Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma

Caldéraro, Julien; Letouzé, Éric; Bayard, Quentin; Boulai, Anaïs; Renault, Victor; Deleuze, Jean‐François; Bestard, Oriol; Franco, Dominique; Zafrani, Elie‐Serge; Nault, Jean‐Charles; Moutschen, Michel; Zucman‐Rossi, Jessica

doi:10.1056/nejmc1805673

Cited by 14 publications

(16 citation statements)

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“…Finally, we identified two IHCA with abnormal 3’ untranslated region (UTR) of IL6 on RNA sequencing (figure 4A) and characterised by activation of JAK/STAT pathway (GSEA analysis, online supplementary figure 3). One case was previously published (#2615T with inflammatory SAA amyloidosis); the tumour showed a deletion of 3’UTR of IL6 due to an inversion of 18.7 megabases validated by whole genome sequencing 12. We identified a second IHCA, #1215T, with a truncation of the 3’UTR regulatory region of IL6 due to a eight megabases deletion identified using RNA sequencing.…”

Section: Resultsmentioning

confidence: 75%

“…RNA samples from the 22 HCA tumours were sequenced comprising 1 previously published12 and 21 new cases. RNA samples were enriched for polyadenylated RNA from 5 µg of total RNA, and the enriched samples were used to generate sequencing libraries with the NEBNext Ultra II Directional RNA (n=13) or Illumina TruSeq Stranded messenger RNA (mRNA) (n=9) kits and associated protocol as provided by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…Inflammatory syndrome, anaemia or fever could be observed in patients with IHCA; these symptoms regress after tumour resection. Recently, we described an IHCA with a rearrangement of the 3’UTR of the IL6 gene leading to a secondary amyloidosis through an autocrine/paracrine mechanism of activation of JAK/STAT pathway by IL-6 in the whole liver 12. However, a subset of IHCA has currently no known genetic alterations explaining the constitutive activation of JAK/STAT pathway.…”

Section: Introductionmentioning

confidence: 99%

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Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas

Bayard

Caruso

Couchy

et al. 2020

Gut

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BackgroundInflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.Methods657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.ResultsWe identified 296 IHCA (45%), 81% of them were mutated in either IL6ST (61%), FRK (8%), STAT3 (5%), GNAS (3%) or JAK1 (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving ROS1, FRK or IL6 genes. ROS1 fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (PLG, RBP4, APOB) fused with exon 33–35 to 43 of ROS1 including the tyrosine kinase domain. In two cases a truncated ROS1 transcript from exon 36 to 43 was identified. ROS1 rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to ROS1 overexpression. Among the 5 IHCA with FRK rearrangements, 5 different partners were identified (MIA3, MIA2, LMO7, PLEKHA5, SEC16B) fused to a common region in FRK that included exon 3–8. No overexpression of FRK transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2–SH3 domains. In two IHCA, we identified truncated 3’UTR of IL6 associated with overexpression of the transcript.ConclusionRecurrent chromosomal alterations involving ROS1, FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.

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Section: Resultsmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas

Bayard

Caruso

Couchy

et al. 2020

Gut

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“…SAA production in hepatocytes is stimulated by the production of high amounts of tumour necrosis factor-alpha (TNF-a) [39]. In inflammatory hepatocellular adenomas, SAA is overexpressed by neoplastic hepatocytes [40]. Coeliac disease may cause AA amyloidosis since T-cell driven inflammation by gluten ingestion results in the release of pro-inflammatory cytokines, although elevated CRP or SAA levels have not been reported [41].…”

Section: New Associationsmentioning

confidence: 99%

Causes of AA amyloidosis: a systematic review

Brunger

Nienhuis

Bijzet

et al. 2019

Amyloid

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From a clinical perspective, there is a need for a reliable and comprehensive list of diseases causing AA amyloidosis. This list could guide clinicians in the evaluation of patients with AA amyloidosis in whom an obvious cause is lacking. In this systematic review, a PubMed, Embase and Web of Science literature search were performed on causes of AA amyloidosis published in the last four decades. Initially, 4066 unique titles were identified, but only 795 full-text articles and letters were finally selected for analysis. Titles were excluded because of non-AA type of amyloidosis, language, no fulltext publication or irrelevance. Hundred and fifty diseases were initially reported to be associated with the development of AA amyloidosis. The presence of AA amyloid was proven in 208 articles (26% of all) of which 140 (67%) showed a strong association with an underlying disease process. Disease associations were categorized and 48 were listed as strong, 19 as weak, 23 as unclear, and 60 as unlikely. Most newly described diseases are not really unexpected because they often cause longstanding inflammation. Based on the spectrum of identified causes, a pragmatic diagnostic approach is proposed for the AA amyloidosis patient in whom an obvious underlying disease is lacking.

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“…Renal cell carcinoma [13, 25,26], ovarian carcinoma [27], hepatocellular adenoma [28][29][30], bronchial carcinoma [6,31], Hodgkin's disease [32,33], cardiac (atrial) myxoma [34] etc. Islet amyloidosis (IA) characterized by islet amyloid polypeptide (IAPP, also called amylin) prohormone fragment deposition localized to the islets of Langerhans is an isolated (localized) form of amyloidosis [35][36][37][38][39][40].…”

Section: Chronic Cachectic Diseases or Malignanciesmentioning

confidence: 99%

β-cell Related Amyloidosis Localized to the Islets of Langerhans, Type II Diabetes Mellitus and Liponecrotic Pancreatitis in Rheumatoid Arthritis: A Postmortem Clinicopathologic Statistical Study of 234 Autopsy Patients

Bély¹,

Apáthy²

2019

IDCD

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The aim of this study was to determine the prevalence of systemic AA amyloidosis (AAa), islet amyloidosis (IA) and liponecrotic pancreatitis (LnP) including acute liponecrotic (aLnP), acute relapsing liponecrotic (aRelLnP), and chronic liponecrotic pancreatitis (chrLnP) in rheumatoid arthritis (RA), and to analyse the possible relationship between them.Patients and methods: At the National Institute of Rheumatology 11558 patients died between 1969 and 1998; among them 234 with RA, and all of them were autopsied. RA was confirmed clinically according to the criteria of the American College of Rheumatology (ACR). The diagnosis of DM was based on clinical data. Tissue samples of pancreas were available for histologic evaluation in 164 of 234 patients. AAa, IA and LnP were diagnosed histologically. Demographics of different patient cohorts were compared with the Student (Welch) t probe. The relationships between AAa and IA, furthermore between IA and DM or LnP (including aLnP, aRelLnP, chrLnP) were analyzed by Pearson’s chi-squared (c2) test.Results: AAa complicated RA in 42 (25.61%) of 164 patients. IA localized to the islets of Langerhans was observed in 16 (9.76%) of 164 pancreases. Clinically diagnosed DM was associated with RA in 31 (18.90%) of 164 patients. Pancreatitis with multiple liponecrotic foci (LnP) was found in 19 (11.58%) of 164 patients; aLnP existed in 9 (47.37%), aRelLnP in 4 (21.05%), and liponecrotic foci in combination with chronic fibrotic pancreatitis (chrLnP) in 6 (31.58%) of these 19 patients.Discussion and conclusions: There was no significant difference between female and male RA patients associated with AAa, IA, DM and LnP. The age, sex and onset of disease did not influence basically the prevalence of AAa, IA, DM and LnP except male patients with IA, whose mean age at death was significantly higher than the general RA population. IA (fibrillar amyloid IAPP deposits -AIAPP) is related to the activity of b cells and may presumably be a faulty product of b-cells (normal islets of Langerhans do not contain IA deposits). The progressive deposition of IAPP prohormon fragments inhibits the function of b-cells because of their toxic effect and/or blocking mechanically the blood supply of b-cells and they “die in their own product”. The significant correlation between IA and DM refers to a close connection between them, but not necessarily a direct cause and effect relationship; it may be an indirect result of damaged (apoptotic) b-cells. The early stage of IA is characterized by minimal IAPP deposits involving only a few islets, which represents a clinically latent DM, and the advanced stage of IA is characterized by massive IAPP deposits involving most of the islets, which correspond to clinically manifest DM. Based on the positive and significant correlation between IA and clinically not diagnosed DM, IA may be a good indicator of potential DM in the latent stage of disease. Therefore we recommend that all biopsy material and surgical specimens of pancreas to be tested for IA or IAPP deposition.

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Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma

Cited by 14 publications

References 4 publications

Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas

Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas

Causes of AA amyloidosis: a systematic review

β-cell Related Amyloidosis Localized to the Islets of Langerhans, Type II Diabetes Mellitus and Liponecrotic Pancreatitis in Rheumatoid Arthritis: A Postmortem Clinicopathologic Statistical Study of 234 Autopsy Patients

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