Abstract In patients with chronic liver disease, especially nonalcoholic fatty liver disease (NAFLD)   was also found in the three groups of patients. In patients with NAFLD, a decrease of serum insulin on fasting  post phlebotomies, р = 0.005

C Marinova

J Ananiev

L Mateva

M Gulubova

M Penkova

R Ivanova

S Dragneva

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International Journal of Business, Humanities and Technology                                      Vol. 2 No. 6; October 2012 
48 
 
 
Phlebotomy in the Treatment of Iron Overload in Patients with Nonalcoholic and 
Alcoholic Fatty Liver Diseases 
 
 
M. Penkova
1
, S. Dragneva
2
, C. Marinova
2
, R. Ivanova
3
, M. Gulubova
4
, J.  Ananiev 
4
, L. Mateva
2 
 
1
Department of internal diseases, Medical Faculty, Trakia University, Stara Zagora, Bulgaria 
2
Clinic of 
Gastroenterology, St. I. Rilski, University Hospital, Medical University Sofia, Bulgaria , 
3
 Laboratory 
ofClinical Pathology, St. I. Rilski University Hospital,Medical University Sofia, Bulgaria 
4
Department 
of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria 
 
Abstract 
 
In patients with chronic liver disease, especially nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease 
(ALD) and chronic hepatitis C, iron overload is an important factor for the severity and course of disease. The 
clinical benefit of phlebotomy as iron reduction therapy in patients with NAFLD and ALD and iron is not clear 
yet. The aim of our study was to evaluate the effect of phlebotomy in the treatment of patients with NAFLD and 
ALD and iron overload. Material and methods: A total of 60 patients (45 –male, 15-female; age 44.56±7.19 y.) 
with serum markers, pointed iron overload (increased levels of serum iron, ferritin and tranferrin saturation > 
30%) were included: 30 patients with NAFLD – steatosis (NAS, n= 8) иsteatohepatitis (NASH, n= 22) and 30 
patients with ALD – steatosis (AS, n= 10) и alcoholic steatohepatitis (ASH, n= 20) with intakeof alcohol more 
than 40 g /daily. In patients with NAFLD serum insulin level and HOMA-IR were also assessed. Phlebotomies 
were carried out periodically according to the standard protocol for a follow-up period of 12 months. Results: In 
response to phlebotomy, there was a significant decrease (р = 0.001-0.0001) in serum levels of iron, ferritin and 
transferrin saturation in the whole group of patients, and also in the groups of patients with NAFLD and ALD. An 
improvement of liver enzymes – AST, ALT and GGT (р = 0.001-0.0001) was also found in the three groups of 
patients. In patients with NAFLD, a decrease of serum insulin on fasting (basal -18.46 ± 4.32 mIU/L vs11.27 ± 
3.54 mIU/L, post phlebotomies, р = 0.005) and HOMA-IR(4.56 ± 2.54 vs 2.68 ± 1.73)  were also present. In 
conclusion, our results show that phlebotomy is a safe and efficient therapy for the patients with nonalcoholic and 
alcoholic fatty liver disease and iron overload. Regular control of serum iron decrease is essential for the 
determination of phlebotomies’ frequency.  
 
Key words: phlebotomy, iron overload, insulin resistance, nonalcoholic fatty liver disease, alcoholic liver disease 
 
Introduction  
 
Secondary (acquired) iron accumulation in the liver is common in patients with chronic liver disease, especially 
those with alcoholic etiology, non-alcoholic fatty liver disease and chronic hepatitis C (1,4-7). As with primary 
haemochromatosis and haemosiderosis the absorption of iron is increased and the ability of the body to increase 
the excretion is limited. Excess iron leads to cellular damage and directly stimulates fibrogenesis. It is a 
cofactorfor collagen synthesis. Extraction of excess iron from the body through phlebotomy(blood letting) is the 
treatment of choice in patients with primary hemochromatosis. The importance of phlebotomy as a method to 
reduce excess iron accumulated in landfills, and improvement in liver damage in chronic liver disease is still not 
completely clear. 
 
 
The aim of our study was to evaluate the effect of phlebotomy in patients with non-alcoholic steatosis and alcohol 
disease and iron overload. 
 
Material and Methods  
 
The study included 60patients (45 men, 15 women; 44.56 ± 7.19) the serum markers of iron overload (elevated 
serum iron, ferritin and transferrin saturation above30%): 30 patients with primary non-alcoholic fatty liver 
disease (NAFLD) - non-alcoholic steatosis (NAS., n = 8) and non-alcoholic steato hepatitis (NASH, (n = 22) and 
30 patients with alcoholic fatty liver disease (AFLD, n = 10) and alcoholic steatosis hepatitis (ASH, n =20) with 
absolute alcohol intake above 40g /L.  
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49 
 
Diagnosis of liver disease was brought on the basis of standard criteria and was confirmed histologically. 
Addition to standardt tests to assess the syndrome of iron overload studied the following parameters: serum iron 
and serum ferritin. It was estimated and the transferrin saturation. Patients with additional NASD identified serum 
fasting insulin and HOMA-IR computed as a surrogate marker for insulin resistance. 
 
It was performed therapeutic phlebotomy of 500 ml of blood per week 1 time (maximum 2 times a week) to 
achieve a mild anemia (hemoglobin up to 110 g / l and hematocrit less than 0.35). Control of hematology and 
surrogate markers of iron metabolism carried out after losing 1-2 g iron, ie every 4 to 8 weeks for phlebotomy of 
500 ml once a week. To ensure the safety of treatment, follow these rules: do not reduce hemoglobin <110 g / l; 
erythrocytes - <3.8.109 / l; leukocytes - <3.5.109 / l; platelets - <80.109 / l; serum iron - <10 μmol / l for men and 
<9 μmol / l for women, transferrin saturation - <15%, serum albumin <34 g / l; within limits - they scrutinized 
before any bleeding. The patients were followed for 12 months. 
 
Static analysis of the results included ANOVA and t-test for paired differences. 
 
Results 
 
Dynamic changes of serum parameters of iron metabolism in tracking studied patients with NAFLD are presented 
in Table 1. We found a significant reduction(p=0.001-0.0001) in serum iron, transferrin saturation and serum 
ferritinin both the total group of subjects and in different subsets of patients with AFLD and NAFLD. It was 
decreased and the rate of increasing in the liver enzymes - AST, ALT and GGT (p=0.001-0.0001) also in the 
whole group and in subgroups of patients with different NASD and ACE(Table 2). In addition to these changes in 
patients with NAFLD was observed a decrease in serum fasting insulin of 18.46 ± 4.32 mIU / L to 11.27 ± 3.54 
mIU / L (p = 0.005) and HOMA-IR from4.56 ± 2.54 to2.68 ± 1.73,no further significant changes in serum fasting 
glucose. Phlebotomy were tolerated well by patients.No serious adversere actions or hypovolaemic effects. 28 of 
60t reated patients we reported mild fatigue and dizzinessfor one day after the phlebotomy and in3 patients-mild 
headaches resolved in the next 2-3days. 
 
Discussion 
 
The high load of iron in the body is not necessarily cause of adisease and shorten the lives of patients, but in the 
presence of underlying disease, such as non-alcoholic fatty and alcohol disease and chronic hepatitis C can lead to 
further damage to the hepatic parenchyma and promoting the forming of fibrosis.(1,4, 6, 8, 9). 
The most reliable and effective treatment for hemochromatosis and secondary overload and the increased 
deposition of iron blood letting. As a treatment it has been used since ancient times, from the ancient Greek 
physicians. This method can relatively quickly to reduce total body iron. With the phlebotomy of 500ml of blood 
is extracted 250 mg iron If there is no anemia, hypoalbuminaemia and ascites, bloodletting is shown and in 
patients with liver cirrhosis(2). 
 
In our study, we follow standard procedure for the implementation of therapeutic phlebotomy and performing 
phlebotomy of 500 ml of blood 1 to 2 times a week until a mild anemia. Later the bloodlettig can be reduced to 1 
time / month and normally have the value of ferritin - to 4 times / year. This is a maintenance therapy for life (2, 
3). 
 
In one year follow-up o fpatients undergoing periodic blood letting, our results show a good correction of the 
syndrome of iron overload in patients with non-alcoholic fatty liver diease and alcohol disease. Serum iron, 
transferrin saturation and ferritin were decreased.  Similar results were reported by other authors(8,10, 11). In 
addition to these changes also was shown that in both groups of patients, along with the extraction of excess iron 
was reduced the activity of serum enzymes AST, ALT and GGT. And other studies have observed a similar 
improvement in liver enzymes. Our data show that phlebotomy is well tolerated and does not lead to serious side 
reactions. Blood letting is safe and is associated  with transient mild weakness and dizziness. Rarely seen short 
headache. 
 
Crurical observation is that therapeutic phlebotomy reduces insulin and surrogate marker of insulin resistance 
HOMA-IR in patients with non-alcoholic fatty disease. Insulin resistance plays an important pathogenic role for 
steatosis and steatosishepatitis. On the other hand, it is also associated with the development of type 2 diabetes in 
these patients. It is known that non-alcoholic fatty disease is an independent risk factor for its frequent and earlier 
onset (5, 10).  
International Journal of Business, Humanities and Technology                                      Vol. 2 No. 6; October 2012 
50 
 
L Valenti et al. (2007) and other researchers have also observed a reduction in insulin resistance in non-alcoholic 
fatty disease or type 2 diabetes. Correction of insulin resistance has an extra-long good effect in patients with non-
alcoholic fatty disease not only in the liver but also to reduce the risk of type 2 diabetes and early atherosclerosis. 
In conclusion, our results show that phlebotomy is an effective and safe method for the treatment of patients with 
non-alcoholic steatosis and alcoho ldisease and iron overload. By  constantly monitoring the level of reduction of 
iron in the blood can be adjusted the frequency of blood letting. Properly conducted blood letting is safe and well 
tolerated by patients. 
 
References 
 
1. Adjarov, D., D. Petkova, O. Koseva, Iron as pathogenetic factor in chronic HCV-infection Bulgarian 
Hepatogastroenterologiya, 2005, 2, 33-37. 
2.  Diagnostic and therapeutic algorithm (consensus) of idiopathic hemochromatosis. Bulgarian 
hepatogastroenterologiya, XII, 2010, 2, 144-147. 
3.  Aaseth, J., T. Flaten, O. Andersen. Hereditary Iron and Copper Deposition: Diagnostics, 
Pathogenesis, and Therapeutics. Scand, J. Gastroenterol., 42, 2007, 6, 673-681. 
4. Aigner E, Theurl I, Theurl M et al. Pathways underlying iron accumulation in human nonalcoholic 
fatty liver disease. Am J ClinNutr., 87, 2008, 5:1374-83. 
5.  Lecube A, Hernbndez C, R. Simu Glucose abnormalities in non-alcoholic fatty liver disease and 
chronic hepatitis C virus infection: the role of iron overload. Diabetes Metab Res Rev., 25, 2009, 5, 
403-10. 
6.  O'Brien J, Powell LW. Non-alcoholic fatty liver disease: is iron relevant? Hepatology International, 
6, 2012, 1, 332-341. 
7.  Powell, L., V. Subramaniam, T. Yapp. Haemochtomatosis in the New Millenium. J. Hepatol., 32, 
2000, suppl. 1, 48-62. 
8.  Powell, E., A. Ali, A. Clouston et al. Stestosis is a Cofactor of Liver Injury in Hemochromatosis. 
Gastroenterology, 2005, 129, 1937-1943. 
9.  Sumida Y, Yoshikawa T, Okanoue T. Role of hepatic iron in non-alcoholic steatohepatitis. Hepatol 
Res., 39, 2009, 3, 213-22. 
10.  Valenti, L., A. Francanzani, P. Dongiovani et al. Iron Depletion by Phlebotomy Improves Insulin 
Resistance in Patients with Nonalcoholic Fatty Liver Disease and Hyperferritinemia: Evidence from a 
Case Control Study. Am. J. Gastroenterol., 102, 2007, 6, 1251-1258. 
11.  Valenti L, Moscatiello S, Vanni E et al. Venesection for non-alcoholic fatty liver disease 
unresponsive to lifestyle counselling - a propensity score-adjusted observational study. QJM, 104, 
2011, 2, 141-9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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51 
 
 
Table1. Serum parameters of iron metabolism (x ± SD) in different groups of patients before and after 
phlebotomy. 
 
 Serum iron 
 (µmol/l) 
Transferrin saturation(%) Serum ferritin 
(ng /l) 
Basic values After 
phlebotomy 
Basic values After 
phlebotomy 
Basic values After 
phlebotomy 
Common 
group 
27,56 ± 9.28 18,49  ± 2.08   39,22 ± 10.32 26,46 ± 8.57 485,68 ±306.29 244,38 ±128.52 
NASD 
 
23.48± 5.69 19,53  ± 2.14 35,46 ± 8.57 22,52 ± 7.48 458,32 ±329.44 276,56 ±105.74 
ASD 
 
32,24 ± 8.63 22,67  ± 4.28   42,33 ±  8.54 30,26 ± 9.49 528,68 ±234.56 215,34 ±187.32 
 
Table 2. Changes in liver enzyme values(x ± SD) in different groups of patients before and after 
phlebotomy. 
 
 AST (х URV) ALT(х URV) GGT(х URV) 
Basic values After 
phlebotomy 
Basic values After 
phlebotomy 
Basic values After 
phlebotomy 
Common 
group 
2,54 ± 1.98 1,54 ± 0,83 3,06 ± 1,57 1,25 ± 1,04 5.28 ± 4.37 2.56 ± 1.57 
NASD 
 
2,16 ± 1.78 1,20 ± 1,46 3,25 ± 1,69 1,52 ± 1,86 3.68 ± 1.29 2.02 ± 1.40 
ASD 
 
3,46 ± 1.45 1,5 ± 0,78 2,84 ± 1,06 1,44 ± 0,86 8.45 ± 4.24 3.29 ± 1.98 
xURV-upper referent value 
 
 


Phlebotomy in the Treatment of Iron Overload in Patients with Nonalcoholic and Alcoholic Fatty Liver Diseases

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Phlebotomy in the Treatment of Iron Overload in Patients with Nonalcoholic and Alcoholic Fatty Liver Diseases

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