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

13-Oct-15

2

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

13-Oct-15

3

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

13-Oct-15

4

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

13-Oct-15

5

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

13-Oct-15

6

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.

13-Oct-15

7

The iron story . . .