Amyloid Deposition in Systemic AL Amyloidosis

Most Frequent Sites of Amyloid Deposition in Systemic AL Amyloidosis: Kidneys, Heart, Liver, Nerves, and GI Tract

Introduction

Systemic primary (AL) amyloidosis is an uncommon but lethal plasma cell dyscrasia due to the misfolding and deposition of immunoglobulin light chains as insoluble amyloid fibrils in various organs, impairing their structure and function. The distribution and degree of organ involvement play a significant role in determining the prognosis and treatment strategy.

Among the most frequently involved organs are the kidneys, heart, liver, peripheral nerves, and GI tract. Familiarity with the clinical presentations and diagnostic pitfalls associated with each location is essential for early diagnosis and enhanced outcomes.

This review article details an extensive survey of these frequent sites of amyloid deposition in systemic AL amyloidosis, emphasizing clinical relevance, diagnostic algorithms, prognostic features, and management options.

1. Kidneys and AL Amyloidosis

1.1 Pathophysiology of Renal Involvement

Amyloid is mostly deposited in the glomeruli, with vascular and interstitial deposits occurring as well.
Deposition impairs the normal architecture, causing proteinuria and, ultimately, nephrotic syndrome.

1.2 Clinical Features

Proteinuria (often in the nephrotic range: >3.5 g/day).
Hypoalbuminemia with resulting edema and ascites.
Progressive renal impairment to chronic kidney disease (CKD).
Hypertension is less frequent than in other renal disorders.

1.3 Workup Diagnosis

Urine protein electrophoresis (UPEP) with immunofixation.
Serum free light chain assay.
Renal biopsy – gold standard, demonstrating Congo red-positive deposits with apple-green birefringence under polarized light.

1.4 Prognostic Implication

Renal involvement in \~70% of AL amyloidosis cases.
Presence of nephrotic syndrome and declining GFR indicates adverse outcomes.
Dependence on dialysis aggravates survival unless patients are responsive to chemotherapy.

1.5 Management

Supportive care: diuretics, ACE inhibitors/ARBs for proteinuria.
Disease-directed therapy: bortezomib-containing regimens, stem cell transplantation.
Renal transplantation: in selected situations with hematologic remission.

2. Heart and AL Amyloidosis

2.1 Pathophysiology

Amyloid involves the myocardium, causing restrictive cardiomyopathy.
Conduction system involvement can result in arrhythmias.

2.2 Clinical Features

Dyspnea with exertion and exercise intolerance.
Orthostatic hypotension and syncope.
Congestive heart failure with preserved ejection fraction (HFpEF).
Arrhythmias – atrial fibrillation, AV block, ventricular tachycardia.

2.3 Diagnostic Workup

Echocardiography: concentric left ventricular hypertrophy, “sparkling” myocardium.
Cardiac MRI: late gadolinium enhancement.
NT-proBNP & troponin: cardiac biomarkers for prognosis.
Endomyocardial biopsy (rarely indicated if systemic amyloidosis already established).

2.4 Prognosis

Cardiac involvement is the strongest predictor of mortality.
Median survival without treatment could be <6 months in advanced cases.

2.5 Management

Supportive care: judicious use of diuretics, refrain from beta-blockers and calcium channel blockers.
Chemotherapy: bortezomib, daratumumab, cyclophosphamide.
Heart transplantation: very rare, only if hematologic remission is attained.

3. Liver and AL Amyloidosis

3.1 Pathophysiology

Amyloid deposition in sinusoids and space of Disse.
Leads to hepatomegaly and cholestasis.

3.2 Clinical Features

Hepatomegaly (firm, enlarged liver on physical exam).
Mild elevation of alkaline phosphatase and transaminases.
Unusual presentation: cholestatic liver failure with jaundice.

3.3 Diagnostic Workup

Liver function tests (LFTs) – mild derangement.
Imaging – hepatomegaly without mass.
Liver biopsy – Congo red-positive amyloid, rules out fibrosis or malignancy.

3.4 Prognostic Implications

Solitary liver involvement is rare.
Severe cholestatic jaundice has median survival ~3 months.

3.5 Management

Supportive treatment: treat pruritus, nutrition.
Chemotherapy for underlying AL amyloidosis.
Liver transplantation not indicated because of systemic disease.

4. Peripheral Nerves and AL Amyloidosis

4.1 Pathophysiology

Amyloid deposits around small vessels and endoneurium.
Causes ischemic and direct toxic nerve damage.

4.2 Clinical Features

Peripheral neuropathy: symmetric, length-dependent sensory > motor.
Carpal tunnel syndrome: frequent because amyloid deposition occurs in flexor retinaculum.
Autonomic neuropathy: orthostatic hypotension, diarrhea, constipation, urinary incontinence, erectile dysfunction.

4.3 Diagnostic Workup

Nerve conduction studies: axonal polyneuropathy.
Nerve or fat pad biopsy: demonstrate amyloid deposition.

4.4 Prognostic Significance

Neuropathy impairs quality of life considerably.
Autonomic dysfunction is a marker of poor prognosis.

4.5 Management

Symptomatic therapy: midodrine, fludrocortisone for hypotension.
Neuropathic pain agents: gabapentin, pregabalin.
Disease-modifying therapy for AL amyloidosis.

5. Gastrointestinal (GI) Tract and AL Amyloidosis

5.1 Pathophysiology

Amyloid deposits in muscularis mucosa, submucosa, and vessels.

5.2 Clinical Features

Malabsorption: weight loss, diarrhea, steatorrhea.
GI bleeding: due to friable mucosa and vascular involvement.
Dysmotility: gastroparesis, pseudo-obstruction.
Macroglossia: classic but uncommon finding.

5.3 Diagnostic Workup

Endoscopy: mucosal friability, thickened folds.
Biopsy (duodenal, rectal, or gastric): Congo red-positive deposits.

5.4 Prognosis

GI involvement exacerbates malnutrition and frailty.
Death often from complications such as bleeding and cachexia.

5.5 Management

Nutritional support: high-protein diet, supplements.
Antidiarrheals, prokinetics for symptom control.
Treat underlying plasma cell dyscrasia.

6. Multi-Organ Involvement: The Real-World Picture

Most patients have multi-organ involvement and not isolated disease.
Common combinations: kidney + heart, or kidney + liver.
Multi-organ disease severely restricts transplant options.

7. Diagnostic Strategies Across Organs

Abdominal fat pad biopsy – minimally invasive, ~70% sensitivity.
Bone marrow biopsy – required to evaluate plasma cell dyscrasia.
Organ-specific biopsy – gold standard if non-invasive biopsies are negative.

8. Treatment Landscape

First-line chemotherapy: daratumumab + bortezomib + cyclophosphamide + dexamethasone (Dara-VCD).
Autologous stem cell transplantation (ASCT): in eligible patients with good performance status.
Organ-specific support: dialysis, diuretics, nutritional therapy.

9. Prognostic Markers

Mayo staging system (NT-proBNP, troponin, free light chain difference).
Renal staging (proteinuria, eGFR).
Cardiac staging most predictive of survival.

10. Future Directions

New therapies: venetoclax (for patients with t(11;14)), CAR-T cell therapies against plasma cells.
Enhanced diagnostic algorithms utilizing mass spectrometry typing.
Early diagnosis is still the cornerstone to enhancing survival.

Conclusion

Systemic AL amyloidosis is a multi-organ disorder with variable presentation. The kidneys, heart, liver, peripheral nerves, and GI tract are the most frequent sites of amyloid deposition. Identification of subtle clinical features, early diagnostic workup, and initiation of treatment can greatly improve results.

Involvement of multiple organs, however, is the biggest challenge and frequently determines prognosis. Physicians must have a high index of suspicion in those with unexplained nephrotic syndrome, restrictive cardiomyopathy, hepatomegaly, neuropathy, or GI dysfunction.

Plasma cell–targeted therapy and supportive approaches are areas of active investigation with the promise of improved outcomes in this once uniformly fatal disease.