3230 PART 12 Endocrinology and Metabolism

■ DEFINITION

Hemochromatosis is a relatively common inherited disorder of iron

metabolism prevalent in European populations. Once thought to be a

single disease entity, it is now known to be an iron-storage disorder with

genetic heterogeneity but with a final common metabolic pathway resulting in the inappropriately high cellular release of iron. This leads to an

increase in intestinal iron absorption and the deposition of excess iron in

parenchymal cells with eventual tissue damage and organ failure. Thus,

the term hemochromatosis now refers to a group of genetic diseases that

predispose to iron overload, potentially leading to fibrosis and organ failure. Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and

hypogonadotropic hypogonadism are the major clinical manifestations.

The following terminology is widely accepted.

1. Hereditary hemochromatosis is most often caused by a mutation in

the homeostatic iron regulator (HFE) gene, which is tightly linked to

the HLA-A locus on chromosome 6p. Persons who are homozygous

for the mutation are at increased risk of iron overload and account

for 80–90% of clinical hereditary hemochromatosis in persons of

northern European descent. In such subjects, the presence of hepatic

fibrosis, cirrhosis, arthropathy, or hepatocellular carcinoma constitutes iron overload–related disease. Rarer forms of non-HFE hemochromatosis are caused by mutations in other genes involved in iron

metabolism (Table 414-1). The disease can be recognized during its

early stages when iron overload and organ damage are minimal. At

this stage, the disease is best referred to as early hemochromatosis or

precirrhotic hemochromatosis.

2. Secondary iron overload occurs as a result of an iron-loading anemia,

such as thalassemia or sideroblastic anemia, in which erythropoiesis

is increased but ineffective. In the acquired iron-loading disorders,

massive iron deposits in parenchymal tissues can lead to the same

clinical and pathologic features as in hemochromatosis.

414 Hemochromatosis

Lawrie W. Powell, David M. Frazer

TABLE 414-1 Classification of Iron Overload States

Hereditary Hemochromatosis

Hemochromatosis, HFE-related (type 1)

C282Y homozygosity

C282Y/H63D compound heterozygosity

Hemochromatosis, non-HFE-related

Juvenile hemochromatosis (type 2A) (hemojuvelin mutations)

Juvenile hemochromatosis (type 2B) (hepcidin mutation)

Mutated transferrin receptor 2, TFR2 (type 3)

Mutated ferroportin 1 gene, SLC40A1 (type 4)

Acquired Iron Overload

Iron-loading anemias

Thalassemia major

Sideroblastic anemia

Chronic hemolytic anemias

 Transfusional and parenteral iron

overload

Dietary iron overload

Chronic liver disease

Hepatitis C

 Alcoholic cirrhosis, especially when

advanced

Nonalcoholic steatohepatitis

Porphyria cutanea tarda

 Dysmetabolic iron overload

syndrome

Post-portacaval shunting

Miscellaneous

Iron overload in sub-Saharan Africa

Neonatal iron overload

Aceruloplasminemia

Congenital atransferrinemia

nature of the mutation. In LDS, components of the TGF-β signaling

pathway are mutated, including the cytokines (TGFβ2, TGFβ3), the

receptors (TGFBR1, TGFBR2), and the downstream effectors (SMAD2,

SMAD3).

The discovery that syndromes similar to MFS are caused by alterations in the TGF-β signaling pathway refocused attention on structural similarity between fibrillin-1 and TGF-β binding proteins that

sequester TGF-β in the extracellular matrix. As a result, some of the

manifestations of MFS have been shown to arise from alterations in

binding sites that modulate TGF-β bioavailability during development

of the skeleton and other tissues. In both MFS and LDS, the pathogenic

mechanisms involve increased TGF-β signaling, which contributes to

aneurysm formation.

Diagnosis When HTAD is present, genetic testing can confirm the

diagnosis and allow identification of at-risk individuals. Referral to a

specialty genetics service is critically important, and genetic counseling

before testing is recommended. In view of phenotypic overlap between

the syndromic HTAD, a multigene panel (usually including genes for

syndromic and nonsyndromic HTAD) is recommended. All patients

with a suspected diagnosis of MFS should have a slit-lamp examination

and an echocardiogram. Also, homocystinuria should be ruled out

by amino acid analysis of plasma (Chap. 420). The diagnosis of MFS

according to the international Ghent standards places emphasis on

two cardinal features, dilation of the ascending aorta with or without

dissection and ectopia lentis. Other cardiovascular and ocular manifestations and findings in other organ systems such as the skeleton, dura,

skin, and lungs contribute to a systemic score that guides diagnosis

when aortic disease is present but ectopia lentis is not.

TREATMENT

Marfan Syndrome and Loeys-Dietz Syndromes

Patients should be advised that vascular risks are increased by

severe physical exertion, smoking, emotional stress, and pregnancy. Low-level moderate aerobic exercise and limits on isometric

exercise are recommended. Prophylactic beta blocker and/or angiotensin II receptor blocker therapy are prescribed in normotensive

individuals, and blood pressure control is important for those with

hypertension. Surgical correction of the aorta, aortic valve, and

mitral valve has been successful in many patients, but tissues are

frequently friable. The scoliosis tends to be progressive, and surgical stabilization may be required. Dislocated lenses rarely require

surgical removal, but patients should be followed closely for retinal

detachment.

ACKNOWLEDGEMENT

Darwin J. Prockop and John F. Bateman contributed to this chapter in

the 20th edition, and some material from that chapter has been retained

here.

■ FURTHER READING

De Backer J et al: Genetic testing for aortopathies: primer for the

nongeneticist. Curr Opin Cardiol 34:585, 2019.

Forlino A, Marini JC: Osteogenesis imperfecta. Lancet 387:1657,

2016.

Loeys BL et al: The revised Ghent nosology for the Marfan syndrome.

J Med Genet 47:476, 2010.

Malfait F et al: The Ehlers-Danlos syndromes. Nat Rev Dis Primers

6:64, 2020.

Marini JC et al: Osteogenesis imperfecta. Nat Rev Dis Primers

3:17052, 2017.

Marzin P, Cormier-Daire V: New perspectives on the treatment of

skeletal dysplasia. Ther Adv Endocrinol Metab 11:2042018820904016,

2020.

Mortier GR et al: Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A 179:2393, 2019.

Prockop DJ, Kivirikko, KI: Collagen: Molecular biology, diseases and

potentials for therapy. Ann Rev Biochem 64:403, 1995.

3231Hemochromatosis CHAPTER 414

examinations, asymptomatic subjects with iron overload can be identified, including young menstruating women.

In contrast to HFE-associated hemochromatosis, the nonHFE-associated forms of hemochromatosis (Table 414-1) are rare,

but they affect all populations and may affect young people (juvenile

hemochromatosis).

These result from mutations in one or more of the genes encoding

proteins in the hepcidin pathway (Fig. 414-1), including hepcidin,

hemojuvelin, and transferrin receptor 2 (TFR2). The resultant clinical

disease is very similar to HFE-related disease because they all lead to

hepcidin deficiency, which is the final common pathway (Fig. 414-1).

A rare autosomal dominant form of hemochromatosis results from

two types of mutations in the gene for the iron transporter ferroportin.

Loss-of-function mutations decrease the cell surface localization of

ferroportin in certain tissues, thereby reducing its ability to export

iron (“ferroportin disease”). A second mutation abolishes the hepcidin-induced ferroportin internalization and degradation resulting in a

■ PREVALENCE

Although HFE-associated hemochromatosis mutations are common,

the prevalence varies in different ethnic groups. It is most common

in populations of northern European extraction in whom ~1 in 10

persons are heterozygous carriers and 0.3–0.5% are homozygotes,

with even higher percentages in some Celtic populations such as those

residing in Ireland and Brittany. However, expression of the disease is

variable and modified by several factors, especially alcohol consumption, dietary iron intake, blood loss associated with menstruation and

pregnancy, and blood donation. Recent population studies indicate

that ~30% of homozygous men develop iron overload–related disease

and about 6% develop hepatic cirrhosis. For women, iron overload–

related disease is closer to 1%. In addition, there are as yet unidentified

modifying genes responsible for expression. Nearly 70% of untreated

patients develop the first symptoms between ages 40 and 60. The

disease is rarely evident before age 20, although with family screening

(see “Screening for Hemochromatosis,” below) and periodic health

Bone marrow

Hepcidin Macrophage

Hepcidin

SMAD

Hepcidin

Erythroferrone

BMP6

HFE/TFR1 TFR2

TMPRSS6

?

HJV

BMPR

Duodenum

Villus

DCYTB

DMT1

Crypt

RBC

FPN

FPN

Heph

Liver

Plasma

Transferrin

P

P

P

FIGURE 414-1 Pathways of normal iron homeostasis. Dietary inorganic iron traverses the brush border membrane of duodenal enterocytes via divalent metal-ion

transporter 1 (DMT1) after reduction of ferric (Fe3+) iron to the ferrous (Fe2+) state by intestinal ferrireductases such as duodenal cytochrome B (DCYTB). Iron then moves

from the enterocyte to the circulation via a process requiring the basolateral iron exporter ferroportin (FPN) and the iron oxidase hephaestin (Heph). In the circulation, iron

binds to plasma transferrin and is thereby distributed to sites of iron utilization and storage. Much of the diferric transferrin supplies iron to immature erythrocyte cells in the

bone marrow for hemoglobin synthesis. At the end of their life, senescent red blood cells (RBCs) are phagocytosed by macrophages, and iron is returned to the circulation

after export through ferroportin. The liver-derived peptide hepcidin represses basolateral iron transport in the gut as well as iron released from macrophages and other

cells and serves as a central regulator of body-iron traffic. At least two separate signals regulate hepcidin production in response to changes in body-iron requirements.

The first involves the detection of circulating diferric transferrin by HFE and TFR2. A second relies on hepatic iron stores activating the hemojuvelin (HJV)-dependent bone

morphogenetic protein (BMP)/SMAD pathway. This pathway is modified by erythroferrone released from erythroid precursor cells, which binds to BMP6 and inhibits its

function. TMPRSS6 is a protease that regulates hepcidin production, possibly by modulating HJV activity. Heme is metabolized by heme oxygenase within the enterocytes,

and the released iron then follows the same pathway. Mutations in the genes encoding HFE, TFR2, HJV, and hepcidin all lead to decreased hepcidin release and increased

iron absorption, resulting in hemochromatosis (Table 414-1).

3232 PART 12 Endocrinology and Metabolism

“gain of function.” Here the tissue iron distribution is similar to that in

HFE-related disease (e.g., in parenchymal cells).

■ GENETIC BASIS

The most common mutation in the HFE gene is a homozygous G

to A transition that leads to a cysteine to tyrosine substitution at

position 282 (C282Y) of the HFE protein. It has been identified in

85–90% of patients with hereditary hemochromatosis in populations of

northern European descent but is found in only 60% of cases from

Mediterranean populations. A second, relatively common HFE variant

(H63D) results in a substitution of aspartic acid for histidine at residue

63 of the HFE protein. Homozygosity for H63D is not associated with

clinically significant iron overload. Some compound heterozygotes

(i.e., one copy each of C282Y and H63D) have mild to moderately

increased body-iron stores but develop clinical disease only in association with cofactors such as heavy alcohol intake or hepatic steatosis.

HFE-associated hemochromatosis is inherited as an autosomal recessive trait, and heterozygotes have no, or minimal, increase in iron

stores. However, this slight increase in hepatic iron can act as a cofactor

that may modify the expression of other diseases such as porphyria

cutanea tarda (PCT) or nonalcoholic steatohepatitis (NASH).

Mutations in other genes involved in iron metabolism are responsible for non-HFE-associated hemochromatosis, including juvenile

hemochromatosis, which affects persons in the second and third

decades of life (Table 414-1). Mutations in the genes encoding hepcidin,

TFR2, and hemojuvelin (Fig. 414-1) result in clinicopathologic features

that are indistinguishable from HFE-associated hemochromatosis.

However, loss-of-function mutations in ferroportin, which is responsible for the efflux of iron from most cell types, result in iron loading of

reticuloendothelial macrophages as well as parenchymal cells.

■ PATHOPHYSIOLOGY AND THE

ROLE OF HEPCIDIN

Normally, the body-iron content of 3–4 g is maintained such that intestinal mucosal absorption of iron is equal to iron loss. This amount is

~1 mg/d in men and 1.5 mg/d in menstruating women. In hemochromatosis, mucosal absorption is greater than body requirements and

amounts to ≥4 mg/d. The progressive accumulation of iron increases

plasma iron and saturation of transferrin and results in a progressive

increase of plasma ferritin (Fig. 414-2). The discovery of a key regulatory hormone that allows the bone marrow and other tissues to communicate their iron requirements has transformed our understanding

of the coordination of absorption, mobilization, and storage of iron

to meet body iron requirements. It was called hepcidin based upon

its antibacterial activity (“HEPatic bacterioCIDal proteIN”). This

liver-derived peptide represses basolateral iron export from intestinal

enterocytes and iron release from macrophages and other cells by

binding to ferroportin. Hepcidin, in turn, responds to signals in the

liver mediated by HFE, TFR2, and hemojuvelin (Fig. 414-1). The development of hepcidin agonists represents a promising new therapeutic

approach for iron overload disorders caused by low hepcidin levels.

The HFE gene encodes a 343-amino-acid protein that is structurally

related to MHC class I proteins. The basic defect in HFE-associated

hemochromatosis is a lack of cell surface expression of HFE (due to the

C282Y mutation). The normal (wild-type) HFE protein forms a complex with β2

-microglobulin and transferrin receptor 1 (TFR1), and the

C282Y mutation completely abrogates this interaction. As a result, the

mutant HFE protein remains trapped intracellularly. Although the precise function of HFE at the cell surface is not known, mutations in this

protein reduce hepcidin production leading to increased dietary iron

absorption (Fig. 414-1). In advanced disease, the body may contain 20

g or more of iron, which is deposited mainly in parenchymal cells of

the liver, pancreas, and heart. Iron deposition in the pituitary causes

hypogonadotropic hypogonadism in both men and women. Tissue

injury may result from disruption of iron-laden lysosomes, from lipid

peroxidation of subcellular organelles by excess iron, or from stimulation of collagen synthesis by activated stellate cells.

Secondary iron overload with iron deposition in parenchymal cells

occurs in chronic disorders of erythropoiesis, particularly in those with

defects in hemoglobin synthesis and ineffective erythropoiesis such as

sideroblastic anemia and thalassemia (Chap. 98). In these disorders,

iron absorption is increased. Moreover, these patients require blood

transfusions and are frequently treated inappropriately with iron.

PCT, a disorder characterized by a defect in porphyrin biosynthesis

(Chap. 416), can also be associated with excessive parenchymal iron

deposits. The magnitude of the iron load in PCT is usually insufficient

to produce tissue damage. However, some patients with PCT also have

mutations in the HFE gene, and some have associated hepatitis C virus

(HCV) infection. Although the relationship between these disorders

remains to be clarified, iron overload accentuates the inherited enzyme

deficiency in PCT and should be avoided along with other agents

(alcohol, estrogens, haloaromatic compounds) that may exacerbate

PCT. Another cause of hepatic parenchymal iron overload is hereditary

aceruloplasminemia. In this disorder, impairment of iron mobilization

due to deficiency of ceruloplasmin (a ferroxidase) causes iron overload

in hepatocytes and a range of other cell types.

Excessive iron ingestion over many years rarely results in hemochromatosis. An important exception has been reported in South Africa

among groups who brew fermented beverages in vessels made of iron.

Hemochromatosis has been described in apparently normal persons

who have taken medicinal iron over many years, but such individuals

probably had genetic disorders.

The common denominator in all patients with hemochromatosis is

excessive amounts of iron in parenchymal tissues. Parenteral administration of iron in the form of blood transfusions or iron preparations results

predominantly in reticuloendothelial cell iron overload. This appears to

lead to less tissue damage than iron loading of parenchymal cells.

In the liver, parenchymal iron is in the form of ferritin and hemosiderin. In the early stages, these deposits are seen in the periportal

parenchymal cells, especially within lysosomes in the pericanalicular

cytoplasm of the hepatocytes. This stage progresses to perilobular

fibrosis and to fibrous septa due to activation of stellate cells. In the

advanced stage, a macronodular or mixed macro- and micronodular

cirrhosis develops. Hepatic fibrosis and cirrhosis correlate significantly

with hepatic iron concentration.

Histologically, iron is increased in many organs, particularly in

the liver, heart, and pancreas, and, to a lesser extent, in the endocrine

1500

1000

500

0

Normal

range

Serum ferritin concentration (µg/L)

0 10 20 30 40 50

Cirrhosis, organ failure

Progressive tissue injury

Increased total body iron

Increased hepatic iron

Increased serum iron

Increased iron absorption

Age

(yrs.)

FIGURE 414-2 Sequence of events in genetic hemochromatosis and their

correlation with the serum ferritin concentration. Increased iron absorption is

present throughout life. Overt, symptomatic disease usually develops between ages

40 and 60, but latent disease can be detected long before this.

3233Hemochromatosis CHAPTER 414

glands. The epidermis of the skin is thin, and melanin is increased in

the cells of the basal layer and dermis. Deposits of iron are present

around the synovial lining cells of the joints.

■ CLINICAL MANIFESTATIONS

C282Y homozygotes can be characterized by the stage of progression as

follows: (1) a genetic predisposition without abnormalities; (2) iron overload without symptoms; (3) iron overload with symptoms (e.g., arthritis

and fatigue); and (4) iron overload with organ damage—in particular, cirrhosis. Thus, many subjects with significant iron overload are asymptomatic. For example, in a study of 672 asymptomatic C282Y homozygous

subjects (identified by either family screening or routine health examinations) there was hepatic iron overload (grades 2–4) in 56% and 34.5%

of male and female subjects, respectively, hepatic fibrosis (stages 2–4) in

18.4% and 5.4%, respectively, and cirrhosis in 5.6% and 1.9%, respectively.

Initial symptoms of hemochromatosis are often nonspecific and

include lethargy, arthralgia, skin pigmentation, loss of libido, and

features of diabetes mellitus. Hepatomegaly, increased pigmentation,

spider angiomas, splenomegaly, arthropathy, ascites, cardiac arrhythmias, congestive heart failure, loss of body hair, testicular atrophy, and

jaundice are prominent in advanced disease.

The liver is usually the first organ to be affected, and hepatomegaly

is present in >95% of symptomatic patients.

Manifestations of portal hypertension and esophageal varices occur

less commonly than in cirrhosis from other causes. Hepatocellular carcinoma develops in ~30% of patients with cirrhosis, and it is the most

common cause of death in treated patients—hence the importance of

early diagnosis and therapy. The incidence increases with age, it is more

common in men, and it occurs almost exclusively in cirrhotic patients.

Excessive skin pigmentation is present in patients with advanced

disease. The characteristic metallic or slate-gray hue is sometimes

referred to as bronzing and results from increased melanin and iron in

the dermis. Pigmentation usually is diffuse and generalized.

Diabetes mellitus occurs in ~65% of patients with advanced disease

and is more likely to develop in those with a family history of diabetes,

suggesting that direct damage to the pancreatic islets by iron deposition occurs in combination with other risk factors. The management is

similar to that of other forms of diabetes.

Arthropathy develops in 25–50% of symptomatic patients. It usually

occurs after age 50, but may occur as a first manifestation or long after

therapy. The joints of the hands, especially the second and third metacarpophalangeal joints, are usually the first joints involved, a feature that

helps to distinguish the chondrocalcinosis associated with hemochromatosis from the idiopathic form (Chap. 372). A progressive polyarthritis

involving the wrists, hips, ankles, and knees may also ensue. Acute

brief attacks of synovitis may be associated with deposition of calcium

pyrophosphate (chondrocalcinosis or pseudogout), mainly in the knees.

Radiologic manifestations include cystic changes of the subchondral

bones, loss of articular cartilage with narrowing of the joint space, diffuse demineralization, hypertrophic bone proliferation, and calcification

of the synovium. The arthropathy tends to progress despite removal of

iron by phlebotomy. Although the relation of these abnormalities to iron

metabolism is not known, the fact that similar changes occur in other

forms of iron overload suggests that iron is directly involved.

Cardiac involvement is the presenting manifestation in ~15% of

symptomatic patients. The most common manifestation is congestive

heart failure, which occurs in ~10% of young adults with the disease,

especially those with juvenile hemochromatosis. Symptoms of congestive heart failure may develop suddenly, with rapid progression to

death if untreated. The heart is diffusely enlarged. This may be misdiagnosed as idiopathic cardiomyopathy if other overt manifestations are

absent. Cardiac arrhythmias include premature supraventricular beats,

paroxysmal tachyarrhythmias, atrial flutter, atrial fibrillation, and varying degrees of atrioventricular block.

Hypogonadism occurs in both sexes and may antedate other clinical

features. Manifestations include loss of libido, impotence, amenorrhea,

testicular atrophy, gynecomastia, and sparse body hair. These changes

are primarily the result of decreased production of gonadotropins due

to impairment of hypothalamic-pituitary function by iron deposition.

■ DIAGNOSIS

The association of (1) hepatomegaly, (2) skin pigmentation, (3) diabetes mellitus, (4) heart disease, (5) arthritis, and (6) hypogonadism

should suggest the diagnosis. However, as stated above, significant iron

overload may exist with none or only some of these manifestations.

Therefore, a high index of suspicion is needed to make the diagnosis

early. Treatment before permanent organ damage occurs can reverse

the iron toxicity and restore life expectancy to normal.

The history should be particularly detailed in regard to disease in

other family members and should include information on alcohol

ingestion; iron intake; and ingestion of large doses of ascorbic acid,

which promotes iron absorption (Chap. 333). Appropriate tests should

be performed to exclude iron deposition due to hematologic disease.

The presence of liver, pancreatic, cardiac, and joint disease should be

confirmed by physical examination, radiography, and standard function tests of these organs.

The degree of increase in total body iron stores can be assessed by

(1) measurement of serum iron and the percent saturation of transferrin (or the unsaturated iron-binding capacity), (2) measurement

of serum ferritin concentration, (3) liver biopsy with measurement

of the iron concentration and calculation of the hepatic iron index

(Table 414-2), and (4) MRI of the liver. In addition, a retrospective

assessment of body-iron storage is also provided by performing

weekly phlebotomy and calculating the amount of iron removed before

iron stores are exhausted (1 mL blood = ~0.5 mg iron).

Each of these methods for assessing iron stores has advantages and

limitations. The serum iron level and percent saturation of transferrin

are elevated early in the course, but their specificity is reduced by significant false-positive and false-negative rates. For example, serum iron

concentration may be increased in patients with alcoholic liver disease

without iron overload; in this situation, however, the hepatic iron index

is usually not increased as in hemochromatosis (Table 414-2). In otherwise healthy persons, a fasting serum transferrin saturation >45% is

abnormal and suggests homozygosity for hemochromatosis.

The serum ferritin concentration is usually a good index of bodyiron stores, whether decreased or increased. In fact, an increase of

1 μg/L in serum ferritin level reflects an increase of ~8–10 mg in body

stores. In most untreated patients with hemochromatosis, the serum

TABLE 414-2 Representative Iron Values in Normal Subjects, Patients with Hemochromatosis, and Patients with Alcoholic Liver Disease

DETERMINATION NORMAL

SYMPTOMATIC

HEMOCHROMATOSIS

HOMOZYGOTES WITH EARLY,

ASYMPTOMATIC HEMOCHROMATOSIS HETEROZYGOTES

ALCOHOLIC LIVER

DISEASE

Plasma iron, μmol/L (μg/dL) 9–27 (50–150) 32–54 (180–300) Usually elevated Elevated or normal Often elevated

Total iron-binding capacity,

μmol/L (μg/dL)

45–66 (250–370) 36–54 (200–300) 36–54 (200–300) Normal 45–66 (250–370)

Transferrin saturation, % 22–45 50–100 50–100 Normal or elevated 27–60

Serum ferritin, μg/L 1000–6000 200–500 Usually <500 10–500

Men 20–250

Women 15–150

Liver iron, μg/g dry wt 300–1400 6000–18,000 2000–4000 300–3000 300–2000

Hepatic iron index <1.0 >2 1.5–2 <2 <2

3234 PART 12 Endocrinology and Metabolism

ferritin level is significantly increased (Fig. 414-2 and Table 414-2), and

a serum ferritin level >1000 μg/L is the strongest predictor of disease

expression among individuals homozygous for the C282Y mutation.

However, in patients with inflammation and hepatocellular necrosis,

serum ferritin levels may be elevated out of proportion to body iron

stores due to increased release from tissues. Therefore, a repeat determination of serum ferritin should be carried out after acute hepatocellular damage has subsided (e.g., in alcoholic liver disease). Ordinarily,

the combined measurements of the percent transferrin saturation and

serum ferritin level provide a simple and reliable screening test for

hemochromatosis, including the precirrhotic phase of the disease. If

either of these tests is abnormal, genetic testing for hemochromatosis

should be performed (Fig. 414-3).

The role of liver biopsy in the diagnosis and management of hemochromatosis has been reassessed as a result of the widespread availability of genetic testing for the C282Y mutation. The absence of severe

fibrosis can be accurately predicted in most patients using clinical

and biochemical variables. Thus, there is virtually no risk of severe

fibrosis in a C282Y homozygous subject with (1) serum ferritin level

<1000 μg/L, (2) normal serum alanine aminotransferase values, (3) no

hepatomegaly, and (4) no excess alcohol intake. However, it should be

emphasized that liver biopsy is the only reliable method for establishing or excluding the presence of hepatic cirrhosis, which is the critical

factor determining prognosis and the risk of developing hepatocellular

carcinoma. Biopsy also permits histochemical estimation of tissue iron

and measurement of hepatic iron concentration. Increased density of

the liver due to iron deposition can be demonstrated by CT or MRI,

and with improved technology, MRI has become more accurate in

determining hepatic iron concentration.

■ SCREENING FOR HEMOCHROMATOSIS

When the diagnosis of hemochromatosis is established, it is important to counsel and screen other family members (Chap. 467).

Asymptomatic and symptomatic family members with the disease

usually have an increased saturation of transferrin and an increased

serum ferritin concentration. These changes occur even before iron

stores are greatly increased (Fig. 414-2). All adult first-degree relatives

of patients with hemochromatosis should be tested for the C282Y

and H63D mutations and counseled appropriately (Fig. 414-3). In

affected individuals, it is important to confirm or exclude the presence

of cirrhosis and begin therapy as early as possible. For children of an

identified proband, testing for HFE mutations in the other parent is

helpful because if normal, the child is merely an obligate heterozygote

and at no risk. Otherwise, for practical purposes, children need not be

checked before they are 18 years old.

The role of population screening for hemochromatosis is controversial. Recent studies indicate that it is highly effective for primary care

physicians to screen subjects using transferrin saturation and serum

ferritin levels. Such screening also detects iron deficiency. Genetic

screening of the normal population is feasible but remains controversial in terms of cost-effectiveness.

TREATMENT

Hemochromatosis

The therapy of hemochromatosis involves removal of the excess

body iron and supportive treatment of damaged organs. Iron

removal is best accomplished by weekly or, with gross iron loading,

twice-weekly phlebotomy of 500 mL. Although there is an initial

modest decline in the volume of packed red blood cells to about 35

mL/dL, the level stabilizes after several weeks. The plasma transferrin saturation remains increased until the available iron stores are

depleted. In contrast, the plasma ferritin concentration falls progressively, reflecting the gradual decrease in body-iron stores. One

500-mL unit of blood contains 200–250 mg of iron, and ≥25 g of

iron may have to be removed. Therefore, in patients with advanced

disease, weekly phlebotomy may be required for 1–2 years, and it

should be continued until the serum ferritin level is ≤100 μg/L.

Thereafter, phlebotomies are performed at appropriate intervals

to maintain ferritin levels at ≤100 μg/L. The transferrin saturation

fluctuates and may still be elevated but should not dictate further

therapy unless it is persistently at 100% when free unbound iron

may circulate. Usually one phlebotomy every 3 months will suffice.

It is important, however, not to overtreat and render the patient

iron deficient.

Chelating agents such as deferoxamine, when given parenterally,

remove 10–20 mg of iron per day, which is much less than that

mobilized by once-weekly phlebotomy. Phlebotomy is also less

expensive, more convenient, and safer for most patients. However,

chelating agents are indicated when anemia or hypoproteinemia is

severe enough to preclude phlebotomy. Subcutaneous infusion of

deferoxamine using a portable pump is the most effective means of

its administration.

Effective oral iron chelating agents, deferasirox (Exjade) and

deferiprone, are now available. These agents are effective in thalassemia and secondary iron overload, but are expensive and carry the

risk of significant side effects.

Alcohol consumption should be severely curtailed or eliminated

because it increases the risk of cirrhosis in hereditary hemochromatosis nearly tenfold. Dietary adjustments are unnecessary, although

vitamin C and iron supplements should be avoided. The management of hepatic failure, cardiac failure, and diabetes mellitus is

similar to conventional therapy for these conditions. Loss of libido

and change in secondary sex characteristics are managed with testosterone replacement or gonadotropin therapy (Chap. 391).

End-stage liver disease may be an indication for liver transplantation, although results are improved if the excess iron can be

removed beforehand. The available evidence indicates that the fundamental metabolic abnormality in hemochromatosis is reversed by

successful liver transplantation.

Adult first-degree

relative of

patient with HH

Subjects with

unexplained

liver disease

Individual with

suggestive

symptoms

(see text)

Transferrin saturation and serum ferritin*

TS <45%

SF <300

TS ≥45% and/or SF >300 µgL

Reassure,

possibly retest

later

HFE genotype

Phlebotomy

Normal Counsel and

 consider non-HFE

 hemochromatosis

Serum ferritin –

300–1000 µg/L

LFT normal

Serum ferritin >

1000 µg/L and/or

LFT abnormal

Serum ferritin

<300 µg/L LFT

normal

Observe,

retest in

1–2 years

C282Y Homozygote

C282Y/H63D (compound heterozygote)

Confirmed

 iron overload

*For convenience both genotype and phenotype (iron tests) can be performed

 together at a single visit in first-degree relatives.

Liver biopsy

No iron

overload Investigate and

 treat as

 appropriate

FIGURE 414-3 Algorithm for screening for HFE-associated hemochromatosis. HH,

hereditary hemochromatosis, homozygous subject (C282Y +/+); LFT, liver function

test; SF, serum ferritin concentration; TS, transferrin saturation.

3235Wilson’s Disease CHAPTER 415

■ PROGNOSIS

The principal causes of death are cardiac failure, hepatocellular failure,

or portal hypertension and hepatocellular carcinoma.

Life expectancy is improved by removal of excessive iron stores and

maintenance of these stores at near-normal levels. The 5-year survival

rate with therapy increases from 33% to 89%. With repeated phlebotomy, the liver decreases in size, liver function improves, pigmentation of skin decreases, and cardiac failure may be reversed. Diabetes

improves in ~40% of patients, but removal of excess iron has little effect

on hypogonadism or arthropathy. Hepatic fibrosis may decrease, but

established cirrhosis is irreversible. Hepatocellular carcinoma occurs as

a late sequela in patients who are cirrhotic at presentation. The apparent

increase in its incidence in treated patients is probably related to their

increased life span. Hepatocellular carcinoma rarely develops if the

disease is treated in the precirrhotic stage. Indeed, the life expectancy

of homozygotes treated before the development of cirrhosis is normal.

The importance of family screening and early diagnosis and treatment cannot be overemphasized. Asymptomatic individuals detected

by family studies should have phlebotomy therapy if iron stores are

moderately to severely increased. Assessment of iron stores at appropriate intervals is also important. With this management approach,

most manifestations of the disease can be prevented.

■ ROLE OF HFE MUTATIONS IN OTHER

LIVER DISEASES

There is considerable interest in the role of HFE mutations and

hepatic iron in several other liver diseases. Several studies have

shown an increased prevalence of HFE mutations in PCT

patients. Iron accentuates the inherited enzyme deficiency in PCT and

clinical manifestations of PCT. The situation in NASH is less clear, but

some studies have shown an increased prevalence of HFE mutations in

NASH patients. The role of phlebotomy therapy, however, is unproven

despite an intriguing fall in liver enzyme levels. In chronic HCV infection, HFE mutations are not more common, but some subjects have

increased hepatic iron. Before initiating antiviral therapy in these

patients, it is reasonable to perform phlebotomy therapy to remove

excess iron stores, because this reduces liver enzyme levels.

HFE mutations are not increased in frequency in alcoholic liver disease. Hemochromatosis in a heavy drinker can be distinguished from

alcoholic liver disease by the presence of the C282Y mutation.

End-stage liver disease may also be associated with iron overload

of the degree seen in hemochromatosis. The mechanism is uncertain,

although studies have shown that alcohol suppresses hepatic hepcidin

secretion. Hemolysis also plays a role. HFE mutations are uncommon.

Whether subjects homozygous for C282Y are at increased risk of

breast and colorectal cancer is controversial.

■ GLOBAL CONSIDERATIONS

The HFE mutation is of northern European origin (Celtic or Nordic)

with a heterozygous carrier rate of ~1 in 10 (1 in 8 in Ireland). Thus,

HFE-associated hemochromatosis is quite rare in non-European populations, e.g., Asia. However, non-HFE-associated hemochromatosis

resulting from mutations in other genes involved in iron metabolism

(Fig. 414-1) is ubiquitous and should be considered when one encounters iron overload.

African iron overload occurs primarily in sub-Saharan Africa and

was previously thought to be due to the consumption of an iron-rich

fermented maize beverage. However, recent evidence suggests that it is

primarily the result of a non-HFE-related genetic trait that is exacerbated by dietary iron loading. A similar form of iron overload has been

described in African Americans. Further research is needed to clarify

this condition.

■ FURTHER READING

Anderson GJ, Bardou-Jacquet E: Revisiting hemochromatosis:

Genetic vs. phenotypic manifestations. Ann Transl Med 9:731, 2021.

Piperno A et al: Inherited iron overload disorders. Transl Gastroenterol

Hepatol 5:25, 2020.

Powell LW et al: Haemochromatosis. Lancet 388:706, 2016.

Wilson’s disease is an inherited human disorder of copper transport

that primarily impacts the liver and brain. This reflects the critical

need for homeostatic mechanisms to properly utilize this trace metal,

both systemically and in the central nervous system. Since the initial

detailed clinical description in 1912, Wilson’s disease has emerged as

arguably one of the best-characterized and most effectively managed

human inborn errors of metabolism. The condition results from variants in ATP7B, a highly evolutionarily conserved P-type ion-motive

ATPase that normally mediates copper ion removal from the liver via

biliary excretion and prevents brain copper accumulation. Prompt

diagnosis in the early symptomatic phase of the illness (or presymptomatic detection) and lifelong treatment are needed to avoid premature mortality in affected individuals.

HISTORY OF WILSON’S DISEASE

Wilson’s disease (hepatolenticular degeneration) was first described in

1912 by neurologist S.A.K. Wilson, who recognized the inherited aspect

of the condition. In 1948, the pathologist J.N. Cumings proposed an

etiologic connection with copper overload. Several years later, a metal

chelator developed to counteract an arsenic-based chemical warfare

agent (lewisite) was used to successfully treat advanced Wilson’s disease.

In 1956, copper chelation by d-penicillamine was introduced and found

preferable to anti-lewisite with respect to administration and side effect

profile. In the early 1970s, an alternative copper chelator, triethylene tetramine, became the second U.S. Food and Drug Administration (FDA)–

approved treatment for Wilson’s disease. Also in the early 1970s, the

first liver transplants were performed for Wilson’s disease, with resultant

correction of both hepatic failure and crippling neurologic impairments

in patients unresponsive to medical therapies. The treatment potential of

zinc salts to reduce gastrointestinal copper absorption in Wilson’s disease

was recognized in the early 1960s, eventually leading to FDA approval

for this indication. Tetrathiomolybdate, which forms a tripartite complex

with copper and albumin, and a bacterial peptide, methanobactin, which

traverses mitochondrial membranes, are more recently proposed copper

chelators with potential for treatment of Wilson’s disease.

In 1993, the gene for Wilson’s disease was identified and found to

encode a copper-transporting ATPase, ATP7B, expressed primarily

in liver and kidney. In addition to providing a molecular basis for

diagnosis and genotype-phenotype correlations, the finding presents

current opportunities for viral gene therapy that could impact future

management of this illness.

PHENOTYPES

■ CLINICAL

Presenting clinical features of Wilson’s disease include nonspecific

liver disease, neurologic abnormalities, psychiatric illness, hemolytic

anemia, renal tubular Fanconi syndrome, and various skeletal abnormalities. Age influences the specific presentation in Wilson’s disease.

Nearly all individuals who present with liver disease are <30 years of

age, whereas those presenting with neurologic or psychiatric signs may

range in age from the first to the fifth decade. This reflects the sequence

of events in the pathogenesis of the illness. However, regardless of

clinical presentation, some degree of liver disease is invariably present.

Hepatic Presentation With hepatic presentations, signs and

symptoms include jaundice, hepatomegaly, edema, or ascites. Viral

hepatitis and cirrhosis are often initial diagnostic considerations in

individuals who, in fact, have Wilson’s disease.

Neurologic Presentation In patients with neurologic presentations, abnormalities include speech difficulty (dysarthria), dystonia,

rigidity, tremor or choreiform movements, abnormal gait, and uncoordinated handwriting. Wilson’s disease may be classified as a movement

415 Wilson’s Disease

Stephen G. Kaler