The Pathology of Hepatic Iron Overload

Deugnier, Yves; Turlin, Bruno

doi:10.1007/978-1-60327-485-2_17

Cited by 25 publications

(40 citation statements)

References 73 publications

(42 reference statements)

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“…No complications were observed with liver biopsy, extending the record of safety of liver biopsy in expert hands [3][4][5]. These results corroborate previous observations from these and other investigators [5][6][7] that support chemical measurement of the iron concentration in a liver-biopsy specimen as the reference standard for measurement of the hepatic iron concentration. Still, dissonance in the details must be acknowledged; no standard method for liver biopsy procedure, specimen processing and analysis has been established.…”

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confidence: 85%

Reference method for measurement of the hepatic iron concentration

Brittenham

2015

American J Hematol

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What should be the reference method for measurement of the hepatic iron concentration? In this issue of the American Journal of Hematology, Urru and colleagues [1] present further evidence that, in patients with thalassemia major and transfusional iron overload, chemical measurement of the iron concentration in a desiccated liver-biopsy specimen obtained by percutaneous biopsy is highly reproducible, as judged by measurement in a successive specimen, provided that two conditions are met. The first condition is the absence of cirrhosis, defined in this study as Ishak scores [2] of 5 or 6, because, with cirrhosis, the iron distribution within the liver is no longer uniform. The second condition is that the liver-biopsy specimen is adequate, 1 mg dry weight; variability increases with smaller samples. No complications were observed with liver biopsy, extending the record of safety of liver biopsy in expert hands [3][4][5]. These results corroborate previous observations from these and other investigators [5][6][7] that support chemical measurement of the iron concentration in a liver-biopsy specimen as the reference standard for measurement of the hepatic iron concentration. Still, dissonance in the details must be acknowledged; no standard method for liver biopsy procedure, specimen processing and analysis has been established. The biopsy needle (cutting needle or Menghini needle with saline flushing), exposure to saline, formalin, and fixation solutions, use of iron-free containers, specimen processing (fresh or paraffin-embedded; methods of deparaffinization and of digestion), methods of analysis (colorimetric, atomic absorption spectroscopy, inductively coupled plasma mass spectroscopy), and other factors differ among published studies and potentially influence results [5,6]. Hepatic iron concentrations measured in deparaffinized samples were a mean of 23% greater than those in desiccated tissue from fresh liver specimens [6]. The minimum weight for an adequate liver sample for analysis remains uncertain; evidence has been provided both for thresholds of 0.4 mg dry weight [8,9] and for 1 mg dry weight [1,4,5]. Reports of variability in the hepatic iron concentration in different areas of the liver have generally been restricted to studies of cirrhotic livers [10][11][12]; data are lacking in patients with transfusional iron overload without cirrhosis. Even so, the close relationship observed between the hepatic iron concentration and total body iron stores [4] in transfused patients with thalassemia who were free of cirrhosis suggests that the extent of variability is limited.An alternative view of the reference method for measurement of the hepatic iron concentration is that magnetic resonance imaging (MRI), recommended in a variety of guidelines, has become the de facto technique. Nonetheless, since acceptance of the manuscript by Urru et al.[1] for publication, a painstaking systematic review and meta-analysis of this use of MRI has appeared, [13] concluding that "measurements of liver iron concentration by ...

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confidence: 85%

Reference method for measurement of the hepatic iron concentration

Brittenham

2015

American J Hematol

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“…In contrast, in the more common autosomal recessive forms of hemochromatosis, including those attributable to mutations in the Hfe and Tfr2 genes, iron is preferentially deposited in periportal hepatocytes. 1,38,39 It has been hypothesized that the periportal distribution of iron seen in most autosomal recessive forms of hemochromatosis is attributable to a first pass effect of intestinally-absorbed iron carried by the portal venous system. 40 In contrast, in hepcidin 4 -and BMP6 16 -deficient mice, iron deposition is predominantly centrilobular.…”

Section: Discussionmentioning

confidence: 99%

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Steinbicker

Bartnikas

Lohmeyer

et al. 2011

Blood

161

170

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Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

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“…11,40,50,59,68,94 In humans, hepatic hemosiderosis and subsequent hepatic toxicity and failure, known as hemochromatosis, is either inherited as an autosomal recessive genetic disorder or secondary to hemolysis, alcoholism, transfusions, and other diseases. 34 Similarly, hepatic iron load in animals can be attributed to genetic and endogenous or exogenous factors, such as excessive dietary intake, alterations in iron metabolism, and hemolytic disorders. 68 In regard to hepatic hemosiderosis in the NMRs, despite abundant accumulation of iron in hepatocytes, overt clinical or histologic evidence of hepatic disease was not seen, and only rare hepatocellular necrosis or lobular collapse was detected.…”

Section: Husbandry-related Lesionsmentioning

confidence: 99%

Spontaneous Histologic Lesions of the Adult Naked Mole Rat (Heterocephalus glaber)

et al. 2013

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Naked mole rats (NMRs; Heterocephalus glaber) are highly adapted, subterranean, eusocial rodents from semiarid regions of the eastern horn of Africa and the longest-living rodent known with a maximum life span of up to 30 years. They are a unique model for aging research due to their physiology, extreme longevity, and, when compared to mice and rats, resistance to cancer. Published surveys of disease in NMRs are sparse. Captive colonies in zoological collections provide an opportunity to monitor spontaneous disease over time in a seminatural environment. This retrospective study describes common lesions of a zoo population over a 15-year period during which 138 adult NMRs were submitted for gross and histologic evaluation. Of these, 61 (44.2%) were male, 77 (55.8%) female, 45 (32.6%) died, and 93 (67.4%) were euthanized. The most frequent cause of death or reason for euthanasia was conspecific trauma (bite wounds) and secondary complications. Some common histologic lesions and their prevalence were renal tubular mineralization (82.6%), hepatic hemosiderosis (64.5%), bite wounds (63.8%), chronic progressive nephropathy (52.9%), and calcinosis cutis (10.1%). In sum, 104 (75.4%) NMRs had more than one of the most prevalent histologic lesions. No malignant neoplasms were noted; however, there was a case of renal tubular adenomatous hyperplasia with nuclear atypia and compression that in rats is considered a preneoplastic lesion. This retrospective study confirms the NMR's relative resistance to cancer in spite of development of other degenerative diseases and highlights the utility of zoological databases for baseline pathological data on nontraditional animal models.

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The Pathology of Hepatic Iron Overload

Cited by 25 publications

References 73 publications

Reference method for measurement of the hepatic iron concentration

Reference method for measurement of the hepatic iron concentration

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Spontaneous Histologic Lesions of the Adult Naked Mole Rat (Heterocephalus glaber)

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