Light-chain amyloidosis with dysphagia as the main symptom: a case report

Abstract

Background

Immunoglobulin light-chain amyloidosis is a relatively rare condition with a worldwide incidence of 5.1–12.8 cases per million person-years (Baker, 2022). It is characterized by a clonal population of immunoglobulin-secreting cells that produce a monoclonal light chain of κ or λ type as either an intact molecule or a fragment.

Case presentation

A 69-year-old East Asian (Chinese) male patient who presented with progressive dysphagia visited multiple hospitals repeatedly for more than 2 years and was finally diagnosed with immunoglobulin light-chain amyloidosis.

Conclusions

Otolaryngologists should consider immunoglobulin light-chain amyloidosis when encountering suspicious clinical manifestations and intervene early to avoid misdiagnosis.

Background

Systemic immunoglobulin light-chain (AL) amyloidosis is a protein-misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states to highly organized amyloid fibrillar aggregates that cause organ dysfunction [2]. It is estimated to have a minimum incidence of 8–12 per million and is the cause of death in 0.58 of 1000 recorded deaths [3]. Currently, there are no precise data on its incidence in China; however, on the basis of renal biopsy data, it accounts for approximately 4% of all cases of secondary kidney disease [4]. AL amyloidosis is predominantly seen in the elderly population, and the median age of patients with this condition is 60 years. Its prevalence was slightly higher in males than in females. The prognosis of AL amyloidosis shows significant heterogeneity, with a median survival of less than 1 year in patients with severe cardiac involvement [4, 5]. The clinical manifestations of AL amyloidosis are diverse, and involve multiple organs. The kidneys and heart are the most commonly affected organs; however, there are other organs, such as the liver, autonomic or peripheral nerves, gastrointestinal tract, skin, and soft tissues, that may be affected. Although most clinical features of AL amyloidosis are nonspecific, macroglossia (enlarged tongue) and periorbital purpura are relatively specific clinical manifestations of AL amyloidosis. Herein, we report this case and expect that it will add to the existing literature on this subject.

Case presentation

A 69-year-old East Asian (Chinese) man with a 2-year history of dysphagia was admitted to the hospital. The patient experienced persistent sensation of dysphagia and pharyngeus accompanied by hoarseness and water aspiration. Over the preceding 2 years, he had experienced persistent and progressive dysphagia, loss of taste, slurred speech, and impaired tongue movement and had sought medical attention at multiple hospitals with inadequate improvement. Additionally, 2 months ago, the patient developed mild dyspnea at rest. Physical examination revealed diffuse swelling and thickening of the posterior pharyngeal wall, left side of the uvula, both arytenoids, and vocal cord mucosa. However, vocal cord movements were unaffected. The skin on his neck was stiff and lacked elasticity. Our laboratory results reported no anemia, no white blood cell elevation, or no thrombocyte abnormalities. The peripheral smear was normal and contained no atypical cells. No renal, hepatic, or electrolyte abnormalities were observed. The rheumatoid panel, autoimmune antibody levels, and liver fibrosis panel were all normal. Routine blood tests revealed elevated eosinophil counts (0.103, reference range: 0.005–0.05). Immunological items included a low Complement 3 titers (0.61 g/l, reference range: 0.79–1.52 g/l), normal Complement 4 titers (0.22 g/l), low immunoglobulin G titers (7.18 g/l, reference range: 7.51–15.6 g/l), and low IgM titers (0.32 g/l, reference range: 0.46–3.04 g/l). Pathological biopsy of the posterior pharyngeal wall and uvula revealed mild squamous epithelium with localized fibrous tissue proliferation, accompanied by collagenization and reactive lymphoid follicle hyperplasia.

After multidisciplinary joint consultation, we considered it to be an immune-related disorder and administered 12 mg of oral prednisolone. The patient’s symptoms did not improve significantly after 2 weeks of treatment. Meanwhile, we observed that his tongue was thickened with widespread nodules on its surface and slightly firm in texture but movable (Fig. 1a). On the skin beneath the lower lip and jaw, numerous pale red papules and nodules ranging in size from millet-seed-sized to soybean-sized, with no itching (Fig. 1b). Therefore, we collected the skin tissue and samples for biopsy. The skin tissue and tongue biopsies revealed stratified squamous epithelium with localized epithelial hyperplasia. In the subepithelial layer, there were focal deposits of homogeneous, eosinophilic material with intervening clefts, consistent with amyloidosis-related morphological changes. Subsequent immunoglobulin light-chain tests and bone marrow biopsies confirmed the diagnosis of systemic light-chain amyloidosis (kappa-type).

Fig. 1

The condition of the patient’s tongue and skin (a Multiple nodules on the surface of the tongue; b numerous pale red papules and nodules ranging from the size of a millet seed to that of a soybean on the skin). The patient’s laryngoscopy (c before treatment; d after treatment. Localized mucosal swelling reduced)

After receiving standard treatment with bortezomib(2 mg, once weekly) and dexamethasone(40 mg, once weekly for three sessions, the patient experienced a reduction in localized mucosal swelling (Fig. 1c, d); however, his symptoms did not improve significantly.

Discussion and conclusions

Amyloidosis is difficult to diagnose because no single imaging, blood, or urine test can be used to diagnose it. The presenting symptoms often mimic those of common disorders. Patients presenting with dysphagia as an initial symptom are less common. The median interval from symptom onset to AL amyloidosis diagnosis was 2.7 years, with 50% of patients visiting at least five physicians [6]. The patient in our case also had similar features.

Most patients have major organ amyloid depositions during the course of the disease, with the most common organ involvements being the heart (75%) and kidney (65%). The liver, spleen, soft tissue, peripheral and autonomic nerves, and gastrointestinal tract may also be involved but at lower rates [7]. Presenting with initial symptoms related to otorhinolaryngology, or with these organs as the primary sites of rare reported conditions, is unusual. The diversity of AL symptoms should warrant our attention.

In “Immunoglobulin light chain amyloidosis: 2024 update on diagnosis, prognosis, and treatment” [2], common conditions requiring the consideration of amyloidosis are listed. An algorithm for the evaluation of a patient with suspected amyloidosis is presented in an article authored by the Mayo Clinic (Fig. 2). The diagnostic criteria are provided in “Chinese Guidelines for the Diagnosis and Treatment of Systemic Light Chain Amyloidosis (Revised in 2021)” [8]. They are as follows: (1) Clinical manifestations, physical examination, laboratory, or imaging examinations confirm organ involvement. (2) Tissue biopsy pathology confirms amyloid protein deposition, and the precursor protein of the amyloid protein is the immunoglobulin light chain or heavy-light chain. Specific pathological features include positive staining with Congo red, exhibiting apple-green birefringence under polarized light and immunohistochemistry, immunofluorescence, or immunoelectron microscopy indicating light-chain restriction expression, or mass spectrometry confirming the precursor protein as an immunoglobulin light-chain. Fine fibrous structures are visible under electron microscopy and non-branching, rigid, disorganized arrangement, with a diameter of 8–14 nm. (3) Evidence is found of monoclonal immunoglobulin or free light chains upon blood or urine or bone marrow examination revealing monoclonal plasma cells/B cells. In this paper, the epidemiology, staging, prognosis, and treatment of AL have been elaborated extensively; therefore, this article will not reiterate them.

Fig. 2

Clinical manifestations and diagnosis of AL [2]

Although both the Mayo Clinic and the Chinese Medical Association have developed guidelines for the diagnosis and treatment of systemic light-chain amyloidosis, its low incidence rate and diverse and atypical clinical manifestations make it prone to misdiagnosis. Also, most initial consultations occur in Cardiology or Nephrology, with very few patients presenting to otolaryngology. This article aims to alert otolaryngologists to consider this disease when encountering suspicious clinical manifestations and to intervene early to avoid misdiagnosis. When a patient presents with unexplained respiratory distress and dysphagia accompanied by tongue enlargement and localized edema, this disease should be considered one of the differential diagnoses.

Since a small clone of plasma cells is responsible for producing the abnormal monoclonal light chains that accumulate and deposit in organs [9], targeting and eliminating these plasma cells with antibodies that selectively bind to them would halt the production of these light chains and stop the progression of the disease. In recent years, several medications proven effective for treating multiple myeloma have been added to the treatment arsenal for AL amyloidosis, such as bortezomib and lenalidomide [10, 11]^. Medications designed to target and stimulate the immune response to eliminate abnormal amyloid deposits are currently under evaluation and show promising potential in the treatment of AL amyloidosis.

Even if treatment is effective, the disease is progressive; therefore, early diagnosis and treatment are vital to prevent irreversible organ damage.