Review Article

Page 1 of 13

Clinical evaluation of hyperferritinemia with or without iron

overload
Shinsaku Imashuku^

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan

Correspondence to: Shinsaku Imashuku, MD, PhD. Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto 611-0041, Japan.
Email: shinim95@mbox.kyoto-inet.or.jp.

Abstract: Serum ferritin is a good biomarker; when it is low, it suggests iron deficiency, but in the case of
hyperferritinemia it is not necessarily an index of iron overload. As a non-iron overload condition, physicians
encounter mildly increased serum ferritin commonly associated with viral or bacterial infectious diseases,
and autoinflammatory diseases like systemic juvenile idiopathic arthritis (sJIA) or adult-onset Still’s disease
(AOSD). When these diseases develop into severe forms like hemophagocytic lymphohistiocytosis (HLH)
or macrophage activation syndrome (MAS), serum ferritin levels rise steeply to a marked increase. HLH
develops as various hereditary forms or a secondary form while MAS is secondary. Precise diagnosis of
hereditary HLH requires genetic study. On the other hand, hyperferritinemia is an index of iron overload
in hemochromatosis and other iron-overloading anemias. The correct diagnosis of hemochromatosis (types
1–4) and various iron-overloading anemias could be made by genetic study. Metabolic hyperferritinemia is a
mixed type with or without iron overload, which is mostly noted in middle-aged men, associated with non-
alcoholic fatty liver disease (NAFLD) or dysmetabolic iron overload syndrome (DIOS). Rare hereditary
hyperferritinemia without iron overload, currently described in 3 types, needs to be kept in mind for
differential diagnosis. One representative type is Hereditary Hyperferritinemia-Cataract Syndrome (HHCS).
Precise cause(s) of hyperferritinemia, if unexplained, require thorough examinations with the use of genetic
study which may lead to the discovery of rare disease(s). In this review, the major causes of hyperferritinemia,
the elevated ranges of serum ferritin, the glycosylation status of serum ferritin in each category, and the gene
panel useful for differential diagnosis are discussed. This review is hoped to be useful for differentiating
hyperferritinemia in daily clinical practice.

Keywords: Ferritin; hyperferritinemia; iron overload; hemophagocytic lymphohistiocytosis (HLH); metabolic

syndrome

Received: 23 October 2023; Accepted: 04 January 2024; Published online: 18 March 2024.
doi: 10.21037/jlpm-23-78
View this article at: https://dx.doi.org/10.21037/jlpm-23-78

Introduction diseases (sepsis) or inflammatory diseases (Still’s disease,

juvenile acute arthritis, etc.), in which serum ferritin levels
In clinical practice, physicians order serum ferritin assay
as a useful biomarker in cases of iron deficiency anemia are employed to evaluate disease activity/severity. Most
(low serum ferritin) or iron overload (high serum ferritin). strikingly, when such conditions progress to hemophagocytic
Besides iron overload, high serum ferritin is caused by a lymphohistiocytosis (HLH) or macrophage activation
non-iron overload condition, such as viral [Epstein Barr syndrome (MAS), a marked increase in serum ferritin
virus, severe acute respiratory syndrome coronavirus 2 develops. In addition, it is not infrequently that metabolic
(SARS-CoV-2) infections, etc.] or bacterial infectious patients with hyperferritinemia are referred to hematologists

^ ORCID: 0000-0001-9795-0819.

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:16 | https://dx.doi.org/10.21037/jlpm-23-78
Page 2 of 13 Journal of Laboratory and Precision Medicine, 2024

who are not familiar with metabolic cases. Although the of a storage function, whereas those rich in H-ferritin may
incidence is very low, physicians need to be aware of have functions beyond iron storage (6). Ferritin synthesis is
Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) regulated by cytokines [tumor necrosis factor (TNF)-alpha
and other hereditary hyperferritinemia. In this review, and interleukin-1 alpha] at various levels (transcriptional,
differential diagnosis of various causes of hyperferritinemia post-transcriptional, translational) during development,
with or without iron overload, characteristics of serum cellular differentiation, proliferation, and inflammation (7-9).
ferritin, and management have been overviewed. Serum ferritin comprises mostly L-ferritin subunits (5,6).
Also, ferritin resides in glycosylated and non-glycosylated
forms (6,10,11). From the clinical point of view, an assay
Characteristics of serum ferritin
of serum ferritin is essential, and the glycosylation status
Iron homeostasis and ferritin of ferritin could be useful for the differential diagnosis of
hyperferritinemia, though the glycosylation status remains a
Hyperferritinemia is largely related to disturbed iron
research test and is not routinely utilized in clinical practice.
homeostasis. Iron homeostasis relies on the amount of
iron absorbed by the intestine and its release from storage
sites and is also dependent on the amount of iron used for Source and characteristics of serum ferritin
erythropoiesis. In iron metabolism, many molecules are There are two probable mechanisms as the source of
involved such as divalent metal-ion transporter 1 (DMT1), increased serum ferritin; one is that it arises from damaged
HFE, hepcidin, ferroportin 1, transferrin, ceruloplasmin, cells, representing a marker of cellular damage (12,13).
transferrin receptor, hemojuvelin, etc. of which hepcidin Increased ferritin release from the injured cells may occur
plays the main regulator (1). Decreased hepcidin synthesis due to chronic viral hepatitis, metabolic hepatic steatosis (see
or disrupted hepcidin binding to ferroportin causes iron metabolic hyperferritinemia), etc. (13). On the other hand,
overload and hyperferritinemia. Within the cells where iron increased ferritin synthesis can be noted most strikingly in
is transferred, iron regulatory proteins (IRPs) bind to the cases of infectious/inflammatory hyperferritinemia, which
iron-responsive element (IRE). The IRE/IRP interaction is caused by a rapid release along the augmented synthesis,
and hepcidin are coordinated with the fluctuation of the not by leakage from damaged cells (14). In a mouse model,
cellular iron level (2). There is also a link between iron ferritin is secreted as an acute reactant from cells such as
and copper metabolism. Ceruloplasmin, which contains splenic macrophages, hepatocytes, Kupffer cells, and proximal
greater than 95% of the copper found in plasma, is also a tubular renal cells where ferritin is rapidly synthesized
player in iron metabolism as ferroxidase that oxidizes toxic under the effect of cytokines (15). Thus, serum ferritin as
ferrous iron (Fe2+) to its nontoxic ferric form (Fe3+), which a well-known acute-phase reactant reflects the degree of
is then taken up by transferrin. Thus, in daily practice, acute and chronic infectious/inflammatory diseases (16).
abnormal serum values of ferritin, hepcidin, transferrin, In hemochromatosis and inherited iron overloading anemias,
and ceruloplasmin are noted in diseases of disturbed increased ferritin synthesis was also suggested (13). Among
iron homeostasis. Hyperferritinemia occurs in various the cases of hereditary hyperferritinemia, in HHCS cases, it
pathological conditions with or without iron overload is due to constitutive L-ferritin production (17). In FTL gene
(3,4). Ferritin, with a molecular weight of approximately mutation cases, an abnormal ferritin secretion is hypothesized
500 kDa, is the major iron-storage glycoprotein found but not confirmed (18). In cases of STAB1 gene mutation
in all tissues. It is comprised of 24 subunits containing cases, the mechanism remains to be clarified (19). Serum
H-chain (heavy or heart, 21 kDa), and L-chain (light ferritin is glycosylated (normally ~50%), but there are two
or liver, 19 kDa) polypeptide chains encoded by two pathological conditions, with low glycosylated (20–42%), or
different genes; H- and L-ferritin (FTH and FTL) genes hyperglycosylated (>90%) as discussed later.
located on chromosomes 11q and 19q (5,6). Thus, ferritin
molecules are heteropolymers of H- and L-ferritin and do
Definition of hyperferritinemia
not function as homopolymers. In terms of intracellular
localization of ferritin subunits, L-ferritin is predominantly Normal values of serum ferritin differ from laboratory
found in the cytosol, while H-ferritin is mainly found in to laboratory. We use 5–157 ng/mL as normal ranges
the nucleus. Ferritin polymers rich in L-ferritin play more in our laboratory. Kowdley et al. employed >1.5 × upper

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Journal of Laboratory and Precision Medicine, 2024 Page 3 of 13

Table 1 Differential diagnosis of various hyperferritinemia

Diseases Causes Hyperferritinemia** Iron overload
Infectious disease/autoimmune disease- No HLH/MAS Mild to moderate No
triggered HLH*/MAS Marked
Hereditary hyperferritinemia HHCS Mild to moderate No
FTL gene mutation Mild to marked
STAB1 gene mutation Mild to moderate
Metabolic syndrome NAFLD Mild Mixed
DIOS Mild to moderate
Hemochromatosis HFE/non-HFE Mild to moderate Yes
Inherited iron overloading anemia DHS1 Mild to marked Yes
PKD
XLAS
CDA
SCD
Thalassemia
Other rare disorders causing iron overload Aceruloplasminemia Mild to moderate Yes
Atransferrinemia
DMT1 deficiency
Inherited iron overloading anemia is caused by hemolysis, ineffective erythropoiesis inhibiting hepcidin synthesis, and increasing iron
absorption and release in the blood. In severe anemic cases, transfusion-related iron overload is also responsible. *, there are two types
of HLH; primary (inherited; see Table 2) and secondary; **, increase of ferritin: mild increase (>1.5 × ULN–500 ng/mL), moderate increase
(>500–3,000 ng/mL) and marked increase (3,000−>100,000 ng/mL). HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation
syndrome; HHCS, Hereditary hyperferritinemia due to cataract syndrome; FTL gene, L-ferritin gene; STAB1, encoding stabilin 1 protein;
NAFLD, non-alcoholic fatty liver disease; DIOS, dysmetabolic iron overload syndrome; DHS1, dehydrated hereditary stomatocytosis 1; PKD,
pyruvate kinase deficiency; XLAS, X-linked sideroblastic anemia; CDA, congenital dyserythropoietic anemia; SCD, sickle cell disease; DMT1,
divalent metal-ion transporter 1.

limit of normal (ULN; >300 ng/mL in women and mean iron overload. To differentiate if hyperferritinemia
>450 ng/mL in men) as a definition of hyperferritinemia in is associated with or without iron overload, serum iron
metabolic diseases (20). If this definition is adapted for our concentration as well as transferrin saturation (TSAT;
laboratory >236 ng/mL could be hyperferritinemia regardless calculated as serum iron/total iron binding capacity × 100),
of males or females. On the other hand, diagnostic criteria for are good indicators for this purpose. In addition, magnetic
HLH and MAS employed ≥500 and >684 ng/mL, respectively, resonance imaging (MRI) of the liver is useful, because
as hyperferritinemia (21,22). Hyperferritinemia could be whenever iron overload is present, the liver is the main
classified from mild (>1.5 × ULN–500 ng/mL), moderate (500– organ involved. For directly assessing the liver iron content
3,000 ng/mL), and markedly high (3,000–>100,000 ng/mL). (LIC), liver biopsy was previously employed as the standard
Thus, as defining hyperferritinemia, strict cut-off values such procedure but is less used than before because the high level
as >1.5 × UNL are employed for mild~moderate increase of precision of T2* measurement by dedicated MRI now
while a cut-off of ≥500–684 ng/mL could be employed for a allows a non-invasive and efficient procedure for measurement
disease showing markedly high serum ferritin. of iron concentration in the liver and other organs (23,24).

Differentiation of hyperferritinemia with or without iron Major causes of hyperferritinemia

overload
Major causes of hyperferritinemia and their characteristics
As mentioned above, hyperferritinemia does not necessarily are shown as an algorithm in Table 1 and Figure 1, and the

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Hyperferritinemia

Yes
No
Iron overload No~yes (high serum Fe and TSAT;
(normal serum Fe and TSAT; normal liver MRI)
abnormal liver MRI)

Infectious/ Hereditary
HLH NAFLD Hemochromatosis
Diseases inflammatory hyper-
MAS DIOS Other iron overload dis
disease ferritinemia

Children~ Middle-
Age distribution Children~adults Children~adults
adults aged

Degree Mild Mild Mild

Markedly Mild increase~
of hyper- ~moderate ~moderate ~moderate
ferritinemia high markedly high
increase increase increase

GCS/CSA/ Accurate Dx/

etoposide/ prevent Healthy
Phlebotomy/Deferasirox/
Management GCS Ruxo/ vision loss/ lifestyle/
genetic counseling
Emapal/ genetic phlebo-tomy
HSCT counseling

Figure 1 Algorithm of hyperferritinemia with or without iron overload. TSAT, transferrin saturation; MRI, magnetic resonance imaging;
HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; NAFLD, non-alcoholic fatty liver disease; DIOS,
dysmetabolic iron overload syndrome; GCS, glucocorticoids; CSA, cyclosporine A; Ruxo, ruxolitinib; Emapal, emapalumab; HSCT,
hematopoietic stem cell transplantation; Dx, diagnosis.

degree of serum ferritin levels are comparatively illustrated compared with the levels in non-severe patients (34). Even
in Figure 2. Hyperferritinemia-related gene panels due to in sepsis, a high level of serum ferritin was an independent
inherited disorders (25,26) are listed in Table 2. Below, each prognostic marker for the prediction of mortality (37,38).
hyperferritinemic disease is overviewed in the order of non- In infectious/inflammatory diseases, serum ferritin, as one
iron overload, mixed type (with or without iron overload), of the key acute-phase reactants, is employed to evaluate
and iron overload. disease activity/severity if the disease develops into HLH
or MAS. For the diagnosis of HLH/MAS, physicians
carefully must refer to the diagnostic criteria of HLH (21)
Hyperferritinemia in infectious/ inflammatory diseases
or MAS (22,39). It is well-recognized that the laboratory
This condition is noted from young children to the elderly. abnormalities in HLH and MAS overlap. Actual serum
Causes of hyperferritinemia are due to acute ferritin levels of ferritin were; in EBV-infectious mononucleosis
synthesis under the cytokine effect. The cellular response by >1,650 ng/mL (33), 2,430 ng/mL (31), and 1,901 ng/mL (32).
cytokines to viral and bacterial infections, or inflammatory In patients with COVID-19, serum ferritin values were
diseases like pediatric systemic lupus erythematosus (SLE), median (ranges) of 1,024 (434–1,821) ng/mL, and a median
systemic juvenile idiopathic arthritis (sJIA), or adult-onset of 501.9 ng/mL in the survivor group vs. 1,722 ng/mL
Still’s disease (AOSD) stimulates the expression of ferritin in the non-survivor group (35). In patients with sepsis,
genes (16,27-30). High serum ferritin levels have been serum ferritin values were median (ranges) of 542
described in viral infectious conditions, such as Epstein- (244–1,125) ng/mL (38), and a median of 430 ng/mL
Barr virus (EBV) (31-33) and SARS-CoV-2 infections, in the survivor group vs. 892 ng/mL in the non-
etc. (34-36). Particularly, during the recent pandemic survivor group (37). In the management of these cases,
of SARS-CoV-2 infection, data on coronavirus disease glucocorticoids (GCS) or cyclosporine A (CSA) are
2019 (COVID-19)-triggered hyperferritinemia has been mostly effective (27). For cases of COVID-19 with severe
accumulated (34-36), in which the serum ferritin levels in systemic hyperinflammation, the Janus kinase 1/2 inhibitor
severe COVID-19 patients were significantly increased ruxolitinib has been employed (40).

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Journal of Laboratory and Precision Medicine, 2024 Page 5 of 13

Serum ferritin (ng/mL)

10 100 1,000 10,000 100,000

50 500 5,000 50,000

Normal range

Infectious/
autoimmune
diseases

HLH or MAS

Hereditary
hyperferritinemia

NAFLD or DIOS

Hemochromatosis &
other iron overload

Figure 2 Comparative serum ferritin levels (on log scale) in various hyperferritinemia. Normal range is in yellow-, non-iron overload in
green-, and iron overload in orange-colored. HLH, hemophagocytic lymphohistiocytosis, MAS, macrophage activation syndrome; NAFLD,
non-alcoholic fatty liver disease; DIOS, dysmetabolic iron overload syndrome.

Table 2 Gene panel for the differential diagnosis of hyperferritinemia*

Primary HLH and related Hemochromatosis Hereditary hyperferritinemia Inherited iron-overloading anemias

FRF1 HFE IRE region of FLT PIEZO1 CP

UNC13D HAMP FLT PKLR TF

STX11 TFR2 STAB1 ALAS2 DMT1 (SCL11A2)

STXB2 SLC40A1 CDAN1 *TMPRSS6

LYST KLF1

RAB27A SEC23B

ADTB3A Thalassemia gene

SH2D1A SCA beta-globin gene

XIAP
*, based on the references (25) and (26); **, TMPRSS6 gene mutation is responsible for IRIDA, which needs to be differentiated from iron-
overloading microcytic anemias. HLH, hemophagocytic lymphohistiocytosis.

Hyperferritinemia in HLH, or MAS 1980s (41), on a literature survey such high values were
only known in cases of Lysinuric Protein Intolerance (LPI),
HLH or MAS develops from the above infectious/
a metabolic disease (42), which was later clarified caused
inflammatory diseases, which fulfill the diagnostic criteria by HLH. To date, significant amounts of data on this type
of either HLH or MAS and occur in young children to of hyperferritinemia have been accumulated and a marked
the elderly. HLH is classified as primary (hereditary) increase of serum ferritin is well recognized in HLH (43-45)
and secondary (21,25), while MAS is secondary under and MAS associated with pediatric sJIA or with SLE (22,
inflammatory diseases, as mentioned above. Historically, 29,39). Hyperferritinemia in this category indicates the
when we first noted significantly higher levels of serum activation of the monocyte-macrophage system, which
ferritin in cases of hemophagocytic syndrome in the mid- is a crucial part of the inflammatory cytokine storm. In

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Page 6 of 13 Journal of Laboratory and Precision Medicine, 2024

the differentiation of hyperferritinemia between HLH or are detected in IRE in the 5' untranslated region of the L
MAS and hemochromatosis, it was once proposed that ferritin mRNA, and L-ferritin synthesis is constitutively
evaluating clinical characteristics, serum triglycerides, upregulated (62) which is responsible for the increase of
and blood counts was the only reliable and rapid way serum low glycosylated (20–40%) serum ferritin (17,62).
to distinguish the two conditions (46). However, more L-ferritin aggregates accumulate preferentially in the lens,
recently, Ishihara et al. proposed that glycosylated ferritin provoking bilateral cataracts since childhood (63). The
could be an improved differential marker between these second type of hereditary hyperferritinemia is caused by
two hyperferritinemia (47). A low percentage (<20%) of a novel heterozygous p.Thr30Ile mutation in the NH2
glycosylated ferritin has been reported as a marker of HLH terminus of L-ferritin subunit (“A” alpha helix) identified
or MAS (48-50). As above mentioned, the highly elevated by sequencing analysis of the ferritin light chain (FTL)
serum ferritin in HLH or MAS cases is due to a rapidly gene. This mutation is hypothesized to increase the efficacy
increased synthesis under the effect of cytokines such as of L-ferritin secretion into sera due to the increased
TNF-alpha (8). Thus, markedly high serum ferritin in hydrophobicity of the N terminal (18). Kannengiesser et al.
HLH or MAS is not normally (~50%) glycosylated. Actual identified this mutation in 25 family cases and 66 isolated
serum ferritin levels of HLH reported were; a maximum cases, aged from 8 to 83 years (18). Similarly, two novel
value ranging from 1,140 to 68,600 ng/mL (43), and in missense L-ferritin variants; p.Gln26Ile and p.Ala27Val.
hospitalized cases, on admission from 757 to 63,919 ng/mL, were also reported (64). These cases were 45- and 75-year-
and a maximum from 994 to 189,721 ng/mL (44). In MAS old. In this FTL gene mutated cases, hyperglycosylated
cases, serum ferritin values were; median (ranges) of 7,838 (>90%) ferritin is characteristic (18,64). As another genetic
(360–150,099) ng/mL in sJIA-MAS, and 4,158 (1,300– cause of hereditary hyperferritinemia, ten subjects from
15,456) ng/mL in SLE-MAS (29). These data indicate that seven families due to bi-allelic STAB1 (encoding stabilin-1)
serum ferritin values in HLH or MAS are much higher, mutations were described, suggesting an important role
compared to mild to moderate increases in other diseases of stabilin-1 in the regulation of serum ferritin levels (19).
showing hyperferritinemia (Figure 2). As management, Actual serum ferritin values reported in HHCS were; from
most HLH and MAS cases could be controlled with GCS 366 to 1,890 ng/mL (60), from 239 to 1,290 ng/mL (61), from
and CSA with/without etoposide (27). HLH-94 or HLH- 919 to 1,143 ng/mL (17), and from 653 to 1,796 ng/mL (63).
2004 regimen (dexamethasone/CSA/etoposide) has most Serum ferritin values in the disease of FTL gene mutations
commonly and globally been employed to date (21,51). were; from 400 to 6,000 ng/mL (18) and from 618 to
More recently, ruxolitinib (52-54) and emapalumab (a 1,200 ng/mL (64), and in the STAB1 mutation disease were;
fully human anti-IFNγ monoclonal antibody) (55-58) have median (ranges) 1,970 ng/mL (365–4,654) ng/mL (19). In
proven to be effective in the control of disease activity. the management of hereditary hyperferritinemia, accurate
However, hereditary HLH requires hematopoietic stem cell diagnosis is essential to avoid unnecessary treatment and
transplantation (59). to prevent early vision loss in HHCS. In addition, genetic
counseling is required for other family members who are at
risk (65).
Hereditary hyperferritinemia: HHCS and others

Hereditary hyperferritinemia is extremely rare and

Metabolic hyperferritinemia with or without iron overload:
has been reported without iron overload in otherwise
healthy individuals. There are three types of hereditary It is well known that mild hyperferritinemia is observed in
hyperferritinemia reported. One type is HHCS which is one-third of patients with non-alcoholic fatty liver disease
an autosomal dominant inheritance disease characterized (NAFLD) (66-69) or patients of dysmetabolic iron overload
by congenital bilateral cataracts associated with high serum syndrome (DIOS), which is also termed Dysmetabolic
ferritin levels. In HHCS, hyperferritinemic children aged Hepatic Iron Overload (DHIO) (70-73). These patients
7–9 years can be diagnosed with a positive family history of exhibit mildly elevated serum ferritin associated with high
early onset cataracts, who have no tissue iron overload or serum alanine aminotransferase due to liver steatosis and
inflammation (17,60,61). The cause of hyperferritinemia in high fasting insulin C-peptide due to insulin resistance. The
HHCS is the dysregulation of the IRE/IRP system due to diagnosis of metabolic hyperferritinemia is mainly made
mutations in the IRE stem-loop, i.e., the gene mutations in middle-aged males, associated with mostly low to normal

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Journal of Laboratory and Precision Medicine, 2024 Page 7 of 13

Hemochromatosis/other inherited iron overload

Atransferrinemia DHS1
TF PIEZO1
DMT1 deficiency Non-HFE PKD
DMT1 PKLR
type2
HJV CDA
HFE HAMP CDAN1
type1 type3 SEC23B
HFE TFR2
type4 XLSA
C282Y ALAS2
SLC40A1
SCD
Aceruloplasminemia thalassemia
CP

Figure 3 Schematic illustration of hemochromatosis (dark brown colored; HFE and non-HFE) and other iron-overloading anemias
(light pink colored) causing iron overload. Extremely rare microcytic anemias showing iron overload (gray colored) are also included.
Hemochromatosis comprises of HFE (type 1) and non-HFE (types 2–4). Responding gene mutations for each disease are shown in italic.
For CDA, gene mutation for type 1 and type 2 alone is shown. For SCD/thalassemia, responsible genes are not shown because of limited
space. DMT1, divalent metal-ion transporter 1; DHS1, dehydrated hereditary stomatocytosis type 1; PKD, pyruvate kinase deficiency;
CDA, congenital dyserythropoietic anemia (type 2 CDA is most common); XLSA, X-linked sideroblastic anemia; SCD, sickle cell disease.

TSAT (22–45%) and with various metabolic abnormalities, in the NAFLD were; from 366 to 1,080 ng/mL (66), from
such as increased body mass index with android fat 283 to 2,190 ng/mL (68), and a case of DIOS showed
distribution, elevated blood pressure, dyslipidemia, 2,210 ng/mL (74). As management, because high serum ferritin
abnormal glucose metabolism, steatohepatitis (66). and hepatic iron stores are associated with the risk of several
Though iron overload is not noted in all cases, DIOS cases liver diseases, type 2 diabetes mellitus, and cardiovascular
mostly show mild hepatic iron excess in MRI studies which damage, a healthy lifestyle, such as a balanced diet low
needs to be differentiated from ferroportin disease (74). in processed foods, regular exercise, and limited alcohol
In cases where phlebotomy was employed, normalized consumption, and the pharmacological control of cardiovascular
liver dysfunction and insulin resistance associated with risk factors are recommended (77). In addition, phlebotomy can
decreased ferritin levels could be obtained (67,68). be employed for cases with iron overload (67,68).
However, its pathophysiology and the degree to which it
reflects tissue iron overload remain unclear. In NAFLD
Hyperferritinemia in hemochromatosis
or DIOS, serum or urinary hepcidin levels are higher,
indicating that synthesis of this hormone is not impaired, Hemochromatosis was previously classified as primary
which thus is not responsive to iron storage (75,76). (hereditary) and secondary (78,79). However, more recently,
One hypothesis is that iron accumulation in metabolic hemochromatosis has been defined as a non-anemic group
diseases is due to the inhibition of iron mobilization from of inherited disorders that cause iron overload due to
hepatocytes and Kupffer cells (66,67,69). Accordingly, failed regulation of hepcidin (26,80,81). Patients with iron
the pathogenesis of hyperferritinemia in these cases overload including hemochromatosis show high serum Fe
seems to differ from that in hemochromatosis, in which levels, TSAT, and abnormal images [computed tomography
serum or urinary hepcidin is impaired. Nevertheless, the (CT), MRI] of the liver (23,24,26,80-82). Clinically, patients
increased production of hepcidin in patients with NAFLD with iron overload initially may be asymptomatic, but if
or with DIOS is not yet fully understood (70). More progressed it presents with hepatic dysfunction, endocrine
recently, metabolic hyperferritinemia is classified as Stage abnormalities like diabetes mellitus or hypogonadism, heart
1 (normal iron stores, serum ferritin <550 ng/mL), Stage failure, CNS diseases, and other organ problems. Precise
2 (increased iron stores, serum ferritin 550–1,000 ng/mL), diagnosis of hemochromatosis, and other iron-overloading
and Stage 3 (DIOS; very increased iron stores, serum ferritin anemias may require genetic studies (26,82) (Table 2, Figure 3).
>1,000 ng/mL) (77). Actual serum ferritin values reported In Japan, of 1,109 iron overload cases analyzed, the

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Page 8 of 13 Journal of Laboratory and Precision Medicine, 2024

number of hemochromatosis was very limited, and the mostly normocytic ~ macrocytic, but in β-thalassemia minor
remaining 1,033 cases (93.1%) were transfusion-related (82). it is microcytic. Also, in severe anemic cases, acquired
Hemochromatosis could have an autosomal recessive transfusion-related iron overload occurs (13,78,79). One
inheritance (HFE type 1 as well as non-HFE types 2 to 4) (80). of the underestimated types of iron overload is DHS1
In Caucasians, type 1 could be the major type, where HFE (92-94), which needs to be emphasized as a cause of non-
homozygous (C282Y) gene mutation is the most common in transfusion-dependent iron overload. Iron overload in
whites (83,84). On the other hand, in other ethnic groups, DSH1 (99-101) could be explained by chronic hemolysis,
non-HFE types may be prevalent (85). Non-HFE-types but the findings that PIEZO1 activation induced Ca2+ influx
consist of mutations in the four main genes: hemojuvelin and suppression of HAMP expression causing low hepcidin
(HJV, type 2A juvenile hemochromatosis), hepcidin indicate a link between PIEZO1 and iron metabolism (93).
(HAMP, type 2B juvenile hemochromatosis), transferrin In these anemias, serum ferritin may be already high on
receptor 2 (TFR2, type 3 hemochromatosis), and type 4 non-transfusion status and become even higher after
hemochromatosis (SLC40A1, previous type 4B) (85-89). transfusions (102). In addition, extremely rare types
Gene mutations of SLC40A1 encoding ferroportin-the of inherited microcytic anemias showing iron overload
unique cellular iron exporter, whose function is controlled include congenital aceluroplasminemia (ACP), congenital
by hepcidin, cause two types of iron overload disease. One atransferrinemia (ATF), and DMT1 deficiency (26,103-105)
is ferroportin disease associated with mild iron overload, (Figure 3). ACP is characteristic of the brain, and other
which is due to "loss of function" mutations causing iron organ damages due to the accumulation of iron but with
retention in reticuloendothelial cells and hyperferritinemia low serum Fe, normal TSAT, and microcytic anemia (103).
with normal TSAT (previous type 4A). The other is type 4 ATF and DMT1 deficiency are characterized by iron-
hemochromatosis, caused by "gain of function" mutations deficient erythropoiesis, severe microcytic anemia with
associated with severe iron overload, showing resistance to high TSAT associated with decreased serum levels of
hepcidin-mediated ferroportin degradation (26). Currently, transferrin and iron, and parenchymal iron overload due to
ferroportin disease is no more included in hemochromatosis. secondary hepcidin suppression (26,104). Of these cases,
Actual serum ferritin values in hemochromatosis were; from ACP and ferroportin disease may belong to the diseases
200 to 1,000 ng/mL in type 1 (84), 2,222–16,000 ng/mL in due to inefficient iron export from storage cells, while ATF
4 cases of type 2A (85,88), 3,000 and 5,696 ng/mL in two and MDT1 deficiency to the diseases due to defects of iron
cases of type 2B (85,89), from 1,057 to 10,191 ng/mL in delivery to maturing erythroblasts or erythroblast iron
5 cases of type 3 (85), and 7,980 ng/mL (85), >1,650 and handling (26). These inherited microcytic anemias need to
10,175 ng/mL (87) in 3 cases of type 4 hemochromatosis. As be differentiated from thalassemias and iron-refractory iron
management, periodic phlebotomy, and oral chelating agent deficiency anemia (IRIDA) (106). Actual serum ferritin values
deferasirox are optionally employed. It is recommended that were; from 815 to 5,141 ng/mL in DHS1 (99,101), median
serum ferritin needs to be reduced to 50–100 ng/mL (90). (ranges) of 228 (58–3,160) ng/mL in non-transfused patients
In addition, genetic counseling is required for any patients with PKD (96), from 890 to 1,493 ng/mL in XLAS (98),
with hemochromatosis. 916±507 ng/mL in cases of post-transfusion CDA type
I (107), 1,996 ng/mL in a case of CDA type II (108). If
transfused cases were included; from 300 to >2,500 ng/mL
Other iron overloading anemias
in cases of SCD (109), and median (ranges) of 1,960 (44–
Other inherited iron-loading anemias are characterized by 21,828) ng/mL in the combined cases of SCD, thalassemia,
ineffective erythropoiesis and hepcidin suppression (91). and other congenital anemias (110). Serum ferritin values
This group of anemias includes some forms of hemolytic in ACP were; from 855 to 1,140 ng/mL (85,111), in
anemias such as dehydrated stomatocytosis 1 (DHS1) ATF were; from 250 to 837 ng/mL (104), and from 58 to
(92-94) and pyruvate kinase deficiency (PKD) (95,96), 305 ng/mL in DMT1 deficiency (105). Management policy
congenital dyserythropoietic anemias (CDAs; classified for these disorders is similar to that in hemochromatosis.
into the 3 major types-I, II, III and the transcription factor-
related CDAs (97), congenital sideroblastic anemias like
Conclusions
X-linked sideroblastic anemia (XLSA) (98), thalassemia
and sickle cell disease (SCD) (Figure 3). These anemias are From the clinical point of view, various conditions of

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:16 | https://dx.doi.org/10.21037/jlpm-23-78
Journal of Laboratory and Precision Medicine, 2024 Page 9 of 13

hyperferritinemia with or without iron overload have been to the accuracy or integrity of any part of the work are
overviewed. Physicians most frequently encounter patients appropriately investigated and resolved.
with hyperferritinemia due to infectious/inflammatory
causes: Especially, HLH and MAS as the most severe forms Open Access Statement: This is an Open Access article
in which markedly high serum ferritin (>3,000 ng/mL) is distributed in accordance with the Creative Commons
caused by rapid synthesis and release into sera under the Attribution-NonCommercial-NoDerivs 4.0 International
cytokine effect. On the other hand, hemochromatosis and License (CC BY-NC-ND 4.0), which permits the non-
inherited iron-loading anemias represent hyperferritinemia commercial replication and distribution of the article with
associated with iron overload. In these diseases, serum the strict proviso that no changes or edits are made and the
ferritin is mild to moderately elevated and becomes original work is properly cited (including links to both the
significantly higher after transfusions. It is not infrequent formal publication through the relevant DOI and the license).
that middle-aged adult patients with metabolic See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
hyperferritinemia are referred to hematologists as unknown
hyperferritinemia. Rare hereditary hyperferritinemia
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Clinical Heterogeneity in Thirteen New Cases with

doi: 10.21037/jlpm-23-78
Cite this article as: Imashuku S. Clinical evaluation of
hyperferritinemia with or without iron overload. J Lab Precis
Med 2024;9:16.

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