Pathological Characteristics of the Livers of Patients with Itai-Itai Disease (Chronic Cadmium Toxicity)
Hayato Baba, Megumi Yazaki, Takashi Minamisaka, Kohei Nagata, Tatsuhiro Tsuda, Koichi Tsuneyama, Keiko Aoshima. University of Toyama, Toyama, Japan; Hagino Hospital, Toyama, Japan
Background: Itai-itai disease (IID), which is recognized in Japan as a pollution-related illness, is caused by chronic exposure to the mineral cadmium (Cd). Excess Cd accumulation in the renal proximal tubules causes renal atrophy and secondary osteomalacia. Liver failure is a well-known complication of acute Cd toxicity, but there are no detailed reports of the liver histopathology of IID patients. In the present study, we assessed the histopathological characteristics of the livers of IID patients.
Design: Autopsy specimens from 49 IID patients and 27 patients not exposed to Cd pollution were examined. Cd concentration was measured using fresh organs. H&E staining was performed along with Berlin blue staining for detecting iron deposition and immunostaining for metallothionein (MT), which binds and detoxifies Cd, and megalin, which binds to Cd–MT complexes and leads to endocytosis.
Results: The Cd concentration in the liver was highest among all of the assessed organs from the IID patients; it was second highest after the kidney among the controls. Cd accumulation in the organs of the IID patients was 5.2 (liver), 4.1 (pancreas), 4.9 (thyroid gland), 7.3 (muscle), 3.3 (rib), 0.38 (renal cortex), and 0.62 (renal medulla) times higher than that of the controls. No common pathological changes such as necroinflammation, fibrosis, or carcinogenesis were observed in the livers of the IID patients. Hemosiderosis was found in 29/49 cases. MT expression was greater in the livers of the IID patients compared with the controls, but there was no remarkable expression of megalin in either group.
Conclusions: Because the liver is a known target of acute Cd toxicity, we hypothesized that Cd specifically accumulates in the liver, resulting in chronic liver injury. However, Cd also accumulated in most of the other organs, and there was no remarkable expression of megalin in the liver. Therefore, we found that Cd accumulation is not liver-specific. Moreover, despite the high Cd concentration in the liver, no specific injury was detected, indicating that the liver can detoxify Cd. Possible reasons for these results are (1) the liver is the main MT-producing organ, and thus, it is easier to retain MT–Cd complexes here, resulting in a high level of Cd in the liver, and (2) the quantity of Cd accumulation in the liver does not easily reach a toxic level because endocytosis of Cd by megalin is not highly activated. Thus, it appears that kidney injury among IID patients is restrained by increasing the expression of MT and by inhibiting the effect of megalin.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 242, Wednesday Morning