Pitfalls in the Diagnosis of Primary Amyloidosis

Cheng E. Chee; Martha Q. Lacy; Ahmet Dogan; Steven R. Zeldenrust; Morie A. Gertz


Clin Lymphoma Myeloma. 2010;10(3):177-180. 

In This Article

Case 3

Patient C is a 52-year-old white woman who presented with a 3-year history of numbness in her feet and progressive bilateral lower extremity weakness to the extent of impairing her mobility. She had also developed intermittent pain and blisters on her finger-tips bilaterally and chronic constipation. Examination revealed an ataxic gait, bilateral foot drop, severe muscle weakness in all muscle groups in the lower extremities and mild weakness in the distal muscle groups in her upper extremities, severe impairment of touch pressure and pin prick sensation in a glove and stocking distribution, and impairment of proprioception and vibration sense in all of her extremities. She was also areflexic.


Electromyography confirmed severe sensorimotor peripheral neuropathy. Right sural nerve and rectal biopsies confirmed amyloidosis on Congo red staining. Laboratory studies were as follows: hemoglobin, 13.3 g/dL (normal, 13.5–17.5 g/dL); normal albumin, carotene, factor X activity, kidney and liver function; negative serum and urine electrophoresis with immunofixation for monoclonal protein; normal IgG, IgA, and IgM levels; κ and λ FLC, troponin T, and NT-proBNP were not available; 24-hour urine protein, 145 mg per 24 hours (normal, < 102 mg per 24 hours) with predominant albumin (39%). Transthoracic echocardiogram showed that the left ventricular wall and intraventricular septum thickness were at the upper limits of normal, but serial echocardiograms did not show restrictive cardiomyopathy or progression of the ventricular wall or septal thickness, ruling out cardiac amyloid involvement. Bone marrow biopsy and fat aspirate was positive for amyloid by Congo red staining. There were < 7% plasma cells in the bone marrow biopsy, and clonality was not established. Plasma cell labeling index was 0%.

The patient was started on vitamin E for treatment of her amyloid neuropathy. Five years after her diagnosis, her older brother was diagnosed with amyloidosis when he presented with upper extremity neuropathy. Genetic testing was pursued in the patient and her brother with amyloidosis, and both had TTR His 58 mutation, confirming the diagnosis of familial amyloidotic polyneuropathy. Family members were screened, and the patient's niece (daughter of the brother with amyloidosis) and the patient's younger brother were heterozygous carriers of TTR His 58. Further information on the cause of death of the patient's mother confirmed cardiac amyloid on autopsy. The patient's sensorimotor neuropathy progressed with autonomic involvement, and she died 6.5 years after her diagnosis. Her brother with amyloidosis also died 8 years after his diagnosis with advancing neuropathy.


This case highlights the importance of identifying hereditary amyloidosis, which has a similar clinical presentation to that of patients with AL amyloidosis. The familial condition has implications of prognosis, genetic counseling of the affected family, and treatment, which is often liver transplantation, not high-dose chemotherapy. Family history is absent in over half of the patients; therefore, the absence of family history cannot be used to exclude the diagnosis. Familial amyloidosis must be considered in patients who do not have an obvious plasma cell dyscrasia.[5] Hereditary amyloidosis is an autosomal-dominant condition in which the amyloid fibrils are commonly derived from genetic variants of TTR,[12] apolipoprotein A-1,[13,14] lysozyme,[15] or fibrinogen A α-chain.[16] In our patient, the precursor protein deposited in the peripheral nerves is a mutant form of TTR that is commonly seen in familial amyloidotic polyneuropathy.[17] In the United States, amyloid derived from TTR is the most common type of hereditary amyloidosis, and more than 100 TTR mutations have been identified.[18,19] TTR, a tetramer produced by the liver, functions as a thyroid hormone transporter and in the binding of retinol. The presence of a mutant of the protein destabilizes the tetramer and leads to the release of monomers, which are believed to be amyloidogenic.[19]

The misdiagnosis of hereditary amyloidosis as AL amyloidosis has been highlighted previously by other investigators. In the United Kingdom, a study of 350 patients with systemic amyloidosis found amyloidogenic mutations in approximately 10% of patients.[20] A low-grade monoclonal gammopathy was concurrently detected in 24% of these patients with mutations. Another group found that of 178 patients referred for amyloidosis at their center, 6% of those screened and 2% of symptomatic patients had both a monoclonal gammopathy and a hereditary variant of amyloidosis.[21] Both studies have highlighted the issue of diagnostic confidence in the view that one patient can have both a monoclonal gammopathy and a hereditary variant, representing 2 possible sources of amyloid-forming proteins.[20,21] Furthermore, it has to be noted that MGUS increases with age and that hereditary variants of amyloidosis in the United States usually present in older patients.[21] Because of the lack of reliable staining of all types of amyloid using immunohistochemistry, ineffective screening methods with family history, and variable penetrance of the hereditary variants, the authors from both studies have recommended screening all new cases of amyloidosis for both AL and hereditary variants.[20,21] Techniques that can be used for screening include polymerase chain reaction and mass spectrometry.[22]


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