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Non-light-chain immunoglobulin amyloidosis: time to expand or refine the spectrum to include light+heavy chain amyloidosis?

2013; Elsevier BV; Volume: 83; Issue: 3 Linguagem: Inglês

10.1038/ki.2012.433

1523-1755

Maria M. Picken,

Drug Transport and Resistance Mechanisms

Among the various systemic amyloidoses, deposits derived from the immunoglobulin light chain (AL) account for 85% of cases. In this issue, Nasr et al. report 16 cases of renal heavy and light+heavy chain amyloidosis and compare them with renal light chain amyloidosis. While additional studies are needed to shed light on the heavy and light+heavy chain amyloidoses, several observations by the authors suggest important practical implications, including differences in clinical picture, prognosis and pathologic diagnosis. Among the various systemic amyloidoses, deposits derived from the immunoglobulin light chain (AL) account for 85% of cases. In this issue, Nasr et al. report 16 cases of renal heavy and light+heavy chain amyloidosis and compare them with renal light chain amyloidosis. While additional studies are needed to shed light on the heavy and light+heavy chain amyloidoses, several observations by the authors suggest important practical implications, including differences in clinical picture, prognosis and pathologic diagnosis. Amyloidosis comprises a group of protein folding disorders of diverse etiology, in which deposits of abnormally folded proteins share unique staining properties and a fibrillar ultrastructural appearance.1Sipe J.D. Benson M.D. Buxbaum J.N. et al.Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.Amyloid. 2012; 19: 167-170Crossref PubMed Scopus (200) Google Scholar Currently, more than 25 amyloid protein types (and many more variants) have been associated with amyloid formation. Several amyloid types are systemic, whereas others are exclusively (or predominantly) localized. A correct diagnosis of the amyloid protein type is important in view of the associated differences in treatment and prognosis. The various treatment protocols that are available may include, depending on the amyloid type, aggressive chemotherapy, targeted treatment of the underlying inflammatory process, or liver transplantation; also, pharmacologic treatments are in clinical trials for some hereditary amyloidoses. Among these various amyloidoses, deposits derived from the immunoglobulin light chain, AL, account for 85% of cases. However, rare instances of amyloid fibrils derived from the immunoglobulin heavy chain, designated heavy chain amyloidosis (AH), have been reported. AL/AH amyloidoses are always associated with an underlying plasma cell dyscrasia ranging from low tumor burden conditions (that is, without myeloma, formerly referred to as ‘primary’ amyloidosis) to those associated with multiple myeloma (formerly referred to as ‘associated with multiple myeloma’).2Picken M.M. Options for amyloid typing in renal pathology: the advantages of frozen section immunofluorescence and a summary of general recommendations for immunohistochemistry (Chaps. 17–19).in: Picken M.M. Dogan A. Herrera G.A. Amyloid and related disorders. Surgical pathology and clinical correlations. Springer NewYork Dordrecht Heidelberg, London: Springer, Verlag2012: 239-248Google Scholar Under physiologic conditions, plasma cells synthesize and secrete specific immunoglobulin molecules, with a minor excess of κ or λ light chains. Each immunoglobulin molecule is composed of two identical heavy (H) chains and two light (L) chains, which are linked by variable numbers of disulfide bonds. The variable regions of the heavy and the light chain (VH and VL, respectively) constitute the antigen binding site, while the components of the constant (C) regions of the heavy chain, containing CH2 and CH3 domains, are involved in effector functions such as binding to complement, Fc receptors, and host tissues (Figure 1). The synthesis of light chains occurs independently from heavy chains. Both heavy and light chain components are combined in the rough endoplasmic reticulum to form the complete immunoglobulin molecule, which is then released and, as such, circulates in the body. Hence, heavy chains do not circulate freely. This is in contrast to free light chains, which readily circulate in the blood. In plasma cell dyscrasia, the production of light and heavy chains is unbalanced, resulting in an excess of physicochemically-abnormal light and/or heavy chains. Also, a number of mutations may lead to amino acid substitutions in the light or heavy chain molecules, which influence their pathogenicity and the type of systemic and/or renal involvement. It is estimated that approximately 85% of all light chains are nephrotoxic. In AL amyloidosis, amyloid fibrils are composed of immunoglobulin light chain fragments containing the V region, or the V and C regions, or a combination, including also a seemingly intact light chain. While earlier studies emphasized the presence of the V region in AL, several recent reports have also highlighted the hitherto-underestimated role of the C region in amyloid fibril formation. Thus, it has now been demonstrated that the C region may be involved in initiating aggregation and providing a template for V region deposition.3Klimtchuk E.S. Gursky O. Patel R.S. et al.The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain.Biochemistry. 2010; 49: 9848-9857Crossref PubMed Scopus (60) Google Scholar In AH amyloidosis, which is exceptionally rare, the amyloid fibril is derived from a truncated heavy chain. Molecular studies of the first case of AH demonstrated an internal deletion of the molecule, leading to the VH domain being directly joined to the CH3 domain—the whole, therefore, bearing a striking resemblance to the light chain.4Eulitz M. Weiss D.T. Solomon A. Immunoglobulin heavy-chain-associated amyloidosis.Proc Natl Acad Sci USA. 1990; 87: 6542-6546Crossref PubMed Scopus (119) Google Scholar In the few other reported cases of AH, the involved heavy chains, either γ or μ, had deletions in the CH1 and CH2 regions. It is likely that these deletions—in particular, deletion of the CH1 region—facilitated the secretion of free heavy chains. Such heavy chains appear to be rapidly cleared from the circulation and deposited in target organs and, therefore, to be difficult to detect by blood tests.5Miyazaki D. Yazaki M. Gono T. et al.AH amyloidosis associated with an immunoglobulin heavy chain variable region (VH1) fragment: a case report.Amyloid. 2008; 15: 125-128Crossref PubMed Scopus (24) Google Scholar This latter point underscores the importance of paraprotein detection in biopsies. Both AL and AH have long been recognized as defined entities and have been included in the official nomenclature list by the International Society of Amyloidosis.1Sipe J.D. Benson M.D. Buxbaum J.N. et al.Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.Amyloid. 2012; 19: 167-170Crossref PubMed Scopus (200) Google Scholar In this issue, Nasr et al.6Nasr S.H. Said S.M. Valeri A.M. et al.The diagnosis and characteristics of renal heavy chain and light+heavy chain amyloidosis and their comparison with renal light chain amyloidosis.Kidney Int. 2013; 83: 463-470Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar report 16 cases of renal heavy chain and light+heavy chain amyloidosis and compare them with renal light chain amyloidosis. The report of a series of five cases of heavy chain amyloidosis adds to our knowledge of this condition, which, hitherto, has been based on only single isolated case reports. Also, and more importantly, the authors report 11 cases of light+heavy chain amyloidosis, a condition that has not, thus far, been widely recognized or accepted. Thus, to date, only four patients had been reported with features suggestive of combined light+heavy chain amyloidosis. Thus, in 2005, Kaplan et al. reported a case of an apparently lung-restricted IgGλ lymphoplasmacytoid lymphoma with amyloid deposits.7Kaplan B. Martin B.M. Boykov O. et al.Co-deposition of amyloidogenic immunoglobulin light and heavy chains in localized pulmonary amyloidosis.Virchows Arch. 2005; 447: 756-761Crossref PubMed Scopus (23) Google Scholar In tissue extracts, the authors detected short sequences corresponding to the C region of the λ light chain and the V region of the IgG heavy chain (VH). In 2006, Nasr et al. reported a case of renal IgG1λ renal amyloidosis diagnosed by immunofluorescence.8Nasr S.H. Colvin R. Markowitz G.S. IgG1 lambda light and heavy chain renal amyloidosis.Kidney Int. 2006; 70: 7Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Also, two other, earlier-reported cases of light+heavy chain amyloidosis were included in a series of four cases of renal heavy chain amyloidosis, and initially labeled as such.9Sethi S. Theis J.D. Leung N. et al.Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain amyloidosis.Clin J Am Soc Nephrol. 2010; 5: 2180-2187Crossref PubMed Scopus (98) Google Scholar These same two cases also appear to be included in the current series of 11 cases of light+heavy chain amyloidosis, diagnosed by either immunofluorescence or laser microdissection and mass spectrometry (LMD/MS) or by both methods. On the basis of the detection of sequences matching segments of both the light and the heavy chain in amyloid-enriched tissue extracts, Nasr et al.6Nasr S.H. Said S.M. Valeri A.M. et al.The diagnosis and characteristics of renal heavy chain and light+heavy chain amyloidosis and their comparison with renal light chain amyloidosis.Kidney Int. 2013; 83: 463-470Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar assume that the amyloid fibrils are formed from both the heavy and the light chains. However, considering the exceptional rarity of AH, it seems unlikely that the same patient would have both heavy and light chain amyloidosis (forming distinct amyloid fibrils). Thus, the possibility that substantial numbers of complete immunoglobulin molecules could be ‘trapped’ in amyloid fibrils formed from light chains should also be considered. Interestingly, although none of the patients was diagnosed with a biclonal gammopathy, in case AH4, both IgG1 and IgG4 were detected by MS. Also, it should be pointed out that the material subjected to MS analysis consists of a tissue extract rather than ‘pure’ fibrils, despite the preferential enrichment of the extract with amyloid deposits by laser microdissection. The authors argue, however, that the presence of abundant spectra for both the light and the heavy chain in tissue extracts supports the notion that the amyloid fibrils are derived from both, that is, light+heavy chain. In contrast, in the case of ALλ light chain amyloid, for example, large spectra of the immunoglobulin λ light chain C region (with or without the λ light chain V region) are detected, while κ light chains are absent or detectable only as very small spectra, along with small spectra of the heavy chain. The latter minor spectra are therefore inferred to represent small amounts of polyclonal reabsorption and/or entrapment of immunoglobulins in deposits of amyloid. Similarly, heavy positivity (≥2–3+) for both light and heavy chain components was reported in most cases in this series by immunofluorescence. In such cases, immunoelectron microscopy may help to determine whether both components colocalize with the fibrils. Ultimately, however, amyloid fibril protein sequencing, if feasible, may be the most convincing proof of amyloid derivation from both components (individually or combined). Considering that the amyloidogenic proteins thus far identified consist of low-molecular weight proteins of less than 30kDa, sequencing data would provide further insight into the fibril structure. If confirmed, the presence of protein-forming fibrils that are composed of light+heavy chain would be expected to be associated with significant truncations of the light and heavy chain components. Collectively, the AL/AH immunoglobulin amyloidoses are the most common forms of disease that feature the deposition in tissues of monoclonal immunoglobulin, or its isolated subunits. Other entities include the non-fibrillar deposits found in light chain deposition disease, heavy chain deposition disease, and light and heavy chain deposition disease, collectively termed the monoclonal immunoglobulin deposition diseases (MIDDs).10Gallo G. Picken M. Buxbaum J. Frangione B. The spectrum of monoclonal immunoglobulin deposition disease associated with immunocytic dyscrasias.Semin Hematol. 1989; 26: 234-245PubMed Google Scholar Other rare entities have also recently been recognized. Although MIDDs and immunoglobulin amyloidoses may be clinically similar, MIDDs differ from immunoglobulin amyloidoses by their lack of affinity for Congo. Although the pathophysiology of the MIDDs is not fully understood, it has been proposed that they result from a one-step precipitation of immunoglobulin components, possibly resulting from the binding of cationic polypeptides to an anionic basement membrane.7Kaplan B. Martin B.M. Boykov O. et al.Co-deposition of amyloidogenic immunoglobulin light and heavy chains in localized pulmonary amyloidosis.Virchows Arch. 2005; 447: 756-761Crossref PubMed Scopus (23) Google Scholar In contrast, amyloid light chains have heterogeneous pI profiles, and amyloid formation appears to be associated with the elongation of a pseudocrystalline structure. Combined isotypic amyloid and non-amyloid deposits are exceedingly rare. These differences notwithstanding, it is feasible that a spectrum of immunoglobulin tissue deposition, similar to that seen in non-fibrillar monoclonal immunoglobulin deposition, may also exist in the case of amyloid. This possibility is intriguing and worth exploring further. MS technology has been very helpful in amyloid typing, particularly in the case of formalin-fixed, paraffin-embedded tissues. It has also been critical for the typing of cases with limited antibody reactivity and in the discovery of new protein types. As Nasr et al. show, MS data may also be helpful in the delineation of the spectrum of immunoglobulin-derived amyloid.6Nasr S.H. Said S.M. Valeri A.M. et al.The diagnosis and characteristics of renal heavy chain and light+heavy chain amyloidosis and their comparison with renal light chain amyloidosis.Kidney Int. 2013; 83: 463-470Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar However, MS technology is not completely free from limitations and should complement rather than replace existing methods. It should be kept in mind that the effectiveness of the MS technique is currently limited by the abundance of amyloid proteins in the tissue; other limitations include the presence (or lack) of trypsin-cleavage sites that allow the generation of suitable peptide fragments, and a reliance on predictive computational algorithms based on a reference human genome obtained from publicly available databases, and so on. In contrast, antibody-based examinations can detect even minute deposits and also have been instrumental in expanding the disease spectrum of non-amyloid monoclonal immunoglobulin deposits.2Picken M.M. Options for amyloid typing in renal pathology: the advantages of frozen section immunofluorescence and a summary of general recommendations for immunohistochemistry (Chaps. 17–19).in: Picken M.M. Dogan A. Herrera G.A. Amyloid and related disorders. Surgical pathology and clinical correlations. Springer NewYork Dordrecht Heidelberg, London: Springer, Verlag2012: 239-248Google Scholar While additional studies are needed to shed light on the heavy and light+heavy chain amyloidoses, several observations by the authors suggest important practical implications. Compared with patients with renal light chain amyloidosis, patients with renal heavy or light+heavy chain amyloidosis had (1) better survival, less frequent concurrent cardiac involvement, a higher incidence of hematuria, and also a higher likelihood of having circulating complete monoclonal immunoglobulin (including those with AH); (2) lower sensitivity of fat pad and bone marrow biopsy for detecting amyloid; and (3) pathology that was atypical of amyloid, such as strong periodic acid–Schiff and silver stain positivity and mesangial hypercellularity. The latter, in particular, underscores the need to expand the use of the Congo red stain in the investigation of various pathologies with atypical features. Now that a wider range of treatments is available, early diagnosis is critical.