This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of the Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

Hemochromatosis Presented by: Ohoud Al Ahmed Medical Student December 12, 2008

also called hereditary haemochromatosis siderophiliabronze diabetes. hereditary haemochromatosis, siderophilia and bronze diabetes. History:History: –First described in 1865 by Armand Trousseau (bronze diabetes). –The recognition of iron infiltration of the pancreas was made by Friedrich Daniel von Recklinghausen in 1890.

Pathophysiology Is a hereditary disease characterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores (up to 10-fold of the normal). leads to deposition of iron as haemosiderin, which is toxic to tissues, in multiple organs: liver, pancreas, heart, joints, pituitary, adrenals and skin.

Middle-aged males (after their forties and fifties), are more frequently and severely affected than women in whom the disease tends to present ~10years later (menstrual blood loss is protective). There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Genetics HH is one of the commonest inherited diseases in those of Northern European in particular those of British or Irish descent (carrier rate ~1:10, homozygosity ~1:200). The gene responsible for most HH is called HFE found on the short arm of chromosome 6 The 2 major allele mutations in the HFE are termed C282Y and H63D. C282Y accounts for % of HH, and H63D accounts for 3-7%, with compound heterozygotes accounting for 1-4%.

Enterocyte DMT-1 (divalent metal transporter), Ferroportin, Lumen Liver HFE gene hepcidin iron Vessel Pathophysiology:-

Recently, a classification has been developed (with chromosome locations): LocusMutationOMIMDescription 6p21.3HFE235200Haemochromatosis type 1: "classical"-haemochromatosis 1q211hemojuvelin ("HJV", also known as HFE2) Haemochromatosis type 2A: juvenile haemochromatosis 9q137hepcidin antimicrobial peptide (HAMP) or HFE2B Haemochromatosis type 2B: juvenile haemochromatosis Q222qtransferrin receptor-2 (TFR2 or HFE3) Haemochromatosis type 3 32ferroportin (SLC11A3)604653Haemochromatosis type 4 autosomal dominant haemochromatosis (all others are recessive), gene mutation

Clinical Features Asymptomatic (incidentaly discovered). Protean in its manifestations.

The more common clinical manifestations include Malaise. Liver cirrhosis (with >10% chance of HCC). Insulin resistance (often patients have already been diagnosed with DM type 2). Erectile dysfunction, hypogonadism and decreased libido. Congestive heart failure, arrhythmias or pericarditis. Arthritis of the hands (esp. 2 nd, 3 rd MCP joints), but also the knee and shoulder joints. Adrenal insufficiency.

Liver cirrhosis

Less common findings include: Deafness Dyskinesias, including Parkinsonian symptoms Dysfunction of certain endocrine organs: –Parathyroid gland (leading to hypocalcaemia) A darkish colour of skin (see pigmentation) An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms: –Vibrio vulnificus infections from eating seafood –Listeria monocytogenes –Yersinia enterocolica –Salmonella enterica (serotype Typhymurium) –Klebsiella pneumoniae –Escherichia coli –Rhizopus arrhizus –Mucor species

Investigations Standard diagnostic tests. Routine tests. Functional tests.

Standard diagnostic tests: –serum transferrin saturation test (>80%). –serum ferritin test (>1000 ng/ml). –Serum iron –TIBC –HFE genotyping Routine tests. Functional tests. Investigations

negative predictive value positive predictive value SpecificitySensitivityTest 87%61%83%68%serum iron > 180 mcg/dL (32 mcmol/L) 93%74%88%82%transferrin saturation > 50% 94%88%95%88%serum ferritin > 400 ng/mL 97%73%86%94%elevation of transferrin saturation or serum ferritin

Investigations Standard diagnostic tests. Routine tests: –CBC –Renal function –U&E –Liver enzymes (elevated but normal in 18%) –Glucose and/or OGTT Functional tests.

Investigations Standard diagnostic tests. Routine tests. Functional tests (based on the history): –ECG and ECHO (CMP, HF) –Blood glucose monitoring. –Joint X-rays (chondrocalcinosis, degenerative OA) –Liver biopsy (quantifies iron loading, assess disease severity esp. cirrhosis). Risks: BBI. –MRI (quantifies iron loading)

Liver biopsy

Major overload Moderate overload Slight overload Normal liver

Differential Diagnosis African iron overload (Bantu siderosis). Secondary haemochromatosis (transfusional iron overload / hemosiderosis): ~40L in total. In those with hereditary anemias such as (B- thalassemia M, SCA, and Diamond-Blackfan anemia). Dyserythropoeisis (myelodysplastic syndrome).

Management Phebotomy (venesection / bloodletting). Initiated when ferritin levels reach 300 mg/L. 1unit/week Every bag of blood ( ml) contains mg of iron. until ferritin levels are less than 20 mg/L. maintenance venesection 1-4 donations/yr for life. Aim: Hct <0.5, ferritin <100 micg/L, TIBC >50 micmol/L, transferrin sat <40%.

Other aspects of management: Diabetes HbA1C levels (may be falsely low) OTC self-medications: make sure that they contain no iron. Dietary intake: maintaining a well-balanced low iron diet. Limiting intake of fruit, fruit juice and red meat. Drinking tea or coffee, Taking calcium and foods containing oxalic and phytic acids with meals reduces iron absorption. Treatment of organ damage (HF with diuretics and ACEI).

Screening Using? –serum ferritin –genotype Whom? –1st-degree relatives –Have any of the following signs & symptoms: Joint disease Severe fatigue Heart disease Elevated liver enzymes Impotence Diabetes.

Prognosis Venesection returns life expectancy to normal if non-cirrhotic and non- diabetic. Arthropathy may improve or worsen. Gonadal failure is irreversible.

References:- Haemochromatosis – wikipedia, the free encyclopedia. last modified on 28 November Oxford handbook of clinical medicine, 7 th edition Assessment of Silent Liver Fibrosis in Hemochromatosis C282Y, Homozygotes With Normal Transaminase Levels. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:713– 714

Studies of Phlebotomy Therapy in Hereditary Hemochromatosis Verified by National Institutes of Health Clinical Center First Received: December 9, 2000 Last Updated: November 20, 2008 Health Authority: United States: Federal Government. 1)Compare the usefulness of the ferritin test with that of MCV in guiding phlebotomy therapy. 2)Examine whether keeping iron levels low during maintenance therapy can help heal severe liver disease and improve arthritis in affected patients. 3)Design a system for making blood collected from hemochromatosis donors available for transfusion into other patients.

Thank you Ohoud M. Al-Ahmed