Transbronchial cryobiopsy proven amyloid diffuse cystic lung disease complicating a transthyretin mutated (ATTRm) amyloidosis: a case report

Abstract

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

Introduction

Systemic amyloidosis is a large group of diseases due to extra-cellular deposit of fibrillar misfolded proteins infiltrating and thus impairing multiple organs. ¹ Amyloidosis is classified according to the precursor and mainly includes immunoglobulin-derived light-chain amyloidosis (AL), secondary systemic amyloidosis (AA) and transthyretin amyloidosis (ATTR) [wild type (‘senile amyloidosis’: ATTRwt) or hereditary/mutated (ATTRm)]. ²

Mutated amyloidosis (ATTRm) is due to point mutations of the gene encoding for transthyretin (TTR) protein. As of September 2020, 133 destabilizing missense TTR-variants have been described with an autosomal dominant transmission. ³ According to TTR gene mutation, ATTRm phenotype is predominantly neurological, cardiac or mixed disease. ⁴ In many cases, as in other amyloidosis, it is a systemic disease involving multiple organs (nerve, heart, brain, eyes, kidney, ligaments, gut and lung). The most common pathogenic variant among people of African descent is valine to isoleucine substitution at position 142 (Val142Ile HGVS nomenclature; Val122Ile legacy nomenclature, V122I), with almost exclusive cardiac involvement.^5,6 The prevalence is approximately 2–3.5% in African Americans, with a penetrance believed to be as high as 80% among men.^7,8 Homozygosity is rarely reported and seems to be associated with earlier onset of the disease. ⁹

Diffuse cystic lung disease (DCLD) is one of the various presentations of pulmonary AL amyloidosis. ¹⁰ Pulmonary involvement of amyloidosis has been rarely described in ATTR (ATTRw or ATTRm).^11,12 Among which, DCLD seems even more uncommon and, to our knowledge, has never been described in ATTRm through cryobiopsy.

Case report

A 51-year-old man, native from Mali presented to the emergency-room with worsening dyspnoea and asthenia over the past year.

He had worked as a mechanic for 20 years, was a former smoker and presented no history of drinking or drug use. He denied any familial medical history among his two brothers, but a nonspecified cardiac-related death of his mother shortly after his birth. He had six healthy children. His past medical history included grade 1 obesity [body mass index (BMI) = 30.5 kg/m²], bilateral carpal tunnel syndrome treated in the past 2 years, high blood pressure, chronic glaucoma, diverticulosis and quiescent chronic B hepatitis. He noted erectile dysfunction for the past year.

Upon admission, his respiratory rate was 28 breaths/min, pulse was 92 beats/min and blood pressure was 149/105 mmHg, without orthostatic hypotension. Physical examination was compatible with a pleural syndrome. There was no cardiac murmur, no dermatological nor neurological and articular clinical abnormalities.

Nasopharyngeal polymerase chain reaction (PCR) was positive for SARS-CoV-2. Cardiac troponin (97.90 ng/l) and type-B BNP (605 ng/l) were elevated. Others relevant blood investigations revealed mild liver dysfunction test without cholestasis. Glomerular filtration was normal, as well as the urinary sediment. Electrocardiography showed a sinus regular rhythm without low voltage criteria nor ventricular hypertrophy.

A thoracic computed tomography (CT) scan revealed bilateral pleural effusion with disseminated bilateral peri-broncho-vascular cystic lesions (Figure 1). There was no mediastinal adenomegaly nor interstitial syndrome. In addition, there was no finding for a COVID-19 pneumopathy. Analysis of the pleural fluid revealed a transudative profile.

Figure 1.

Diffuse cystic lung disease on CT scan.

An echocardiography noted a moderate bi-ventricular concentric hypertrophy with a septal maximal thickness of 15 mm, with normal ventricular cavity size. There was no valvulopathy nor diastolic dysfunction. Left atria was measured at 34 cm². The left ventricular ejection fraction (LVEF) was estimated at 38%.

A cardiac magnetic resonance imaging (MRI) showed lesions compatible with a left ventricular hypertrophic aspect combined with an impaired global longitudinal strain, elevated native T1 and extracellular volume upon 45% and a late gadolinium enhancement (LGE) characteristic pattern. ^99mTc-HMDP bone scintigraphy displayed a moderate cardiac tracer uptake (PERUGINI visual score of 2). Histopathological examination of salivary glands revealed typical amyloid deposits with immunohistochemical study positive for transthyretin. There was no lymphocyte infiltrate. Additional testing revealed no evidence of gammopathy with a normal serum electrophoresis, a normal serum free light-chain (FLC) ratio of 1.01 and the absence of Bence–Jones’s urine protein.

Genetic analysis of the TTR gene demonstrated a homozygote V122I (pVal142Ile) mutation. Pulmonary transbronchial cryo-biopsies were performed to rule out any other differential diagnosis. Four specimens were obtained from the lower and upper right lobes under general anaesthesia. In the hours following the procedure, a few lightly haemoptoic expectorations were observed and spontaneously resolved. A chest X-ray performed the day after ruled out pneumothorax. The patient discharged after an overnight stay. Biopsies revealed diffuse TTR-stained amyloid deposits within alveolar walls and around capillaries (Figure 2). There was no lymphocytic infiltration. CD1a immunohistochemical staining and anti-HMB45 staining were negative, excluding Langerhans histiocytosis and lymphangioleiomyomatosis, respectively. Bronchoalveolar lavage (BAL) analysis did not reveal pneumocystis cysts.

Figure 2.

Histological pattern revealing amyloid deposit on cystic pulmonary lesions targeted cryobiopsy.

Dyspnoea improved after depletion, Tafamidis was then introduced. Upon follow-up, patient has no complain except erectile dysfunction, with regular visits to cardiologist, neurologist and pneumologist.

Discussion

Pulmonary amyloidosis can occur as a localized process (primary pulmonary amyloidosis) or as part of a systemic involvement. ¹³

In clinical practice, lung involvement is common in AL amyloidosis but extremely rare in ATTR amyloidosis and AA amyloidosis. In contrast, autopsy studies revealed alveolar–septal wall amyloid deposition in 58–100% of patients with ATTR amyloidosis.^10–12

Lung involvement in systemic amyloidosis may present as a tracheobronchial infiltration, nodules, mass or as a diffuse alveolar-septal deposition (reticular opacities, interlobular septal thickening, micronodules and, less frequently, ground-glass opacification, traction bronchiectasis, honeycombing and cysts).^13,14 DCLD refers to the presence of multiple air-filled spaces with a wall thickness less than 2 mm and clear boundaries with the lung tissues. DCLD has many possible etiologies: ¹⁵ lymphangioleiomyomatosis, Birt–Hogg–Dubé syndrome, Sjogren’s syndrome, pulmonary Langerhans cell histiocytosis, lung tumours, Castleman disease, antineutrophil cytoplasmic antibody–associated vasculitis, systemic lupus erythematosus, Marfan syndrome, amyloidosis ¹⁶ , congenital cystic adenomatoid malformation of the lung and pleuro-parenchymal fibroelastosis.

Zamora et al. ¹¹ reviewed 21 cases of diffuse cystic lesions histologically proven to be associated with primary AL or secondary systemic amyloidosis. Among them, two cases (84 and 91 years old) were found to be due to ATTRwt. Similarly, Eggleston et al. ¹² reported four cases of ATTRwt cystic lesions; these were single and small in all cases. In our case, radiological lesions were large and diffuse and were due to ATTRm, which to our knowledge, has never been described previously. Although homozygosity is rarely reported in ATTRm, it seems to be associated with earlier onset of the disease and greater severity. ⁹

When noninvasive testing does not allow to establish a diagnosis of interstitial lung diseases (ILDs), lung biopsy is necessary. Transbronchial lung biopsies (TBLB) and video-assisted thoracoscopic (VATS) surgical lung biopsies (SLBs) are the most common methods used in this situation. TBLB is easy to perform and accessible, but the small size and the forceps-induced crush of the samples may impair histological analysis. On the other hand, the diagnostic rate of SLB, especially through VATS, is estimated as high as 95% but is associated with perioperative complications. ¹⁷ Notably, in a review of 32,022 VATS SLB for ILD diagnostic from 2000 to 2011, Hutchinson et al. ¹⁸ report an overall in-hospital mortality of 1.7% for scheduled procedures, but up to 16% in the context of emergency.

As an alternative, transbronchic lung cryobiopsy (TBLC) performed with a frozen-tipped probe has been more recently developed to obtain large biopsy samples during a flexible bronchoscopy. Interest for this procedure is growing in the ILD field, but data about safety and utility are variable.^18–25 Bronchial bleeding is the major complication reported, in up to 22% of patients, but rarely severe. Pneumothorax complications are reported in approximately 10% of cases (70% of which requiring chest tube drainage) in a recent review of 15 investigation studies including 781 patients. ²² Three prospective randomized studies have tried to compare diagnosis efficiency of VATS and TBLC, with variable results.^19,23,24 Nonetheless, the most recent studies published in 2020 ²³ and 2021 ¹⁹ were consistent with a raw agreement between VATS and TBLC of almost 70% with a Kappa coefficient of 0.6, thus underlying its clinical utility. TBLC value in diagnosis of DCLD is less documented. A recent case series of 17 TBLC diagnosed lymphangioleiomyomatosis found a similar diagnostic yield of 70%, with no serious adverse effect reported. This case adds safety data on TBLC clinical value in this particular ILD pattern. ²⁵

Upon Zamora’s 21 reported cases of pulmonary amyloid cystic lesions, ¹¹ 70% of histological diagnosis were performed through surgical biopsy and the remaining 30% through transbronchial biopsy. To our knowledge, only three patients with cryobiopsy proven amyloidosis lung disease have been reported before. ²⁶ Nevertheless, none of these cases were ATTR related, nor presenting with a diffuse cystic pulmonary disease pattern.

In conclusion, our case supports that ATTR amyloidosis can be suspected with a diffuse cystic pulmonary radiological pattern. Nonetheless, ATTRm homozygosity probably explains the early onset of this patient. This clinical case also enhances the possibility of less invasive transbronchial lung cryobiopsy for histological diagnosis of DCLDs, including amyloid-related.