Amyloidosis is the extracellular deposition of insoluble amyloid fibrilprotein in any tissue or organ.[1] The most common subtypes of the disease are AL amyloidosis and AA reactive amyloidosis.[1] AL amyloidosis is a systemic disease caused by immunoglobulin light chain fragments, while AA amyloidosis is a potential complication of recurrent inflammation leading to the production of serum amyloid A, an acute phase reactant.[2] Pulmonary amyloidosis is a localized form of amyloid deposition that is confined to the lung parenchyma.[3] Consequences of pulmonary amyloidosis include hoarseness, stridor, airway obstruction, dysphagia, chronic pleural effusions, and pulmonary hypertension.[4]

Case data

A 60-year-old female with a 6-month history of chronic cough and recalcitrant pneumonias was referred to a community respirologist. An X-ray image [Figure 1] and CT images [Figure 2] showed a cystic consolidation in the right upper lobe that was concerning for cavitation with bronchiectasis.

The patient’s past medical history was notable for type 2 diabetes mellitus and auto­immune hepatitis with esophageal varices. The initial differential diagnosis included infectious disease leading to cavitation and bronchiectasis, such as a polymicrobial bacterial infection, nocardiosis, actinomycosis, and tuberculosis. Malignancy and inflammatory conditions were also considered.

A bronchoscopy revealed a difficult-to-access right upper lobe with a friable endobronchial lining. Bronchoalveolar lavage was undertaken to obtain specimens for cytological evaluation, white blood cell count and differential, and bacterial, fungal, and mycobacterium cultures. Pulmonary amyloidosis was confirmed by cytology, with results from Congo Red staining considered diagnostic [Figure 3].

As part of the workup for her newly diagnosed pulmonary amyloidosis, the patient underwent a serum protein electrophoresis test. A diagnosis of monoclonal gammopathy of unknown significance (MGUS) was made based on the presence of immunoglobulin class IgG and lambda type free light chain.[5] A urine protein electrophoresis test found no abnormalities. A bone marrow biopsy showed no advanced blood cell dyscrasias or amyloid deposition. No systemic signs of multiple myeloma were found, with tests revealing a normal serum calcium level, normal renal function, and no proteinuria. A skeletal survey revealed no lytic bone lesions. No cutaneous findings, heart failure findings, or peripheral neuropathies were identified when other organs likely to be affected by amyloidosis were assessed.[6]

Because of the multiple potential causes for the patient’s pulmonary amyloidosis, including her previously known autoimmune hepatitis and newly diagnosed MGUS, the amyloid samples from her bronchoalveolar lavage were sent to the Mayo Clinic for further analysis. Testing revealed AL kappa type amyloid deposits. These findings pointed to the patient’s amyloid lung deposition being secondary to her MGUS. Given the localized extent of the patient’s amyloidosis, a decision was made in conjunction with the patient’s hematologist to defer chemotherapy and plan for close clinical follow-up.

The patient was reassessed 5 months after her initial bronchoscopy. Although CT images obtained for reassessment showed a complete collapse of the right upper lobe [Figure 4], her cough had resolved and her exercise tolerance remained normal. She had no classic signs of systemic amyloidosis on reassessment but was found to have atrial fibrillation, and her echocardiogram showed evidence of elevated pulmonary artery pressures, with a moderately elevated right ventricular systolic pressure of 53 mm Hg.

Discussion

In this case amyloid typing was necessary because there were at least two potential mechanisms for the patient’s amyloidosis: her MGUS (AL amyloidosis) and her autoimmune hepatitis (AA amyloidosis). The diagnosis of AL amyloidosis could not be assumed based on the presence of monoclonal light chains in the serum because it is not uncommon for a patient with another form of amyloidosis to have a concomitant and unrelated MGUS.[5]

Historically, amyloid typing has been performed using immunohistochemistry and immunofluorescence analysis.[6] However, immunohistochemistry can yield inconclusive results because the antigenic epitope may be lost during tissue preparation and samples may be contaminated by serum proteins that result in high background staining.[7] The Mayo Clinic uses laser capture microdissection of clinical biopsy samples followed by liquefied chromatography combined with tandem mass spectrometry to identify the subtype of amyloid with a high degree of accuracy. Testing for this case revealed AL kappa type amyloid deposits and indicated the patient’s amyloid lung deposition was secondary to her MGUS.

The elevated pulmonary artery pressures and atrial fibrillation found when the patient was reassessed are in keeping with reports that have cited pulmonary hypertension and lobar atelectasis as sequelae of AL pulmonary amyloidosis.[8-10] Increased left ventricular wall thickness is the most common feature of cardiac amyloidosis[11] and was not seen in this patient, while atrial fibrillation, which affects up to 20% of systemic amyloidosis cases,[11] was eventually diagnosed in this patient.

Current management of amyloidosis is based on treatment of the underlying cause of the abnormal deposition of proteins in extracellular sites. Treatment may involve chemotherapy, immunosuppression, stabilizer proteins, or small interfering ribonucleic acids, depending on the amyloid subtype identified.[12] AL amyloidosis, which is caused by abnormal immunoglobulin light chain production by a plasma cell neoplasm, can be treated with high-dose chemotherapy and/or stem cell transplantation.[13,14] The preferred therapy for AA amyloidosis is control of the underlying inflammatory disease and thus suppression of serum amyloid protein production. ATTR amyloidosis, which is caused by a mutation in the transthyretin (TTR) gene, can be treated with liver transplantation or tafamidis, a chaperone protein for the stable form of transthyretin.[15]

Given the risks associated with amyloidosis and the progressive nature of the disorder, a prognosis relies on accurate identification of specific amyloid subtypes, which can vary in invasiveness and require drastically different therapies. As the number of unique protein aggregates identified via tandem mass spectrometry increases and targeted therapies become more widely available, subtype identification will undoubtedly become more important.

Summary

The patient in this case was found to have cavitation with bronchiectasis in the right upper lobe, initially thought to be secondary to infection. She underwent a bronchoscopy and bronchoalveolar lavage. Based on cytological evaluation, including Congo Red staining, she was eventually diagnosed with pulmonary amyloidosis. Because of the multiple potential causes for this disorder, the patient’s amyloid samples were sent to the Mayo Clinic for further analysis using laser capture microdissection, liquid chromatography, and tandem mass spectrometry. Testing revealed AL kappa type amyloid deposits and contributed to the decision made to defer chemotherapy and plan for close clinical follow-up.

This case demonstrates the utility of amyloid subtype analysis in clinically ambiguous circumstances. Management of localized pulmonary amyloidosis is dependent on the severity of symptoms, and asymptomatic patients may not require treatment.

Competing interests

None declared.

This article has been peer reviewed.

Dr Baumann is completing a residency in internal medicine at the University of British Columbia. Dr Salina is a pathologist at Royal Jubilee Hospital in Victoria and a clinical assistant professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. Dr Aboulhosn is a respirologist at Island Health and a clinical instructor in the Division of Respiratory Medicine at the University of British Columbia.