Immunoglobulin-Related Amyloidosis Clinical Presentation

Updated: Jan 29, 2015
  • Author: Slavomir Urbancek, MD, PhD; Chief Editor: Emmanuel C Besa, MD  more...
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Presentation

History

The most common presenting symptoms of immunoglobulin-related amyloidosis, including weakness and weight loss followed by purpura, particularly in loose facial tissue, are nonspecific. Other symptoms and physical findings vary widely, depending on which organs contain deposits. Amyloid deposition in a particular organ leads to similar clinical consequences and, therefore, similar complaints, regardless of the type of amyloid deposited. For example, cardiac L chain–type amyloidosis and cardiac transthyretin (TTR) amyloidosis cause similar symptoms.

Clinical features and management outcome were evaluated in a case series of 24 patients with periocular and orbital amyloidosis. [3] Signs and symptoms included a visible or palpable periocular mass or tissue infiltration (95.8%), ptosis (54.2%), periocular discomfort or pain (25%), proptosis or globe displacement (21%), limitations in ocular motility (16.7%), recurrent periocular subcutaneous hemorrhages (12.5%), and diplopia (8.3%). [3] Seven patients had B cells or plasma cells producing monoclonal immunoglobulin chains that were deposited as amyloid light chains. [3]

The kidneys are the most frequent sites of deposition, with nephrotic syndrome being common; therefore, complaints of peripheral edema are common. Patients can present with renal failure.

Involvement of the heart and the peripheral vasculature often leads to postural hypotension, with patients complaining of lightheadedness. Patients also develop weakness, palpitations, dyspnea, and peripheral edema due to congestive heart failure and arrhythmias. Occasionally, deposits in the coronary arteries (usually the smaller intracardiac arterioles) may cause anginal symptoms similar to those typical of atherosclerotic coronary artery disease.

Peripheral neuropathy may also occur. Patients whose disease involves the peripheral nerves often report dysesthesia, decreased sensation, and decreased strength. Symptoms usually affect the lower extremities more severely than the upper extremities.

Gastrointestinal (GI) involvement is typical, but may not be clinically evident. Most patients with L chain–type amyloidosis have histologic evidence of infiltration of the gut, particularly in the blood vessels. However, deposition is symptomatic in only a minority of patients.

The most common GI symptoms are constipation or alternating constipation and diarrhea. Gastric L chain–type amyloidosis can cause hematemesis, nausea, and vomiting. Intestinal L chain–type amyloidosis can impair motility and cause hemorrhage, obstruction, constipation, and diarrhea or alternating constipation and diarrhea. Myeloma-associated amyloidosis may rarely be first evident as subacute liver failure. [4]

Carpal tunnel syndrome may be part of the presentation. Approximately 20% of patients with L chain–type amyloidosis initially report weakness and paresthesia of one or both hands, suggesting carpal ligament involvement.

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Causes

No cause is known for any of the monoclonal plasma cell dyscrasias. Some evidence supports an etiologic role for human herpesvirus 8 (HHV-8), but this proposed etiology remains controversial.

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Physical Examination

The most common initial physical findings in individuals with immunoglobulin-related amyloidosis include the following:

  • Peripheral edema
  • Orthostatic hypotension
  • Purpura
  • Peripheral neuropathy
  • Carpal tunnel syndrome
  • Hepatomegaly
  • Macroglossia

Peripheral edema and hypotension result from congestive heart failure and nephrotic syndrome. Purpura results from vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.

Orthostatic hypotension

L chain–type amyloidosis and other systemic amyloidoses can lead to severe orthostatic hypotension, to the point of producing syncope and preventing normal activity. Poor cardiac contractility resulting from myocardial deposition, autonomic neuropathy resulting from amyloid deposits in the peripheral nerves, and impaired arteriolar responsiveness resulting from endothelial deposition may contribute to orthostatic hypotension. Treating heart failure or the nephrotic syndrome with diuretics may exacerbate hypotension.

Cardiac amyloidosis can also result in arrhythmias, including the following:

  • Heart block
  • Premature ventricular contractions
  • Tachyarrhythmias

Purpura and ecchymosis

Bleeding may be a severe manifestation of L chain–type amyloidosis or of any of the systemic amyloidoses. Subendothelial deposition in these disorders leads to capillary fragility and mucocutaneous bleeding. A deficiency in coagulation factor X, resulting from its binding to L chain–type amyloid fibrils, can exacerbate bleeding.

Neuropathy

In approximately 20% of people with L chain–type amyloidosis, deposition occurs in the peripheral nerves, causing sensorimotor peripheral neuropathy. Nerve deposition leads to symmetric sensory impairment and weakness, accompanied at times by painless ulcers similar to those of diabetic neuropathy. Cranial neuropathy is occasionally observed. Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, or impotence.

Patients with familial TTR amyloidosis commonly present with a combination of severe peripheral and autonomic neuropathy. Consider the alternative diagnosis of TTR amyloidosis in a young patient with severe amyloid neuropathy but no other severe organ involvement (see Amyloidosis, Transthyretin-Related and Amyloidosis, Overview).

Hepatosplenomegaly

Hepatic and splenic depositions causing hepatomegaly and/or splenomegaly are common and usually asymptomatic. Rarely, spontaneous rupture of the liver or the spleen may present as a surgical emergency.

Macroglossia

Macroglossia is present less frequently at diagnosis than was reported in earlier case series, probably because of earlier diagnosis. When present, macroglossia can become severe enough to interfere with swallowing and breathing. Macroglossia has apparently been described only in L chain–type and, occasionally, β2 -microglobulin (B2M) amyloidosis.

Musculoskeletal manifestations

L chain–type amyloidosis deposits in the joints can produce a clinical picture resembling seronegative rheumatoid arthritis. Deposits in the glenohumeral articulation may cause localized pain and swelling ("shoulder pad" sign), whereas deposits in skeletal muscle may produce pseudohypertrophy.

Localized L chain–type amyloidosis

For unknown reasons, localized L chain–type amyloidosis most commonly occurs in the respiratory tract. It may also may involve the ureter or the urinary bladder, causing hematuria. Amyloidomas are often found in the soft tissues, including the mediastinum and the retroperitoneum. Skin involvement can manifest as plaques and nodules. Localized pulmonary L chain–type amyloidosis often remains localized (ie, does not progress to systemic disease).

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