INTRODUCTION:

Amyloidosis refers to a group of diseases characterized by abnormal deposits of amyloid proteins in various tissues and organs. It can be primary (AL-light chain) or secondary(AA).

In secondary amyloidosis, also known as AA amyloidosis, these amyloid deposits are formed from a protein called serum amyloid A (SAA), which is produced in response to inflammation. Chronic inflammatory or infectious diseases lead to a sustained increase in SAA levels, increasing the likelihood of amyloid buildup and subsequent organ damage.

CASE REPORT:

A 63 year old male, k/c/o Type II Diabetes mellitus for 10 years with recent history of right great toe amputation and has non healing ulcer presented to nephrology OPD with history of bilateral lower limb swelling for 1 month. on evaluation urine routine revealed  Albumin 3+,RBCs nil , serum urea-19mg/dl ,serum creatinine -0.9mg/dl ,serum albumin-1.3 mg/dl.clinical diagnosis of adult onset nephrotic syndrome was made and renal biopsy was done. Light microscopy revealed in  nodular amorphous material that is weakly PAS positive, silver stain negative and blue on trichrome stain is deposited in mesangium of all glomeruli. This material is Congo red positive ,giving apple green birefringence under polarised light consistent with amyloid. In Immunofluorescence all stains were negative. Immunohistochemical stain for amyloid A is positive on the amyloid deposits, suggestive of secondary amyloidosis, AA type.

Image Courtesy – www.researchgate.net

(A) Hematoxylin and eosin stain at low power showing deposition of an eosinophilic amorphous substance in the mesangium and blood vessels). (B) Jones’ silver methenamine stain showing the amyloid to be negative for silver stain. (C) Congo red stain under polarized light showing the amyloid to be birefringent. (D) Immunofluorescence stain with AA amyloid stain showing the amyloid to be strongly positive).

Discussion:

Secondary amyloidosis often develops as a complication of chronic inflammatory diseases or infections. Common conditions associated with this type of amyloidosis include:

Rheumatoid Arthritis, Ankylosing Spondylitis:, Inflammatory Bowel Disease (IBD): Chronic Infections, Familial Mediterranean Fever (FMF)

Pathophysiology of Secondary Amyloidosis in Chronic Leg Ulcers

1. Chronic Inflammation: Chronic leg ulcers perpetuate a cycle of inflammation and infection, which can lead to sustained elevation of acute-phase reactants, particularly SAA. SAA, synthesized primarily in the liver, is a precursor protein that can misfold and deposit as amyloid fibrils in tissues under chronic inflammatory conditions.
2. Cytokine Cascade and SAA Production: Prolonged ulceration and inflammation lead to continuous activation of immune cells (e.g., macrophages) and release of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. These cytokines drive hepatic production of SAA, contributing to a chronic increase in SAA levels, which predisposes individuals to amyloid deposition.
3. Amyloid Fibril Formation and Organ Involvement: The high turnover of SAA in chronic inflammation leads to accumulation and misfolding of amyloid fibrils, primarily affecting the kidneys, gastrointestinal tract, liver, and spleen. In AA amyloidosis, renal involvement is common and can manifest as proteinuria, leading to nephrotic syndrome and, ultimately, renal failure if untreated.

The symptoms of secondary amyloidosis vary depending on the organs affected by amyloid deposits. The most commonly affected organs are the kidneys, leading to symptoms associated with kidney dysfunction. Typical symptoms may include:

Kidney-related Symptoms: Proteinuria (protein in urine), swelling (edema) in the legs, and eventually kidney failure are common kidney-related symptoms.

Digestive Symptoms: Nausea, diarrhea, malabsorption, and weight loss may occur if the gastrointestinal tract is affected.

Liver and Spleen Enlargement: Enlargement of the liver (hepatomegaly) and spleen (splenomegaly) can lead to discomfort in the abdomen.

Fatigue and Weakness: Generalized fatigue and weakness are common symptoms, often due to anemia or organ dysfunction.

Heart Involvement: Although rare in secondary amyloidosis, heart-related symptoms like shortness of breath or arrhythmias may develop if the heart is affected.

Since secondary amyloidosis often progresses silently, symptoms may be subtle until organ function is significantly impaired, particularly in the kidneys.

Management

1.Treating the Underlying Ulcer:

A)Infection control: Regular debridement, antimicrobial therapy, and dressing changes.

B)Inflammation management: Systemic anti-inflammatory agents may help lower SAA levels.

C)Wound care and vascular health: Optimizing wound care and managing venous or arterial insufficiency can reduce chronic inflammation.

2.Targeting Inflammation and SAA Reduction:

Anti-inflammatory drugs: Medications like colchicine, corticosteroids, or anti-IL-6 biologics (e.g., tocilizumab) can help reduce SAA production.

Immunosuppressive therapy: For patients with significant organ involvement, immunosuppressive agents might be considered.

3.Monitoring and Supportive Care:

Regular monitoring of renal function, protein levels, and systemic markers of inflammation.

Symptomatic management of organ-specific complications, such as diuretics for nephrotic syndrome or nutritional support for gastrointestinal symptoms.

CONCLUSION:

Our case showed that AA amyloidosis may be secondary to a leg ulcer. Physicians need to be aware of such complication and must first of all prevent it. The prognosis of AA amyloidosis largely depends on controlling the underlying inflammatory source. Early and effective management of chronic leg ulcers and minimizing inflammatory episodes are critical to reducing the risk of developing AA amyloidosis. Once AA amyloidosis is established, it becomes challenging to reverse organ damage, highlighting the importance of early intervention.

References:

1.AA amyloidosis: a little-known complication of chronic leg ulcer]J Waton 1, S Fays-Michel, M L Chandeclerc, S Corby, J F Cuny, A Barbaud, J-L Schmutz.

2.KI reports AA AMYLOIDOSIS: A RARE COMPLICATION OF CHRONIC LEG ULCER B.Rajaet.al∙

Dr.S.Vishnu Shankar 
DrNB (Nephrology) Final Year Resident
Kauvery Hospital, Chennai.

Dr. R. Balasubramaniyam
Chief Nephrologist
Kauvery Hospital, Chennai