Cutaneous and lingual papules as a sign of β2 microglobulin-derived amyloidosis in a long-term hemodialysis patient

ARTICLE

Auteur(s) : Takeshi UENOTSUCHI^{1, 4}, Shinichi IMAFUKU¹, Masaharu NAGATA², Hiromaro KIRYU³, Keisuke MORITA⁴, Tetsuya KOGA⁴, Masutaka FURUE⁴

¹ Departments of Dermatology and
² Nephrology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
³ Department of Dermatology, School of Medicine, Fukuoka University, Fukuoka, Japan
⁴ Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Article accepted on 1/04/2003

Beta2-microglobulin-derived amyloidosis (Aβ2M amyloidosis) is a systemic amyloidosis that has become a major concern in patients who have undergone long-term hemodialysis for more than 10 years [1]. Aβ2M amyloidosis was initially believed to occur only in chronic hemodialysis patients, and was termed “dialysis related amyloidosis”, it soon became clear that the amyloidosis can develop in patients on any type of renal replacement therapy and even in uremic, predialysis patients. Clinical symptomatology is largely restricted to articular and periarticular sites, and in rare cases cutaneous and lingual manifestations have been described [2-4]. There are three types of cutaneous manifestations in Aβ2M amyloidosis, namely, lichenoid plaque type, hyperpigmentation type, and subcutaneous type which have been previously reported. Lichenoid plaque type is rare. We herein report a male patient with the lichenoid type of Aβ2M amyloidosis.

Case report

The 56-year-old man had been on maintenance hemodialysis for 29 years for renal failure due to chronic glomerulonephritis. He developed dialysis arthropathy and had a bilateral decompression operation for carpal tunnel syndrome. He had no other history that would indicate another cause of amyloidosis, nor was there a family history of amyloidosis.
He had asymptomatic papules on his chest wall, abdominal wall, back, and extremities. The papules gradually increased in number, although the patient did not remember when the first lesion had appeared.
Physical examination revealed many skin-colored tiny papules grouped all over the body except for the face. The surface of the papules was smooth and glossy. Multiple small, pale-yellow papules were noted on the surface of the tongue without macroglossia (Fig. 1a, b).
Histology of the papules on the abdomen and the right hand revealed deposits of amorphous eosinophilic material in the papillary dermis. The covering epidermis was thin (Fig. 2). The deposits were proved to be amyloid because they were positively stained with Congo red and showed characteristic apple-green birefringence under polarization.
Using an indirect immunoperoxidase technique, deposits stained positive with antibody to β2 microglobulin (DAKO, Kyoto, Japan) (Fig. 3), but not to serum amyloid A (AA) protein, pre-albumin, κ or λ light chain. The deposits were also negative for immunostaining using anti-advanced glycation end products (AGEs) antibody (6D12, anti CML and CLE antibody), which was kindly provided by Dr Seiko Horiuchi (Kumamoto University, Kumamoto, Japan).
Histology also revealed some ductal structures in the area of amyloid deposits. The ductal structures showed positive staining with antibody to either CD 34 or CEA, which indicated that small vessels and sweat ducts were trapped without exclusion. However, eccrine glands, hair follicles, and the walls of large blood vessels were not affected by amyloid deposits.
The histopathological evidence and history of long-term hemodialysis confirmed that the skin lesions were a manifestation of β2-microglobulin-derived amyloidosis (Aβ2M amyloidosis).

Discussion

Aβ2M amyloidosis can develop in patients on any type of renal replacement therapy and even in uremic, predialysis patients. Its incidence becomes higher after duration of hemodialysis of more than 10 years [1].
The Aβ2M amyloidosis of the tongue has been reported in patients underlying long-term hemodialysis. Matsuo et al. reported that its prevalence was nil in patients dialyzed for less than 20 years and 20 % in those treated for more than 20 years [2, 3]. The yellowish nodules are the pattern of Aβ2M amyloidosis rather than the usual diffuse pattern that caused macroglossia in primary amyloidosis.
Several case reports about the cutaneous manifestations of Aβ2M amyloidosis have been reported. According to histological and clinical features, skin manifestation was classified into three types, namely, lichenoid plaque, hyperpigmentation, and subcutaneous tumor types [4-7].
Concerning lichenoid plaque type, to our knowledge, only one case was previously reported in the English language, but several cases were reported in the Japanese language [4]. Characteristic features of the lichenoid plaque type are lesions consisting of groups of pinhead-sized shiny papules, usually without subjective symptoms, such as pain, itching, and numbness. Histologically, amyloid deposits are present in the dermal papillae, along the dermo-epidermal junction, and often cause expanded dermal papillae, thinned overlying epidermis, and elongated and displaced rete ridges [4].
Three cases of Aβ2M amyloidosis of the hyperpigmentation type have been reported [5]. The histological features of this type are similar to those of the lichenoid plaque type except for the presence of melanin pigment in the papillary dermis.
In the subcutaneous tumor type almost all lesions are located in the buttocks, which may be caused by local mechanical stress in daily life [6, 7]. Major symptom is pain. Amyloid deposits are observed in the reticular dermis and subcutaneous tissue, and, characteristically, the infiltration of mononuclear phagocytes and other inflammatory cells around the amyloid deposits are observed frequently.
β2 microglobulin is reported to be a precursor of amyloid in Aβ2M amyloidosis and has an affinity for condroitin sulfate proteoglycans in the extracellular matrix [8]. Deposits of β2 microglobulin have been observed most frequently in condroitin sulfate-rich tissues such as the carpal ligament, synovium of large joints, juxta-articular tissue of bone, and intervertebral disks, and may cause carpal tunnel syndrome, bone cysts, destructive spondyloarthropathy, arthropathy, and fracture [8, 9]. On the contrary, these deposits have rarely been observed in the skin [10].
In contrast to other types of amyloidosis, Aβ2M amyloidosis is characterized by inflammatory infiltration around amyloid deposits, which is striking especially around bone and periarticular areas, leading to bone and joint destruction [11, 12]. The inflammation may be induced by the following mechanism. Amyloid deposits composed of β2 microglobulin convert into AGEs. Mononuclear phagocytes have a receptor for AGE (RAGE), a cell surface polypeptide of the immunoglobulin superfamily. AGE engagement of RAGE is the first step in an inflammatory response as well as AGE-β2 microglobulin-induced monocytic chemotaxis and tumor necrosis factor-α (TNF-α) expression [11-13].
Immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in the amyloid deposits in patients with long-term (over 10 years) hemodialysis, but negative in those with short-term (under 5 years) treatment [8, 14, 15]. The formation of AGEs and the infiltration of mononuclear phagocytes are considered to take place over a long period.
With regard to the infiltration of inflammatory cells, the difference between the lichenoid plaque type and subcutaneous tumor type seems to be closely related to the duration of the lesions. In the lichenoid plaque type, the amyloid deposits are superficial, and the eruption may be noticed early in the course. On the contrary, in the subcutaneous tumor type, lesions are deeper and may be noticed late, during which time the inflammatory response is initiated.
Hemodialysis has permitted long-term survival in patients with severe renal failure. As the number of patients undergoing long-term hemodialysis increases, more cases of skin lesions can be expected. < 

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