InternalMed_Harrison

InternalMed_Harrison. An estimated 24,050 new cases of myeloma were diagnosed in 2014, and 11,090 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years; it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for 1.3% of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks. FIGURE 136-3 Multiple myeloma (marrow). The cells bear characteristic morphologic features of plasma cells, round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen. The incidence of myeloma is highest in African Americans


InternalMed_Harrison

InternalMed_Harrison. The incidence of myeloma is highest in African Americans American whites; and lowest in people from developing countries including Asia. The higher incidence in more developed countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites. Immunoproliferative small-intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area. Despite these differences in prevalence, the characteristics, response to therapy, and prognosis of myeloma are similar worldwide.


InternalMed_Harrison

InternalMed_Harrison. Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu (Fig. 136-4). These effects are due both to direct MM cell–BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1α. Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively.


InternalMed_Harrison

InternalMed_Harrison. Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. Unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activat ing factors (OAFs) made by the myeloma cells (OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-κB [RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor necrosis factor [TNF]). The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning


InternalMed_Harrison

InternalMed_Harrison. are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull (Fig. 136-5), clavicles, and sternum; and the collapse of vertebrae may lead to spinal cord compression. The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the


InternalMed_Harrison

InternalMed_Harrison. and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. In ~25% of patients, recurrent infections are the presenting features, and >75%


InternalMed_Harrison

InternalMed_Harrison. FIGURE 136-4 Pathogenesis of multiple myeloma. Multiple myeloma (MM) cells interact with bone marrow stromal cells (BMSCs) and extracellular matrix proteins via adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokinemediated signaling that provides growth, survival, and antiapoptotic effects as well as development of drug resistance.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 136-5 Bony lesions in multiple myeloma. The skull dem-onstrates the typical “punched out” lesions characteristic of multiple myeloma. The lesion represents a purely osteolytic lesion with little or no osteoblastic activity. (Courtesy of Dr. Geraldine Schechter; with permission.) of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results


InternalMed_Harrison

InternalMed_Harrison. IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results in fractional catabolic rates of 8–16% instead of the normal 2%. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Most measures of T-cell function in myeloma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infection, and bortezomib predisposes to herpesvirus


InternalMed_Harrison

InternalMed_Harrison. Some commonly used therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infection, and bortezomib predisposes to herpesvirus reactivation.


InternalMed_Harrison

InternalMed_Harrison. Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50%. Many factors contribute to this. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage


InternalMed_Harrison

InternalMed_Harrison. and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal. When the glomeruli are involved, nonselective proteinuria is also observed. Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3−)] because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal


InternalMed_Harrison

InternalMed_Harrison. of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal dysfunction due to light chain deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.


InternalMed_Harrison

InternalMed_Harrison. Normocytic and normochromic anemia occurs in ~80% of myeloma patients. It is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoiesis by factors made by the tumor, to reduced production of erythropoietin by the kidney, and to the effects of long-term therapy. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are rare except when therapy-induced. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly; the interaction of the M component with clotting factors I, II, V, VII, or VIII; antibody to clotting factors; or amyloid damage of endothelium. Deep venous thrombosis is also observed with use of thalidomide, lenalidomide, or pomalidomide in combination with dexamethasone. Raynaud’s phenomenon and impaired circulation


InternalMed_Harrison

InternalMed_Harrison. damage of endothelium. Deep venous thrombosis is also observed with use of thalidomide, lenalidomide, or pomalidomide in combination with dexamethasone. Raynaud’s phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined based on the relative viscosity of serum as compared with water. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA; however, depending on chemical and physical properties of the paraprotein molecule, it can occasionally be observed at lower levels.


InternalMed_Harrison

InternalMed_Harrison. Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, and coma. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor monoand polyneuropathies. Neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) and myeloma is more frequently sensory than motor neuropathy and is associated with IgM more than other isotypes. In >50% of patients with neuropathy, the IgM monoclonal protein is directed against myelin-associated globulin (MAG). Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy.


InternalMed_Harrison

InternalMed_Harrison. Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of myeloma requires marrow plasmacytosis (>10%), a serum and/or urine M component, and end organ damage detailed in Table 136-1. Bone marrow plasma cells are CD138 and either monoclonal kappa or lambda light chain positive. The most important differential diagnosis in patients with myeloma involves their separation from individuals with MGUS or smoldering multiple myeloma (SMM). MGUS is vastly more common than myeloma, occurring in 1% of the population older than age 50 years and in up to 10% of individuals older than age 75 years. The diagnostic criteria for MGUS, SMM, and myeloma are described in Table 136-1. Although ~1% of patients per year with MGUS go on to develop myeloma, all TABLE 136-1 DIAgNOsTIC CrITErIA fOr MuLTIPLE MYELOMA, MYELOMA VArIANTs, AND MONOCLONAL gAMMOPATHY Of uNDETErMINED sIgNIfICANCE Monoclonal Gammopathy of Undetermined Significance (MGUS)


InternalMed_Harrison

InternalMed_Harrison. TABLE 136-1 DIAgNOsTIC CrITErIA fOr MuLTIPLE MYELOMA, MYELOMA VArIANTs, AND MONOCLONAL gAMMOPATHY Of uNDETErMINED sIgNIfICANCE Monoclonal Gammopathy of Undetermined Significance (MGUS) M protein in serum <30 g/L Bone marrow clonal plasma cells <10% No evidence of other B cell proliferative disorders No myeloma-related organ or tissue impairment (no end organ damage, M protein in serum ≥30 g/L and/or Bone marrow clonal plasma cells ≥10% No myeloma-related organ or tissue impairment (no end organ damage, M protein in serum and/or urine Bone marrow (clonal) plasma cellsb or plasmacytoma Myeloma-related organ or tissue impairment (end organ damage, including No M protein in serum and/or urine with immunofixation Bone marrow clonal plasmacytosis ≥10% or plasmacytoma Myeloma-related organ or tissue impairment (end organ damage, including Solitary Plasmacytoma of Bone Single area of bone destruction due to clonal plasma cells Bone marrow not consistent with multiple myeloma


InternalMed_Harrison

InternalMed_Harrison. Solitary Plasmacytoma of Bone Single area of bone destruction due to clonal plasma cells Bone marrow not consistent with multiple myeloma Normal skeletal survey (and magnetic resonance imaging of spine and pelvis if done) All of the following four criteria must be met: 1. 2. 3. Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease; (c) elevated levels of vascular endothelial growth factor (VEGF) 4.


InternalMed_Harrison

InternalMed_Harrison. Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f ) thrombocytosis/polycythemiad aMyeloma-related organ or tissue impairment (end organ damage): calcium levels increased: serum calcium >0.25 mmol/L above the upper limit of normal or >2.75 mmol/L; renal insufficiency: creatinine >173 mmol/L; anemia: hemoglobin 2 g/dL below the lower limit of normal or hemoglobin <10 g/dL; bone lesions: lytic lesions or osteoporosis with compression fractures (magnetic resonance imaging or computed tomography may clarify); other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months). bIf flow cytometry is


InternalMed_Harrison

InternalMed_Harrison. (magnetic resonance imaging or computed tomography may clarify); other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months). bIf flow cytometry is performed, most plasma cells (>90%) will show a “neoplastic” phenotype. cA small M component may sometimes be present. dThese features should have no attributable other causes and have temporal relation with each other.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes.


InternalMed_Harrison

InternalMed_Harrison. myeloma is preceded by MGUS. Non-IgG subtype, abnormal kappa/ lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/ dL) are associated with higher incidence of progression of MGUS to myeloma. Absence of all three features predicts a 5% chance of progression, whereas higher risk MGUS with the presence of all three features predicts a 60% chance of progression over 20 years. The features responsible for higher risk of progression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/dL). Patients with only one of these three features have a 25% chance of progression to MM in 5 years, whereas patients with high-risk SMM with all three features have a 76% chance of progression. There are two important variants 715 of myeloma—solitary bone plasmacytoma and solitary extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals,


InternalMed_Harrison

InternalMed_Harrison. 715 of myeloma—solitary bone plasmacytoma and solitary extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress.


InternalMed_Harrison

InternalMed_Harrison. The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare patients (~1%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by


InternalMed_Harrison

InternalMed_Harrison. chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis. A 24-h urine specimen is necessary to quantitate Bence Jones protein excretion. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum β2-microglobulin and albumin (see below).


InternalMed_Harrison

InternalMed_Harrison. The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important


InternalMed_Harrison

InternalMed_Harrison. an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains is unclear. The heavy chain isotype may have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2–4% of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentrationand temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations.


InternalMed_Harrison

InternalMed_Harrison. Serum β2-microglobulin is the single most powerful predictor of survival and can substitute for staging. β2-Microglobulin is a protein of 11,000 mol wt with homologies to the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLAA, -B, -C) on the surface of every cell. Patients with β2-microglobulin levels <0.004 g/L have a median survival of 43 months, and those with levels >0.004 g/L have a survival of only 12 months. Combination of serum β2-microglobulin and albumin levels forms the basis for a three-stage International Staging System (ISS) (Table 136-2) that predicts survival. With the use of high-dose therapy and the newer agents, the Median Survival, Stage Months β2M <3.5, alb ≥3.5 I (28%)a 62 β2M <3.5, alb <3.5 or II (39%) 44 β2M = 3.5–5.5 β2M >5.5 III (33%) 29 Other features suggesting high-risk disease: aPercentage of patients presenting at each stage.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: β2M, serum β2-microglobulin in mg/L; alb, serum albumin in g/dL; FISH, fluorescent in situ hybridization. Durie-Salmon staging system is unable to predict outcome and thus is no longer used. High labeling index, circulating plasma cells, performance status, and high levels of lactate dehydrogenase are also associated with poor prognosis. Other factors that may influence prognosis are the presence of cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent in situ hybridization (FISH)–identified chromosome 17p deletion, and translocations t(4;14), (14;16), and t(14;20). Chromosome 13q deletion, previously thought to predict poor outcome, is not a predictor following the use of newer agents. Microarray profiling and comparative genomic hybridization have formed the basis for RNAand DNA-based prognostic staging systems, respectively. The ISS system, along with cytogenetic changes, is the most widely used method for assessing prognosis (Table 136-2).


InternalMed_Harrison

InternalMed_Harrison. No specific intervention is indicated for patients with MGUS. Follow-up once a year or less frequently is adequate except in higher risk MGUS, where serum protein electrophoresis, complete blood count, creatinine, and calcium should be repeated every 6 months. A patient with MGUS and severe polyneuropathy is considered for therapeutic intervention if a causal relationship can be assumed, especially in absence of any other potential causes for neuropathy. Therapy can include plasmapheresis and occasionally rituximab in patients with IgM MGUS or myeloma-like therapy in those with IgG or IgA disease. About 10% of patients with myeloma are asymptomatic (SMM) and will have an indolent course demonstrating only very slow progression of disease over many years. For these patients, no specific therapeutic intervention is indicated, although early intervention with lenalidomide and dexamethasone may prevent progression from high-risk SMM to active MM. At present, patients with SMM only require


InternalMed_Harrison

InternalMed_Harrison. intervention is indicated, although early intervention with lenalidomide and dexamethasone may prevent progression from high-risk SMM to active MM. At present, patients with SMM only require antitumor therapy when the disease becomes symptomatic with development of anemia, hypercalcemia, progressive lytic bone lesions, renal dysfunction, or recurrent infections. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy at a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually identified because their serum M component falls slowly or disappears initially, only to return after a few months. These patients respond well to systemic therapy.


InternalMed_Harrison

InternalMed_Harrison. Patients with symptomatic and/or progressive myeloma require therapeutic intervention. In general, such therapy is of two sorts: (1) systemic therapy to control the progression of myeloma and (2) symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients. The therapy of myeloma includes an initial induction regimen followed by consolidation and/or maintenance therapy and, on subsequent progression, management of relapsed disease. The therapy is partly dictated by the patient’s age and comorbidities, which may affect a patient’s ability to undergo high-dose therapy and transplantation.


InternalMed_Harrison

InternalMed_Harrison. Thalidomide (200 mg daily), when combined with dexamethasone, achieved responses in two-thirds of newly diagnosed MM patients. Subsequently, lenalidomide (25 mg/d on days 1–21 every 4 weeks), an immunomodulatory derivative of thalidomide, and bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks), a proteasome inhibitor, have each been combined with dexamethasone (40 mg once every week) and obtained high response rates (>80%) in newly diagnosed patients with MM. Importantly, their superior toxicity profile with improved efficacy has made them the preferred agents for induction therapy. Efforts to improve the fraction of patients responding and the degree of response have involved adding agents to the treatment regimen. The combination of lenalidomide, bortezomib, and dexamethasone achieves close to a 100% response rate and 30% complete response rate, making it one of the preferred induction regimens in transplant-eligible patients. Other similar three-drug combinations


InternalMed_Harrison

InternalMed_Harrison. achieves close to a 100% response rate and 30% complete response rate, making it one of the preferred induction regimens in transplant-eligible patients. Other similar three-drug combinations (bortezomib, thalidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) also achieve >90% response rate. Herpes zoster prophylaxis is indicated if bortezomib is used, and neuropathy attendant to bortezomib can be decreased both by its subcutaneous administration and administration on a weekly schedule. Lenalidomide use requires prophylaxis for deep vein thrombosis (DVT) with either aspirin or warfarin or low-molecular-weight heparin if patients are at a greater risk of DVT. In patients receiving lenalidomide, stem cells should be collected within 6 months, because the continued use of lenalidomide may compromise the ability to collect adequate numbers of stem cells. Initial therapy is continued until maximal cytoreduction. In patients who are transplant candidates,


InternalMed_Harrison

InternalMed_Harrison. use of lenalidomide may compromise the ability to collect adequate numbers of stem cells. Initial therapy is continued until maximal cytoreduction. In patients who are transplant candidates, alkylating agents such as melphalan should be avoided because they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant.


InternalMed_Harrison

InternalMed_Harrison. In patients who are not transplant candidates due to physiologic age >70 years, significant cardiopulmonary problems, or other comorbid illnesses, the same twoor three-drug combinations described above are considered standard of care as induction therapy. Previously, therapy consisting of intermittent pulses of melphalan, an alkylating agent, with prednisone (MP; melphalan, 0.25 mg/kg per day, and prednisone, 1 mg/kg per day for 4 days) every 4–6 weeks was used. However, a number of studies have combined novel agents with MP and reported superior response and survival outcomes. In patients >65 years old, combining thalidomide with MP (MPT) obtains higher response rates and overall survival compared with MP alone. Similarly, significantly improved response (71 vs 35%) and overall survival (3-year survival 72 vs 59%) were observed with the combination of bortezomib and MP compared with MP alone. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged


InternalMed_Harrison

InternalMed_Harrison. survival (3-year survival 72 vs 59%) were observed with the combination of bortezomib and MP compared with MP alone. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged progression-free survival compared with MP alone. These combinations of novel agents with MP also achieve high complete response rates (MPT, ~15%; MP plus bortezomib, ~30%; MP plus lenalidomide, ~20%; and MP, ~2–4%). Although combinations of MP with newer agents are an alternative in these patients, most studies favor continuous therapy with nonMP-containing regimens (e.g., lenalidomide plus dexamethasone) due to longer term safety profile and efficacy.


InternalMed_Harrison

InternalMed_Harrison. Improvement in the serum M component may lag behind the symptomatic improvement. The fall in M component depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin, which in turn depends on the serum concentration (for IgG). Light chain excretion, with a functional half-life of ~6 h, may fall within the first week of treatment. Because urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill, especially in patients with renal dysfunction; however, improvements in serum free light chain measurement are often seen sooner. Although patients may not achieve complete remission, clinical responses may last for long periods of time.


InternalMed_Harrison

InternalMed_Harrison. High-dose therapy and consolidation/maintenance are standard practice in the majority of eligible patients. Randomized studies comparing standard-dose therapy to high-dose melphalan therapy (HDT) with hematopoietic stem cell support have shown that HDT can achieve high overall response rates, with up to 25–40% additional complete responses and prolonged progression-free and overall survival; however, few, if any, patients are cured. Although two successive HDTs (tandem transplantations) are more effective than single HDT, the benefit is only observed in the subset of patients who do not achieve a complete or very good partial response to the first transplantation, which is rare. Moreover, a randomized study failed to show any significant difference in overall survival between early transplantation after induction therapy versus delayed transplantation at relapse. These data allow an option to delay transplantation, especially with the availability of more agents and combinations.


InternalMed_Harrison

InternalMed_Harrison. after induction therapy versus delayed transplantation at relapse. These data allow an option to delay transplantation, especially with the availability of more agents and combinations. Allogeneic transplantations may also produce high response rates, but treatment-related mortality may be as high as 40%. Nonmyeloablative allogeneic transplantation can reduce toxicity but is recommended only under the auspices of a clinical trial to exploit an immune graft-versus-myeloma effect while avoiding attendant toxicity.


InternalMed_Harrison

InternalMed_Harrison. Maintenance therapy prolongs remissions following standard-dose regimens as well as HDT. Two phase 3 studies have demonstrated improved progression-free survival, and one study showed prolonged overall survival in patients receiving lenalidomide compared to placebo as maintenance therapy after HDT. In non-transplant candidates, another phase 3 study showed prolonged progression-free survival with lenalidomide maintenance after MP plus lenalidomide induction therapy. Although there is concern regarding an increased incidence of second primary malignancies in patients receiving lenalidomide maintenance, its benefits far outweigh the risk of progressive disease and death from myeloma. In patients with high-risk cytogenetics, lenalidomide and bortezomib have been combined and show promise as maintenance therapy after transplantation.


InternalMed_Harrison

InternalMed_Harrison. Relapsed myeloma can be treated with a number of agents including lenalidomide and/or bortezomib. These agents in combination with dexamethasone can achieve a partial response rate of up to 60% and a 10–15% complete response rate in patients with relapsed disease. The combination of bortezomib and liposomal doxorubicin is active in relapsed myeloma. Thalidomide, if not used as initial therapy, can achieve responses in refractory cases. The second-generation proteasome inhibitor carfilzomib and immunomodulatory agent pomalidomide have shown efficacy in relapsed and refractory MM, even MM refractory to lenalidomide and bortezomib. High-dose melphalan and stem cell transplantation, if not used earlier, also have activity as salvage therapy in patients with refractory disease.


InternalMed_Harrison

InternalMed_Harrison. The median overall survival of patients with myeloma is 7–8+ years, with subsets of younger patients surviving more than 10 years. The major causes of death are progressive myeloma, renal failure, sepsis, or therapy-related myelodysplasia. Nearly a quarter of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke—all intercurrent illnesses related more to the age of the patient group than to the tumor.


InternalMed_Harrison

InternalMed_Harrison. Supportive care directed at the anticipated complications of 717 the disease may be as important as primary antitumor therapy. Hypercalcemia generally responds well to bisphosphonates, glucocorticoid therapy, hydration, and natriuresis, and rarely requires calcitonin as well. Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life, decrease bone-related complications, and may also have antitumor effects. Osteonecrosis of the jaw and renal dysfunction can occur in a minority of patients receiving aminobisphosphonate therapy. Treatments aimed at strengthening the skeleton such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested, but are not of proven efficacy. Kyphoplasty or vertebroplasty should be considered in patients with painful collapsed vertebra. Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to


InternalMed_Harrison

InternalMed_Harrison. efficacy. Kyphoplasty or vertebroplasty should be considered in patients with painful collapsed vertebra. Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to prevent dehydration and enhance excretion of light chains and calcium. In the event of acute renal failure, plasmapheresis is ~10 times more effective at clearing light chains than peri toneal dialysis; however, its role in reversing renal failure remains controversial. Importantly, reducing the protein load by effective antitumor therapy with agents such as bortezomib may result in improvement in renal function in over half of the patients. Use of lenalidomide in renal failure is possible but requires dose modification, because it is renally excreted. Urinary tract infections should be watched for and treated early. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococ cal polysaccharide


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InternalMed_Harrison. for and treated early. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococ cal polysaccharide vaccines may not elicit an antibody response. Prophylactic administration of intravenous γ globulin preparations is used in the setting of recurrent serious infections. Chronic oral antibiotic prophylaxis is not warranted. Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency MRI and local radiation therapy and glucocorticoids if cord compression is identified. In patients in whom neurologic deficit is increasing or substantial, emergent surgical decompression may be necessary. Most bone lesions respond to analgesics and systemic therapy, but certain painful lesions may respond most promptly to localized radiation. The anemia associated with myeloma may respond to erythropoietin along with


InternalMed_Harrison

InternalMed_Harrison. respond to analgesics and systemic therapy, but certain painful lesions may respond most promptly to localized radiation. The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin). The pathogenesis of the anemia should be established and specific therapy instituted, whenever possible.


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InternalMed_Harrison. In 1948, Waldenström described a malignancy of lymphoplasmacytoid cells that secreted IgM. In contrast to myeloma, the disease was associated with lymphadenopathy and hepatosplenomegaly, but the major clinical manifestation was hyperviscosity syndrome. The disease resembles the related diseases chronic lymphocytic leukemia, myeloma, and lymphocytic lymphoma. It originates from a post– germinal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-bearing memory B cell. Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a similar clinical course, but therapeutic options are different. The diagnosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells in the bone marrow. Such patients are at greater risk of pathologic fractures than patients with WM.


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InternalMed_Harrison. A familial occurrence is common in WM, but its molecular bases are yet unclear. A distinct MYD88 L265P somatic mutation has been reported in over 90% of patients with WM and the majority of IgM MGUS. Presence of this mutation is now used as a diagnostic test to discriminate WM from marginal zone lymphomas (MZLs), IgM-secreting myeloma, and chronic lymphocytic leukemia (CLL) with plasmacytic differentiation. This mutation also explains the molecular pathogenesis of the disease, with involvement of Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling leading to 718 activation of IL-1R–associated kinase (IRAK) 4 and IRAK1 followed by nuclear factor-κB (NF-κB) activation. The disease is similar to myeloma in being slightly more common in men and occurring with increased incidence with increasing age (median 64 years). There have been reports that the IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that


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InternalMed_Harrison. with increasing age (median 64 years). There have been reports that the IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a greater extent than the better known myelin basic protein in patients with multiple sclerosis. Sometimes patients with macroglobulinemia develop a peripheral neuropathy, and half of these patients are positive for anti-MAG antibody. The neuropathy may precede the appearance of the neoplasm. There is speculation that the whole process begins with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component. Like myeloma, the disease involves the bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Bone marrow shows >10% infiltration with lymphoplasmacytic cells (surface IgM+, CD19+, CD20+, and CD22+, rarely CD5+,


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InternalMed_Harrison. bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Bone marrow shows >10% infiltration with lymphoplasmacytic cells (surface IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and CD23−) with an increase in number of mast cells. Like myeloma, an M component is present in the serum in excess of 30 g/L (3 g/dL), but unlike myeloma, the size of the IgM paraprotein results in little renal excretion, and only ~20% of patients excrete light chains. Therefore, renal disease is not common. The light chain isotype is kappa in 80% of the cases. Patients present with weakness, fatigue, and recurrent infections similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms such as peripheral neuropathy, dizziness, headache, and transient paresis are much more common in macroglobulinemia. Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic examination may reveal vascular segmentation and dilation of the


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InternalMed_Harrison. paresis are much more common in macroglobulinemia. Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic examination may reveal vascular segmentation and dilation of the retinal veins characteristic of hyperviscosity states. Patients may have a normocytic, normochromic anemia, but rouleaux formation and a positive Coombs’ test are much more common than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10% of macroglobulins are cryoglobulins. These are pure M components and are not the mixed cryoglobulins seen in rheumatoid arthritis and other autoimmune diseases. Mixed cryoglobulins are composed of IgM or IgA complexed with IgG, for which they are specific. In both cases, Raynaud’s phenomenon and serious vascular symptoms precipitated by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have


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InternalMed_Harrison. by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood drawn into a warm syringe and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin.


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InternalMed_Harrison. Control of serious hyperviscosity symptoms such as an altered state of consciousness or paresis can be achieved acutely by plasmapheresis because 80% of the IgM paraprotein is intravascular. The median survival of affected individuals is ~50 months, similar to that of MM. However, many patients with WM have indolent disease that does not require therapy. Pretreatment parameters including older age, male sex, general symptoms, and cytopenias define a high-risk population. Treatment is usually not initiated unless the disease is symptomatic or increasing anemia, hyperviscosity, lymphadenopathy, or hepatosplenomegaly is present. Bortezomib and bendamustine are two agents with significant efficacy in WM. Rituximab (anti-CD20) can produce responses, alone or combined with either of these two agents. Rituximab can produce IgM flare, so its use is initially withheld in patients with high IgM levels. Fludarabine (25 mg/m2 per day for 5 days every 4 weeks) and cladribine (0.1 mg/kg per day for


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InternalMed_Harrison. Rituximab can produce IgM flare, so its use is initially withheld in patients with high IgM levels. Fludarabine (25 mg/m2 per day for 5 days every 4 weeks) and cladribine (0.1 mg/kg per day for 7 days every 4 weeks) are also highly effective single agents. With identification of the MYD88 mutation, BTK and IRAK1/4 inhibitors are being evaluated and show significant responses. Although high-dose therapy plus autologous transplantation is an option, its use has declined due to the availability of other effective agents.


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InternalMed_Harrison. The features of this syndrome are polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS). Diagnostic criteria are described in Table 136-1. Patients usually have a severe, progressive sensorimotor polyneuropathy associated with sclerotic bone lesions from myeloma. Polyneuropathy occurs in ~1.4% of myelomas, but the POEMS syndrome is only a rare subset of that group. Unlike typical myeloma, hepatomegaly and lymphadenopathy occur in about two-thirds of patients, and splenomegaly is seen in one-third. The lymphadenopathy frequently resembles Castleman’s disease histologically, a condition that has been linked to IL-6 overproduction. The endocrine manifestations include amenorrhea in women and impotence and gynecomastia in men. Hyperprolactinemia due to loss of normal inhibitory control by the hypothalamus may be associated with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes


InternalMed_Harrison

InternalMed_Harrison. inhibitory control by the hypothalamus may be associated with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in about one-third of patients. Hypothyroidism and adrenal insufficiency are occasionally noted. Skin changes are diverse: hyperpigmentation, hypertrichosis, skin thickening, and digital clubbing. Other manifestations include peripheral edema, ascites, pleural effusions, fever, and thrombocytosis. Not all the components of POEMS syndrome may be present initially.


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InternalMed_Harrison. The pathogenesis of the disease is unclear, but high circulating levels of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have been documented, and levels of the inhibitory cytokine transforming growth factor β are lower than expected. Treatment of the myeloma may result in an improvement in the other disease manifestations. Patients are often treated similarly to those with myeloma. Plasmapheresis does not appear to be of benefit in POEMS syndrome. Patients presenting with isolated sclerotic lesions may have resolution of neuropathic symptoms after local therapy for plasmacytoma with radiotherapy. Similar to multiple myeloma, novel agents and high-dose therapy with autologous stem cell transplantation have been pursued in selected patients and have been associated with prolonged progression-free survival.


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InternalMed_Harrison. The heavy chain diseases are rare lymphoplasmacytic malignancies. Their clinical manifestations vary with the heavy chain isotype. Patients have absence of light chain and secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared. Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted.


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InternalMed_Harrison. This disease affects individuals of widely different age groups and countries of origin. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. It is frequently associated with autoimmune diseases, especially rheumatoid arthritis. Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer’s ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstration of an anomalous serum M component (often <20 g/L [<2 g/dL]) that reacts with anti-IgG but not anti–light chain reagents. The M component is typically present in both serum and urine. Most of the paraproteins have been of the γ1 subclass, but other subclasses have been seen. The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow that may show increased numbers of lymphocytes or plasma cells that do not stain for light chain. Patients usually have a rapid downhill course and die of


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InternalMed_Harrison. eosinophilia, and nondiagnostic bone marrow that may show increased numbers of lymphocytes or plasma cells that do not stain for light chain. Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy. Therapy is indicated when symptomatic and involves chemotherapeutic combinations used in low-grade lymphoma. Rituximab has also been reported to show efficacy.


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InternalMed_Harrison. This is the most common of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease. Without J chain–facilitated dimerization, viscosity does not increase dramatically. Light chains are absent from serum and urine. The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs


InternalMed_Harrison

InternalMed_Harrison. absent from serum and urine. The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may develop diffuse aggressive histologies of malignant lymphoma. Chemotherapy may produce long-term remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone. Immunoproliferative small-intestinal disease (IPSID) is recognized as an infectious pathogen–associated human lymphoma that has association with Campylobacter jejuni. It involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy


InternalMed_Harrison

InternalMed_Harrison. mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. Early-stage IPSID responds to antibiotics (30–70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma. Patients not responding to antibiotic therapy are considered for treatment with combination chemotherapy used to treat low-grade lymphoma.


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InternalMed_Harrison. The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with CLL. The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine. The diagnosis requires ultracentrifugation or gel filtration to confirm the nonreactivity of the paraprotein with the light chain reagents, because some intact macroglobulins fail to interact with these serums. The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm. There is no evidence that such patients should be treated differently from other patients with CLL (Chap. 134).


InternalMed_Harrison

InternalMed_Harrison. erone proteins during the process of synthesis and secretion, to ensure that they achieve correct tertiary conformation and function, and to eliminate proteins that misfold. However, genetic mutation, incorrect processing, and other factors may favor misfolding, with consequent loss of normal protein function and intracellular or extracellular aggregation. Many diseases, ranging from cystic fibrosis to Alzheimer’s disease, are now known to involve protein misfolding. In the amyloidoses, the aggregates are typically extracellular, and the misfolded protein subunits assume a common antiparallel, β-pleated sheet–rich structural conformation that leads to the formation of higher-order oligomers and then of fibrils with unique staining properties. The term amyloid was coined around 1854 by the pathologist Rudolf Virchow, who thought that these deposits resembled starch (Latin amylum) 719 under the microscope.


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InternalMed_Harrison. Amyloid diseases, defined by the biochemical nature of the protein composing the fibril deposits, are classified according to whether they are systemic or localized, whether they are acquired or inherited, and their clinical patterns (Table 137-1). The standard nomenclature is AX, where A indicates amyloidosis and X represents the protein present in the fibril. This chapter focuses primarily on the systemic forms. AL refers to amyloid composed of immunoglobulin light chains (LCs); this disorder, formerly termed primary systemic amyloidosis, arises from a clonal B cell or plasma cell disorder and can be associated with myeloma or lymphoma. AF refers to the familial amyloidoses, which are most commonly due to mutations in transthyretin (TTR), the transport protein for thyroid hormone and retinol-binding protein. AA amyloid is composed of the acute-phase reactant protein serum amyloid A (SAA) and occurs in the setting of chronic inflammatory or infectious diseases; for this reason, this


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InternalMed_Harrison. protein. AA amyloid is composed of the acute-phase reactant protein serum amyloid A (SAA) and occurs in the setting of chronic inflammatory or infectious diseases; for this reason, this type was formerly known as secondary amyloidosis. Aβ2M amyloid results from misfolded β2-microglobulin, occurring in individuals with long-standing renal disease who have undergone dialysis, typically for years. Aβ, the most common form of localized amyloidosis, is found in the brain of patients with Alzheimer’s disease after abnormal proteolytic processing and aggregation of polypeptides derived from the amyloid precursor protein.


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InternalMed_Harrison. Diagnosis and treatment of the amyloidoses rest upon the histopathologic identification of amyloid deposits and immunohistochemical, biochemical, or genetic determination of amyloid type (Fig. 137-1).


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InternalMed_Harrison. In the systemic amyloidoses, the clinically involved organs can be biopsied, but amyloid deposits may be found in any tissue of the body. Historically, blood vessels of the gingiva or rectal mucosa were often examined, but the most easily accessible tissue—positive in more than 80% of patients with systemic amyloidosis—is fat. After local anesthesia, fat is aspirated from the abdominal pannus with a 16-gauge needle. Fat globules expelled onto a glass slide can be stained, thus avoiding a surgical procedure. If this material is negative, more invasive biopsies of the kidney, heart, liver, or gastrointestinal tract can be considered in patients in whom amyloidosis is suspected. The regular β-sheet structure of amyloid deposits exhibits a unique “apple green” birefringence by polarized light microscopy when stained with Congo red dye; other regular protein structures (e.g., collagen) appear white under these conditions. The 10-nm-diameter fibrils can also be visualized by electron


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InternalMed_Harrison. light microscopy when stained with Congo red dye; other regular protein structures (e.g., collagen) appear white under these conditions. The 10-nm-diameter fibrils can also be visualized by electron microscopy of paraformaldehyde-fixed tissue. Once amyloid is found, the protein type must be determined by immunohistochemistry, immunoelectron microscopy, or extraction and biochemical analysis employing mass spectrometry; gene sequencing is used to identify mutants causing AF amyloid. The patient’s history, physical findings, and clinical presentation, including age and ethnic origin, organ system involvement, underlying diseases, and family history, may provide helpful clues as to the type of amyloid. However, there can be considerable overlap in clinical presentations, and accurate typing is essential to guide appropriate therapy.


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InternalMed_Harrison. The mechanisms of fibril formation and tissue toxicity remain controversial. The “amyloid hypothesis,” as it is currently understood, proposes that precursor proteins undergo a process of reversible unfolding or misfolding; misfolded proteins form oligomeric aggregates, higher-order polymers, and then fibrils that deposit in tissues. Accumulating evidence suggests that the oligomeric intermediates may constitute the most toxic species. Oligomers are more capable than large fibrils of interacting with cells and inducing formation of reactive oxygen species and stress signaling. Ultimately, the fibrillar tissue deposits are likely to interfere with normal organ function. A more sophisticated understanding of the mechanisms leading to amyloid formation and cell and tissue dysfunction will continue to provide new targets for therapies.


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InternalMed_Harrison. The clinical syndromes of the amyloidoses are associated with relatively nonspecific alterations in routine laboratory tests. Blood counts are usually normal, although the erythrocyte sedimentation rate is frequently elevated. Patients with glomerular kidney involvement generally have proteinuria, often in the nephrotic range, leading to Amyloidosis David C. Seldin, John L. Berk GENERAL PRINCIPLES Amyloidosis is the term for a group of protein folding disorders char-acterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. A robust cellular machinery exists to chap-137 aLocalized AL deposits can occur in skin, conjunctiva, urinary bladder, and the tracheobronchial tree. bSecondary to chronic inflammation or infection or to a hereditary periodic fever syndrome such as familial Mediterranean fever. Wild-type transthyretin (usually males >65, cardiac)


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InternalMed_Harrison. Wild-type transthyretin (usually males >65, cardiac) Mutant ApoAI, ApoAII, fibrinogen, lysozyme, gelsolin No further work-up (Screen for cardiac, renal, hepatic, autonomic involvement, and factor X deficiency) (Screen for renal, (Screen for neuropathy, cardiomyopathy; screen relatives) Familial amyloidosis of rare type (Screen for renal, hepatic, GI involvement) FIGURE 137-1 Algorithm for the diagnosis of amyloidosis and determination of type. Clinical suspicion: unexplained nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy, and macroglossia. ApoAI, apolipoprotein AI; ApoAII, apolipoprotein AII; GI, gastrointestinal.


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InternalMed_Harrison. hypoalbuminemia that may be severe; patients with serum albumin levels below 2 g/dL generally have pedal edema or anasarca. Amyloid cardiomyopathy is characterized by concentric ventricular hypertrophy and diastolic dysfunction associated with elevation of brain natriuretic peptide or N-terminal pro–brain natriuretic peptide as well as troponin. These cardiac biomarkers can be used for disease staging, prognostication, and disease activity monitoring in patients with AL amyloidosis. Notably, renal insufficiency can falsely elevate levels of these biomarkers. Recently, biomarkers of cardiac remodeling— i.e., matrix metalloproteinases and tissue inhibitors of metalloproteinases—have been found to be altered in the serum of patients with amyloid cardiomyopathy. Electrocardiographic and echocardiographic features of amyloid cardiomyopathy are described below. Patients with liver involvement, even when advanced, usually develop cholestasis with an elevated alkaline phosphatase


InternalMed_Harrison

InternalMed_Harrison. and echocardiographic features of amyloid cardiomyopathy are described below. Patients with liver involvement, even when advanced, usually develop cholestasis with an elevated alkaline phosphatase concentration but minimal alteration of the aminotransferases and preservation of synthetic function. In AL amyloidosis, endocrine organs may be infiltrated with fibrils, and hypothyroidism, hypoadrenalism, or even hypopituitarism can occur. Although none of these findings is specific for amyloidosis, the presence of abnormalities in multiple organ systems should raise suspicion regarding this diagnosis.


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InternalMed_Harrison. AL AMYLOIDOSIS Etiology and Incidence AL amyloidosis is most frequently caused by a clonal expansion of bone-marrow plasma cells that secrete a monoclonal immunoglobulin LC depositing as amyloid fibrils in tissues. Whether the clonal plasma cells produce an LC that misfolds and leads to AL amyloidosis or an LC that folds properly, allowing the cells to inexorably expand over time and develop into multiple myeloma (Chap. 136), may depend upon primary sequence or other genetic or epigenetic factors. AL amyloidosis can occur with multiple myeloma or other B lymphoproliferative diseases, including non-Hodgkin’s lymphoma (Chap. 134) and Waldenström’s macroglobulinemia (Chap. 136). AL amyloidosis is the most common type of systemic amyloidosis diagnosed in North America. Its incidence has been estimated at 4.5 cases/100,000 population; however, ascertainment continues to be inadequate, and the true incidence may be much higher. AL amyloidosis, like other plasma cell diseases, usually occurs


InternalMed_Harrison

InternalMed_Harrison. at 4.5 cases/100,000 population; however, ascertainment continues to be inadequate, and the true incidence may be much higher. AL amyloidosis, like other plasma cell diseases, usually occurs after age 40 and is often rapidly progressive and fatal if untreated.


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InternalMed_Harrison. Pathology and Clinical Features Amyloid deposits are usually widespread in AL amyloidosis and can be present in the interstitium of any organ outside the central nervous system. The amyloid fibril deposits are composed of full-length 23-kDa monoclonal immunoglobulin LCs as well as fragments. Accessory molecules co-deposited with LC fibrils (as well as with other amyloid fibrils) include serum amyloid P component, other proteins, glycosaminoglycans, and metal ions. Although all kappa and lambda LC subtypes have been identified in AL amyloid fibrils, lambda subtypes predominate. The lambda 6 subtype appears to have unique structural properties that predispose it to fibril formation, often in the kidney.


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InternalMed_Harrison. AL amyloidosis is often a rapidly progressive disease that presents as a pleiotropic set of clinical syndromes, recognition of which is key for initiation of the appropriate workup. Nonspecific symptoms of fatigue and weight loss are common; however, the diagnosis is rarely considered until symptoms referable to a specific organ develop. The kidneys are the most frequently involved organ and are affected in 70–80% of patients. Renal amyloidosis usually manifests as proteinuria, often in the nephrotic range and associated with hypoalbuminemia, secondary hypercholesterolemia and hypertriglyceridemia, and edema or anasarca. In some patients, interstitial rather than glomerular amyloid deposition can produce azotemia without proteinuria. The heart is the second most commonly affected organ (50–60% of patients), and cardiac involvement is the leading cause of death from AL amyloidosis. Early on, the electrocardiogram may show low voltage in the limb leads with a pseudo-infarct pattern.


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InternalMed_Harrison. (50–60% of patients), and cardiac involvement is the leading cause of death from AL amyloidosis. Early on, the electrocardiogram may show low voltage in the limb leads with a pseudo-infarct pattern. Echocardiographic features of disease include concentrically thickened ventricles and diastolic dysfunction with an abnormal strain pattern a “sparkly” appearance has been described but is often not seen with modern high-resolution echocardiographic techniques. Poor atrial contractility occurs even in sinus rhythm, and patients with cardiac amyloidosis are at risk for development of atrial thrombi and stroke. Cardiac MRI can show increased wall thickness, and characteristic enhancement of the subendocardium has been described following injection of gadolinium contrast. Nervous system symptoms include peripheral sensorimotor neuropathy and/or autonomic dysfunction manifesting as gastrointestinal motility disturbances (early satiety, diarrhea, constipation), impotence, orthostatic


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InternalMed_Harrison. symptoms include peripheral sensorimotor neuropathy and/or autonomic dysfunction manifesting as gastrointestinal motility disturbances (early satiety, diarrhea, constipation), impotence, orthostatic hypotension, and/or neurogenic bladder. Macroglossia (Fig. 137-2A), a pathognomonic sign of AL amyloidosis, is seen in only ~10% of patients. Liver involvement causes cholestasis and hepatomegaly. The spleen is frequently involved, and there may 721 be functional hyposplenism in the absence of significant splenomegaly. Many patients experience “easy bruising” due to amyloid deposits in capillaries or deficiency of clotting factor X, which can bind to amyloid fibrils; cutaneous ecchymoses appear, particularly around the eyes, producing the “raccoon-eye” sign Fig. 137-2B), another uncommon but pathognomonic finding. Other findings include nail dystrophy (Fig. 137-2C), alopecia, and amyloid arthropathy with thickening of synovial membranes in the wrists and shoulders. The presence of a


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InternalMed_Harrison. but pathognomonic finding. Other findings include nail dystrophy (Fig. 137-2C), alopecia, and amyloid arthropathy with thickening of synovial membranes in the wrists and shoulders. The presence of a multisystemic illness or general fatigue along with any of these clinical syndromes should prompt a workup for amyloidosis.


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InternalMed_Harrison. Diagnosis Identification of an underlying clonal plasma cell or B lymphoproliferative process and a clonal LC are key to the diagnosis of AL amyloidosis. Serum protein electrophoresis and urine protein electrophoresis, although of value in multiple myeloma, are not useful screening tests if AL amyloidosis is suspected because the clonal LC or whole immunoglobulin often is not present in sufficient amounts to produce a monoclonal “M-spike” in the serum or LC (Bence Jones) protein in the urine. However, more than 90% of patients with AL amyloidosis have serum or urine monoclonal LC or whole immunoglobulin detectable by immunofixation electrophoresis of serum (SIFE) or urine (UIFE) (Fig. 137-3A) or by nephelometric measurement of “free” LCs (i.e., LCs circulating in monomeric form rather than in an immunoglobulin tetramer with heavy chain). Examining the ratio as well as the absolute amount of free LCs is essential, as renal insufficiency reduces LC clearance, elevating both isotypes. In


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InternalMed_Harrison. in an immunoglobulin tetramer with heavy chain). Examining the ratio as well as the absolute amount of free LCs is essential, as renal insufficiency reduces LC clearance, elevating both isotypes. In addition, an increased percentage of plasma cells in the bone marrow—typically 5–30% of nucleated cells—is found in ~90% of patients. Kappa or lambda clonality should be demonstrated by flow cytometry, immunohistochemistry, or in situ hybridization for LC mRNA (Fig. 137-3B).


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InternalMed_Harrison. A monoclonal serum protein by itself is not diagnostic of amyloidosis, since monoclonal gammopathy of uncertain significance is common in older patients (Chap. 136). However, when monoclonal gammopathy of uncertain significance is found in patients with biopsy-proven amyloidosis, the AL type should be strongly suspected. Similarly, patients thought to have “smoldering myeloma” because of a modest elevation of bone-marrow plasma cells should be screened for AL amyloidosis if they have signs or symptoms of renal, cardiac, or neurologic disease. Accurate tissue amyloid typing is essential for appropriate treatment. Immunohistochemical staining of the amyloid deposits is useful if they bind one LC antibody in preference to the other; some AL deposits bind antibodies nonspecifically. Immunoelectron microscopy is more reliable, and mass spectrometry–based microsequencing of small amounts of protein extracted from fibril deposits can also be undertaken. In ambiguous cases, other forms of


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InternalMed_Harrison. microscopy is more reliable, and mass spectrometry–based microsequencing of small amounts of protein extracted from fibril deposits can also be undertaken. In ambiguous cases, other forms of amyloidosis should be thoroughly excluded with appropriate genetic and other testing.


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InternalMed_Harrison. Extensive multisystemic involvement typifies AL amyloidosis, and the median survival period without treatment is usually only ~1–2 years from the time of diagnosis. Current therapies target the FIGURE 137-2 Clinical signs of AL amyloidosis. A. Macroglossia. B. Periorbital ecchymoses. C. Fingernail dystrophy.


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InternalMed_Harrison. FIGURE 137-3 Laboratory features of AL amyloidosis. A. Serum immunofixation electrophoresis reveals an IgGκ monoclonal protein in this example; serum protein electrophoresis is often normal. B. Bone-marrow biopsy sections stained by immunohistochemistry with antibody to CD138 (syndecan, highly expressed on plasma cells) (left) or by in situ hybridization with fluorescein-tagged probes (Ventana Medical Systems) binding to κ mRNA (center) and λ mRNA (right) in plasma cells. (Photomicrograph courtesy of C. O’Hara; with permission.) clonal bone-marrow plasma cells, using approaches employed for multiple myeloma. Treatment with oral melphalan and prednisone can decrease the plasma cell burden but rarely leads to complete hematologic remission, meaningful organ responses, or improved survival and is no longer widely used. The substitution of dexamethasone for prednisone produces a higher response rate and more durable remissions, although dexamethasone is not always well tolerated by


InternalMed_Harrison

InternalMed_Harrison. and is no longer widely used. The substitution of dexamethasone for prednisone produces a higher response rate and more durable remissions, although dexamethasone is not always well tolerated by patients with significant edema or cardiac disease. High-dose IV melphalan followed by autologous stem cell transplantation (HDM/SCT) produces complete hematologic responses in ~40% of treated patients, as determined by loss of clonal plasma cells in the bone marrow and disappearance of the monoclonal LC, as determined by SIFE/UIFE and free LC quantitation. Hematologic responses can be followed in the subsequent 6–12 months as improvements in organ function and quality of life. Hematologic responses appear to be more durable after HDM/SCT than in multiple myeloma, with remissions continuing in some patients beyond 15 years without additional treatment. Unfortunately, only about half of AL amyloidosis patients are suitable for aggressive treatment, and, even at specialized treatment centers,


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InternalMed_Harrison. patients beyond 15 years without additional treatment. Unfortunately, only about half of AL amyloidosis patients are suitable for aggressive treatment, and, even at specialized treatment centers, transplantation-related mortality rates are higher than those for other hematologic diseases because of impaired organ function. Amyloid cardiomyopathy, poor nutritional and performance status, and multiorgan disease contribute to excess morbidity and mortality. A bleeding diathesis resulting from adsorption of clotting factor X to amyloid fibrils also increases mortality rates; however, this syndrome occurs in only 5–10% of patients. A randomized multicenter trial conducted in France compared oral melphalan and dexamethasone with HDM/ SCT and failed to show a benefit of dose-intensive treatment, although the transplantation-related mortality rate in this study was very high. It has become clear that careful selection of patients and expert peritransplantation management are essential in


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InternalMed_Harrison. although the transplantation-related mortality rate in this study was very high. It has become clear that careful selection of patients and expert peritransplantation management are essential in reducing transplantation-related mortality.


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InternalMed_Harrison. For patients with impaired cardiac function or arrhythmias due to amyloid involvement of the myocardium, the median survival period is only ~6 months without treatment. In these patients, cardiac transplantation can be performed and followed by HDM/SCT to eliminate the noxious clone and prevent amyloid deposition in the transplanted heart or other organs. Novel anti–plasma cell agents have been investigated for treatment of plasma cell diseases. The immunomodulators thalidomide, lenalidomide, and pomalidomide display activity; dosing may need to be adjusted compared to their usage for myeloma. The proteasome inhibitor bortezomib has also been found to be effective in single-center and multicenter trials. Anti-fibril small molecules and humanized monoclonal antibodies are also being tested. Clinical trials are essential in improving therapy for this rare disease.


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InternalMed_Harrison. Supportive care is important for patients with any type of amyloidosis. For nephrotic syndrome, diuretics and supportive stockings can ameliorate edema; angiotensin-converting enzyme inhibitors should be used with caution and have not been shown to slow renal disease progression. Effective diuresis can be facilitated with albumin infusions to raise intravascular oncotic pressure. Congestive heart failure due to amyloid cardiomyopathy is best treated with diuretics; it is important to note that digitalis, calcium channel blockers, and beta blockers are relatively contraindicated as they can interact with amyloid fibrils and produce heart block and worsening heart failure. Amiodarone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators have reduced effectiveness due to the thickened myocardium, but they may benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be


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InternalMed_Harrison. due to the thickened myocardium, but they may benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid cardiomyopathy and is an indication for anticoagulation even in the absence of atrial fibrillation. Autonomic neuropathy can be treated with α agonists such as midodrine to support the blood pressure; gastrointestinal dysfunction may respond to motility or bulk agents. Nutritional supplementation, either oral or parenteral, is also important.


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InternalMed_Harrison. In localized AL disease, amyloid deposits can be produced by clonal plasma cells infiltrating local sites in the airways, bladder, skin, or lymph nodes (Table 137-1). These deposits may respond to surgical intervention or low-dose radiation therapy (typically only 20 Gy); systemic treatment generally is not appropriate. Patients should be referred to a center familiar with management of these rare manifestations of amyloidosis.


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InternalMed_Harrison. AA AMYLOIDOSIS Etiology and Incidence AA amyloidosis can occur in association with almost any chronic inflammatory state (e.g., rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever [Chap. 392], or other periodic fever syndromes) or chronic infections such as tuberculosis or subacute bacterial endocarditis. In the United States and Europe, AA amyloidosis has become less common, occurring in fewer than 2% of patients with these diseases, presumably because of advances in anti-inflammatory and antimicrobial therapies. It has also been described in association with Castleman’s disease, and patients with AA amyloidosis should undergo CT scanning to look for such tumors as well as serologic and microbiologic studies. AA amyloidosis can also be seen without any identifiable underlying disease. AA is the only type of systemic amyloidosis that occurs in children.


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InternalMed_Harrison. Pathology and Clinical Features Organ involvement in AA amyloidosis usually begins in the kidneys. Hepatomegaly, splenomegaly, and autonomic neuropathy can also occur as the disease progresses; cardiomyopathy occurs, albeit rarely. The symptoms and signs of AA disease cannot be reliably distinguished from those of AL amyloidosis. AA amyloid fibrils are usually composed of an 8-kDa, 76-amino-acid N-terminal portion of the 12-kDa precursor protein SAA. This acute-phase apoprotein is synthesized in the liver and transported by high-density lipoprotein (HDL3) in the plasma. Several years of an underlying inflammatory disease causing chronic elevation of SAA levels usually precede fibril formation, although infections can lead to AA deposition more rapidly.


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InternalMed_Harrison. Primary therapy for AA amyloidosis consists of treatment of the underlying inflammatory or infectious disease. Treatment that suppresses or eliminates the inflammation or infection also decreases the SAA concentration. For familial Mediterranean fever, colchicine at a dose of 1.2–1.8 mg/d is the standard treatment. However, 723 colchicine has not been helpful for AA amyloidosis of other causes or for other amyloidoses. Tumor necrosis factor and interleukin 1 antagonists can be effective in syndromes related to cytokine elevation. For this disease, there is also a fibril-specific agent: eprodisate was designed to interfere with the interaction of AA amyloid protein with glycosaminoglycans and to prevent or disrupt fibril formation. The drug is well tolerated and delays progression of AA renal disease. Randomized phase III clinical trials with eprodisate are ongoing; the drug is not otherwise available.


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InternalMed_Harrison. The familial amyloidoses are autosomal dominant diseases in which, beginning in midlife, a variant (FINE) plasma protein forms amyloid deposits. These diseases are rare, with an estimated incidence of <1 case/100,000 population in the United States, although founder effects in isolated areas of Portugal, Sweden, and Japan have led to a much higher incidence. The most common form of AF amyloidosis is ATTRm in the updated nomenclature, caused by mutation of the abundant plasma protein transthyretin (TTR, also known as prealbumin). More than 100 TTR mutations are known, and most are associated with ATTR amyloidosis. One variant, V122I, has a carrier frequency that may be as high as 4% in the African-American population and is associated with late-onset cardiac amyloidosis. The actual incidence and penetrance of disease in the African-American population is the subject of ongoing research, but ATTR amyloidosis warrants consideration in the differential diagnosis of African-American


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InternalMed_Harrison. and penetrance of disease in the African-American population is the subject of ongoing research, but ATTR amyloidosis warrants consideration in the differential diagnosis of African-American patients who present with concentric cardiac hypertrophy and evidence of diastolic dysfunction, particularly in the absence of a history of hypertension. Other familial amyloidoses, caused by variant apolipoproteins AI or AII, gelsolin, fibrinogen Aα, or lysozyme, are reported in only a few families worldwide. New amyloidogenic serum proteins continue to be identified periodically, including recently the leukocyte chemotactic factor LECT2, a cause of renal amyloidosis in Hispanic and Pakistani populations. To date, no mutation in the coding sequence for the LECT2 gene has been identified, so the heritability of ALECT2 is uncertain.


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InternalMed_Harrison. TTR deposits composed of unmutated fibrils occur with aging, and ATTRwt is being diagnosed with increasing frequency in Caucasian men >65 years of age with amyloid cardiomyopathy. Formerly termed senile systemic amyloidosis, ATTRwt has been found at autopsy in 25% of hearts from patients older than age 80 years. Why a wild type protein becomes amyloidogenic, and why patients bearing mutant TTR genes do not express disease until adulthood, remains a mystery.


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InternalMed_Harrison. Clinical Features and Diagnosis AF amyloidosis has a presentation that is variable but is usually consistent within kindreds affected by the same mutant protein. A family history makes AF disease more likely, but many patients present sporadically with new mutations. ATTR amyloidosis typically presents as a syndrome of familial amyloidotic polyneuropathy or familial amyloidotic cardiomyopathy. Peripheral neuropathy begins as a small-fiber lower-extremity sensory and motor neuropathy and progresses to the upper extremities. Autonomic neuropathy manifests as diarrhea with weight loss and orthostatic hypo-tension. Patients with TTR V30M, the most common mutation, have normal electrocardiograms but may develop conduction defects late in the disease. Patients with TTR T60A and several other mutations have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common and long-term survival rates are usually better. Vitreous opacities caused by amyloid


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InternalMed_Harrison. have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common and long-term survival rates are usually better. Vitreous opacities caused by amyloid deposits are pathognomonic for ATTR amyloidosis.


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InternalMed_Harrison. Typical syndromes associated with other forms of AF disease include renal amyloidosis with mutant fibrinogen, lysozyme, or apolipoproteins; hepatic amyloidosis with apolipoprotein AI; and amyloidosis of cranial nerves and cornea with gelsolin. Patients with AF amyloidosis can present with clinical syndromes that mimic those of patients with AL disease. Rarely, AF carriers can develop AL disease or AF patients may have monoclonal gammopathy without AL. 724 Thus, it is important to screen both for plasma cell disorders and for mutations in patients with amyloidosis. Variant TTRs can usually be detected by isoelectric focusing, but DNA sequencing is now standard for diagnosis of ATTR and other AF mutations.


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InternalMed_Harrison. Without intervention, the survival period after onset of ATTR disease is 5–15 years. Orthotopic liver transplantation replaces the major source of variant TTR production with a source of normal TTR. While liver transplantation can slow disease progression and improve chances of survival, it does not reverse sensorimotor neuropathy. Liver transplants are most successful in young patients with early peripheral neuropathy; older patients with familial amyloidotic cardiomyopathy or advanced polyneuropathy often experience end-organ disease progression despite successful liver transplantation. Progressive disease has been attributed to accumulation of wild-type TTR in fibrillar deposits initiated by the mutant.


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InternalMed_Harrison. The rate-limiting step in ATTR amyloidosis is dissociation of the TTR tetramer into monomer followed by misfolding and aggregation. TTR tetramers can be stabilized by thyroxine binding or by small molecules such as the non-steroidal anti-inflammatory drug diflunisal or the rationally designed small-molecule therapeutic tafamidis. A placebo-controlled randomized trial of diflunisal demonstrated a reduction in the progression of polyneuropathy and maintenance of quality of life in patients with a wide variety of ATTR mutations who received the “repurposed” diflunisal. Tafamidis tested in a similar fashion in patients with the V30M ATTR mutation failed to meet its primary endpoints, but tafamidis was approved by the European Medicines Agency since most secondary endpoints favored the drug. These agents are now being investigated for effects on cardiomyopathy, and in ATTRwt. In vitro data and serendipitous observations in patients suggest that ATTRm disease can be ameliorated by


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InternalMed_Harrison. drug. These agents are now being investigated for effects on cardiomyopathy, and in ATTRwt. In vitro data and serendipitous observations in patients suggest that ATTRm disease can be ameliorated by “trans-suppression,” in which a T119M TTR variant stabilizes tetramers that also contain amyloidogenic subunits. Interestingly, in a large population study in Denmark, 0.5% of participants were heterozygous for the T119M allele, and this small group had higher levels of TTR in their blood, a reduced incidence of cerebrovascular disease, and a 5to 10-year survival advantage compared with participants lacking this allele.


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InternalMed_Harrison. Aβ2M amyloid is composed of β2-microglobulin, the invariant chain of class I human leukocyte antigens, and produces rheumatologic manifestations in patients undergoing long-term hemodialysis. β2Microglobulin is excreted by the kidney, and levels become elevated in end-stage renal disease. The molecular mass of β2M is 11.8 kDa— above the cutoff of some dialysis membranes. The incidence of this disease appears to be declining with the use of newer membranes in high-flow dialysis techniques. Aβ2M amyloidosis usually presents as carpal tunnel syndrome, persistent joint effusions, spondyloarthropathy, or cystic bone lesions. Carpal tunnel syndrome is often the first symptom. In the past, persistent joint effusions accompanied by mild discomfort were found in up to 50% of patients who had undergone dialysis for >12 years. Involvement is bilateral, and large joints (shoulders, knees, wrists, and hips) are most frequently affected. The synovial fluid is noninflammatory, and β2M amyloid can be


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InternalMed_Harrison. dialysis for >12 years. Involvement is bilateral, and large joints (shoulders, knees, wrists, and hips) are most frequently affected. The synovial fluid is noninflammatory, and β2M amyloid can be found if the sediment is stained with Congo red. Although less common, visceral β2M amyloid deposits do occasionally occur in the gastrointestinal tract, heart, tendons, and subcutaneous tissues of the buttocks. There is no specific therapy for Aβ2M amyloidosis, but cessation of dialysis after renal allografting may lead to symptomatic improvement.


InternalMed_Harrison

InternalMed_Harrison. A diagnosis of amyloidosis should be considered in patients with unexplained nephropathy, cardiomyopathy (particularly with diastolic dysfunction), neuropathy (either peripheral or autonomic), enteropathy, or the pathognomonic soft tissue findings of macroglossia or periorbital ecchymoses. Pathologic identification of amyloid fibrils can be made with Congo red staining of aspirated abdominal fat or of an involved-organ biopsy specimen. Accurate typing by a combination of immunologic, biochemical, and genetic testing is essential in selecting appropriate therapy (Fig. 137-1). Systemic amyloidosis should not be considered an untreatable condition, as anti–plasma cell chemotherapy is highly effective in AL disease and targeted therapies are being developed for AA and ATTR disease. Tertiary referral centers can provide specialized diagnostic techniques and access to clinical trials for patients with these rare diseases.


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InternalMed_Harrison. This chapter represents a revised version of a chapter that was coauthored by Dr. Martha Skinner and Dr. David Seldin in previous editions of Harrison’s Principles of Internal Medicine. transfusion Biology and therapy Jeffery S. Dzieczkowski, Kenneth C. Anderson BLOOD GROUP ANTIGENS AND ANTIBODIES The study of red blood cell (RBC) antigens and antibodies forms the 138e foundation of transfusion medicine. Serologic studies initially characterized these antigens, but now the molecular composition and structure of many are known. Antigens, either carbohydrate or protein, are assigned to a blood group system based on the structure and similarity of the determinant epitopes. Other cellular blood elements and plasma proteins are also antigenic and can result in alloimmunization, the production of antibodies directed against the blood group antigens of another individual. These antibodies are called alloantibodies.


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InternalMed_Harrison. Antibodies directed against RBC antigens may result from “natural” exposure, particularly to carbohydrates that mimic some blood group antigens. Those antibodies that occur via natural stimuli are usually produced by a T cell–independent response (thus, generating no memory) and are IgM isotype. Autoantibodies (antibodies against autologous blood group antigens) arise spontaneously or as the result of infectious sequelae (e.g., from Mycoplasma pneumoniae) and are also often IgM. These antibodies are often clinically insignificant due to their low affinity for antigen at body temperature. However, IgM antibodies can activate the complement cascade and result in hemolysis. Antibodies that result from allogeneic exposure, such as transfusion or pregnancy, are usually IgG. IgG antibodies commonly bind to antigen at warmer temperatures and may hemolyze RBCs. Unlike IgM antibodies, IgG antibodies can cross the placenta and bind fetal erythrocytes bearing the corresponding antigen, resulting


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InternalMed_Harrison. bind to antigen at warmer temperatures and may hemolyze RBCs. Unlike IgM antibodies, IgG antibodies can cross the placenta and bind fetal erythrocytes bearing the corresponding antigen, resulting in hemolytic disease of the newborn, or hydrops fetalis.


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InternalMed_Harrison. Alloimmunization to leukocytes, platelets, and plasma proteins may also result in transfusion complications such as fevers and urticaria but generally does not cause hemolysis. Assay for these other alloantibodies is not routinely performed; however, they may be detected using special assays.


InternalMed_Harrison

InternalMed_Harrison. The first blood group antigen system, recognized in 1900, was ABO, the most important in transfusion medicine. The major blood groups of this system are A, B, AB, and O. O type RBCs lack A or B antigens. These antigens are carbohydrates attached to a precursor backbone, may be found on the cellular membrane either as glycosphingolipids or glycoproteins, and are secreted into plasma and body fluids as glycoproteins. H substance is the immediate precursor on which the A and B antigens are added. This H substance is formed by the addition of fucose to the glycolipid or glycoprotein backbone. The subsequent addition of N-acetylgalactosamine creates the A antigen, whereas the addition of galactose produces the B antigen.


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InternalMed_Harrison. The genes that determine the A and B phenotypes are found on chromosome 9p and are expressed in a Mendelian codominant manner. The gene products are glycosyl transferases, which confer the enzymatic capability of attaching the specific antigenic carbohydrate. Individuals who lack the “A” and “B” transferases are phenotypically type “O,” whereas those who inherit both transferases are type “AB.” Rare individuals lack the H gene, which codes for fucose transferase, and cannot form H substance. These individuals are homozygous for the silent h allele (hh) and have Bombay phenotype (Oh).


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InternalMed_Harrison. The ABO blood group system is important because essentially all individuals produce antibodies to the ABH carbohydrate antigen that they lack. The naturally occurring anti-A and anti-B antibodies are termed isoagglutinins. Thus, type A individuals produce anti-B, whereas type B individuals make anti-A. Neither isoagglutinin is found in type AB individuals, whereas type O individuals produce both anti-A and anti-B. Thus, persons with type AB are “universal recipients” because they do not have antibodies against any ABO phenotype, whereas persons with type O blood can donate to essentially all recipi-138e-1 ents because their cells are not recognized by any ABO isoagglutinins. The rare individuals with Bombay phenotype produce antibodies to H substance (which is present on all red cells except those of hh phenotype) as well as to both A and B antigens and are therefore compatible only with other hh donors.


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InternalMed_Harrison. In most people, A and B antigens are secreted by the cells and are present in the circulation. Nonsecretors are susceptible to a variety of infections (e.g., Candida albicans, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae) because many organisms may bind to polysaccharides on cells. Soluble blood group antigens may block this binding.


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InternalMed_Harrison. The Rh system is the second most important blood group system in pretransfusion testing. The Rh antigens are found on a 30to 32-kDa RBC membrane protein that has no defined function. Although >40 different antigens in the Rh system have been described, five determinants account for the vast majority of phenotypes. The presence of the D antigen confers Rh “positivity,” whereas persons who lack the D antigen are Rh negative. Two allelic antigen pairs, E/e and C/c, are also found on the Rh protein. The three Rh genes, E/e, D, and C/c, are arranged in tandem on chromosome 1 and inherited as a haplotype, i.e., cDE or Cde. Two haplotypes can result in the phenotypic expression of two to five Rh antigens. The D antigen is a potent alloantigen. About 15% of individuals lack this antigen. Exposure of these Rh-negative people to even small amounts of Rh-positive cells, by either transfusion or pregnancy, can result in the production of anti-D alloantibody.


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InternalMed_Harrison. More than 100 blood group systems are recognized, composed of more than 500 antigens. The presence or absence of certain antigens has been associated with various diseases and anomalies; antigens also act as receptors for infectious agents. Alloantibodies of importance in routine clinical practice are listed in Table 138e-1. Antibodies to Lewis system carbohydrate antigens are the most common cause of incompatibility during pretransfusion screening. The Lewis gene product is a fucosyl transferase and maps to chromosome 19. The antigen is not an integral membrane structure but is adsorbed to the RBC membrane from the plasma. Antibodies to Lewis antigens are usually IgM and cannot cross the placenta. Lewis antigens may be adsorbed onto tumor cells and may be targets of therapy.