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Bronze diabetes- Celtic Curse
Dr .Lalaj Ruchiranga
Introduction
• “Celtic Curse”- also known as “Bronze diabetes”
• Hemochromatosis is the abnormal accumulation of
iron in p...
Epidemiology
• Hereditary hemochromatosis (HH) remains the most
common genetic disorder in Caucasians.
• Women typically p...
Genetic basis
• Principal HFE gene defect was first described in
1996,
• Tightly linked to the HLA-A locus on chromosome
6...
Schematic representation of the protein product of HFE
Pathophysiology
(1) Increased absorption of dietary iron in the
upper intestine,
(2) Decreased expression of the iron-regu...
Hepcidin
Interactions between duodenal enterocytes,
hepatocytes, and macrophages in iron homeostasis
regulated by hepcidin.
Classification of iron overload syndromes
Hereditary Hemochromatosis
• HFE-related
• C282Y/C282Y
• C282Y/H63D
• C282Y/S65C...
Classification of iron overload syndromes cont.;
• Secondary Iron Overload
• Iron-loading anemia
• Thalassemia major
• Sid...
It’s a spectrum of disease
• Phenotypic expression only occurs in
approximately 70% of C282Y homozygotes,
• Fewer than 10%...
EuropeanAssociationfor the Study of
Liver Diseases staging system
• Stage 1 -genetic disorder +, no increase in iron store...
Natural progression of disease
CLINICAL MANIFESTATIONS
• Liver function abnormalities — 75 %
• Weakness and lethargy — 74 %
• Skin hyperpigmentation — 70...
Hepatic manifestations
• Liver is usually the first organ to be affected
• Hepatomegaly in >95% of symptomatic
patients.
•...
Skin
• Skin pigmentation -characteristic metallic or slate-gray
hue.
• Results from increased melanin and iron in the
derm...
Diabetes
• Diabetes mellitus occurs in about 65%
• More likely to develop in those with a family
history of diabetes,
• In...
Arthropathy
• Arthropathy develops in 25–50% of
symptomatic patients
• Usually occurs after age 50.
• 2nd and 3rd mcp join...
Calcium pyrophosphate
deposition disease, atypical
osteoarthritis involving the
2nd & 3rd MCP joints & KJ
Cardiac involvement
• Presenting manifestation in about 15%.
• Most common manifestation is congestive heart
failure.
• Ca...
Hypogonadism
•Occurs in both sexes.
•Impairment of hypothalamic-pituitary
function by iron deposition
• Loss of libido,
• ...
Screening for HH
• High risk groups;
• Family history of HH (1st degree)
• Those with suspected organ involvement
• Those ...
Diagnosis
1. Transferrin saturation —
• If transferrin saturation >45%
• the presence of the C282Y or H63D mutation
confir...
Liver biopsy
Liver biopsy should be considered;
•For the purpose of determining the
presence or absence of advanced fibros...
Treatment of Hemochromatosis
• Phlebotomy remains the sole recommended treatment -
simple, inexpensive, and safe.
• Each 5...
Maintenance phase
• The phlebotomy should be performed every 2-4
months.
• The interval between procedures is determined b...
Response to phlebotomy treatment in patients with HH
• Improved survival if diagnosis and treatment before
Development of ...
ChelationTherapy
• Treatment with iron chelation agents is recommended;
• (heart disease, anemia, poor venous access)
• De...
• We recommend that patients with abnormal
Iron studies should be evaluated as patients with
Hemochromatosis, even in the ...
• In a patient with suggestive symptoms, physical findings,
or family history, a combination of TS and ferritin should
be ...
• Patients with hemochromatosis and iron overload should
undergo therapeutic phlebotomy weekly (as tolerated). (1a)
• Targ...
References
Diagnosis and Management of Hemochromatosis:
2011 Practice Guideline by the American Association
for the Study...
Hereditary Hemochromatosis
Hereditary Hemochromatosis
Hereditary Hemochromatosis
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Hereditary Hemochromatosis

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Hereditary Hemochromatosis

  1. 1. Bronze diabetes- Celtic Curse Dr .Lalaj Ruchiranga
  2. 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. 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. 4. 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)
  5. 5. Schematic representation of the protein product of HFE
  6. 6. 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.
  7. 7. Hepcidin Interactions between duodenal enterocytes, hepatocytes, and macrophages in iron homeostasis regulated by hepcidin.
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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.
  12. 12. Natural progression of disease
  13. 13. 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%
  14. 14. 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
  15. 15. 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.
  16. 16. 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
  17. 17. 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.
  18. 18. Calcium pyrophosphate deposition disease, atypical osteoarthritis involving the 2nd & 3rd MCP joints & KJ
  19. 19. 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.
  20. 20. Hypogonadism •Occurs in both sexes. •Impairment of hypothalamic-pituitary function by iron deposition • Loss of libido, • Impotence, • Amenorrhea, • Testicular atrophy, • Gynecomastia, • sparse body hair.
  21. 21. 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
  22. 22. 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
  23. 23. 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.
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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.
  28. 28. • 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
  29. 29. • 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)
  30. 30. • 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)
  31. 31. References Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases(AASLD). UpToDate 19.3 version

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