Bronze diabetes- Celtic Curse

Dr .Lalaj Ruchiranga

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

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.

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)

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-regulatory hormone hepcidin, (3) Altered function of HFE protein,

(4) Tissue injury and fibrogenesis induced by iron.

Hepcidin

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

Classification of iron overload syndromesHereditary 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

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

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

European Association for the Study ofLiver 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.

Natural progression of disease

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%

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

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.

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

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.

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.• Cardiac arrhythmias ;• premature supraventricular beats,• Paroxysmal tachyarrhythmia's,• Atrial flutter, • Atrial fibrillation,• Varying degrees of AV block.

Hypogonadism•Occurs in both sexes.• Impairment of hypothalamic-pituitary function by iron deposition• Loss of libido,• Impotence, • Amenorrhea, • Testicular atrophy, • Gynecomastia, • sparse body hair.

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

Diagnosis 1. Transferrin saturation — • If transferrin saturation >45% • the presence of the C282Y or H63D mutation

confirm the diagnosis of hemochromatosis2.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

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.

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

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

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

Chelation Therapy• 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.

• We recommend that patients with abnormalIron studies should be evaluated as patients withHemochromatosis, even in the absence of symptoms.(A)

• All patients with evidence of liver disease should be evaluated for hemochromatosis. (1b)

AASLD Recommendations

• 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)

• 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)

References Diagnosis and Management of Hemochromatosis:2011 Practice Guideline by the American Associationfor the Study of Liver Diseases(AASLD).

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