New Approaches to Using Knowledge Gained from HH · 30% of adults have fatty liver ... Hazeldine S,...
Transcript of New Approaches to Using Knowledge Gained from HH · 30% of adults have fatty liver ... Hazeldine S,...
New Approaches to Using Knowledge Gained from HH
PROFESSOR JOHN K. OLYNYKDepartment of Gastroenterology, Fiona Stanley &
Fremantle Hospitals;Curtin Innovation Health Research Institute;
Institute for Immunology & Infectious Diseases, Murdoch University
KNOWN KNOWNS
(Andrews, 1999)
Gan et al Expert Rev Endocrinol Metab 2009;4:229
Too much or too little iron Too much
Absolute – iron overload diseases
Too little Absolute
Low intake Loss – bleeding
Too much Functional
Cancer
Too little Functional
Chronic diseases Obesity
Testing for iron overload
Kruger et al CCR 2012
INTERPRETATION OF BLOOD TESTS
ELEVATIONS OF SERUM IRON STUDIES ARE COMMON
31% Australian males and 5% of females have elevated serum ferritin levels > 300 μg/L 35% increase in the number of males exceeding
limits since 1995 40% of haemodialysis patients have ferritin
levels > 500 μg/L 30% of adults have fatty liver
30-50% of these can have elevated ferritin levels
Olynyk et al NEJM 1999; Ombiga et al Semin Liv Dis 2005; ANZDATA 2009; McKinnon et al Clin Gastroenterol Hepatol 2014
SO WHAT SHOULD BE THE REFERENCE RANGE FOR FERRITIN?
CURRENT LAB RANGES
McKinnon et al Clin Gastroenterol Hepatol 2014
McKinnon et al Clin Gastroenterol Hepatol 2014
Detection of Hereditary Haemochromatosis using Haematology ParametersBentley P, Ferman M, Trinder D, Chua A, Hazeldine S, Olynyk JK
MCH – ROC AUC 0.82> 31 pg sensitivity 80% specificity 76%
HOW MUCH IRON DO I REALLY HAVE
St Pierre et al Blood 2005;105:855-861
0
50
100
150
200
250
300
0 10 20 30 40
HepatitisHemochromatosis-thalassemia/ Hb E-thalassemia
Mea
n tr
ansv
erse
rela
xatio
n ra
te <
R2>
(s-1
)
Biopsy iron concentration (mg.g-1 dry tissue)
p<0.0001r=0.98 n=105 20
40
60
0.5 2
Application of new technology
Which patient has haemochromatosis?
TRS 75%Ferritin 1200 g/L
Which patient has haemochromatosis?
TRS 75%Ferritin 1200 g/L
TRS 45%Ferritin 1400 g/L
Which patient has haemochromatosis?
TRS 75%Ferritin 1200 g/L
TRS 45%Ferritin 1400 g/L
TRS 90%Ferritin 1100 g/L
ASSUMPTION
Serum ferritin levels reflect iron stores Ferritin < 20 μg/L = Fe depletion Ferritin < 10 μg/L = Fe deficiency What about ferritin > ULN?
Clark Curr Opinion Gastroenterol 2009
FERRITIN OVERVIEWROLE IN DIAGNOSIS
Ferritin is to hemochromatosis as fecal occult blood screening is to bowel cancer An elevated result requires a definitive test
to confirm the diagnosis Invasive – liver biopsy Non-invasive – MRI methods Quantitative phlebotomy (retrospective
method)
FERRITIN AS A PREDICTOR OF HIC
0 1000 2000 3000 4000 50000
100
200
300
400
500
Ferritin vs HIC HH
r=0.542p=0.009
Serum Ferritin (g/L)
HIC
( m
ol/g
)
Olynyk et al Clin Gastroenterol Hepatol 2009
Ferritin vs HIC in HFE wild-type individuals
0 1000 2000 3000 40000
20
40
60
80
r2=0.002p=0.75
Ferritin g/L
HIC
(m
ol/g
)
0
1000
2000
3000
4000
5000 Wild type
HFE HH
Isolated hyperferritinemia
Renal
Ferr
itin
(ng/
ml)
Olynyk et al Clin Gastro Hepatol 2009;7:359-362
0
100
200
300
400 Wild type
HFE HH
**
** P<0.01 vs No HFE orIsolated hyperferritinemia
Isolated hyperferritinemia
Renal
**
HIC
(um
ol/g
)
Chronic kidney disease – a balancing act between too little and too much
REGULATION OF FE ABSORPTION AND RELEASE IN CKD
REASON FOR IRON THERAPYANEMIA IN CKD
48% predialysis CKD patients anemic (range 26-75% dependent on GFR)
35% HD patients anemia Treatment of anemia with ESA/Fe improves
QOL, reduces hospitalisation, reduces transfusion
Criteria for Fe – ferritin < 100 μg/L & TSAT < 20%
McClellan et al Curr Med Res Opin 2004;9:1501-10 Roger. CARI guidelines Nephrology 2006;11:S217KDOQI guidelines. Am J Kidney Dis 2006;47:S11 ANZDATA 2009;5:16Jones et al Kidney Int 2004;65:757-767
TOO MUCH OF A GOOD THING?
Increasing mortality Hb > 120g/L Cost > $150 million per annum and rising Ferritin > 2000 μg/L – risk of
hemochromatosis Ferritin 300-1200 μg/L – lowest risk of
morbidity and mortality Cease Fe supplementation when ferritin >
500 μg/LUnger et al N Engl J Med 2010;362:182-192 ANZDATA 2009Carter et al Brit Med J 1969;3:206 Kalantar-Zadeh et al J Am Soc Nephrol 2005;16:3070-80Roger. CARI guidelines Nephrology 2006;11:S217KDOQI guidelines. Am J Kidney Dis 2006;47:S11
Ferrari et al CJASN 2011;6:77
15 subjects > 12 months HD
900 day mean 217 mg Fe monthly Ferritin > 500 μg/L
on 2 occasions over 3 months
Ferrari et al CJASN 2011;6:77
LIVER and CARDIAC IRON LOADING –MODERN CARI CARE
Holman et al Nephrology 2016
Novel treatments for anaemia of CKD
Ferrari et al Nephrology 2010; Gummer et al Nephrology 2016
New understanding of mechanisms of anaemia during treatment with interferon alpha
Van Rijnsoever et al J Int Cytokine Res 2016
OBESITY AND TOO LITTLE IRON
Background Overweight and obesity are risk factors for
iron deficiency and dysregulated iron metabolism
Dysregulated iron metabolism in obesity is related to a chronic inflammatory state, possibly via a hepcidin-mediated mechanism
The specific effects of NAFLD on iron metabolism vs those mediated by obesity is unclear
Hutchinson C Eur J Clin Nutr 2016
Discrete effects of obesity and NAFLD on iron metabolism and haematology parametersMcKinnon EJ, Chua AC, Trinder D, Ayonrinde OT, Adams LA, Olynyk JK
Raine study 17 year old cohort (n=963) Measured haematological, iron
parameters Determined NAFLD (US – 53/727 lean
7%, 33/145 overweight 23%, 60/91 obese 66%
Linear regression – adjustment for sex, BMI
020
4060
8010
0
020
4060
8010
0
16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Coun
t
Coun
t
Body mass index Body mass index
MALES FEMALESResults – adiposity and NAFLD
No fatty liver NAFLD(non-alcoholic fatty liver disease)
Fatty liver more prevalent in those with higher BMI, but not exclusively associated with being overweight or
obese
Healthy Overweight
Obese
No fatty liver
674 112 31
NAFLD 53 (7%) 33(23%) 60(66%)
hs-CRP Ferritin TSAT
0.5
1.0
2.0
4.0
3040
5060
70
0.5
1.0
2.0
4.0
3040
5060
70Se
urm
ferri
tin (μ
g/L
)SF
(μg/
L )
Tran
sfer
rin s
atur
atio
n (%
)TS
AT (%
)
hs-C
RP (m
g/L
)hs
-CRP
(mg/
L )
1520
2530
1520
2530
17 years
20 years
Results
no fatty liver NAFLD(sex and BMI-adjusted, 2 SE)From 17 to 20 years of age:• consistent increases across demographic groups in serum ferritin • increased impact of NAFLD on serum iron and TSAT especially
TSAT
SERUMFERRITIN
TSAT TSAT5 10 50
510
5010
0
5 10 50
510
5010
0
5 10 50
510
5010
0
Lean Overweight Obese
By 20 years of age• Evidence NAFLD with excess adiposity increases risk of
functional iron deficiency, but usefulness of serum ferritin as marker compromised by chronic inflammation.
NAFLD diagnosed at 17 yearshs-CRP >40 Serum ferritin & TSAT both below limits indicating iron deficiency
Results – obesity impacts on iron parameters
HaemoglobinMean corpuscular
volumeMean corpuscular
haemoglobin
14.0
14.5
15.0
15.5
8283
8485
8687
88
28.0
29.0
30.0
MCV
(fL
)
MCH
(pg)
HB (g
/L )17 years
no fatty liver NAFLD (sex and BMI-adjusted, 2 SE)
Results
At 17 years of age:• Evidence of impaired haemoglobinisation associated with NAFLD,
particularly in overweight/obese
Summary NAFLD independently increased risk of
functional iron deficiency and impaired Hb production
?could functional iron deficiency in NAFLD / obese individuals impair ability to exercise and lose weight
IRON AND CANCER
Conflicting evidence that iron status relates to risk of cancer Human studies show links between iron
content of diet and risk of cancer No links between ferritin levels and cancer
(in fact negative if anything)
Background
Fonseca-Nunes et al Cancer Epidemiol Biomarkers Prevention 2014
Background C282Y homozygosity
3-fold increased risk of colorectal cancer in men and women 3-fold increased risk of breast cancer in women
H63D homozygosity Genetic modifier of cancer development in HNPCC with mutations in MMR
genes 3-fold increased risk of cancer in MMR gene mutation carriers and earlier
onset of cancer Iron reduction
1200 subjects (male, mean age 67) randomised to phlebotomy (fer 80) vs no phleb (fer 120)
4.5 year FU Risk of new visceral malignancy 0.65 in phlebotomy group
Osborne et al. Hepatology 2010;51:1311-18Shi et al. Int J Cancer 2009;125:78-83Zacharski et al JNCI 2008;100:996-1002
Serum iron and cancer
Wen et al Cancer Res 2014120 ug/dl = 21 umol//L35% men and 20% women exceed this value
Serum iron and cancer
Wen et al Cancer Res 2014
Prospective study of subjects who participated in the 1994/1995 health survey
Eligibility: had data on relevant variables, no history of cancer before survey and serum ferritin ≥ 20 μg/L
1597 men and 1795 women aged 25-79 years Ferritin, Fe and Transferrin Saturation (TRS) examined
as continuous variable (after log transformation) and age specific tertiles
Evaluated death from cancer, incident non-skin cancer, incident breast cancer, prostate cancer and colorectal cancer at 2010 by data linkage
Busselton Health Cohort
Iron and cancer outcomes in womenAdjusted* HR for log Iron = increase in risk of cancer per each unit increase in log Iron
*Adjusted for age, smoking, drinking, bmi, waist, sbp, dbp, HDL, logTrig, logGlucose, logHOMA-R, logCRP, logALT, LogGGT, bilirubin, and albumin. Model for breast cancer also adjusted for menopausal status.
n=76 n=268 n=80 n=45
n = number of cancer outcome eventsChua et al Am J Clin Nutr in press
Adjusted* HR for log TS = increase in risk of cancer per each unit increase in log TS
Transferrin saturation and cancer outcomes in women
*Adjusted for age, smoking, drinking, bmi, waist, sbp, dbp, HDL, logTrig, logGlucose, logHOMA-R, logCRP, logALT, LogGGT, bilirubin, and albumin. Model for breast cancer also adjusted for menopausal status.
n=76 n=268 n=80 n=45
n = number of cancer outcome eventsChua et al Am J Clin Nutr in press
Common cancers in women and risk of cancer death may be iron sensitive diseases
Raises questions regarding: Iron supplementation of women – is it good or
bad? Men are different to women! Will reducing iron status in women reduce the
risk of cancer? E.g. encourage more women to be blood donors
Conclusions