First described in studies searching for proteins with leukocyte chemotactic activity [11], LECT2 protein was well characterized before its discovery as an amyloid fibril precursor. It was also shown to be involved in the restructuring of cartilage and, therefore, was named chondromodulin [12].

The in vivo function of LECT2 has yet to be established. LECT2 is synthesized principally by the liver, and it has been shown that increased expression of LECT2 may occur with hepatocellular tumors [13]. LECT2 is also a cytokine involved in the regulation of hepatocyte activity and functions as an immunomodulator [14]. LECT2 mRNA was specifically detected in adult and fetal liver but not in other tissues [15]. Initial immunohistochemical (IHC) studies using polyclonal antisera demonstrated that LECT2 is physiologically synthesized by a variety of cells other than hepatocytes and endothelial cells and becomes positively stainable under pathological conditions in cells originally negative [16]. But more recent IHC and mRNA in-situ hybridization assays have failed to identify expression outside liver tissue. LECT2 expression may be related to the cell cycle and damage/repair process [17, 18].

The pathogenesis of ALECT2 amyloidosis still needs to be elucidated. It has been suggested that an increased expression of LECT2 or other factors involved in the metabolism of LECT2 or a genetic defect in LECT2 catabolic pathway/LECT2 transport may result in an increased local tissue concentration of LECT2 leading to the initiation of fibril formation [1, 2]. LECT2 has extensive β-structure, and the entire secreted LECT2 protein is incorporated into the amyloid fibrils suggesting that the proteolytic degradation is not necessary for fibril formation [19]. LECT2 serum levels are elevated in hepatic disorders [20, 21] but no increased levels have been detected so far in ALECT2 amyloidosis [2, 22].

The human LECT2 gene (LECT2) is found on chromosome 5q31.1 by fluorescence in situ hybridization, in close proximity to cytokine genes, including interleukin (IL)-4, IL-5, and IL-9. LECT2 consists of four exons and three introns [23]. The gene codes for 151 amino acids (MW 16,376 Da) including an 18 amino acid signal peptide [1]. Genetic analysis performed in 35 patients with kidney involvement and one case of hepatic amyloidosis did not detect LECT2 mutations [1, 2, 4, 5, 24]. Although ALECT2 amyloidosis does not appear to be caused by genetic mutations, homozygosity for a non-synonymous single nucleotide variant in exon 3 seems to be required for disease. All 35 patients sequenced thus far show homozygosity for the G nucleotide at position 172 (SNP rs31517) resulting in replacement of isoleucine by valine at position 40 of mature protein. This is a common polymorphism which has previously been demonstrated to be a risk factor for the progression of rheumatoid arthritis [25]. It has been hypothesized that the polymorphism might increase the amyloidogenic propensity of LECT2. It is also possible that the polymorphism might segregate with another causative mutation though this is considered less likely since this variant is homozygous in patients of varying ethnicities [2]. The preponderance of disease in certain ethnicities as well as the description in siblings [4] suggests a genetic etiology. If this is the case then ALECT2 might be considered a digenic disease in which homozygosity for the common SNP rs31517 is required in addition to some other yet-unknown variant.

The possibility of an ethnic background as a predisposing factor in the development of amyloidosis had been raised for the first time in an autopsy study performed at Los Angeles County-University of Southern California Medical Center [26]. The study included 467 patients with amyloidosis found among 52,370 autopsies. Classification of amyloidosis (AA vs. other types) was accomplished by using the potassium permanganate CR staining method and a specific anti-AA antiserum, supplemented by the anatomical distribution of the amyloid in some instances. The study found a statistically significant increase in amyloidosis among Hispanic patients as compared with Caucasians. Interestingly, the increase was mostly among the non-AA amyloid cases (negative for anti-AA antibody) and not anatomically compatible with senile cardiac (systemic) amyloidosis defined by the heart as the principal organ involved and the confinement of amyloid in other organs to small blood vessels. Hispanics accounted for 76 % of these cases as compared with 18.5 % for Caucasians. The cases did not fit the inheritance or clinical patterns of familial amyloidosis so these cases were considered principally AL-type. Because of the technical limitations of the study, we can only assume that most of these Hispanic patients could have been affected by ALECT2 amyloidosis, but this hypothesis cannot be supported without an accurate amyloid typing of the specimens. However, the findings suggest that the frequency of amyloidosis may vary significantly in different ethnic groups.

The main clinical and pathological features of ALECT2 amyloidosis involving the kidney and the liver are summarized in Table 4.1.