Leucocyte cell-derived chemotaxin 2 related amyloidosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]
Synonyms and keywords:LECT2 amyloidosis
Overview
Historical Perspective
- The first case of ALECT2 was discovered by Benson et al in 2008.
Classification
Pathophysiology
- The pathogenesis of this disease is related to accumulation of a protein called LECT2.
- LECT2 protein is a multi functional factor involved in
- Chemotaxis
- Inflammation
- Immunomodulation
- Damage/repair process.
- LECT2 is synthesized mainly by hepatocytes but also expressed in many organs, including vascular endothelial cells, smooth muscle cells, adipocytes, and epithelial cells such as renal tubular epithelial cells.
- According to the literature, ALECT2 involves G/A polymorphism affecting nucleotide 172 in exon 3 of the LECT2 protein.
- Substitution of the isoleucine with valine at position 40 makes the protein unstable imparting an amyloidogenic property to the LECT2 protein.
- Alternately the disease could be due to interference in the LECT2 catabolic pathway or LECT2 transport.
- Possibly resulting from a genetic defect which ultimately results in an increased local tissue concentration of LECT2 leading to amyloid fibril formation.
- The kidney is the primary target of this disease. '
- Other common organs involved other than the kidney include liver, spleen, prostate, gastrointestinal tract, peripheral nervous system, and lungs.
- Cardiac involvement never occurs, which gives this disease a survival advantage compared to other forms of amyloidosis.
- Other organs which are not involved include brain, pancreas, and fibroadipose tissue.
| Unidentified Genetic Mutation | Hepatocelluar Damage | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| LECT2 overexpression by hepatocytes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Misfolded LECT2 protein | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased local concentrations Interactions with components of extracellular matrix, such as laminin and type IV collagen Bindings with serum amyloid P (SAP) apoE, and glycosaminoglycans (GAGs) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amyloid fibril formation and stabilization. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALECT2 amyloidosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Causes
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications, and Prognosis
- Patient survival in ALECT2 amyloidosis is significantly better than that of AL amyloidosis and AA amyloidosis, likely because of the rarity or absence of cardiac involvement in ALECT2 amyloidosis.
- In a series of 72 patients with renal ALECT2 amyloidosis, only 6% of 64 patients with available data died after a median follow-up of 22 months.
- The renal survival, however, is guarded; 39% of patients in the above-mentioned study progressed to ESRD .
- Independent predictors of renal survival in renal ALECT2 amyloidosis without concurrent kidney disease on biopsy were serum creatinine at diagnosis, with a value of 2.0 mg/dl being the best cutoff for predicting ESRD, degree of glomerulosclerosis, and presence of diabetes
- Renal amyloid load and degree of proteinuria did not predict outcome
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography or Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
- There is currently no specific therapy for ALECT2 amyloidosis.
- Because the precursor protein is normal (nonmutant) LECT2, liver transplantation probably is not effective, although this approach has not been tested.
- Preliminary data suggest that renal transplantation is a reasonable therapeutic option for patients with advanced renal failure. I
- In one recent series, the disease recurred in one of five patients transplanted, but the short-term outcome was good: after a mean duration of 20 months of post-transplant follow-up, no patient had graft loss, and two patients had normal final serum creatinine.
- Some potential future therapies for ALECT2 amyloidosis include reducing the supply of LECT2 (such as by Wnt/β-catinin signaling pathway inhibitors, etinoids, exisulind, and endostatin), inhibiting fibrillogenesis (such as by blocking the binding of glycosaminoglycans to amyloid fibrils), enhancing clearance of amyloid by immunotherapy, and promoting amyloid regression by targeting SAP.
- SAP is a major component of amyloid deposits of any type.
- Antibodies to human SAP were shown to eliminate visceral AA deposits in mice .
- It is critical not to misdiagnose ALECT2 amyloidosis as AL amyloidosis to avoid harmful therapy.