BACKGROUND:Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA).METHODS:We defined AA as self-identified AA, blacks, or non-Hispanic blacks. We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D. We compiled prevalences of these genotypes in AA using published population and cohort data and numbers of men and women ≥18 y‬ in 2018 U.S. Census estimates. We defined iron overload (IO) and IO-related disease by genotype as previously reported in population and cohort studies of hemochromatosis in whites of European ancestry. We used these definitions to estimate prevalences and numbers of AA with IO and IO-related disease associated with hemochromatosis-associated HFE genotypes.RESULTS:There were ∼16,287,599 men and ∼17,644,898 women. HFE genotypes and their respective prevalences were: p.C282Y/p.C282Y, 0.00017 (6/34,905) [95% confidence interval 0.000034, 0.00031] and p.C282Y/p.H63D, 0.0012 (41/33,596) [0.000084, 0.0016]. IO prevalences were: men 0.000076 [0.000072, 0.000081] and women 0.0000061 [0.0000050, 0.0000073]. IO-related disease prevalences were: men 0.000063 [0.000059, 0.000067] and women 0.0000021 [0.0000014, 0.0000027]. There were ∼1021 [961, 1091] men and ∼36 [25, 48] women with IO-related disease.CONCLUSIONS:We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/32,103 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.

Porphyria cutanea tarda (PCT) is characterized by decreased uroporphyrinogen decarboxylase activity in hepatocytes, uroporphyrin I and heptacarboxyl porphyrin III accumulation, photosensitivity dermatitis, and increased storage iron. In women, estrogen therapy, including oral contraceptives, postmenopausal hormone replacement, and tamoxifen for breast cancer treatment, is a risk factor for PCT. We report the case of a woman who presented with PCT, HFE C282Y homozygosity, and hepatic iron overload and was using a contraceptive vaginal ring containing ethinyl estradiol, an estrogen. We discuss this case in the context of characteristics of other persons with PCT, including common HFE mutations, iron overload, and estrogen exposure.

BackgroundPrimary iron overload in African Americans has been reported predominantly from autopsy studies.MethodsWe characterized hepatic iron phenotypes in 83 African Americans who underwent liver biopsy during the interval 1990 to 1995. We tabulated pathology report form data, iron grades in hepatocytes (0–4) and Kupffer cells (0–3) and abnormal liver histology. Increased iron was defined as hepatocyte or Kupffer iron grades ≥2, respectively. Heavy iron was defined as hepatocyte iron grade 3 or 4. Primary iron overload was defined as the presence of grade 3 or 4 hepatocellular iron in the absence of evidence of chronic alcohol effect, viral hepatitis, steatosis, unexplained inflammation, chronic erythrocyte transfusion or chronic ingestion of iron supplements.ResultsThere were 37 men and 46 women (mean age: 53±15 [SD] years). We observed heavy ethanol consumption, 12.0%; viral hepatitis, 26.5%; steatosis without heavy ethanol consumption, 43.4%; inflammation, 45.6%; fibrosis, 26.2% and bridging fibrosis/ cirrhosis, 29.4%. Logistic regression on bridging fibrosis/cirrhosis revealed positive associations with heavy ethanol consumption (P=0.0410) and viral hepatitis (P=0.0044). The 22 patients (26.5%) with increased iron had greater mean age, proportion of men and heavy ethanol consumption. Five patients had heavy iron staining, among whom were 3 women (mean age: 54 years) with primary iron overload. Two of the 3 women had cirrhosis and diabetes mellitus.ConclusionsAmong 83 adult African Americans who underwent liver biopsy, 3.6% had hepatic iron phenotypes consistent with primary iron overload.

The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.

UNLABELLED:Few recommendations exist for management of chronic lead toxicity in instances when the source of lead exposure cannot be removed. CASES:We describe 2 patients who had shotgun wounds resulting in multiple retained lead pellets. They developed elevated blood lead levels and were treated with 2 weeks of high-dose oral succimer before being placed on maintenance oral succimer therapy with the goal of sustaining suppressed lead levels. DISCUSSION:Retained lead pellets have been associated with increasing blood lead levels over time. Chronic lead toxicity can cause significant morbidity. Few treatments for lead toxicity are available, and there is scarce data on maintenance therapy for patients who have large numbers of retained shotgun pellets. CONCLUSIONS:This case series documents 2 patients who continue on maintenance oral chelation therapy with succimer in an effort to prevent the sequelae of chronic lead toxicity by maintaining blood lead levels less than 20 μg/dL.

Few recommendations exist for management of chronic lead toxicity in instances when the source of lead exposure cannot be removed.We describe 2 patients who had shotgun wounds resulting in multiple retained lead pellets. They developed elevated blood lead levels and were treated with 2 weeks of high-dose oral succimer before being placed on maintenance oral succimer therapy with the goal of sustaining suppressed lead levels.Retained lead pellets have been associated with increasing blood lead levels over time. Chronic lead toxicity can cause significant morbidity. Few treatments for lead toxicity are available, and there is scarce data on maintenance therapy for patients who have large numbers of retained shotgun pellets.This case series documents 2 patients who continue on maintenance oral chelation therapy with succimer in an effort to prevent the sequelae of chronic lead toxicity by maintaining blood lead levels less than 20 μg/dL.

Neonatal hemochromatosis (NH) is a heterogeneous group of disorders characterized by severe fetal or neonatal liver injury including cirrhosis, and hepatic and extrahepatic iron overload that occurs in a distribution similar to that of HFE hemochromatosis. Extensive liver injury and dysfunction are the dominant clinical features. Fetal loss or early neonatal death is usual, although some children survive. Despite its rarity, NH is one of the most commonly recognized causes of liver failure in neonates, has a high recurrence rate in sibships, and is a frequent indication for liver transplantation in the first 3 months of life. There is mounting evidence that many cases are caused by maternal alloimmunity against a fetal liver determinant. Treating at-risk mothers during pregnancy with intravenous IgG markedly decreases the risk and severity of NH in their subsequent offspring. Other NH cases are due to other acquired conditions of the mother, to intrauterine infection, or to rare heritable disorders of the fetus.

Iron overload is characterized by excessive iron deposition in and consequent injury and dysfunction of target organs, especially the heart, liver, anterior pituitary, pancreas, and joints (Chapter 5). Because physiologic mechanisms to excrete iron are very limited, patients with iron overload and its complications need safe, effective therapy that is compatible with their co-existing medical conditions. Worldwide, prevention of death due to cardiac siderosis is the most important potential benefit of therapy. The incidence of cardiac complications is greatest in patients with beta-thalassemia major and other heritable anemias treated with multiple transfusions. The liver is the primary target organ of iron overload in hemochromatosis and African iron overload, although maintaining normal hepatic function is important in all patients with iron overload. Preventing injury to endocrine organs is critical in children with iron overload. Successful treatment or prevention of iron overload increases quality of life and survival in many patients.

Iron is an essential element, but in excess it can result in cell injury (Table 3.1). When storage mechanisms are overwhelmed, iron in low molecular weight forms can play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates, resulting in wide-ranging impairment in cellular function and integrity. The rate of free radical production must overwhelm the cytoprotective defenses of cells before injury occurs.