Abstract:

Systemic amyloidoses are multisystem disorders caused by abnormal proliferation and deposition

Keywords

Systemic amyloidosis, carpal tunnel syndrome, amyloid protein

Amyloidoses are a heterogenous group of disorders caused by extracellular deposition of insoluble fibrillar proteins arranged in a β-pleated sheet conformation throughout the body.¹ Term “amyloid” was given by Rudolph Virchow in 1854 to describe tissue deposits that stained like cellulose when exposed to iodine. Amyloid deposits, after staining with Congo red stain, appear red under normal light microscopy and have apple-green birefringence under polarized light.²

Traditionally, amyloidosis was classified as localized and systemic, familial and nonfamilial form. However, nowadays amyloidosis can be classified chemically depending on chemical nature of amyloid protein. Capital letter A is designated for amyloid followed by an abbreviation for the type of fibril protein. In previously so called primary amyloidosis and myeloma-associated amyloidosis, the fibril protein is an immunoglobulin light chain or light chain fragment (abbreviated L), therefore this type of amyloidosis is now know as  light chain amyloidosis (AL). Common clinical forms of systemic amyloidosis are AL, AA, ATTR and Aβ2M types.³

Case Report

A 59-year-old male presented with history of tingling sensation, paresthesia of thumb, index and middle fingers of both hands for last 3 years, predominantly during night time, difficulty in gripping objects and difficulty in doing fine motor activities for last 2 years. There was no history of numbness over the hands as patient could perceive hot and cold sensation.

He also had complaints of rash over face, neck and upper chest for last 1½ years, initially erythematous then papulonodular followed by hyperpigmentation over face and patches of waxy discoloration (hypopigmentation) below eyes for last 5-6 months, interspersed with punctate bleeding points. He took homeopathic treatment for 1 year but had no relief. Dermatologist diagnosed it as a case of seborrheic dermatitis with pyoderma and started oral steroids for 6-7 months without improvement. He also had significant weight loss of around 10 kg in the last 1 year without decreased appetite, low backache for 3-4 months and swelling of tongue and ulcerations over tongue for last 15-20 days. There was no history of diabetes and hypothyroidism.

General physical examination revealed coarse facies, pallor, waxy papules over face and chest, purpuric lesions to almost confluent ecchymotic patches, macroglossia (Fig. 1). On per abdominal examination, there was no organomegaly. Central nervous system (CNS) examination revealed weakness of small muscles of hand in median nerve distribution. Tinel’s and Phalen’s sign were positive, ankle jerk was decreased on right side and absent on left side. Straight leg raise (SLR) was positive bilaterally (left-50°, right-60°). Autonomic function tests were normal. Peripheral nerves were not palpable.

A functional diagnosis of bilateral (B/L) carpal tunnel syndrome with B/L L5-S1 radiculopathy with papulonodular and purpuric rashes with macroglossia and significant weight loss was made. Possibility of a multisystem disease involving peripheral nerves, nerve roots, skin and soft tissue, small vessels and tongue was kept. Differentials considered were connective tissue disorders, systemic amyloidosis, sarcoidosis and paraneoplastic disorders.

Routine investigations revealed: Fasting blood sugar (FBS) - 86 mg/dL, blood urea - 58 mg/dL, serum creatinine - 1.6 mg/dL, serum uric acid - 3.6 mg/dL, serum calcium - 9.7 mg/dL, phosphate - 2.7 mg/dL, sodium - 142 mEq/L, potassium - 4.0 mEq/L, total bilirubin - 0.8 mg/dL, serum glutamic oxaloacetic transaminase (SGOT) - 24 IU/L, serum glutamic pyruvic transaminase (SGPT) - 51 IU/L, alkaline phosphatase - 106 IU/L, lactate dehydrogenase (LDH) - 433 U/L, creatine phosphokinase (CPK) - 99 U/L, thyroid-stimulating hormone (TSH) - 3.31 mIU/L, serum vitamin B₁₂ - 483 pg/mL, hemoglobin - 7.7 g/dL, total leukocyte count (TLC) - 5,460/mm³, erythrocyte sedimentation rate (ESR) - 80 mm/hr, rheumatoid factor - negative, C-reactive protein (CRP) - positive. Peripheral blood smear - normocytic normochromic, no abnormal cells, urine-protein-trace, RBC - 10-12/hpf. Total protein - 6.8 mg/dL, albumin - 3.5 mg/dL, A:G ratio = 1:1, human immunodeficiency virus (HIV) - nonreactive, serum cortisol - 9.63 µg/dL (5-25). ECG and chest radiographs were normal. Nerve conduction study showed sensorimotor axonal and demyelinating neuropathy affecting both median nerves suggestive of B/L carpal tunnel syndrome. Sympathetic skin response was negative. Ultrasonography of abdomen and pelvis showed B/L early medical renal disease. Magnetic resonance imaging (MRI) LS spine showed disc bulge at L4-5 and L5-S1 levels with ligamentum flavum hypertrophy causing B/L lateral recess stenosis and compression of exiting nerve roots. Dermatology consultation confirmed waxy papules and pinch purpura over face and chest, but skin biopsy was negative for amyloid stain. Rectal biopsy showed evidence of chronic inflammation but negative for amyloid stain on Congo red. CT thorax and abdomen was negative for any hilar lymph nodes but hepatomegaly was present. Skull radiograph did not show any lytic lesion and urine for Bence-Jones protein was negative. Serum protein electrophoresis was positive for M-band (g-globulin fraction - 32.8%) with A/G ratio reversal (0.73).

At this point, hemato-oncologist opinion was taken and bone marrow aspiration and biopsy was done. Bone marrow smear showed normoblastic erythroid hyperplasia with increased no. of plasma cells (12%). Bone marrow biopsy was hypercellular with M:E ratio of 4:1 with 35% plasma cells suggestive of plasma cell myeloma. Tongue biopsy revealed submucosal deposits of pink acellular hyaline material with apple-green birefringence on polarizing microscopy suggestive of amyloidosis (Fig. 2). 2D Echo study was negative for any cardiac deposits.

So, a final diagnosis of AL amyloidosis secondary to plasma cell myeloma was considered with multiple organ system involvement in the form of neuropathy, radiculopathy, skin, subcutaneous tissue and small blood vessels involvement, macroglossia, hepatomegaly, nephropathy and bone marrow plasmacytosis.

Patient was started on a chemotherapy regimen which included induction with bortezomib, lenalidomide and dexamethasone once a week for 24 weeks followed by maintenance with lenalidomide and plan for bone marrow transplantation after complete remission. After 6 months of chemotherapy, skin lesions showed healing with serum electrophoresis showing g-globulin fraction of 15.4% with A/G ratio of 1.47 and bone marrow plasma cells reduced from 35% to 8% suggestive of partial to near complete remission of myeloma.

Discussion

AL amyloidosis is usually associated with plasma cell dyscrasias. Insidious onset, diverse clinical manifestations and initial presentation with vague symptoms make diagnosis more difficult. Multiple organ systems are involved, kidney and heart being most commonly affected. Liver involvement is seen in 15-25% of patient and cardiac involvement in up to 50%.⁴

Approximately 90% patients present with profound fatigue, weight loss and edema. Edema may have multiple causes including hypoalbuminemia (from kidney, bowel or liver involvement) and right-heart failure.⁵

Our patient presented with tingling sensation, paresthesia of thumb, index and middle finger with weakness of both hand in the median nerve distribution suggestive of carpal tunnel syndrome. While systemic amyloidosis presenting as a carpal tunnel syndrome is very rare, this syndrome results from progressive infiltration of flexor retinaculum and synovial tissue with amyloid fibrils causing compression of the medium nerve.

Peripheral nerve involvement in amyloidosis occurs very late in the disease course. The typical pattern of amyloid neuropathy is diffuse, symmetrical, length-dependent, lower-limb predominant, primarily axonal with prominent involvement of small (pain and autonomic features) fibers.⁶ Nerve conduction studies show changes of axonal neuropathy with low amplitude or absent sensory nerve action potentials (SNAPs) and low amplitude compound muscle action potentials (CMAPs)  but preserved motor conduction velocities. Distal median motor latencies are prolonged in patients with carpal tunnel syndrome. 

Skin involvement in the form of petechiae, purpura and ecchymoses occur due to infiltration of blood vessel walls by amyloid deposits.⁷ Similar cutaneous lesions were also seen in our patient in the form of erythematous papulonodular rash and ecchymotic patches over face, neck and upper chest. Vascular infiltrates result in easy bruising typically seen around the eyes producing “raccoon-eyed” appearance.

References

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