This document provides an overview and 2017 update on the diagnosis and treatment of genetic haemochromatosis. It discusses the epidemiology, genetic basis, clinical manifestations, diagnosis and treatment recommendations for this iron overload disorder. The key points are: genetic haemochromatosis is one of the most common genetic disorders in Northern Europeans and is caused by mutations in the HFE gene; diagnosis involves testing ferritin levels and transferrin saturation; treatment is regular phlebotomy to reduce iron levels and prevent organ damage.

1. WELCOME TO
JOURNAL PRESENTATION
DR MD KAWSER HAMID
ASSISTANT REGISTRAR
DEPARTMENT OF GASTROENTEROLOGY
SSMC & MH

2. DIAGNOSIS AND THERAPY OF GENETIC
HAEMOCHROMATOSIS (REVIEW AND 2017
UPDATE)

4. INTRODUCTION
• “Celtic Curse” also known as “ Bronze diabetes”
• Genetic haemochromatosis is one of the most
frequent genetic disorders found in Northern
Europeans.
• Abnormal accumulation of iron in parenchymal organs
such as liver, pancreas, heart and causes widespread
tissue damage including diabetes mellitus & cirrhosis.

5. HISTORY
• Classic triad described in 1865 by Trousseau.
• Named “Haemochromatosis” in 1889 by Von
Reckhinghaussen.
• Inheritence described in 1935
• HLA linkage to chromosome 6 identified 1976

6. METHODOLOGY
• The original literature review was based on a total 40
years of experience in GH by the authors.
• The author compared the survival of treated patients
with that patients presenting with GH but not
receiving phlebotomy.
• For patients receiving venesection therapy, life
expectancy was significantly improved compared with
untreated patients.

7. EPIDEMIOLOGY
• Hereditary haemochromatosis remains the most
common genetic disorder in Caucasian.
• Female : male – 1: 10
• Population screening has shown prevalence of
heterozygous is about 10%
• C282Y homozygous account for 80 - 85%

8. GENETIC BASIS
• HFE gene mutation- identified 1996
• Autosomal recessive
• C282Y or H63D
• Cysteine tyrosine at 282 (C282Y)
• Histidine aspartate at 63 (H63D)

9. THE HFE GENE
• HFE gene on chromosome 6
- involves in iron homeostasis
• Two common mutations on HFE
- C282Y allele : over 90% patients
- H63D allele
• HFE gene mutations produces altered HFE protein
unable to properly regulate iron metabolism results in
excess of iron storage.

10. SCHEMATIC REPRESENTATION OF THE
PROTEIN PRODUCT OF HFE

11. IRON BALANCE
• Total body iron is 4 gm :
Haemoglobin – 3 gm
Myoglobin - 300 mg
Enzymes & cytochromes – 100
mg
Transferrin - 4 mg
• Daily loss : 1mg (due to desquamation of
cells)
In females : 15-40 mg/menstruation

12. IRON LOADING GENOTYPES
a) HFE GH (Type 1 GH)
b)Type 2 Juvenile GH.
c) Type 3 GH, Transferrin receptor 2 deficiency.
d)Type 4 GH, Ferroportin disease.
e)Type 5 GH

13. PATHOPHYSIOLOGY
• Increased absorption of dietary iron in upper intestine.
• Decreased expression of iron regulatory hormone
hepcidin.
• Altered function of HFE protein.
• Tissue injury and fibrogenesis induced by highly toxic
non transferrin bound iron (NTBI).

14. HEPCIDIN MODEL IN HFE MUTATION

16. CLINICAL MANIFESTATIONS
• Liver function abnormalities – 75%
• Weakness and lethargy – 74%
• Skin hyperpigmentation – 70%
• Diabetes mellitus – 48%
• Arthralgia – 44%
• Impotence in males – 45%
• ECG abnormalities – 31%

17. HEPATIC
• Liver is usually first organ to be affected.
• Hepatomegaly: >95% of symptomatic patients.
• HCC : about 30% of patients with cirrhosis.

18. SKIN
• Skin pigmentation – characterstitic metallic or slate
gray hue
• Results from increased melanin and iron in the dermis
• Pigmentation usually is generalized

19. DIABETES
• Diabetes mellitus in about 65%.
• More likely to develop in those with family history of
diabetes.
• Insulin resistance is more common in association with
haemochromatosis.

20. ARTHROPATHY
• Arthropathy: 25-50% of symptomatic pts.
• Usually occurs after age 50
• 2nd and 3rd MCP joints (painful hand-
shake sign)

21. CARDIAC
• Presenting manifestation in about 15%
• Most common manifestation is congestive heart failure
• Cardiac arrhythmias :
Premature supraventricular beats
Atrial fibrillation
Varying degrees of AV block

22. HYPOGONADISM
• Occurs in both sexes
• Impairment of hypothalamic – pituitary function by iron
deposition
Loss of libido
Impotence
Amenorrhoea
Testicular atrophy
Gynecomastia

23. DIAGNOSIS
• Transferrin saturation : >45% indicate significant iron
accumulation
• Plasma ferritin : normal 40 to 200 ng/ml
> 200 mcg/L in premenopausal women
> 300 mcg/L in men and postmenopausal women
• Liver biopsy – if ferritin > 1000 mcg/L
• Consider genetic testing – DNA testing for common
mutation (C282Y, H63D)

24. LIVER BIOPSY
Liver biopsy should be considered :
• For the purpose of determining the presence or
absence of advanced fibrosis or cirrhosis.
• Screening of HCC.
• For measurement of HII.

25. GENETIC TESTING
Should be offered to those patients with-
• Appropriate clinical presentation.
• Elevated transferrin saturation and ferritin.
• Liver biopsy suggestive of iron overload.
• First degree relative of known case.

26. TREATMENT: at diagnosis
Venesection is indicated for all fit patients with
biochemical iron overload with or without clinical
features.
• Initially once weekly (450-500 ml, ~200-250 mg iron)
• Monitor Hb levels weekly, SF monthly, Tsat 1-3
monthly and reduce rate of venesection if anaemia
develops.
• Continue until SF is 20-30 mcg/L and Tsat is <50%

27. VENESECTION

28. maintainance phase
• Once excess iron removed and venesection ceased,
iron will begin to re-accumulate.
• Patients usually come to follow-up in every 3-6
months and venesection is carried out if necessary, to
maintain SF <50 mcg/L.
• Patients should advice about dietary restriction of iron
rich foods or use of PPI to reduce iron absorption.

30. CHELATION THERAPY
• Recommende for patients who cannot tolerate
venesection.
• Deferasirox (Exjade) : oral iron chelator.
- patients with C282Y homozygous GH and
modest iron
loading (median SF 645 mcg/L)

31. PROGNOSIS
• Pre-cirrhotic and pre-diabetic patients with GH,
treated by venesection have a normal life expectancy.
• If patient present with cirrhosis, 100-fold increased
risk of developing primary liver cancer.

32. RECOMMENDATION 1
Unselected population screening for HFE
gene mutation is not recommended.

33. RECOMMENDATION 2
GH patients who present with SF >1000 mcg/L
and any with raised transaminases should be
referred to a hepatologist for fibrosis
assessment and exclusion of cirrhosis.

34. RECOMMENDATION 3
Liver biopsy is no longer required for diagnosis
of HFE GH but may be required to assess the
severity of fibrosis in GH patients with SF >1000
mcg/L and or elevated transaminases. Transient
elastography could be used to select which
patients from this group require liver biopsy.

35. RECOMMENDATION 4
Patients with north European ancestry with
clinical features suggestive of GH should have
the following laboratory investigations; full
blood count, LFTs, SF and transferrin saturation.
Molecular testing for HFE GH should bfollow if
results fulfil the criteria of recommendation 5.

36. RECOMMENDATION 5
All adult patients of north European ancestry
with unexplained raised SF and random Tsat
(>300 mcg/L and >50% males; >200mcg/L and
>40% females) and normal FBC should have
molecular testing for HFE GH.

37. RECOMMENDATION 6
Laboratory screening to include FBC, LFTs, SF, Tsat and
HFE should be offered to family members after the
diagnosis of HFE GH. Family screening should include
parents (if available), siblings, partner and children
(over the age of consent). Extended family screening is
not recommended if an individual is identified as a
C282Y/H63D compound heterozygote.

38. RECOMMENDATION 7
Investigations of all confirmed C282Y
homozygotes should include FBC, LFTs, SF &
Tsat. Thereafter further investigation may be
required as follows;
a)SF <1000 mcg/L, normal LFTs, normal clinical
examination; no further investigation
required.

39. b) SF > 1000 mcg/L and or abnormal LFTs. All
such patients require referral to Hepatology for
fibrosis assessment to exclude the presence of
cirrhosis. A minimum would be elastography.
For patients with confirmed cirrhosis monitor
with α-fetoprotein (AFP) and hepatic ultrasound every 6
months.

40. RECOMMENDATION 8
Non C282Y homozygotes with significant iron
loading as confirmed by magnetic resonance
imaging and or liver biopsy should be
investigated for rare iron loading genotypes or
digenic inheritance.

41. RECOMMENDATION 9
At diagnosis, all fit GH patients with biochemical iron
loading should undergo weekly venesection until SF ~
20-30 mcg/L and Tsat < 50%. During this phase of venesection
FBC should be monitored weekly and SF ± Tsat monitored
monthly. Homozygotes with normal iron indices and compound
heterozygotes with minimal elevation of iron indices may be
suitable for blood donation and annual monitoring of SF and Tsat.

42. RECOMMENDATION 10
During maintainance, venesect as required,
preferably at a blood donation centre to
maintain normal FBC, SF <50 mcg/L and Tsat
<50%

43. RECOMMENDATION 11
HFE GH with cirrhosis; Treat as per
recommendation 9 and 10 but not suitable for
blood donation. Monitor AFP and hepatic
ultrasonography every 6 months.

44. TAKE HOME WORD

45. T
H
A
N
K
Y
O
U