Older Woman With Dysphagia, Fatigue, Dyspnea, and Weight Loss
An 80-year-old woman has a 3-month history of increasing dysphagia (withboth solids and liquids), fatigue, and dyspnea on exertion. She has also involuntarilylost 50 lb during the same period. She reports no abdominal pain orchange in bowel function.
Older Woman With Dysphagia, Fatigue, Dyspnea, and Weight Loss
An 80-year-old woman has a 3-month history of increasing dysphagia (withboth solids and liquids), fatigue, and dyspnea on exertion. She has also involuntarilylost 50 lb during the same period. She reports no abdominal pain orchange in bowel function.
PHYSICAL EXAMINATION
This elderly woman appears frail. Heart rate is 92 beats per minute; respirationrate, 16 breaths per minute; and blood pressure, 100/80 mm Hg. Temporalwasting and patchy alopecia are evident. Parotid glands are enlarged bilaterally;the tongue is also enlarged, and indentations made by the teeth arevisible. Results of a chest examination are normal. The liver and spleen are notenlarged. Her shoulders appear muscular and are out of proportion to the restof her frame. The remainder of the examination is unremarkable.
LABORATORY RESULTS
Hemoglobin level is 9.9 g/dL. Mean corpuscular volume (MCV) is 96 fL.White blood cell count and platelet count are normal. Results of a chemistrypanel and liver function tests are within normal limits.
Which of the following is the most appropriate next step?
A.
Esophagogastroduodenoscopy (EGD).
B.
Serum protein electrophoresis and immunofixation.
C.
Radionucleotide bone scan.
D.
Iron studies.
CORRECT ANSWER: B
The clinical findings in this patient are consistent with a diagnosis of amyloidosis,a rare monoclonal plasma cell disorder. The classification of amyloidosisis based on which precursor plasma proteins form amyloid deposits. In primaryamyloidosis, fragments of immunoglobulin light chains deposit in a varietyof organs and cause dysfunction.The most common symptoms associated with primary amyloidosis arefatigue, weight loss, and periorbital purpura.
1
Common physical findings includepalpable liver, enlarged tongue, and edema. An enlarged liver is seen in onlyabout 15% of patients but may be associated with concomitant congestive heartfailure.
2
Enlargement of the tongue is seen in only about 10% of patients. Softtissue infiltration may also occur in a variety of other areas,which can result in alopecia, the "shoulder-pad sign," andsubmandibular swelling.
3
All of these were present in thispatient.Because the signs and symptoms of the disease arerelatively nondescript, it may be parenchymal organ involvementthat brings amyloidosis to the clinician's attention.The kidneys, heart, liver, and peripheral nerves aremost commonly involved. Consider amyloidosis in a patientwith nephrotic syndrome with no alternative explanation,such as long-standing diabetes. Consider cardiacamyloid involvement in any patient with unexplained cardiomyopathyand no history of ischemic heart disease.Liver infiltration is often relatively asymptomatic, butit may be signaled by isolated elevations in alkaline phosphatase.Axonal peripheral neuropathy is also seen in primaryamyloidosis; symptoms generally occur in the lowerextremities, and sensory changes predominate. However,other neurologic involvement, such as carpal tunnel syndromeor autonomic neuropathy, may also prompt considerationof the diagnosis. Pulmonary involvement is relativelycommon in amyloidosis but rarely causes symptoms.Infiltration of the thyroid or adrenal gland may alsooccur and can cause endocrine dysfunction.Because its signs and symptoms are relatively nonspecific,amyloidosis can be somewhat difficult to diagnose.Recognition that the disease is a plasma cell disorderis the key to its diagnosis.
Electrophoresis and immunofixation
(choice
B
) of the serum and urine reveal the presence of a monoclonal light chain inabout 90% of patients. The presence of a monoclonal protein is a strong clueto the diagnosis, and its absence is a strong negative finding in ruling outamyloidosis.Biopsy can confirm the diagnosis in a patient with clinical manifestationsin whom monoclonal protein is detected. Subcutaneous fat aspiration andbone marrow biopsy with Congo red staining of the specimen are relativelynoninvasive and have sensitivities of about 80% and 50%, respectively. If neitherof these is diagnostic, biopsy of an affected organ may be an appropriatenext step.EGD (choice A) is frequently useful in the evaluation of patients with dysphagia(eg, when dysphagia is the result of esophageal carcinoma), and it isnot an inherently incorrect choice. However, because so many of the less common features of amyloidosis are present here, a more directed diagnostic approach(ie, serum protein studies, biopsy) is more appropriate.A radionucleotide bone scan (choice C) is a poor test for the evaluationof bone involvement in plasma cell disease. The bone lesions in plasma celldyscrasias are primarily lytic; thus, in the absence of fracture, bone scans thatdetect osteoblastic activity will be negative. Plain radiography or MRI wouldbe a better study in this setting.Most patients with amyloidosis are anemic; however, the anemia is a resultof marrow involvement rather than of iron deficiency. In addition, this patient'sMCV is 96 fL, which makes iron deficiency or related diagnoses veryunlikely and iron studies (choice D) of scant usefulness.
Prognosis.
The prognosis for patients with primary amyloidosis is generallypoor. Cardiac involvement portends the poorest prognosis, and the mediansurvival of affected patients is 6 months. Once the diagnosis of amyloidosisis established, obtain an echocardiogram to determine cardiac involvement.
Treatment.
The treatment of amyloidosis is evolving. Because it is amonoclonal plasma cell disorder, the history of its treatment parallels in manyways that of the treatment of multiple myeloma. In fact, it may be difficult todifferentiate between the 2 diseases in certain patients. Several trials haveconfirmed that therapy with oral melphalan and prednisone is more effectivethan no therapy or therapy with colchicine.
4
Unfortunately, the response ratesassociated with the melphalan-prednisone combination are low, and the timeto response often approaches 1 year. More intense chemotherapy regimenshave not been uniformly effective.A recent study evaluated the role of high-dose melphalan and autologousstem-cell transplantation in patients with primary amyloidosis. A substantialnumber of the patients in the study showed significant improvement in 5-yearsurvival and reversal of end-organ disease.
5
Outcome of this case.
The patient's condition deteriorated over the ensuingweeks; her dyspnea increased to the point that oxygen was required. Eventually,she went into respiratory arrest; intubation was difficult because of apparentinfiltration of the larynx and trachea by amyloid deposits, and she wasunable to be resuscitated.
References:
REFERENCES:
1.
Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis and therapy.
MayoClin Proc.
1999;74:490-494.
2.
Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical laboratory features in 474 cases.
Semin Hematol.
1995;32:45-59.
3.
Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses.
N Engl J Med.
1997;337:898-909.
4.
Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone,melphalan and prednisone, and melphalan, prednisone, and colchicine.
N Engl J Med.
1997;336:1202-1207.
5.
Skinner M, Sanchorawaia V, Seldin DC, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study.
Ann Intern Med.
2004:140:85-93.
