Hereditary haemochromatosis -Quick revision card

several inherited disorders – characterized by increased gastrointestinal iron absorption due to mutations in genes that participate in iron homeostasis Type 1 or classical HH is an autosomal recessive disorder leading cause in people of European ancestry is homozygosity of the C282Y variant in the HFE gene seen in 1 in 300 non-Hispanic whites in US and up to 1 in 150 in people of NW European ancestry not all C282Y homozygotes would develop the disease presentation is generally between ages 40-60 yrs men suffer more with haemochromatosis than women.

decreased expression of iron regulatory hormone hepcidin normally hepcidin reduces the export of iron from the reticuloendothelial cells due to mutation of the HFE gene ‘ brake ‘ on iron absorption is lost and cellular iron absorption happens unabated ( in the duodenum )

milder variant can predispose to haemochromatosis if they inherit a C282Y variant from one parent and a H63D variant from another parent they are called as compound heterozygotes

very low risk of developing iron overload

liver abnormalities ( seen in > 70 % patients ) can manifest as abdominal pain , hepatomegaly , cirrhosis , portal hypertension , ascites and splenomegaly pancreas ( diabetes- advanced disease ) hypogonadotropic hypogonadism heart ( restrictive or dilated cardiomyopathy , arrhythmias , cardiac failure ) arthritis involving the 2nd and 3rd MCP jts slate-grey ( melanin ) pigmentation , seen in more than 90 % patients koilonychia ( affecting thumb and index finger ) hepat0cellular carcinoma ( in up to 30 % with untreated HH )

Presentation will depend upon the organ involved iron deposition is slow ie manifestation may not happen before age 30 most common presenting symptoms may be arthralgias , fatigue and lethargy O/E finding may include hepatomegaly , bronze pigmentation of skin , cardiac abnormalities , signs of liver cirrhosis , testicular atrophy , swelling and thickening of 2nd and 3rd MCP joint delayed presentation in women ( due to menstruation / pregnancy )

Serum ferritin and Transferrin saturation are first line tests if both are normal iron overload is unlikely raised transferrin > 40 % in women or 50 % in men ferritin level > 200 mcg/ L in women or 300 mcg/ L in men

REFERENCES

1. Diagnosis and treatment of hereditary hemochromatosis: an update Expert Rev. Gastroenterol. Hepatol. 7(6), 517–530 (2013 *cadae1312.pdf (sah.org.ar)
2. Fleming, Robert E et al. “Pathophysiology of hereditary hemochromatosis.” Seminars in liver disease vol. 25,4 (2005): 411-9. doi:10.1055/s-2005-923313 Pathophysiology of Hereditary Hemochromatosis (nih.gov)
3. Haemochromatosis UK General Practitioners Quick Guide to Genetic Haemochromatosis *Download.ashx (haemochromatosis.org.uk)
4. Postgraduate Haematology  A Victor Hoffbrand et al 7th edition
5. Porter JL, Rawla P. Hemochromatosis. [Updated 2021 Dec 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430862/
6. Grosse, S., Gurrin, L., Bertalli, N. et al. Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes. Genet Med 20, 383–389 (2018). https://doi.org/10.1038/gim.2017.121
7. Hereditary hemochromatosis Diagnosis and management Hereditary haemochromatosis – Diagnosis and management (racgp.org.au)