Hereditary (primary) hemochromatosis

(HHC)

Introduction

Hereditary hemochromatosis is an inherited predisposition to absorb excess iron (Fe) from the diet

Total body iron may reach up to 20-60g, normal body iron is 3-4g Mutations in the HFE gene are the most common cause of adult

onset iron overload In some predisposed individuals, excessive iron absorption and

subsequent storage in various organs (i.e. liver, pancreas, heart, joints and pituitary) eventually lead to cellular injury

If untreated, over time this can cause irreversible tissue/organ damage and shorten life expectancy

Prevalence and incidence Autosomal recessive inheritance HFE– associated Hemochromatosis accounts for > 90% of cases and

is the most common adult onset form: Single point gene mutation C282Y and H63D can occur Cystine to tyrosine substitution (C282Y) Histadine to aspartic acid (H63D) Carrier rate 1 in 7 - 10 Caucasians Incidence 1 in 200 - 400

Autosomal Recessive Inheritance

HFE gene HFE gene on chromosome 6 Involved in iron homeostasis by interacting with transferrin

receptor in basolateral membrane of intestinal epithelial cells HFE protein normally limits amount of iron uptake by gut and

regulates amount of iron stored in the tissues A defect in uptake of transferrin associated iron may lead to up

regulation of enterocyte iron specific divalent metal transporters and excessive iron absorption

Hepcidin model in HFE mutation

Clinical manifestationsInfluenced by Age Sex Dietary iron Alcohol Blood loss in menstruation and pregnancy Unknown factors Alcohol abuse and Hepatitis C accelerate Classic description: cutaneous hyperpigmentation and

diabetes in a patient with cirrhosisTypically, symptoms of hereditary hemochromatosis present in men aged 40-60 and in post-menopausal women; however, onset is variable and can occur much earlier or much later.

Clinical manifestationsSymptoms are nonspecific and include: weakness, lethargy skin discoloration (bronze or grey) abdominal pain with or without hepatomegaly joint pain and/or stiffness, arthritis diabetes cardiomyopathy cirrhosis hepatocellular carcinoma testicular atrophy, erectile dysfunction menstrual irregularity

Clinical manifestations

Diagnostic testing for HH Transferrin saturation: >45% indicates significant Fe accumulation Serum ferritin - levels indicating significant iron accumulation:1. >200 mcg/L pre-menopausal women2. >300 mcg/L post-menopausal women3. >300 mcg/L for men CT may show features suggesting excess hepatic iron Liver biopsy if ferritin >1000 to assess damage Consider genetic testing – DNA testing for common mutations

(C282Y, H63D)

Genetic Testing for HH should be offered to patients with following Appropriate clinical presentation Any adult with biochemical evidence of iron overload >45% transferrin saturation (TS) and >300mg/L serum ferritin (SF) in

men and post-menopausal women or >200mg/L SF in pre-menopausal women

Unexplained chronic liver disease and increased TS An adult with a first-degree relative (sibling, parent or child) with one of

the following genetic test results:1. C282Y/C282Y (homozygote)2. C282Y/H63D (compound heterozygote)3. C282Y/S65C (compound heterozygote)4. C282Y heterozygote (carrier) Liver biopsy suggestive of iron overload

What is the value of genetic testing?

To confirm diagnosis Sequential screening of family members Family members with identified mutations can be offered: Screening plan to monitor for iron overload. Normal life expectancy if diagnosed before DM or cirrhosis Treatment plan to prevent further organ damage, morbidity & mortality. Prolonged survival with serial phlebotomy Goal of ferritin <50 may take > 1 year Environmental modification Diet, alcohol, viral hepatitis A/B immunization

Treatment

Reserved for evidence of iron overload/complications Venesection Deferoxamine (DFO) Avoid iron supplements, red meat Avoid alcohol and tobacco

Venesection Removal of 500 ml of blood Removes 250 mg ironDo weekly until iron depletion1. Hgb < 122. Ferritin < 503. Transferritin saturation < 50%4. 2-3 years may be required to remove >20g Long term maintenance about once every 3 months

Deferoxamine chelation

The greatest challenge with DFO is patients’ adherence to therapy Poor oral bioavailability Short plasma half-life Slow subcutaneous administration over 8–12 hours, 5–7 days/week Poor compliance

Prognosis

Pre cirrhotic patients with HHC have a normal life expectancy Cirrhotic patients have a relatively good prognosis as compared to

other forms of cirrhosis Screening for hepatocellular carcinoma is mandatory as it is the

main cause of death affecting 1/3 of patients with cirrhosis

Case

60 years old male 3 month history of fatigue & joint pain drinks 2 beers/day brother with type 2 diabetes

Physical exam: hepatomegaly enlarged and tender knuckles several tattoos

Case

Routine blood work: Fasting glucose - normal Bilirubin - normal ALT 67 U/L (reference range 0-40) AST 73 U/L (reference range 0-37) GGT 92 U/L (reference range 5-35)

Patient stops drinking 6 weeks later: ALT & AST levels are

unchanged GGT - normal Hepatitis A & B serology

negativeWhat next?

Case

Further blood work: Ferritin 640 mcg/L(reference range <300mcg/L) Transferrin saturation 60% (reference range <45%)

What is the diagnosis?

Thank you