HEMOCHROMATOSIS UPDATE

May 24, 2015

Paul C Adams

• To develop an approach to the diagnosis and

management of hemochromatosis

• To discuss several cases with arthropathy and

hemochromatosis

• To consider the differential diagnosis of an elevated

serum ferritin

2

Learning Objectives

• Research Grant – Gilead – Liver Fibrosis

• Advisor – LaJolla Pharmaceuticals - Hepcidin

Disclosures

Hunters and Gatherers – 4,000 B.C.

Distante S et al, Hum Genet 2004

Searching for the hemochromatosis gene

Rust in peace PC Adams

Searching for the hemochromatosis gene

Identification of a familiar sequence

PC Adams 2002

Hepcidin

Iron

Transferrin receptor 1,2, HFE, hemojuvelin

BMP6

Smad

Erythroferrone

Ferristatin II

19 year old man presents with sore knees, no sports injuries,

found to have Transferrin saturation 100 %, Serum ferritin 78,

C282Y homozygote

By age 30, bilateral knee replacements

Can hemochromatosis arthropathy occur without iron overload?

Heel pain - hemochromatosis

Menard, HA 2015

Probability of haemochromatosis decreases as

ALT increases

Adams PC et al, Hepatology 2012

Fasting does not improve TS in the

detection of C282Y homozygotes

Blood

test

n Sensitivity

(%)

Specificity

(%)

PPV

(%)

Fasting

TS

31,796 77

(65-86)

93

(92 – 93)

2.3

(2 – 3)

Random

TS

64,230 75

(67-81)

95

(95-96)

3.5

(3 – 4)

Adams PC et al, Am J Med 2007

A comparison of TS at initial presentation and at clinical examination

Adams et al, Am J Med 2007

Adams, P. C. et al. N Engl J Med 2005;352:1769-1778

Serum Ferritin Levels in Men and Women According to Genotype

Bernoulli Regression

Male

Female

Lim A, Adams PC, AASLD 2013

Android Phone App Hemochromatosis App

Proportion of Caucasians with an elevated serum ferritin that have the C282Y genotype

N = 44,625 Adams PC et al, Can J Gastro 2013

Chasing the ferritin

Ferritin 300-1000

NAFLD

EtOH

Uncertain

4% Misc

7% Hep C

2% Secondary

Fe Overload

HH

13%

20% 17%

33%

Wong K, Adams PC, Can J Gastro 2006

n = 363

Chasing the ferritin

Ferritin > 1000

HH

EtOH

NAFLD

Uncertain

3% Hep C 1% Misc9%

Secondary Fe

Overload

9%

11%

20%

42%

Wong K, Adams PC, Can J Gastro 2006

n = 119

MRI in the assessment of liver iron in hemochromatosis

Fifty shades of gray

29 year old C282Y homozygote scanned serially during phlebotomy

T1 map

Iron load ~ 15 g - 5.5 g Fe - 12.5 g Fe

Liver iron = 437 umol/g

Effect of iron depletion on liver fibrosis C282Y homozygote – 46 year old man

Serum ferritin = 3,833 Serum ferritin = 157, 3 years later

Exome sequencing for co-modifying genes

PC Adams 2014

Next Generation Sequencer

Hepcidin – met50del, Ceruloplasmin, Hephaestin, DMT1, Beta-2 microglobulin

HFE – C282Y, H63D, S65C, Ferroportin – 144, 162, 248 , TFR2 – 60, 172, 250

23andMe

Med Care 2012; 50:394-398

Acknowledgments

Leslie Valberg, Peter Flanagan

Mark Speechley, Ann Kertesz

Subrata Chakrabarti, Helen Harrison

Lawrie Powell, June Halliday

Mark Bassett, Gary Jeffrey

Greg Anderson, Grant Ramm

Yves Deugnier, Pierre Brissot

Romain Moirand, Dominique Guyader

Veronique David, Jean-Yves LeGall

Phyliss Sholinsky, Jim Barton, Ron Acton

Vic Gordeuk, Fitzroy Dawkins,

Emily Harris, Elizabeth Thomson

Christine and Gordon McLaren,

Dave Reboussin, John Eckfeldt, NHLBI