AA (Inflammatory) Amyloidosis Clinical Presentation

Updated: Dec 06, 2015
  • Author: Richa Dhawan, MD, CCD; Chief Editor: Herbert S Diamond, MD  more...
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Presentation

History

The most common presentation of amyloid A (AA) amyloidosis is renal. Renal involvement is found in as many as 90% of patients. Thus, signs and symptoms reflect the appearance of proteinuria, progressive development of renal insufficiency, or nephrotic syndrome. [17] Weakness, weight loss, and peripheral edema are the most common manifestations.

In patients with active rheumatoid arthritis (RA), some of those symptoms may be incorrectly attributed to progression of the inflammatory disease or to adverse effects of drugs. However, the development of proteinuria in patients with RA should always raise the suspicion of AA amyloidosis.

Amyloid deposits also occur in the spleen and liver, but even a significant splenic and hepatic load may remain asymptomatic for long periods. Splenic involvement might be suspected if Howell-Jolly bodies are found in a peripheral blood smear of a nonsplenectomized patient, or if frequent episodes of infection occur.

Rarely, evidence of bowel involvement dominates the presentation. GI involvement may lead to motility disorders and pseudo-obstruction. Amyloid accumulations in the small intestine can cause generalized malabsorption. The weakened bowel wall can rupture, leading to peritonitis. Blood vessel wall and tissue amyloid predispose to bleeding. [18]

Again, in patients with inflammatory joint disease, the GI symptoms can also be secondary to treatment, particularly with nonsteroidal anti-inflammatory drugs.

Goiter has also been reported as a possible feature of symptomatic AA amyloidosis.

Cardiac AA deposits may be revealed with echocardiography in about 10% of patients. Clinical evidence of cardiac involvement occurs in as many as 50% of patients with L chain–type (AL) amyloidosis compared with less than 5% with AA amyloidosis. Amyloid accumulation in the heart may be suggested by the following:

  • Decreased voltage in the electrocardiogram limb leads
  • Pseudoinfarction pattern in form of Q waves in the anterior chest leads
  • Thickening of the left ventricular wall disproportionate to the degree of current or prior hypertension

The hypomotile and pathological heart wall and failing heart predispose to mural thrombosis and embolic complications. Such right-sided heart involvement is a major prognostic determinant in AL amyloidosis, but is uncommon in AA amyloidosis. Amyloid in the conduction pathways can lead to high-grade blocks. [19]

Congestive heart failure, peripheral neuropathy, or carpal tunnel syndrome occasionally occurs during the course of AA amyloidosis. In contrast to AL amyloidosis and other amyloidoses, however, they are rarely, if ever, a presenting manifestation.

In patients with familial Mediterranean fever (FMF), the history of periodic fever, arthritis, serositis, and the presence of the same disorder in other family members are characteristic. Some instances have been reported in which febrile episodes are not apparent, and renal amyloid is the first manifestation of disease.

In patients with atrial myxoma or renal carcinoma, the appearance of symptoms consistent with nephrotic syndrome or renal failure due to amyloidosis may be the first evidence of the primary neoplastic disease.

In general, the appearance of symptoms suggesting renal disease in a patient with chronic infectious or noninfectious inflammation should raise a warning flag with respect to the presence of AA amyloidosis as a complication.

Rarely, a more specific symptom, such as abdominal fullness or right upper quadrant discomfort (reflecting hepatomegaly), might bring the patient to the physician.

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Physical

Findings on physical examination may include the following:

  • Patients with amyloid renal disease are commonly hypertensive, although whether the hypertension is associated with the renal amyloidosis or is a coincidental finding is not always clear.

  • Sallow complexion and peripheral edema are the main physical findings in individuals with either renal failure or nephrotic syndrome.

  • The major physical findings may be those associated with the primary inflammatory disease, notably deforming arthritis.

  • The appearance of hepatosplenomegaly in a patient with ongoing inflammation should prompt investigation for amyloidosis, although some patients with severe RA develop splenomegaly with subsequent Felty syndrome (splenomegaly and neutropenia or pancytopenia in the course of RA). These patients with Felty syndrome generally have normal renal function, although they might have a renal disease other than AA deposition.

The purpura and macroglossia observed in AL amyloidosis are not features of AA amyloidosis. Nor is the orthostatic hypotension associated with AL amyloidosis or the familial amyloidoses, unless gastrointestinal bleeding or other forms of hypovolemia associated with renal dysfunction are present.

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Causes

Both infectious and noninfectious diseases have been associated with AA amyloidosis. Chronic infectious diseases that have been associated with AA amyloidosis include the following:

The precise frequencies of AA amyloidosis in those disorders are difficult to ascertain, but they may be as high as 10% in some chronic suppurative disorders (eg, osteomyelitis). The overall incidence in autopsies in Western countries is estimated at 0.5-0.86%, where the most frequent underlying diseases are RA (23-51%), juvenile idiopathic arthritis (7-48%), and AS (0-12%). [10, 20]

RA is the most common rheumatic cause of AA amyloidosis. However, most patients with RA do not have development of AA amyloidosis. Prolonged duration of disease, continuous disease activity, and inadequate treatment are risk factors for AA amyloidosis. Renal failure due to amyloid deposition usually occurs in the fifth decade of life. In living patients with RA, the incidence of AA found on biopsies ranges from 7-29%.

In industrialized countries, chronic noninfectious inflammatory diseases are more commonly the cause of AA amyloidosis. In RA, the incidence is 5-26%, being found more often on autopsy than biopsy. The frequency of AA amyloidosis may be lower in patients treated earlier and more aggressively.

Other inflammatory disorders associated with AA amyloidosis include the following:

The most common cause of renal involvement in ankylosing spondylitis is AA amyloidosis (62%), followed by IgA nephropathy (30%). [3]

AA amyloidosis is a rare complication of inflammatory bowel disease and occurs more commonly in Crohn disease and in males. The reason that Crohn disease is more readily complicated by AA amyloidosis than ulcerative colitis is not known but may be secondary to greater degree of sustained inflammation in association with the former and, in particular, the suppurative features of Crohn disease such as abscesses and fistulae may be risk factors. [21]

Chronic juvenile arthritis seems to be a special case, with a large geographic variance (7-48%) in the incidence of AA amyloidosis depending on whether the analysis was performed in the United States (low) or Eastern Europe (high).

In the 1980s, a high frequency of renal AA amyloidosis was observed among subcutaneous drug abusers in some cities in the United States. Whether this was related to the drug or to some contaminating substance that elicited chronic inflammation when injected subcutaneously is not clear. More recently, AA amyloidosis associated with subcutaneous drug abuse was reported in 24 patients seen at a San Francisco hospital from 1998 to 2013. [22]

FMF is characterized by recurrent attacks of fever, arthritis, pleuritis, peritonitis, or erysipelas like erythema lasting 24–48 hours. FMF begins in childhood and usually affects persons of Mediterranean origin. AA amyloidosis develops in up to one-quarter of patients with FMF. Renal AA amyloidosis is virtually a universal complication of FMF in some populations if the patients are not compliant with colchicine prophylaxis.

Other hereditary fever syndromes that may be complicated by AA amyloidosis include the following:

  • Tumor necrosis factor receptor–associated periodic syndrome (TRAPS)
  • Chronic infantile neurologic cutaneous articular syndrome (CINCA)
  • Muckle-Wells syndrome
  • Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

Among tumors, hypernephroma has been associated with AA amyloidosis. More recently, Castleman disease (angiofollicular lymph node hyperplasia) has been recognized as a cause of amyloidosis. Resection of the tumor can lead to the regression of clinical signs of amyloid nephropathy. [23, 24]

Among other noninfectious chronic inflammatory diseases, AA amyloidosis has been reported in systemic lupus erythematosus, polymyositis, and polymyalgia rheumatica and has been observed in temporal artery biopsy samples of such patients. AA amyloidosis has also been noted in patients with gout, pseudogout, and some cases of apparently noninflammatory sarcoidosis.

 Because SAA production is mediated through inflammatory cytokines, primarily IL-6, AA deposition has been noted in other disorders associated with increased IL-6 production. Occasionally, patients with atrial myxomas, renal cell carcinomas, Hodgkin lymphoma, hairy cell leukemia, and carcinomas of the lung and stomach have been found to have renal AA amyloidosis, presumably because of production of the cytokine by the tumor cells. Paradoxically, some patients with agammaglobulinemia also have developed AA amyloidosis, demonstrating the dissociation between cytokine production and the synthesis of its normal downstream effector molecules, immunoglobulins.

Few case reports have described patients with cyclic neutropenia developing AA amyloidosis. [25]

As many as 6% of patients with AA amyloidosis have no clinically overt inflammatory disease.

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