Diseases of the Blood and Blood-forming Organs
Hematologic abnormalities are varied in nature, in its causation as well as in its clinical manifestations, most of which manifest in the oral cavity. In fact the oral site in many instances could act as the forerunner of its manifestations before overt systemic signs and symptoms express. The need of a thorough oral examination is a requisite in any attempt to look into manifestations of hematologic abnormalities and therefore its role as a clinical adjunct cannot be overemphasized.
The symptoms of hematologic disorders are so varied and nonspecific that in themselves they may not suggest a hematologic problem. Thus, unexplained fever, extreme fatigability, or recurrent infections may or may not be caused by a hematologic condition. Likewise, physical examinations may or may not direct attention to the hematopoietic system. Certain details of history must receive special enquiry. These include exposure to physical or chemical agents that may have caused injury and to drugs prescribed or self-medicated. Also deserving special enquiry is the diet, the degree and frequency of chronic blood loss, and the presence or absence of fever. In addition, family history is important in the differential diagnosis of hematologic disorders. Knowledge of ethnic origin or a history of jaundice, anemia, or bleeding in male rather than in female members of the family, for example, may offer useful clues. Furthermore, history alone may be insufficient. Although symptoms may be denied, a palpable spleen on physical examination or morphologic changes seen in blood smear, may direct attention to a hitherto unsuspected hereditary disorder. A family history is only as good as the thoroughness of the enquiry (Wintrobe, 1998).
The formed elements of the blood, as well as its liquid portion, play extraordinary roles in many physiologic mechanisms and processes in the human body. When a disturbance of one of these constituents occurs, severe clinical manifestations result. In some cases, the alteration of cells, serum, or other components is a result of a hereditary diathesis, nutritional deficiency, or exposure to certain chemicals. Other times, a focal or disseminated infection or a defect in one of the elements associated with the clotting mechanism causes the disturbance. A neoplastic overproduction of white cells is recognized as one of the most dreaded of blood dyscrasias.
The various blood diseases present polymorphic clinical expressions, one of which is the relatively constant involvement of oral structures. The dentist is often consulted by the patient suffering from one of the hematologic disorders who, unaware of his condition, only seeks relief of his harassing physical discomforts. Oral manifestations of many diseases of the blood are clinically similar to those lesions which occur in the oral cavity as a result of some local phenomenon, usually irritation or infection. For this reason a specific diagnosis of blood dyscrasia is difficult, if not impossible, to establish on the basis of the oral findings alone.
The hematologic disorders discussed in the following section are grouped, for ease of consideration, according to the cell type involved. No attempt is made to describe every known blood disease or even all the common ones. The sole criterion for inclusion in this section is the occurrence of oral manifestations and their obvious dental implications.
Anemia is defined as an abnormal reduction in the number of circulating red blood cells, the quantity of hemoglobin and the volume of packed red cells in a given unit of blood. The etiologies of the condition are extremely varied, and the classification presented in Table 18-1 based upon causes has been offered by Wintrobe.
In addition to this etiologic classification, a morphologic classification (Table 18-2) has been found of great value. It expresses the characteristic changes in the size and hemoglobin content of the red blood cell and thus acts as a guide to treatment. A recent classification based on cellular kinetic parameters was suggested (Table 18-3).
A number of different types of anemia may exhibit oral manifestations. These may be unusually varied, but often are so characteristic that the dentist should at least strongly suspect, if not actually confirm, the diagnosis of the anemia. In the discussion to follow, only those forms of anemia which are known to exhibit specific oral signs and symptoms will be considered.
Pernicious Anemia: (Vitamin B12 deficiency, Addisonian anemia, Biermer anemia, Hunter-Addison anemia, Lederer anemia, Biermer-Ehrlich anemia, Addison-Biermer disease)
Pernicious anemia is a relatively common chronic hematologic disease. It is an adult form of anemia that is associated with gastric atrophy and a loss of intrinsic factor production in gastric secretions and a rare congenital autosomal recessive form in which intrinsic factor (IF) production is lacking without gastric atrophy. The term pernicious anemia is reserved for patients with vitamin B12 deficiency due to a lack of production of IF in the stomach. Intrinsic factor in gastric secretions is necessary for the absorption of dietary vitamin B12. Vitamin B12, a substance now thought to be synonymous with the ‘erythrocyte-maturing factor’ or ‘hemopoietic principle’ and present in many foods, particularly liver, beef, milk and dairy products. Body stores of the vitamin usually exceed 1000 mcg and the daily requirement is about 1 mcg.
Pernicious anemia probably is an autoimmune disorder with a genetic predisposition and the disease is associated with human leucocyte antigen (HLA) types A2, A3, and B7 and A blood group. Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only 5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients with pernicious anemia. A greater association than anticipated exists between pernicious anemia and other autoimmune diseases, which include thyroid disorders, type I diabetes mellitus, ulcerative colitis, Addison disease, and acquired agammaglobulinemia. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven.
Pernicious anemia is rare before the age of 30 years and increases in frequency with advancing age. In the United States, males are affected more commonly than females; in other countries, notably Scandinavia, females are more commonly affected. No apparent racial predilection is noticed.
The disease is often characterized by the presence of a triad of symptoms: generalized weakness, a sore, painful tongue, and numbness or tingling of the extremities. In some cases the lingual manifestations are the first sign of the disease. Other typical complaints are easy fatigability, headache, dizziness, nausea, vomiting, diarrhea, loss of appetite, shortness of breath, loss of weight, pallor and abdominal pain.
Patients with severe anemia exhibit a yellowish tinge of the skin and sometimes of the sclerae. The skin is usually smooth and dry. Nervous system involvement is present in over 75% of the cases of pernicious anemia, and this consists of sensory disturbances including the paresthetic sensations of the extremities described above, weakness, stiffness and difficulty in walking, general irritability, depression or drowsiness as well as incoordination and loss of vibratory sensation. These nervous aberrations are referable to the degeneration of posterior and lateral tracts of the spinal cord with loss of nerve fibers and degeneration of myelin sheaths. Degeneration of the peripheral nerves also occurs.
Glossitis is one of the more common symptoms of pernicious anemia. The patients complain of painful and burning lingual sensations which may be so annoying that the dentist is often consulted first for local relief.
The tongue is generally inflamed, often described as ‘beefy red’ in color, either in entirety or in patches scattered over the dorsum and lateral borders (Fig. 18-1). In some cases, small and shallow ulcers — resembling aphthous ulcers — occur on the tongue. Characteristically, with the glossitis, glossodynia and glossopyrosis, there is gradual atrophy of the papillae of the tongue that eventuate in a smooth or ‘bald’ tongue which is often referred to as Hunter’s glossitis or Moeller’s glossitis and is similar to the ‘bald tongue of Sandwith’ seen in pellagra. Loss or distortion of taste is sometimes reported accompanying these changes. The fiery red appearance of the tongue may undergo periods of remission, but recurrent attacks are common. On occasion, the inflammation and burning sensation extend to involve the entire oral mucosa but, more frequently, the rest of the oral mucosa exhibits only the pale yellowish tinge noted on the skin. Millard and Gobetti have emphasized that a nonspecific persistent or recurring stomatitis of unexplained local origin may be an early clinical manifestation of pernicious anemia. Not uncommonly the oral mucous membranes in patients with this disease become intolerant to dentures.
Figure 18-1 Pernicious anemia. The tongue is inflamed and painful in each case, and there is beginning of atrophy of the papillae in (A) and advanced atrophy in (B) (Courtesy of Dr Boynton H Booth and Dr Stephen F Dachi).
Farrant and Boen and Boddington have reported that cells from buccal scrapings of patients with pernicious anemia presented nuclear abnormalities consisting of enlargement, irregularity in shape and asymmetry. These were postulated to be due to a reduced rate of nucleic acid synthesis with a reduced rate of cell division. These epithelial cell alterations are rapidly reversible after administration of vitamin B12.
This chronic disease often exhibits periods of remission and exacerbation, and the blood changes generally parallel these clinical states. The red blood cell count is seriously decreased, often to 1,000,000 or less per cubic millimeter. Many of the cells exhibit macrocytosis; this, in fact, is one of the chief characteristics of the blood in this disease, although poikilocytosis, or variation in shape of cells, is also present (Fig. 18-2). The hemoglobin content of the red cells is increased, but this is only proportional to their increased size, since the mean corpuscular hemoglobin concentration is normal. A great many other red blood cell abnormalities have been described, particularly in advanced cases of anemia, including polychromatophilic cells, stippled cells, nucleated cells, Howell-Jolly bodies and Cabot’s rings punctate basophilia. Leukocytes are also often remarkably reduced in number, but are increased in average size, in number of lobes to the nucleus (becoming the so-called macropolycytes) and anisopoikilocytosis. Mild to moderate thrombocytopenia is noticed. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Striking reticulocyte response and improvement in hematocrit values after parenteral administration of cobalamin is characteristic.
The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactic dehydrogenase usually is markedly increased. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased. Serum antibodies for IF are highly specific.
Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. IF is either absent or is markedly decreased.
The bone marrow biopsy and aspirate usually are hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval. The nucleus is large and contains coarse motley chromatin clumps, providing a checkerboard appearance. Nucleoli are visible in the more immature erythroid precursors. Imbalanced growth of megakaryocytes is evidenced by hyperdiploidy of the nucleus and the presence of giant platelets in the smear. Lymphocytes and plasma cells are spared from the cellular gigantism and cytoplasmic asynchrony observed in other cell lineages. The bone marrow histology is similar in both folic acid and cobalamin deficiency.
The treatment of pernicious anemia consists of the administration of vitamin B12 and folic acid. Early recognition and treatment of pernicious anemia provides a normal, and usually uncomplicated, lifespan. Delayed treatment permits progression of the anemia and neurological complications. The mental and neurological damage can become irreversible without therapy.
Sprue is one disease of a large group which constitutes the ‘malabsorption syndrome’. It is a chronic disease of the digestive tract that interferes with the absorption of nutrients from food. Sprue is not basically an anemic disorder. It is considered here; however, because it presents so many signs and symptoms in common with pernicious anemia that the differentiation is often difficult. This disease, also called ‘idiopathic steatorrhea’ to distinguish it from steatorrhea resulting from fibrocystic disease of the pancreas with resultant decrease in pancreatic enzyme secretion.
People with celiac sprue cannot tolerate gluten, a protein commonly found in wheat, rye, barley, and sometimes, oats. When affected individuals ingest gluten, the mucosa of their small intestine is damaged by an immunologically mediated inflammatory response, resulting in maldigestion and malabsorption. Genetics play an important role in celiac sprue. The incidence of disease in relatives of celiac sprue patients is significantly higher than in the general population. The prevalence in first-degree relatives of celiac sprue patients is approximately 10%. Concordance for the disease in HLA identical siblings is about 30% and that for identical twins approaches 70%. Strong association exists between the disease and two human leukocyte antigen (HLA) haplotypes, DR3 and DQw2.
Sprue occurs both in tropical countries and in temperate zones in persons of all ages, including infants. For example, the frequency of the disease is between 1 in 250 persons and 1 in 300 persons in Italian and Irish populations. In comparison, the disease is rare in Africans or Asians. The symptoms of untreated celiac sprue are divided into gastrointestinal and extraintestinal symptoms.
Gastrointestinal symptoms include diarrhea, which is the most common symptom in untreated celiac sprue due to maldigestion and malabsorption of nutrients. Malabsorption of ingested fat (steatorrhea) resulting in excessive amount of fat passed in the stools. Flatulence results from the release of intestinal gas by the bacterial flora flourishing on undigested and unabsorbed food materials. In infants and young children with untreated celiac sprue, failure to gain weight and growth retardation is common. Other symptoms include weakness and fatigue, severe abdominal pain and excessive malodorous flatus. Occasionally, severe hypokalemia due to the loss of potassium in the stool can cause muscle weakness.
Extraintestinal symptoms include anemia which is usually due to impaired absorption of iron or folate from the proximal small intestine. In severe disease with ileal involvement, absorption of vitamin B12 might be impaired. A bleeding diathesis caused by prothrombin deficiency due to impaired absorption of fat-soluble vitamin K. Excessive amounts of fat are passed in the stools, inducing a concomitant excessive loss of calcium, which in turn causes a calcium deficiency with ensuing low blood calcium levels and occasional tetany. Bone pain occurs due to osteoporosis as a result of calcium and vitamin D deficiency. Nervous irritability as well as numbness and tingling of the extremities occurs, but seldom is there spinal cord involvement as in pernicious anemia. Malaise and generalized weakness are also common. The skin changes are often identical with those of pernicious anemia, but also include irregular brownish pigmentation, particularly on the face, neck, arms and legs, and drying of the skin with a scaly eruption.
The oral changes in sprue are similar to those of pernicious anemia and have been described by Adlersberg from observation of 40 cases. There may be a severe glossitis with atrophy of the filiform papillae, although the fungiform papillae often persist for some time on the atrophic surface. Painful, burning sensations of the tongue and oral mucosa are common, and small, painful erosions may occur. These severe oral manifestations are seldom absent in cases of sprue (Fig. 18-3). Tyldesley has reviewed this problem recently and concluded that there is an association between recurrent oral ulceration, or recurrent aphthous ulcers, and celiac disease and that proper dietary treatment leads to remission of the oral lesions.
The blood and bone marrow changes are often identical with those of pernicious anemia and include a macrocytic anemia and leukopenia. Hypochromic microcytic anemia occasionally occurs. A low serum iron level is common. The prothrombin time (PT) might be prolonged because of malabsorption of vitamin K. The patients do not usually exhibit achlorhydria, nor is the ‘intrinsic’ factor absent.
Celiac sprue primarily involves the mucosa of the small intestine. The submucosa, muscularis, and serosa usually are not involved. The villi are atrophic or absent, and crypts are elongated. The cellularity of the lamina propria is increased with a proliferation of plasma cells and lymphocytes. The number of intraepithelial lymphocytes per unit length of absorptive epithelium is increased.
Sprue responds well in most cases to the administration of vitamin B12 and folic acid, although the diet must be carefully supervised and supplemented with vitamins and minerals. Use of food grains containing gluten should be avoided. A small percentage of celiac sprue patients fail to respond to a gluten free diet. In some patients who are refractory, corticosteroids might be helpful. The patients who fail to respond to corticosteroids, other conditions such as lymphomas of the small intestine should be suspected.
Aplastic anemia is a bone marrow failure syndrome characterized by peripheral pancytopenia and general lack of bone marrow activity. It may affect not only the red blood cells but also the white cells and platelets, resulting in a pancytopenia. The clinical manifestations of the disease vary according to the type of cell chiefly affected. Paul Ehrlich, introduced the concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 when this disorder was termed aplastic anemia by Chauffard.
It is common to recognize two chief forms of aplastic anemia, primary and secondary. Primary aplastic anemia is a disease of unknown etiology which occurs most frequently in young adults, develops rapidly and usually terminates fatally. A disease known as Fanconi’s syndrome consists of congenital, and sometimes familial, aplastic anemia associated with a variety of other congenital defects including bone abnormalities, microcephaly, hypogenitalism and a generalized olive-brown pigmentation of the skin.
Secondary aplastic anemia, on the other hand, is of known etiology, occurs at any age and presents a better prognosis, particularly if the cause is removed. The etiology of this secondary anemia is the exposure of the patient to various drugs or chemical substances or to radiant energy in the form of X-rays, radium or radioactive isotopes. In many cases the development of aplastic anemia after exposure to the drug or chemical seems to be an allergic phenomenon, since the amount of the substance absorbed is too small to result in an actual poisoning or intoxication. The chemicals which have been found most frequently to cause the development of this condition are acetophenetidine, amidopyrine, organic arsenicals, particularly sulfarsphenamine, benzol, chloramphenicol, quinacrine hydrochloride (Atabrine), trinitrotoluene, dinitrophenol, colloidal silver, bismuth, mercury, sulfonamides and penicillin, although many others have also produced the disease. On few occasions aplastic anemia is preceded by infection by hepatitis viruses, Epstein-Barr virus (EBV), HIV, parvovirus, and mycobacterial infections.
The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia who had failed to engraft after marrow transplantation. It was proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Subsequently, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function. Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, HLA-DR2 is over represented among European and American patients with aplastic anemia.
Suppression of hematopoiesis likely is mediated by an expanded population of the cytotoxic T lymphocytes (CD8 and HLA-DR+), which are detectable in both the blood and bone marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as gamma interferon and tumor necrosis factor, which are capable of suppressing progenitor cell growth. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing through induction of Fas-mediated apoptosis. It also has been shown that these cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and elimination of hematopoietic cells.
The clinical manifestations of aplastic anemia are referable not only to the anemia, but also to the leukopenia and thrombocytopenia which are variably present. There are few differences in the clinical features of the primary and secondary forms of the disease except in the ultimate prognosis. The onset is insidious, with the initial symptom relating to anemia or bleeding, but fever or infections often are noted at presentation.
The patients usually complain of severe weakness with dyspnea following even slight physical exertion and exhibit pallor of the skin. Numbness and tingling of the extremities and edema are also encountered due to anemia. Petechiae in the skin and mucous membranes occur, owing to the platelet deficiency, while the neutropenia leads to a decreased resistance to infection.
Petechiae purpuric spots or frank hematomas of the oral mucosa may occur at any site, while hemorrhage into the oral cavity, especially spontaneous gingival hemorrhage, is present in some cases. Such findings are related to the blood platelet deficiency (Fig. 18-4). As a result of the neutropenia there is a generalized lack of resistance to infection, and this is manifested by the development of ulcerative lesions of the oral mucosa or pharynx. These may be extremely severe and may result in a condition resembling gangrene because of the lack of inflammatory cell response.
The red blood cell count is remarkably diminished, often to as low as 1,000,000 cells per cubic millimeter, with a corresponding reduction in the hematocrit and hemoglobin levels. A paucity of granulocytes, monocytes, and reticulocytes is found. The thrombocytopenia results in a prolonged bleeding time; the clotting time remains normal. Clot retraction is poor and the tourniquet test is positive. The degree of cytopenia is useful in assessing the severity of aplastic anemia. The presence of teardrop poikilocytes and leucoerythroblastic changes suggest marrow aplasia from infiltrative and dysplastic causes.
Bone marrow smears exhibit variable findings depending on the extent of the anemia and/or pancytopenia. If only an anemia exists, there is erythropoietic depression. Occasionally, however, the marrow appears normal or even hyperplastic. In pancytopenia there is hypoplasia of all marrow elements, and only occasional cells of any type may be found. In cases of less severe damage, moderate numbers of primitive cells persist. In severe cases, hypocellular bone marrow with fatty replacement and relatively increased nonhematopoietic elements such as plasma cells and mast cells may be found. Hemoglobin electrophoresis and blood group testing may show elevated fetal hemoglobin and red cell 1 antigen suggesting stress erythropoiesis, which is observed in both aplastic anemia and myelodysplastic syndromes.
Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted. Infections should be treated appropriately as it is the major cause of mortality. Other treatment options are bone marrow transplantation and immunosuppressive therapy.
Thalassemic syndromes are genetically determined disorders of hemoglobin synthesis with decreased production of either alpha or beta polypeptide chains of hemoglobin molecules, which results from markedly decreased amounts of globin messenger ribonucleic acid. Features first described by Thomas B Cooley in 1925 are seen primarily in Mediterranean populations, in races bordering the Eastern Mediterranean sea or in families originating from these areas (thalassa means ‘sea’ in Greek).
Normal adult hemoglobin is a large complex molecule in which an iron-containing pigment (heme) is conjugated to a complex protein (globin). The globin component consists two pairs of unlike polypeptide chains, alpha and nonalpha chains (e.g. beta, gamma, delta). In the normal adult hemoglobin (HbA), which constitutes over 95% of the hemoglobin in normal persons older than one year, the globin component consists of two alpha and two beta chains. The thalassemia group of anemias is a heterogeneous group characterized by diminished synthesis of the alpha (α)-or beta (β)-globin chain of hemoglobin A. The disease is termed α thalassemia when there is deficient synthesis of the α-chain and β-thalassemia when the β-chain is deficient. Thus, in β-thalassemia there is an excess of α-chains, producing ‘unstable hemoglobins’ that damage the erythrocytes and increase their vulnerability to destruction. In heterozygotes, the disease is mild and is called thalassemia minor or thalassemia trait. It represents both α-and β-thalassemia. Homozygotes may exhibit a severe form of the disease that is called thalassemia major or homozygous β-thalassemia, in which the production of β-chains is markedly decreased or absent, and a consequent decrease in synthesis of total hemoglobin occurs. This results in severe hypochromic anemia. Furthermore, excess α-chains, which synthesize at the normal rate, precipitate as insoluble inclusion bodies within the erythrocytes and their precursors. The presence of such intracellular inclusion bodies (Fessas bodies) leads to increased erythrocyte hemolysis and severe ineffective hematopoiesis. Approximately 70–85% of marrow normoblasts are destroyed in severely affected patients. These processes result in profound anemia and an associated increase in marrow activity, which is estimated to increase 5- to 30-fold.
In high-risk areas (i.e. Greek and Italian islands), 10% of the population may have homozygous β-thalassemia; 5% in Southeast Asian populations; and 1.5% in African and American black populations. The onset of the severe form of the disease (homozygous β-thalassemia) occurs within the first two years of life, often in the first few months. Siblings are commonly affected. The child has a yellowish pallor of the skin and exhibits fever, chills, malaise and a generalized weakness. Splenomegaly and hepatomegaly may cause protrusion of the abdomen. The face often develops mongoloid features due to prominence of the cheek bones, protrusion or flaring of the maxillary anterior teeth, and the depression of the bridge of the nose which gives rise to the characteristic rodent facies. The child does not appear acutely ill, but the disease follows an ingravescent course which is often aggravated by intercurrent infection. Some patients; however, die within a few months, especially when the disease is manifested at a very early age. Logothetis and his associates have shown that the degree of cephalofacial deformities in this disease (including prominent frontal and parietal bones, sunken nose bridge, protruding zygomas and mongoloid slanting eyes) is closely related to the severity of the disease and the time of institution of treatment.
An unusual prominence of the premaxilla has been described in cases of erythroblastic anemia, such as that reported by Novak, and this results in an obvious malocclusion. The oral mucosa may exhibit the characteristic anemic pallor observed on the skin.
The pronounced anemia is of a hypochromic microcytic type, the red cells exhibiting a poikilocytosis and anisocytosis. These cells are extremely pale, but in some instances appear as ‘target’ cells with a condensation of coloring matter in the center of the cell. The presence of typical safety-pin cells and of normoblasts or nucleated red blood cells in the circulating blood is also a characteristic feature. The white blood cell count is frequently elevated, often as high as 10,000–25,000 or more per cubic millimeter. Supravital staining (methyl violet) of peripheral blood can demonstrate inclusion bodies. Bone marrow smears show cellular hyperplasia with large numbers of immature, primitive and stem forms of red blood cells, all indicating maturation arrest. The serum bilirubin in these patients is also elevated, indicative of the severe hemosiderosis which is almost invariably present. This systemic hemosiderosis has suggested a possible block in iron utilization with accumulation of iron pigment and subsequent inadequate formation of hemoglobin.
The skeletal changes in thalassemia are most striking and have been thoroughly described by Caffey. A frequent finding in rib has been referred to as the rib-within-a-rib appearance and is noted particularly in the middle and anterior portions of the ribs. The finding consists of a long linear density within or overlapping the medullary space of the rib and running parallel to its long axis. In the skull, there is extreme thickening of the diploe (medulla), the inner and outer plates (cortices) become poorly defined, and the trabeculae between the plates become elongated, producing a bristle like crew-cut or hair-on-end appearance of the surface of the skull (Fig. 18-5). Because of the lack of hematopoietic marrow, the occipital bone usually is not involved.
Both the skull and long bones exhibit some degree of osteoporosis, but spontaneous fracture of bones is not common. There is typically a widening of the medulla with thinning of the cortices of the long bones. The bony changes may occur early in life and tend to persist, particularly those in the skull.
Proliferation of marrow within the frontal and facial bones impedes pneumatization of the paranasal sinuses. This results in hypertrophy of osseous structures and a consequent prominence of the lateral margins of the malar eminences, together with anterior and medial displacement of developing teeth. Characteristically, ethmoidal sinuses are not involved, a factor attributable to the absence of red marrow in the sinus walls.
Intraoral radiographs in some cases reveal a peculiar trabecular pattern of the maxilla and mandible, characterized by an apparent coarsening of some trabeculae and the blurring and disappearance of others, resulting in a salt and pepper effect. In general, thinning of the lamina dura and circular radiolucencies in the alveolar bone are also found (Dewey et al).
There is no treatment for this form of anemia. The administration of liver extract, iron or vitamin B6 is fruitless. Blood transfusions do provide temporary remissions. Bone marrow transplantation may be a definitive treatment option, but long-term results from transplants already performed are not available. The disease is usually fatal, although mild forms which are compatible with life apparently exist. Generally, the earlier in infancy the disease occurs, the more rapidly it proves fatal. Death is generally due to intercurrent infection, cardiac damage as a result of anoxia, or liver failure.
Sickle cell anemia is a hereditary type of chronic hemolytic anemia transmitted as a mendelian dominant, nongenderlinked characteristic, which occurs almost exclusively in blacks, and in whites of Mediterranean origin. Malaria is possibly the selecting agent for sickle cell disease because a concordance exists between the prevalence of malaria and HbS. The name is derived from the peculiar microscopic appearance of sickle-or crescent-shaped erythrocytes found in the circulating blood. Normal adult hemoglobin (HbA) is genetically altered to produce sickle hemoglobin (HbS) by the substitution of valine for glutamine at the sixth position of the β-globin chain. In the heterozygote, only about 40% of the hemoglobin is HbS, so that the individual has only the sickle-cell trait and manifests clinical evidence of sickling only under conditions of severe hypoxia. About 8% of American blacks are heterozygous for hemoglobin S. In the homozygote, nearly all hemoglobin is HbS, and the individual suffers from sickle cell anemia. This occurs in about 1 in 600 American blacks.
Deoxygenation of the heme moiety of HbS leads to hydrophobic interactions between adjacent HbS molecules, which then aggregate into larger polymers, distorting the red blood cell (RBC) into the classic sickle shape. The RBCs with sickle shape become much less deformable; therefore, obstructing the microcirculation and thus caused tissue hypoxia, further promotes sickling. Sickle-shaped RBCs are rapidly hemolyzed and have a life span of only about 10–20 days.
Sickle cell anemia is more common in females and usually becomes clinically manifest before the age of 30 years. Patients manifest a variety of features related to the anemia per se. Thus the patient is weak, short of breath and easily fatigued. Pain in the joints, limbs and abdomen, as well as nausea and vomiting, is common. Systolic murmur and cardiomegaly also occur. One additional feature characteristically seen is packing of red blood cells in peripheral vessels with erythrostasis and subsequent local tissue anoxia. An infarct of the mandible on this basis has been reported by Walker and Schenck. Sickle cell crises (vaso-occlusive, hematologic, and infectious crises) may occur under a variety of situations, including the administration of a general anesthetic, probably as a result of decreased oxygenation of the blood. Other triggering causes of deoxygenation may include exercise or exertion, infections, pregnancy or even sleep.
According to the studies of Robinson and Sarnat, a majority of patients with sickle cell anemia exhibit significant bone changes in the dental radiographs. These alterations consist of a mild to severe generalized osteoporosis and a loss of trabeculation of the jaw bones with the appearance of large, irregular marrow spaces. The trabecular change is prominent in the alveolar bone. There are no alterations in the lamina dura or periodontal ligament. Similar findings were reported by Morris and Stahl and by Prowler and Smith, not only in patients with sickle cell anemia but also in many with only the sickling trait. However, in a study of 80 patients with sickle cell anemia who were compared with an apparently normal group of patients, Mourshed and Tuckson stated that these two radiographic features of the jaws—increased radiolucency and coarse trabeculation—cannot be considered reliable diagnostic criteria for the disease.
Goldsby and Staats have reported morphologic alterations in the nuclei of epithelial cells in scrapings of the oral mucosa in 90% of all studied cases of patients with homozygous sickle cell disease. These changes were chiefly nuclear enlargement, binucleation and an atypical chromatin distribution. These changes are similar to those that have been reported occurring in pernicious anemia and sprue (Fig. 18-6A, B).
Radiographs of the skull exhibit an unusual appearance, with perpendicular trabeculations radiating outward from the inner table producing a ‘hair-onend’ pattern, identical to that seen in thalassemia, congenital hemolytic jaundice and sometimes in chronic iron deficiency anemia and secondary polycythemia of cyanotic congenital heart disease. The outer table of bone may appear absent and the diploe thickened. Generalized osteoporosis may be present. The long bones of children may exhibit enlarged medullary cavities with thin cortices, while the same bones in adults become sclerotic with cortical thickening due to fibrosis of the marrow.
The red blood cell count may reach a level of 1,000,000 cells or less per cubic millimeter with a decreased hemoglobin level. High reticulocyte count indicates anemia and increased marrow response. A major drop in hemoglobin (i.e. more than 2 gm/dl) from previous values indicates a hematological crisis. If the reticulocyte count is low, an aplastic crisis is the probable cause.
On the blood smear, typical sickle-shaped red blood cells are commonly seen, although they are present also in cases of the sickle trait without clinical evidence of the disease (Fig. 18-6C). Elevated levels of lactate dehydrogenase and decreased levels of haptoglobin confirm the presence of hemolysis. Hemoglobin electrophoresis can be done to differentiate homozygous from heterozygous.
The Rh factor, named after the rhesus monkey, was discovered by Landsteiner and Wiener in 1940 as a factor in human red blood cells that would react with rabbit antiserum produced by administration of red blood cells from the rhesus monkey. The Rh factor, a dominant hereditary characteristic, is present in the red blood cells of approximately 85% of the Caucasian population of the United States.
Erythroblastosis fetalis is essentially due to the inheritance by the fetus of a blood factor from the father that acts as a foreign antigen to the mother. The transplacental transfer of this antigen, actually transplacental leaks of red cells, from the fetus to the mother results in immunization of the mother and formation of antibodies which, when transferred back to the fetus by the same route, produce fetal hemolysis. Occasionally, the ABO system may produce a similar type of immunization and hemolysis.
The basic inheritance of the Rh factor is relatively simple. If both parents are homozygously Rh-positive (have the Rh factor), the infant will be Rh-positive, but maternal immunization cannot occur, since both mother and fetus have the same antigen. If the mother is homozygously positive, but the father Rh-negative, the same situation actually exists, since both the mother and the fetus have the same antigen and no immunization can occur. If the father is Rh-positive and the mother Rh-negative; however, the fetus inherits the paternal factor, which may then act as an antigen to the mother and immunize her with resultant antibody formation.
The problem is complicated; however, by the occurrence of numerous immunologically distinct Rh antigens. The strongest of these antigens have been termed C, D and E, and the presence of any one of them constitutes an Rh-positive person. Each of these antigens is normally present in a specific gene, but, if absent, their place is taken by less potent Hr antigens, known as c, d and e. Thus, three Rh or Hr genes are inherited from each parent, constituting three pairs of factors. Any combination of C, D, E and c, d, e is therefore possible, but the only combination producing an Rh-negative person is cde-cde. The D antigen, by far the strongest, is most frequently responsible for the clinical manifestations of erythroblastosis fetalis, and the 85% of the population generally considered Rh-positive actually have the D antigen homozygously (DD) or heterozygously (D-d). The 15% who are Rh-negative have the d antigen homozygously (d-d). Mathematically, according to the laws of random mating, there should be 10 cases of erythroblastosis fetalis in every 100 pregnancies. Clinically, it has been found that only one case in every 200 pregnancies occurs. There are several possible explanations for this discrepancy:
Subsequent pregnancies might cause further immunization with increased antibody formation, so that in ensuing pregnancies clinical hemolysis does occur. This latter explanation is plausible since it explains adequately why the first pregnancy is often uneventful, while erythroblastosis frequently occurs in succeeding pregnancies.
It is of great interest to note that the frequency of erythroblastosis fetalis of Rh incompatibility has shown a dramatic decrease in the past few years and that the eventual elimination of the disease through immunization prevention techniques is a probability. At present, Rh-negative mothers are being given anti-D gamma globulin to prevent immunization, since it binds to antigenic receptor sites on fetal red cells, making them nonimmunogenic.
The manifestations of the disease depend upon the severity of the hemolysis. Some infants are stillborn. Those that are born alive characteristically suffer from anemia with pallor, jaundice, compensatory erythropoiesis, both medullary and extramedullary, and edema resulting in fetal hydrops. It is of considerable interest that the severe anemia and jaundice do not begin to develop until at least several hours after birth and frequently not for several days. The most important aid in diagnosis of the disease is a positive direct Coombs test on cord blood.
Erythroblastosis fetalis may be manifested in the teeth by the deposition of blood pigment in the enamel and dentin of the developing teeth, giving them a green, brown or blue hue (Fig. 18-7). Ground sections of these teeth give a positive test for bilirubin. The stain is intrinsic and does not involve teeth or portions of teeth developing after cessation of hemolysis shortly after birth.
Figure 18-7 Pigmentation of teeth in erythroblastosis fetalis. The teeth had a definite blue cast. The sharp line of separation between affected and unaffected tooth substance is seen near the cervical area of the mandibular cuspids and first molars (Courtesy of Dr Ralph E McDonald).
Enamel hypoplasia is also reported occurring in some cases of erythroblastosis fetalis. This usually involves the incisal edges of the anterior teeth and the middle portion of the deciduous cuspid and first molar crown. Here a characteristic ring-like defect occurs which has been termed the Rh hump by Watson.
Many infants with this disease are stillborn, but an increasing number of those born alive have survived after a total replacement of their blood by transfusion at birth. Thus the dentist may expect to see more children with the peculiar pigmentations of teeth characteristic of the condition, and should be aware of its nature.
The red blood count at birth may vary from less than 1,000,000 cells per cubic millimeter to near a normal level. There are characteristically large numbers of normoblasts, or nucleated red cells, in the circulating blood. Ultimately, severe anemia usually develops within a few days. The icterus index is invariably high and may reach a level of 100 units.
Iron Deficiency Anemia and Plummer-Vinson Syndrome: (Paterson-Brown-Kelly syndrome, Paterson-Kelly syndrome, sideropenic dysphagia)
Iron deficiency is an exceedingly prevalent form of anemia, particularly in females. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. It has been estimated that between 5 and 30% of women in the United States are iron deficient, while in some parts of the world, this may reach 50%. Men are only rarely affected. In healthy people, the body concentration of iron (approximately 60 parts per million) is regulated carefully by absorptive cells in the proximal small intestine, which alter iron absorption to match body losses of iron. Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis.
An adult male absorbs and loses about 1 mg of iron from a diet containing 10–20 mg of iron daily. During childbearing years, an adult female loses an average of 2 mg of iron daily (extra 500 mg of iron with each pregnancy, menstrual losses are highly variable is about 4–100 mg of iron) and must absorb a similar quantity of iron in order to maintain equilibrium. Growing children must obtain approximately 0.5 mg more iron daily.
The Plummer-Vinson syndrome is one manifestations of iron-deficiency anemia and was first described by Plummer in 1914 and by Vinson in 1922 under the term ‘hysterical dysphagia’. Not until 1936; however, was the full clinical significance of the condition recognized. Ahlbom then defined it as a predisposition for the development of carcinoma in the upper alimentary tract. It is, in fact, one of the few known predisposing factors in oral cancer. It is thought that the depletion of iron-dependent oxidative enzymes may produce myasthenic changes in muscles involved in the swallowing mechanism, atrophy of the esophageal mucosa, and formation of webs as mucosal complications. It is also thought to be an autoimmune phenomenon as the syndrome is seen in association with autoimmune conditions such as rheumatoid arthritis, pernicious anemia, celiac disease, and thyroiditis. Other factors such as nutritional deficiencies, genetic predisposition are thought to play roles in the causation of this disease.
While an iron-deficiency anemia may occur at any age, the Plummer-Vinson syndrome occurs chiefly in women in the fourth and fifth decades of life. Presenting symptoms of the anemia and the syndrome are cracks or fissures at the corners of the mouth (angular cheilitis), a lemon-tinted pallor of the skin, a smooth, red, painful tongue (glossitis) with atrophy of the filiform and later the fungiform papillae, and dysphagia limited to solid food resulting from an esophageal stricture or web. These oral findings are reminiscent of those seen in pernicious anemia. The mucous membranes of the oral cavity and esophagus are atrophic and show loss of normal keratinization. Koilonychia (spoon-shaped fingernails) or nails that are brittle and break easily have been reported in many patients; splenomegaly has also been reported in 20–30% of the cases.
The depletion of iron stores in the body, manifested as iron-deficiency anemia, may be the direct cause of the mucous membrane atrophy, since the integrity of epithelium is dependent upon adequate serum iron levels. The atrophy of the mucous membranes of the upper alimentary tract predisposes to the development of carcinoma in these tissues. This relationship was first noted by Ahlbom, who reported that half of all women with carcinoma of the hypopharynx and upper part of the esophagus seen at Radiumhemmet in Stockholm suffered from Plummer-Vinson syndrome. Subsequently the predisposition to the development of oral carcinoma was also established.
Blood examination reveals a hypochromic microcytic anemic of varying degree, while sternal marrow examination shows no megaloblasts typical of pernicious anemia. The red blood cell count is generally between 3,000,000 and 4,000,000 cells per cubic millimeter, and the hemoglobin is invariably low. That the anemia is of an irondeficiency type can be confirmed by lack of a reticulocyte response following administration of vitamin B12. A low serum iron and ferritin with an elevated total iron binding capacity (TIBC) are diagnostic of iron deficiency. There is an absence of free hydrochloric acid in the stomach. The achlorhydria is generally the cause of the faulty absorption of iron, since the absence of hydrochloric acid prevents the conversion of unabsorbable dietary ferric iron to the absorbable ferrous state. The absence of stainable iron in a bone marrow aspirate is further diagnostic of iron deficiency. Unusual alterations in exfoliated squamous epithelial cells of the tongue in cases of severe iron-deficiency anemia have been reported by Monto and his associates. These changes consisted of a deficiency of keratinized cells, a reduced cytoplasmic diameter of cells with a paradoxical enlargement of the nucleus, and abnormal cellular maturation characterized by a disturbed nuclear pattern, an increase in nucleoli, presence of double nuclei and karyorrhexis. Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia; however, they produce a high incidence of false-positive results in people who eat meat.
The anemia responds well to iron therapy and a high-protein diet. Because of the predisposition to the development of carcinoma of oral mucous membranes, it is essential that the diagnosis be established early so that treatment may be instituted as soon as possible. Dysphagia may improve with iron replacement alone, particularly in patients whose webs are not substantially obstructive. Dysphagia caused by more advanced webs is unlikely to respond to iron replacement alone, and thus is managed with mechanical dilation.
Polycythemia is defined as an abnormal increase in the number of red blood cells in the peripheral blood, usually with an increased hemoglobin level. Three forms of the disease are recognized: relative polycythemia; primary polycythemia or erythremia (polycythemia rubra vera) of unknown etiology; and secondary polycythemia or erythrocytosis, due to some known stimulus.
Relative polycythemia is an apparent increase in the number of circulating red blood cells that occurs as a result of loss of blood fluid with hemoconcentration of cells, and is seen in cases of excessive loss of body fluids such as chronic vomiting, diarrhea, or loss of electrolytes with accompanying loss of water. This increase in the number of red blood cells is only relative to the total blood volume, and therefore, is not a true polycythemia.
Primary polycythemia, or polycythemia rubra vera, is characterized by a true idiopathic increase in the number of circulating red blood cells and of the hemoglobin level. It is characterized by bone marrow with an inherent increased proliferative activity.
Secondary polycythemia is similar to primary polycythemia except that the etiology is known. Secondary polycythemia is caused due to absolute increase in red blood cell mass resultant to enhanced stimulation of red blood cell production. In general, the stimulus responsible for producing a secondary polycythemia is either bone marrow anoxia or production of an erythropoietic stimulating factor. Bone marrow anoxia may occur in numerous situations such as pulmonary dysfunction, heart disease, habitation at high altitudes or chronic carbon monoxide poisoning. Erythropoietic stimulatory factors include a variety of drugs and chemicals such as coal-tar derivatives, gum shellac, phosphorus, and various metals such as manganese, mercury, iron, bismuth, arsenic and cobalt. Some types of tumors such as certain brain tumors, liver and kidney carcinomas and the uterine myoma have also been reported associated with polycythemia. The mechanism for increased production of the red blood cells by these tumors is unknown, but has been postulated as due to elaboration of a specific factor which stimulates erythropoiesis.
Polycythemia vera (PV) is a chronic stem cell disorder with an insidious onset characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. The most prominent feature is an absolute increase in the number of circulating red blood cells and in the total blood volume because of uncontrolled red blood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation.
The bone marrow of patients with polycythemia vera shows normal and abnormal stem cells (Figs. 18-8, 18-9, and 18-10). The clonal proliferation of abnormal stem cells interfere with or suppress normal stem cell growth and maturation. Evidence indicates that the etiology of this panmyelosis is unregulated neoplastic proliferation. The cause of the stem cell transformation remains unknown.
Polycythemia vera often manifests itself primarily by headache or dizziness, weakness and lassitude, tinnitus, visual disturbances, mental confusion, slurring of the speech and inability to concentrate. The skin is flushed or diffusely reddened, as a result of capillary engorgement and high red cell mass, as though the patient were continuously blushing. This condition is most obvious on the head, neck and extremities, although the digits may be cyanotic. Increased red blood cell mass increases blood viscosity and decreases tissue perfusion, and also predisposes for thrombosis. If secondary polycythemia is secondary to hypoxia, patients can also appear cyanotic or may have acrocyanosis which is caused by sluggish blood flow through small blood vessels. The skin of the trunk is seldom involved. Splenomegaly is one of the most constant features of polycythemia vera, and the spleen is sometimes painful. Gastric complaints such as gas pains, belching and peptic ulcers are common, and hemorrhage from varices in the gastrointestinal tract may occur. Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower in up to 40% of patients. The disease is more common in men and usually occurs in middle age or later.
Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with PV, depending on the stage of the disease. Approximately 20% of patients have cytogenetic abnormalities at diagnosis, increasing to more than 80% for those with more than 10 years of follow-up care.
The chromosomal abnormalities observed in patients with PV are deletion of 20q (8.4%), deletion of 13q (3%), trisomy 8 (7%), trisomy 9 (7%), trisomy of 1q (4%), deletion of 5q or monosomy 5 (3%), deletion of 7q or monosomy 7 (1%). These are similar to the abnormal karyotypes observed in patients with myelodysplastic syndromes and other myeloproliferative disorders.
The oral mucous membranes appear deep purplish red, the gingiva and tongue being most prominently affected. The cyanosis is due to the presence of reduced hemoglobin in amounts exceeding 5 gm/dl. The gingivae are often engorged and swollen and bleed upon the slightest provocation. Submucosal petechiae are also common, as well as ecchymoses and hematomas. Intercurrent infection may occur, but this is not related directly to the disease.
Red blood cell mass and plasma volume can be measured directly using radiochromiumlabeled red blood cells which show an increase in mass with a normal or slightly decreased plasma volume. The red blood cell count is elevated and may even exceed 10,000,000 cells per cubic millimeter (Figs. 18-11). The red blood cells in patients with PV are usually normochromic normocytic. The hemoglobin content of the blood is also increased, often as high as 20 gm/dl, although the color index is less than 1.0. Because of the great number of cells present, both the specific gravity and the viscosity of the blood are increased.
Figure 18-11 Polycythemia vera, peripheral blood. It is often difficult to prepare a good peripheral blood smear in PV due to the increased viscosity of the blood. The red cells are crowded together (Wright Giemsa).
Leukocytosis is usual, as is a great increase in the number of platelets (400,000–800,000/dl) (Figs. 18-12, 18-13); in addition, the total blood volume is elevated through distention of even the smallest blood vessels of the body. The leukocyte alkaline phosphatase score is elevated (>100 U/L) in 70% of patients. There is usually hyperplasia of all elements of the bone marrow. Bleeding and clotting times are normal.
No specific treatment for polycythemia is known, although several methods are used for relieving its symptoms. The patient may be periodically bled, or substances may be administered either to destroy blood cells (phenylhydrazine) or to interfere with its formation (nitrogen mustard or even X-ray radiation). In recent years, the radioactive isotope of phosphorus, P32, has been used. Any such treatment; however, produces only a remission of the disease; it does not affect a cure. The course of the disease may be protracted over many years.
Leukopenia is an abnormal reduction in the number of white blood cells in the peripheral blood stream. This decrease involves predominantly the granulocytes, although any of the cell types may be affected. The etiology of this particular sign of disease is extremely varied, but the classification shown in Table 18-4 has been devised by Wintrobe.
Oral lesions are present in certain diseases that are characterized by a reduction in the number of white cells. These lesions are related to the inability of the tissues to react in the usual manner to infection or trauma. Because of the dangerous sequelae which may result if the disease is not recognized, the dentist must be fully acquainted with each disorder and its serious consequences.
Agranulocytosis is a serious disease involving the white blood cells. It is characterized by decreased number of circulating granulocytes. It is often classified with reference to etiology as primary or secondary in type, primary agranulocytosis being that form of the disease in which the etiology is unknown, and secondary agranulocytosis being that form in which the cause is recognized. Since the clinical and laboratory findings in both forms are identical, the disease will be discussed here as a single entity.
The most common known cause of agranulocytosis is the ingestion of any one of a considerable variety of drugs (Table 18-5) and infections. Those compounds chiefly responsible for the disease are also those to which patients commonly manifest idiosyncrasy in the form of urticaria, cutaneous rashes and edema. For this reason and because often only small amounts of these drugs are necessary to produce the disease, it appears that the reaction may be an allergic phenomenon, although attempts to demonstrate antibodies in affected patients have not been successful. Moreover, in the case of some of the drugs, the disease occurs only after continued administration.
Kracke, in 1931, was one of the first to point out that a rapid increase in the number of cases of agranulocytosis occurred at the time of the introduction of certain coal-tar derivatives for use in therapy. The following drugs and compounds are some of those which have been reported to produce agranulocytosis in some persons:
The mechanism that causes agranulocytosis is not understood completely. In drug-induced agranulocytosis, the drug may act as a hapten and induce antibody formation. Thus produced antibodies destroy the granulocytes or may form immune complexes which bind to the neutrophils and destroy them. Autoimmune neutropenia due to antineutrophil antibodies is seen in few cases.
Other uncommon causes of agranulocytosis include Kostmann syndrome (severe congenital neutropenia) which is most often inherited in autosomal recessive pattern. Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the granulocyte colony-stimulating factor (G-CSF) receptor.
Chronic severe neutropenia has an underlying unknown cause. Myelodysplasia occurs in early infancy and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors.
Agranulocytosis can occur at any age, but is somewhat more common in adults, particularly women. The disease frequently affects workers in the health professions and in hospitals (e.g. physicians, dentists, nurses, hospital orderlies, and pharmacists), probably because they have easy access to the offending drugs and often use drug samples injudiciously.
The disease commences with a high fever, accompanied by chills and sore throat. The patient suffers malaise, weakness and prostration. The skin appears pale and anemic, or in some cases, jaundiced. The most characteristic feature of the disease is the presence of infection, particularly in the oral cavity, but also throughout the gastrointestinal tract, genitourinary tract, respiratory tract and skin. Regional lymphadenitis accompanies the infection in any of these locations. If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may be life threatening.
The oral lesions constitute an important phase of the clinical aspects of agranulocytosis. These appear as necrotizing ulcerations of the oral mucosa, tonsils and pharynx. Particularly involved are the gingiva and palate. The lesions appear as ragged necrotic ulcers covered by a gray or even black membrane (Fig. 18-12). Usually no purulent discharge is noticed. Significantly, there is little or no apparent inflammatory cell infiltration around the periphery of the lesions, although hemorrhage does occur, especially from the gingiva. In addition, the patients often manifest excessive salivation.
The microscopic appearance of sections through the ulcerated oral lesions is a pathognomonic one and accounts for certain clinical features of the disease. Since the essential fault is the lack of development of normal granular leukocytes, the ulcerated areas exhibit no polymorphonuclear reaction to the bacteria in the tissues, and rampant necrosis ensues.
Bauer studied the microscopic appearance of the jaws in agranulocytosis and reported necrosis of the gingiva, beginning adjacent to the sulcus and spreading into the free gingiva, periodontal ligament and even alveolar bone. Rapid destruction of the supporting tissues of the teeth follows.
The white blood cell count in agranulocytosis is often below 2000 cells per cubic millimeter with an almost complete absence of granulocytes or polymorphonuclear cells. The red blood cell count and platelet count are usually normal, although occasionally anemia is present.
The bone marrow is relatively normal except for the absence of granulocytes, metamyelocytes and myelocytes. Promyelocytes and myeloblasts are usually present in near normal numbers; however, and for this reason it appears that the basic defect is an arrest in cell maturation.
The treatment of agranulocytosis is not specific, but should consist principally in recognition and withdrawal of the causative drug and in administration of antibiotic drugs to control the infection.
Death is usually related to massive infection, and for this reason the disease carried a high mortality before the advent of the antibiotics. Today, although it is still a serious disease, agranulocytosis has a good prognosis if the responsible agent is discovered. Agranulocytosis secondary to viral infections is usually self-limited, and patients with such conditions have a good prognosis.
Cyclic neutropenia is an unusual form of agranulocytosis characterized by a periodic or cyclic diminution in circulating polymorphonuclear neutrophilic leukocytes as a result of bone marrow maturation arrest, accompanied by mild clinical manifestations, which spontaneously regresses only to recur subsequently in a rhythmic pattern. The etiology of this disease is unknown. Excellent reviews of cyclic neutropenia with its oral manifestations have been published by Page and Good, Becker and his coworkers, and Gorlin and Chaudhry. Although the role of hormonal and allergic factors in the etiology of the disease has been suggested by some workers, there is no sound evidence to indicate that this is the case. There appear to exist at least two additional rare hereditary forms of the disease, one cyclic and the other noncyclic. In addition, a chronic idiopathic neutropenia, noncyclic and nonfamilial, associated with severe persistent gingivitis has been reported by Kyle and Linman.
This type of agranulocytosis may occur at any age, although the majority of cases have been reported in infants or young children. The symptoms are similar to those of typical agranulocytosis except that they are usually milder. The patients manifest fever, malaise, sore throat, stomatitis and regional lymphadenopathy, as well as headache, arthritis, cutaneous infection and conjunctivitis. In contrast to other types of primary agranulocytosis, rampant bacterial infection is not a significant feature (Table 18-6), presumably because the neutrophil count is low for such a short time. Entities closely mimic the clinical characteristics of cyclic neutropenia are variable, encompassing a wider spectra (Table 18-7).