Recognize when to consider the diagnosis of hemochromatosis and how to recognize common mimics of an elevated ferritin level. We’re joined by Dr. Elliot Tapper, @ebtapper on twitter (University of Michigan)
Hemochromatosis=iron overload. Hereditary hemochromatosis (HH) is iron overload that occurs as a result of two inherited genetic mutations that interfere with the normal cycle of iron absorption and feedback, typically leading to loss of iron-regulated hepcidin production and reduced hepcidin levels (Olynyk 2022). Potential complications of hemochromatosis include iron deposition in the joints, liver, heart and skin. With advancements in lab-based recognition, patients typically receive the diagnosis of hemochromatosis prior to developing complications such as the classic “bronze diabetes”. Most people present with the most common complication- liver disease
Iron absorption happens in the proximal duodenum and it occurs via a portal called ferroportin. Hepcidin controls ferroportin, and hepcidin is hepatically synthesized. When iron stores are full, there is a negative feedback loop to turn on hepcidin production (Kowdley 2019).
The mutation in C282Y is the most common genetic mutation associated with hereditary hemochromatosis. 1 in 240 Americans carry 2 copies of this genetic mutation. Prevalence is geographically variable and the greatest density of mutations is in Ireland where 11% of the population is carrying at least 1 copy (Cabrera 2022). Although the prevalence of hemochromatosis genes is high, the penetrance of disease is much lower. For example ~1 in 200 has the genetic mutation but 1 in 100 of individuals has penetrant disease. Penetrance varies across series with higher penetrance estimates of 14 in 100 women and 24 in 100 men when penetrance is defined as a diagnosis by ICD code.
In the hospital, hemochromatosis is not a common etiology of an elevated ferritin (Senjo 2018)
1 in 3 people with nonalcoholic steatohepatitis (NASH) will have hepatic iron overload on liver biopsy (Nelson 2011). Two likely reasons for this include 1) chronic inflammation will influence the way hepcidin behaves in the liver 2) inflammation of hepatocytes causes hepatocellular death and iron spills out. Similarly 2 out of 3 patients with alcohol related liver disease (ALD) will have hepatic iron overload. The reasons for iron overload in ALD are the same as NASH with the addition of 3) alcohol decreases hepcidin production due to ethanol-induced downregulation of the transcription factor regulating hepcidin expression (Kowdley 2019,Mehta 2019).
Liver disease-Current guidelines recommend screening all patients with cirrhosis for hemochromatosis by checking a transferrin saturation (TSAT) and ferritin level. Dr. Tapper notes that acute illness or hospitalization is not the time to check iron indices as they are acute phase reactants. Two additional factors to consider that change the pretest probability of hereditary hemochromatosis are 1) metabolic syndrome or 2) alcohol use disorder. Dr. Tapper typically checks iron studies during the first visit for patients who lack risk factors for dysmetabolic iron overload syndrome. If liver enzymes are mildly elevated, Dr. Tapper tries to focus on global health and lifestyle change such as weight loss and cessation of alcohol use first. If liver enzymes and ferritin don’t decrease after 3-6 months following changes in risk factors, Dr. Tapper will test for hemochromatosis
Family history- HH is an autosomal recessive condition with variable penetrance. Guidelines recommend screening all first degree relatives for hereditary hemochromatosis following a diagnosis (Kowdley 2019).
If you have an elevated ferritin >200 for women or >300 for men with a TSAT >45-50% the probability that the individual has hemochromatosis increases. Genetic testing for HFE mutations should be considered and commercial testing probes for C282Y and H63D mutations. Homozygosity for C282Y or compound heterozygosity with C282Y & H63D carry an increased risk for iron overload and penetrant hereditary hemochromatosis. Simple heterozygosity for C282Y affects 1 in 7 individuals of European descent and carries no risk of iron overload (Olynyk 2022).If you have an individual with evidence of iron deposition in liver such as MRI evidence but the genetic testing is negative- if TSAT low to normal these individuals can have mutations in ferroportin.
Although the genetic mutations that cause hemochromatosis affect 1 in 200 individuals, the penetrance is much lower leading to clinically significant liver disease in only 1 in 100 individuals with the genetic mutation. Therefore, it is important to recognize the potential harm associated with a misdiagnosis of hemochromatosis as the cause of an elevated ferritin or TSAT (Odufalu 2017) Males are more likely to present with severe iron overload- the penetrance of the disease is higher in men. Cumulative exposure to iron is higher so they will present at an earlier age as females are more likely to have menstruation throughout a considerable part of life. As continuous birth control changes patterns of menstruation, earlier ages at presentation are possible.
Dr. Tapper recommends considering the following to evaluate for the presence of liver disease
For further prognostic information a FIB-4 can be calculated to evaluate for the likelihood of advanced fibrosis & transient elastography can further evaluate fibrosis.
MRI imaging can diagnose and quantify hepatic & cardiac iron overload due to hemochromatosis, and a liver biopsy is rarely needed (Kowdley 2019). MRI liver imaging is particularly helpful in cases with competing risk factors for manifestation of dysmetabolic iron overload syndrome such as obesity, diabetes and alcohol use disorder. Iron overload that is visualized on MRI is typically the result of hereditary hemochromatosis when isolated to the liver or secondary hemochromatosis when found in both the liver and spleen. In secondary iron overload, iron is being deposited in the endothelial cells from etiologies such as excess transfusions (Kowdley 2019).
In addition to liver disease, hemochromatosis is associated with multiple clinical manifestations including fatigue & arthritis (most common), cardiomyopathy, and diabetes (Olynyk 2022).
Liver– avoid toxins including alcohol, ensure vaccination for HAV & HBV. Ensure no iron in multivitamin if taking one, cut back on dietary sources of iron like red meat. Individuals with cirrhosis secondary to hemochromatosis are also at increased risk of HCC. The risk of HCC will decline if the iron overload is treated with phlebotomy and ferritin is decreased to a level <50 but remains higher than the average population(Kowdley 2019).Patients with an elevated TSAT and low hepcidin levels are at increased risk of invasive infections from sideroblastic bacterium such as Vibrio vulnificus (Arezes 2015). Counseling should be provided to avoid eating uncooked or raw seafood such oysters. (Tweetorial by Dr. Tapper)
Phlebotomy is the mainstay of treatment- the goal is to decrease the ferritin to <50 to 100 (Olynyk 2022). Typically Dr. Tapper will make a decision about how fast to drop the ferritin based on patient condition and comorbidities.
Dr. Tapper reports previously working as a consultant for Malinckrodt, Kaleido Biosciences, Takeida, Novo Nordisk, Bausch Health, Axcella, Ambys, and Lipocine. The Curbsiders report no relevant financial disclosures.
Gibson EG, Tapper E, Syed, F, Williams PN, Watto MF. “#380 Hemochromatosis”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Feb 6, 2023.
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