Page 52 - EASL POSTGRADUATE COURSE
P. 52
VAT has all activated genes necessary to handle iron. VAT iron overload has been reported in
overweight subjects as well as in experimental models of DIOS where a high fat diet results in a shift of
hepatic iron to adipose tissue. Then, in MetS, even in the absence of identified hepatic iron overload,
hyperferritinemia could be related to increased body iron stores due to iron deposition in VAT, and not
to subclinical inflammation as previously thought. The production of adiponectin, the main adipokine
protective against IR, is down-regulated by iron at the transcriptional level. This strongly suggests a key
role of iron in the onset and/or the worsening of IR.
Consequences of iron excess. Experimental and clinical studies indicate that iron excess is associated
with increased risks of cardiovascular complications, cancer, abnormal glucose metabolism and, perhaps,
liver fibrosis, via the increased production of ROS.
Treatment [10]
Lifestyle modifications are mandatory with, if necessary, antihypertensive, lipid lowering and antidiabetic
drugs.This results in serum ferritin normalization in less than 1/3 of cases, mainly when baseline serum
ferritin levels are <500 µg/l.
Currently, there is no consensus on whether phlebotomy therapy could be beneficial for the patient.
However, this type of therapy is known to improve IS in diabetic and non-diabetic subjects, and in
patients with NAFLD. Furthermore, phlebotomy improves liver histology in patients with NAFLD and
decreases cancer and cardiovascular risks in patients with peripheral arterial disease. Phlebotomy is also
well tolerated by DIOS patients when venesections are performed every 14 days, allowing the removal
of 2.5 g of iron, on average.
Large, controlled studies of phlebotomy therapy in DIOS patients with or without NAFLD are
warranted. Moreover, iron may be a promising therapeutic target in such subjects.
References
[1] Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011;31:260-271.
[2] Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload.
Gastroenterology 1999;117:1155-1163.
[3] Moirand R, Mortaji AM, Loreal O, et al. A new syndrome of liver iron overload with normal transferrin
saturation. Lancet 1997;349:95-97.
[4] Dongiovanni P, Fracanzani AL, Fargion S, et al. Iron in fatty liver and in the metabolic syndrome: a
promising therapeutic target. J Hepatol 2011;55:920-932.
[5] Gabrielsen JS, Gao Y, Simcox JA, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J
Clin Invest 2012;122:3529-3540.
[6] Hansen JB, Moen IW, Mandrup-Poulsen T. Iron: the hard player in diabetes pathophysiology. Acta Physiol
(Oxf) 2014;210:717-732.
[7] Orr JS, Kennedy A, Anderson-Baucum EK, et al. Obesity alters adipose tissue macrophage iron content
and tissue iron distribution. Diabetes 2014;63:421-432.
[8] Ruivard M, Laine F, Ganz T, et al. Iron absorption in dysmetabolic iron overload syndrome is decreased
and correlates with increased plasma hepcidin. J Hepatol 2009;50:1219-1225.
[9] Vecchi C, Montosi G, Garuti C, et al. Gluconeogenic signals regulate iron homeostasis via hepcidin in
mice. Gastroenterology 2014;146:1060-1069.
[10] Guillygomarc’h A, Mendler MH, Moirand R, et al. Venesection therapy of insulin resistance-associated
hepatic iron overload. J Hepatol 2001;35:344-349.
52 Postgraduate Course Syllabus • Metabolic Liver Disease
overweight subjects as well as in experimental models of DIOS where a high fat diet results in a shift of
hepatic iron to adipose tissue. Then, in MetS, even in the absence of identified hepatic iron overload,
hyperferritinemia could be related to increased body iron stores due to iron deposition in VAT, and not
to subclinical inflammation as previously thought. The production of adiponectin, the main adipokine
protective against IR, is down-regulated by iron at the transcriptional level. This strongly suggests a key
role of iron in the onset and/or the worsening of IR.
Consequences of iron excess. Experimental and clinical studies indicate that iron excess is associated
with increased risks of cardiovascular complications, cancer, abnormal glucose metabolism and, perhaps,
liver fibrosis, via the increased production of ROS.
Treatment [10]
Lifestyle modifications are mandatory with, if necessary, antihypertensive, lipid lowering and antidiabetic
drugs.This results in serum ferritin normalization in less than 1/3 of cases, mainly when baseline serum
ferritin levels are <500 µg/l.
Currently, there is no consensus on whether phlebotomy therapy could be beneficial for the patient.
However, this type of therapy is known to improve IS in diabetic and non-diabetic subjects, and in
patients with NAFLD. Furthermore, phlebotomy improves liver histology in patients with NAFLD and
decreases cancer and cardiovascular risks in patients with peripheral arterial disease. Phlebotomy is also
well tolerated by DIOS patients when venesections are performed every 14 days, allowing the removal
of 2.5 g of iron, on average.
Large, controlled studies of phlebotomy therapy in DIOS patients with or without NAFLD are
warranted. Moreover, iron may be a promising therapeutic target in such subjects.
References
[1] Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011;31:260-271.
[2] Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload.
Gastroenterology 1999;117:1155-1163.
[3] Moirand R, Mortaji AM, Loreal O, et al. A new syndrome of liver iron overload with normal transferrin
saturation. Lancet 1997;349:95-97.
[4] Dongiovanni P, Fracanzani AL, Fargion S, et al. Iron in fatty liver and in the metabolic syndrome: a
promising therapeutic target. J Hepatol 2011;55:920-932.
[5] Gabrielsen JS, Gao Y, Simcox JA, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J
Clin Invest 2012;122:3529-3540.
[6] Hansen JB, Moen IW, Mandrup-Poulsen T. Iron: the hard player in diabetes pathophysiology. Acta Physiol
(Oxf) 2014;210:717-732.
[7] Orr JS, Kennedy A, Anderson-Baucum EK, et al. Obesity alters adipose tissue macrophage iron content
and tissue iron distribution. Diabetes 2014;63:421-432.
[8] Ruivard M, Laine F, Ganz T, et al. Iron absorption in dysmetabolic iron overload syndrome is decreased
and correlates with increased plasma hepcidin. J Hepatol 2009;50:1219-1225.
[9] Vecchi C, Montosi G, Garuti C, et al. Gluconeogenic signals regulate iron homeostasis via hepcidin in
mice. Gastroenterology 2014;146:1060-1069.
[10] Guillygomarc’h A, Mendler MH, Moirand R, et al. Venesection therapy of insulin resistance-associated
hepatic iron overload. J Hepatol 2001;35:344-349.
52 Postgraduate Course Syllabus • Metabolic Liver Disease
