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E. Kaffu, M.B. B.A.O., M.B.B.Ch., Ph.D.

Medical Instructor, University of Mississippi School of Medicine

In severe hyperparathyroid bone disease, pseudocysts or brown tumors may be observed. However, signs of increased bone resorption may be seen on radiographs reflecting past resorption activity, which may have been succeeded by the accumulation of osteoid. Because osteoid is radiolucent, the superimposed osteomalacia will be missed by x-ray examination. Looser zones that are straight bands of radiolucency abutting onto the cortex and running perpendicular to the long axis of bone are of relatively low sensitivity and low specificity for the diagnosis of osteomalacia. Although correlations exist between random serum aluminum levels and the extent of stainable aluminum in bone, no threshold value allows a clear-cut distinction between patients with and patients without aluminum-related bone 1413 disease. The deferoxamine infusion test is advocated to improve the sensitivity of random serum aluminum levels. An increase in serum aluminum levels of greater than 200 mug/L 48 hours after a standardized infusion constitutes a positive result. This test does improve the sensitivity of predicting aluminum-related bone disease, but the specificity is greatly reduced. However, the sensitivity is greatly reduced and many patients will have false-negative results. Secondary hyperparathyroidism can be prevented by avoiding deviations of serum phosphorus and calcium levels from normal. None of the available dialytic methods is efficient in removing phosphorus because of compartmentalization and slow efflux of phosphorus from the intracellular space. However, because phosphate is present in most protein-containing food products, phosphate restriction is limited by the need for appropriate dietary protein intake. With the current recommendations, the protein intake of dialyzed patients should be at least 1 g/kg/day, which provides a minimum of 1 g of phosphorus per day. They are most effective when given with meals and in proportion to the size of the meal. Calcium citrate should be avoided because it promotes intestinal aluminum absorption. Aluminum-containing phosphate binders, even though more potent than calcium salts, should not be used because of the risk of aluminum-related bone disease. However, in severe cases of hyperphosphatemia, when calcium-containing phosphate binders have proved to be insufficient, low doses of aluminum-containing phosphate binders can be used in addition to calcium salts for a limited period. Hypocalcemia in chronic renal failure may be corrected by control of serum phosphorus and also by administration of calcium salts between meals. Replacement of the missing hormone calcitriol in patients with chronic renal failure is an established practice. In moderate hyperparathyroidism with or without mineralization defects, daily oral administration of calcitriol (0. It is advisable to start with low doses and increase the daily dose in steps of 0. However, episodes of hypercalcemia may occur but can be circumvented by decreasing oral calcium salts and/or by lowering the dialysate calcium content. Alternative approaches have been developed and include pulse oral (Rocaltrol) or intravenous (Calcijex) calcitriol administration two or three times per week at doses as high as 3 mug. Both measures are effective even though the positive response is clearly reduced if deposits of stainable aluminum are present in bone or when the parathyroid glands undergo monoclonal growth transformation and become refractory to the action of calcitriol. Newly developed vitamin D analogues with similar potency to calcitriol but with less hypercalcemic effects are currently under investigation. Despite treatment, overt secondary hyperparathyroidism develops in some patients and may necessitate parathyroidectomy. Before parathyroidectomy, histologic evidence of severe hyperparathyroidism and absence of aluminum accumulation need to be documented. The most frequently used surgical approaches to parathyroidectomy are subtotal parathyroidectomy and total parathyroidectomy with parathyroid autotransplantation. Subtotal parathyroidectomy risks the possibility of inadequate reduction in parathyroid gland mass or the recurrence of hyperparathyroidism in the remaining tissue. These complications might require re-exploration of the neck, which can be difficult because of the formation of scar tissue.

Most patients experience progressive anemia requiring frequent red blood cell transfusions and massive hepatosplenomegaly associated with the hypercatabolic symptoms of profound fatigue, weight loss, night sweats, and low-grade fever. In addition, some patients may develop extramedullary hematopoiesis in the spinal cord, the pleural and peritoneal cavities, and other organs. Disease progression into a clinical picture identical to agnogenic myeloid metaplasia occurs in approximately 9% of patients with polycythemia vera and less than 2% of those with essential thrombocythemia. Treatment of patients with post-polycythemic or post-thrombocythemic myelofibrosis is similar to that of patients with agnogenic myeloid metaplasia. Therefore, treatment efforts have been largely palliative and mostly directed at improving anemia and alleviating symptomatic organomegaly. In the very few patients who are appropriate candidates for allogeneic transplantation, the procedure is potentially curative in one-third. As initial treatment of anemia, a combination of an androgen preparation (fluoxymesterone, 10 mg orally twice a day) and a corticosteroid (prednisone, 30 mg orally) is used. After 1 month of therapy, fluoxymesterone treatment is continued in responding patients, whereas the corticosteroid is tapered. For steroid-dependent patients and for those who do not respond to fluoxymesterone, danazol (400 mg orally twice a day) may be useful in approximately 20% of patients. All patients treated with androgens should have periodic monitoring of liver function, and male patients should be screened for prostate cancer before initiating therapy. Despite these treatment options, periodic red blood cell transfusion remains the major supportive therapy. Secondary hemosiderosis from chronic blood transfusion may result in heart failure and liver injury. Deferoxamine (2 g by daily continuous 12-hour subcutaneous injection) may prevent complications of iron overload. Splenectomy is considered for patients with symptomatic splenomegaly (mechanical discomfort, refractory thrombocytopenia, hypercatabolic symptoms, portal hypertension). Laboratory evidence of disseminated intravascular coagulation before splenectomy may increase the risk of perioperative bleeding, and it is recommended that the procedure be postponed until the abnormalities are corrected. At experienced centers, the mortality rate associated with the procedure should be less than 10%. Postsurgical complications include intra-abdominal bleeding, subphrenic abscess, sepsis, large vessel thrombosis, extreme thrombocytosis, and accelerated hepatomegaly. The thrombocytosis and hepatomegaly may be transiently controlled with hydroxyurea (starting dose 500 mg orally three times daily) or 2-chlorodeoxyadenosine. After splenectomy, almost all patients experience improvement in hypercatabolic symptoms and portal hypertension. In addition, approximately one-half of patients with refractory anemia or thrombocytopenia may benefit from splenectomy. In poor surgical candidates, the alternative to splenectomy is splenic irradiation (200 to 300 cGy delivered in 10 to 15 daily fractions), which usually provides a transient (3 to 6 months) benefit. Radiation therapy is most useful in the management of extramedullary hematopoiesis. Cortelazzo S, Finazzi G, Ruggeri M, et al: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. Randomized study in patients with essential thrombocythemia, proving the benefit of hydroxyurea in high-risk patients. Gruppo Italiano Studio Policitemia: Polycythemia vera: the natural history of 1213 patients followed for 20 years. The largest study of patients with polycythemia vera, it contains information on the incidence and outcome of thrombotic and bleeding events. A study showing pathogenetic heterogeneity of essential thrombocythemias with both monoclonal and polyclonal hematopoiesis. An authoritative and comprehensive review of mechanisms of thrombosis and hemorrhage. Sterkers Y, Preudhomme C, Lai J-L, et al: Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: High proportion of cases with 17p deletion. Discusses the leukemogenic effect of hydroxyurea in patients with essential thrombocythemia. Summarizes therapeutic options in essential thrombocythemia and polycythemia vera and discusses their mechanism of action. However, the incidence increases dramatically with age, with an incidence of 25 to 50 per 100,000 per year in populations older than the age of 60.

Peripheral smear shows leukocytosis, with representation by the entire spectrum of leukocyte differentiation, ranging from myeloblasts to mature neutrophils. Peripheral smear shows fragmented red cells alongside larger, polychromatophilic cells and a nucleated red cell that reflect hemolysis, as well as a paucity of platelets. At least some degree of anemia is detectable in 20 to 40% of hospitalized patients. A considerable amount of information that is useful in determining severity, pathophysiology, and etiology of anemia is provided by electronic, automated blood cell counters (Table 159-1). The hemoglobin (Hgb), measured in grams per deciliter, represents the total amount of hemoglobin in all of the erythrocytes in 100 mL of blood. The hematocrit (Hct) is the percentage of the total blood volume that is composed of erythrocytes. In addition to these standard measurements, automated absolute reticulocyte counts per microliter of blood or evaluations of new methylene blue-stained peripheral blood smears for the percent of positive-staining erythrocytes (reticulocytes) give a measure of the number of newly released (generally 1- to 2-day old) erythrocytes. It is a non-nucleated, non-dividing cell, in which more than 90% of the protein content is the oxygen-carrying molecule, hemoglobin. Although this classification makes it easier to understand the pathophysiology of anemia and to determine the proper diagnostic studies to perform, in many patients more than one mechanism may occur simultaneously. A wide variety of conditions can be responsible for impaired erythropoiesis (Table 159-2). A second mechanism of anemia due to reduced production of cells by the bone marrow is deficiency of hematopoietic stem cells and/or committed erythroid progenitor cells. Any condition that is characterized by a deficiency of hematopoietic stem cells and/or committed erythroid precursor cells also will result in anemia. In almost all such cases, the defect is a more generalized bone marrow abnormality that results in reduced production of all lineages of bone marrow-derived cells, particularly erythrocytes, granulocytes, and platelets. Idiopathic bone marrow failure, commonly known as aplastic anemia, is the prototype of such disorders (see Chapter 160). Patients with severe malnutrition, including anorexia nervosa, also may have bone marrow hypoplasia. A minority of patients with myelodysplasia or paroxysmal nocturnal hemoglobinuria also have significant bone marrow hypoplasia. Viral infection, particularly with parvovirus B19, which selectively infects committed erythroid progenitor cells, also can cause transient or prolonged pure red cell aplasia because of the cytotoxic effect of this virus on the infected erythroid precursor cells. This category covers a broad range of disorders, including intrinsic erythrocyte abnormalities, exogenous inhibitory effects, and nutritional deficiencies. Folate deficiency frequently may be due to insufficient dietary intake but also may be due to diffuse intestinal disorders and to drugs that interfere with folate metabolism, such as ethanol, sulfonamides or sulfa-related drugs, trimethoprim, methotrexate, anticonvulsants, and possibly oral contraceptives. Folate deficiency may occur in patients with an increased requirement for folate in such conditions as chronic hemolytic anemias, pregnancy, and in childhood. In addition, severe alcoholics, patients with general malnutrition from any cause, and patients with certain unconventional dietary habits are susceptible to developing folate deficiency. A severely folate-deficient diet will result in clinically significant folate deficiency within about 6 weeks. Cobalamin deficiency almost never occurs because of lack of dietary cobalamin intake; instead, it most often is due to impaired absorption of cobalamin due to lack of intrinsic factor, gastric atrophy, and abnormalities of cobalamin absorption in the terminal ileum. Because of substantial stores and very low daily requirements for cobalamin in normal individuals, deficiency of cobalamin usually takes at least 3 to 5 years to become manifest. The heme synthetic pathway and its defects are described in more detail in other chapters. Iron is required for the final stage of synthesis of heme, and iron deficiency impairs heme synthesis and results in anemia. Although iron-deficiency anemia is associated classically with microcytosis, most patients with mild iron-deficiency anemia actually have normocytic erythrocytes. One of the hallmarks of anemia of chronic disease or inflammation is impaired transfer of iron into developing erythroid cells, resulting in a functional iron deficiency in normoblasts even when iron stores in the bone marrow and the rest of the body are adequate. The result is impaired heme synthesis and a mild to moderate normocytic or microcytic anemia. In many of the circumstances in which anemia of chronic disease/inflammation occurs, there also may be concomitant iron deficiency. Impaired synthesis of alpha-globin chains in alpha-thalassemias or beta-globin chains in beta-thalassemias results in unbalanced synthesis of globin chains and a reduction in the number of hemoglobin alpha2/beta2 hemoglobin tetramers (see Chapter 167).

No cancers were reported in either of these two studies, and the addition of a progestin essentially eliminated the hyperplasia. The risk of developing endometrial cancer is the same for a woman taking estrogen and progestin (hormone replacement therapy) as for the general population. The addition of a progestin merely eliminates the excess risk induced by estrogen. Other endometrial cancers occurring in postmenopausal women are not thought to be hormonally related. Although the risk of developing endometrial cancer is increased significantly in estrogen users, the risk of death from this type of endometrial cancer does not increase proportionately. Endometrial cancers associated with estrogen use are thought not to be as aggressive as spontaneously occurring cancers or that tumors in women taking estrogen are likely to be discovered and treated at an earlier stage, thus improving survival rates. Several meta-analyses have suggested either no significantly increased risk, a relative risk hovering around 1. It has also been suggested that there is no additional risk for women with a family history of breast cancer. Admittedly, a slightly increased surveillance bias exists for women who see their doctors regularly. It is also possible that estrogen use causes breast cancer to occur earlier in some women, but it is not clear which women are at greatest risk. However, breast cancer-related mortality has not been shown consistently to be increased, and indeed there are data to suggest that it may be lower among estrogen users. Thus, we are left with the question of whether estrogen use carries any increased relative risk for breast cancer or a real risk that may be relatively small. For moderate doses of estrogen, the risk of breast cancer is probably in the range of 20 to 30% in those women who are susceptible. Recent trends in prescribing have suggested lowering the dose of estrogen for long-term use, as both dose and duration are associated with risk. One of the greatest concerns of women receiving estrogen is the return of menstrual bleeding. Such concerns should be discussed with the patient, and the choice of regimen should remain flexible. Idiosyncratic reactions including hypertension, thrombosis, and allergic manifestations have also been observed in users of estrogen, particularly oral estrogen. Hypertension with estrogen use, the cause of which is not entirely clear, occurs in about 5% of oral contraceptive users. Estrogen usually causes no change in blood pressure; it may actually reduce blood pressure, a finding that has relevance for normotensive as well as hypertensive individuals. Alterations in the route of estrogen administration and dose have resulted in improved blood pressure in such individuals. However, several recent observational studies have suggested a twofold increase in venous thromboembolic phenomena with oral estrogen. This did not increase mortality, and the rate is low (background prevalence of 11 per 100,000 women). Although it is unclear if this level of risk is real, it would be prudent to inform patients of these findings. Women who have a family history of thrombosis or have had thrombotic events with oral contraceptives or any prior estrogen use should be counseled very carefully and monitored closely. Non-oral estrogen is a consideration for these patients and can be used judiciously. Follicular phase levels of E2 during the normal menstrual cycle range between 40 and 100 pg/mL. Threshold levels of E2 for achieving benefit for osteoporosis and cardiovascular disease are in the range of 50 to 60 pg/mL for most women. Nevertheless, any increment of estrogen levels from baseline is expected to exert some significant effect, thus leading to the concept of a minimal effective dose.

If the particular antigen that causes immune complex disease can be identified and avoided, for instance, a drug, immune complex disease can be expected to resolve. Serum sickness following drug therapy or therapeutic use of autologous serum proteins, such as rattlesnake horse antiserum, usually resolves spontaneously over 7 to 14 days. Symptoms usually respond to antihistamine therapy with or without corticosteroid treatment. Although controlled treatment studies are not available, moderate doses of prednisone (20 to 40 mg) given twice a day for 3 to 5 days followed by a tapering dose of corticosteroids over 10 to 14 days usually resolve the symptoms in severe cases. In many of these cases, the increase in susceptibility is quite weak and, in some, may represent faulty statistical analysis or a chance occurrence. It is in this manner that the immune system differentiates molecules and tissues that must be protected from immunologic attack from those that are possibly derived from pathogenic organisms and are thus appropriate targets. To understand how this process might occur it is important to appreciate the basic molecular principles underlying T-cell recognition of antigen, which differ dramatically from those that determine antigen recognition by antibodies. Others have no specific known role in the immune system, such as the 21-hydroxylase genes involved in steroid biosynthesis. Both beta2 -microglobulin and the membrane-proximal alpha3 -domain of the heavy chain have structural features that define them as members of the immunoglobulin superfamily, including an intrachain disulfide bond and a secondary structure of antiparallel beta-pleated sheets with loop connections. The crystallographic surprise, and new insight, derived from the structure of the alpha1 - and alpha2 -domains. Together these domains form a beta-pleated sheet platform surmounted by two alpha-helical loops. Moreover, the initial crystal revealed the presence of an amorphous material bound within the cleft formed by the opposing helical loops. It has since been shown that this cleft at the exterior-most surface of the class I molecule does indeed serve as a binding site for peptide fragments of partially digested proteins eight to nine amino acids in length. A, Side view of the molecule showing the three domains of the heavy chain non-covalently associated with beta2 -microglobulin. B, Top view of the antigen binding cleft with the alpha-helices on top of a beta-pleated sheet platform. Foreign endogenous antigens include viral proteins and proteins from intracytosolic bacteria. The membrane-proximal alpha2 - and beta2 -domains, like the alpha3 -domain of the class I heavy chain, are composed of antiparallel beta-pleated sheets and contain a single intrachain disulfide bond. The alpha1 and beta1 (amino terminal) domains come together to form an intermolecular beta-pleated sheet platform that is also surmounted by two alpha-helical coils, one of which is contributed by each chain. These coils together with the beta-pleated sheet floor again form an antigen binding cleft into which peptide fragments are bound for presentation to T lymphocytes. In contrast, the helices of class I molecules come together to close the antigen binding groove at both ends. A, A class I molecule illustrating the three-domain heavy chain, which penetrates the cell membrane and is non-covalently associated with beta2 -microglobulin. An antigenic peptide (P) is illustrated in the antigen binding groove formed by the alpha1 and alpha2 domains. The amino terminal domains of both chains together form an intermolecular antigen binding groove. A new nomenclature has been developed to distinguish related molecular subtypes of major alleles. The specific gene designated is separated by an asterisk from a four-digit number, the first two digits of which denote the major allelic specificity and the last two, the molecular subtype. First, polymorphisms within the binding groove determine the peptide binding specificity (motif). Second, polymorphisms within the alpha-helices also serve as the markers of "self" upon which T-cell receptors are selected. This situation would occur when both siblings inherited the same 6th chromosome from both parents.