Case Presentation: A 68 year-old man with prior Agent Orange exposure in Vietnam presents with 6 months of progressive orthostatic hypotension (OH), syncope, 60 lb weight loss, and lower extremity weakness, parasthesias, and allodynia.Prior workup found mildly elevated troponin and BNP, but a normal stress test. Midodrine had no improvement in OH, and BP on admission dropped 138/75 to 67/42. Exam showed lack of pupillary reaction to accommodation, anhidrosis, urinary retention, 3/5 strength in both legs, and decreased sensation below the knees. Routine labs were unremarkable, MRI brain, C/T/L spine was noncontributory, and CT C/A/P showed no malignancy. TTE revealed severe BiV hypertrophy and a small pericardial effusion.Further workup showed increased serum lambda (λ) free light chains, and urine immunofixation revealed faint monoclonal free λ elevation. Cardiac MRI showed LVEF 38% with diffuse subendocardial gadolinium enhancement suggestive of amyloid cardiomyopathy. An abdominal fat pad biopsy was inconclusive so a Cardiac biopsy was done, confirming AL amyloid (AL) deposition. Bone Marrow biopsy stained positive for amyloid and exhibited a population of lambda-restricted plasma cells (<10%) consistent with plasma cell dyscrasia. TTR amyloid genetic testing was negative.EMG & NCS showed axonal large fiber polyneuropathy favoring amyloid over inflammatory demyelinating neuropathy. Paraneoplastic and autoimmune blood panels were negative.Controlling the OH was difficult despite a slew of nonpharmacologic interventions such as abdominal binders, and max dose Florinef & Midodrine. Addition of Droxidopa was required to control symptoms. He was discharged with plans to start chemotherapy.
Discussion: AL amyloidosis is an accumulation of monoclonal Ig light chains into pathologic fibrils that deposit in extracellular spaces and result in tissue dysfunction and cell death, known as proteotoxicity. Our patient showed cardiac involvement as well as autonomic, sensory and motor neuropathy, but manifestations vary depending on location and amount of deposition. Also, while not causal, recognition that the Department of Veteran Affairs lists AL as a disease associated with Agent Orange is relevant to this case. One study found an odds ratio of 3.02.Pharmocologic management of OH includes fludrocortisone, which increases sodium and water reabsorption, and midodrine, an alpha-1 agonist, which increases vascular resistance. Droxidopa is an oral synthetic precursor to norepinephrine and while not studied in AL, did show a benefit in OH in familial amyloid polyneuropathy and was FDA approved in 2014 for OH.The mainstay of treatment for AL is chemotherapy directed at the plasma cell dyscrasia producing the abnormal protein. Immunotherapies targeting the amyloid deposits are currently in development.
Conclusions: Recognizing symptoms of AL amyloidosis and its association with Agent Orange exposure is important for early diagnosis and treatment in order to prevent progression of symptoms. When refractory orthostatic hypotension results, addition of oral droxidopa to standard therapies should be considered.