Diabetes Mellitus

Diabetes mellitus is an extremely important disease from a periodontal standpoint. It is a complex metabolic disorder characterized by chronic hyperglycemia. Diminished insulin production, impaired insulin action, or a combination of both result in the inability of glucose to be transported from the bloodstream into the tissues, which in turn results in high blood glucose levels and excretion of sugar in the urine. Lipid and protein metabolism is altered in diabetes as well. Uncontrolled diabetes (chronic hyperglycemia) is associated with several long-term complications, including microvascular diseases (retinopathy, nephropathy, or neuropathy), macrovascular diseases (cardiovascular, cerebrovascular), an increased susceptibility to infections, and poor wound healing. An estimated 23.6 million individuals (children and adults), or 7.8% of the United States (US) population, have diabetes.¹⁹² Approximately 5.7 million of these individuals are unaware that they have the disease.

There are two major types of diabetes, type 1 and type 2, with several less common secondary types. Type 1 diabetes mellitus, formerly insulin-dependent diabetes mellitus (IDDM), is caused by a cell-mediated autoimmune destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas, which results in insulin deficiency. Type 1 diabetes accounts for 5% to 10% of all cases of diabetes and most often occurs in children and young adults. This type of diabetes results from a lack of insulin production and is very unstable and difficult to control. It has a marked tendency toward ketosis and coma, is not preceded by obesity, and requires injected insulin to be controlled. Patients with type 1 diabetes mellitus present with the symptoms traditionally associated with diabetes, including polyphagia, polydipsia, polyuria, and predisposition to infections.

Type 2 diabetes mellitus, formerly non–insulin-dependent diabetes mellitus (NIDDM), is caused by peripheral resistance to insulin action, impaired insulin secretion, and increased glucose production in the liver. The insulin-producing beta cells in the pancreas are not destroyed by cell-mediated autoimmune reaction. It typically begins as insulin resistance leading to reduced pancreas production of insulin as the demand increases. Type 2 diabetes is the most common form of diabetes, accounting for 90% to 95% of all cases, and usually has an adult onset. Individuals often are not aware they have the disease until severe symptoms or complications occur. Type 2 diabetes generally occurs in obese individuals and can often be controlled by diet and oral hypoglycemic agents. Ketosis and coma are uncommon. Type 2 diabetes can present with the same symptoms as type 1 diabetes but typically in a less severe form.

An additional category of diabetes is hyperglycemia secondary to other diseases or conditions. A prime example of this type of hyperglycemia is gestational diabetes associated with pregnancy. Gestational diabetes develops in 2% to 5% of all pregnancies but disappears after delivery. Women who have had gestational diabetes are at increased risk of developing type 2 diabetes later in life. Other secondary types of diabetes are those associated with diseases that involve the pancreas and destruction of the insulin-producing cells. Endocrine diseases, such as acromegaly and Cushing’s syndrome, tumors, pancreatectomy, and drugs or chemicals that cause altered insulin levels, are included in this group. Experimentally induced types of diabetes generally belong in this category rather than in type 1 or 2 diabetes mellitus.

Oral Manifestations

Numerous oral changes have been described in diabetic patients, including cheilosis, mucosal drying and cracking, burning mouth and tongue, diminished salivary flow, and alterations in the flora of the oral cavity, with greater predominance of Candida albicans, hemolytic streptococci, and staphylococci.^2,22,99,158 An increased rate of dental caries has also been observed in poorly controlled diabetes.^74,84 Importantly, however, these changes are not always present, are not specific, and are not pathognomonic for diabetes.¹⁶¹ Furthermore, these changes are less likely to be observed in well-controlled diabetic patients. Individuals with controlled diabetes have a normal tissue response, a normally developed dentition, a normal defense against infections, and no increase in the incidence of caries.²³³

The influence of diabetes on the periodontium has been thoroughly investigated. Although it is difficult to make definitive conclusions about the specific effects of diabetes on periodontium, a variety of changes have been described, including a tendency toward enlarged gingiva, sessile or pedunculated gingival polyps, polypoid gingival proliferations, abscess formation, periodontitis, and loosened teeth¹¹² (Figure 27-1). Perhaps the most striking changes in uncontrolled diabetes are the reduction in defense mechanisms and the increased susceptibility to infections, leading to destructive periodontal disease. In fact, periodontal disease is considered to be the sixth complication of diabetes.¹⁴⁴ Periodontitis in type 1 diabetic patients appears to start after age 12 years.⁴⁷ The prevalence of periodontitis has been reported as 9.8% in 13- to 18-year-old patients, increasing to 39% in those 19 years and older.

Figure 27-1 Periodontal condition in patients with diabetes. A, Adult with diabetes (blood glucose level > 400 mg/dl). Note the gingival inflammation, spontaneous bleeding, and edema. B, Same patient as in A. Improved control of diabetes following 4 days of insulin therapy (blood glucose level <100 mg/dl). The clinical periodontal condition has improved without local therapy. C, Adult patient with uncontrolled diabetes. Note the enlarged, smooth, erythematous gingival margins and papilla in the anterior area. D, Same patient as in C. Lingual view of the right mandibular area. Note the inflamed and swollen tissues in the anterior and premolars area. E, Adult patient with diabetes. Suppurating abscess on the buccal surface of the maxillary premolars in a patient with uncontrolled diabetes.

The extensive literature on this subject and the overall impression of clinicians indicate that periodontal disease in diabetic patients follows no consistent or distinct pattern. Severe gingival inflammation, deep periodontal pockets, rapid bone loss, and frequent periodontal abscesses often occur in poorly controlled diabetic patients with poor oral hygiene³ (Figures 27-2 and 27-3). Children with type 1 diabetes tend to have more destruction around the first molars and incisors than elsewhere, but this destruction becomes more generalized at older ages.⁴⁷ In juvenile diabetic patients, extensive periodontal destruction often occurs as a consequence of having more severe disease at a younger age.

Figure 27-2 Sixty-year-old patient with long-term history of type 2 diabetes. A, Anterior retracted view of dental/periodontal condition. Note missing posterior teeth, supereruption of premolars, and mild generalized gingival inflammation. B, Periapical radiographs of remaining teeth. Note mild, generalized bone loss with localized areas of severe bone loss. Failure to replace posterior teeth adds to the occlusal burden of the remaining dentition. C, Clinical photograph of maxillary premolar area presenting with abscess. Notice diffuse erythema, inflammation surrounding abscess area. D, Periapical radiograph of maxillary premolar showing extensive bone loss associated with abscess.

Figure 27-3 Abscess in 28-year-old patient with poorly controlled type 1 diabetes. A, Periodontal abscess in patient with poorly controlled diabetes. He presented with pain and abscess a few weeks after scaling and root planing of the area. B, Radiograph of mandibular right premolar area demonstrating severe localized destruction of bone in the area of periodontal abscess. C, Radiograph of mandibular right premolar area taken 2 months before presentation of abscess. Note presence of calculus and level of interproximal bone before abscess.

Other investigators have reported that the rate of periodontal destruction appears to be similar for those with diabetes and those without diabetes, up to 30 years of age.^90,227 After age 30, diabetic patients have a greater degree of periodontal destruction, possibly related to more disease destruction over time. Patients showing overt diabetes over more than 10 years have greater loss of periodontal support than those with a diabetic history of less than 10 years.⁹⁰ This destruction may also be related to the diminished tissue integrity that continues to deteriorate over time (see later section for description of altered collagen metabolism).

Although some studies have not found a correlation between the diabetic state and the periodontal condition, the majority of well-controlled studies show a higher prevalence and severity of periodontal disease in individuals with diabetes than in nondiabetic persons with similar local factors.* Findings include a greater loss of attachment, increased bleeding on probing, and increased tooth mobility. A study of risk indicators for a group of 1426 patients, ages 25 to 74, revealed that individuals with diabetes are twice as likely to exhibit attachment loss as nondiabetic individuals.¹⁰⁶ The lack of consistency across studies is most likely related to the different degrees of diabetic involvement, variations in level of disease control and diversity of indices, and patient sampling from one study to another.

Recent studies suggest that uncontrolled or poorly controlled diabetes is associated with an increased susceptibility to and severity of infections, including periodontitis.^16,207 As with other systemic conditions associated with periodontitis, diabetes mellitus does not cause gingivitis or periodontitis, but evidence indicates that it alters the response of the periodontal tissues to local factors, hastening bone loss and delaying postsurgical healing. Frequent periodontal abscesses appear to be an important feature of periodontal disease in diabetic patients.

Approximately 40% of adult Pima Indians in Arizona have type 2 diabetes. A comparison of individuals with or without diabetes in this Native American tribe has shown a clear increase in prevalence of destructive periodontitis, as well as a 15% increase in edentulousness, in diabetic patients.²¹⁷ The risk of developing destructive periodontitis increases threefold in these individuals.⁷¹

Female Sex Hormones

Gingival alterations during puberty, pregnancy, and menopause are associated with physiologic hormonal changes in the female patient. In puberty and pregnancy, these changes are characterized by nonspecific inflammatory reactions with a predominant vascular component, leading clinically to a marked hemorrhagic tendency. Oral changes during menopause may include thinning of the oral mucosa, gingival recession, xerostomia, altered taste, and burning mouth. The changes associated with each phase of the female life cycle from puberty to menopause are briefly described here. Chapter 38 provides a detailed description of and management considerations for periodontal manifestations of hormonal changes in the female patient.

Puberty

Puberty is often accompanied by an exaggerated response of the gingiva to plaque.²²⁴ Pronounced inflammation, edema, and gingival enlargement result from local factors that might ordinarily elicit a comparatively mild gingival response (Figure 27-4). As adulthood approaches, the severity of the gingival reaction diminishes, even when local factors persist. However, complete return to normal health requires removal of these factors. Although the prevalence and severity of gingival disease are increased in puberty, gingivitis is not a universal occurrence for all adolescents, with good oral hygiene, it can be prevented (see Chapter 11).

Figure 27-4 Gingivitis in puberty, with edema, discoloration, and enlargement of the entire gingival margin and papillary areas around the mandibular incisors.

Pregnancy

Gingival changes in pregnancy were described as early in the late 1800s, even before any knowledge about hormonal changes in pregnancy was available.^25,191 As with other systemic conditions, pregnancy itself does not cause gingivitis. Gingivitis in pregnancy is caused by bacterial plaque, just as it is in nonpregnant women. The hormonal changes of pregnancy accentuate the gingival response to plaque and modify the resultant clinical picture (Figure 27-5). No notable changes occur in the gingiva during pregnancy in the absence of local factors.

Figure 27-5 Periodontal condition in pregnancy. A, Marginal erythema and easily bleeding gingiva in a woman who is 5 months pregnant. B, Localized, incipient gingival enlargement between the maxillary central and lateral incisors in a woman who is 4 months pregnant. C, Generalized gingival enlargement of the interdental papilla and gingival margins on the facial surface of the maxillary incisors in a pregnant woman. D, Extensive gingival enlargement localized on the buccal surface of the mandibular premolars in a pregnant woman. These lesions are often referred to as “pregnancy tumors.”

The reported incidence of gingivitis in pregnancy in well-conducted studies varies from 50% to 100%.^143,150 Pregnancy affects the severity of previously inflamed areas but does not alter healthy gingiva. Impressions of increased incidence may be created by the aggravation of previously inflamed but unnoticed areas. Tooth mobility, pocket depth, and gingival fluid are also increased in pregnancy.^115,140,195 The severity of gingivitis is increased during pregnancy beginning in the second or third month. Patients with mild chronic gingivitis that attracted no particular attention before the pregnancy become aware of the gingiva because previously inflamed areas become enlarged, edematous, and more notably discolored (Figure 27-5, A to C).

Gingivitis becomes more severe by the eighth month and decreases during the ninth month of pregnancy.¹⁴³ Plaque accumulation follows a similar pattern. Some investigators report that the greatest severity is between the second and third trimesters.⁵¹ The correlation between gingivitis and the quantity of plaque is greater after parturition than during pregnancy, which suggests that pregnancy introduces other factors that aggravate the gingival response to local factors.¹³²

Partial reduction in the severity of gingivitis occurs by 2 months postpartum, and after 1 year the condition of the gingiva is comparable to that of patients who have not been pregnant.⁵¹ Tooth mobility, pocket depth, and gingival fluid are also reduced after pregnancy. In a longitudinal investigation of the periodontal changes during pregnancy and for 15 months postpartum, no significant loss of attachment was observed.⁵¹

Pronounced ease of bleeding is the most striking clinical feature. The gingiva is inflamed and varies in color from a bright red to bluish red.^262,263 The marginal and interdental gingivae are edematous, pit on pressure, appear smooth and shiny, are soft and pliable, and sometimes present a raspberry-like appearance. The extreme redness results from marked vascularity, and there is an increased tendency to bleed. The gingival changes are usually painless unless complicated by acute infection. In some cases the inflamed gingiva forms discrete “tumorlike” masses, referred to as pregnancy tumors (Figure 27-5, D). Microscopically, gingival disease in pregnancy appears as nonspecific, vascularizing, and proliferative inflammation.^150,263 Marked inflammatory cellular infiltration occurs, with edema and degeneration of the gingival epithelium and connective tissue. The epithelium is hyperplastic, with accentuated rete pegs, reduced surface keratinization, and various degrees of intracellular and extracellular edema and infiltration by leukocytes.²³⁸ Newly formed engorged capillaries are present in abundance.

The possibility that bacterial-hormonal interactions may change the composition of plaque and lead to gingival inflammation has not been extensively explored. Kornman and Loesche¹³³ reported that the subgingival flora changes to a more anaerobic flora as pregnancy progresses. P. intermedia appears to be the only microorganism that increases significantly during pregnancy. This increase appears to be associated with elevations in systemic levels of estradiol and progesterone and to coincide with the peak in gingival bleeding. It has also been suggested that during pregnancy, a depression of the maternal T-lymphocyte response may be a factor in the altered tissue response to plaque.¹⁷⁷

The aggravation of gingivitis in pregnancy has been attributed principally to the increased levels of progesterone, which produce dilation and tortuosity of the gingival microvasculature, circulatory stasis, and increased susceptibility to mechanical irritation, all of which favor leakage of fluid into the perivascular tissues.^170,176 A marked increase in estrogen and progesterone occurs during pregnancy, with a reduction after parturition. Animal studies with radioactive estradiol have demonstrated that the gingiva is a target organ for female sex hormones.⁸⁰ The severity of gingivitis varies with the hormonal levels in pregnancy.¹¹⁵

It has also been suggested that the accentuation of gingivitis in pregnancy occurs in two peaks: during the first trimester, when there is overproduction of gonadotropins, and during the third trimester, when estrogen and progesterone levels are highest.¹⁴³ Destruction of gingival mast cells by the increased sex hormones and the resultant release of histamine and proteolytic enzymes may also contribute to the exaggerated inflammatory response to local factors.¹⁴²

Hyperparathyroidism

Parathyroid hypersecretion produces generalized demineralization of the skeleton, increased osteoclasis with proliferation of the connective tissue in the enlarged marrow spaces, and formation of bone cysts and giant cell tumors.²⁴⁹ The disease is called osteitis fibrosa cystica, or von Recklinghausen’s bone disease. Loss of the lamina dura and giant cell tumors in the jaws are late signs of hyperparathyroid bone disease, which in itself is uncommon. Complete loss of the lamina dura does not occur often, and clinicians may attach too much diagnostic significance to it. Loss of lamina dura may also occur in Paget’s disease, fibrous dysplasia, and osteomalacia.

Reports have suggested that 25% to 50% of patients with hyperparathyroidism have associated oral changes.^202,220,223 These changes include malocclusion and tooth mobility, radiographic evidence of alveolar osteoporosis with closely meshed trabeculae, widening of the periodontal ligament space, absence of the lamina dura (Figure 27-6), and radiolucent cystlike spaces (Figure 27-7). Bone cysts become filled with fibrous tissue with abundant hemosiderin-laden macrophages and giant cells. These cysts have been called brown tumors, but they are not tumors. More accurately, these cysts are reparative giant cell granulomas. In some cases these lesions appear in the periapical region of teeth and can lead to a misdiagnosis of a lesion of endodontic origin.¹⁴⁵ A relationship has been suggested between periodontal disease in dogs and hyperparathyroidism secondary to calcium deficiency in the diet,¹¹⁰ but this has not been confirmed by other studies.²²⁵

Figure 27-6 Secondary hyperparathyroidism in 35-year-old woman with advanced kidney disease. This periapical radiograph shows ground-glass appearance of bone and loss of lamina dura.

(Courtesy Dr. L. Roy Eversole, San Francisco.)

Figure 27-7 Brown tumor in patient with hyperparathyroidism. A, Periapical radiograph of brown tumor in patient with hyperparathyroidism. B, Occlusal radiographic view of brown tumor. Note expansion of lingual cortical plate and movement of premolar.

(Courtesy Dr. L. Roy Eversole, San Francisco.)

Leukocyte (Neutrophil) Disorders

Disorders that affect production or function of leukocytes may result in severe periodontal destruction. The PMN (neutrophil) in particular plays a critical role in bacterial infections because PMNs are the first line of defense (see Chapter 25). Quantitative deficiency of leukocytes (neutropenia, agranulocytosis) are typically associated with a more generalized periodontal destruction affecting all teeth.

Agranulocytosis

Agranulocytosis is a more severe neutropenia involving not only the neutrophil but also basophils and eosinophils. It is defined as an ANC of less than 100 cells/µl. It is characterized by a reduction in the number of circulating granulocytes and results in severe infections, including ulcerative necrotizing lesions of the oral mucosa, skin, and gastrointestinal and genitourinary tracts. Less severe forms of the disease are called neutropenia or granulocytopenia.

Drug idiosyncrasy is the most common cause of agranulocytosis, but in some cases, its cause cannot be explained. Agranulocytosis has been reported after the administration of drugs such as aminopyrine, barbiturates and their derivatives, benzene ring derivatives, sulfonamides, gold salts, or arsenical agents.^{134,149,166,194} It generally occurs as an acute disease. It may be chronic or periodic with recurring neutropenic cycles (e.g., cyclic neutropenia).²³¹

The onset of disease is accompanied by fever, malaise, general weakness, and sore throat. Ulceration in the oral cavity, oropharynx, and throat is characteristic. The mucosa exhibits isolated necrotic patches that are black and gray and are sharply demarcated from the adjacent uninvolved areas.^126,153 The absence of a notable inflammatory reaction caused by lack of granulocytes is a striking feature. The gingival margin may or may not be involved. Gingival hemorrhage, necrosis, increased salivation, and fetid odor are accompanying clinical features. In cyclic neutropenia, the gingival changes recur with recurrent exacerbation of the disease.⁴⁹ The occurrence of generalized aggressive periodontitis has been described in patients with cyclic neutropenia²¹⁵ (Figure 27-10).

Figure 27-10 Aggressive periodontitis in 10-year-old male with cyclic neutropenia and agammaglobulinemia. A, Clinical presentation of periodontal condition. Note the severe swelling and inflammation of marginal and papillary gingiva. There is gross migration of teeth caused by loss of bone support. B, Panoramic radiograph demonstrating severe bone loss around all permanent teeth that have erupted into the oral cavity.

Because infection is a common feature of agranulocytosis, differential diagnosis involves consideration of such conditions as necrotizing ulcerative gingivitis, noma, acute necrotizing inflammation of the tonsils, and diphtheria. Definitive diagnosis depends on the hematologic findings of pronounced leukopenia and almost complete absence of neutrophils.

Leukemia

Leukemia is an important disease to understand and appreciate because of the seriousness of the disease and the periodontal manifestations. The leukemias are malignant neoplasias of WBC precursors characterized by (1) diffuse replacement of the bone marrow with proliferating leukemic cells, (2) abnormal numbers and forms of immature WBCs in the circulating blood, and (3) widespread infiltrates in the liver, spleen, lymph nodes, and other body sites.²⁰⁰

According to the cell type involved, leukemias are classified as lymphocytic or myelogenous. A subgroup of the myelogenous leukemias is monocytic leukemia. The term lymphocytic indicates that the malignant change occurs in cells that normally form lymphocytes. The term myelogenous indicates that the malignant change occurs in cells that normally form RBCs, some types of WBCs and platelets. According to their evolution, leukemias can be acute, which is rapidly fatal, subacute, or chronic. In acute leukemia, the primitive “blast” cells released into the peripheral circulation are immature and nonfunctional, whereas in chronic leukemia the abnormal cells tend to be more mature with normal morphologic characteristics and function when released into the circulation.

All leukemias tend to displace normal components of the bone marrow elements with leukemic cells, resulting in reduced production of normal RBCs, WBCs, and platelets, which leads to anemia, leukopenia (reduction in number of nonmalignant WBCs) and thrombocytopenia. Anemia results in poor tissue oxygenation, making tissues more friable and susceptible to breakdown. A reduction of normal WBCs in the circulation leads to a poor cellular defense and an increased susceptibility to infections. Thrombocytopenia leads to bleeding tendency, which can occur in any tissue but in particular affects the oral cavity, especially the gingival sulcus (Figure 27-11). Some patients may have normal blood counts while leukemic cells reside primarily in the bone marrow. This type of disease is called aleukemic leukemia.⁹⁷

Figure 27-11 Spontaneous bleeding from the gingival sulcus in patient with thrombocytopenia. Normal coagulation is evident by the appearance of the large clot that forms in the mouth. However, platelets are inadequate to establish hemostasis at the site of hemorrhage.

The Periodontium in Leukemic Patients

Oral and periodontal manifestations of leukemia may include leukemic infiltration, bleeding, oral ulcerations, and infections. The expression of these signs is more common in acute and subacute forms of leukemia than in chronic forms.

Leukemic Infiltration

Leukemic cells can infiltrate the gingiva and less frequently the alveolar bone. Gingival infiltration often results in leukemic gingival enlargement (see Chapter 9).

A study of 1076 adult patients with leukemia showed that 3.6% of the patients with teeth had leukemic gingival proliferative lesions, with the highest incidence in patients with acute monocytic leukemia (66.7%), followed by acute myelocytic-monocytic leukemia (18.7%), and acute myelocytic leukemia (3.7%).⁶³ It should be noted, however, that monocytic leukemia is an extremely rare form of the disease. Leukemic gingival enlargement is not found in edentulous patients or in patients with chronic leukemia, suggesting that it is the accumulation of immature leukemic blast cells in the gingiva adjacent to tooth surfaces with bacterial plaque. Leukemic gingival enlargement consists of a basic infiltration of the gingival corium by leukemic cells that increases the gingival thickness and creates gingival pockets in which bacterial plaque accumulates, initiating a secondary inflammatory lesion that contributes to the enlargement of the gingiva. It may be localized to the interdental papilla area (Figure 27-12) or expand to include the marginal gingiva and partially cover the crowns of the teeth (Figure 27-13, C and D). Clinically, the gingiva appears bluish red and cyanotic, with a rounding and tenseness of the gingival margin. The abnormal accumulation of leukemic cells in the dermal and subcutaneous connective tissue is called leukemia cutis and forms elevated and flat macules and papules^63,200 (Figure 27-13, A and B).

Figure 27-12 Leukemic infiltration causing localized gingival swelling of the interdental papillae between the maxillary lateral and central incisor. Note the tense induration of the area.

Figure 27-13 Adult male with acute myelocytic leukemia. A, View of patient’s face. Note the elevated, flat macules and papules (leukemia cutis) on the right cheek. B, Close-up view of skin lesions. C, Intraoral view showing pronounced gingival enlargements of the entire gingival margin and interdental papilla areas of both arches. D, Occlusal view of maxillary anterior teeth. Note the marked enlargement in both the facial and the palatal aspects.

(Courtesy Dr. Spencer Woolfe, Dublin, Ireland.)

Microscopically, the gingiva exhibits a dense, diffuse infiltration of predominantly immature leukocytes in the attached and marginal gingiva. Occasionally, mitotic figures indicative of ectopic hematopoiesis may be seen. The normal connective tissue components of the gingiva are displaced by the leukemic cells (Figure 27-14). The nature of the cells depends on the type of leukemia. The cellular accumulation is denser in the entire reticular connective tissue layer. In almost all cases the papillary layer contains comparatively few leukocytes. The blood vessels are distended and contain predominantly leukemic cells, and the RBCs are reduced in number. The epithelium presents a variety of changes and may be thinned or hyperplastic. Common findings include degeneration associated with intercellular and intracellular edema and leukocytic infiltration with diminished surface keratinization.

Figure 27-14 Human histologic appearance of leukemic infiltrate with dense, diffuse infiltration of predominantly immature leukocytes. The normal connective tissue components of the gingiva are displaced by the leukemic cells. The cellular accumulation is denser in the entire reticular connective tissue layer.

(Courtesy of Dr. Russell Christensen, University of California, Los Angeles.)

The microscopic picture of the marginal gingiva differs from that of other gingival locations in that it usually exhibits a notable inflammatory component, in addition to the leukemic cells. Scattered foci of plasma cells and lymphocytes with edema and degeneration are common findings. The inner aspect of the marginal gingiva is usually ulcerated, and marginal necrosis with pseudomembrane formation may also be seen.

The periodontal ligament and alveolar bone may also be involved in acute and subacute leukemia. The periodontal ligament may be infiltrated with mature and immature leukocytes. The marrow of the alveolar bone exhibits a variety of changes, such as localized areas of necrosis, thrombosis of the blood vessels, infiltration with mature and immature leukocytes, occasional RBCs, and replacement of the fatty marrow by fibrous tissue.

In leukemic mice the presence of infiltrate in marrow spaces and the periodontal ligament results in osteoporosis of the alveolar bone with destruction of the supporting bone and disappearance of the periodontal fibers^31,39 (Figure 27-15).

Figure 27-15 Leukemic infiltrate in alveolar bone in leukemic mouse. Note the leukemic infiltrate causing destruction of bone and loss of periodontal ligament.

Bleeding

Gingival hemorrhage is a common finding in leukemic patients (see Figure 27-11), even in the absence of clinically detectable gingivitis. Bleeding gingiva can be an early sign of leukemia. It is caused by the thrombocytopenia resulting from replacement of the bone marrow cells by leukemic cells and from the inhibition of normal stem cell function by leukemic cells or their products.²⁰⁰ This bleeding tendency can also manifest in the skin and throughout the oral mucosa, where petechiae are often found, with or without leukemic infiltrates. A more diffuse submucosal bleeding manifests as ecchymosis (see Figure 27-9). Oral bleeding has been reported as a presenting sign in 17.7% of patients with acute leukemia and in 4.4% of patients with chronic leukemia.¹⁴⁸ Bleeding may also be a side effect of the chemotherapeutic agents used to treat leukemia.

Oral Ulceration and Infection

In leukemia, the response to bacterial plaque or other local irritation is altered. The cellular component of the inflammatory exudate differs both quantitatively and qualitatively from that in nonleukemic individuals in that there is a pronounced infiltration of immature leukemic cells in addition to the usual inflammatory cells. As a result, the normal inflammatory response may be diminished.

Granulocytopenia (diminished WBC count) results from the displacement of normal bone marrow cells by leukemic cells, which increases the host susceptibility to opportunistic microorganisms and leads to ulcerations and infections. Discrete, punched-out ulcers penetrating deeply into the submucosa and covered by a firmly attached white slough can be found on the oral mucosa.¹⁵ These lesions occur in sites of trauma such as the buccal mucosa in relation to the line of occlusion or on the palate. Patients with past history of herpesvirus infection may develop recurrent herpetic oral ulcers, often in multiple sites, and large atypical forms, especially after chemotherapy is instituted¹⁰² (Figure 27-16).

Figure 27-16 Large ulcerations on the palate of patient with granulocytopenia secondary to leukemia. These atypical ulcerations are caused by herpesvirus opportunistic infection. Notice the smaller, discrete, round ulcerations that have coalesced into the larger lesion.

A gingival (bacterial) infection in leukemic patients can be the result of an exogenous bacterial infection or an existing bacterial infection (e.g., gingival or periodontal disease). Acute gingivitis and lesions resembling necrotizing ulcerative gingivitis are more frequent and severe in terminal cases of acute leukemia²¹ (Figures 27-17 and 27-18). The inflamed gingiva in patients with leukemia differs clinically from that in nonleukemic individuals. Gingiva is a peculiar bluish red, is spongelike and friable, and bleeds persistently on the slightest provocation or even spontaneously in leukemic patients. This greatly altered and degenerated tissue is extremely susceptible to bacterial infection, which can be so severe as to cause acute gingival necrosis with pseudomembrane formation (Figure 27-19) or bone exposure (Figure 27-20). These are secondary oral changes superimposed on the oral tissues altered by the blood dyscrasia. They produce associated disturbances that may be a source of considerable difficulty to the patient, such as systemic toxic effects, loss of appetite, nausea, blood loss from persistent gingival bleeding, and constant gnawing pain. Eliminating or reducing local factors (e.g., bacterial plaque) can minimize severe oral changes in leukemia. In some patients with severe acute leukemia, symptoms may only be relieved by treatment that leads to remission of the disease.

Figure 27-17 Adult female with acute myelocytic leukemia. A, Anterior view of patient with acute myelocytic leukemia. Interdental papillae are necrotic with a highly inflamed and swollen gingival tissue at the base of the lesions. B, Palatal view demonstrating extensive necrosis of interdental and palatal tissues behind the maxillary incisors.

Figure 27-18 Same patient as in Figure 27-17 after chemotherapy that resulted in remission of leukemia. A, Anterior view reveals dramatic improvement in gingival health following remission of leukemia. Note the loss of interdental papillae as well as gingival recession in the anterior areas. B, Palatal view shows extensive loss of gingival tissue around maxillary incisors.

Figure 27-19 Opportunistic bacterial infection of gingiva in patient with hospitalized with leukemia. Gingival tissue is highly inflamed, bleeding, and necrotic with pseudomembrane formation.

Figure 27-20 Opportunistic bacterial infection in immunosuppressed patient caused complete destruction of gingiva, exposing underlying alveolar bone.

In chronic leukemia, oral changes suggesting a hematologic disturbance are rare. The microscopic changes in chronic leukemia may consist of replacing the normal fatty marrow of the jaws with islands of mature lymphocytes or lymphocytic infiltration of the marginal gingiva without dramatic clinical manifestations.

The existence of leukemia is sometimes revealed by a gingival biopsy performed to clarify the nature of a troublesome gingival condition. In such cases the gingival findings must be corroborated by medical examination and hematologic study. In patients with diagnosed leukemia, gingival biopsy may indicate the extent to which leukemic infiltration is responsible for the altered clinical appearance of the gingiva. Although such findings are of interest, their benefit to the patient is insufficient to warrant routine gingival biopsy studies in patients with leukemia. Furthermore, it is important to note that the absence of leukemic involvement in a gingival biopsy specimen does not rule out the possibility of leukemia. A gingival biopsy in a patient with chronic leukemia may reveal typical gingival inflammation without any suggestion of a hematologic disturbance.

Anemia

Anemia is a deficiency in the quantity or quality of the blood, as manifested by a reduction in the number of erythrocytes and in the amount of hemoglobin. Anemia may be the result of blood loss, defective blood formation, or increased RBC destruction. Anemias are classified according to cellular morphology and hemoglobin content as (1) macrocytic hyperchromic anemia (pernicious anemia), (2) microcytic hypochromic anemia (iron deficiency anemia), (3) sickle cell anemia, and (4) normocytic-normochromic anemia (hemolytic or aplastic anemia).

Pernicious anemia results in tongue changes in 75% of patients. The tongue appears red, smooth, and shiny because of atrophy of the papillae (Figure 27-21). There is also marked pallor of the gingiva (Figure 27-22). Iron deficiency anemia induces similar tongue and gingival changes. A syndrome consisting of glossitis and ulceration of the oral mucosa and oropharynx, inducing dysphagia (Plummer-Vinson syndrome) has been described in patients with iron deficiency anemia. Sickle cell anemia is a hereditary form of chronic hemolytic anemia that occurs almost exclusively in blacks. It is characterized by pallor, jaundice, weakness, rheumatoid manifestations, and leg ulcers. Oral changes include generalized osteoporosis of the jaws, with a peculiar stepladder alignment of the trabeculae of the interdental septa, along with pallor and yellowish discoloration of the oral mucosa. Periodontal infections may precipitate sickle cell crisis.¹⁹⁴ Aplastic anemia results from a failure of the bone marrow to produce erythrocytes. The etiology is usually the effect of toxic drugs on the marrow or displacement of RBCs by leukemic cells. Oral changes include pale discoloration of the oral mucosa and increased susceptibility to infection because of the concomitant neutropenia.

Figure 27-21 Smooth tongue in patient with pernicious anemia.

Figure 27-22 Diffuse pallor of gingiva in patient with anemia. The discolored, inflamed gingival margin stands out in sharp contrast to the adjacent pale, attached gingiva.

Thrombocytopenia

Thrombocytopenia is a term used to describe the condition of reduced platelet count resulting from either lack of platelet production or increased loss of platelets. Purpura refers to the purplish appearance of the skin or mucous membranes where bleeding has occurred as a result of decreased platelets. Thrombocytopenic purpura may be idiopathic (i.e., of unknown etiology, as in Werlhof’s disease) or may occur secondary to some known etiologic factor responsible for a reduced amount of functioning marrow and a resultant reduction in the number of circulating platelets. Such etiologic factors include aplasia of the marrow; displacement of the megakaryocytes in the marrow, as in leukemia; replacement of the marrow by tumor; and destruction of the marrow by irradiation or radium or by drugs such as benzene, aminopyrine, and arsenical agents.

Thrombocytopenic purpura is characterized by a low platelet count, a prolonged clot retraction and bleeding time, and a normal or slightly prolonged clotting time. There is spontaneous bleeding into the skin or from mucous membranes. Petechiae and hemorrhagic vesicles occur in the oral cavity, particularly in the palate, tonsillar pillars, and the buccal mucosa. The gingivae are swollen, soft, and friable. Bleeding occurs spontaneously or on the slightest provocation and is difficult to control. Gingival changes represent an abnormal response to local irritation. The severity of the gingival condition is dramatically alleviated by removal of the local factors (Figure 27-23).

Figure 27-23 Thrombocytopenic purpura. A, Hemorrhagic gingivitis in patient with thrombocytopenic purpura. B, Same patient as in A. Marked reduction in severity of gingival disease after removal of surface debris and careful scaling.

Antibody Deficiency Disorders

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome is a rare disease that affects the production of organelles found in almost every cell. It affects mostly the melanocytes, platelets, and phagocytes. It causes partial albinism, mild bleeding disorders, and recurrent bacterial infections. Neutrophils contain abnormal, giant lysosomes that can fuse with the phagosome, but their ability to release their contents is impaired. As a result, killing of ingested microorganisms is delayed. Patients with Chédiak-Higashi syndrome are susceptible to repeated infections that can be serious and life-threatening. Aggressive periodontitis has been described in these patients. Chédiak-Higashi syndrome has been described as a genetically transmitted disease in ranch-raised mink^11,185 (see Chapter 24).

Lazy Leukocyte Syndrome

Lazy leukocyte syndrome is characterized by susceptibility to severe microbial infections, neutropenia, defective chemotactic response by neutrophils, and an abnormal inflammatory response.¹⁸⁸ Individuals diagnosed with lazy leukocyte syndrome are susceptible to aggressive periodontitis with destruction of bone and early tooth loss.

Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) is a very rare genetic disorder. Only a few hundred cases have been diagnosed. Because LAD is an inherited disease, it is categorized as a primary immunodeficiency most often diagnosed at birth. Many children do not survive.

LAD results from the inability to produce or failure to normally express an important cell surface integrin (CD18), which is necessary for leukocytes to adhere to the vessel wall at the site of infection. When leukocytes cannot effectively adhere to the vessel wall near the site of infection, they cannot migrate to the infection. As a result, bacterial infections are able to continue to destroy host tissues unimpeded by the normal host immune response. Infections act similarly to those observed in neutropenic patients because phagocytes are unable to reach the site of infection.

Cases of periodontal disease attributed to LAD are rare. They begin during or immediately after eruption of the primary teeth. Extremely acute inflammation and proliferation of the gingival tissues with rapid destruction of bone are found. Profound defects in peripheral blood neutrophils and monocytes and an absence of neutrophils in the gingival tissues have been noted in patients with LAD.^184,185 These patients also have frequent respiratory tract infections and sometimes otitis media. Both primary and permanent teeth are affected, often resulting in early tooth loss.²⁴⁷

Papillon-Lefèvre Syndrome

Papillon-Lefèvre syndrome, first described by French physicians Papillon and Lefèvre,¹⁸⁶ is a very rare inherited condition that appears to follow an autosomal recessive pattern. Parents are not affected, and both must carry the autosomal genes for the syndrome to appear in the offspring. It may occur in siblings and has no gender predilection. The estimated frequency is 1 to 4 cases per 1 million individuals. Rare cases of adult onset of this syndrome, although with mild periodontal lesions, have also been described.³⁵

The syndrome is characterized by hyperkeratotic skin lesions, severe destruction of the periodontium, and in some cases, calcification of the dura.^40,75 The cutaneous and periodontal changes usually appear together between the ages of 2 and 4 years. The skin lesions consist of hyperkeratosis and ichthyosis of localized areas on palms, soles, knees, and elbows (Figure 27-24).

Figure 27-24 Papillon-Lefèvre syndrome in a 17-year-old male. A, Clinical view of palms demonstrating hyperkeratosis of skin. B, Clinical view of knees with hyperkeratotic, scaly lesions.

Periodontal involvement consists of early inflammatory changes that lead to bone loss and exfoliation of teeth. Primary teeth are lost by 5 or 6 years of age. The permanent dentition then erupts normally, but within a few years, the permanent teeth are also lost because of destructive periodontal disease (Figure 27-25). At a very early age, usually 15 to 20 years, patients are often edentulous except for the third molars. These may be lost as well a few years after eruption. Tooth extraction sites heal uneventfully.⁷⁶

Figure 27-25 Same case as in Figure 27-24. Intraoral clinical view of 17-year-old boy with Papillon-Lefèvre syndrome showing early tooth loss and severe bone loss around remaining teeth as evidenced by gingival recession. The missing teeth were exfoliated.

There are few case reports of successful tooth retention in patients with Papillon-Lefèvre syndrome.^235,252 Successful retention of permanent teeth may be associated with timing treatment (antibiotics and extraction of erupted teeth) with severity of syndrome symptoms.²⁵² Extraction of all primary teeth followed by a period of edentulousness may partially explain the lack of recurrent infection. In their review of the literature, Wiebe et al reported that the symptoms of Papillon-Lefèvre syndrome diminish with age and teeth that erupt later may not be lost.²⁵²

The microscopic changes reported include marked chronic inflammation of the lateral wall of the pocket with a predominantly plasma cell infiltrate, considerable osteoclastic activity and apparent lack of osteoblastic activity, and an extremely thin cementum.¹⁵⁴ Bacterial flora studies of plaque in a patient with Papillon-Lefèvre syndrome revealed a similarity to bacterial flora in chronic periodontitis.¹⁴⁶ Spirochete-rich zones in the apical portion of the pockets, as well as spirochete adherence to the cementum and microcolony formation of Mycoplasma species, have been reported in Papillon-Lefèvre syndrome.¹²² Gram-negative cocci and rods appear at the apical border of plaque.²⁴³ Although Schroeder et al²¹⁴ failed to show defects in peripheral blood neutrophils in a 10-year-old male patient with Papillon-Lefèvre syndrome, others have implicated neutrophil defects as a contributing factor. Firatli et al⁷⁸ reported depressed chemotaxis of peripheral neutrophils and suggested that it explained the pathogenesis of the Papillon-Lefèvre syndrome. Ghaffar et al found significantly depressed neutrophil function in probands with Papillon-Lefèvre syndrome with respect to phagocytic and lytic activity.⁸⁹

Down Syndrome

Down syndrome (mongolism, trisomy 21) is a congenital disease caused by a chromosomal abnormality and characterized by mental deficiency and growth retardation. The prevalence of periodontal disease in Down syndrome is high (occurring in almost 100% of patients younger than 30 years).^52,59 Although plaque, calculus, and local irritants (e.g., diastemata, crowding of teeth, high frenum attachments, and malocclusion) are present and oral hygiene is poor, the severity of periodontal destruction exceeds that explainable by local factors alone.^{48,50,52,198,226}

Periodontal disease in Down syndrome is characterized by formation of deep periodontal pockets associated with substantial plaque accumulation and moderate gingivitis (Figure 27-26). These findings are usually generalized, although they tend to be more severe in the lower anterior region. Moderate recession is sometimes seen in this region as well. The disease progresses rapidly. The high prevalence and increased severity of periodontal destruction associated with Down syndrome is most likely explained by poor PMN chemotaxis, phagocytosis, and intracellular killing.*

Figure 27-26 Severe periodontal destruction in 14-year-old patient with Down syndrome. Note the extensive loss of periodontal support around the mandibular incisors as evidenced by severe gingival recession. Moderate-heavy bacterial plaque is associated with moderate gingival inflammation in the area.

Psychosocial Stress, Depression, and Coping

Recently, several clinical studies and a systematic review of the subject have documented a positive relationship between psychosocial stress and chronic forms of periodontal disease.¹⁹⁰ In case-controlled studies, individuals with stable lifestyles (based on family structure and employment status) and minimal negative life events had less periodontal disease destruction than individuals with less stable lifestyles (e.g., unmarried, unemployed) and more negative life events.⁵⁶ Interestingly, it is now becoming apparent that the effect is not simply a matter of the presence of stress versus a lack of stress but rather the type of stress as well as the ability of the individual to cope with stress that correlate with destructive periodontal disease.

All individuals experience stress, but these events do not invariably result in destructive periodontitis. The types of stress that lead to periodontal destruction appear to be more chronic or long term and less likely to be controlled by the individual. Life events, such as the loss of a loved one (e.g., spouse or family member), a failed relationship, loss of employment, and financial difficulties, are examples of stressful life events that are typically not controllable by the individual or not perceived by the individual as being under his or her control, rendering the person with a feeling of “helplessness.” The duration of the stressful life event will also have an influence on the total impact of the stress-induced disease destruction.

Financial stress is an example of a long-term, constant pressure that may exacerbate periodontal destruction in susceptible individuals. Genco et al⁸⁶ found that individuals with high levels of financial stress and poor coping skills had twice as much periodontal disease as those with minimal stress and good coping skills. Psychologic tests were used to identify and weigh the causes of stress, such as children, spouse, finances, single life, and work, and to measure individual coping skills. Individuals with problem-focused (practical) coping skills fared better than individuals with emotion-focused (avoidance) coping skills with respect to periodontal disease. As part of their analysis, the researchers also found that chronic stress and inadequate coping could lead to changes in daily habits, such as poor oral hygiene, clenching, and grinding, as well as physiologic changes such as decreased saliva flow and suppressed immunity.

Comparing 89 patients with periodontal disease to 63 periodontally healthy individuals, Wimmer et al²⁵³ found that patients with defensive (emotional) coping skills were more likely to refuse responsibility and downplay their condition. All patients completed a comprehensive stress assessment questionnaire (German language) to evaluate their coping behavior. Patients with periodontal disease were less likely to use “active” coping skills (i.e., situation control) and more likely to cope with stress by averting blame (emotional) than were periodontally healthy individuals.

These studies support the concept that one of the most important aspects related to the influence of stress on periodontal disease destruction is the manner in which the individual copes with the stress. Emotional coping methods appear to render the host more susceptible to the destructive effects of periodontal disease than do practical coping methods. Furthermore, emotional coping is more common in situations that must be accepted and by individuals who feel helpless in the situation.

Stress-Induced Immunosuppression

Stress and psychosomatic disorders most likely impact the periodontal health through changes in the individual’s behavior and through complex interactions among the nervous, endocrine, and immune systems. Individuals under stress may have poorer oral hygiene, may start or increase clenching and grinding of their teeth, and may smoke more frequently. All these behavioral changes increase their susceptibility to periodontal disease destruction. Likewise, individuals under stress may be less likely to seek professional care.

In addition to the many behavioral changes that may influence periodontal disease destruction, psychosocial stress may also impact the disease through alterations in the immune system. The influence of stress on the immune system and systemic health conditions, such as cardiovascular disease, is well known. Stress-related immune system changes clearly have the potential to affect the pathogenesis of periodontal disease as well. One possible mechanism involves the production of cortisol. Stress increases cortisol production from the adrenal cortex by stimulating an increase in the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Increased cortisol suppresses the immune response directly through suppression of neutrophil activity, IgG production, and salivary IgA secretion. All these immune responses are critical for the normal immunoinflammatory response to periodontal pathogens (see Chapter 21). The resulting “stress-induced” immunosuppression increases the potential for destruction by periodontal pathogens. Stress may also affect the cellular immune response directly through an increased release of neurotransmitters, including epinephrine, norepinephrine, neurokinin, and substance P, which interact directly with lymphocytes, neutrophils, and monocytes/macrophages via receptors causing an increase in their tissue-destructive function. Thus, in a manner similar to cortisol production, the “stress-induced” release of these neurotransmitters results in an upregulated immune response that increases the potential for destruction by the cellular response to periodontal pathogens.

It is important to remember that although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains as the essential etiologic factor (i.e., stress alone does not cause or lead to periodontitis in the absence of periodontal pathogens).

Influence of Stress on Periodontal Therapy Outcomes

Psychologic conditions, such as stress and depression, may also influence the outcome of periodontal therapy. In a large-scale retrospective study of 1299 dental records from a health maintenance organization (HMO) database, 85 individuals with depression had posttherapy outcomes that were less favorable (below median) compared to those without depression.⁷⁰ More than half (697) were complete enough for a comprehensive evaluation, including both periodontal diagnosis and psychologic profiles. The authors concluded that depression might have a negative effect on periodontal treatment outcomes.

A recent study investigating the relationship between psychologic stress and wound repair in patients after routine surgery (inguinal hernia open incision repair) revealed that stress impairs the inflammatory response and matrix degradation.³⁰ Forty-seven adults were given a standardized questionnaire before surgery to assess their psychologic stress before surgery. Wound fluids were collected over the first 20 hours after surgery to measure inflammatory markers (interleukin-1 [IL-1], IL-6, and matrix metalloproteinase-9 [MMP-9]). Greater psychologic stress was significantly associated with lower levels of IL-1 and MMP-9, as well as significantly more painful, poorer, and slower recovery.

Another study compared the psychiatric characteristics of individuals with different outcomes to periodontal therapy.¹⁰ Two groups were compared to evaluate the psychologic characteristics of 11 individuals who were responsive to periodontal treatment compared with 11 individuals who were not responsive to periodontal treatment. The responsive group had a more rigid personality, whereas the nonresponsive group had a more passive, dependent personality. Furthermore, the nonresponsive group reported more stressful life events in their past.

These studies suggest that both stressful life events and the individual’s personality and coping skills are factors to consider in assessing the risk of periodontal disease destruction and the potential for successful periodontal therapy. If patients are identified with emotional or defensive coping skills, care should be taken to ensure that they receive information in a manner that does not elicit a “defensive” reaction.

Psychiatric Influence of Self-Inflicted Injury

Psychosomatic disorders may result in harmful effects to the health of tissues in the oral cavity through the development of habits that are injurious to the periodontium. Neurotic habits, such as grinding or clenching the teeth, nibbling on foreign objects (e.g., pencils, pipes), nail biting, and excessive use of tobacco, are all potentially injurious to the teeth and the periodontium. Self-inflicted gingival injuries, such as gingival recession, have been described in both children and adults (Figure 27-27). However, these types of self-inflicted, factitious injuries do not appear to be common in psychiatric patients.²⁰⁹

Figure 27-27 Severe gingival recession localized to the labial surface of all mandibular incisors. This finding was discovered under general anesthesia in an uncooperative, institutionalized adult with mental disorders. The patient was known to pace around the home with all four fingers inside his lower lip.

Fat-Soluble Vitamin Deficiency

Vitamins A, D, and E are fat-soluble vitamins required in the human diet.

Water-Soluble Vitamin Deficiency

Vitamins B and C are water-soluble vitamins required in the human diet.

Protein Deficiency

Protein depletion results in hypoproteinemia with many pathologic changes, including muscular atrophy, weakness, weight loss, anemia, leukopenia, edema, impaired lactation, decreased resistance to infection, slow wound healing, lymphoid depletion, and reduced ability to form certain hormones and enzyme systems. Protein deprivation has been shown to cause changes in the periodontium of experimental animals.⁴⁵ The following observations have been made in protein-deprived animals: degeneration of the connective tissue of the gingiva and periodontal ligament, osteoporosis of alveolar bone, impaired deposition of cementum, delayed wound healing, and atrophy of the tongue epithelium.^39,221,222 Similar changes occur in the periosteum and bone in other nonoral areas. Osteoporosis results from reduced deposition of osteoid, reduction in the number of osteoblasts, and impairment in the morphodifferentiation of connective tissue cells to form osteoblasts, rather than from increased osteoclastic activity.

These observations are of interest in that they reveal a loss of alveolar bone resulting from the inhibition of normal bone-forming activity rather than from the introduction of destructive factors. Protein deficiency also accentuates the destructive effects of bacterial plaque and occlusal trauma on the periodontal tissues, but the initiation of gingival inflammation and its severity depend on the bacterial plaque.²²² In other words, protein deprivation results in periodontal tissues that lack integrity and as a result, are more vulnerable to breakdown when challenged by bacteria.

Bisphosphonates

Bisphosphonate medications are primarily used to treat cancer (intravenous [IV] administration) and osteoporosis (oral administration). They act by inhibiting osteoclastic activity, which leads to less bone resorption, less bone remodeling, and less bone turnover.²⁰⁶ The use of bisphosphonates in cancer treatment is aimed at preventing the often lethal imbalance of osteoclastic activity. In the treatment of osteoporosis, the goal is simply to harness osteoclastic activity to minimize or prevent bone loss and in many cases, to increase bone mass by creating an advantage for osteoblastic activity. The major difference in the use of bisphosphonates for cancer versus osteoporosis is the potency and route of administration of the specific bisphosphonate medication used. Potency is influenced by the chemical properties, as well as the binding and release pharmacokinetic properties, of these agents with bone. Specifically, the strength of binding and the ease of release of bisphosphonates with hydroxyapatite make them more or less potent.

Bisphosphonates were first synthesized in the 1950s as a substitute for pyrophosphate, a compound used in detergent. The ability of bisphosphonates to increase bone mass was discovered after animal studies in 1966, but the potential advantage of using bisphosphonates in humans with low bone mass was not appreciated until 1984.²⁴⁴ The Food and Drug Administration (FDA) approved the use of alendronate for osteoporosis in 1995.

The chemical structure of bisphosphonate consists of two phosphate groups covalently bonded to a central carbon (Figure 27-28). In addition to the two phosphate groups, the central carbon also has two side chains, R1 and R2. Both the short R1 side chain and the long R2 side chain influence the chemical properties and pharmacokinetics. The long R2 side chain also influences the mode of action and determines the strength or potency of the medication. Bisphosphonates inhibit osteoclasts by two mechanisms that depend on whether the R2 side chain contains nitrogen. Non-aminobisphosphonates are metabolized by osteoclasts to form an adenosine triphosphate (ATP) analog that interferes with energy production and causes osteoclast apoptosis. Aminobisphosphonates (risedronate, zoledronate, ibandronate, and alendronate) are more potent and have multiple effects on osteoclasts, including (1) inactivation of ATP, (2) osteoclast cytoskeletal disruption, (3) impairment of osteoclast recruitment, and (4) induction of osteoblasts to produce osteoclast-inhibiting factor.¹⁸¹ Table 27-1 lists some of the common bisphosphonate medications used for osteoporosis and cancer treatment that are currently available in the US.

Figure 27-28 Chemical structure of bisphosphonate molecule. Two phosphate groups are covalently bonded with a central carbon. The carbon also has two side chains, R1 and R2.

TABLE 27-1 Current Nonaminobisphosphonate and Aminobisphosphonate Medications and Common Therapeutic Uses

Bisphosphonates have a high affinity for hydroxyapatite and are rapidly absorbed in bone, especially in areas of high activity, which may explain why bisphosphonate-induced osteonecrosis is only found in the jaws.²⁴⁴ The bisphosphonate molecule gets incorporated into bone without being metabolized or modified. During osteoclastic resorption of bone, the trapped bisphosphonate is released and able to affect osteoclasts again. As a result, the half-life of bisphosphonates in the bone is estimated to be 10 years or more.

Osteonecrosis of the jaw associated with bisphosphonates was first reported in 2003 by Marx in a report of 36 cases of patients with avascular necrosis of the jaws who were treated with IV bisphosphonate for malignant tumors.¹⁵⁵ Several case series reporting an association between bisphosphonates and osteonecrosis of the jaws were published in the months and years after this initial report.^157,204 Various terms have been used to describe this type of osteonecrosis of the jaw, including avascular necrosis, bisphosphonate-related or -associated ONJ (BRONJ), and bisphosphonate-induced ONJ (BIONJ).²⁴⁴ Today, with the widespread recognition of BIONJ, it is important to remember that necrotic bone exposure of the jaw (ONJ) is a condition with multiple possible etiopathogenic factors, including systemic medications, radiation, infection, trauma, direct chemical toxicity, or other idiopathic mechanisms, and clinicians should carefully consider all factors before concluding a diagnosis of BIONJ.⁸

The condition of BIONJ has been defined as exposure/necrosis of portions of the jaw bone in patients exposed to bisphosphonates that has persisted more than 8 weeks with no past history of radiation therapy to the jaws.²⁰³ The stage of osteonecrosis is used to categorize patients and make treatment decisions.^1,156,157 Stage 0 is defined as patients at risk who have been treated with IV or oral bisphosphonates but have no apparent exposed/necrotic bone. Stage 1 is exposed/necrotic bone in patients who are asymptomatic with no infection. Stage 2 is exposed/necrotic bone in patients with pain and clinical evidence of infection. Stage 3 is exposed/necrotic bone in patients with pain, infection, and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border.

Clinically, BIONJ presents as exposed alveolar bone occurring spontaneously or after a dental procedure (Figures 27-29 and 27-30). The sites may be painful with surrounding soft tissue induration and inflammation. Infection with drainage may be present. Radiographically, lesions appear radiolucent with sclerosis of lamina dura, loss of lamina dura, or widening of periodontal ligament in areas where teeth are present. Histologically, bone appears necrotic with empty lacunae demonstrating a lack of living osteocytes. In advanced cases, pathologic fracture may be present through the area of exposed/necrotic bone.

Figure 27-29 Clinical photograph of exposed bone on palatal surface of maxilla adjacent to molar root in 60-year-old female with bisphosphonate-induced osteonecrosis of bone (maxilla). The bone exposures were noted about 1 year during treatment with bisphosphonate (Aredia and Zometa).

(Courtesy of Drs. Eric S. Sung and Evelyn M. Chung, University of California, Los Angeles.)

Figure 27-30 Clinical photograph of exposed bone on lingual surface of posterior mandible in 70-year-old male with bisphosphonate-induced osteonecrosis of bone (mandible). The bone exposure was noted after 3 years of bisphosphonate (Aredia and Zometa) for multiple myeloma.

(Courtesy of Drs. Eric S. Sung and Evelyn M. Chung, University of California, Los Angeles.)

The high potency of nitrogen-containing bisphosphonates, especially those administered via IV for cancer treatment (e.g., zoledronate), may explain the high incidence of BIONJ in these patients as compared to osteoporotic patients taking oral bisphosphonates. The incidence in patients treated for cancer has been reported to range from 2.5% to 5.4%.²⁴⁸ Estimating the incidence in patients taking oral bisphosphonates for osteoporosis is more difficult due to the large number of patients taking this medication (prescriptions) and lack of good reporting or documentation for these patients. Estimates from different sources project the incidence to range from 0.007% to 0.04%.²⁴⁴ Clearly, the incidence is low.

In addition to bisphosphonate therapy, other factors make individuals susceptible to BIONJ. Potential risk factors that may contribute to BIONJ include systemic corticosteroid therapy, smoking, alcohol, poor oral hygiene, chemotherapy, radiotherapy, diabetes, and hematologic disease.²⁸ The precipitating factors or events leading to BIONJ are reported to include extractions, root canal treatment, periodontal infections, periodontal surgery, and dental implant surgery, yet some cases appear to be idiopathic with spontaneous exposures.¹⁵⁷ In a retrospective evaluation of patients treated with IV bisphosphonates for metastatic bone cancer from 1996 to 2006, Estilo et al⁷³ found that type of cancer, duration of bisphosphonate therapy, sequential IV bisphosphonate treatment with pamidronate followed by zoledronate, comorbid osteoarthritis, rheumatoid arthritis, and benign hematologic conditions were significantly associated with an increased likelihood of ONJ. In their study, systemic administration of corticosteroids was not found to be associated with an increased risk BRONJ.⁷³

Patients being treated for cancer with IV bisphosphonates are at greater risk than patients being treated for osteoporosis with oral bisphosphonates. Dental health care providers should evaluate patients carefully, consider the risks, communicate with medical health care providers, inform patients, and consider treatment options and risks carefully.

Not surprisingly, the bone-preserving action of bisphosphonates has been studied and advocated for use in the prevention of bone loss from periodontal disease.²³² Several animal studies have shown that bisphosphonates, applied topically or administered systemically, have the potential to prevent alveolar bone loss caused by periodontitis.* The use of bisphosphonates in bone regeneration has been proposed as well.²³² Although some studies have demonstrated bone preservation with low doses of bisphosphonate, higher doses and longer administration may have a neutral or detrimental effect on bone loss caused by periodontitis.^34,41 In a 2 to 3 year follow-up report of 4 female patients with periodontitis treated with etidronate (200 mg daily for periods of 2 weeks with 10-week “off drug” periods), the potential of this agent to prevent periodontal bone loss was reported.²²⁹ In a 2-year randomized, placebo-controlled clinical trial of 335 patients treated with alendronate (70 mg once weekly), no significant difference in alveolar bone loss or alveolar bone density was found.¹²⁰ Interestingly, alendronate was found to significantly reduce bone loss relative to controls in a subset of this group (i.e., patients with low mandibular bone mineral density at baseline), suggesting that the effect may be more perceptible in cases with less bone mass or less bone density. In another clinical trial of 24 patients (12 experimental and 12 control), alendronate was shown to have a significant positive effect (bone preserving) on bone density in jaws.⁶⁸ Bone mineral density of the maxilla and mandible was measured for all patients using dual energy x-ray absorptiometry (DEXA) at baseline and following 6 months of treatment (10 mg daily for 6 months).

Corticosteroids

In humans, systemic administration of cortisone and ACTH appears to have no effect on the incidence or severity of gingival and periodontal disease. However, renal transplant patients receiving immunosuppressive therapy (prednisone or methylprednisone, azathioprine, or cyclophosphamide) have significantly less gingival inflammation than control subjects with similar amounts of plaque.^{20,125,180,236135}

Exogenous cortisone may have an adverse effect on bone quality and physiology. The systemic administration of cortisone in experimental animals results in osteoporosis of alveolar bone.⁹⁵ There was capillary dilation and engorgement with hemorrhage into the periodontal ligament and gingival connective tissue, as well as a degeneration and reduction in the number of collagen fibers in the periodontal ligament and increased destruction of the periodontal tissues associated with inflammation.⁹⁵

Stress increases circulating endogenous cortisol levels through stimulation of the adrenal glands (hypothalamic-pituitary-adrenal axis). This increased exposure to endogenous cortisol may have adverse effects on the periodontium by diminishing the immune response to periodontal bacteria (see section on psychosocial stress).

Osteoporosis

Osteoporosis is a disease characterized by low bone mass and structural deterioration leading to an increased risk of bone fracture that affects approximately 10 million people in the US with a higher predilection for females (80%) as compared to males (20%). An additional 34 million individuals in the US are estimated to have osteopenia or low bone density. Loss of bone mass and the incidence of osteoporosis increases with age for both men and women, with women affected earlier than men. The rate of bone loss is greatest for women during the perimenopausal years when estrogen levels decrease.

A bone mineral density (BMD) test is used to measure an individual’s bone mass. BMD is measured using a DEXA scan. The DEXA value, or T-score, is a comparison of the patient’s BMD to that of a healthy 30-year-old adult with peak bone mass. The World Health Organization (WHO) defines osteoporosis and osteopenia by measures of “standard deviations” as compared to that of a normal healthy young adult. Thus a T-score between +1 and −1 is considered normal, whereas a T-score between −1 and −2.5 indicates low bone density or osteopenia and a T-score less than −2.5 (i.e., more than 2.5 standard deviations below normal) is diagnostic for osteoporosis (Table 27-2).

TABLE 27-2 Definitions of Osteoporosis and Osteopenia Indicated by T-Scores

Ranges of T-scores are based on standard deviations outside of normal, which is based on the BMD of a healthy 30-year-old adult.

Adapted from World Health Organization definitions.

One of the most significant consequences of osteoporosis is the increased risk of bone fracture. All bones affected by osteoporosis are susceptible to fracture, but fractures of the pelvis and vertebrae carry the most serious risk of morbidity and mortality. Studies have reported that approximately 20% of patients with hip fractures die within a year and 50% experience significant disability (e.g., inability to walk unassisted).¹³⁷

Although it is logical to surmise a relationship between osteoporosis and periodontitis, it has been a challenging hypothesis to prove. One of the difficulties is the fact that both osteoporosis and periodontitis are chronic, multifactorial diseases that result in bone loss, and bone loss in each condition is exacerbated by local and systemic factors.¹⁷⁹ Gender, genetic predisposition, inactivity, deficient diets (e.g., deficient in calcium or vitamin D), alcohol, smoking, hormones, and medications put individuals at risk for osteoporosis, with some of these factors putting them at risk for the progression of periodontitis as well. Variations in populations studied, measurements used to assess disease, and study design have also hindered the ability to clearly define a relationship between osteoporosis and periodontitis.

Attempts to use tooth loss as an indirect measure of periodontitis in individuals with osteoporosis have offered mixed conclusions. Several studies have reported greater tooth loss, more alveolar bone loss and edentulism in individuals with osteoporosis.^{58,64,107,260} However, some other studies have suggested that tooth loss is not correlated to osteoporosis or BMD.^27,66,168 One large study (1365 Caucasian postmenopausal females) investigating systemic BMD (lumbar spine and proximal femur) and tooth loss, found no significant correlation.⁶⁶ Part of the challenge and the reason for conflicting results in these studies may be attributed to differences in measurement methods. Another problem in translating any tooth loss study conclusions to the question of whether osteoporosis contributes to periodontitis is that the cause of tooth loss in these studies is often unknown (i.e., tooth loss may or may not be related to periodontal disease).

Studies that attempt to correlate osteoporosis with periodontitis are fraught with similar, if not greater, challenges. Again, some studies have concluded or suggested that osteoporosis does contribute to the progression of periodontitis,^{117,130,169,234} whereas others refute this conclusion.^69,147 One study by Elders et al failed to show a correlation between BMD (lumbar BMD) and clinical parameters of periodontitis in a dentate group of 46- to 55-year-old females.⁶⁹ They used intraoral periodontal examinations (probing depth, bleeding on probing, and missing teeth) and bitewing radiographs to assess clinical parameters of periodontitis and interproximal alveolar bone loss. This study included edentulous subjects (286) as well, but no significant difference in BMD was found between edentulous (60) and dentate (226) subjects, suggesting that neither periodontitis nor tooth loss was related to osteoporosis. The mean age of subjects in this study was relatively young, which may have contributed to the lack of correlation.⁸⁸

Most studies citing a positive correlation between osteoporosis or BMD and periodontitis are cross-sectional studies of postmenopausal females. Klemetti et al evaluated 227 healthy postmenopausal women aged 48 to 56 years and found that women with higher skeletal BMD were more likely to retain teeth with periodontitis (deep periodontal pockets) than those with osteoporosis.¹³⁰ Tezal et al concluded that skeletal BMD (measured by DEXA at multiple sites) is related to alveolar bone loss and to a lesser extent to clinical attachment loss, implicating postmenopausal osteopenia as a risk indicator for periodontal disease in 70 postmenopausal white women aged 51 to 78 years.²³⁴ Periodontal parameters included probing depth, supragingival plaque, calculus, bleeding on probing, clinical attachment loss, and interproximal alveolar bone loss. Analysis was adjusted for age, age at menopause, estrogen supplementation, cigarette smoking, body mass, and supragingival plaque. Inagaki et al evaluated the association between periodontal conditions, tooth loss, and metacarpal BMD (m-BMD) in a cross-sectional study of 356 Japanese women (171 premenopausal, mean age 37.9 years and 185 postmenopausal, mean age 63.3 years) and concluded that periodontal status and tooth loss after menopause could be a useful indicator of m-BMD loss in Japanese women.¹¹⁷ These cross-sectional studies are suggestive but do not consider the periodontal condition or existence of periodontitis before the onset of osteoporosis or loss of systemic bone mineral density.

The effect of estrogen deficiency and osteopenia/osteoporosis on periodontitis is not known but may be an important factor to consider. Reinhardt et al¹⁹⁶ conducted a 2-year, prospective, longitudinal study of postmenopausal women (59 with moderate/advanced periodontitis and 16 with no periodontitis) to evaluate the effect of estrogen (serum estradiol) levels on periodontitis in these patients. Clinical measurements, including supragingival plaque, bleeding on probing, and relative clinical attachment, were taken at baseline and every 6 months for 2 years. They concluded that estrogen deficiency and osteopenia/osteoporosis together are risk factors for alveolar bone loss in postmenopausal women with a history of periodontitis.¹⁹⁶ Lerner¹³⁸ also proposed that estrogen deficiency might play a significant role in the progression of periodontitis in osteopenic/osteoporotic women citing that the cytokines believed to be involved in inflammation-induced remodeling are very similar to those suggested to play crucial roles in postmenopausal osteoporosis. In patients with periodontal disease and concomitant postmenopausal osteoporosis, the possibility exists that the lack of estrogen influences the activities of bone cells and immune cells in such a way that the progression of alveolar bone loss will be enhanced.¹³⁸ In fact, there are numerous studies that report less risk for tooth loss and improved oral health in postmenopausal women on hormone replacement therapy.* More prospective, longitudinal studies evaluating the effect of estrogen and osteopenia/osteoporosis on periodontitis are needed to improve our understanding.

Congenital Heart Disease

Congenital heart disease occurs in about 1% of live births. Approximately 40% of individuals born with heart defects would die without treatment. However, the prognosis has been dramatically improved with advances in cardiac surgery. Cardiac defects can involve the heart, the adjacent vessels, or a combination of both. The most striking feature of congenital heart disease is cyanosis caused by shunting of deoxygenated blood from the right to left, resulting in a return of poorly oxygenated blood to systemic circulation. In severe cases, cyanosis is obvious at birth, particularly in tetralogy of Fallot. Chronic hypoxia causes impaired development, compensatory polycythemia (increase in RBCs/hemoglobin) and clubbing edema of toes and fingers (Figure 27-31). Polycythemia is significant because it can result in hemorrhagic or thrombotic tendencies. Patients with congenital heart defects are often at risk for infective endocarditis because of turbulent blood flow in the heart and associated cardiovascular defects. The need for prophylactic antibiotics should be evaluated before dental therapy.

Figure 27-31 Characteristic clubbing of the fingers in adolescent patient with tetralogy of Fallot, consistent with untreated congenital cyanotic heart disease.

In addition to the obvious cyanosis of lips and oral mucosa, oral abnormalities associated with cyanotic congenital heart disease include delayed eruption of both primary and permanent dentitions, increased positional abnormalities, and enamel hypoplasia. The teeth often have a bluish white appearance with an increased pulp vascular volume. Gingival disease and other oral symptoms have been reported in children with congenital heart disease.^26,124 Reports seem to indicate more severe caries and periodontal disease in patients with cyanotic congenital heart defects. However, the apparent increase in dental disease may be attributed to poor oral hygiene and a general lack of dental care rather than a disease-related etiology.

Tetralogy of Fallot

As its name implies, tetralogy of Fallot is characterized by four cardiac defects: (1) ventricular septal defect, (2) pulmonary stenosis, (3) malposition of the aorta to the right, and (4) compensatory right ventricular enlargement. Clinical features include severe cyanosis, audible heart murmurs, and breathlessness. Cyanosis and breathlessness cause cerebral anoxia and syncope. Oral changes include a purplish red discoloration of the lips and gingiva. Severe marginal gingivitis and periodontal destruction have been reported (Figure 27-32). The discoloration of the lips and gingiva corresponds to the general degree of cyanosis and returns to normal after corrective heart surgery. The tongue appears coated, fissured, and edematous, and there is extreme reddening of the fungiform and filiform papillae. The number of subepithelial capillaries is increased but also returns to normal after heart surgery.⁸¹

Figure 27-32 Extensive marginal inflammation with ulceronecrotic lesions and periodontal destruction in patient with tetralogy of Fallot shown in Figure 27-31.

Hypophosphatasia

Hypophosphatasia is a rare familial skeletal disease characterized by rickets, poor cranial bone formation, craniostenosis, and premature loss of primary teeth, particularly the incisors. Patients have a low level of serum alkaline phosphatase, and phosphoethanolamine is present in serum and urine.

Teeth are lost with no clinical evidence of gingival inflammation and show reduced cementum formation.²³ In patients with minimal bone abnormalities, premature loss of deciduous teeth may be the only symptom of hypophosphatasia. In adolescents, this disease resembles localized “juvenile” (aggressive) periodontitis.²⁵⁹

Metal Intoxication

The ingestion of metals, such as mercury, lead, and bismuth, in medicinal compounds and through industrial contact may result in oral manifestations caused by either intoxication or absorption without evidence of toxicity.

Bismuth Intoxication

Chronic bismuth intoxication is characterized by gastrointestinal disturbances, nausea, vomiting, and jaundice, as well as by an ulcerative gingivostomatitis, generally with pigmentation and accompanied by a metallic taste and burning sensation of the oral mucosa. The tongue may be sore and inflamed. Urticaria, different types of exanthematous eruptions, bullous and purpuric lesions, and herpes zoster–like eruptions and pigmentation of the skin and mucous membranes are among the dermatologic lesions attributed to bismuth intoxication. Acute bismuth intoxication, which is seen less frequently, is accompanied by methemoglobin formation, cyanosis, and dyspnea.¹¹¹

Bismuth pigmentation in the oral cavity usually appears as a narrow, bluish black discoloration of the gingival margin in areas of preexisting gingival inflammation (Figure 27-33) (see Chapter 8). Such pigmentation results from the precipitation of particles of bismuth sulfide associated with vascular changes in inflammation; it is not evidence of intoxication but simply indicates the presence of bismuth in the bloodstream. Bismuth pigmentation in the oral cavity also occurs in cases of intoxication; it assumes a linear form if the marginal gingiva is inflamed.

Figure 27-33 Bismuth line. A, Linear discoloration of the gingiva in relation to local irritation in a patient receiving bismuth therapy. B, Biopsy specimen showing bismuth particles engulfed by monocytes/macrophages.