celtic curse

1. Bronze diabetes- Celtic Curse
Dr .Lalaj Ruchiranga

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.

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)

6. Schematic representation of the protein product of HFE

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.

8. Hepcidin
Interactions between duodenal enterocytes,
hepatocytes, and macrophages in iron homeostasis
regulated by hepcidin.

9. Classification of iron overload syndromes
Hereditary Hemochromatosis
• HFE-related
• C282Y/C282Y
• C282Y/H63D
• C282Y/S65C
• Non–HFE-related
• Hemojuvelin (HJV)
• Transferrin receptor-2 (TfR2)
• Ferroportin (SLC40A1)
• Hepcidin (HAMP)
• African iron overload

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.

13. Natural progression of disease

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

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.

19. Calcium pyrophosphate
deposition disease, atypical
osteoarthritis involving the
2nd & 3rd MCP joints & KJ

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

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