Amyloidosis in an Older Man

A 62-year-old previously healthy man is admitted for right upper quadrant pain; a workup reveals acute cholecystitis as the cause. During evaluation for surgery, his creatinine level is found to be 6.0 mg/dL; 1 year earlier it was 1.0 mg/dL. A trial of fluids does not lower the creatinine level. Renal ultrasonography shows no obstruction but reveals increased kidney size (left, 11.4 × 4.4 × 5.0 cm; right, 10.1 × 4.6 × 4.5 cm) with increased diffuse echogenicity.

PHYSICAL EXAMINATION

Vital signs are normal, as are the head, ears, eyes, nose, and throat. There are no enlarged lymph nodes in the neck, supraclavicular spaces, or axillary areas.

Chest is clear. No murmurs or gallops are audible; however, frequent extra beats are heard. The liver and spleen are not palpable. There is 2+ pedal edema.

OTHER LABORATORY AND IMAGING RESULTS

Blood glucose and potassium levels are normal. Calcium level is 6.8 mg/dL; phosphorus, 5.0 mg/dL; and serum albumin, 2.0 g/dL. The serum total protein level is 6.0 g/dL. Urinalysis reveals no blood but shows 4+ proteinuria. Hemoglobin level is 9.4 g/dL; the remainder of the complete blood cell count is normal.

An echocardiogram reveals a normal-sized heart but an ejection fraction of 40% and thickening of the left ventricular wall and septum. A renal biopsy is scheduled.

Which additional study or set of studies is most likely to help confirm the underlying diagnosis in this patient?

A.

Measurement of serum iron and total iron-binding capacity.

B.

Enzyme-linked immunosorbent assays for HIV-1.

C.

Genetic testing for the HFE gene mutations.

D.

Serum protein electrophoresis, immunofixation of the serum and urinary proteins, and quantification of serum free light chains.

CORRECT ANSWER: D

This patient has a multisystem illness affecting his kidney, heart, and blood. The clinical findings are consistent with amyloidosis, an uncommon monoclonal plasma cell disorder. Classification of the systemic amyloidoses is based on which plasma proteins form the ß-pleated sheets of amyloid deposits. In primary (AL) amyloidosis, which is the most likely type in this previously healthy man, fragments of immunoglobulin light chains produced by monoclonal plasma cells are deposited in a variety of organs and cause dysfunction.¹

Amyloidosis: typical presentation. The signs and symptoms of the disorder can be quite nonspecific. Thus, parenchymal organ involvement is often what brings the illness to clinical attention, as occurred with the somewhat explosive onset of nephrotic syndrome in this patient. The kidney is the most common site of amyloid deposition. The first sign of amyloid deposits in the kidney is usually proteinuria, which is often massive; the impairment of kidney function leads to classic nephrotic syndrome and eventually progresses to renal impairment and renal insufficiency.² Amyloidosis must always be high on the list of possible causes of nephrotic syndrome in adults (other causes include intrinsic renal diseases [eg, glomerulonephropathies, IgA nephropathy] and other systemic diseases [such as diabetes, HIV infection, and certain cancers]).^2,3

The concomitant cardiac involvement here (manifested by a lowered ejection fraction, abnormal echocardiogram, and possible arrhythmias) is a strong clue to the systemic nature of the illness and moves amyloidosis to the forefront of the differential diagnosis. In addition to the kidney and heart, areas targeted by amyloid include:

•The peripheral nerves (with resultant peripheral or autonomic neuropathy).

•The liver--less common but still typical (manifesting in hepatomegaly and elevated alkaline phosphatase levels).

•The tongue (resulting in macroglossia).

•The joints (causing painless swelling of the joints, especially the shoulders ["shoulder pad sign"]).

Diagnosis. Confirmation of amyloidosis usually involves tissue biopsy. When a specific organ is involved (eg, the kidney), that is where the biopsy should be performed. In patients with nephrotic syndrome who do not have diabetes (such as this man) and in patients with congestive heart failure (CHF) and cardiac hypertrophy who are not hypertensive, biopsy to detect amyloid deposition is especially important and useful. Other sites where biopsies can be performed relatively easily include the subcutaneous fat pad, bone marrow, and rectal mucosae; these have sensitivities of 80%, 50%, and 80%, respectively.⁴

An important ancillary study is examination of the plasma proteins (choice D). Because amyloidosis is a monoclonal disorder of plasma cells in the vast majority of cases, immunofixation of serum proteins reveals an M protein in the serum or urine in about 90% of patients. If amyloidosis is strongly suspected but results of immunofixation are negative, quantification of serum free light chains may be useful. The free light chain ratio is abnormal in most patients with amyloidosis, regardless of immunofixation results. A normal free light chain ratio makes a diagnosis of amyloidosis highly unlikely.²

Hemochromatosis is another systemic illness that frequently targets the heart, liver, joints, and kidneys. Measurement of serum iron and transferrin levels (choice A) remains the best screening test for hemochromatosis, and genetic testing (choice C) is useful for confirmation of the diagnosis and screening of family members. However, nephrotic syndrome would be unusual in a patient with hemochromatosis who--like this man--did not have long-standing diabetes.

HIV infection (choice B) is also a cause of nephrotic syndrome and cardiomyopathy in adults. However, the infection is usually quite advanced when these conditions develop. This patient seemed healthy until shortly before the onset of his current illness; a more obvious natural history of HIV infection would be expected before the development of these more advanced manifestations.

Prognosis and treatment. The prognosis of amyloidosis worsens as the number of organ systems involved increases. Cardiac involvement portends the worst prognosis, with a median survival of about 6 months.²

Attempts at therapy have typically involved treating the plasma cell dyscrasias in a manner similar to that used in multiple myeloma. A variety of approaches, including melphalan and thalidomide regimens and even stem cell transplantation techniques, have been evaluated; the best results have been associated with high-dose melphalan and autologous stem cell transplantation.⁵ However, the best outcomes have been achieved in veryhighly selected patient populations, and extrapolation of these results to more typical populations remains conjectural.

Outcome of this case. A renal biopsy revealed amyloid deposition in a vascular distribution diffusely in all glomeruli sampled. Serum protein immunofixation showed a monoclonal IgG lambda and a monoclonal lambda light chain in the urine (urinary protein was 9.0 g/24 hours). Unfortunately, the patient's clinical course progressively worsened; increasingly serious renal failure required dialysis, and CHF led to eventual respiratory failure that necessitated mechanical ventilation. He died on the 30th hospital day.

References:

REFERENCES:

1.

Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses.

N Engl J Med.

1997;337:898-909.

2.

Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment.

Mayo Clin Proc.

2006;81:693-703.

3.

Dember LM, Shepard JA, Nesta F, Stone JR. Case records of the Massachusetts General Hospital. Case 15-2005: an 80-year-old man with shortness of breath, edema, and proteinuria.

N Engl J Med.

2005;352:2111-2119.

4.

Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis, and therapy.

Mayo Clin Proc

. 1999;74:490-494.

5.

Gertz MA, Lacy MQ, Dispenzieri A. Therapy for immunoglobulin light chain amyloidosis: the new and the old.

Blood Rev.

2004;18:17-37.