Iron Overload (Hemochromatosis)


Definition

Hereditary hemochromatosis is an inherited disorder that leads to iron overload due to excessive absorption of dietary iron because of a deficiency of hepcidin, which is an iron regulatory peptide hormone. A homozygous C282Y mutation in HFE is responsible for the vast majority of hereditary cases. However, iron overload due to hyperabsorption of dietary iron may result from other genetic mutations, chronic anemias associated with ineffective erythropoiesis (e.g., thalassemia; Chapter 148 ), chronic liver disease, and iatrogenic causes (see Table 196-1 ).

TABLE 196-1
CLASSIFICATION OF IRON OVERLOAD SYNDROMES
HEREDITARY HEMOCHROMATOSIS
Type 1- HFE Related Autosomal Recessive
C282Y/C282Y
C282Y/H63D
Other mutations
Type 2-4-Non– HFE Related
Hemojuvelin ( HJV ) mutations (autosomal recessive)
Hepcidin ( HAMP ) mutations (autosomal recessive)
Transferrin receptor 2 ( TFR2 ) mutations (autosomal recessive)
Ferroportin ( SLC40A1 ) mutations (autosomal dominant)
Aceruloplasminemia
​Divalent metal transporter 1 ( SLC11A2 ) mutations (rare)
Atransferrinemia
Miscellaneous
African iron overload
Neonatal iron overload (rare)
SECONDARY IRON OVERLOAD
Anemia Caused by Ineffective Erythropoiesis
Thalassemia major
Sideroblastic anemias
Congenital dyserythropoietic anemias
Liver Disease
Alcoholic liver disease
Chronic viral hepatitis B and C
Porphyria cutanea tarda
Nonalcoholic steatohepatitis
After portacaval shunt
Miscellaneous
Transfusional iron overload
Excessive parenteral iron administration

Epidemiology

Three common HFE mutations (C282Y, H63D, and S65C) have been described in the general population, but only the homozygous C282Y and the C282Y/H63D compound heterozygous mutations have been associated with the hemochromatosis phenotype in the absence of another contributing factor for iron overload. A North American study that screened almost 100,000 patients found an estimated prevalence of C282Y homozygosity in 0.44% of non-Hispanic Whites, 0.11% of Native Americans, 0.027% of Hispanics, 0.014% of Blacks, 0.12% of Pacific Islanders, and 0.000039% of Asians. The H63D mutation is associated with phenotypic hemochromatosis only when present along with the C282Y mutation, whereas the S65C mutation is considered a polymorphism and has not been shown to contribute to iron overload. The true prevalence of these other, nonclassic forms 2 to 4 are unknown.

Pathobiology

Dietary iron absorption is regulated by body iron needs. Under circumstances of iron deficiency, iron absorption is increased until body iron stores are replete, at which time iron absorption decreases to basal levels. Iron from the diet is absorbed in the proximal duodenum either as inorganic iron or as heme iron ( Fig.196-1 ). Iron balance in humans is regulated primarily at the level of intestinal absorption because the body does not have a mechanism to excrete iron other than by the physiologic loss of desquamated cells or by menses. Hepcidin, which is a 25–amino acid peptide hormone synthesized mainly in the liver and secreted into the blood, is considered the master regulator of iron homeostasis. Hepcidin acts by blocking iron absorption from the intestine and blocking iron release from reticuloendothelial cell storage sites, which are mainly within the liver (see Fig. 196-1 ). Genetic iron overload disorders are caused when mutations in iron regulatory genes result in reduced production and inappropriately low levels of hepcidin in response to stored and circulating levels of iron, the net effect of which is lifelong hyperabsorption of dietary iron. Progressive iron loading of various organs can eventually cause the characteristic tissue injuries of the hemochromatosis phenotype.

FIGURE 196-1, Hepcidin, the master regulator of iron absorption and secretion. Plasma iron levels are controlled primarily at the level of absorption by duodenal enterocytes and reticuloendothelial system (RES) macrophages. Heme-iron can also be directly absorbed from the gastrointestinal tract through a carrier protein, possibly heme carrier protein. Non-heme (inorganic) iron is absorbed via divalent metal transporter 1 after conversion from ferric (Fe 3+) to ferrous (Fe 2+) iron through duodenal cytochrome b–related ferric reductase. RES macrophages acquire iron through erythrophagocytosis. Efflux of iron from both enterocytes and RES macrophages occurs through the iron export protein ferroportin. Fe 2+ is reduced back to ferric iron (Fe 3+) through hephaestin before being transported out of the enterocyte. Iron is bound to transferrin as it enters the plasma and then travels through the circulation, where it is taken up by various organs and used in the development of erythrocytes and other biologic processes. The principal regulator of iron levels is the hormone hepcidin, which is produced by hepatocytes. As iron stores increase, hepcidin inhibits iron efflux from both duodenum enterocytes and RES macrophages through downregulation of ferroportin. Serum iron levels influence hepcidin expression through the interaction of the HFE protein with TFR1/TFR2 along with BMP6 and HJV. BMP = bone morphogenic protein; DCYTB = duodenal cytochrome b–related ferric reductase; DMT1 = divalent metal transporter 1; HCP = heme carrier protein; HJV = hemojuvelin; TFR1 = transferrin receptor 1; TFR2= transferrin receptor 2.

Absorption of inorganic iron follows a coordinated process beginning with conversion of iron from the ferric form to the ferrous form by the duodenal cytochrome b–related ferric reductase (dcytb) that is present on the luminal surface of duodenal enterocytes. Ferrous iron then traverses the apical membrane of enterocytes via the divalent metal transporter 1. The absorbed iron may be utilized for intracellular processes, stored as ferritin in enterocytes, or converted back to ferric iron by hephaestin, thereby allowing it to be transferred across the basolateral membrane of enterocytes into circulating plasma via the iron export protein, ferroportin. Iron is bound to transferrin at the transferrin receptor (TfR1) in the circulation. Hepatocytes take up transferrin-bound iron via the receptors TfR1 and possibly TfR2, as well as by non–receptor-mediated mechanisms. Hepatocytes may also absorb free iron from the circulation when transferrin becomes highly saturated. In contrast, reticuloendothelial system cells (Kupffer cells in the liver) take up iron primarily by phagocytosis of senescent erythrocytes or possibly apoptotic hepatocytes. Kupffer cells can also sequester transferrin-bound iron via TfR1.

Mutations in the HFE , TfR2 , and HJV genes result in markedly depressed hepcidin levels, thereby permitting persistently increased absorption of iron from a normal diet. Mutations in the HAMP (hepcidin) gene may likewise lead to inappropriately low levels of hepcidin, thereby resulting in iron overload. Parenchymal iron overload may also be caused by mutations in the ferroportin gene.

Classical ( HFE ) hemochromatosis is defined as type 1 hemochromatosis, whereas other rare types of hereditary hemochromatosis are now classified as types 2 to 4. , Juvenile hemochromatosis, which is a severe form of hemochromatosis that is associated with severe iron overload and that presents in the second to third decade of life, consists of type 2A and type 2B forms. Type 2A is caused by a mutation in the hemojuvelin ( HJV ) gene, which is located on chromosome 1 and which encodes the hemojuvelin protein. Type 2B is caused by a mutation in the hepatic antimicrobial protein ( HAMP ) gene, which encodes hepcidin. Type 3 is due to a mutation in the transferrin receptor 2 ( TFR2 ) gene that is located on the long arm of chromosome 7; TFR2 is similar to TFR1 but expressed predominantly in the liver. Type 4 is caused by dominant gain-in-function mutations in the ferroportin ( SLC40A1 ) gene, which is located on chromosome 2, thereby leading to hepcidin resistance. A different mutation resulting in loss of function in ferroportin has been termed “ferroportin disease” because its clinical, biochemical, and histologic features are very different from other forms of hereditary hemochromatosis.

Population-based screening studies have shown that the penetrance and clinical expressivity of the homozygous C282Y mutation is low, especially in women. A number of factors may be associated with phenotypic expression, such as physiologic blood loss due to menses or factors leading to increased iron absorption (e.g., excess alcohol intake or other liver diseases such as chronic hepatitis C or steatohepatitis) and increased intake of ascorbic or citric acid.

Iron overload is associated with reduced function in immune cells. It is also associated with altered regulation of CD8 T lymphocytes from both HFE patients and Hfe -null mice. Siderophilic microbes grow rapidly in niches where iron is more available, and these organisms may cause severe infections in patients with iron overload. The putative mechanisms for diabetes include direct damage to pancreatic beta cells by iron, with some component of insulin resistance in the liver due to the organ’s iron loading. Hypothyroidism is thought to be due to direct iron toxicity in the thyroid gland, whereas rare hypogonadotropic hypogonadism and adrenal insufficiency in hereditary hemochromatosis may be due to iron deposition in the anterior pituitary. Arthropathy is believed to be caused by the deposition of calcium pyrophosphate crystals in joint spaces, thereby leading to inflammation, joint space narrowing, chondrocalcinosis, formation of subchondral cysts, and osteopenia.

Clinical Manifestations

The clinical features vary among the different forms of genetic hemochromatosis ( Table 196-2 ). Many patients who carry HFE mutations, whether heterozygous or homozygous, do not express the clinical phenotype of iron overload disease ( Tables 196-3 and 196-4 ) or even biochemical evidence of iron overload (increased serum transferrin-iron saturation, ferritin), and the majority of patients with the homozygous C282Y mutation may never develop end-organ damage from iron overload. For example, among C282Y homozygotes with normal serum ferritin values at diagnosis, less than 15% develop ferritin values >1000 ng/mL over 12 years of follow-up. An estimated 50% of female and 25% of male adults who are homozygous for the C282Y mutation have normal serum ferritin levels and will never require phlebotomy therapy. However, about 1 in 10 male C282Y homozygotes will eventually develop liver disease if hemochromatosis is not diagnosed early, usually by screening, and treated.

TABLE 196-2
THE TYPES OF HEREDITARY HEMOCHROMATOSIS AND CLINICAL FEATURES
TYPE AGE MUTATION/GENE INHERITANCE COMMON CLINICAL FEATURES
1A Middle-age C282Y+/+
HFE
AR Arthropathy, diabetes, hypothyroidism, hypogonadism, adrenal insufficiency, liver disease, endocrine dysfunction, cardiomyopathy, skin discoloration
1B Middle-age C282Y/H63D
HFE
AR
2A <30 years G3290V /HJV AR Hypogonadism, cardiomyopathy
2B <30 years Several /HAMP AR
3 Intermediate Several/ TfR2 AR May have juvenile hereditary hemochromatosis or type 2 features
4 Variable Several/ SLC40A1 AD Hepcidin resistance, fatigue, joint pain
AD = autosomal dominant; AR = autosomal recessive.

TABLE 196-3
SYMPTOMS IN PATIENTS WITH HEREDITARY HEMOCHROMATOSIS
From Bacon BR. Chapter 212 . Iron overload (hemochromatosis). In: Goldman-Cecil Medicine . 25th ed. Philadelphia: Elsevier; 2016.
ASYMPTOMATIC
Abnormalities of serum iron studies on routine screening chemistry panel
Abnormal liver test results
Identified by family screening
Identified by population screening
NONSPECIFIC SYSTEMIC SYMPTOMS
Weakness
Fatigue
Lethargy
Apathy
Weight loss
SPECIFIC ORGAN-RELATED SYMPTOMS
Abdominal pain (hepatomegaly)
Arthralgias (arthritis)
Symptoms of diabetes mellitus (pancreas)
Amenorrhea (cirrhosis)
Loss of libido, impotence (pituitary, cirrhosis)
Heart failure symptoms (heart)
Arrhythmias (heart)

TABLE 196-4
PHYSICAL FINDINGS IN PATIENTS WITH HEREDITARY HEMOCHROMATOSIS
From Bacon BR. Chapter 212 . Iron overload (hemochromatosis). In: Goldman-Cecil Medicine . 25th ed. Philadelphia: Elsevier; 2016.
ASYMPTOMATIC
No physical findings
Hepatomegaly
SYMPTOMATIC
Liver
Hepatomegaly
Cutaneous stigmata of chronic liver disease
Splenomegaly
Signs of liver failure: ascites, encephalopathy
Joints
Arthritis
Joint swelling
Heart
Dilated cardiomyopathy
Congestive heart failure
Skin
Increased pigmentation
Endocrine
Testicular atrophy
Hypogonadism
Hypothyroidism

Furthermore, the H63D mutation does not result in iron overload unless present in compound heterozygous form with C282Y. In addition, the S65C mutation is now recognized to be a polymorphism that is not associated with iron overload.

Based on genetics, phenotypic expression, and long-term natural history, hereditary hemochromatosis may be classified into three clinical stages, as shown:

  • Stage 1: genetic predisposition for hereditary hemochromatosis without evidence for increase in iron stores (normal serum iron studies)

  • Stage 2: genetic predisposition for hereditary hemochromatosis and some phenotypic characteristics of iron overload in the absence of organ damage

  • Stage 3: genetic predisposition for hereditary hemochromatosis accompanied by evidence for iron overload with tissue injury or organ damage

Symptoms and Signs Associated with Hereditary Hemochromatosis

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