2. Introduction
• “Celtic Curse”- also known as “Bronze diabetes”
• Hemochromatosis is the abnormal accumulation of
iron in parenchymal organs, such as the liver,
pancreas, and heart leading to organ toxicity.
• Most common autosomal recessive genetic disorder
3. Epidemiology
• Hereditary hemochromatosis (HH) remains the most
common genetic disorder in Caucasians.
• Women typically presented approximately 10 years
later than men
• Female: male- 1 : 10
• Population screening has shown prevalance of
heterozygotes is about 10 %.
• Prevalence of HH in the USA is 1 in 200-500
individuals.
4.
5. Genetic basis
• Principal HFE gene defect was first described in
1996,
• Tightly linked to the HLA-A locus on chromosome
6p
• G-to-a missense mutation ;
• Cysteine tyrosine at 282 (C282Y)
• C282Y homozygotes account for 80%-85%
• Histidine aspartate at 63 (h63d)
• Serine cysteine at 65 (s65c)
7. Pathophysiology
(1) Increased absorption of dietary iron in the
upper intestine,
(2) Decreased expression of the iron-regulatory
hormone hepcidin,
(3) Altered function of HFE protein,
(4) Tissue injury and fibrogenesis induced by iron.
10. Classification of iron overload syndromes cont.;
• Secondary Iron Overload
• Iron-loading anemia
• Thalassemia major
• Sideroblastic anemia
• Chronic hemolytic anemia
• Aplastic anemia
• Parenteral iron overload
• Red blood cell transfusions
• Iron–dextran injections
• Long-term hemodialysis
• Chronic liver disease
• Porphyria cutanea tarda
• Hepatitis C
• Hepatitis B
• Alcoholic liver disease
• Nonalcoholic fatty liver disease
11. It’s a spectrum of disease
• Phenotypic expression only occurs in
approximately 70% of C282Y homozygotes,
• Fewer than 10% of C282Y homozygotes will
develop severe iron overload accompanied by
organ damage and clinical manifestations of
hemochromatosis
12. EuropeanAssociationfor the Study of
Liver Diseases staging system
• Stage 1 -genetic disorder +, no increase in iron stores
‘‘genetic susceptibility.’’
• Stage 2- genetic disorder +, phenotypic evidence of iron
overload without tissue or organ damage.
• Stage 3 genetic disorder +, with iron overload with tissue
and organ damage.
15. Hepatic manifestations
• Liver is usually the first organ to be affected
• Hepatomegaly in >95% of symptomatic
patients.
• Portal hypertension and esophageal varices
occur less commonly than in cirrhotic.
• Hepatocellular carcinoma develops in about
30% of patients with cirrhosis.
• Incidence increases with age, common in men,
almost exclusively in cirrhotic patients
16. Skin
• Skin pigmentation -characteristic metallic or slate-gray
hue.
• Results from increased melanin and iron in the
dermis.
• Pigmentation usually is generalized,
More pronounced on;
• The face, neck,
• Extensor aspects of the lower forearms,
• Dorsa of the hands, lower legs,
• Genital regions,
• In scars.
17. Diabetes
• Diabetes mellitus occurs in about 65%
• More likely to develop in those with a family
history of diabetes,
• Insulin resistance is more common in
association with hemochromatosis
18. Arthropathy
• Arthropathy develops in 25–50% of
symptomatic patients
• Usually occurs after age 50.
• 2nd and 3rd mcp joints, are usually the first
joints involved.
• Calcium pyrophosphate (chondrocalcinosis or
pseudogout), mainly in the knee.
20. Cardiac involvement
• Presenting manifestation in about 15%.
• Most common manifestation is congestive heart
failure.
• Cardiac arrhythmias ;
• premature supraventricular beats,
• Paroxysmal tachyarrhythmia's,
• Atrial flutter,
• Atrial fibrillation,
• Varying degrees of AV block.
21. Hypogonadism
•Occurs in both sexes.
•Impairment of hypothalamic-pituitary
function by iron deposition
• Loss of libido,
• Impotence,
• Amenorrhea,
• Testicular atrophy,
• Gynecomastia,
• sparse body hair.
22. Screening for HH
• High risk groups;
• Family history of HH (1st degree)
• Those with suspected organ involvement
• Those with chance detection of biochemical and/or
radiological abnormalities
• Optimal timing for screening family members is
between the ages of 18 and 30,
• Generally recommended that all patients with
abnormal liver function have iron studies done at some
point
23. Diagnosis
1. Transferrin saturation —
• If transferrin saturation >45%
• the presence of the C282Y or H63D mutation
confirm the diagnosis of hemochromatosis
2.Plasma ferritin — normal 40 to 200 ng/ml
• >200 mcg/L in premenopausal women
• > 300 mcg/L in men and postmenopausal women
indicate primary iron overload
• False +ve elevations related to inflammation.
• In the absence of increased iron stores in patients
With necroinflammatory liver disease
• Serum ferritin levels have an additional value as a predictor
of advanced fibrosis and cirrhosis in confirmed HH
24.
25. Liver biopsy
Liver biopsy should be considered;
•For the purpose of determining the
presence or absence of advanced fibrosis
or cirrhosis.
•Screening for hcc
•For measurement of HIC.
26. Treatment of Hemochromatosis
• Phlebotomy remains the sole recommended treatment -
simple, inexpensive, and safe.
• Each 500 mL of whole blood removed contains 200 to 250 mg of iron.
Induction phase
• One phlebotomy (500 mL) one to two per week.
• Check hematocrit (Hct) prior to each phlebotomy;
• do not allow Hct to fall by more than 20 percent of prior
level
• Check serum ferritin every 10 to 12 phlebotomies
27. Maintenance phase
• The phlebotomy should be performed every 2-4
months.
• The interval between procedures is determined by
the level of ferritin, which should be 50 -
100mcg/ml.
• Dietary adjustments are unnecessary.
• Vitamin c supplements and iron supplements should be
avoided.
• Check hematocrit/hemoglobin prior to each phlebotomy.
• Allow hematocrit/hemoglobin to fall by no more than 20% of
prior level
28. Response to phlebotomy treatment in patients with HH
• Improved survival if diagnosis and treatment before
Development of cirrhosis and diabetes
• Improved sense of well-being, energy level
Cardiac function
Control of diabetes
• Reduction of tissue iron stores to normal
Of portal hypertension in patients with cirrhosis
In skin pigmentation
• Reversal of hepatic fibrosis (in approximately 30% of cases)
• No reversal of established cirrhosis or diabetes
Arthropathy
Testicular atrophy
• Elimination of risk of hh-related HCC if iron removal is
Achieved before development of cirrhosis
29. ChelationTherapy
• Treatment with iron chelation agents is recommended;
• (heart disease, anemia, poor venous access)
• Deferoxamine intravenously or subcutaneously
(25 to 40 mg/kg)
• IV 8-10 hours 5 nights per week.
• subcutaneous bolus injections B.d
• Deferasirox (exjade) orally
• 100 mg/kg administered once daily 5 times a week.
• Very efficient in liver iron removal.
• Less effective in the splenic & pancreatic iron.
• Renal functions should be monitored.
30. • We recommend that patients with abnormal
Iron studies should be evaluated as patients with
Hemochromatosis, even in the absence of symptoms.(A)
• All patients with evidence of liver disease should be evaluated
for hemochromatosis. (1b)
AASLD Recommendations
31. • In a patient with suggestive symptoms, physical findings,
or family history, a combination of TS and ferritin should
be obtained rather than relying on a single test. (1B) if
either is abnormal (TS 45% or ferritin above the upper
limit of normal), then HFE mutation analysis should be
performed. (1b)
• We recommend screening (iron studies and hfe mutation
analysis) of first-degree relatives of patients with hfe-
related hh to detect early disease and prevent
complications. (1a)
32. • Patients with hemochromatosis and iron overload should
undergo therapeutic phlebotomy weekly (as tolerated). (1a)
• Target levels of phlebotomy should be a
Ferritin level of 50-100 lg/L. (1b)
• Iron chelation with either deferoxamine mesylate or deferasirox
is recommended in iron overloaded patients with
dyserythropoietic syndromes or chronic hemolytic anemia. (1a)
33. References
Diagnosis and Management of Hemochromatosis:
2011 Practice Guideline by the American Association
for the Study of Liver Diseases(AASLD).
UpToDate 19.3 version