Leucocyte cell-derived chemotaxin 2 related amyloidosis

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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

Amyloidosis derived from leukocyte cell–derived chemotaxin 2 is a recently recognized form of amyloidosis, and it has already been established as a frequent form of systemic amyloidosis in the United States, with predominant involvement of kidney and liver. The disease has a strong ethnic bias, affecting mainly Hispanics (particularly Mexicans). Additional ethnic groups prone to develop amyloidosis derived from leukocyte cell–derived chemotaxin 2 include Punjabis (native to India and Pakistan), First Nations people in British Columbia, and Native Americans. Most patients are elderly who present with chronic renal insufficiency and bland urinary sediment. Proteinuria is variable, being absent altogether in about one third of patients. Liver involvement is frequently an incidental finding. Amyloidosis derived from leukocyte cell–derived chemotaxin 2 deposits shows a characteristic distribution: in the kidney, there is consistent involvement of cortical interstitium, whereas in the liver, there is a preferential involvement of periportal and pericentral vein regions. Concurrent renal disease is frequent, with diabetic nephropathy and IgA nephropathy being the most common. Patient survival is excellent, likely because of the rarity of cardiac involvement, whereas renal survival is guarded, with a median renal survival of 62 months in those without concurrent renal disease. There is currently no efficacious therapy for amyloidosis derived from leukocyte cell–derived chemotaxin 2 amyloidosis. Renal transplantation seems to be a reasonable treatment for patients with advanced renal failure, although the disease may recur in the allograft. The pathogenesis of amyloidosis derived from leukocyte cell–derived chemotaxin 2 amyloidosis has not yet been elucidated. It could be a result of leukocyte cell–derived chemotaxin 2 overexpression by hepatocytes either constitutively (controlled by yet-uncharacterized genetic defects) or secondary to hepatocellular damage. It is critical not to misdiagnose amyloidosis derived from leukocyte cell–derived chemotaxin 2 amyloidosis as Immunoglobulin light chain-derived amyloidosis to avoid harmful chemotherapy..

Historical Perspective

  • The first case of ALECT2 was discovered by Benson et al in 2008.
Fibril proteins Year protein structure characterized
Immunoglobulin light chain (AL) 1971
Amyloid A (AA) 1972
Transthyretin 1981
Cystatin C 1986
Apolipoprotein A-I 1988
Gelsolin 1990
Fibrinogen Aα -chain 1993
Lysozyme 1993
Apolipoprotein A-II 2001
LECT2 2008

Pathophysiology

  • The pathogenesis of this disease is related to accumulation of a protein called LECT2.[1]
  • LECT2 protein is a multi functional factor involved in
    • Chemotaxis
    • Inflammation
    • Immunomodulation
    • Damage/repair process.[2]
  • 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.[2]
  • 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
 
 
 
 
 
Association of leukocyte cell‐derived chemotaxin‐2 with pathophysiology and disease in different organ systems
Inflammation and fibrosis LECT2 expression changes with signs of inflammation or fibrosis
Immune system Activated immune response and prosurvival role with infection and sepsis
Bone Involved in the pathogenesis of osteoarthritis and rheumatoid arthritis

Polymorphisms of LECT2 associated with more severe forms of RA

Histopathology

Kidney

  • Histologically, renal ALECT2 amyloidosis involves diffuse cortical interstitium.[3]
  • The glomerular and vascular amyloid deposits are variable.
  • ALECT2 deposits stain strongly positive with Congo red and demonstrates apple-green birefringence, under polarized light.
  • Immunofluorescence is usually negative.
  • A minority of patients may demonstrate false-positive staining for serum amyloid A (SAA).
Histopathology in Kidney
Renal ALECT2 amyloidosis Diffuse cortical interstitium
AL amyloidosis and AA amyloidosis Gomeruli and vessels
AApo AI amyloidosis and AApo AIV amyloidosis Medullary interstitium

Liver

  • ALECT2 deposits in the liver have a characteristic histologic morphology.
  • ALECT2 deposits are seen preferentially surrounding the central veins and in the periphery of portal tracts.
  • Exhibits a distinctive globular appearance.
Histopathology in Liver
ALECT2 amyloidosis Preferentially surrounding the central veins and in the periphery of portal tracts
AL amyloidosis and AA amyloidosis Perisinusoidal

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.[4]
  • 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

History

  • ALECT2 amyloidosis mainly affects the older population.
  • Patients with kidney involvement are slightly older at diagnosis (median age of 69 years old) than those with liver involvement (median age of 61 years old)

Symptoms

Common symptoms of LECT2 amyloidosis include:

Symptoms of ALECT2 Amyloidosis
Renal ALECT2 amyloidosis
  • Majority of the patients with renal ALECT2 amyloidosis present with chronic renal insufficiency.
  • Proteinuria is an inconsistent finding in renal ALECT2 amyloidosis.
  • Full nephrotic syndrome is uncommon in renal ALECT2 amyloidosis.
  • Microhematuria is uncommon
  • Chronic hypertension and diabetes mellitus are frequently associated conditions.
Hepatic ALECT2 amyloidosis
  • Mostly discovered as an incidental finding in liver biopsy performed during surgery for nonhepatic conditions
  • Commonly associated with chronic viral hepatitis and steatohepatitis.
  • The most frequent clinical abnormality in patients with liver ALECT2 amyloidosis is an elevation of alkaline phosphatase.

Laboratory Findings

  • Typing amyloid deposits by LC/MS-based proteomics is currently the best tool to diagnose ALECT2 amyloidosis and other forms of amyloidosis because of its high sensitivity and specificity and because it is a single test that can detect the culprit protein in contrast to IHC typing of amyloidosis, which requires staining for multiple antibodies using several tissue sections (6,50,51).
  • LECT2 protein has many lysine and arginine residues and therefore, can readily be digested by trypsin into peptides, and the amino acid sequence of the peptides can be determined by LC/MS.
  • The diagnosis of ALECT2 amyloidosis by LC/MS is made according to clinically established criteria by identification of LECT2 peptide spectra and amyloid-associated proteins (serum amyloid P [SAP] and apoE).
  • Because plasma concentration of LECT2 is trivial, contamination of amyloid deposits by serum LECT2 is not an issue, and the diagnosis is usually straightforward. Unfortunately, clinical amyloid typing by proteomics is available only in few selected centers, such as the Mayo Clinic.
  • There are now several commercially available antibodies for IHC detection of LECT2 that seem to be highly sensitive however, weak false-positive staining may occur , which may result from aggressive antigen retrieval. Therefore, it is crucial that LECT2 antibody is carefully validated and optimized for the diagnosis of ALECT2.
  • In cases that exhibit only weak staining for LECT2, false-positive staining for SAA, or staining for Ig light or heavy chains by immunofluorescence or immunoperoxidase, confirmation by LC/MS is strongly recommended.
  • When amyloid typing is performed by IHC, it is critical that the testing is done with a panel of antibodies against several types of amyloidosis, so-called comparative IHC, instead of staining for a single precursor protein.
  • In general, better results are obtained if amyloid typing by IHC is performed in specialized laboratories.
  • Of note, monoclonal gammopathy of undetermined significance was present in 10% and 8% of patients reported by Said et al. and Larsen et al. respectively, highlighting the importance of accurate typing of amyloid deposits to avoid misdiagnosing ALECT2 amyloidosis as AL amyloidosis
 
 
 
 
 
 
 
Congo red-positve amyloid deposits
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal tissue
 
 
 
 
 
 
 
In Non-renal tissues
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoflorescence
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Positive
 
Negative
 
 
 
 
 
Mass Spectometry
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AL Amyloidosis
 
 
 
 
 
 
 
 
 
 
 
 
Large Spectra for LECT2
 
 
 
 
 
 
 
 
 
IHC staining positive for LECT2
 
=IHC staining negative for LECT2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LECT2 amyloidosis
 
 
 
 
 
LECT2 Amyloidosis
 
Mass Spectometry
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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.

References

  1. Tanaka T, Nangaku M (2011). "Pathogenesis of tubular interstitial nephritis". Contrib Nephrol. 169: 297–310. doi:10.1159/000314577. PMID 21252528.
  2. 2.0 2.1 Said SM, Sethi S, Valeri AM, Chang A, Nast CC, Krahl L, Molloy P, Barry M, Fidler ME, Cornell LD, Leung N, Vrana JA, Theis JD, Dogan A, Nasr SH (August 2014). "Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis". Kidney Int. 86 (2): 370–7. doi:10.1038/ki.2013.558. PMID 24451324.
  3. Said SM, Sethi S, Valeri AM, Leung N, Cornell LD, Fidler ME, Herrera Hernandez L, Vrana JA, Theis JD, Quint PS, Dogan A, Nasr SH (September 2013). "Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases". Clin J Am Soc Nephrol. 8 (9): 1515–23. doi:10.2215/CJN.10491012. PMC 3805078. PMID 23704299.
  4. Khalighi MA, Yue A, Hwang MT, Wallace WD (December 2013). "Leukocyte chemotactic factor 2 (LECT2) amyloidosis presenting as pulmonary-renal syndrome: a case report and review of the literature". Clin Kidney J. 6 (6): 618–21. doi:10.1093/ckj/sft126. PMC 4438374. PMID 26120458.



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