Hemochromatosis in Two Female Olive Baboons (Papio anubis)

This report describes hemochromatosis associated with chronic parenteral iron dextran administration in 2 female olive baboons (Papio anubis). These baboons were enrolled on an experimental protocol that induced and maintained anemia by periodic phlebotomy for use in studying potential treatments for sickle cell anemia. The 2 baboons both presented with clinical signs consistent with iron overload, including decreased appetite, weight loss, elevated liver enzymes, and hepatosplenomegaly. Histopathologic findings supported a morphologic diagnosis of systemic hemosiderosis, as evidenced by the overwhelming presence of iron in the reticuloendothelial system and liver after the application of Prussian blue stain. This finding, combined with the clinical presentation, lead to a final diagnosis of hemochromatosis. This case report suggests that providing anemic patients with chronic parenteral iron supplementation in the absence of iron deficiency can result in iatrogenic iron overload and subsequent systemic toxicity. Furthermore, these subjects may present with hemochromatosis and its associated clinical signs many years after cessation of iron supplementation.

Iron is an essential micronutrient that plays an important role in cellular proliferation, oxygen transport, and cellular energy generation.^13,26,31 The highest levels of iron in the body is found in the erythrocytes, followed by the liver, reticuloendothelial system, and skeletal muscle.⁹ Three main mechanisms regulate iron: 1) dietary absorption through the proximal duodenum; 2) recycling of senescent red blood cells by macrophages; and 3) storage in the liver. The liver produces the hormone hepcidin, which is the primary negative regulator of systemic iron metabolism.³⁸ Hepcidin controls the release of iron from enterocytes and macrophages into the circulation by binding to and degrading ferroportin, the only mammalian iron exporter.³⁵ When plasma iron levels are high, hepatocytes increase hepcidin synthesis. The increased hepcidin subsequently suppresses gastrointestinal absorption of exogenous iron and iron release from macrophages into circulation.³¹Approximately 1 to 2 mg of iron is lost per day through enterocyte and skin sloughing.³⁸ Iron can also be lost by hemorrhage, menstruation, and parasitic infestation.³⁸ Other than these, the body has no active mechanism for iron excretion. Iron overload can result from acute iron toxicity or chronic accumulation of iron over time.³⁵ Iron is primarily stored in the liver in the form of ferritin, and excess iron is transformed into hemosiderin, an oxidized form of ferritin. Hemosiderin is an iron-containing pigment found primarily in macrophages and hepatocytes.³⁵Hemosiderosis occurs when iron accumulates in tissues, but causes no subsequent organ injury or dysfunction. It is not typically pathologic and can be reversed.⁹ In contrast, hemochromatosis occurs when iron accumulation results in organ injury and dysfunction.³⁵ The 2 types of hemochromatosis are primary and secondary. Primary hemochromatosis, also known as hereditary hemochromatosis, is the result of inherited mutations in genes that are important for iron homeostasis. The most common gene involved in primary hemochromatosis is HFE, an autosomal recessive trait.¹¹ Almost all forms of primary hemochromatosis involve low levels of hepcidin expression.¹¹ Secondary hemochromatosis can occur due to iron-loading anemias such as thalassemia and sideroblastic anemia, chronic liver disease (for example, hepatitis C), and iatrogenic causes, such as excess iron in the diet or parenteral administration.¹⁶ Hemolytic anemia and repeated blood transfusions can also result in secondary hemochromatosis.³⁵ In primary hemochromatosis, iron typically accumulates in the liver, pancreas, heart, and endocrine glands for many years.^16,24 In contrast, secondary hemochromatosis patients often accumulate iron in the reticuloendothelial system, bone marrow, and lymph nodes¹⁶ over a shorter time period,²⁴ with excess iron accumulating in the hepatocytes after the reticuloendothelial system has become saturated with iron.¹⁶ Symptoms of iron overload can vary among individuals due to the number of organ systems affected. These symptoms may include lethargy, arthralgia, skin hyperpigmentation, abdominal pain, abnormal liver chemistry tests, and hepatomegaly.¹⁵ In the current report, we describe 2 cases of hemochromatosis in female baboons after chronic parenteral administration of iron dextran as part of an anemia maintenance protocol used to study sickle cell anemia treatments.