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Review

A diagnostic approach to hyperferritinemia with
a non-elevated transferrin saturation
Paul C. Adams1,⇑, James C. Barton2
1

Department of Medicine, University Hospital, University of Western Ontario, London, Ontario, Canada; 2Southern Iron
Disorders Center and University of Alabama at Birmingham, Birmingham, AL, USA

Elevated serum ferritin concentrations are common in clinical
practice. In this review, we provide an approach to interpreting
the serum ferritin elevation in relationship to other clinical
parameters including the patient history, transferrin saturation,
serum concentrations of alanine, and aspartate aminotransferases (ALT, AST), testing for HFE mutations, liver imaging, liver
biopsy, and liver iron concentration. We used observations from
a large series of patients with hepatic iron overload documented
by liver iron concentration measurement from two referral practices as a gold standard to guide the interpretation of the predictive values of non-invasive iron tests. Three case studies illustrate
common problems in interpreting iron blood tests.
Ó 2011 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.

Introduction
Elevated serum ferritin concentrations are common. The cause of
an elevated ferritin concentration is usually increased ferritin
synthesis (including acquired/genetic conditions with or without
iron overload) or increased release of ferritin from damaged cells
(Table 1). A clue to the cause of the elevation is often the accompanying clinical setting. For example, an isolated elevation of
serum ferritin <1000 lg/L with a normal transferrin saturation
(TS) in the context of daily alcohol consumption or obesity is a
common presentation. Another group of patients with an isolated
elevation of serum ferritin <1000 lg/L and normal TS values have
hyporegenerative anemia untreated with transfusion (usually
due to renal insufficiency, chronic disease, or marrow failure),
malignancy, or chronic inflammation of diverse etiologies. In
either situation, iron overload is usually not present and thus
diagnosis and management of the disorders that contribute to
hyperferritinemia is indicated. The diagnostic approach to elevated serum ferritin concentrations in patients who also have
elevated serum concentrations of liver enzymes is more complicated. Genetic hemochromatosis is often considered when evaluating an elevated ferritin. Regardless of this, most patients

Keywords: Haemochromatosis; Iron overload.
Received 10 December 2010; received in revised form 26 January 2011; accepted 4
February 2011
⇑ Corresponding author. Address: Department of Medicine, University Hospital,
339 Windermere Rd., London, Ontario, Canada N6A 5A5. Fax: +1 519 663 3549.
E-mail address: padams@uwo.ca (P.C. Adams).

without an elevated TS have hyperferritinemia related to inflammation, chronic alcohol consumption, cell damage, or metabolic
abnormalities (e.g., obesity).
Reference concentrations of serum ferritin and TS vary across
laboratories due to differences in analytical techniques and reference populations; age and sex are also important determinants of
these measures. A large, multi-ethnic, multi-racial screening
study of iron overload in North Americans recruited in primary
care settings defined that serum ferritin concentrations greater
than 300 lg/L in men and greater than 200 lg/L in women were
elevated [1]. By definition, TS values greater than 50% in men and
greater than 45% in women were defined as elevated. Analysis of
race/ethnicity groups within this large cohort revealed that mean
SF and percentages of participants with elevated SF were significantly greater in blacks, Asians, and Pacific Islanders than in
whites. Mean TS values were greatest in Asians and Pacific Islanders, intermediate in whites, and lowest in African Americans. This
indicates that ‘‘elevated’’ serum ferritin or TS concentrations are
probably not always the indicators of disease, although the
biological basis and clinical significance of these race/ethnicity
differences in iron phenotypes are incompletely understood.
Using transferrin saturation to interpret elevated serum
ferritin level
Serum ferritin concentrations are often measured to investigate
fatigue, possible liver disease, anemia, malignancy, or other
conditions. Many clinicians interpret the serum ferritin concentration together with TS to determine if iron overload, iron deficiency,
or subnormal iron mobilization for erythropoiesis is present. Thus,
many clinicians rely on inferences made from TS measurements as
an aid to the diagnosis of a variety of abnormalities [2,3].
In a large population screening study, we have demonstrated
that there is significant biological variability in serum TS [4]. In
64,230 participants, a non-fasting TS >45% in women and >50%
in men had a sensitivity of 75% and specificity of 95% in the
detection of C282Y homozygotes. This variability decreases the
reliability and specificity of TS as a test to clarify the diagnostic
significance of elevated serum ferritin concentrations. Withinperson biological variability in iron test values has been reported
previously; diurnal fluctuations in test values have been described
primarily for serum iron measurements [4,5]. TS is a calculated
value determined as the quotient of the serum iron level divided
by one of the following: total iron-binding capacity; unsaturated

Journal of Hepatology 2011 vol. 55 j 453–458

Review
Table 1. Mechanism of hyperferritinemia in selected disorders.

Increased apoferritin (or L ferritin) synthesis/secretion: chronic ethanol ingestion; malignancy (malignant histiocytosis;
carcinomas of lung, breast, ovary, and kidney; lymphoma; liposarcoma); Gaucher disease; reactive histiocytosis; hereditary
hyperferritinemia-cataract syndrome
Increased ferritin release from injured cells: hepatic steatosis and steatohepatitis; chronic viral hepatitis; massive liver necrosis
due to sepsis, acute hepatitis, or toxic injury; autoimmune disorders; acute and chronic infections; acute myocardial infarction;
splenic infarct
Increased ferritin synthesis due to iron overload: HFE and other types of hemochromatosis; heritable and acquired anemias
associated with ineffective erythropoiesis; increased iron absorption from supplemental iron or ingestion of traditional beer (subSaharan African Natives); transfusion iron overload; parenteral iron overload; aceruloplasminemia

Relationship between transferrin saturation and liver iron
concentration
Elevated TS is an important prerequisite for iron loading of hepatocytes typical of hemochromatosis due to mutations in genes
that encode HFE, hemojuvelin, transferrin receptor 2, and hepcidin. Elevated TS depends partly on increased iron absorption,
because food iron deprivation causes TS to decrease [7] and supplemental iron increases TS. Increased release of iron from macrophages into plasma also contributes to elevated plasma iron
and TS concentrations. Overall, the elevated TS that may be
observed in relatively young persons suggests that iron absorption is increased. Acute infections, menses, recent blood donation
may temporarily reduce TS concentrations in persons with excessive hepatocyte iron deposition [8]. Due to this variability, we
recommend testing Caucasian patients with serum ferritin
>1000 lg/L for the HFE C282Y mutation.
We investigated the relationship between an elevated TS and
liver iron concentration further. Using observations from two
tertiary referral centers (London, Ontario and Birmingham,
Alabama), we tabulated data from patients who underwent
measurement of TS and liver iron concentration (Fig. 1). In the Alabama samples, liver iron concentrations were measured in
patients with iron overload initially determined by liver iron
454

histochemical grading criteria. In the London, Ontario samples,
liver iron was measured on a more diverse group, because many
of the patients participated in a study of MRI and liver iron [9].
Patients from both locations were separated into two groups:
HFE C282Y homozygotes and other cases. Diagnoses in these
patients included hemochromatosis, non-HFE iron overload,
juvenile hemochromatosis, alcoholic liver disease, fatty liver, hepatitis C, and hepatitis B. Because most patients do not undergo routine liver biopsy, this sample does not represent the general
population. We analyzed these data using receiver operator characteristic (ROC) curves; we calculated positive likelihood ratios for
predicting hepatic iron overload (LIC >40 lmol/g) (Table 2). From
these results, we conclude that: (1) TS predicts hepatic iron overload better in C282Y homozygotes than in non-homozygotes; and
(2) some patients with a normal TS and an elevated serum ferritin
concentration have iron overload proven by liver biopsy.
Assessment of patients with an elevated ferritin concentration
and a non-elevated transferrin saturation
In this setting, it is useful to measure serum concentrations of AST,
ALT, alkaline phosphatase (AP), gamma-glutamyl transpeptidase
(GGT), HBsAg, and anti-HCV; assess alcohol history and body mass
index; and perform abdominal ultrasonography. If a patient has elevated serum concentrations of hepatic enzymes, the next question is
whether the elevated serum ferritin level is the sequel of hepatocyte
necrosis or, less likely, whether iron overload caused the liver damage [10,11]. Typical patients with hyporegenerative anemia have
normal serum concentrations of hepatic enzymes, and anemia is

900

Liver iron concentration (µmol/g)

iron-binding capacity + serum iron concentration; or serum transferrin concentration multiplied by a constant. Liver disease sometimes causes low serum transferrin concentrations that may lead
to increased TS without iron overload. The higher variability of TS
than the serum iron level may be due to the fact that measurement of TS is a two-step, rather than a single-step, test. It has been
reported that most HFE C282Y homozygotes have persistently elevated TS, and that false positive tests in non-homozygotes would
likely return to normal on a second test [6]. This was the previous
rationale for using two TS tests (first test random, second test fasting) for the presumptive diagnosis of hemochromatosis before
proceeding to more specific diagnostic tests, including liver
biopsy or DNA-based testing. Regardless, this and other studies
failed to confirm that fasting iron tests had greater specificity
for the diagnosis of HFE C282Y-linked hemochromatosis than iron
tests drawn without regard to fasting [2,3]. In addition, variability
of TS measurements in this study was similar in homozygotes and
non-homozygotes [4]. The second fasting value was as likely to
increase as to decrease, and regression to the mean is the most
likely explanation for this phenomenon. Fasting as a condition
for testing adds a level of complexity and inconvenience to a
screening program. In addition, any biochemical test with such
wide biological variation is unlikely to be an ideal screening test.

800
700
600
500
400
300
200
100
0

0

20

40

60

80

100

Transferrin saturation (%)
Fig. 1. The relationship between transferrin saturation and hepatic iron
overload in C282Y homozygotes (d) and non-homozygotes (s).

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JOURNAL OF HEPATOLOGY
rare in persons with hemochromatosis due to HFE C282Y homozygosity who have not been treated with phlebotomy.
Obesity or fatty liver detected by ultrasonography suggest the
presence of steatohepatitis. Chronic alcohol consumption may be
suspected based on the clinical history and an elevated level of
GGT. In patients with viral hepatitis B or C, serum ferritin is often
elevated but usually does not indicate iron overload. A clinical syndrome has been described in France associated with insulin resistance and features of the metabolic syndrome [12,13]. Patients
with dysmetabolic syndrome usually have elevated serum ferritin
concentrations and a normal TS. Liver biopsy in such patients usually demonstrates iron in Kupffer cells and steatosis; insulin resistance in such patients may decrease with phlebotomy therapy [14].
Obesity, diabetes mellitus, dyslipidemia, and hypertension are
other common although not diagnostic features of this syndrome.
Hereditary hyperferritinemia–cataract syndrome (HHCS) is
caused by heterogeneous mutations in the iron-responsive
element (IRE) of L-ferritin that reduce the binding affinity of
iron-responsive proteins (IRPs) to IREs and thereby diminish the
negative control of L-ferritin (but not H-ferritin) synthesis. This
leads to the constitutive up-regulation of ferritin L-chain synthesis
characteristic of HHCS. Serum ferritin concentrations are elevated
and relatively constant; TS is normal. Patients with HHCS do not
develop iron overload, although common HFE mutations, especially H63D, may occur in HHCS patients coincidentally. L-ferritin
deposition in the ocular lens causes bilateral cataracts at an early
age [15–17]. It may be possible to have an elevated ferritin on this
basis without cataracts [18]. The concurrence of hyperferritinemia
and cataract do not establish the diagnosis of HHCS [19]. Although
routine genetic testing to verify HHCS is usually not feasible, demonstration of hyperferritinemia and cataract syndrome in two
or more members of the same kinship is usually diagnostic [19].
Aceruloplasminemia is a rare genetic syndrome due to mutations in the CP gene that encodes ceruloplasmin. This condition is
associated with normal TS, hyperferritinemia, and iron overload;
retinal abnormalities; and prominent neurological problems.
Anemia is uncommon. Aceruloplasminemia can be distinguished
from Wilson disease by the absence of ceruloplasmin in the
serum, by the absence of excess urinary copper, and by the
absence of excess storage copper in the liver [20,21].
Ferroportin is an iron transport protein and the receptor for
hepcidin. ‘‘Loss-of-function’’ mutations of the SLC40A1 gene that
encodes the ferroportin result in an uncommon, iron overload disorder characterized by normal TS, elevated serum ferritin concentration, and hepatic iron overload. This condition is inherited as an
autosomal dominant trait. Ferroportin normally occurs at the
basolateral surfaces of enterocytes, macrophages, hepatocytes,
and placental syncytiotrophoblasts. In patients with a pathogenic
SLC40A1 mutation, ferroportin multimers consists of both normal
Table 2. Receiver operating curve assessment of transferrin saturation to
predict hepatic iron overload.

TS for iron overload

Sensitivity
(%)

Specificity
(%)

>55%* (n = 371)

81

73

>50% (n = 371)

85

69

>45 (n = 371)

89

61

>55% in C282Y homozygotes

92

40

(n = 209)


Iron overload is defined as a liver iron concentration >40 lmol/g dry weight.

and abnormal molecules, causing a dominant negative effect of
the mutant SLC40A1 allele that prevents normal function of the
wild-type (normal) ferroportin. Excessive iron is typically deposited in macrophages in the liver, spleen, bone marrow, and lymph
nodes; decreased iron mobilization from macrophages decreases
serum iron and TS values [22]. ‘‘Gain-of-function’’ SLC40A1
mutations, in contrast, result in iron overload that is usually
associated with elevated TS, hyperferritinemia, and parenchymal
iron deposition similar to that of HFE hemochromatosis.
A trial of clinical observation
There are many patients in whom observation and follow-up is
more appropriate than an invasive investigation or a trial of phlebotomy. It is informative to observe whether the serum ferritin
concentration is stable over time. Stable serum ferritin concentrations are typical of hyperferritinemia in some patients with HFE
hemochromatosis, patients of certain race/ethnicity groups, and
persons with HHCS. In patients with hepatic steatosis or steatohepatitis or alcohol-induced hyperferritinemia, serum ferritin concentrations typically fluctuate greatly. Progressively increasing
serum ferritin concentrations suggest iron overload. During an
interval of observation, there are opportunities to repeat the TS.
Management of non-iron overload causes of
hyperferritinemia
Treatment of hyperferritinemia involves management of disorders that results in increased synthesis of apoferritin or cell injury.
Interventions, such as alcohol abstinence, improved diabetes control, weight reduction, or lowering triglyceride concentrations
with diet and medications may reduce serum ferritin concentrations during the observation period. Treatment of hyporegenerative anemia, causes of chronic inflammation, malignancy, viral
hepatitis, or other non-iron overload causes of hyperferritinemia
can reduce serum ferritin concentrations and substantiate provisional diagnoses of the cause(s) of hyperferritinemia. Treatment
of hyperferritinemia in persons with HHCS is not indicated.
MRI scanning to detect iron overload
MRI scanning has been used to estimate liver iron concentrations
indirectly. Overall, MRI technology for iron quantification is
improving, but requires a dedicated radiology team and appropriate machine-specific calibration. MRI scanning is better at detecting and quantifying severe hepatic iron overload than mild iron
overload usually associated with mild elevations of serum ferritin
concentrations [23,24].
Trial of phlebotomy
One diagnostic criterion for iron overload is a trial of phlebotomy;
this method was typically used before other methods were
devised. It was assumed that a patient had significant iron overload if they could tolerate, e.g., 20 weekly phlebotomies without
developing anemia. It has been estimated that a 500 ml phlebotomy removes 0.25 g of mobilizable body iron. If the patient developed anemia after a few phlebotomies, it was assumed that the
elevated serum ferritin value was due to inflammation or other
non-iron overload cause, rather than to iron overload, because
many normal persons have sufficient storage iron to support this
level of phlebotomy. Quantitative phlebotomy has great utility

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Review
today; its few adverse effects include venous access, phlebitis,
vasovagal symptoms, anemia, and the costs and potential inconvenience of arranging treatments. The positive aspects of this
approach to measuring body iron stores are that the patient feels
that something is being done to correct their laboratory abnormalities. Many patients report positive physical and mental
effects after phlebotomy. An alternative to arranging weekly phlebotomy therapy is to suggest that the patient be a voluntary blood
donor every 2–3 months [25]. Patients with HHCS should not be
treated with phlebotomy. Some patients with iron overload due
to ‘‘loss-of-function’’ SLC40A1 mutations reconstitute circulating
erythrocyte concentrations very slowly after phlebotomy treatments and should be managed with relatively low phlebotomy
volumes and long intervals between treatments.
The choice of observation, MRI, phlebotomy, or liver biopsy is
based on clinical judgment, patient preferences, and local
resources. There is not always a preferred pathway and different
approaches may suit different patients.

Genetic testing
HFE genotyping is often used to test patients with an elevated
serum ferritin level. Some HFE C282Y homozygotes, and less
commonly HFE H63D homozygotes and compound heterozygotes
(HFE C282Y/H63D) develop iron overload secondary to a genetic
abnormality in iron absorption and metabolism [1]. An increasing
number of pathogenic mutations in other iron related genes
(hemojuvelin, hepcidin, ferroportin, transferrin receptor 2) have

been identified, but there is no widely available commercial testing, if any, for these mutations [26]. In many of the rare cases of
non-HFE iron overload, the genes most likely involved must be
deduced from clinical features in the patient and his/her family
members. Even after the probable causative gene is identified
by these provisional methods, sequencing of the gene, rather than
mutation-specific analysis, is often required. In many cases, there
are no abnormal findings, because there are heritable forms of
iron overload for which no explanatory gene or mutation has
yet been reported. Furthermore, it is becoming increasingly difficult to differentiate between genetic polymorphisms and mutations with functional and clinically significant implications. For
a clinician, it can be helpful to test siblings and children of index
patients for iron overload (TS, serum ferritin level) in this setting
to screen for an unusual iron overload disorder. The study of
genomics is rapidly advancing and large scale high-throughput
genetic sequencing is becoming widely available (exome and
NextGen sequencing, total genome sequencing). The storage
and interpretation of these huge volumes of data, their costs,
and the genetic counseling that would be provided to the patient
and their family as an accompaniment to such testing are a great
future challenge, although whether such maneuvers will be feasible diagnostic tools for many patients is unproven.

Liver biopsy
Percutaneous liver biopsy is a well-established method for evaluation of iron overload [27] and concomitant liver disease (Fig. 2).

Fig. 2. A liver biopsy in an 88 year C282Y homozygous woman with severe iron overload but without liver fibrosis. (PERLS Prussian Blue stain).

456

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JOURNAL OF HEPATOLOGY
The safety of the procedure has been well-documented [28] and
accepted by hepatologists, although other physicians and some
patients are reluctant to accept or recommend the procedure.
In patients who have isolated hyperferritinemia, liver biopsy is
often used to exclude iron overload. Liver biopsy is also useful
for staging steatohepatitis, alcoholic liver disease, or viral hepatitis, or to diagnose liver disease that cannot be identified with
non-invasive methods. A liver biopsy is not routinely recommended to assess iron overload in patients with elevations of
serum ferritin <1000 lg/L, because the risks of the procedure
may outweigh the possibility that a diagnosis will be made that
would change management recommendations [29,30].
Case study 1
A 39 year-old woman was referred to liver clinic because she had
serum ferritin of 1822 lg/L. She is a native of the Philippine
Islands with no known European ancestors. She denies any alcohol use and has no history of liver diseases or hepatitis. Initial
investigations included AST 72 IU/L, ALT 123 IU/L, bilirubin
9.7 lmol/L, hemoglobin 138 g/L, MCV 92, platelets 314 103/
lL, INR 1.0, albumin 45 g/L, HBsAg negative, anti-HCV negative,
TS 47%, and repeat serum ferritin 2913 lg/L. She has a body mass
index of 32 kg/m2 and an abdominal ultrasound suggesting fatty
infiltration of the liver without splenomegaly or ascites. HFE
mutation analyses did not detect C282Y or H63D.
Clinical commentary
Serum ferritin concentration >1000 lg/L is an indication for further
investigations because this level of ferritin has been associated with
increased risk of hepatic fibrosis. HFE-linked hemochromatosis is an
unlikely diagnosis in a Filipino, although European colonization
could account for HFE C282Y in that geographic region. A clinical
diagnosis of steatohepatitis seems likely, although the ferritin elevation is more elevated than usually expected. Although the TS is
within the reference range, with what degree of certainty does this
exclude iron overload? Options to consider at this point include:
liver biopsy with hepatic iron concentration; MRI imaging with
indirect estimate of liver iron concentration; trial of phlebotomy;
and further observation and monitoring.
The patient has already had a period of observation and the
serum ferritin level is rising. Thus, we would not consider this
option. A trial of phlebotomy is commonly done in community
practice. If the serum ferritin elevation is not due to iron overload, the patient will not tolerate the treatment, and will probably develop anemia after 3–4 units of blood are removed by
phlebotomy. MRI scanning to estimate liver iron concentration
is feasible and yields good estimates of liver iron content in
centers with a special interest in this technique. This would
be a reasonable option, if available. In this case, a liver biopsy
was performed; the specimen revealed severe steatohepatitis
without iron overload or fibrosis. Liver iron concentration
was 17 lmol/g (reference 0–40 lmol/g). This case illustrates
that serum ferritin elevation may be extreme in persons with
severe liver inflammation (non-alcoholic steatohepatitis = NASH). Her normal TS may have been a clue to the
absence of iron overload, but there can be marked biological
variability in TS values. In patients without HHCS, serum ferritin can be composed of different ferritin moieties including glycosylated ferritin, a protein secreted by macrophages, and/or
tissue ferritins or ferritin light- or heavy-chains released from

damaged cells. Isoferritin analysis is not a practical diagnostic
tool to differentiate serum ferritin of iron overload from that
of inflammation or HHCS. The ferritin iron concentration has
also been studied as a diagnostic test, but was tedious and
never reached widespread clinical use despite initially
promising results. The correlations of concomitant markers of
inflammation such as C-reactive protein (CRP) or erythrocyte
sedimentation rate (ESR) with serum ferritin of inflammation
have been inconsistent. Nonetheless, markedly elevated values
of CRP or ESR suggest that hyperferritinemia is probably due
to inflammation or infection. Phlebotomy has been studied as
a treatment for steatohepatitis [14,31] and can reduce serum
ferritin concentrations; a beneficial effect on liver fibrosis or
long-term outcomes has not been clearly established. In this
context, persons with HFE C282Y may benefit more from phlebotomy than those without this common HFE mutation [32].
Case study 2
A 55 year-old Scottish woman complained of fatigue. She was
told by a friend that fatigue is a symptom of iron overload in
some patients, and she asked her physician to perform iron tests.
Her serum ferritin level was 4400 lg/L. She has no known liver
diseases or family history of liver disease. She lives with her
identical twin sister. She consumes 2–3 alcoholic drinks daily.
Two weeks after the initial test, her serum ferritin level was
2307 lg/L; TS was 53%; AST, ALT, and GGT concentrations were
223, 172, and 582 IU/L, respectively; and HBsAg and anti-HCV
were negative. Abdominal ultrasound was normal. Her twin
sister volunteered for blood testing that showed a serum ferritin
level of 217 lg/L and TS 29%. Testing for the C282Y and H63D
mutations of the HFE gene was normal in both twins.
Clinical commentary
We have screened approximately 30,000 patients for hemochromatosis in our community, and it interests us that a member of
the general public suggests iron overload as a cause of fatigue
rather than iron deficiency. In this unusual case, the demonstration
that an identical twin did not have an elevated serum ferritin concentration was a helpful diagnostic tool to exclude HFE hemochromatosis or other types of iron overload in the index twin, although
there were other risk factors (alcohol). Elevations of AST > ALT are
more typical of alcoholic liver disease than hemochromatosis. Elevated GGT values are also typical of chronic alcohol consumption.
The TS in this index twin was within the reference range, whereas
it is expected that a patient with iron overload and serum ferritin
of 4400 lg/L would have a markedly elevated value of TS. A liver
biopsy was performed in the index twin that demonstrated severe
alcoholic hepatitis without visible iron staining. Liver iron concentration was normal (17 lmol/g; reference 0–40 lmol/g). The
patient admitted that she was depressed and had abused alcohol
daily. She stopped drinking after the initial serum ferritin of
4400 lmol/g was detected; after two weeks of alcohol abstinence,
serum ferritin decreased to 2307 lg/L. After 4 months of abstinence, the serum ferritin level decreased to 257 lg/L.
Case 3
An asymptomatic 55 year-old Caucasian physician was referred
for evaluation of serum ferritin 660 lg/L. He was obese and drank
two glasses of wine daily. TS was 40%, and serum concentration

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of ALT and AST were 58 and 37 IU/L, respectively. Testing for HFE
C282Y and H63D mutations showed that he is a H63D heterozygote. The patient was told not to worry that the serum ferritin
level was likely due to inflammation due to fatty liver or to stimulation of ferritin synthesis induced by regular alcohol intake. He
decided to become a regular blood donor; after donation of six
units, his serum ferritin was 77 lg/L.
This is a common clinical scenario, and mild elevations of
serum ferritin (300–1000 lg/L) are frequent in clinical practice.
The usual risk factors are daily alcohol consumption and fatty
liver. The cause of the elevation is often not clearly established,
or may be multifactorial, and invasive testing with liver biopsy
is not recommended in such patients. It is paradoxical that if
the serum ferritin level is elevated due to inflammation that it
decreases with phlebotomy, although phlebotomy may have
anti-inflammatory effects, including the removal of relatively
small amounts of iron that participate in causing tissue injury.

Key Points
Approximately 90% of patients with hyperferritinemia
encountered in routine medical practice do not have iron
overload
Serum ferritin levels greater than the upper reference
limit are often encountered in well persons of subSaharan Native African descent or Asian/Pacific Islander
descent
Mutation analysis to detect common HFE mutations is
commercially available, and such testing is most useful in
evaluating European whites with hyperferritinemia.
Hyperferritinemia remains unexplained after evaluation in
many patients

Conflict of interest
The authors declared that they do not have anything to disclose
regarding funding or conflict of interest with respect to this
manuscript.
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Journal of Hepatology 2011 vol. 55 j 453–458


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