Tag Archives: hemochromatosis

Curing Iron Overload with Liver Transplantation

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The role of hepcidin in iron metabolism has been described in detail.  Yet, a new study provides another line of evidence that the liver has a primary role in regulating iron absorption (Hepatology 2014; 59: 839-47, editorial 749-50).

Background: Hereditary hemochomatosis (HH) is mainly due to defects in the gene encoding the human hemochromatosis protein (HFE), particularly the C282Y mutation.  Initially, HH was thought to be related to the role of HFE in regulation iron absorption at the intestinal crypt.  However, the discovery of hepcidin, which is mainly secreted by the liver, was shown to regulate iron absorption through its interaction with ferroportin, the cellular iron exporter. With HH, inappropriately low hepcidin was associated with excessive iron absorption.

Despite this understanding, many questions remain, especially regarding the fact that some C282Y homozygotes have a normal serum ferritin and transferrin saturation.  In addition, whether liver transplantation prevents further iron overload in patients transplanted for HH is not entirely certain.

Methods: This study evaluated 18 liver transplant (LT) patients with HH and who were homozygous for C282Y mutations.  16 of these patients had HCC.  All patients underwent iron evaluations (iron, hepcidin, hepatic iron concentrations) prior to LT and most (n=11) had evaluations following LT with a median followup of 57 months.

Key findings:

  • After LT, no patients received iron depletion therapy (eg. phlebotomy).  9 of 11 had no iron overload based on bloodwork (normal transferrin saturation) and MRI without iron overload.
  • One patient with hereditary spherocytosis continued to have iron overload, and one patient with metabolic syndrome had mild iron overload.
  • Hepcidin was normal (11.12 nmol/L) in 10 patients at the end of followup and low in one patient with iron deficiency anemia; prior to LT, serum hepcidin levels were low in all patients (mean 0.54 nmol/L)

Bottomline: This study shows that LT corrects hepcidin dysregulation caused by the HFE mutation and that post-LT HH patients do not require phlebotomy.  Thus, HH is clearly a liver disease and not an intestinal disease.

Related blog post: Help with hepcidin | gutsandgrowth (with annotated references)

Why Some Genetic Mutations May Be Helpful: HFE

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When one looks at diseases, it is important to consider that the mutations that cause the disease may confer other selective advantages.

A classic example has been sickle-cell disease.  The heterozygous state is usually asymptomatic and makes an individual less prone to malaria.  “In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and will tend to be selected out of the affected population via natural selection.” —Sickle–cell disease – Wikipedia, the free encyclopedia

Another common disorder is hemochromatosis.  A recent letter in the New England Journal of Medicine (NEJM 2013; 369: 785-6) explains why having the HFE gene could be advantageous.  According to the authors the genetic mutation arose in Celtic populations who were notably taller than other populations.  As such, the authors hypothesized that the patients with HFE hemochromatosis would have better growth by having an abundant supply of iron during periods of rapid development.

They assessed a cohort of 176 Swiss patients with HFE hemochromatosis.  93% were homozygous for the C282Y mutation, 7% had a compound H63D-C282Y mutation.  All of the patients had verified iron overload determined as a ferritin > 300 mcg/L or a transferrin saturation >45%.

Compared with an age-matched, sex-matched Swiss reference population, men with hemochromatosis (n=120) were 4.3 cm taller on average. In women (n=56), the difference was 3.3 cm.  To avoid bias due to population origin, the cohort was also compared with data from Ireland where the data remained validated.

Take-home message: Extra iron in the first two decades of life promote better growth (and probably other advantages).  However, iron overload later in life can lead to cirrhosis, diabetes, heart disease, and reproductive problems.

Related blog post:

AASLD Hemochromatosis Guidelines:

Help with hepcidin

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Over the past several years, the mechanisms involved in iron overload have been carefully examined and the genetic basis for most of these disorders is now understood.  Several review articles on these disorders have been published; the most recent with excellent diagrams is in last week’s NEJM (NEJM 2012; 366: 348-59 & NEJM 2012; 366: 376-77). Although the process is quite complicated, the most important aspect regarding iron homeostasis is a feedback loop involving hepcidin-ferroportin.  Hepcidin functions as a ‘hypoferremia hormone.’  It down regulates ferroportin release of iron into the circulation.  Hepcidin is also an acute-phase protein and inflammation affects its function.

Hepcidin levels fluctuate in response to the body’s iron needs: more hepcidin causes less iron absorption & less hepcidin causes more iron absorption.

  • Iron balance disorders can usually be attributed to altered hepcidin production.
  • Anemia of chronic disease, though multifactorial, is mostly due to increased hepcidin production in response to inflammation.
  • Hemochromatosis results from genetic mutations causing lack of normal hepcidin production.  The severity of these disorders correlates with hepcidin levels.
  • Hepcidin agonists could be used to treat hemochromatosis and other iron overload conditions (eg. thalassemia with transfusion therapy).  For hemochromatosis, phlebotomy will be less expensive.
  • Hepcidin antagonists could treat anemia of chronic disease

Additional references:

  • -Hepatology 2011; 54: 328.  Review.  Guidelines.
  • -Hepatology 2010; 52: 925.  HFE homozygotes, n=31,192 w low risk of clinical symptoms if ferritin <1000.
  • -Gastroenterology 2010; 139: 393. Review –pathogenesis/dx/Rx
  • -Hepatology 2009; 50: 94.  C282Y/H63D compound heterozygotes (n=180) are at low risk for hemochromatosis-related morbidity compared with control group.
  • -Hepatology 2008; 48: 991.  Review.
  • -Hepatology 2007; 46: 960, 1071.  Review of clinical phenotypes.  Of C282Y homozygotes, only 1-2% develop HCC, 6% cirrhosis, 25% liver fibrosis, 38% Fe overload, 61-75% develop raised serum iron indices.
  • -Hepatology 2007; 46: 1291. Review of hemochromatosis
  • -Hepatology 2007; 45: 253. Review of iron metabolism
  • -NEJM 2004; 350: 2383. Review.  Several genetic mutations associated with clinical phenotype.  type 1: Classic HFE, types 2A & 2B: (Juvenile type)  HJV & HAMP (gene products hemojuvelin & hepcidin), type 3:TFR2 (transferrin receptor 2), and type 4:SLC40A1
  • -NEJM 2005; 352: 1011. Algorithm.  If transferrin saturation <16%, check ferritin.  If ferritin less than 30, Fe-deficiency; if >100, anemia of chronic disease.  If 30-100, check soluble transferrin receptor (level of sTranReceptor/log ferritin less than 1 is c/w anemia of chronic disease whereas when this ratio is greater than 2, c/w combined Fe-def anemia and anemia of chronic disease).  Hepcidin is produced by hepatocytes and regulates iron homeostasis.  Hepcidin interacts with ferroportin, an iron export protein on enterocytes (& other cells), & facilitates internalization and degradation of ferroportin.  It may lead to decreased dietary iron absorption and to retention of iron body stores.  Hepcidin expression can be up-regulated by high iron levels or during acute phase inflammatory responses (thus can contribute to anemia of chronic disease).  Hereditary hemochromatosis associated with low hepcidin levels in the face of increased iron body stores.  Several genes can affect hepcidin loss of function, including HFE, hemojuvelin (HJV), and transferrin receptor 2 (TFR2).
  • -Gastroenterology 1996; 110: 1107.  Sentinel article discussing long-term survival in hemochromatosis and role of iron.