Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study.
OBJECTIVE
Hyperferritinemia is frequently observed in nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome characterized by hepatic insulin resistance and considered high cardiovascular risk. Iron depletion by phlebotomy has been reported to decrease insulin resistance in NAFLD in small, uncontrolled studies. Aims of this study were to define the relationship between ferritin and iron stores in patients with NAFLD, the effect of iron depletion on insulin resistance, and whether basal ferritin levels influence treatment outcome.


METHODS
Subjects were included if ferritin and/or ALT were persistently elevated after 4 months of standard therapy. Sixty-four phlebotomized subjects were matched 1:1 for age, sex, ferritin, obesity, and ALT levels with patients who underwent lifestyle modifications only. Insulin resistance was evaluated by insulin levels, determined by RIA and the HOMA-R index, at baseline and after 8 months.


RESULTS
Baseline ferritin levels were associated with body iron stores (P<0.0001). Iron depletion produced a significantly larger decrease in insulin resistance (P=0.0016 for insulin, P=0.0042 for HOMA-R) compared with nutritional counseling alone, independent of changes in BMI, baseline HOMA-R, and the presence of the metabolic syndrome. Iron depletion was more effective in reducing HOMA-R in patients in the top two tertiles of ferritin concentrations (P<0.05 vs controls), and in carriers of the mutations in the HFE gene of hereditary hemochromatosis (P<0.05 vs noncarriers).


CONCLUSIONS
Given that phlebotomy reduces insulin resistance, which is associated with liver tissue damage, future studies should evaluate the effect of iron depletion on liver histology and cardiovascular end points.
Valenti
Luca
L
Department of Internal Medicine, Universita' di Milano, Ospedale Policlinico Mangiagalli Regina Elena IRCCS, Milano, Italy.
Fracanzani
Anna Ludovica
AL
Dongiovanni
Paola
P
Bugianesi
Elisabetta
E
Marchesini
Giulio
G
Manzini
Paola
P
Vanni
Ester
E
Fargion
Silvia
S
D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D016022:Case-Control Studies; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005293:Ferritins / Q000097:blood* / Q000378:metabolism; D006432:Hemochromatosis / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance; D007501:Iron / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018962:Phlebotomy
D001786:Blood Glucose; D005293:Ferritins; D007501:Iron