2,1). In high magnification it can be seen that between enamel and junctional
epithelium there is an electron dense-zone and an electron-lucent. Structurally these two zones
are similar to the lamina densa and lamina lucida of the basement membrane area (where the
junctional epitheliums interface the connective tissue). The cells of junctional epithelium
harbor hemidesmosomes towards both the connective tissue and the enamel. However it
should be noted that in the junctional epithelium towards the enamel there are no anchoring
fibers attached to the lamina densa-like structure comparable with those between the
junctional epithelium and connective tissue (2). This epithelium has some character in
common with the col region, the saddle like depression in the interdental gingiva (3), which is
covered by a fine non-keratinized epithelium (2). The difference between the junctional
epithelium and the oral sulcular epithelium/the oral epithelium is that the junctional
epithelium has, relative to the tissue volume, larger cells, wider intercellular space and less
numerous desmosomes (2). This indicates a higher rate of turn over, an approximately six
days turn over has been reported (1). The junctional epithelium becomes thinner in apical
direction, by the cemento-enamel junction the epithelium is only about 3 to 4 cell-layer thick
(2).
Connective tissue
Immediately below the epithelium we will find lamina propria, the connective tissue. In the
connective tissue there are vessels, nerves and collagen fibers, all within the extracellular
matrix (1). Cells present in lamina propria are fibroblasts, mastcells, macrophages and
inflammatory cells (2). The connective tissue bears most of the mechanical stress that the
tissue may be exposed to. The extracellular matrix helps cells and tissues to hold together and
offers an organized lattice within which cells can interact and migrate on (4).
Periodontal ligament
The periodontal ligament links the root of the tooth to the alveolar bone. It’s a soft, richly
vascular and cellular connective tissue (2). Also found in the periodontal ligament are
fibroblasts, osteoblasts, cementoblasts, osteoclasts and nerve cells (3). Bundles of collagen
fibres (Sharpey´s fibers) join the tooth to the bone (2).
Root cementum
The cementum enfolds the root surface and has similarities to bone tissue. Unlike bone
cementum it does not demonstrate alternating periods of apposition and resorption but instead
new layers of cementum are deposited throughout life (2).
Alveolar bone
Bone is connective tissue with the ability to resist load and to also function as a mineral
reservoir to maintain the homestasis of the body. This is possible because bone is composed
of a mineralised organic matrix. As mentioned above the bone undergoes resorption and
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apposition, these processes are present in so called bone multiceller units (BMUs). A BMU is
composed of a resorption front of osteoclasts, a compartment with vessels and periocytes and
a deposition front of newly formed organic matrix made by osteoblasts (2). The osteoclast
secret acids and hydrolases through their ruffled border, acids to dissolve the bone mineral
and hydrolases to digest the organic components of the matrix. Bone matrix is secreted by
osteoblasts, these cells lie on the existing surfaces of the matrix and deposit fresh layers onto
it. This freshly made, some what soft matrix will convert into hard matrix by the deposition of
calcium phosphate crystals into it (4).
Periodontal diseases
Periodontal diseases are infectious diseases caused by specific microorganisms of dental
plaque that colonize the gingival sulcus, and subsequently, the periodontal pocket throughout
life (2). 500 different species are estimated to be able to colonize the oral cavity (5), typically
an individual harbors approximately 150 species or more. Supragingival plaque on one single
tooth surface may harbor 1.000.000.000 microorganism. In a healthy shallow pocket, numbers
may be 1.000 compared to about 100.000.000 in a deep periodontal pocket (2). But if
periodontal diseases are caused by microorganisms, why are there local destructions? And
why do some individuals develop a fast progressing periodontal disease without having a lot
of plaque, when others with an impaired oral hygiene, may develop a plaque induced
gingivitis but still don’t develop a comprehensive parodontitis? (6). As well as other
infectious diseases, a pathogen is necessary but not sufficient for a periodontal disease to
occur. Further, different species have diverse special interest in/effect on different tissues.
Microorganisms produce enzymes able to digest extracellularly host molecules. For example
Porphyromonas gingivalis is a microorganism which has the ability to produce the proteas
enzyme Arg-1-proteas. Proteases digest collagen, elastin, fibronectin etc. The Arg-1-proteas,
in addition, has the capacity to induce a strong humoral immune response (2). Mandianos et al
(1997) could during their experiment observe P. gingivalis ability to block neutrophile
migration across the epithelium (7). Periodontal diseases seem to be caused by a limited
group of periodontal pathogens acting solitary or in combination. Periodontal tissue affected
by diseases, can act as a renewing reservoir for spillover of several different mediators into
the circulation. It can be considered that a patient with moderate periodontal disease, may
have a tissue damage area in the size of the palm of the hand or larger (2).
Microorganisms
Microorganisms involved in periodontal disease are: Actinobacillus actinomycetemcomitans,
Porphyromonas gingivalis, Bacteroides forsythus, Campylobacter rectus, Eubacterium
nodatum, Fusobacterium nucleatum, Prevotella intermedia and Treponema denticola (8).
There are several studies regarding periodontopathogen Actinobacillus
actinomycetemcomitans’ capability to produce toxins with capacity to develop periodontal
disease (8). For example, through apoptosis in B-lymfocytes (9) or through apoptotic cell
death induced via caspase in A. actinomycetemcomitan-infected macrophages (10). Ohguchi
et al (1998) emphasize that since findings show that A. actinomycetemcomitan also has been
associated with endocarditis, pericarditis, osteomyelitis, empyema, meningitis and
subcutaneous abscess which indicates that the pathological roles of the toxin from A.
actinomycetemcomitan is not only important in periodontitis but also in severe systemic
infections (9). The use of the16S ribosomal RNA method has found more than 100
noncultivable bacterial species in the subgingival microflora. Due to lack of direct evidence of
which microbes initiate the first step to subgingival pocket formation, the search for
noncultivable microorganism must continue (8). Rhemrev et al (2006) found the following
microorganisms in deep pockets: Porphyromonas gingivalis, Prevotella intemedia,
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Healthy gingiva
A clinically healthy gingiva has a coral pink color and may have brown pigmentation from
the melanocytes located in the basal layer of the epithelium. Gingiva generally follows the
contours of the cemento-enamel junctions of the teeth, it is firm by touch and attached to the
underlying bone and/or tooth. The surface of a healthy gingiva is typical stippled (10).
Healthy gingiva seems to cope with microorganisms without progressing to a diseased state.
This is, possibly because defense mechanisms such as regularly shedding epithelial cells and
the cleansing flow of gingival crevicular fluid may wash away, for example, non-attached
microorganisms and antimicrobial antibodies (2). The first detectable sign of inflammation is
an increase in gingival crevicular fluid (GCF), once this has occurred GCF is referred to as
exudates (3).
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example Il-1, they go across the endothelium via diapedesis, pass through the celljunction and
cross the basement membrane out into the extracellular space. The neutrophiles will find the
foci of infection via chemotaxi (14). During neutrophile activation elastase is released extra-
cellulary in its active form. It has been shown that the periodontitis patient has a higher
concentration of free elastase compared with the gingivitis patient. This could clarify the
tissue destruction seen in the periodontal disease (15).
Periodontitis
With the advanced lesion, periodontitis, the final stage develops as the pocket deepens and
has all the same features as the established lesion but with the distinct difference in that now
alveolar bone loss occurs. Fiber damage is widespread and the juntional epithelium migrates
apically. Now, the lesion is not only localized to the gingiva. The inflammatory cell infiltrate
migrates into the connective tissue apically and laterally into the tooth attachment apparatus
of the jaw (2). The height of the alveolar bone decreases by age, with the annual mean of 0.06
mm (16). The result of periodontits is however a more pronounced loss of connective tissue
and alveolar bone support. Chronic periodontitis has in twin studies indicated to have a high
inherited component (2). Severe periodontit may lead to tooth loss, occasional pain,
discomfort and impaired mastication. In the USA it is estimated that approximately 22% of
adults have the mild variant of the diseases and 13% have the moderate or severe variant (5).
In a Swedish study, on Swedish material, it was shown that subjects in the intermediate group
(more than 20% at 1-5 sites) represented 54% of the total material and the group with the
more severe criteria for alveolar bone loss (more than 20% at ≥ 6 sites) represented 13% of
the total material (16). The periodontal diseases, in the USA, are more prevalent in Mexican-
Americans and black people than in white people. Pathogenic microorganisms in the biofilm,
genetics and environmental factors such as tobacco smoking, causes the disease. It is, in the
USA, estimated that 50% of the risk of periodontits can be ascribed to tobacco smoking.
Individuals that have experienced previous periodontitis run a higher risk of a progressing
periodontal disease (17). Conditions such as genetic, dermatological, granulomatous,
immunosuppressive and neoplastic disorders may also show periodontal manifestation (5).
The immunosuppressed HIV-patient slightly more often presents a distinct form of
necrotising gingivitis and periodontitis (2). The “burste theory”, described in 1989, proposed
that the progression of periodontal destruction is episodic, relatively brief episodes and not in
a time-dependent manner (8). Studies published more recently propose that the finding of
”burst” is due to incorrect analysis of clinical data and that the periodontitis progression may
have a more continuous course of events (2).
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Tobacco smoking
Lindhe et al (2003) presents several studies that have established that smoking periodontitis
patients have:
• more numerous pockets (18)
• more attachment loss (19)
• more alveolar bone loss (20)
• more tooth loss (21, 22)
• less bleeding on probing (23)
• more teeth with furcation involvement (24)
Smoking is significantly associated with a more pronounced periodontal alveolar bone loss
(16). Bolin et al (1993) showed, during a 10-year period, that smoking individuals had more
proximal marginal alveolar bone loss than non-smoking individuals. Moreover they showed
that individuals that had given up smoking during the 10-year period, compared with the
smoking individuals, less proximal marginal alveolar bone (25). If rats are exposed to
cigarette smoke inhalation and periodontal fenestrations are made, these rats will encounter a
significantly reduced self-healing capacity compared with a control group (26). The
periodontal health status of former smokers more closely resembles non-smokers, additionally
former smokers respond to treatment is also similar to non-smokers. But the time to revert to
this status is unclear (2). Cèsaro-Neto et al (2006) could in their study see indications that it
seems that cigarette smoke inhalation, in rats, effected the tooth-supporting tissue after only 2
months but if the cigarette smoke inhalation ceases, 2 months after 3 months of cigarette
smoke inhalation, the negative impact on the alveolar bone may be reverted (27).
Cytokines
The immunological defense systems response to microbial agents in the gingival tissue has a
protective purpose. These protective measurements can be harmful to the host in that cytokine
and prostanoid mediated inflammation can induce breakdown of both soft and hard
surrounding tissue (2, 5). Cytokines are proteins that are produced and secreted by cells and
act as messenger molecules to other cells. They play many important roles in the immune and
inflammatory response and regulation system. An important member of the cytokine group
are interleukins (Il). Il-1α, TNF-α and Il- β are potent immunologic mediators with
proinflammatory properties. Additionally Il-1 and TNF-α can regulate fibroblast proliferation
and increase bone resorption. The periodontits patient has increased levels of Il-1 and TNF-α
within the gingival crevicular fluid and the gingival tissue. A difference in the gene coding for
Il-1 and TNF-α, has shown to play a roll in susceptibility and/or severity factor (2). I1-β is an
inflammatory interleukin associated with periodontitis. Increased levels of Il-1β in gingival
crevicular fluid is likely to be found in all parodontitis patients regardless of the severity of
the disease (28).
Focal infection
About 50 years ago, medicine and dentistry discussed focal infection. This was before the
great medical discovery of the correct etiologies of several diseases and when dentistry
learned how to prevent and treat caries and periodontal disease. Then it was apparent to
dentistry and medicine that patients with infections in the oral cavity seemed to be stricken
with a wider range of systemic diseases. Although some researchers and clinicians continued
to wonder about how dental infection foci could influence the rest of the body (2), one of
them Thoden van Velsen (1984), described 3 pathogenic ways for a dental infection foci to
spread (29):
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The liver
The liver is next to the skin the largest organ and it weighs about 1.4 kg in an average adult
(31). The liver consists of many small functional units called lobules (31). Hepatocytes
arranged in a branching pattern around a central vein form such a lobule. In the periphery of
each lobule a branch of the hepatic artery and also a branch from the hepatic portal vein along
with a bile duct and a small lymphatic vessel are situated (32,). There are no capillaries in the
liver but larger so called sinusoids, through which blood passes (31).
The liver has an energy consumption comparable to that of the brain and it uses about 25 %
of the total energy available when the body is at rest (33). This high consumption is due to the
manifold chemical reactions that take place in this organ (33).
The blood supply of the liver is special because it receives blood from two sources. From
the hepatic portal vein it receives about 80 % of its total blood supply and the rest comes from
the hepatic artery. The hepatic portal vein collects venous blood from the entire
gastrointestinal tract and brings nutritious blood relatively deficient in oxygen to the liver.
From the hepatic artery oxygenated blood is obtained. The blood mixes in the periphery of
each lobule and passes then through the sinusoids to the central vein (33). In this way the
hepatocytes are in direct contact with the blood which can explain why the liver has such an
effective detoxifying capacity (33). Blood from the central veins ends up in the V.cava
inferior (33).
The liver is responsible for performing many vital functions (31) and a liver failure is
therefore a serious condition that may be life-threatening (34). The liver plays an important
role in the metabolism of carbohydrates and it is responsible for maintaining a normal blood
glucose level which is done through the conversion of glycogen or other substances to glucose
when glucose level is low. In the opposite way the liver is also able to convert sugar to
glycogen and triglycerides and store it until the body needs energy (31). Vitamin A, B12, D, E
and K and iron and copper are also stored in the liver and released when needed. The liver is
also deeply involved in the metabolism of lipids and proteins. For example, the liver is
responsible for the production of most blood proteins such as prothrombin, fibrinogen,
albumin and globulins (31) and for the synthesis of cholesterol. Prothrombin and fibrinogen
play an important role in the coagulation of the blood along with many other so called clotting
factors produced in the liver. The liver also participates in the synthesis of the active form of
vitamin K which is necessary for the production of some of these blood clotting factors (31).
Another important function is detoxifying our blood from toxic substances (31) through the
conversion into more water soluble substances that can be eliminated from the body (35).
In addition, the liver produces and secretes bile which is important for the emulsification and
absorption of lipids (31).
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(37, 38). The normal architecture of the liver is irreversible destroyed which leads to an
impairment of hepatic function and ultimately hepatic failure (37).
The most important causes of liver cirrhosis are alcohol abuse, chronic viral hepatitis,
hemochromatosis and nonalcoholic steatohepatitis (37). In addition, drug toxicity, metabolic
diseases such as Wilsons disease and alfa-1-antitrypsin deficiency, cholestasis of long
duration secondary to diseases as primary biliary cirrhosis and primary sclerosing cholangitis,
are other causes known to result in the formation of a cirrhotic liver (35). The term
cryptogenic cirrhosis is used when the cause for the cirrhosis can not be found (38).
Primary sclerosing cholangitis (PSC) is a chronic syndrome characterized by fibrosing
inflammation of the biliary ducts (36) that eventually leads to cholestasis, cirrhosis and liver
failure (37). Cholestasis is an arrest of the flow of bile (39) The disease is of unknown cause,
but autoimmune mechanisms are suggested to be involved in the pathogenesis (37). Men are
twice as often affected as women (36) and the disease is often seen in association with
inflammatory bowel disease, especially ulcerative colitis and Crohn´s colitis (37). Examples
of other diseases associated with PSC are Sjögren´s syndrome, rheumatoid arthritis and
autoimmune chronic hepatitis (37).
Another chronic cholestatic disease that affects the liver is Primary biliary cirrhosis (PBC).
90-95 % of the affected patients are women in the middle age (37). The aetiology of PBC is
still unknown, but genetic and immunological factors seem to be of importance for the disease
to occur (37). Examples of other autoimmune diseases associated with PBC are Sjögren´s
syndrome, rheumatoid arthritis, thyroiditis, hypothyroidism and scleroderma (37). It is
suggested that T-lymphocytes are responsible for the chronic destruction of the intrahepatic
bile ducts which leads to cholestasis and eventually portal inflammation and scarring of the
liver. Cirrhosis and liver failure will occur as the disease progresses (37).
Patients with end-stage PBC require liver transplantation (40) and the one-year survival after
such an operation is 85-90 % (37).
In patients with chronic cholestasis Osteomalacia can develop due to abnormal calcium and
vitamin D metabolism. This condition may lead to a resorption of the alveolar bone and
eventually to loosening of the teeth (38).
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world
(37). The incidence of HCC is increased in areas where hepatitis B and C are more common
and in patients with hemochromatosis (41). HCC is more common in men than in women
(37). There is an increased risk for cirrhotic patients to develop hepatocellular carcinoma (36)
and more than 80 % of all hepatocellular carcinomas are found in patients with livercirrhosis
(41). Clinical symptoms may be abdominal pain and weight loss but many patients are also
asymptomatic (37). The prognosis for patients with primary liver cancer, where HCC is the
most common form, is poor. Without treatment the patient dies within 1-2 month and the only
curable treatment is resection or liver transplantation. The reported 5- year survival rate after
transplantation is 10-15 % (36).
Currently five human hepatitis viruses have been identified, namely A, B, C, D and E (42).
Hepatitis A and E are enterically transmitted viruses whereas hepatitis B, C and D are blood-
borne viruses (37). All of these viruses can produce acute viral hepatitis which is the most
common cause of liver disease in the world (37). Approximately 1-2 million people die every
year in the sequel of acute viral hepatitis (37) and it remains a major health problem
worldwide. Chronic hepatitis is defined as a persistent inflammation in the liver for more than
six months (35) and it can only be caused by hepatitis B, C or D virus (37).
Approximately 350 million people are infected with hepatitis B (HBV) and the highest
prevalence is seen in the southeast Asia and Africa (42). Scandinavian countries and North
America have a low prevalence of hepatitis B with less than 1% affected with the virus (36).
The virus can be transmitted through percutaneous inoculation and the sharing of infected
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needles among intravenous drug users is a common mode of spread of HBV (42). Another
major route of transmission is through sexual intercourse and a high prevalence of chronic
HBV infection has been reported in heterosexuals with multiple sexual partners and in
homosexuals (42). The risk for acquiring a HBV infection via an accidental needlestick or
other contaminated instruments may be as high as 20 % depending on how contagious the
patient is at that particular moment (43). The corresponding risk for hepatitis C (HCV) is
5-10 % (37). The hepatitis B vaccine provides an effective coverage against hepatitis B but
currently there is no vaccine against HCV. Patients with chronic HBV are at increased risk for
development of hepatocellular carcinoma (37).
Hepatitis D was discovered in the end of the seventies and it only affects those who already
are infected with the hepatitis B virus (36). Hepatitis D virus is a defect virus that is
depending on a helper virus as HBV for its replication in humans (36).
Hepatitis C has a worldwide prevalence of 2-3 %, which corresponds to 170 million people
(42). The majority of patients affected with an acute hepatitis C infection are asymptomatic
whereas clinical signs of a chronic hepatitis C infection may be fatigue, weight loss,
depression, nausea, difficulties with concentration and abdominal discomfort (37). The most
common and also the highest (90%) risk factor for hepatitis C is intravenous drug use (42, 37)
and in 38 % of all patients with hepatitis C, injection drug use is the cause of infection (42).
Another route of transmission is exposure to HCV during sexual intercourse but the risk of
achieving a new infection in this way is less than 5 % (37).
Georgiou et al (2004) studied the prevalence of systemic diseases in periodontal patients
compared to the general practice population. The authors reported that periodontal patients
have a higher prevalence of systemic diseases and that hepatitis, rheumatoid arthritis and
bronchitis were the most common systemic diseases seen in patients with advanced
periodontitis (44).
Liver transplantation
The first orthotopic liver transplantation (OLT) in a human was performed in 1963 (45) but
not until almost two decades later it became a reliable treatment accepted widely by health
professionals and patients (36). Today it has evolved into the major treatment option for end-
stage chronic liver disease and for severe acute liver failure (46). Orthotopic means that the
liver is transplanted in the same place where the removed host liver was located (47).
In Sweden the first liver transplantation was performed in 1984 at Huddinge hospital in
Stockholm (36). Refinement of surgical techniques, better knowledge about patient selection
and when to transplant, increased acceptance for retransplantation if the first one was
unsuccessful and improved immunosuppressive therapy agents as Cyclosporin A are the most
important factors that have led to the current status of liver transplantation (36). In addition,
advances in organ preservation, has contributed to the improvement in survival.
Today a five-year survival-rate after liver transplantation of approximately 75 % can be
reported (46). Patients who receive liver transplants because of nonneoplastic disease have, in
general, a greater survival rate compared to those with neoplastic liver disease (45).
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Active alcohol and narcotic abuse are other absolute contraindications and patients with
alcohol-related liver disease are not candidates for an OLT unless there is a period of
abstinence prior to transplantation. The risk for these patients to relapse into alcoholism is
related to the duration of this period (49). Studies have reported that between 10-50 % of
patients transplanted due to alcoholic cirrhosis relapse into alcohol abuse within 5 years (50).
Organ regeneration
The liver possesses an extraordinary capacity for regeneration. After extensive hepatectomi,
the liver is fully recovered within a few weeks (14). The ability to regenerate and regulate its
size makes it possible for the allograft to adjust the volume in order to reach a size appropriate
to that of the recipient and also to recover from ischemic injury and acute rejection reactions
(45).
Organ rejection
Transplant rejection occurs in about 50 % of patients, but immunosuppressive therapy permits
successful management of this problem in most cases (46). Three types of allograft rejection
can be seen after liver transplantation, namely hyperacute, acute and chronic rejection (49).
The most common form of allograft rejection is acute rejection (49) which usually occurs
within the first weeks after transplantation (51). The acute rejection occurs when antigens on
the cell surface of the allograft are recognized as foreign by the immune system of the
recipient (49).
The hyperacute rejection occurs within minutes or hours after transplantation and is caused
by pre-formed antibodies directed to antigens on the donor transplant (49). This form of
rejection is a rare complication in liver transplantation (51) but is more often seen in kidney-,
heart- and lung transplants. The reason for this is unknown (49).
Chronic rejection is considered to be the primary cause of late graft failure (51). Prior
episodes of acute rejection, infection with cytomegalovirus, chronic ischemia and chronic
antibody-mediated injury are factors increasing the risk for chronic rejection to occur (49).
Causes of death
Far more patients require a liver transplantation than there are available organ donors and
approximately 15-20 % of all patients awaiting a liver transplantation die prior to receiving an
organ (37). In a study by Cuervas-Mons et al (1986), the causes of early death in 40
consecutive liver transplant patients were reported. Twenty-one patients died of
complications secondary to infection, eight died of multiorgan failure and three of acute
rejection of the allograft. The remaining eight patients died of other causes. The most
common cause (80%) of infection deaths was bacterial sepsis caused by Pseudomonas and
other enteric gram-negative bacteria (45).
Portal hypertension
Portal hypertension is defined as an increase in portal venous pressure and it is the most
common and lethal complication of chronic liver diseases (42). Clinically signs of portal
hypertension include ascites, gastrointestinal bleeding, hypersplenism and hepatic
encephalopathy (36). Ascites is a swelling of the abdomen due to accumulation of fluid (38).
Hepatic encephalopathy is a disturbance in the nervous system with various neurologic
manifestations such as confusion, memory loss, disorientation and tremor. Cirrhosis is the
most common cause of portal hypertension (42).
Starzl et al have shown that the patient`s pretransplant status is of importance for the
survival after liver transplantation. For example patients living at home prior to surgery had a
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1,5 greater chance of survival six month after receiving a new liver compared to those who
were under intensive care (49).
Immunosuppressive drugs
The immunosuppressive drugs used after liver transplantation in order to prevent organ
rejection, have several side effects. Earlier Azathioprine was the key agent for
immunosuppression in these patients which caused a suppression of the bone marrow with
resulting thrombocytopeni, leukemi and anemia. These side effects increased the risk for
infection and excessive bleeding in transplant patients (45) and the addition of Cyclosporin A
to the immunosuppressive protocol, which does not suppress the bone marrow, has resulted in
increased survival rates (52).
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panoramic images provide a great overview of the facial bones and teeth. Panoramic images
can also be used when the patient is unable to open the mouth (58).
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metabolized primary by the liver. Other examples of drugs metabolized by the liver are
sedatives as Diazepam and antibiotics as Ampicillin and Tetracycline (45).
As mentioned earlier the posttransplant treatment with immunosuppressive drugs has
several side effects. An overimmunosuppressed patient is at a higher risk for opportunistic
infections. Oral findings such as recurrent herpes simplex infections, herpes zoster, large
aphthous ulcers, candidiasis, Kaposi´s sarcoma, hairy leukoplakia and lymphoma indicate
overimmunosuppression (45). Transplant recipients are prone to infection not only due to the
posttransplant immunosuppressive therapy but also due to the fact that patients with liver
disease are apt to present with conditions as leukopenia, malnutrition and hypoalbuminemia,
which further impair immune defence mechanisms (49). The dentist plays an important role in
detecting and recognising signs of infection at an early stage (34). Very little has been
published regarding the effect of dental infections after organ transplantation (34).
Elevated levels of cytokines are seen in patients with liver disease and due to the fact that
various cytokines are known to be involved in the destructive process of periodontal disease it
is suggested that patients with liver disease are at a higher risk of developing periodontitis
(34). The cytokines IL-1, IL-6 and TNFα, known to stimulatate bone resorption and inhibit
bone formation are all seen in elevated levels in patients with liver cirrhosis (34).
In a study by Oettinger-Barak (2002) it was concluded that cirrhotic patients do demonstrate a
greater alveolar bone loss compared to healthy controls but it was also suggested that further
studies are necessary to substantiate these data (52). In contrary to these findings no
significant differences regarding periodontal disease in patients with cirrhosis compared to
healthy controls have been reported (34).
Larech (2005) examined the oral health in 116 patients with different liver diseases and
analyzed the correlation between their oral health and the outcome of liver transplantation. It
was found that periodontal disease was significantly more advanced in patients that died
either prior to or after liver transplantation, compared to survivors. The periodontal status was
determined by analyzing different kinds of radiographs using the concept of dental infection
foci. A periodontal foci was defined as:
“loss of supporting tissues >1/3 of the root length in combination with angular bony
defects, infrabony pockets and furcation involvement” (34).
The aim of our retrospective study was to evaluate these previous findings regarding the
periodontal health in patients with severe liver disease and also to evaluate the method of
estimating the alveolar bone loss in panoramic radiographs.
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Jessica Brorsdotter, Marie Eriksson
(Planmeca 2002 EC Proline, Finland) and automatically developed at the Hospital dentistry
clinic at Huddinge hospital.
The radiographs were inspected in a darkened room on a viewing box and measurements of
the proximal alveolar bone loss were independently performed by two observers after
calibration. 25 panoramic radiographs were read by observer A and 41 by observer B. 15
panoramic radiographs were used for calibration.
In order to assess alveolar bone loss distances between the cementoenamel junction (CEJ)
or, if destroyed after restorative treatment, the apical termination of a restoration or crown
margin, and the apex was measured as well as the distance between the alveolar bone crest
and the apex. The measurements were made with a translucent ruler in millimeters with an
accuracy of 0,5 mm. The proximal bone loss was calculated as part of the rootlength in
percentage.
In each OPG all availible teeth and radici relictae (rr) were registered but measurements
were only made from the distal surface of the canine and on the mesial and distal surfaces of
all premolars and molars. Incisors were excluded because of the image of the cervical spine in
this area.
If one or more of the chosen fixed reference points could not be determined the tooth was
excluded. The reason for exclusion was noted for each surface. The exclusion criterias were
overlaps, inability to distinguish the cementoenamel junction, the apex or the marginal bone
level. In some cases caries was the reason for inability to determine the CEJ which was noted
separately. Additionally, no measurements were made on root rests.
The subjects were divided into two groups. Patients still awaiting a liver transplantation,
those who received a new liver and survived and finally those who were not accepted for
transplantation were considered as uniform group, the survivors (S). The other group included
patients who died either prior to or shortly after liver transplantation, the diseased (D).
All data were statistically processed with the software JMP 5.0.1 (SAS Institute, Cary, NC
US) using nonparametric analysis.
Results
Panoramic radiographs were assessed from 40 men and 26 women with a mean age of 54.7 ±
9.9 and 51.6 ± 12.3 years respectively. On average, the subjects had 25.8 teeth (range: 9-32).
In order to assess alveolar bone loss a total of 2090 tooth surfaces were evaluated. Due to
non-readability, 914 tooth surfaces were excluded (44 %). The main reasons for non-
readability were an overlap of teeth (65 %), inability to distinguish the apex of the tooth
(22 %) or the cementoenamel junction (15%). The reasons for non-readability and the
distribution of excluded surfaces are illustrated in figure 1.
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Jessica Brorsdotter, Marie Eriksson
700
584
600
numbers of surfaces
500
400
300
193
200 135
100 64 44
34 31
0
overlaps caries CEJ rr apex other bone
reason level
Figure 1. The reasons for non-readability and exclusion. Overlaps were the most common
problem.
The number of overlapped surfaces were most frequently seen in the maxilla, especially in
the premolar region (Figure 2). In 51.5 % of the cases, the distal surfaces of both maxillary
canines were excluded due to overlaps.
300
250 239
numbers of surfa
200
158
150
100 82
50 40 32 33
0
maxillary maxillary maxillary mandibular mandibular mandibular
molars premolars canines molars premolars canines
The most common liver disease was hepatitis C (22/66), followed by liver cirrhosis (19/66)
and hepatocellular carcinoma (17/66).
The most common combined diagnoses were hepatocellular carcinoma and hepatitis C
(10/66), followed by cirrhosis combined with hepatitis C (8/66).
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Jessica Brorsdotter, Marie Eriksson
The group of diseased patients (D) consisted of 11 subjects with a mean age of 40.7 years.
The surviving group of patients (S) consisted of 55 subjects with the mean age of 53.8 years.
24 % of the patients were smokers, whereas 32 % of the patients reported that they had been
smokers in the past. 44 % of the patients were non-smokers.
There was no significant difference in alveolar bone loss between survivors (S) and diseased
patients (D) (Figure 3).
Figure 3. Differences between alveolar bone loss in deceased patients (D) and survivors (S).
There was no significant difference in alveolar bone loss between the two groups.
There was no correlation between age of the patients and the severity of alveolar bone loss.
Smokers had a significantly greater alveolar bone loss compared to non-smokers (p<0.01).
Moreover the alveolar bone loss in previous smokers was significantly more pronounced than
in non-smoking individuals (p<0.01). Patients with current and past smoking habits showed a
significantly more extensive alveolar bone loss compared to non smokers (p<0.001). No
significant difference in alveolar bone loss was seen between smokers and previous smokers
(Figure 4).
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Jessica Brorsdotter, Marie Eriksson
Figure 4. Differences in alveolar bone loss in smokers, non-smokers and previous smokers.
The smokers had a significantly more pronounced alveolar bone loss compared to non-
smokers (p<0,01). Previous smokers had a more pronounced alveolar bone loss compared to
non-smokers (p<0.01). Patients with current and past smoking habits showed a significantly
more extensive alveolar bone loss compared to non-smokers (p<0.001)
Discussion
Currently, there is very little data regarding the relationship between radiographic alveolar
bone loss and liver disease (52). It has been documented that cirrhotic patients demonstrate a
greater bone loss than healthy individuals (52). A possible explanation is elevated levels of
cytokines as IL-1, IL-6 and TNFα, which are known to be involved in the destructive process
of periodontal disease (34). In contrast to this other studies have fail to prove a relationship
between periodontal disease and liver cirrhosis when compared to healthy controls (34). In the
present study no healthy controls were included and the alveolar bone loss was analyzed only
in patients with different liver disease in order to evaluate if diseased patients in this group
had more alveolar bone loss than survivors.
There was no significant difference in alveolar bone loss between patients who died either
prior to or after liver transplantation (n=11) compared to survivors (n=55). These findings are
in contrast to previous data indicating that periodontal disease is more advanced in patients
that died either before or after receiving a new liver, compared to the periodontal health of
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Jessica Brorsdotter, Marie Eriksson
survivors (34). In the present study however, a relative small material of only 66 panoramic
images were included and the follow-up period was very short. To substantiate our data more
studies with a longer follow-up period are necessary.
Because of various reasons alcohol and drug abusers often present a very poor oral health.
Due to the high prevalence of alcohol and drug related disorders among patients with severe
liver disease it was expected that the oral status of the subjects in this study in general should
be rather poor. The subjects however had an average of 26 remaining teeth and the number
root rests and extensive carious lesions were surprisingly low in this material. A possible
reason for this may be that panoramic radiography to a greater degree has been used on
patients with a relative good oral status. It is however standard procedure at the dental clinic
at Huddinge to perform a panoramic radiography on all patients undergoing dental
examination prior to liver transplant evaluation. In many cases a panoramic radiograph
together with four bitewing radiographs provide all information necessary for diagnosis and
adequate treatment of the patient. In other cases a full-mouth series of both periapical and
bitewing radiographs might be necessary and as a panoramic radiograph in those cases
provide little or no additionally useful information (58), a panoramic image is not taken. It is
therefore uncertain if the radiographic findings in this study reflect the oral conditions seen in
the majority of patients with severe liver disease.
The periodontal status was in this study only determined on the basis of radiological
findings of the interproximal bone level. Clinical findings as pocket depth, bleeding on
probing, tooth mobility and oral hygiene and factors as socio-economic condition and
medications were not taken in concern. The parameter “bleeding on probing” is considered a
sign of gingivitis (57). Due to the increased bleeding risk seen in patients with severe liver
disease the “bleeding on probing” does however not necessary indicate an inflammation in the
periodontal tissues and the diagnostic value of this parameter is uncertain in these patients.
Muller and Ulbrich (2004) investigated the prevalence and extent of alveolar bone loss and
infrabony defects in 240 panoramic radiographs. They reported that periodontal bone loss
increased with age (53), which is not in accordance to our results where a correlation between
the extent of bone loss and increasing age could not be found.
The present study was not only conducted to gain more information about the periodontal
health in patients with liver disease but also to evaluate the method of assessing alveolar bone
loss in panoramic radiographs.
There are different methods for the assessment of alveolar bone loss in radiographs (54).
Some are quite advanced and include digital imaging and computer programs whereas others
are quite simple (54). To calculate bone height relative to the root length is a simple way to
assess periodontal destruction (53). In our study bone loss measurements were made with a
graded ruler on the panoramic image with an accuracy of 0,5 mm and thus the method was
not very advanced.
Panoramic images provide a great overview of the severity and extent of the periodontal
disease and were therefore thought to give a more adequate picture of these patients
periodontal status compared to when only separate I-O radiographs are observed. The
information obtained from a partial radiographic examination may be limited, as it is believed
that periodontal disease does not affect all a parts of the dentition with the same extent and
severity (54).
There are however some limitations of assessing the alveolar bone loss in panoramic
images. Studies have reported that panoramic radiographs underestimate the bone loss up to
32 % (56). The degree of underestimation is depending on the location and extent of the bone
loss (57). Other problems associated with panoramic radiography are geometric distorsion and
uneven magnification (58). As panoramic images do not display fine anatomical details (58),
it is difficult to distinguish structures as the cementoenamel junction in these radiographs.
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Jessica Brorsdotter, Marie Eriksson
Additionally, the proximal surfaces of premolars are often overlapped (58). Whenever the
observers were unable to distinguish the location of a structure, such as the cementoenamel
junction, no reading was made and this surface was excluded. The high number of excluded
surfaces (approximately 44 %) mainly due to overlaps, inability to distinguish structures as
the cementoenamel junction and apex of the tooth resulted in an essential loss of information
about the alveolar bone loss in the material. Additionally, the incisors and the mesial surfaces
of the canines were excluded in this study because of the overlapping image of the cervical
spine. Data regarding the alveolar bone loss in this area is therefore unknown. The method of
assessing alveolar bone loss used in this study was also very time-consuming, thus rendering
it difficult to use in a routine clinical setting.
An appropriate position of the patients head in the focal trough is important to obtain
diagnostically useful panoramic images (58). In order to avoid major differences in how the
patient is positioned in the machine and to get images highly comparative to each other a
standardized technique is necessary. When different panoramic radiographs are compared as
in this study it is therefore desirable if all images are taken by the same dental assistant. As
this was a retrospective study with only 66 panoramic radiographs included this could not be
taken in concern. Radiographs taken by several different persons may result in radiographs
with variations in image.
Smoking is considered a major risk factor for periodontal disease. Numerous different
studies have shown that cigarette smoking may be the environmental risk most strongly
associated with periodontitis in adults (16). In a longitudinal study by Nordenryd et al (1999)
it was found that smoking was significantly associated with more extensive periodontal bone
loss (16). In addition, Bohlin et al (1993) have documented that the proximal alveolar bone
loss is more pronounced in smokers compared to non-smoking individuals (25). Furthermore
the alveolar bone loss in patients who had quit smoking was more severe than in non-smoking
patients. This is in agreement with the present study where a strong correlation between
smoking and the extent of alveolar bone loss was found (Figure 4). Smokers had a
significantly greater alveolar bone loss compared to non-smokers (p<0.01). Moreover, the
alveolar bone loss in previous smokers was significantly more pronounced than in non-
smokers (p<0.01). ). Patients with current and past smoking habits showed a significantly
more extensive alveolar bone loss compared to non smokers (p<0.001). These findings
indicate that the method of assessing alveolar bone loss in panoramic radiographs used in this
study is justifiable and can be used in purpose to assess alveolar bone loss in panoramic
radiographs.
In conclusion there was no significant difference in alveolar bone loss in patients who died
either prior to after liver transplantation compared to survivors. A strong correlation was
however found between smoking and the extent of alveolar bone loss, which indicate that the
method of assessing alveolar bone loss in panoramic images used in the present study is
justifiable.
Acknowledgement
We wish to express our gratitude to our supervisor Peter Lundholm, DDS, PhD, Head of the
Hospital dentistry clinic at the University Hospital of Huddinge, who has been a great support
during the work with this study. Thank you for always being so positive and enthusiastic.
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Jessica Brorsdotter, Marie Eriksson
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