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59-Year-Old Man With Fatigue, Weight Loss, and Hepatomegaly

      A 59-year-old man with type 2 diabetes, hypertension, and hyperlipidemia presented to his primary care physician with a 2-year history of fatigue and a 30-kg weight loss over a period of 6 months. His appetite remained stable, but he experienced early satiety. The patient reported no new joint or bone pains, light-headedness, dizziness, chest discomfort, or shortness of breath. He had never smoked, and his medications included glimepiride, labetalol, and simvastatin. His surgical history was notable for bilateral carpal tunnel release performed 5 years previously. He had no history of any recent travel. Family history was remarkable for type 2 diabetes and hyperlipidemia.
      Physical examination revealed a blood pressure of 136/87 mm Hg without orthostasis and a heart rate of 81 beats/min. He appeared fatigued, and his mouth examination revealed moist mucous membranes, with no ulcerations or macroglossia. The abdomen was mildly distended but not tender to palpation. Hepatosplenomegaly was noted, with the liver palpable 3 cm below the right costal margin and the spleen tip palpable 2 cm below the left costal margin. Findings on pulmonary, cardiovascular, and lymph node examinations were unremarkable. Computed tomography (CT) of the abdomen and pelvis confirmed the presence of hepatosplenomegaly and also revealed several partially calcified omental masses and periportal adenopathy.
      • 1.
        Which one of the following is the best course of action at this time?
        • a.
          Imaging-guided biopsy
        • b.
          Abdominal magnetic resonance imaging (MRI)
        • c.
          Whole-body 2-deoxy-2-[18F]-fluorodeoxyglucose ([18F]-FDG) positron emission tomography/CT
        • d.
          Stereotactic radiation
        • e.
          Chemotherapy
      A patient with a history of substantial weight loss and the presence of multiple abdominal masses should raise suspicion for malignancy vs infection. Tissue confirmation of the underlying pathology is critical. Thus, imaging-guided biopsy of the omental mass is the best option at this time. Abdominal MRI may better characterize the extent of masses but will not provide definitive diagnosis. Similarly, whole-body [18F]-FDG positron emission tomography/CT will better characterize the extent of the disease process in the setting of high [18F]-FDG uptake by these masses; however, it will not provide a definitive diagnosis. Stereotactic radiation and chemotherapy are not appropriate at this time as no definitive tissue diagnosis has been obtained to warrant definitive treatment.
      Subsequent CT-guided biopsy of one of the omental masses revealed a light pink, amorphous, extracellular material on hematoxylin-eosin staining, with an apple-green birefringence on Congo red stain under polarized light. This staining pattern is characteristic of amyloid deposits and is produced by the mixture of negative (blue color) and positive (yellow color) birefringence of tangled amyloid fibrils that appear green. Although all amyloid fibrils have the same characteristic cross-β sheet quaternary structure that stains positive with Congo red, they can be comprised of various misfolded proteins whose underlying source determines the subtype classification.
      • 2.
        Which one of the following modalities will best determine the patient's subtype of amyloidosis?
        • a.
          Immunohistochemistry
        • b.
          Liquid chromatography tandem mass spectrometry
        • c.
          Thioflavin T stain
        • d.
          Transthyretin (TTR) genotyping
        • e.
          Hematoxylin-eosin staining
      Immunohistochemistry using immunoperoxidase staining of formalin-fixed, paraffin-embedded tissue was typically used before the advent of LMD-MS but is less sensitive and specific than newer methods.
      • Gilbertson J.A.
      • Theis J.D.
      • Vrana J.A.
      • et al.
      A comparison of immunohistochemistry and mass spectrometry for determining the amyloid fibril protein from formalin-fixed biopsy tissue.
      The criterion standard for amyloid subtyping is laser microdissection followed by mass spectrometry (LMD-MS). In brief, known amyloid deposits on a slide from a tissue biopsy are microdissected by laser microscopy. This dissected material containing the amyloid deposit is broken down by tryptic digestion, and the breakdown peptides are analyzed by liquid chromatography tandem mass spectrometry. The resultant spectrometric peak pattern of peptides can be compared to known peptide databases that confirm the amyloid subtype such as immunoglobulin light chain amyloidosis (AL) or immunoglobulin heavy chain amyloidosis, TTR amyloidosis, and leukocyte chemotactic factor 2 amyloidosis. Although Thioflavin T binds to the β sheet–rich structures of amyloid deposits, it is unable to differentiate subtypes of amyloidosis, much like Congo red. Genotyping of TTR should be performed only after a diagnosis of TTR amyloidosis is confirmed by mass spectrometry. Hematoxylin-eosin staining will not offer additional information regarding the patient's amyloidosis subtype.
      The LMD-MS results in this patient's biopsy specimen demonstrated a peptide profile consistent with AL λ-type amyloid deposition.
      • 3.
        Given the biopsy results, which one of the following diagnostic tests is most likely to be useful in this patient?
        • a.
          QuantiFERON-TB Gold test
        • b.
          Serum and urine protein electrophoresis (SPEP/UPEP) with immunofixation (IFE) and serum free light chain (sFLC) assay
        • c.
          C-reactive protein
        • d.
          β2-Microglobulin
        • e.
          Antinuclear antibody test
      The QuantiFERON-TB Gold test could be used to assess for tuberculosis, which has been commonly associated with the formation of AA-type amyloid deposits, but would not be the most useful option. Given the AL λ-type amyloid deposititions, the presence of a monoclonal gammopathy forming these amyloid deposits, and arising from either clonal plasma cells or B cells, must be suspected. Hence, a SPEP/UPEP with IFE should be performed in conjunction with an sFLC assay. The latter test is crucial because patients with AL amyloidosis may have a normal SPEP/UPEP result and even a normal IFE result despite the presence of clonal immunoglobulin free light chains in the serum. The C-reactive protein level may be elevated in various inflammatory or infectious conditions and is not specific to diagnosing an underlying monoclonal gammopathy. β2-Microglobulin is a serum protein commonly elevated in various hematologic diseases, especially monoclonal gammopathies. Although it may be abnormal in the patient in this case, similar to C-reactive protein, it is not specific for confirming the presence of a monoclonal gammopathy. If the LMD-MS results from the omental mass biopsy had demonstrated AA-type amyloid deposits, it could suggest the presence of a chronic inflammatory disease or chronic infection. In such a situation, the antinuclear antibody test can be performed to screen for chronic autoimmune diseases.
      The initial laboratory evaluation revealed the following (reference ranges provided parenthetically): SPEP with IFE revealed the presence of a 0.6-g/dL monoclonal IgG λ paraprotein; the κ sFLC was 1.78 mg/dL (0.33-1.94 mg/dL); λ sFLC was 16.7 mg/dL (0.57-2.63); and the serum free κ:λ ratio was 0.1 (0.26-1.65). A 24-hour urine protein assessment yielded 60 mg of protein, 8 mg of which were fragments of a monoclonal IgG λ paraprotein. No albuminuria was noted. A subsequent bone marrow biopsy revealed hypercellular bone marrow, with 60% cellularity and 8% λ-restricted plasma cells.
      Further laboratory evaluation revealed the following: hemoglobin, 11.3 g/dL (13.5-17.5 g/dL); platelet count, 983 × 109/L (150-450 × 109/L); white blood cell count, 9.2 × 109/L (3.5-10.5 × 109/L); ferritin, 92 μg/L (24-336 μg/L); creatinine, 1.1 mg/dL (0.8-1.3 mg/dL); alkaline phosphatase, 720 U/L (45-155 U/L); troponin T, 40 ng/L (<15 ng/L); N-terminal pro-B-type natriuretic peptide (NT-proBNP), 952 pg/mL (10-76 pg/mL); and β2-microglobulin, 2.56 μg/mL (1.21-2.70 μg/mL). A peripheral blood smear detected the presence of Howell-Jolly bodies. Electrocardiography revealed normal sinus rhythm with signs of an old anterior infarct based on the absence of R waves in the right precordial leads (V1 through V3). Transthoracic echocardiography identified borderline increased concentric left ventricular wall thickness with grade II/IV diastolic dysfunction. Cardiac MRI with intravenous gadolinium revealed patchy mid and basal ventricular septum enhancement as well as patchy subepicardial delayed enhancement in the anterior and lateral walls. Low-dose whole-body CT did not identify any lytic bone lesions.
      • 4.
        Given this patient's laboratory and imaging results, which one of the following is most likely to be substantially affected by AL amyloid involvement?
        • a.
          Liver only
        • b.
          Kidney only
        • c.
          Heart only
        • d.
          Heart and liver
        • e.
          Heart and kidney
      Different organs can be affected by AL amyloidosis, most commonly the heart (37%), kidney (28%), nerves (25%), gastrointestinal tract (7%), and liver (5%).
      • Gertz M.A.
      • Buadi F.K.
      • Zeldenrust S.R.
      • Hayman S.R.
      Immunoglobulin light-chain amyloidosis (primary amyloidosis).
      Nearly half of all patients diagnosed with systemic AL amyloidosis will have 2 or more organs involved. In our patient, the presence of unexplained hepatomegaly and splenomegaly with features of hyposplenism on the peripheral blood smear, as well as an elevated alkaline phosphatase level, is highly suggestive of liver involvement with amyloid. In patients with substantial kidney involvement, AL amyloid deposits disrupt the glomerular basement membrane, causing a considerable amount of proteinuria consisting mostly of albumin. This patient had only 60 mg of total protein in his 24-hour urine collection, suggesting no major kidney involvement. Patients with notable cardiac infiltration of AL amyloid have early development of a restricted ventricular filling pattern with early diastolic—but not systolic—dysfunction. This scenario leads to a decreased end-diastolic volume and consequently a low cardiac output causing dyspnea and fatigue. Troponin T levels are elevated due to cardiac muscle injury and so are the NT-proBNP levels in response to increased myocardial wall stress. Together, these factors serve as sensitive biomarkers for early cardiac injury in patients with cardiac AL amyloid. Patients can sometimes be misdiagnosed as having ischemic heart disease because of a pseudoinfarction pattern seen in AL amyloidosis, with loss of the R wave in leads V1 through V3. Finally, global or patchy and transmural or subendocardial late gadolinium enhancement is common in cardiac amyloid and detects interstitial expansion from amyloid deposition. This patient had laboratory and imaging findings of cardiac amyloidosis; however, his clinical symptoms were not as obvious, likely because of relatively minimal involvement.
      Patients with AL amyloid who have greater than 10% bone marrow plasma cells have inferior outcomes compared to similar patients with 10% or fewer bone marrow plasma cells.
      • Kourelis T.V.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis.
      Other important prognostic factors in the Mayo Revised Prognostic Staging System include difference between involved and uninvolved serum immunoglobulin free light chain levels of 18 mg/dL of more, troponin T level of 0.025 ng/mL or higher, and NT-proBNP level of 1800 pg/mL or more.
      • Kumar S.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements.
      This patient's diagnosis was consistent with stage I systemic AL amyloidosis per the revised Mayo Clinic 2012 staging system with cardiac and hepatic involvement. A detailed discussion regarding treatment options was undertaken with the patient and his family.
      • 5.
        For this patient, which one of the following is the most appropriate initial treatment regimen?
        • a.
          Radiation therapy
        • b.
          Surgical debridement
        • c.
          Plasma cell–directed cytotoxic therapy
        • d.
          Liver transplant
        • e.
          Observation
      Radiation therapy and surgical debridement are not indicated in systemic AL amyloidosis. Rarely, such therapies are utilized for the management of localized AL amyloidosis, which tends to have a very different natural history and disease course.
      • Kourelis T.V.
      • Kyle R.A.
      • Dingli D.
      • et al.
      Presentation and outcomes of localized immunoglobulin light chain amyloidosis: the Mayo Clinic experience.
      The primary treatment approach in systemic AL amyloidosis has been to decrease amyloidogenic light chain production, arising from the clonal plasma cell population within the bone marrow. Thus, as in multiple myeloma, patients with AL amyloidosis are treated with plasma cell–directed cytotoxic therapy. Commonly, this includes high-dose melphalan chemotherapy followed by autologous stem cell rescue (ie, autologous stem cell transplant [ASCT]) or less intense, outpatient-based chemotherapy regimens. These regimens may include either alkylators (commonly melphalan or cyclophosphamide) or proteasome inhibitors (commonly bortezomib) alone or in combination, along with corticosteroids like dexamethasone. At this time, there are no adequate randomized trials to suggest that one modality of cytotoxic therapy is better than the other. Decisions on treatment choice include consideration of patient age, performance status, extent of cardiac involvement as well as function, other critical organ involvement (ie, kidney, liver, and autonomic nerves), and patient preference.
      • Dingli D.
      • Ailawadhi S.
      • Bergsagel P.L.
      • et al.
      Therapy for relapsed multiple myeloma: guidelines from the Mayo Stratification for Myeloma and Risk-Adapted Therapy.
      Irrespective of modality selected, the main goal is to eliminate the source of misfolding proteins. Liver transplant has no role in the up-front treatment of systemic AL amyloidosis because it is not the source of amyloidogenic proteins (immunoglobulin free light chains). Organ transplant will only lead to the recurrence of AL amyloid deposits in the transplanted organ without eliminating the plasma cell clone. However, transplant is considered an option in certain forms of mutant transthyretin amyloidosis, in which the liver is the primary source of abnormal amyloidogenic TTR protein, which results from inherited mutations within the TTR gene.
      • Kumar K.S.
      • Lefkowitch J.
      • Russo M.W.
      • et al.
      Successful sequential liver and stem cell transplantation for hepatic failure due to primary AL amyloidosis.
      Finally, observation will not combat or correct the underlying disorder.
      After discussion of available options, the patient underwent treatment with the chemotherapy regimen consisting of cyclophosphamide, bortezomib, and dexamethasone over 8 months. He had a complete hematologic response, which comprised normalization of his serum immunoglobulin free light chain levels and serum immunoglobulin light free chain ratio. Two years later, his serum alkaline phosphatase had normalized, his hepatosplenomegaly had improved with complete resolution of hyposplenism noted on his peripheral blood smear, and his cardiac biomarkers (troponin T and NT-proBNP) had also normalized.

      Discussion

      Systemic immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare plasma cell disorder characterized by misfolding of immunoglobulin light chains or, rarely, heavy chains to form amyloid fibrils capable of depositing in various organs in the body. Of all the different forms of systemic amyloidosis caused by various misfolding proteins, AL amyloidosis is the most common. It most commonly affects the heart, kidneys, skin, nerves, liver, and gastrointestinal tract.
      • Gertz M.A.
      • Buadi F.K.
      • Zeldenrust S.R.
      • Hayman S.R.
      Immunoglobulin light-chain amyloidosis (primary amyloidosis).
      Without treatment, progressive damage to critical organs results in high morbidity and mortality. One of the most important aspects of treating patients with systemic AL amyloidosis is to make the diagnosis as early as possible and initiate therapy with the goal of stopping further organ damage.
      • Dingli D.
      • Ailawadhi S.
      • Bergsagel P.L.
      • et al.
      Therapy for relapsed multiple myeloma: guidelines from the Mayo Stratification for Myeloma and Risk-Adapted Therapy.
      Amyloidosis should be suspected in patients with heart failure and/or nephrotic syndrome of unknown cause. Work-up in these cases should include SPEP/UPEP with IFE as well as the sFLC assay. The sFLC assay is especially important because the SPEP/UPEP as well as the IFE results can be negative in patients with systemic AL amyloidosis.
      Diagnosis is made by examining tissue histology for the classic apple-green birefringence on Congo red staining. The tissue of choice with the highest likelihood (>95%) of yielding a diagnosis is the organ suspected of involvement based on clinical and laboratory assessments. However, less invasive sources such as bone marrow and fat aspiratation can yield sensitivity results of 65% and 80%, respectively, making them attractive alternatives to performing a biopsy on critical organs like the heart, kidney, or liver.
      • Gertz M.A.
      • Buadi F.K.
      • Zeldenrust S.R.
      • Hayman S.R.
      Immunoglobulin light-chain amyloidosis (primary amyloidosis).
      It is not necessary to obtain more than one biopsy specimen containing AL amyloid deposits for the diagnosis of systemic AL amyloidosis.
      • Muchtar E.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition.
      Subtyping of the amyloid deposits detected on tissue biopsy is critical for the management of patients because it allows confirmation of the amyloid precursor protein, thus aiding in treatment decisions. For example, treating a patient with mutant TTR amyloidosis with cytotoxic chemotherapy will provide no benefit. In such patients, the problem lies within the liver and is not related to clonal bone marrow plasma cells; rather, chemotherapy would only expose such patients to unwarranted adverse effects.
      The mainstay of therapy for systemic AL amyloidosis is to reduce the clonal plasma cell population responsible for the amyloidogenic immunoglobin fragments. This treatment can result in symptomatic improvement in the affected organs over a period of time and subsequently leads to improved survival. However, it is important to be aware that organ responses can lag behind hematologic responses by several months, as outlined in this case. This time lag should be considered when evaluating concerns of premature therapy failure. Traditionally, treatment has consisted of cytotoxic chemotherapy such as high-dose melphalan followed by stem cell rescue or less intense forms of chemotherapy such as alkylators, proteasome inhibitors, or immunomodulators. Newer treatment approaches, which are currently under investigation, include monoclonal antibodies directed against the CD38 antigen on plasma cells and novel agents directed at dissolving already deposited amyloid fibrils to improve organ function and limit early mortality.
      • Sher T.
      • Fenton B.
      • Akhtar A.
      • Gertz M.A.
      First report of safety and efficacy of daratumumab in 2 cases of advanced immunoglobulin light chain amyloidosis.
      • Gertz M.A.
      • Landau H.
      • Comenzo R.L.
      • et al.
      First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction.
      A recent cohort study found that early diagnosis and the availability of plasma cell–directed therapies improved mortality for patients with systemic AL amyloidosis treated with ASCT or with less intense chemotherapy.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      This case highlights the progressive damage of infiltrating misfolded light chain protein that can occur in various organs. It stresses the importance of an early and accurate diagnosis because subsequent therapy can produce durable disease remission and improvement in the end-organ damage.

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        • et al.
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