Hereditary Haemochromatosis (A pint too many: discussing haemochromatosis) John Lee

Transcription

1 Hereditary Haemochromatosis (A pint too many: discussing haemochromatosis) John Lee

2 Hereditary Haemochromatosis A disorder of iron metabolism Inherited disorder

3 Iron Essential micro-nutrient Toxicity when in excess Toxicity Intracellular organelles Activation of cells involved in inflammation and fibrosis

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5 Iron overload states Primary iron overload HH: HFE-associated Juvenile HH Other mutations Secondary iron overload Anaemia (transfusion) Thalassemia, Sideroblastic anaemia Chronic liver disease Viral, alcohol, fatty liver disease

6 Hereditary Haemochromatosis (HH) A condition of iron overload due to abnormal regulation of iron absorption in the duodenum (gut) Due to inheritance of a mutated gene (HFE) which stops the body from correctly regulating iron intake Patients with HH continue to absorb iron from the diet despite excess stores Excess iron is toxic and may cause irreversible damage to body tissues and organs in which it is stored Increased ferritin levels Increased transferrin saturation Increased liver iron concentration

7 HEMOCHROMATOSIS VARIANTS Type Comments Chromosome 1. HFE1 C282Y/C282Y > 80% cases worldwide 6 C282Y/H63D 11% present phenotypically H63D/H63D often has a potentiator C282Y/S65C mild H63D/S65C mild S65C/S65C mild 2. HFE2 (Juvenile) < 30 YEARS 1 3. HFE3 mutation in TfR2 gene 7 4. HFE4 autosomal dominant 2 mutation in ferroportin gene (SLC11A3) 5. Other African iron overload? Iron overload in Solomon Islanders

8 Hereditary Haemochromatosis (HFE gene associated) Autosomal recessive disorder Excessive iron absorption from GI tract Multiple potential pathological sequelae 1977: nonsecondary Iron overload related to HLA complex 1996: Description of HFE mutation Simon et al. NEJM 1977; 297(19): Bomford et al. Lancet 1977; 1 (8007):327-9 Feder et al. Nature Genetics 1996; 13( ) Most common genetic disorder in Caucasian population (Celtic and Nordic ancestry) Prevalence: % in NW Europe 0.7% in UK > 1% in Ireland

9 Haemochromatosis: potential course over time

10 Iron overload and potential organ damage Liver: Cirrhosis Liver Cancer (HCC) Endocrine: Diabetes Mellitus Thyroid disease Hypogonadism hypogonadotrophic hypogonadism gonadal failure Heart: Cardiomyopathy (HEART FAILURE) Arrhythmias

11 Iron overload and potential organ damage Joints: arthralgia arthritis (m-p joint) pseudogout Skin: pigmentation General: Fatigue

12 Skin pigmentation

13 Arthropathy

14 Liver: iron deposition and cirrhosis

15 PENETRANCE OF HFE GENE MUTATIONS Do all patients with mutations in the HFE gene get iron overload? NO Do all mutation profiles cause the same degree of iron overload? NO

16 How does all of this apply to individual patients and their families Presentation Symptoms Investigation of abnormal LFTS Screening tests in view of family history Diagnosis and evaluation Treatment Family screening

17 Hereditary Haemochromatisis Diagnosis An interpretation of data Clinical information Laboratory information Every case is different! Usually, but not always, straight forward

18 Haemochromatosis Diagnosis

19 Diagnosis (continued) Genetic testing For patient Considered for family members Liver biopsy considered in selected cases When there are parameters to suggest the possibility of advanced fibrosis or cirrhosis When there is doubt about the diagnosis

20 Liver biopsy findings

21 Management Phlebotomy/venesection (ferritin = 50ng/mL) Advice Family screening Dietary considerations Avoiding other hepatotxins (excessive alcohol) Consider Liver Biopsy If cirrhosis present Screen for oesophageal varices Screen for hepatoma (afp and imaging) Consider role of liver transplant

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23 Hereditary Haemochromatosis: Diet A normal balanced diet iron overload cannot be corrected by control of diet alone Avoid excessive alcohol intake Caution Ascorbic acid (Vitamin C) Iron supplementation Uncooked seafood Vibrio Vulificus

24 62 year old man noted to have abnormal LFTs at a Life Assurance assessment. Further investigations were carried out. Ferritin = 2500, TS% = 98% LFTs AST = 70 ALT = 80 GGT = 110 HFE GENE: C282Y + + H63D - - THOUGHTS ON: DIAGNOSIS MANAGEMENT

25 45 year old man had tests done because his brother was diagnosed with haemochromatosis Ferritin = 600, TS% = 95% LFTs AST = 40 ALT = 30 GGT = 50 HFE GENE: C282Y + - H63D - + THOUGHTS ON: DIAGNOSIS MANAGEMENT

26 55 year old obese man (20 stone) who drinks 40 units alcohol per week attended his GP for investigation of fatigue LFTs AST = 50 ALT = 80 GGT = 310 Ferritin = 500, TS% = 49% HFE GENE: C282Y + - H63D - - THOUGHTS ON: DIAGNOSIS MANAGEMENT

27 23 year old student back in Ireland for few weeks after travelling for a year. Now noticed to be jaundiced. Ferritin = 1500, TS% = 48% LFTs AST = 2070 ALT = 1800 GGT = 310 HFE GENE: C282Y?? H63D?? THOUGHTS ON: DIAGNOSIS MANAGEMENT

28 Haemochromatosis and Genetics HFE GENE (C282Y MUTATION) Father Mother (+ -) (+ -) (+ -) (+ -)

29 Haemochromatosis and Genetics HFE GENE (C282Y MUTATION) Father Mother (+ +) (+ +) (+ -) (+ -)

30 SUMMARY Haemochromatosis is common Early detection is important treatment prevents the development of organ damage The mainstay of treatment is venesection or phlebotomy

31 Causes of hyperferritinaemia With iron overload Primary Secondary Transfusion overload Excess dietary iron Porphyria cutanea tarda (PCT) Ineffective erythropoiesis Sideroblastic anaemia Thalassemia Without iron overload Liver disease NASH*, viral, autoimmune Alcohol excess* Inflammatory conditions Infections, IBD, RA, Autoimmune Thyrotoxicosis Familial hyperferritinaemia and cataract syndrome *CAN HAVE IRON OVERLOAD IN CERTAIN SETTINGS