CLINICAL PRACTICE
CASE REPORT |
Systemic amyloidosis manifesting as localized, severe periodontitis
SAMER KHOURY,
JOSEPH J. DUSEK, D.D.S.,
GISSELA B. ANDERSON, D.D.S., M.S. and
NADARAJAH VIGNESWARAN, B.D.S., D.M.D., DR.MED.DENT.
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ABSTRACT
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Background. Amyloidosis comprises a heterogenous group of disorders characterized by amyloid deposition in various organs. The authors document a case in which amyloidosis manifested as a localized, severe, periodontal disease.
Case Description. A 73-year-old woman visited her dentist because of pain and increased mobility of her mandibular bridge. Radiographic examination revealed severe vertical bone loss associated with tooth no. 27. One of the authors extracted the tooth, removed tissue with a curet from this site and submitted it for pathological examination. He made a diagnosis of amyloidosis on the basis of histological and immunohistochemical findings.
Clinical Implications. Clinicians should consider periodontal involvement in amyloidosis as a possible cause of severe, localized, periodontal disease, particularly in patients with chronic inflammatory disorders or a history of amyloidosis.
Amyloidosis is made up of a heterogenous group of progressive disorders characterized by extracellular deposition of insoluble proteinaceous amyloid fibrillar material in various tissues.1 These disorders have an annual age-adjusted incidence of 12 cases per million.1 Some of these disorders can be fatal if not diagnosed and treated early.1
Amyloidosis belongs to a group of diseases known as conformational diseases, which include Alzheimer’s disease, Creutzfeldt-Jakob disease and transmissible spongiform encephalopathies.2 Conformational disease occurs when a constituent protein undergoes a change in size or shape, with resultant self-aggregation and tissue deposition.2 Although pathologists described the existence of disorders consistent with amyloidosis as early as the 17th century, the term "amyloidosis" was coined in the mid-19th century by Virchow,3 the founder of modern pathology.
Clinicians should consider amyloidosis as one of the systemic diseases that can lead to accelerated periodontal destruction in affected patients.
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AMYLOID DEPOSITION
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Amyloid is defined as a fibrillar protein deposit that appears as a pink amorphous substance in tissue sections stained with hematoxylin and eosin.4–6 When stained with Congo red, amyloid produces apple-green birefringence under polarized light microscopy, which is the gold standard for the diagnosis of amyloid deposition in tissue sections.4–6 Electron microscopic examination of amyloid reveals fine non-branching fibrils with diameters ranging from 7.5 to 10 nanometers. X-ray crystallographic analysis of amyloid fibrils exhibits a distinct X-ray diffraction pattern known as cross ß-pleated sheet structure, which is responsible for the specific staining properties of amyloid.4–6
Major components of deposits.
Amyloid deposits consist of three major components known as amyloid protein fibrils (> 80 percent of the deposits), amyloid P (pentagonal) component (< 15 percent) and sulfated glycosaminoglycans.4 The biochemical nature of the amyloid fibrils is diverse, and more than 20 different fibril proteins have been described.5,6 These precursor proteins differ from each other with respect to primary structure and function (Table
). The only trait that is common to all of these proteins is their ability to form aggregates under specific circumstances.4–6
Classification.
Amyloid deposits may be systemic—distributed throughout many organs of the body—or localized to a single organ such as the brain (Table
). The organ distribution pattern of amyloid deposits and the resulting disease outcome depend on the origin and type of fibrillar protein deposited.4–6 Hence, amyloidosis is classified on the basis of the origin and biochemical composition of the precursor proteins that form the fibrillar deposits (Table). In this review, we focus on the more common of these conditions, which are primary (amyloid light chain), secondary (amyloid A) and familial amyloidosis.4–6
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PRIMARY AMYLOIDOSIS
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Primary amyloidosis develops as a complication of plasma-cell dyscrasia, such as multiple myeloma and Waldenström’s macroglobulinemia.7 Monoclonal immunoglobulin light chains (
or 
), produced by plasma cells in these disorders, lead to the formation and deposition of fibrils (Figure 1). Approximately 10 to 20 percent of patients with multiple myeloma develop primary amyloidosis.8,9 The kidney and heart are the most commonly involved organs.8,9
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Figure 1. Pathogenesis of primary and secondary systemic amyloidosis. Proteolysis consists of proteolytic cleavage of amyloidogenic proteins of immunoglobulin light chains and serum amyloid A protein that generate insoluble amyloid light chain, or AL, and amyloid A, or AA, fibrils, respectively. Systemic deposits of amyloid fibrils are associated with serum amyloid P (pentagonal) component, or SAP, and sulfated glycosaminoglycans, or GAG, complex of connective tissue. IL-1: Interleukin 1. IL-6: Interleukin 6. TNF- : Tumor necrosis factor-alpha.
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Signs.
One of the earliest signs of this disorder is nephrotic syndrome, found in 65 percent of patients with primary amyloidosis.8,9 (Patients with nephrotic syndrome exhibit an excess of protein in their urine [proteinuria], a reduction in serum albumin levels [hypoalbuminemia] and generalized edema.) Cardiac involvement is seen in 33 percent of patients with primary amyloidosis and is the cause of death in up to one-half of these patients.9 Rapidly progressive right-sided heart failure in the absence of a history of chest pain is typical of amyloidosis-induced cardiomyopathy.9
The peripheral nerves, skin and tongue also are frequently involved in primary amyloidosis.1 Peripheral nerve involvement leading to carpal tunnel syndrome is common in patients with this disorder.1 Skin involvement, which commonly appears as purpuric waxy plaques, is seen in approximately 30 to 40 percent of patients.9
Intraoral findings.
Macroglossia is the most important intraoral finding associated with primary amyloidosis, and is seen in 20 percent of patients.1,9 The affected tongue appears diffusely enlarged, with multiple surface papules, as well as nodules with petechiae and ecchymoses that develop spontaneously or after minor trauma. These hemorrhagic nodules are caused by increased capillary fragility resulting from amyloid deposition around the blood vessels.1,9 Diffuse enlargement of the tongue results in tooth indentation on the lateral borders. The enlarged tongue may interfere with speech and swallowing, and may cause sleep apnea. Macroglossia is found exclusively in patients with primary amyloidosis, not secondary or familial amyloidosis.1 Amyloid infiltration of salivary glands in patients with this disorder can lead to xerostomia.1
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SECONDARY AMYLOIDOSIS
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Chronic inflammatory conditions.
Secondary amyloidosis, representing approximately 45 percent of all cases of systemic amyloidosis, is associated with various chronic inflammatory conditions such as rheumatoid arthritis, sarcoidosis, Crohn’s disease, ulcerative colitis and tuberculosis.10 Secondary amyloidosis also is associated with malignant diseases such as Hodgkin’s disease and mesothelioma.10 With the decline of tuberculosis in the West, rheumatoid arthritis and inflammatory bowel disease remain the leading causes of secondary amyloidosis.10 In southeast Asia and Africa, however, chronic infectious diseases such as tuberculosis and leprosy are the major causes.10
Amyloid A fibril protein in secondary amyloidosis is designated as AA protein, which is derived from the precursor protein known as serum amyloid A, or SAA. SAA protein is an acute-phase reactant produced by liver cells in response to macrophage-derived inflammatory cytokines such as interleukin 1, interleukin 6 and tumor necrosis factor-alpha.10 The progressive course of secondary amyloidosis depends on the nature and status of the underlying chronic inflammatory disease. For example, secondary amyloidosis–associated tuberculosis has been shown to undergo remission when the chronic infection has been eliminated.11
Organ involvement.
The spleen, liver and kidney are the most commonly involved organs in secondary amyloidosis.1,10 Amyloid is deposited initially in the spleen, followed by the liver and kidneys, before progressing to generalized vascular and interstitial deposits.1 Clinical findings of secondary amyloidosis include splenomegaly, hepatomegaly and proteinuria.1 Adrenal gland involvement leading to adrenocortical insufficiency also is commonly found in patients with secondary amyloidosis.1
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FAMILIAL AMYLOIDOSIS
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Familial amyloidosis consists of a group of inherited autosomal-dominant diseases in which a mutant protein causes amyloid deposition beginning in midlife.1 Also included in this group is an autosomal recessively inherited disorder known as familial Mediterranean fever, which is characterized by episodes of fever with abdominal pain.1 The most common form of familial amyloidosis is caused by the mutation of the protein transthyretin and is known as ATTR.1 Transthyretin is synthesized primarily in the liver and functions as a transporter protein for vitamin A and thyroxine. Approximately 4 percent of the African-American population carries the amyloidogenic mutation involving this transthyretin gene.12
Other less common forms of familial amyloidosis are caused by mutations in a number of serum proteins such as apolipoprotein A-I, fibrinogen and gelsolin.13 The clinical features of familial amyloidosis overlap significantly with those of primary amyloidosis, except for its prominent peripheral sensorimotor and autonomic neuropathy.1 Furthermore, macroglossia is not seen in patients with familial amyloidosis.1
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CLINICAL FEATURES
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Systemic amyloidosis is a multisystem disorder; hence, clinical findings may vary depending on the organs involved (Box). Organ involvement and the resulting clinical findings vary among the different clinical types of amyloidosis (discussed above). Some of the clinical symptoms and signs common to all cases of systemic amyloidosis include fatigue, weight loss, diarrhea, numbness or tingling in the hands or feet, shortness of breath, change in voice and periorbital purpura.1,9,13 Periorbital purpura, commonly described as "raccoon eye sign," can be provoked with minimal trauma, such as simply rubbing over the eyes, as a result of increased vascular fragility in patients with the disease.13
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DIAGNOSIS
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Histopathologic confirmation of amyloid in a tissue biopsy specimen is essential for the diagnosis and classification of amyloidosis.1,5–7,14 No other clinical or laboratory tests can replace histopathologic examination in establishing the diagnosis of amyloidosis.1,5–7,14 The sensitivity and specificity of the histopathologic diagnosis depend on the biopsy site and the adequacy of the tissue sample.13 The most common biopsy sites are subcutaneous fat in the abdominal wall and the rectum, kidney and liver.13 Intraoral biopsy sites include gingivae and labial salivary glands.15,16
A pathologist should confirm amyloid in the tissue biopsy specimen with Congo red staining.1,13 After the pathologist makes the diagnosis, he or she can precisely classify the amyloid type, either immunohistochemically using specific antibodies against defined fibril proteins or biochemically through amino acid sequencing.10,13
Clinicopathologic correlation also is helpful in determining the specific type of amyloidosis.10,13 Laboratory work-up of patients includes urine and blood analyses, liver function tests and bone marrow biopsies.13 Electrocardiographic and echocardiographic examination may be necessary if cardiac involvement is suspected.13 Radiolabeled serum amyloid P component scintigraphy is useful to elucidate the patterns of amyloid deposition and to monitor progress after treatment.17
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PROGNOSIS AND TREATMENT
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The prognosis depends primarily on the extent of vital organ involvement. Untreated primary amyloidosis carries the worst prognosis, with a median survival time of one to two years.1,13 The prognosis for patients with secondary amyloidosis is determined by the underlying chronic inflammatory disease.1,13 Patients diagnosed as having familial amyloidosis have a median survival of 15 years from the time of diagnosis.1
Treatment varies depending on the type of amyloidosis and the extent of multiorgan system involvement.1,13 Supportive treatments are directed toward managing nephrotic syndrome and congestive heart failure. Conservative surgical excision may be needed to reduce the size of the enlarged organ or tissue. Primary amyloidosis is treated with melphalan, an alkylating agent, combined with prednisolone.13 Chemotherapy is indicated if the patient has underlying multiple myeloma. However, the current treatment of choice for patients with primary amyloidosis is high-dose melphalan and autologous bone marrow transplantation.13 The most effective treatment for secondary amyloidosis involves control of the underlying chronic inflammatory disease.10,13 Familial amyloidosis can be treated with liver transplantation.18
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CASE REPORT
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A 73-year-old woman visited her dentist with the chief complaint of pain and loosening of her anterior mandibular bridge. The patient stated that she was having difficulty eating owing to the pain and increased mobility of her anterior mandibular teeth. She reported that symptoms initially manifested approximately three months previously. She was unable to associate the onset of these symptoms with trauma to the teeth involved. At the time of the examination, the patient stated that she recently had experienced weakness, fatigue and significant weight loss (> 15 pounds).
The patient’s medical history was significant for hypertension, chronic renal disease, hypothyroidism and rheumatoid arthritis. Her current medications included simvastatin for hypercholesterolemia, levothyroxine for hypothyroidism, and amlodipine besylate and sodium bicarbonate for hypertension. The patient had been receiving fairly regular dental care and her last complete dental examination was approximately one year before. She denied ever having used tobacco or alcohol.
Intraoral examination findings.
A head-and-neck examination revealed no palpable masses or lymphadenopathy and no visible extraoral abnormalities. An intraoral examination revealed that the patient was partially edentulous and wore a porcelain-fused-to-metal fixed partial denture, or FPD, that spanned teeth nos. 22 through 27. She also wore two cantilever FPDs distal to teeth nos. 21 and 29. Tooth no. 27 exhibited mild gingival swelling and Class III mobility, leading to pain and hypermobility of the FPD. A radiographic examination showed generalized, moderate, horizontal bone loss of most of the remaining mandibular teeth (Figure 2). Tooth no. 27 exhibited severe vertical bone loss on the mesial surface, which was associated with periapical radiolucency (Figure 2).
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Figure 2. Radiographic findings from the patient described in this case report. Left: Severe vertical bone loss and periapical radiolucency associated with tooth no. 27. Right: Remaining teeth reveal generalized, moderate, horizontal bone loss.
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Histopathologic examination findings.
One of us (J.D.) extracted tooth no. 27 under local anesthesia, removed tissue with a curet from the extraction site and submitted it for histopathologic examination. Microscopic examination of the tissue showed granulation tissue with chronic inflammation; the chronic inflammatory cell infiltrate was composed predominantly of lymphocytes and plasma cells. Intermixed with the granulation tissue were extracellular deposits of eosinophilic amorphous material (Figure 3). The amorphous deposits showed a perivascular distribution and elicited foreign-body giant-cell reaction (Figure 3). These deposits stained positively with Congo red stain and produced the characteristic apple-green birefringence under polarized light microscopy, confirming the presence of amyloid deposits.
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Figure 3. Top. Hematoxylin-eosin staining of the biopsy specimen shows granulation tissue with chronic inflammation; the chronic inflammatory cell infiltrate was composed of predominately lymphoplasmacytic infiltrate. C. Note the extracellular deposits (asterisks) of eosinophilic material and reactive foreign-body giant cells (arrows). Magnification: A, x 40; B, x 100; C, x 200. Bottom. D. The amorphous extracellular material stains positively (arrows) with Congo red. E. This Congo red–positive material appears apple-green when viewed under polarized light. F. Extracellular (arrow) and perivascular (asterisks) deposits of amyloid reveal positive immunoreactivity with an antibody against amyloid A protein.
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The pathologist (N.V.) performed immunohistochemical staining of the tissue sections using antibodies against immunoglobulin light chains and (that is, primary amyloidosis) and amyloid A protein (secondary amyloidosis). Amyloid deposits were nonreactive with the antibodies against immunoglobulin light chains, but stained positively with the antibody to amyloid A protein (Figure 3).
Based on the clinical, radiographic and histopathologic findings, the pathologist diagnosed the patient as having amyloid deposition secondary to systemic secondary amyloidosis, resulting in accelerated periodontal destruction. The patient’s internist examined her and made the diagnosis of systemic amyloidosis secondary to rheumatoid arthritis on the basis of clinical and pathological findings. To date, the patient is receiving periodontal treatment from one of us (G.A.), and her internist is treating her arthritis and systemic amyloidosis.
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DISCUSSION
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Patients with recent-onset, severe, localized periodontitis involving a single tooth are seen fairly often in dental practices. Localized, rapidly progressive, periodontal destruction leading to severe horizontal and vertical bone loss with periapical involvement, as developed in our patient, can be due to a number of factors. Etiologic factors of inflammatory origin, such as vertical root fracture or a nonvital tooth with lateral canals, are the most frequent causes of localized, severe periodontitis with periapical involvement, commonly described as combined periodontal-endodontic defect.19,20
However, it is important to conduct a pathological examination of the tissue sample from the extraction site to exclude other causes that can lead to rapidly destructive localized periodontitis. In the early stages, metastatic carcinomas and primary odontogenic tumors, such as squamous odontogenic tumor, can mimic combined periodontal-endodontic defect.21,22 Gingival and periodontal involvement in systemic granulomatous diseases, such as sarcoidosis and Crohn’s disease, can lead to rapid destruction of the periodontium.23,24 In addition, our report highlights the possibility that amyloid deposition in patients with systemic amyloidosis causes accelerated periodontal destruction and bone loss of affected teeth.
Our patient developed reactive amyloidosis (AA-type), most likely secondary to her longstanding rheumatoid arthritis. Deposition of amyloid within the periodontium could have been precipitated by chronic periodontal disease in this patient. Amyloid deposition within the periodontium elicited an inflammatory reaction similar to that of foreign body material. Accelerated destruction of periodontium and associated supporting bone apparently is caused by this foreign-body–type giant-cell reaction.
In addition to the fact that the localized deposits of amyloid in patients with systemic amyloidosis can aggravate periodontal disease, chronic periodontal diseases could exaggerate secondary amyloidosis via increased levels of systemic inflammatory mediators. Indeed, patients with chronic periodontal diseases have higher levels of SAA—the precursor protein of amyloid fiber in secondary amyloidosis—than do patients without periodontal disease.25 Therefore, elimination of local infection associated with periodontal diseases will aid in reducing levels of systemic inflammatory mediators, which may slow the progression of secondary amyloidosis.
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CONCLUSION
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To our knowledge, this is the first case report that documents systemic secondary amyloidosis causing accelerated periodontal destruction and bone loss of affected teeth. Thus, clinicians should consider amyloidosis as one of the systemic diseases that can lead to accelerated periodontal destruction in affected patients. Finally, controlling periodontal disease in patients with secondary amyloidosis may slow the progression of this disorder.
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Mr. Khoury is a fourth-year dental student, University of Texas Health Science Center at Houston, Dental Branch.
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Dr. Anderson is an associate professor of periodontology, Department of Endodontics and Periodontics, University of Texas Health Science Center at Houston, Dental Branch.
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Dr. Vigneswaran is an associate professor of oral and maxillofacial pathology, Department of Diagnostic Sciences, University of Texas Health Science Center at Houston, Dental Branch, 6516 M.D. Anderson Blvd., Room 3.094G, Houston, Texas 77030, e-mail "Nadarajah.vigneswaran{at}uth.tmc.edu". Address reprint requests to Dr. Vigneswaran.
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ABSTRACT
AMYLOID DEPOSITION
