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13-Oct-15
1
Interpreting iron studiesiron overload & deficiency
tips & traps
Dr David Iser10TH October 2015
Gastroenterologist & Hepatologist
St. Vincent’s & The Alfred Hospitals
Outline
Interpreting iron studies
Low iron
Iron deficiency
How to replace
How to investigate
High ferritin
Hereditary haemochromatosis
Fatty liver disease
Other causes
Aims
To understand the basics of iron metabolism
To be able to interpret iron studies
To have a greater understanding of how to
investigate abnormal iron studies
To know when to refer to a gastroenterologist or
haematologist
Disclosures
I am a gastroenterologist, not a haematologist
or pathologist
I have no disclosures relevant to this presentation
Interpreting iron studies
What do we get?
Iron µmol/L
Transferrin g/L
Ferritin µg/L
Transferrin saturation %
What did we previously receive?
TIBC (Total iron binding capacity) µmol/L
= another way of expressing transferrin
Basics of iron metabolism
65% of the body’s iron is stored in
haemoglobin
15% is stored in muscle
some in cellular enzymes
The remainder (excess):
ferritin in the liver
haemosiderin in macrophages
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Iron
Absorption
Mainly in duodenum
Some from distal small bowel
Ferroportin (protein channel on cell membrane)
Controls export of iron from cells (RBCs,
enterocytes, macrophages)
Increases free iron
Important because free iron causes tissue
damage via reactive oxygen species
Free iron favours bacteria
Hepcidin
Main hormone controlling iron metabolism
Produced in the liver
Reduces free iron
Binds ferroportin and degrades it
Reduces iron absorption from gut
Reduces iron release from macrophages
Reduces free iron available to bacteria
More on hepcidin
More hepcidin when less iron is required
Infection
Inflammation
Anaemia of chronic disease
Less hepcidin when more iron is required
Iron deficiency
Hypoxia
Anaemia due to haemorrhage or haemolysis
Hepcidin Ferroportin Iron
Normal absorption
Ferroportin
Hepcidin
Enterocyte
Iron deficiency
Less hepcidin
HFE haemochromatosis
Inactive
hepcidin
Back to iron studies: Ferritin
Intracellular storage protein in most cells and most organisms, also in serum
Binds up to 4000 iron atoms
Serum ferritin reflects intracellular ferritin
Also acute-phase reactant, increased in hypoxia, inflammation, infection, malignancy, liver disease, renal disease, anorexia, malnutrition, haemophagocytic syndrome
Low = iron deficiency
Transferrin (& transferrin saturation)
Transferrin = apotransferrin + 1 or 2 iron atoms
apotransferrin = iron transporting protein
Produced in the liver
High levels in iron deficiency or high oestrogen
Low levels in liver disease, high iron or as acute
phase reactant
Transferrin saturation = calculated ratio of
iron:transferrin
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Iron deficiency – ‘classic’
Case 1: 84 yo woman admitted with back pain
Case 1: response to IV iron
IV iron
Iron deficiency – ‘functional’
Case 2: 56 yo woman with previous gastric
surgery, recurrent sepsis and anaemia
Case 2: response to IV ironIV iron
Iron replacement options
Oral (many options, slow, adherence, tolerability)
First line, especially if not anaemic and no
significant comorbidities (e.g. IHD)
IM (iron dextran): painful, skin staining
Intravenous
Ferric carboxymaltose (Ferinject ®) = 30 mins
First line if anaemic with comorbidities
Ferric polymaltose (Ferrum H) = 4-5 hours
Oral replacement options
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Iron deficiency - investigations
Blood loss
GI – gastroscopy and colonoscopy
GI – capsule endoscopy (for patients with no
source identified on Gas/Colon and with
recurrent or persistent bleeding and either
anaemia or active bleeding)
Other sources
Menorrhagia or recent delivery/ lactation
Haemolysis with haemoglobinuria
Multiple blood donations
Recent examples
Iron deficiency – other causes
Decreased absorption
Coeliac disease
Gastric bypass
Gastritis
Autoimmune atrophic gastritis
H. pylori gastritis
Inadequate dietary iron
Excess dietary calcium, soy protein, polyphenols (e.g. tea) or phytates (e.g. bran, oats, rye)
Iron Overload
Iron overload
Hereditary haemochromatosis (HH)
Genetic testing for HFE gene mutations
C282Y (Cys to Tyr) (+/+ in 69-83% of HH)
H63D (His to Asp)
Non-HFE iron overload
Ferroportin mutations
Transferrin receptor-2 mutations
Juvenile haemochromatosis
Other causes of iron overload
Increased absorption in beta thalassaemia
Massive increase in oral iron intake
Multiple infusions
Liver disease
Alcoholic liver disease
Porphyria cutanea tarda
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Other causes of raised ferritin
Acute phase reactant
Infection
Inflammation
Malignancy
Metabolic syndrome
Liver disease (without true iron overload)
Viral hepatitis
Alcoholic liver disease
Fatty liver disease
Case 3: iron overload
50 yo man with chronic hepatitis B, controlled on Rx
2005 Range
Iron 35 7-32 µmol/L
Transferrin 1.6 1.8-3.3 g/L
Ferritin 239 30-300 µg/L
Transferrin satn 86 <50 %
ALT 29 <52 U/L
GGT 90 <62 U/L
Albumin 42 33-46 g/L
Bilirubin 11 <23 µmol/L
Haemoglobin 135 128-175 g/L
Case 3: HFE genes
C282Y (Cys to Tyr) mutation:
Cys/Tyr = -/+
H63D (His to Asp) mutation:
His/Asp = -/+
ie compound heterozygote, which carries 25-fold
increased risk of iron overload
Case 3: liver biopsy
Liver biopsy
Tissue dry weight 0.7 mg (ideal 1-2 mg)
Iron (tissue) 143 µmol/L (5-40 µmol/L)
Iron index(tissue) 3.0 (normal < 2.0)
Chronic active hepatitis, consistent with HBV
Grade 3 lobular inflammation
Stage 2 fibrosis
Iron overload, granular iron in hepatocytes
Minor fatty change
Case 3: response to venesection
2009 2014 Range
Iron 35 25 7-32 µmol/L
Transferrin 1.6 2.3 1.8-3.3 g/L
Ferritin 239 44 30-300 µg/L
Transferrin satn 86 45 <50 %
ALT 29 32 <52 U/L
GGT 90 134 <62 U/L
Albumin 42 41 33-46 g/L
Bilirubin 11 7 <23 µmol/L
Haemoglobin 135 155 128-175 g/L
Case 4: raised ferritin
48 yo man with HIV, BMI 27
2011 Range
Iron 30 7-32 µmol/L
Transferrin 2.6 1.8-3.3 g/L
Ferritin 3730 30-300 µg/L
Transferrin satn 45 <50 %
ALT 220 <52 U/L
GGT 400 <62 U/L
Albumin 43 33-46 g/L
Bilirubin 17 <23 µmol/L
Haemoglobin 140 128-175 g/L
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Case 4: liver investigations
FibroScan
Liver stiffness measurement 25.1kPa (<7.0kPa)
IQR 2.3kPa (ratio 0.09 (<0.30))
Proceeded to liver biopsy
Tissue dry weight 6.2 mg (ideal 1-2 mg)
Iron (tissue) 12 µmol/L (5-40 µmol/L)
Iron index(tissue) 0.2 (normal < 2.0)
Severe steatosis, steatohepatitis
Severe fibrosis (stage 3)
FibroScan: transient elastography
FibroScan does not directly measure fibrosis
Fibrosis is inferred by Liver Stiffness Measurement (LSM)
What does FibroScan measure?
2.5 cm
4 cm
1 cm
Region assessed
The probe induces an elastic
wave through the liver
The velocity of the wave is evaluated in a
region located from 2.5 to 6.5 cm below the
skin surface (approx 100x volume of biopsy)
Case 4: progress
Concentrated on lifestyle factors, diet & exercise
2011 2015 Range
Iron 30 26 7-32 µmol/L
Transferrin 2.6 2.4 1.8-3.3 g/L
Ferritin 3730 270 30-300 µg/L
Transferrin satn 45 43 <50 %
ALT 220 33 <52 U/L
GGT 400 41 <62 U/L
Albumin 43 41 33-46 g/L
Bilirubin 17 10 <23 µmol/L
Haemoglobin 140 138 128-175 g/L
Summary
Iron deficiency
‘classic’ iron deficiency with low ferritin
‘functional’ iron deficiency with normal ferritin
Ferritin is also an acute phase reactant
Need to consider GI losses & coeliac disease
Iron excess
Consider hereditary haemochromatosis
Consider liver disease, including NAFLD
Further reading
Lam Q. Interpreting Serum Ferritin. Accessed at www.rcpa.edu.au
Weiss G & Goodnough L, Anemia of Chronic Disease N Engl J Med 2005; 352:1011-1023
Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003; 101:3359.
Goot K, Hazeldine S, Bentley P, et al. Elevated serum ferritin - what should GPs know? Aust FamPhysician 2012; 41:945.
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The iron story . . .
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