Metal Storage Disorders

The current issue of Seminars in Liver Disease is devoted to iron and copper metabolism and related diseases. Iron and copper are transition metals, essential for the survival of most organisms, particularly those existing in an oxygen-rich environment, due to their capacity to participate in one-electron exchange reactions. Their “essentiality” relates both to our need to obtain a supply of these transitional metals from our diet and from their function as critical cofactors in numerous essential proteins: iron in the heme-containing proteins, electron transport chain, and microsomal electron transport proteins; and copper in superoxide dismutase, lysyl oxidase, cytochrome c oxidase, tyrosinase and dopamine-β-hydroxylase. Interestingly, the same property that makes iron and copper essential also may generate noxious free radicals that can cause injury to cell membranes and organelles. Therefore, concentrations of circulating iron and copper demand a concerted and tight regulation as both excess or deficiency impairs cellular functions and causes cell toxicity and organ disease. Excess tissue iron or copper is found in numerous human diseases, and is typified by hereditary hemochromatosis (HH) and Wilson disease (WD), two of the more common genetic disease states associated with deranged metabolism of metals in humans. Recently, we have witnessed dramatic advances in iron and copper biology and learned how their dysregulated metabolism in the liver may lead to severe systemic diseases. The parallel rapid progress in genetics has impacted diagnostic strategies and management of common iron and copper disorders.

Since the identification of the gene responsible for classic HFE-HH, there have been further major advances in understanding the handling of iron, and the liver, the source of the iron-regulatory hormone hepcidin, is now placed at the center of iron homeostasis. In this issue of the Seminars, two distinct chapters are devoted to the dramatic advances made over the past few years in the field of iron metabolism. De Domenico, Ward, and Kaplan, from the University of Utah, Salt Lake City, review the basic regulatory mechanisms of iron homeostasis as elucidated by the hepcidin–ferroportin axis. They especially focus on ferroportin biology, its hepcidin-dependent and independent degradation pathways, and the relevance of ferroportin mutations in human diseases, as recapitulated in the recently described ferroportin disease. Babitt and Lin, from the Massachusetts General Hospital and Harvard Medical School in Boston, review the current understanding of hepcidin regulation, with emphasis on the molecular mechanisms by which iron regulates the hormone and the key role played by the bone morphogenetic protein-hemojuvelin-SMAD signaling pathway in this process. They also show the central role of this hormone–peptide in the pathogenesis of human hemochromatosis syndromes that, despite their genetic and phenotypic diversity, all appear to be caused by reduced hepcidin synthesis/activity, leading to a failure to prevent excess iron from entering the circulation.

Olynyk and collaborators from the Fremantle Hospital, in Fremantle, Australia, discuss management and natural history of classic HFE-HH in the post-HFE era. Longitudinal population studies have now defined the natural history of HH and recognized the influence of genetic and environmental modifiers on phenotypic expressivity. The authors extensively discuss how the diagnostic workout of HH has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches, and propose a diagnostic algorithm to manage HH.

Pietrangelo and collaborators from the “Mario Coppo” Liver Research Center in Modena, Italy, review pathogenesis and clinical manifestations of hepatic iron overload. They update the genetics, epidemiology, and clinical features of non HFE-hemochromatosis syndromes, and discuss in-depth ferroportin disease, the most common non-HFE-hereditary iron-loading disorder in humans, caused by a loss of the iron export function of ferroportin. An overview of common causes of nonhereditary hepatic iron excess is also presented.

Deugnier and Turlin, from the University of Rennes, France, review liver pathology during genetic and acquired causes of hepatic iron overload. They emphasize the impact of HH genetic testing, improved imaging techniques for liver iron, and noninvasive methods for liver fibrosis on the traditional diagnostic approach to these disorders. They revisit the role of liver biopsy in HH particularly in a prognostic perspective emphasizing objectives and limitations of a modern histopathologic approach.

As much as the discovery of HFE and hepcidin have changed our understanding of iron-overload disorders, the identification of ATP7B on chromosome 13 as the gene responsible for WD has ushered in a new era in our understanding of copper metabolism and enabled new diagnostic testing. Sections of this issue devoted to copper metabolism focus mainly on WD and molecular genetic studies of ATP7B. For completeness, however, the article by Johncilla and Mitchell, from Yale University Medical Center, not only reviews the pathology of copper-induced hepatic injury in WD, but also describes pathologic changes in the liver in other copper-overload disorders.

Our knowledge of the pathophysiology of copper metabolism and the natural history of WD are continuing to evolve even though the syndrome was described over a century ago. Our present day knowledge owes much to the early investigations of hepatic copper metabolism and has accelerated since the identification of ATP7B. Rosencrantz and Schilsky, from Yale University Medical Center, highlight this journey from an invariably fatal neurologic curiosity to a disorder treatable with medical therapy or liver transplantation. Furthermore, they discuss the integrated role of phenotypic characterization and molecular testing that has broadened and enhanced our criteria for patient identification. This is complemented by discussions in the chapter on ATP7B by Bennet and Hahn (see below), along with an approach to treatment for WD for asymptomatic or symptomatic patients with liver or neurologic disease.

The evolution of molecular testing has enabled full-length sequencing and other technical improvements that allow testing for ATP7B mutations; this has impacted greatly on practice. In the contribution by Bennet and Hahn from the University of Washington, Seattle, the current knowledge of the molecular genetics for WD is reviewed, along with their viewpoint on the diagnostic utility and pitfalls of molecular genetic testing and the future of genotype and phenotype correlations. This area will clearly continue to evolve with time.

The chapter devoted to the pathology of copper overload and WD by Johncilla and Mitchell highlights that there are identifiable but not necessarily specific patterns that are present with disease progression in untreated patients with WD that may be helpful for disease diagnosis and prognostication. They point out the wide variety of findings at the light microscopic and ultrastructural level for the liver in disorders of copper overload and WD.

We are grateful to the authors for compiling these outstanding contributions based on their deep knowledge and experience. We hope that our readers enjoy this issue as much as we have enjoyed assembling it, and come away with a better appreciation how progress in genetics has impacted our understanding, diagnostic strategies, and management of inherited disorders of iron and copper metabolism.