Mustafa Özay and Zafer Bıçakcı..
Department of Pediatric Hematology, Faculty of Medicine, Ataturk University.
Mustafa Özay, MD. Division of Pediatric Hematology/Oncology, Faculty of Medicine, Atatürk University, 25240 Erzurum, Turkey. Tel: +90 4423447171, Fax: +90 4422361301. E-mail: email@example.com
Published: September 1, 2022
Received: July 24, 2022
Accepted: August 19, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022070 DOI 10.4084/MJHID.2022.070
| This is an Open Access article distributed
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medium, provided the original work is properly cited.
(ACP) is a rare, adult-onset autosomal recessive disorder characterized
by systemic iron overload caused by mutations in the
ceruloplasmin-encoding gene (CP), which leads to severe reduction or
absence of ceruloplasmin activity. Ceruloplasmin is
a copper-containing ferroxidase enzyme involved in iron efflux from
cells and is considered to possess neuroprotective functions.
Deterioration in the ceruloplasmin ferroxidase activity causes
pathological cellular iron retention and iron-mediated oxidative
damage. Therefore, brain iron accumulation - specific to ACP - is a
reliable feature for distinguishing this condition from other genetic
hemochromatosis syndromes.[1,2] The main clinical
features of ACP include diabetes, retinopathy, liver disease, and
progressive neurological symptoms indicating iron accumulation in the
target organs. The disease's biochemical symptoms
include mild anemia resembling iron deficiency anemia with microcytosis
and low transferrin saturation (TS). Thus, the
initial differential diagnosis should be with the frequent iron
deficient anemia and with the more rare forms of iron-refractory iron
deficiency anemia acquired or congenital. However,
"paradoxical" hyperferritinemia, which typically appears decades before
the onset of clinical symptoms, indicates the route of the right
ACP should be considered in
patients with unexplained atypical microcytic anemia untransfused
without inflammation, low TS, and high ferritin levels. ACP diagnosis
can be easily confirmed by low serum ceruloplasmin levels and is
usually based on very low or undetectable serum CP levels and clinical,
biochemical, or radiological signs of iron accumulation in the target
organs.[1,4] In addition to these
findings, biallelic pathogenic variants in CP are determined using
molecular genetic tests in a proband (index case) to make a definitive
diagnosis.[4,5] Early diagnosis and treatment are
essential for preventing neurological complications of the disease, as
once they occur, such complications are irreversible.[1,2,4]
present the case of a 15-year-old girl with unexplained microcytic
anemia, high ferritin levels, and low TS without inflammation.
patient had anemia and growth retardation for approximately 5-6 years.
Her parents were first-degree cousins. Her height was 148 cm (3%↓), and
her body weight was 44 kg (3%↓). Her physical examination revealed
pallor; however, other systemic functions were normal.
According to the laboratory results, the patient had mild hypochromic microcytic anemia, reduced TS, and hyperferritinemia (Table 1).
"Atypical (Ferritin↑) microcytic anemia" is characterized by this
biochemical triad, as opposed to the typical cases caused by iron
deficiency wherein serum ferritin levels are consistently low.
A differential diagnosis could also be with iron-refractory anemia,
usually acquired and often associated with gastrointestinal
pathologies. However, a rare genetic form called iron deficiency
anemia, iron-resistant iron deficiency anemia (IRIDA), also exists. In
some pathological circumstances - congenital or acquired - hepcidin
level increases, limiting the absorption of iron in the
gastrointestinal tract and remobilizing and recycling iron, thereby
reducing iron levels in plasma. Hence, conditions with high hepcidin
levels are often underestimated as iron-refractory anemia, leading to
inappropriate and unsuccessful treatments.[1,3]
When evaluated in terms of differential diagnosis, the causes of
hypochromic microcytic anemia include IRIDA, thalassemia (α and β),
sideroblastic anemia, anemia of chronic disease (infection, cancer,
inflammation, and renal disease), lead poisoning, hemoglobin E
carriage, and severe malnutrition, were not detected in our patient.
Hence, congenital iron metabolism disorders or copper deficiencies were
considered the differential diagnoses of hypochromic microcytic anemia.[6,7]
||Table 1. Laboratory findings.
features of congenital iron metabolism disorders with iron deficiency
and accumulation, which are considered causes of hypochromic microcytic
anemia in differential diagnosis, are summarized in Table 2.
||Table 2. Laboratory features of congenital iron metabolism disorders with iron deficiency and accumulation.
clinical characteristics of our patient were consistent with
copper/ceruloplasmin deficiency inducing hyperferritinemia, low TS, low
serum copper and ceruloplasmin levels, and normal urinary copper
levels. Copper/ceruloplasmin deficiency can also be observed in ACP,
heterozygous carriers of asymptomatic ceruloplasmin mutation, Wilson's
disease, Menkes disease, or hypoproteinemias.
patient's laboratory results were consistent with ACP's diagnostic
criteria. Molecular genetic analysis was performed to determine ACP
diagnosis, and a homozygous mutation was found. Disease-related
mutations in CP cause destruction or severe reduction of
ceruloplasmin's ferroxidase activity. To date, 28 missense, 17
frameshift, 13 insertion, and 8 nonsense mutations have been
identified. A frameshift mutation was detected in
our patient. Most pathogenic variants in CP are predicted to be
loss-of-function mutations, which deteriorate or alter the protein
stability of the copper binding sites. As most aceruloplasminemia cases
are caused by homozygous mutations, investigating the consanguinity
between parents is crucial. A milder disease course has been reported
in some individuals with a single CP mutation (simple heterozygosity).[1,4]
consanguinity (first cousin) was documented between our patient's
parents, and the patient's parents and sister were heterozygous
carriers of the mutation. The family members did not exhibit anemia;
however, their serum copper and ceruloplasmin levels were lower than
normal (Table 3).
||Table 3. Comparison of
some biochemical values of patients with aceruloplasminemia
(homozygous) and family members who are the carriers of heterozygous
mutation in the ceruloplasmin gene.
was no difference in the hemogram values of other family members.
Endocrine and neurology consultations performed for iron accumulation
were normal. Fundus examination revealed subretinal deposits around the
optic disk and macula. No significant degenerative findings were
observed in the retina or choroid. Visual acuity was bilaterally
complete, and intraocular pressure was bilaterally normotensive. Exams
made to evidentiate iron overload were negative. Cardiac iron T2* value
was a normal 21-22 Hz (47-48 ms) in measuring iron accumulation by
magnetic resonance imaging (MRI). Moderate iron accumulation was
detected in the liver (6.9–7.2 [0.2–1.6] mg/g iron). Brain MRI findings
However, the clinical presentation of ACP frequently
includes cerebellar manifestations (dysarthria and ataxia) and
involuntary movements (dystonia, chorea, and tremor), with onset
typically occurring at 40–60 years. In contrast to this typical picture
in Japanese patients with ACP, the age of onset tends to be earlier in
Caucasians, with cognitive–psychiatric changes and extrapyramidal
findings.[8,9] However, cognitive (apathy and memory
loss) and behavioral changes have low specificity; hence, they are
often underestimated. Our patient exhibited no
cerebellar symptoms or involuntary movements. There is no globally
accepted treatment regimen for ACP. Iron chelating agents, which are
highly effective in reducing liver iron deposition and can prevent
further brain iron accumulation, are the first-choice drug; however,
they are ineffective for patients with neurological damage that has
already occurred. According to expert opinion, the
brain and visceral zinc concentrations in these patients decrease, zinc
distribution exhibits a pattern opposite to that of iron, and zinc
shows antioxidant activity; therefore, treatment with zinc-accompanied
iron chelator in patients with ACP may be favorable in reducing iron
deposition in the brain and other organs and in preventing or improving
systemic and neurological symptoms.
diagnosis of ACP, deferiprone 75 mg/kg/day three times a day was
started for iron chelation. As a result, hemoglobin and serum iron
levels increased, whereas serum iron-binding capacity and ferritin
levels decreased. However, after three months of treatment, a decrease
in hemoglobin levels was observed. Therefore, deferiprone was stopped.
Zinc (50 mg/day orally) was initiated; subsequently, the patient's
hemoglobin levels began to increase, and the patient's clinical
Also, in patients with signs of iron
overload, mild microcytic anemia was often observed in childhood as the
earliest biochemical manifestation of ACP in both Japanese and
non-Japanese cases. Still, ACP was rarely diagnosed in the early
symptomatic period.[8,9] However, in our case, mild
microcytic anemia, which our patient experienced for approximately 5-6
years, eventually led to a diagnosis of ACP as an early biochemical
sign of the disease.
Other possible differential diagnoses are an
iron transporter DMT1 (SLC11A2) deficiency, characterized by congenital
hypochromic microcytic anemia; slow progressive hepatic iron
accumulation; low hemoglobin, mean corpuscular volume (MCV),
transferrin, and hepcidin levels; and high serum iron, ferritin, and TS
levels; glutaredoxin (GLRX5) deficiency, WHICH present with
pyridoxine-refractory sideroblastic anemia; hepatosplenomegaly;
jaundice; cirrhosis; low hemoglobin and MCV levels; and high serum
iron, ferritin, and TS levels. Moreover, ring sideroblasts are observed
in the bone marrow of such patients. Congenital hypochromic microcytic
anemia and hemochromatosis are present in a(hypo)transferrinemia cases
wherein the transferrin levels are negligible/undetectable; hemoglobin,
MCV, serum iron, and hepcidin levels are low; and ferritin and TS
levels are high. Iron accumulation in the liver and brain and mild iron
deficiency anemia is associated with ACP. In patients with ACP,
ceruloplasmin is reduced/undetectable; MCV is low/normal; hemoglobin,
serum iron, serum copper, TS, and hepcidin levels are low; transferrin
and ferritin levels are high.[7,10]
conclusion, unexplained atypical microcytic anemia without
inflammation, low TS, and high ferritin suggest ACP, and low serum
ceruloplasmin levels can easily confirm the diagnosis. The early
diagnosis is crucial to prevent delayed treatment and irreversible
neurological damage onset.
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