Dysphagia unveiling systemic immunoglobulin light-chain amyloidosis with multiple myeloma

Abstract

Dysphagia is an uncommon presentation of systemic immunoglobulin light-chain (AL) amyloidosis with multiple myeloma (MM). Gastrointestinal (GI) involvement usually manifests with altered motility, malabsorption or bleeding. Furthermore, patients identified with GI amyloidosis, without previous diagnosis of a plasma cell disorder, are extremely rare. We report an elderly woman who presented with acute on chronic cardiac dysfunction, sick sinus syndrome and acute renal failure. While admitted, she developed intermittent dysphagia to both solids and liquids. Oesophagogastroduodenoscopy showed ulcerations of oesophagus and duodenum. Biopsies revealed focal amyloid deposition, stained with Congo red. Renal biopsy revealed amyloid deposition in renal arterioles. She underwent a bone marrow biopsy confirming MM, represented by more than 15% plasma cell population. She was started on treatment for heart failure, induction chemotherapy for MM and percutaneous gastrostomy tube for feeding. However, she continued to deteriorate, eventually opting for hospice, and ultimately died 2 days after discharge from hospital.

Background

Amyloidosis is a disorder characterised by the extracellular deposition of insoluble fibrils of various protein subunits (amyloid) in numerous tissues leading to organ dysfunction. The amyloid protein gives an apple-green birefringence following staining with Congo red dye when viewed under polarised light microscope.^1–3 This condition could be hereditary, but most of the cases are acquired. The acquired variant is usually manifested later in life, between 45 and 64 years of age.⁴ The common amyloid protein precursors include immunoglobulin light-chain (AL amyloidosis), serum amyloid A (AA amyloidosis), beta-2 microglobulin (dialysis related) and apolipoprotein E (Alzheimer’s related).⁴ Based on the extent of amyloid deposition, amyloidosis can be classified as local or systemic types.³ We report a case of systemic AL amyloidosis associated multiple myeloma (MM) with gastrointestinal (GI), cardiac and renal involvement. This case is unique as the patient did not present with typical signs and symptoms of MM. She was admitted due to heart failure (HF) and sick sinus syndrome (SSS). During her hospital course, she developed dysphagia to both solids and liquids. She underwent Oesophagogastroduodenoscopy (OGD) that demonstrated oesophageal and duodenal ulcers, with biopsies exhibiting amyloidosis. Further workup revealed systemic AL amyloidosis with MM.

Case presentation

We present an elderly woman with prior history of chronic HF with preserved ejection fraction (HFpEF), chronic kidney disease stage III, chronic obstructive pulmonary disease and rheumatoid arthritis who had been evaluated by her primary care physician for progressive fatigue, lightheadedness, bilateral leg swelling and increased abdominal girth for 5-week duration. ECG done at the office revealed bifascicular heart block with bradyarrhythmia. She was transferred to the hospital for further evaluation.

On arrival, she has shortness of breath, dizziness and generalised weakness. Telemetry confirmed severe bradycardia with frequent pauses, longest sustained 6–10 s with frequent drop of heart rate to 20 s. ECG demonstrated bifascicular heart block. Therefore, she immediately underwent emergent dual chamber pacemaker placement due to symptomatic SSS.

Additional laboratory studies reported elevated brain natriuretic peptide (BNP) 847 pg/mL (normal range 2–100) and creatinine 3.59 mg/dL (baseline 1.7). Chest radiograph (CXR) showed pulmonary venous congestion with bilateral pleural effusions. Transthoracic echocardiogram (TTE) revealed mild biatrial enlargements, thickened mitral and aortic valves, normal left ventricular cavity size with increased left ventricular wall thickness and left ventricular ejection fraction (EF) estimated at 70%–75% and grade II diastolic dysfunction. Based on the clinical presentation and diagnostic workup, she was also diagnosed with acute on chronic HFpEF and acute kidney injury (AKI). The patient was severely hypotensive and fluid overloaded and was started on intravenous diuretics and dopamine.

Further evaluation of AKI showed antinuclear antibody positive at 1:40, urine total protein to creatinine ratio of 0.6, elevated kappa free light-chains (FLC) serum 146 (0.33–1.94 mg/dL), elevated kappa/lambda FLC ratio serum 74.112 (0.260–1.650) and M spike 1.29 g/dL. Serum immunoelectrophoresis revealed IgG kappa paraproteinaemia. She had no prior history of skeletal lesions, anaemia or hypercalcaemia. Therefore, the patient was thought to be a case of monoclonal gammopathy of undetermined significance (MGUS) on the preliminary assessment.

On the tenth of admission, the patient reported intermittent difficulty swallowing both solids and liquids. OGD was performed on the 11th day of admission which showed multiple oesophageal and duodenal ulcers; biopsy specimens were obtained. No mechanical cause of dysphagia was identified. Pantoprazole 40 mg every day was initiated. Meanwhile, her cardiac and renal functions were improving with supportive treatment. She was discharged in stable condition to the extended care facility (ECF) on the 15th day of admission.

Three weeks later, she returned to the hospital due to worsening shortness of breath with minimal exertion despite diuretics. Vital signs included blood pressure 90/66 mm Hg, heart rate 91/min, temperature 36.4°C, respiratory rate 20/min and oxygen saturation 100% on 5 L oxygen by nasal cannula. On examination, she appeared frail, pale and fatigued. There was no periorbital rash, macroglossia, lymphadenopathy or thyromegaly. Cardiac examination was negative for murmur. Pulmonary examination was significant for diminished bilateral breath sounds. Abdominal examination was negative for ascites or hepatosplenomegaly. Extremities showed bilateral lower extremity oedema +2 extending to the thighs. The skin showed no purpura or rash.

Investigations

On readmission, laboratory studies showed white cell count 10.3 (4.5–11.0×10⁹/L), platelet count 178 (140–440×10⁹/L), haemoglobin 10.7 (12.0–15.7 g/dL), blood urea nitrogen 37 (7–22 mg/dL), creatinine 1.85 (0.5–1.50 mg/dL), glomeurlar fitration rate 32 (60–240 mL/min), glucose 108 (70–105 mg/dL), sodium 135 (134–145 mM/L), potassium 3.6 (3.5–5.1 mM/L), ionised calcium 1.20 (1.10–1.30 mmol/L), chloride 102 (98–112 mM/L), bicarbonate 23 (24–30 mM/L), BNP 838 (2–100 pg/mL), troponin-I 0.1 and 0.2 ng/mL (0.0–0.5 ng/mL). CXR again revealed pulmonary oedema with pleural effusions. ECG exhibited paced sinus rhythm, low voltage P wave, non-specific T-wave changes and bifascicular block. Repeat TTE had findings consistent with the previous echocardiogram, without significant change.

Differential diagnosis

She was diagnosed with acute pulmonary oedema secondary to acute on chronic HFpEF and started on intravenous furosemide. The exact cause of HF exacerbation could not be ascertained. However, the ischaemic cause of HF was clinically ruled out as the patient reported no chest pain and cardiac enzymes were negative. Furthermore, there was no myocardial hypokinesia seen on echocardiogram. On re-evaluation of the biopsy reports from her previous admission, there was concern for amyloidosis (figure 1A–B and D–E). Oesophageal portion of the biopsy showed oesophageal squamous mucosa with ulceration, acute on chronic inflammation and reactive/regenerative epithelial changes. There was no evidence of foci of fungal or viral elements on biopsy. However, the foci of local deposition of amyloid were seen stained with Congo red (figure 1A, D). The duodenal specimen was without significant histopathological changes in duodenal mucosa. However, the submucosa of duodenum was stained positive with Congo red dye (figure 1B, E). Biopsies were sent for a second opinion to confirm systemic amyloidosis involving GI tract; renal biopsy and bone marrow (BM) biopsy to rule out plasma cell dyscrasia were performed. Fat biopsy, though planned, could not be completed.

Figure 1.

Histological sections demonstrate deposition of a homogeneous, acellular eosinophilic material within the (A) oesophageal submucosa, (B) duodenal submucosa and (C) arteriolar renal wall. A Congo red stain highlights a characteristic orangeophilic waxy appearance within the (D) oesophageal submucosa, (E) duodenal submucosa and (F) arteriolar renal wall consistent with amyloidosis.

In our patient, the diagnosis of systemic AL amyloidosis with MM was confirmed by following features:

1. Normochromic normocytic anaemia with mild anisocytosis and rouleaux formation on peripheral blood picture.

2. IgG kappa paraproteinaemia on serum immunoelectrophoresis.

3. A restrictive cardiomyopathy on recent TTE showing an increased E/A ratio of approximately 3.0 and elevated pulmonary artery pressure of 44 mm Hg.

4. Biopsy of oesophageal and duodenal ulcers revealing amyloid deposits stained with Congo red.

5. AL amyloidosis of kappa light-chain composition on renal biopsy involving arteries confirming the diagnosis of systemic AL amyloidosis (figure 1C, F).

6. Hypercellular BM for patient’s age, containing almost 15% of plasma cells, immunostained for CD138. Congo red stain performed on BM aspirate smear showed no evidence of amyloid deposition. The corresponding flow cytometry showed a small population of monoclonal plasma cells with kappa light-chain restriction.

Bone survey in our patient showed no lytic or blastic lesions. Serum immunoglobulin quantification showed IgA and IgM within normal limits, and elevated IgG 1610 (700–1600 mg/dL) and elevated B2-microglobulin 11.4 (1.4–2.9 mg/dL).

Treatment

Given the patient had systemic AL amyloidosis with MM, she was started on induction chemotherapy Velcade®(bortezomib)-dexamethasone regimen containing subcutaneous bortezomib one time a week and intravenous dexamethasone one time a week. The supportive treatment for HF was continued. The patient’s dysphagia continued to worsen requiring a percutaneous gastrostomy tube placement for nutrition. Despite intervention, the patient continued to deteriorate. After multiple family meetings given the patient’s comorbid conditions and grave prognosis, the patient and her family decided not to pursue any aggressive treatments, including chemotherapy. She opted for hospice care and was discharged to an ECF with comfort measures on 21st day of hospitalisation.

Outcome and follow-up

She was declared deceased 2 days after her discharge from the hospital

Discussion

AL amyloidosis is characterised by the clonal expansion of BM plasma cells that produce a monoclonal light chain of kappa or lambda variety as either intact molecules or their fragments.² The epidemiology of amyloidosis is difficult to describe because of its rareness and delay in diagnosing due to wide spectrum of aetiologies and manifestations. One study reported the overall prevalence of AL amyloidosis between 6 and 10 cases per million person years, with approximately 2200 cases in the USA.⁵ Of all AL amyloidosis cases, up to 15 per cent of patients have MM, although the majority are asymptomatic.¹ The most common organs involved in AL amyloidosis include heart and kidney, followed by nervous system, soft tissues, lung and liver.⁶ GI involvement, on the other hand, is uncommon with a reported incidence of 3%.⁷

Among patients with GI involvement, the majority of the cases occur due to systemic amyloidosis compared with localised amyloidosis (79% vs 21%).⁷ According to the literature, the more frequent amyloid type found in the GI tract is AL lambda amyloidosis whereas the least frequent type is AA amyloidosis (53% vs 10%).⁸ Any part of the GI tract could be affected in AL amyloidosis but small bowel (50%) has been reported as the most frequent site, followed by stomach in 44% cases, colorectal in 32% cases and oesophagus in 14% cases. Common symptoms of GI amyloidosis include nausea, vomiting, diarrhoea, anorexia and weight loss.^{6 7}

Common symptoms of oesophageal involvement are dysphagia, chest pain, heartburn and haematemesis. Radiological features reported in these cases include a dilated, atonic oesophagus with decreased peristalsis. Rare endoscopic findings comprise ulcerations or masses suggestive of infections or malignancy.¹ Although there is no consensus regarding endoscopic findings associated with the specific type of amyloidosis, it has been proposed that AL amyloidosis is associated more with polypoid protrusions and thickened intestinal folds, whereas AA amyloidosis is associated more with mucosal fragility and ulcerations.⁹ This proposition antagonises with the endoscopic findings of our patient with diffuse oesophageal and duodenal ulcerations caused by AL amyloidosis.

Among other parts of GI, the degree of AL amyloid deposition is greatest in small intestine, and the most common site involved is duodenum.^{1 3} Clinical manifestations in intestinal cases are diarrhoea, steatorrhoea, protein loss, haemorrhage, obstruction, infarction, mesenteric ischaemia, perforation, intussusception, pneumatosis intestinalis, constipation and pseudo-obstruction. Duodenal ulcers associated with AL amyloidosis, as in our case, are exceptionally rare. Malabsorption is found in up to 8.5% of patients with AL amyloidosis.¹ Endoscopic presentation of intestinal amyloidosis includes a fine granular appearance and polypoid protrusions in duodenum or duodenitis.³

Diagnosis of AL amyloidosis is challenging to make as clinical manifestations are non-specific, no single imaging, blood or urine test is diagnostic.¹ All these factors contribute to delay in diagnosis; 40% of patients undiagnosed even after a year of onset of symptoms.¹⁰ Patients with MGUS (21%) and smouldering multiple myeloma (78%) are at risk to develop MM and amyloidosis.⁷ One principal factor in the delay of amyloidosis diagnosis in patients with MGUS is the absence of sensitive markers to detect early onset of organ involvement like renal or cardiac.¹⁰ Patients, such as ours, diagnosed with GI amyloidosis without previously diagnosed with inflammatory or plasma cell disorders are exceptionally rare.¹¹

Diagnosis of AL amyloidosis should be suspected in the presence of unexplained fatigue, oedema or weight loss in patients with monoclonal gammopathy.² If suspected, immunofixation of serum and urine FLC assay should be obtained.¹² The high frequency of kappa IgG FLC proteinaemia is a hallmark of AL amyloidosis.² After the former has been established, the tissue diagnosis of amyloidosis is needed. Preferred approach includes iliac crest BM biopsy combined with abdominal subcutaneous fat aspiration and has a diagnostic sensitivity of 90%.¹⁰

It should also be suspected in any patient with non-ischaemic cardiomyopathy since patient’s EF and cardiac silhouette are normal, and the ventricular thickening is often reported as ‘hypertrophy’ rather than infiltration on echocardiography.¹³ Cardiac, renal and liver biopsies are invasive and increase the risk of postprocedure haemorrhage.¹² If amyloid deposits are identified, it is imperative to determine the extent of amyloidosis (localised or systemic) and the specific type of amyloid deposits, since it helps to avoid misdiagnosis and future treatment approach.^{2 12} This includes screening for BM malignancy, cardiomyopathy and nephropathy.⁴ Ninety-one per cent of patients with GI amyloidosis also have concomitant renal amyloid deposits, as found in our case.¹⁴ For identifying the type of amyloid deposits, mass spectrometry is superior to immunohistochemistry, and is considered to be the standard to confirm protein composition of amyloid deposits.² Confirmation of organ involvement by AL amyloidosis is an indication for treatment of any underlying monoclonal gammopathy.⁴

Localised GI amyloidosis can be cured by surgical resection, whereas cornerstone of systemic disease treatment includes chemotherapy and autologous stem-cell transplantation (SCT).⁴ Recent developments have expanded the available therapeutic options for AL amyloidosis including chemotherapy with bortezomib or thalidomide. Early detection is imperative as it provides more therapeutic options. Specific GI symptoms need to be addressed; for example, malabsorption and diarrhoea should involve nutritional and vitamin supplementation and occasionally octreotide administration, respectively.⁶ Additionally, infections from immunocompromised status should be investigated and treated. AL amyloidosis has been associated with a worse prognosis due to its association with underlying malignancy.^{6 10} Furthermore, It has been reported that prognosis is even poorer in patients with GI involvement than without it (median survival time of 7.95 months vs 15.84 months, respectively). This can be explained by more organ involvement and advanced stage of disease in the former group compared with the latter group.⁶ Patients treated with melphalan and prednisone have a worse prognosis with a median survival of less than 2 years. In those who undergo SCT, the 5-year survival rate is 60%¹⁵; unfortunately, the majority of patients do not qualify for this treatment. Most frequent causes of death in patients with GI involvement are cardiac and renal failure.¹⁴ Additional causes include chronic GI obstruction, severe cachexia or hepatic failure.¹¹

Amyloidosis commonly presents with nephrotic-range proteinuria, cardiomyopathy and/or peripheral neuropathy. However, the index case highlights that any GI symptom could be the initial manifestation of amyloidosis. Prognosis depends on the type of amyloid deposits and the degree of organ involvement. Unfortunately, our patient was diagnosed with systemic AL amyloidosis that is associated with worse prognosis and with GI involvement that has worse outcomes.

Learning points.

• The gastrointestinal (GI) involvement by amyloidosis should prompt investigation for concomitant involvement of other organs (cardiac, renal and bone marrow) and to identify the specific type of amyloid deposit.

• Dysphagia is an uncommon presentation of GI AL amyloidosis. Oesophagogastroduodenoscopy can reveal oesophageal ulcerations and concomitant involvement of other more common affected areas like duodenum.

• The involvement of the GI tract by systemic AL amyloidosis indicates an unfavourable prognosis.

• Patients with monoclonal gammopathy of undetermined significance and smouldering multiple myeloma are at risk to develop multiple myeloma and systemic AL amyloidosis.