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Continuing Medical Education

Interpretation of an
elevated serum ferritin
Leanne Berkhan is a haematologist with a special interest in lymphoma and myeloma and CLL. She is
currently working for Diagnostic Medlab in Auckland.

The interpretation of an elevated serum to haemochromatosis is the transfer- risk factors


ferritin requires consideration of sev- rin saturation. A transferrin satura- for iron
eral separate disease categories. These tion of >60% in males and >50% in overload
come under the broad headings of: females has a sensitivity of >90% for but can
Iron overload iron overload.1,2 If the transferrin satu- transmit
Acute inflammatory conditions ration is elevated on more than one the gene
Liver disease occasion then testing for the common mutation
Alcohol excess mutations of the HFE gene is indi- to their
cated in Caucasian patients. children.
Causes of iron overload Try to test patients when they are Fifteen to
otherwise well and avoid screening 20 per cent
Primary tests for haemochromatosis if a pa- of the pa-
Hereditary haemochromatosis tient is acutely unwell. If the patient tient population is heterozygous for
Hereditary aceruloplasminemia is sick, the serum ferritin may be a different mutation resulting in the
(Wilsons disease) misleadingly high as it is an acute substitution of aspartate for histidine
phase reactant. Conversely the serum at amino acid 63 termed H63D. This
Secondary transferrin saturation falls during mutation alters the binding affinity
Transfusion overload acute illness and therefore may mask for the transferrin receptor and does
Excess dietary iron the presence of iron overload. If a not usually contribute to increased
Porphyria cutanea tarda high transferrin saturation is unex- iron overload in the absence of the
Ineffective erythropoiesis (Sidero- plained a fasting sample may be use- C282Y mutation. Patients hetero-
blastic anaemia, Thalassemia) ful as iron saturation can be affected zygous for both C282Y and H63D
by a high iron meal. mutations are termed heterozygotes
Causes of high serum ferritin and can develop haemochromatosis.
without iron overload Hereditary haemochromatosis Patients heterozygous for either
Liver disease non-alcoholic The most common cause of iron over- C282Y or H63D mutations can de-
hepatitic steatosis (NASH)* or vi- load is mutation of the HFE gene, by velop iron overload in the setting of
ral hepatitis (B/C?G) the substitution of tyrosine for alcohol excess, non-alcoholic hepatic
Alcohol excess* cysteine at amino acid 282. Homozy- steatosis or porphyria cutanea tarda.
Chronic inflammatory conditions gosity for the C282Y mutation is Other mutations involving the trans-
Rheumatoid arthritis, inflam- found in 8590% of patients of North- ferrin 2 receptor and ferroportin are
matory bowel disease ern European origin who have typi- termed HFE 3 and HFE 4 respectively.
Bacterial infections cal hereditary haemochromatosis and Juvenile haemochromatosis (HFE2) is
Malignancy especially haema- results in absence of the HFE gene on an autosomal recessive disorder also
tological the cell surface. and involves mutation of chromo-
Thyrotoxicosis There is high prevalence of this some 1q. Affected children have a
Familial hyperferritinemia and mutation with 1014% C282Y het- profound defect in regulation of in-
cataract syndrome erozygosity rates and 0.5% homozy- testinal iron absorption, and develop
* Can have iron overload in cer- gosity amongst Caucasians. Homo- symptomatic haemochromatosis in
tain settings zygous patients have a 5075% their early 20s.
The most sensitive method for pre- chance of developing iron overload. Clinical manifestations of heredi-
dicting whether the elevated serum Heterozygotes are unlikely to develop tary haemochromatosis can be
ferritin represents iron overload due the disease in the absence of other grouped as early or late.

Volume 29 Number 1, February 2002 45


Continuing Medical Education

Early Figure 1. Guidelines for management of hereditary haemochromatosis5


Asthenia
Arthralgia
Elevation of serum transaminses
Late
Hepatomegaly
Cirrhosis and hepatoma
Diabetes
Arthritis of the 2nd and 3rd MC P
joints painful handshake
Cardiomyopathy
Pigmentation
Impotence
Patients with a diagnosis of heredi-
tary haemochromatosis genotype
must therefore have serum glucose
and liver enzymes checked on a regu-
lar basis. If there is hepatomegaly,
elevation of the liver enzymes or the
serum ferritin is greater than
1 000 ug/L then a liver biopsy to ex-
clude liver cirrhosis is indicated.3 If
cirrhosis is present the patient re-
quires screening for hepatocellular
carcinoma at regular intervals.
Liver biopsy
A liver biopsy should be considered
if the patient has an unexplained
high ferritin especially in the setting
of high transferrin saturation. The
pattern of iron distribution in HH is
periportal and hepatocytic rather
than predominantly in the Kuppfer
cells. Liver biopsy provides the he-
patic iron concentration a semi- continuing until the goal ferritin is usual criteria for safe blood dona-
quantitative evaluation of iron ex- reached. The frequency or volume of tion. A study of patients with haemo-
cess. A value greater than 1.9 is very venesections are reduced if the pa- chromatosis undergoing venesection
suggestive of HH. Liver biopsy fre- tient does not maintain a normal at a hospital clinic found 40% ful-
quently detects associated lesions haemoglobin or has difficulty toler- filled criteria for blood donation.4
such as steatosis. ating the procedure. Once the patient
has achieved the desired ferritin level Expectations of the venesection
Management of haemochromatosis then maintenance (36 monthly) programme
venesections are scheduled. Life expectancy returns to normal pro-
Venesection Other than in the patient with vided neither diabetes nor cirrhosis
Patients with elevated serum ferritin juvenile haemochromatosis vene- were present at the time of diagnosis.
and HFE mutations C282Y +/+ or sections are not recommended to Specific symptoms respond variably.
C282Y+/H63D+ should be referred commence before 18 years of age in Improvement likely: asthenia, skin
for venesection. The goal of venesec- view of the importance of iron in pigmentation, liver enzymes
tion is to reach and then maintain a childhood and adolescence Improvement possible: diabetes,
serum ferritin at the lower end of the Blood from haemochromatosis non-cirrhotic fibrosis, arthralgias
normal range, usually 50 ug/l. This patients can be used by the New Zea- No improvement: cirrhosis is ir-
is achieved by initiating 400500 mL land Blood Service for transfusion reversible. Hepatocellular carcinoma
venesections on a weekly basis and provided the patient fulfils all their can still develop in cirrhotic patients

46 Volume 29 Number 1, February 2002


Continuing Medical Education

despite iron overload reversal by ve- taneous infusion 812 hours/day to histological grounds from alcoholic
nesection. remove excess iron particularly in iron overload and HH.
There is a national support group transfusion dependent thalassemic
for haemochromatosis, IRONZ, which patients. Alcohol
is supported by the Leukemia and Porphyria cutanea tarda is usually It is known that the regular consump-
Blood Foundation. manifest as cutaneous photosensitiv- tion of alcohol is responsible for the
Family screening is indicated of ity and hepatic iron disruption of normal
C282Y positive proband. overload and is diag- Due to the high iron metabolism in hu-
Homozygous C282Y are at high nosed by an increased mans, resulting in the
prevalence of the
risk of developing disease. urinary and faecal excess deposition of
Heterozygotes will likely not de- porphyrin excretion. mutation of the HFE iron in the liver in ap-
velop the disease but can transmit to Management includes gene, the probability proximately one-third
their children. venesection and of a heterozygote of alcoholic subjects.
Due to the high prevalence of the avoidance of alcohol, marrying another The mechanisms in-
mutation of the HFE gene, the prob- exogenous eostrogen
heterozygote is 10% volved are largely un-
ability of a heterozygote marrying and certain drugs. known; however, it is
another heterozygote is 10%. Excess dietary iron likely that the two ma-
Phenotypic screening should pre- as a cause of secondary iron over- jor proteins of iron metabolism, fer-
cede or accompany gene testing. load classically refers to inhabitants ritin and transferrin are intimately
of sub-Saharan Africa who consume involved in the process. The eleva-
Dietary issues a traditional fermented beverage tion of serum ferritin caused by al-
Alcohol (>60 g/day) has been shown brewed in iron cans that is rich in cohol excess can occur without el-
to exacerbate liver damage due to iron. This condition is distinctive on evation of other liver enzymes often
iron overload.
Avoid taking vitamin C when eat-
ing foods high in iron such as red Figure 2. Guideline for the investigation and management of hyperferritinemia
meat. Tea with meals is felt to be ben-
eficial as the phytates in tea bind iron.
Hereditary aceruloplasminemia
Hereditary aceruloplasminemia
(Wilsons disease) is a rare disorder
due to a mutation in chromosome 3
which causes marked hyper-
ferritinemia as well as copper over-
load. Aceruloplasminemia mimics
HH as it is familial and can cause
hepatic iron overload and diabetes.
It is, however, associated with neu-
rologic abnormalities such as de-
mentia, cerebellar ataxia which are
not seen in HH. It can be distin-
guished from HH by a low serum
transferrin saturation and an
undetectable serum ceruloplasmin
concentration.
Secondary iron overload
Iron overload secondary to multiple
blood transfusions or haematological
conditions such as sideroblastic anae-
mia are usually self-evident and do
not present a diagnostic problem.
Management is more difficult as ve-
nesection is not appropriate.
Desferroxamine is given as a subcu-

Volume 29 Number 1, February 2002 47


Continuing Medical Education

falls dramatically with abstinence Chronic infection with hepatitis C or Active infection will also be as-
from alcohol. B may be less obvious clinically and sociated with an elevated serum fer-
serologies should be checked even if ritin in the absence of iron overload.
Increased ferritin without iron there is only minimal disturbance of An elevated CRP or ESR should alert
overload liver enzymes in cases of unexplained you to these possibilities in patients
hyperferritinemia. with occult inflammation.
Steatohepatitis Heavy exercise as in ultra-
Increased ferritin with normal trans- Inflammatory conditions marathon running can cause an el-
ferrin saturation is frequently found Patients with autoimmune inflamma- evated serum ferritin amongst other
in patients with hepatic steatosis. The tory diseases, such as SLE and rheu- acute phase reactants.8
elevated ferritin is thought to be due matoid arthritis commonly have an Malignancy is also an important
to the combination of disrupted glu- elevated serum ferritin which more cause of an acute phase reaction but
cose, lipid and iron metabolism. The likely reflects disease activity, espe- is unlikely to manifest as an isolated
elevated ferritin reflects iron over- cially in the case of SLE, than iron elevation of serum ferritin in the ab-
load only in those patients in whom status.7 Where the patient is anae- sence of other clinical signs or labo-
it persists despite an appropriate (dia- mic the serum ferritin is an unreli- ratory abnormalitites.
betic) diet.6 able guide to the patients iron sta- The serum ferritin is elevated in
tus. The soluble transferrin receptor thyrotoxicosois.
Viral hepatitis is a more reliable guide to the pres- Familial hyperferritinemia and
Acute hepatitis secondary to viral in- ence of iron deficiency than the se- cataract syndrome is a rare disorder
fection with hepatitis A, B, C, EBV, rum ferritin because of its dual role which is not associated with iron
and CMV will cause an elevation in as acute phase reactant. Unfortu- overload. Affected family members
serum ferritin indicative of the liver nately the soluble transferrin receptor do require ophthalmology assessment
inflammation but not iron overload. is not available as a routine test. and cataract removal.

References
1. Olynk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L. A 5. Brissot P, Laine F, Guillygomarh A, Guyader D, Moirand R,
Population-based study of the clinical expression of the Deugnier Y. Advances in the diagnosis and management of he-
hemochromatosis gene. New England Journal of Medicine 1999; reditary hemochromatosis. American Society of Haematology, San
341:718724. Fransisco, USA, 2000. American Society of Haematology.
2. McLaren C, McLachlan G, Halliday J. Distribution of transferrin 6. Fargion S, Mattioli M, Fracanzani A, et al. Hyperferritinemia,
saturation in an Australian population: relevance to the early di- iron overload, and multiple metabloic alterations identify pa-
agnosis of hemochromatosis. Gastroenterology 1998; 114:543549. tients at risk for nonalcoholic steatohepatitis. American Journal
3. Guyader D, Jacquelinet C, Moirand R. Noninvasive prediction of of Gastroenterology 2001; 96:24482455.
fibrosis in C282Y homozygous hemochromatosis. Gastroenterol- 7. Lim M, Lee C, Ju Y, et al. Serum ferritin as a serologic marker of
ogy 1998; 115:929936. activity in systemic lupus erythematosus. Rheumatology Interna-
4. Blacklock H, Dewse M, Bollard C, Hudson P, Barnhill D, Jackson tional 2001; 20:8993.
S. Blood donation by healthy individuals with haemochromato- 8. Fallon K. The acute phase response and exercise: the ultramarathon
sis. New Zealand Medical Journal 2000; 113:7778. as prototype exercise. Clinical Journal of Sport Medicine 2001;
11:3843.

48 Volume 29 Number 1, February 2002