Clinical characteristics of amyloidosis depend on the specific type of offending fibrillar amyloid. AL amyloidosis, in particular, may cause deposition in multiple vital organs, and leads to various kinds of clinical syndromes such as cardiomyopathy, proteinuria, macroglossia, autonomic dysfunction, and neuropathy. AA amyloidosis is linked with various chronic inflammatory disorders, chronic infections, and rarely with neoplasms [15]. Systemic amyloidosis is an important disease that can lead to dysfunction in vital organs, deterioration in quality of life, and death. AA amyloidosis is also an important life-threatening complication in the course of rheumatologic diseases by causing morbidity and mortality [16]. AA amyloidosis is the main complication of FMF. Amyloidosis risk factors in FMF cases are male gender, and presence of arthritis, M694V and serum apolipoprotein A (SAA) A/A homozygosity, and familial amyloidosis history. The typical phenotype of AA amyloidosis includes the involvement of the kidneys, gastrointestinal tract, spleen, and liver, in addition to thyroid and adrenal gland involvement which occurs rarely [17]. The physician should consider the presence of amyloidosis, especially in the presence of proteinuria, hepatomegaly, or splenomegaly in a patient with FMF. Proteinuria and splenomegaly of our patient suggested amyloidosis and the main AA amyloidosis risk factors in our patient were her M694V homozygous status and (possible) family history of amyloidosis.
A scarce number of gynecological amyloidosis cases have been reported in the literature. Of them, the majority is in localized form. Affected sites were described as uterus, vagina, and cervix [5, 7, 8]. Existing literature suggests uterine (endometrial or myometrial) amyloidosis is a rare condition. Amyloid deposition confined to a site may be associated with several endocrine organs or tumors, taking its origin from the relevant hormones or local protein precursors [2]. Localized uterine amyloidoses have also been described in malignancy- or pregnancy-associated fashion [5, 6]. In our literature search on uterine amyloidoses associated with systemic amyloidosis, as a rare site of involvement compared to other organs, we have identified five cases only. Four of them were AL amyloidosis and just one was AA amyloidosis [9,10,11,12,13]. Two of the AL amyloidosis patients had multiple myeloma and two had primary amyloidosis. Moreover, localized primary amyloidosis formerly reported in one patient was exclusively localized in the uterus [18]. (Causes of uterine amyloidosis according to the literature are summarized in Table 2.) In our search, the single patient with systemic AA amyloidosis was under follow-up for RA. On the other hand, uterine involvement of amyloidosis/amyloid deposits from systemic amyloidosis associated with FMF has not been described so far. Our case is the first-of-its-kind that FMF-induced AA amyloidosis has been observed in the uterus (and ovaries). The previously reported AA amyloidosis was in an RA patient who had undergone endometrial biopsy that was retrospectively explored as a part of an investigation targeting dysfunctional uterine bleeding, and in turn, secondary amyloidosis was eventually diagnosed. That patient had samples collected from other organs before the diagnosis of uterine amyloidosis which were re-stained to indicate that there were no amyloid deposits in liver biopsy, surgical bone, or synovial samples. Later, a gastric biopsy was performed for stomach ulcers which revealed amyloids. Likewise, splenic, ovarian, and gastric biopsies of our patient were accommodating amyloid deposition. Neither of the patients had undergone a renal biopsy, but they were deemed to have renal amyloidosis based on proteinuria and renal insufficiency. Consequently, both patients were suffering diffuse involvement of systemic AA amyloidosis where the uterus was a part of such systemic involvement. Yue et al. have highlighted the importance of exploring the previously obtained tissues before conducting any invasive procedures in a patient with suspected amyloidosis [13]. Once we have encountered the previously documented uterine amyloidosis in our literature search, we have specifically requested amyloid staining. Thereupon, staining was done by the pathologist and demonstrated amyloid accumulation in the uterus. (The features of our patient with uterine involvement of AA amyloidosis and the other case in literature are given in Table 3.)
Table 2 Causes of uterine amyloidosis Table 3 Characteristics of our patient and other case in the literature AA amyloidogenesis may take place at various layers of the uterus. While AA amyloidosis in RA patient was detected at perivascular regions of the endometrium, the case with AL amyloidosis was shown to have deposition at myometrial blood vessels [9, 13]. Amyloids were determined in the superficial myometrium and endometrium in our case. In the AL amyloidosis case described by Copeland et al., on the other hand, a broader involvement covering uterus, cervix, corpus, fallopian tubes, and ovaries as well as the appendix and omentum was mentioned [11]. AA amyloidosis secondary to tuberculosis involving adrenal glands, liver, and kidneys in addition to ovaries which is accompanied by calcification has been described in the literature. However, it was not clarified whether the uterus was involved or not [19]. Similar to the case reported by Copeland et al., we have histopathological evidence of ovarian amyloidosis in our case.
Amyloidosis patients are predisposed to potentially life-threatening hemorrhage. Pathogenic factors contributing to the amyloidosis-induced bleeding depend on the type and organ deposition of amyloidosis. Abnormal bleedings stemming from amyloidosis may be ascribed to acquired haemostatic abnormalities, abnormal fibrin polymerization and hyperfibrinolysis, platelet dysfunction, and amyloid deposition [20]. Coagulation factor deficiencies are peculiar to AL amyloidosis patients and have been reported only in specific cases in other amyloidoses, where accumulated amyloid is mainly held responsible for the bleed. Amyloid angiopathy composed of increased fragility of the blood vessels and impaired vasoconstriction may cause bleeding. The exact pathophysiology mechanisms, however, remain unclear. Definite diagnosis of local amyloid deposition can only be made upon a histological investigation [20].
Yue et al. have speculated bleeding suffered by cases with uterine amyloidosis which is arising from the fragile blood vessels inflicted by amyloids [13]. According to Copeland et al., amyloid infiltration of corpus uteri compromises uterine contractions, eventually promoting prolonged bleeding events during menstrual periods [11]. Jongen et al. also proposed that amyloidosis-related bleeding diathesis is most probably caused by increased fragility and impaired contractility of the vasculature (amyloid angiopathy) due to subendothelial amyloid build-up [18]. Although our patient had hypersplenic thrombocytopenia (with an onset of menometrorrhagia while PLT within normal limits), platelet dysfunction was considered due to uraemia and systemic amyloidosis. She had normal results for haemostatic parameters and clotting factors. We believe that platelet dysfunction along with uterine amyloid deposition (amyloid angiopathy) was the major risk factor for bleeding in our case. Jongen et al. claim that uterine amyloidosis, despite infrequent, must be included in the differential diagnosis of postmenopausal bleeding [18]. Nevertheless, our patient was of premenopausal age. Therefore, not only postmenopausal bleeding but also treatment-resistant premenopausal menorrhagia warrants considering uterine amyloid deposition, especially in the event of any other organ involvement of systemic amyloidosis.
In conclusion, endometrial amyloid existence may be more common than the currently anticipated and established figures. As we understood from our literature review, which is in line with our own experience, so far, the patients could usually be diagnosed through a retrospective search for amyloid as uterine amyloidosis is not a well-recognized site of involvement. While taking care of any diseases which may cause amyloidosis, rheumatologists should be cautious about possible uterine involvement and ensure that histopathological amyloid testing is carried out at diagnostic samples, particularly in patients presented with other organ involvement and menometrorrhagia.