D i a g n o s i s an d

M a n a g e m e n t o f H e red i t a r y
H e m o c h ro m a t o s i s
Reena J. Salgia, MD*, Kimberly Brown, MD

KEYWORDS
 Hemochromatosis  Iron saturation  Ferritin  Cirrhosis  Liver transplant

KEY POINTS
 Hereditary hemochromatosis (HH) is a diagnosis most commonly made in patients with
elevated iron indices (transferrin saturation and ferritin), and HFE genetic mutation testing
showing C282Y homozygosity.
 The HFE mutation is believed to result in clinical iron overload through altering hepcidin
levels resulting in increased iron absorption.
 The most common clinical complications of HH include cirrhosis, diabetes, nonischemic
cardiomyopathy, and hepatocellular carcinoma.
 Liver biopsy should be performed in patients with HH if the liver enzymes are elevated or
serum ferritin is greater than 1000 mg/L. This is useful to determine the degree of iron over-
load and stage the fibrosis.
 Treatment of HH with clinical iron overload involves a combination of phlebotomy and/or
chelation therapy. Liver transplantation should be considered for patients with HH-related
decompensated cirrhosis.

INTRODUCTION

Although hereditary hemochromatosis (HH) is a less common cause of cirrhosis than

chronic viral hepatitis, it remains the most commonly identified genetic disorder in the
white population. The prevalence of HH varies worldwide, with the highest frequency
of disease occurring among those of northern European ancestry.1 Since this disease
was first described by Trousseau in 1865, many studies have led to a greater under-
standing of the underlying pathophysiology. HH was initially noted to be associated
with increased iron deposition in organ tissue, leading to cirrhosis, heart failure, dia-
betes, arthritis, and a high risk for hepatocellular carcinoma (HCC).2 Then a seminal

Disclosures: The authors have no relevant affiliations or financial involvement.

Division of Gastroenterology and Hepatology, Henry Ford Hospital, 2799 West Grand
Boulevard, Detroit, MI 48202, USA
* Corresponding author.
E-mail address: rsalgia1@hfhs.org

Clin Liver Dis 19 (2015) 187198

http://dx.doi.org/10.1016/j.cld.2014.09.011 liver.theclinics.com
1089-3261/15/$ see front matter 2015 Elsevier Inc. All rights reserved.
188 Salgia & Brown

paper in 1996 revealed the HFE gene mutation, which causes a substitution of tyrosine
for cysteine at the amino acid 282 position (C282Y).3 Subsequently two additional mu-
tations were noted, aspartate for histidine (H63D), and cysteine for serine (S65C). The
most common form of HFE-related HH is associated with the C282Y homozygous
mutation, and less commonly compound heterozygotes with either C282Y/H63D or
C282Y/S65C.4 Non-HFE associated hemochromatosis is rare, accounting for less
than 15% of inherited iron overload.5 This article provides a brief overview of the path-
ophysiology of hemochromatosis, and an up-to-date summary of the diagnosis and
management of HH.

PATHOPHYSIOLOGY

HH is a genetic disorder broadly characterized by excessive total body iron stor-

age.1,6 Several mechanisms explain this imbalance of iron homeostasis in HH. The
initial theory was noted as the crypt cell hypothesis, reflecting the interplay be-
tween the HFE protein and b2-microglobulin.7,8 Together these two proteins form
a complex with transferrin receptor-1, which is located predominantly in the
duodenal crypt enterocytes. There the complex would sense and regulate dietary
iron absorption. It is also hypothesized that this complex acts at the level of the he-
patocyte membrane to sense iron stores.9 However, the more recent discovery of
hepcidin, a small peptide hormone that is encoded by a gene expressed in the liver,
has altered the predominant theory of iron overload associated with HH. Hepcidin
controls iron absorption in the duodenum. The levels of circulating hepcidin vary
based on systemic iron stores.10 The interaction between HFE and the transferrin re-
ceptors is paramount to the sensing of iron at the hepatocyte membrane.11 When
iron stores are elevated, hepcidin is released and binds to ferroportin in macro-
phages and enterocytes. There it blocks the export of iron from macrophages and
decreases intestinal iron absorption (Fig. 1).12,13 When the HFE protein is mutated,
the expression of hepcidin decreases and intestinal iron absorption increases.
Although it remains unclear how the mutated HFE gene controls hepcidin in HH, a
decrease in hepcidin results in a rise of iron efflux from macrophages and entero-
cytes, and increased intestinal iron absorption into organ tissue.14 Hence the liver
is the major regulator of iron metabolism, and in patients with HH this mechanism
is altered by abnormally low hepcidin levels.15
The presence of elevated iron stores in the liver over time can lead to hepatic fibrosis
and cirrhosis. Iron has been shown to cause increased oxidative stress and damage to
hepatocytes and mitochondrial function.1618 These hepatocytes are injured and
release Kupffer cells, which stimulate hepatic stellate cells to increase production of
collagen.19 Over time this process leads to the development of cirrhosis.

DIAGNOSIS
Clinical Presentation
Because of variable penetrance of clinical HH, end-organ damage is noted in less than
10% of patients who are homozygous for the C282Y mutation.20 The clinical pheno-
type is expressed in 24% to 43% of males and 1% to 14% of females.21 Clinical dis-
ease is noted even less frequently in patients who are compound heterozygotes
(C282Y/H63D positive), who account for approximately 5% of cases of HH.4,22
Women also present with clinical features later in life, largely related to monthly
menstruation resulting in iron loss and having a protective effect. However, the dis-
ease prevalence is similar between men and women, resulting from earlier recognition
and screening for this disease.23,24
 Diagnosis and Management of Hemochromatosis 189

Fig. 1. Iron homeostasis as regulated by hepcidin. BMPR, bone morphogenetic protein

receptor; FPN, ferroportin; HJV, hemojuvelin; SMAD, Sma and Mad related protein. (From
Camaschella C. BMP 6 orchestrates iron metabolism. Nat Genet 2009;41(4):3868; with
permission.)

The clinical features of HH are highly variable, with signs and symptoms that can
involve multiple organ systems. Aside from liver involvement leading to cirrhosis,
iron overload from HH can involve the heart, pancreas, skin, pituitary gland, gonads,
and joints (Table 1).1,4 Multiple studies have found that the predominant clinical fea-
tures in patients with HH include (from most common to least common) cirrhosis, leth-
argy, hyperpigmentation of the skin, loss of libido, testicular atrophy, diabetes,
abdominal pain, and arthralgias.2527

Laboratory Testing
The initial suspicion for HH is largely made based on clinical features, biochemical ab-
normalities, and genetic testing, with liver biopsy less commonly needed to make an
initial diagnosis. Elevated serum ferritin (SF) levels and transferrin-iron saturation (TS)
are readily available serum markers that help to identify patients with HH. These tests
should be performed on patients with chronically elevated liver enzymes.1 Ferritin
levels greater than 200 mg/L for females and greater than 300 mg/L for males are
considered abnormal.23,28 Ferritin is known to be elevated in the absence of elevated
iron stores. For example, the presence of viral hepatitis, nonalcoholic fatty liver dis-
ease, or alcoholic liver disease and other chronic inflammatory conditions can all
cause elevations in SF levels.1 The TS is calculated based on total body iron divided
190 Salgia & Brown

Table 1
Signs, symptoms, and clinical presentation of HH

Organ System Sign/Symptom Physical Examination

General Weakness, fatigue, lethargy
Weight loss
Apathy
Liver Abdominal pain Hepatomegaly
Splenomegaly
Cutaneous stigmata (spider angiomata,
palmar erythema)
Gynecomastia
Cardiac Heart failure Cardiomegaly
Arrhythmia Elevated JVP
Pancreas Hyperglycemia from diabetes
Skin Hyperpigmentation, bronze skin
Porphyria cutanea tarda
Endocrine Loss of libido Testicular atrophy
Hypothyroidism
Joints Arthralgias Arthritis (second and third MCP)
Joint swelling

Abbreviations: JVP, jugular venous pressure; MCP, metacarpophalangeal joint.

by total iron-binding capacity. A saturation level higher than 45% again raises suspi-
cion for HH.23,28 If either the SF or TS is abnormal, then the HFE genetic mutation anal-
ysis should be performed.1 A result of C282Y homozygous genotype is consistent with
a diagnosis of HH in the setting of iron overload.29 It is less common for C282Y/H63D
compound heterozygous genotype or H63D homozygous genotype to develop clini-
cally significant iron overload; however, it has been described.22,30 The Hemochroma-
tosis and Iron Overload Screening study screened 99,711 North American patients
and found that SF was elevated (>200 mg/L in women and >300 mg/L in men) in
57% of female and 88% of male C282Y homozygotes.23 Multiple studies have shown
that marked elevations in SF to values greater than 1000 mg/L are a stronger predictor
of advanced hepatic fibrosis and cirrhosis in patients with documented HH.29,3133
When an elevated ferritin greater than 1000 mg/L is combined with elevated transam-
inases and platelet count less than 200  10(9)/L, the positive predictive value for
cirrhosis is 80% in patients with C282Y homozygosity.34 These findings have also
been shown to increase the mortality risk associated with HH.35 Patients with
C282Y homozygosity who have normal iron studies should have an annual measure-
ment of their ferritin level.4

Screening for Hereditary Hemochromatosis

Screening for HH should also be performed in patients with a family history of HH or a
suspicion based on suspected organ involvement of elevated iron stores.1,23 Fig. 2 is a
diagnostic algorithm for screening patients at-risk for HH. It is recommended that all
first-degree relatives of a patient with HH should undergo family screening. Screening
can be performed with SF, TS, and HFE mutation testing. The inheritance pattern is
autosomal-recessive with mutations in the HFE gene on chromosome 6.3,36 Children
of an affected parent can be tested or alternatively the other parent can be tested.37 It
is generally recommended that if children are going to be screened, testing should be
 Diagnosis and Management of Hemochromatosis 191

Fig. 2. Diagnostic algorithm for HH. Elevated SF is greater than 200 mg/L in females and
greater than 300 mg/L in males.

done once they reach adulthood.38 There is a negligible risk of developing clinical HH
before the age of 18.

Histology
The main purpose of liver biopsy in the diagnosis of HH is to stage the degree of fibrosis.
It is important to determine if patients have cirrhosis for prognosis and to initiate
surveillance for HCC and esophageal varices.39 SF is valuable to discriminate which
patients should proceed with a biopsy. Specifically, ferritin greater than 1000 mg/L in
C282Y homozygotes has been shown in several studies to be predictive of cirrhosis,
with a prevalence of 20% to 45%.32,34 Ferritin levels less than 1000 mg/L in the same
population is associated with a low prevalence of 2% for determining cirrhosis. How-
ever, this does not apply in patients with a coexisting cause for liver disease, such as
chronic viral hepatitis, alcoholic liver disease, or nonalcoholic fatty liver dis-
ease.29,31,32,34 Additionally, liver biopsy should be performed in patients with elevated
iron studies, elevated liver enzymes, and non-C282Y genotypes of HH. This can
exclude the presence of a coexisting cause of liver injury.1
Liver biopsy specimens should be processed using standard hematoxylin-eosin
stain, Masson trichrome stain, and an additional Perl Prussian blue stain. The Prussian
blue stain helps to capture the distribution of hepatic iron (Fig. 3).40 A quantitative
assessment of hepatic iron stores can also be performed. This measurement, the he-
patic iron concentration or similarly the hepatic iron index, is abnormal at levels higher
than 36 mmol/g and 1.9, respectively.4144 In the clinical setting, hepatic iron concen-
tration is more commonly used, with hepatic iron index reserved more for the research
192 Salgia & Brown

Fig. 3. Perl Prussian blue stain on a liver biopsy in hemochromatosis. (Reproduced from Uni-
versity of Utah WebPath slide set; with permission.)

setting. Hepatic iron concentration has been shown to correlate well with a noninva-
sive method of estimating hepatic iron stores using T2-weighted MRI.45,46 Addition-
ally, another noninvasive method of determining cirrhosis that is gaining popularity
is use of transient elastography. These methods reduce the need for performing liver
biopsy as frequently.

Non-HFE Hereditary Hemochromatosis

There are other inherited forms of HH that are less common, and nonHFE-related.
These account for less than 5% of cases of inherited HH. Examples include juvenile
hemochromatosis, mutation in the transferrin receptor 2 gene, and a mutation in the
ferroportin (SLC40A1) gene.5 The most common of these is juvenile hemochromato-
sis, which has two potential genetic mutations.47 Most common is type 2a HH, which
is caused by a mutation in the hemojuvelin gene on chromosome 1q.48 Less common
is type 2b HH, caused by a mutation in the hepcidin gene. The presence of this muta-
tion results in upregulation of iron absorption.47 A mutation in the transferrin receptor 2
gene results in abnormal sensing of iron stores by hepatocytes. In turn this leads to an
autosomal-recessive form of HH, also known as type 3 HH.49 The excess iron is
deposited in the hepatocytes, as is similar to HFE-related HH. A rare cause of HH re-
sults from mutations in the SLC40A1 gene, responsible for the iron transporter protein,
ferroportin. Mutations in this gene result in impaired iron export, with deposition of iron
noted in the hepatocytes and in reticuloendothelial cells.50 The inheritance pattern is
autosomal-dominant, and also known as type 4 HH.51 Genetic testing for all of these
mutations is often unavailable in the clinical setting, particularly for the SLC40A1 gene
mutation. Liver biopsy can be a useful diagnostic tool in patients with non-HFE HH to
determine the extent of iron overload and the distribution.5,52 Presently, there are no
recommendations to screen patients for nonHFE-related HH.1

MANAGEMENT AND TREATMENT

Goals of Management
Early identification and treatment of patients with HH with clinical iron overload can
improve their morbidity and mortality. The mainstay of treatment has been through
phlebotomy. Although no randomized controlled trial has been performed comparing
phlebotomy with no phlebotomy for these patients, there is evidence of improvement
in certain clinical features with treatment.53,54 Phlebotomy in patients with liver disease
 Diagnosis and Management of Hemochromatosis 193

can slow the progression to cirrhosis, and also reduces the risk of developing HCC.
HCC is rare in patients with HH in the absence of cirrhosis.55 However, patients
with HH-related cirrhosis are at an elevated risk of developing HCC, with 30% of
disease-related deaths noted to be from the development of liver cancer.54,56 Tissue
iron overload has in fact been shown to increase the likelihood of a variety of cancers,
not just HCC.57 In early stages of hepatic fibrosis, reversal of fibrosis can be noted in
some patients with reduction of tissue iron stores, and can also normalize liver en-
zymes. Once cirrhosis is established, improvement in fibrosis is not expected with
phlebotomy.58 Phlebotomy can also improve diabetes management and control,
decrease fatigue, improve cardiac function, reduce skin hyperpigmentation, and
improve abdominal pain. Patients with arthropathy or hypogonadism rarely see
improvement in symptoms with phlebotomy.5861

Phlebotomy
The initial goal of therapeutic phlebotomy is to decrease the SF level to between 50
and 100 mg/L to assume that the excess iron stores have been depleted.1 Each unit
of blood removed is 400 to 500 mL of whole blood and contains approximately 200
to 250 mg of iron. Phlebotomy should be initiated once weekly, depending on the
baseline hemoglobin. The hemoglobin needs to be monitored closely, ensuring that
this does not decrease to less than 80% of the baseline value.1 During the first year
of phlebotomy, it is recommended that a hemoglobin is checked before each phlebot-
omy, and that ferritin levels are monitored with every 10 to 12 phlebotomies. TS usually
does not decrease until iron stores are depleted, so it is more accurate to initially
monitor the ferritin.1 Once the ferritin is reduced to 50 to 100 mg/L, testing should
be done more frequently so as to avoid iron deficiency, and maintenance phlebotomy
can be scheduled. The frequency of maintenance is variable, ranging for some pa-
tients every 4 weeks to yearly or even less often for others.1 During the maintenance
phase, a ferritin level up to 100 mg/L is tolerated, because prior recommendations to
aggressively keep the ferritin levels very low (<50 mg/L) may paradoxically decrease
hepcidin stores and then promote reaccumulation of iron.1 Presently, there are insuf-
ficient data to support phlebotomy for asymptomatic patients with HH who do not
have elevated iron stores.

Iron Chelators and Dietary Modification

Few patients with HH are intolerant of phlebotomy because of baseline anemia or he-
matologic disorders. These patients should be considered for iron chelation therapy,
such as deferoxamine or deferasirox.62,63 Dietary changes have not been shown to be
necessary for patients undergoing treatment, except in the setting of patients who
may eat diets very rich in iron. Pharmacologic iron supplementation is advised
against.4 Vitamin C can interfere with the mobilization of iron stores by saturating
transferrin. This results in increased free radical activity.64 Most commonly this is
seen with pharmacologic doses of vitamin C, which is also not recommended in pa-
tients undergoing treatment of HH.

Cirrhosis Management
Progression to advanced cirrhosis or decompensated cirrhosis is not reversed with
phlebotomy. Patients who have developed decompensation of their liver disease
should be considered for orthotopic liver transplantation. Over the past few decades,
the outcome of patients transplanted for HH-related cirrhosis has improved, with
posttransplant survival now similar to other patients postorthotopic liver transplanta-
tion. A recent study showed postliver transplant survival for patients with HH to be
194 Salgia & Brown

83% at 1 year and 67% at 5 years.65,66 The most likely explanation for this is because
of earlier identification of the disease, instituting early treatment and adequate
removal of iron excess before transplant. This has decreased the likelihood of periop-
erative mortality associated with cardiac disease and infection, and posttransplant
malignancy.67
Similar to other patients with cirrhosis, the American Association for the Study of
Liver Diseases guidelines recommends that all patients with cirrhosis from HH un-
dergo surveillance for HCC. Patients with HH have an annual incidence of HCC of
3% to 4% in the setting of underlying cirrhosis.68 This risk remains elevated despite
adequate phlebotomy and removal of excess tissue iron, although long-term studies
are needed.55 Screening and surveillance is recommended with a combination of
abdominal ultrasound  alpha fetoprotein every 6 to 12 months.68

SURVIVAL AND PROGNOSIS

Overall, the survival of patients with HFE-related HH is affected by their clinical pheno-
type; the presence or absence of cirrhosis; and other HH-related comorbidities, such
as diabetes and cardiac disease. Patients who express the clinical phenotype and
have untreated disease have a higher mortality risk than the general population.27,54
Patients without the clinical phenotype have a similar overall survival to the general
population.27 In the setting of cirrhosis, patients with HH have a higher risk of death
regardless of their treatment status.27 There has been no prospective study
comparing phlebotomy with placebo. This is unlikely to occur because it would be
deemed unethical given the effectiveness and safety profile of phlebotomy. However,
phlebotomy seems to improve survival, likely because of slowing the rate of clinical
progression and associated comorbid conditions. Patients with decompensated
cirrhosis from HH who undergo a liver transplant have overall comparable survival out-
comes with other transplant recipients, and have a normalization of their hepcidin
levels after transplantation.66 This prevents the development of iron overload from
HH in the graft.

SUMMARY

Because of a greater understanding of the genetic factors causing HH, there is an

earlier recognition and diagnosis of patients with HH. The clinical phenotype of iron
overload associated with HH remains a rare liver disease in comparison with viral hep-
atitis or fatty liver disease. However, it can have important clinical consequences that
affect multiple organ systems including the liver, heart, skin, joints, and endocrine
function if not recognized and managed at an early stage. HFE-associated hemochro-
matosis is responsible for most cases of HH. Liver biopsy is performed in select cases
to stage the degree of hepatic fibrosis and/or quantify hepatic iron content. Patients
with biochemical evidence of iron overload and clinical features of hemochromatosis
should be managed ideally with phlebotomy. Patients with advanced cirrhosis and
decompensation should be considered for liver transplantation, and should undergo
regular surveillance for HCC. In the future, clinicians will likely continue to better under-
stand the central mechanism underlying iron metabolism in HH. Although genetic
testing for the HFE genetic mutation is now commonly available, gene testing for rarer
causes of HH can be difficult to perform in the clinical setting. Given the infrequent pre-
sentation of these disorders, it is unclear if this testing will become commercially avail-
able in the near future. Overall the future for patients undergoing liver transplantation
for HH remains bright, with comparable posttransplant outcomes with other liver
transplant recipients.
 Diagnosis and Management of Hemochromatosis 195

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