Abstract
Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.
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References
Pietrangelo A (2010) Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 139:393–408
Winter WE, Bazydlo LA, Harris NS (2014) The molecular biology of human iron metabolism. Lab Med 45:92–102
Granick S, Michaelis L (1942) Ferritin and apoferritin. Science 95:439–440
Lillie RD (1939) Experiments on the solubility of hemosiderin in acids and other reagents during and after various fixations. Am J Pathol 15:225–239
Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, Fletcher L, Loréal O, Brissot P, Halliday JW (1993) Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology 17:30–34
Ganz T (2003) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102:783–788
Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093
Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200
Hattori A, Miyajima A, Tomosugi N, Tatsumi Y, Hayashi H, Wakusawa S (2012) Clinicopathological study of Japanese patients with genetic iron overload syndromes. Pathol Int 62:612–618
Hayashi H, Wakusawa S, Yano M, Okada T (2007) Genetic background of Japanese patients with adult-onset storage diseases in the liver. Hepatol Res 37:777–783
Hawkins-Salsbury JA, Reddy AS, Sands MS (2011) Combined therapies for lysosomal storage disease: is the whole greater than the sum of its parts? Hum Mol Genet 20:R54–R60
Reuser AJ, Van Den Hout H, Bijvoet AG, Kroos MA, Verbeet MP, Van Der Ploeg AT (2002) Enzyme therapy for Pompe disease: from science to industrial enterprise. Eur J Pediatr 161(Suppl 1):S106–S111
Ono Y, Ishigami M, Hayashi K, Wakusawa S, Hayashi H, Kumagai K, Morotomi N, Yamashita T, Kawanaka M, Watanabe M, Ozawa H, Tai M, Miyajima H, Yoshioka K, Hirooka Y, Goto H (2015) Copper accumulates in livers of patients with iron overload syndromes. J Clin Transl Hepatol 3:85–92
Collins JF, Prohaska JR, Knutson MD (2010) Metabolic crossroads of iron and copper. Nutr Rev 68:133–147
Hanaichi T, Kidokoro R, Hayashi H, Sakamoto N (1984) Electron probe X-ray analysis on human hepatocellular lysosomes with copper deposits: copper binding to a thiol-protein in lysosomes. Lab Invest 51:592–597
Koyama C, Hayashi H, Wakusawa S, Ueno T, Yano M, Katano Y, Goto H, Kidokoro R (2005) Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene. J Hepatol 43:740–742
Watanabe M, Asai C, Ishikawa K, Kiyota A, Terada T, Kono S, Miyajima H, Okumura A (2010) Central diabetes insipidus and hypothalamic hypothyroidism associated with aceruloplasminemia. Intern Med 49:1581–1585
Tstuchida K, Taneda S, Misawa K, Akimoto Y, Bando H, Hagiwara S, Komori K, Hattori A, Tatsumi Y, Hayashi H, Nakayama H, Mada N (2010) Novel compound heterozygote mutations in a Japanese patient with hemochromatosis who has severe diabetes, pituitary hypogonadism and liver fibrosis. Diabetes 53:247–252 (in Japanese)
Yamashita T, Morotomi N, Sohda T, Hayashi H, Yoshida N, Ochi K, Ohkura I, Karita M, Fujiwara H, Yamashita H, Hattori A, Tatsumi Y (2014) A male patient with ferroportin disease B and a female patient with iron overload similar to ferroportin disease B. Clin J Gastroenterol 7:260–264
Kaneko Y, Miyajima H, Piperno A, Tomosugi N, Hayashi H, Morotomi N, Tsuchida K, Ikeda T, Ishikawa A, Ota Y, Wakusawa S, Yoshioka K, Kono S, Pelucchi S, Hattori A, Tatsumi Y, Okada T, Yamagishi M (2010) Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders. J Gastroenterol 45:1163–1171
Kurz T, Eaton JW, Brunk UT (2011) The role of lysosomes in iron metabolism and recycling. Int J Biochem Cell Biol 43:1686–1697
Blaby-Haas CE, Merchant SS (2014) Lysosome-related organelles as mediators of metal homeostasis. J Biol Chem 289:28129–28136
Vashchenko G, MacGillivray RT (2013) Multi-copper oxidases and human iron metabolism. Nutrients 27:2289–2313
Zhao M, Matter K, Laissue JA, Zimmermann A (1995) Copper/zinc and manganese superoxide dismutase immunoreactivity in hepatic iron overload diseases. Histol Histopathol 10:925–935
Schröder JM (2005) Ferritinopathy: diagnosis by muscle or nerve biopsy, with a note on other nuclear inclusion body diseases. Acta Neuropathol 109:109–114
Yoshida K, Hayashi H, Wakusawa S, Shigemasa R, Koide R, Ishikawa T, Tatsumi Y, Kato K, Ohara S (2017) Ikeda SI (2016) Coexistence of copper in the iron-rich particles of aceruloplasminemia brain. Biol Trace Elem Res 175:79–86
Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier BS, Siani V, Benson MD, Calvas P, Miravalle L, Rascol O, Delisle MB (2004) Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J Neuropathol Experiment Neurol 63:363–380
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Hayashi, H., Tatsumi, Y., Wakusawa, S. et al. Inclusion bodies of aggregated hemosiderins in liver macrophages. Med Mol Morphol 50, 205–210 (2017). https://doi.org/10.1007/s00795-017-0163-x
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DOI: https://doi.org/10.1007/s00795-017-0163-x