Iron Absorption and Serum Ferritin in Chronic Inflammatory Bowel Disease U. BARTELS, N. STRANDBERG PEDERSEN & S. JARNUM Medical Dept. P, Division of Gastroenterology, and Dept. of Clinical Chemistry CL, Rigshospitalet, and Protein Laboratory, University of Copenhagen, Copenhagen, Denmark
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
Bartels, U., Strandberg Pedersen, N. & Jarnum, S. Iron absorption and serum ferritin in chronic inflammatory bowel disease. Scand. J. Gasfroent. 1978, 13, 649-656. Iron absorptionand serum ferritin concentrationwere studied in 44 patients with chronic intlammatory bowel disease (CIBD) (31 with Crohn’s disease (CD) and 13 with ulcerative colitis (UC)), in 11 control subjects and in 3 patients with simple irondeficiencyanaemia. lion absorption was determined from both whole body counting and red cell ’9Fe incorporation following oral administration of 59FeCI, with a small carrier dose (0.5 mg Fe). Serum fenitin was measured by a two-site immunoradiometric assay. Iron stores were estimated from the amount of stainable iron in sternal marrow. Normal range of iron absorption was 7-86%. In patients with CD and UC no correlation was present between iron absorption and disease activity, site of lesion, intestinal resection (no patient with severe short-bowel syndrome was studied), serum iron, transfenin, albumin or haemoglobin. In contrast, a significant and inverse correlation was found between iron absorption and serum ferritin, and a significantly positive correlation was found between serum ferritin and the iron content of sternal marrow. Following intravenous supply of 1 g iron (as iron-dextran) in 8 patients with CIBD, iron absorption decreased and serum ferritin increased,both on a statistically significant level. It is concluded that : (1) The ability to absorb iron is well preserved in CIBD, even in severe cases. (2) A decreased serum iron concentration does not imply an iron-deficiency state in CIBD. (3) Serum ferritin determination is a sensitiveand little invasive way to assess whether a patient with CIBD is iron-deficient or not. (4)Parenteral supply of iron is in practice superior to oral iron medication in iron-deficientpatients with CIBD. Keywords: Chronic inflammatory disease; Crohn’s disease; ferritin; iron absorption;
ulcerative colitis Stig Jarnum, M.D., Medical Dept. P, Division of Gastroenterology, Rigshospitalef, Blegdamsvej 9, DK-2100 Copenhagen 0,Denmark
In simple iron-deficiency anaemia the iron stores of the body are depleted, and serum ferritin, which reflects the amount of iron stores (12, 16, 21), is low. In chronic inflammatory bowel disease (CIBD) a low serum iron concentration is a common finding. It may simply be due to iron deficiency caused by chronic intestinal bleeding, but quite often a decreased serum iron is associated with normal haemoglobin, low normal or decreased serum transferrin, and a normal ‘saturation index’ of transferrin. The latter type of decreased serum iron is similar to that found in other non-bleeding, chronic, inflammatory conditions like rheumatoid arthritis (2, 3), where no depletion of iron stores occurs.
In the present study we compared serum iron with serum transferrin, serum ferritin, iron stores as estimated from the iron content of bone marrow, and intestinal iron absorption in CIBD. Patients with simple iron-deficiency anaemia due to non-inflammatory gastrointestinal lesions with bleeding and normal subjects served as controls. Furthermore, we studied the effect of parenteral iron therapy on serum ferritin and iron absorption.
CASE MATERIAL Fifty-eight subjects were studied. Informed consent was obtained in every case.
U.Bartels, N . Strandberg Pedersen & S. Jarnum
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
650
Crohns’s disease (CD): 3 1 cases. The diagnosis was established by clinical, laboratory and radiographic findings. In 16 cases the diagnosis was confirmed by the pathoanatomical lesions of resected intestinal specimens at the time of the study, and in 5 patients the diagnosis was later confirmed at operation (Case Nos. 17, 23, 2 5 , 26, 29). Subgrouping was made according to site of lesion in unoperated patients and kind of operation in operated patients and according to disease activity (mild, moderate, severe) (Table I) (1 1). Ulcerative colitis (UC): 13 cases. All fulfilled widely accepted diagnostic criteria ( 1 1). A smallintestinal X-ray series was normal in everyone. The extent of the lesion and the disease activity are listed in Table 11. The type of medical treatment given to patients with CIBD is recorded in Tables I and 11. Seventeen
patients (1 1 with C D , 6 with U C ) received prednisone, and 5 (4 with C D , 1 with UC) received salicylazosulphapyridine. Iron medication was stopped at least 14 days before the study. Simple iron-deficiency anaemia. Three patients with chronic bleeding were studied: one with a bleeding peptic ulcer, one with haemangioma of the small intestine, and one with severe menorrhagia. Control subjecfs. Eleven subjects with normal haemoglobin, serum iron and transferrin, and no gastrointestinal bleeding served as controls.
METHODS Iron absorption. Iron absorption was determined by whole-body counting and by red cell incorporation of 5yFefollowing oral administration of 10 pCi
Table 1. Clinical data in patients with Crohn’s disease (CD)with disease activity of grade I (mild), I1 (moderate)and HI (severe) (1 1) Case No.
Sex/Age
Disease activity
Resection*
Site of lesion *
Treatment?
Serum Ferritin ng/ml
Iron content of sternal
marrow
~
-
2 3
F/5 8 F/45 F/28
C D gr. 1 C D gr. 1 C D gr. 1
None None None
1.c. 1.c. t.i.+ r.c.
SASP P 10mg
8.2 28 140
0 0
4
F/28
C D gr. 1
I.
P 5 mg
5
+
5
MI37
C D gr. 1
t.i.
-
120
+
6
F/25
CDgr. 1
-
P 7.5 mg
220
++
7
€7125
C D gr. 1
-
-
5
0
8
Fl5 9
CDgr. 1
-
-
100
+
9
FI3 6
C D gr. 1
-
SASP
32
+
10
F/34
C D gr. 1
-
-
14
+
11
MI5 5
C D gr. 1
I.C.
-
160
++
12 13
Mi23 F/52
C D gr. 1 C D gr. 1
P 10 mg + Im -
300 26
+++ ++
14 15
MI55 F/22
C D gr. 2 C D gr. 2
i. 10 cm +r.c. i. 15 cm +r.c. i. 20 cm +r.c. i. 40 cm +r.c. i. 5 0 cm +r.c. i. 50 cm +t.c. i. 140 cm +r.c. i. 200 cm + rc. j. i. 50 cm + r.c. None None
-
150
+++
300
+++
1
i.
+ t.c. -
t.c. t.c. + t.i.
0
651
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
Iron Absorption and Serum Ferritin in CIBD Disease activity
Resection *
Case No.
Sex/Age
16
MI26
C D gr. 2
None
17
Fl55
CD gr. 2
None
18
MI30
C D gr. 2
19
Fl33
C D gr. 2
20
MI2 1
C D gr. 2
21 22 23 24 25
MI50 MI3 3 Fl23 F/28 Fl30
C D gr. 2 C D gr. 3 C D gr. 3 C D gr. 3 C D gr. 3
26
MI35
CD gr. 3
Site of lesion *
Treatment7
t.C. + ti. t.c. + t.i.
P 15 mg
75
-
P 15mg
10
+
P 7.5 mg + SASP -
10
0
11
0
I.C. i. 10 cm. + r.c. r. i. 35 cm + r.c. Duodenum t.c. + 10 cm duodenum j. 160cm j. r.c. None t.c. None t.c. None t.i. + None t.C. t.i. ++ None
Serum Ferritin nglml
Iron content of sternal marrow
-
3600
-
-
19 280 150 10 104
0
-
10
0
-
180
-
5
0
P 10mg + SASP P 80 mg -
92
-
5 -
-
P 6 0 mg P 15mg -
++ +++
-
t.C.
27
MI28
C D gr. 3
None
28
MI40
CD gr. 3
None
29
MI18
C D gr. 3
None
30 31
MI3 1 Fl30
CD gr. 3 CD gr. 3
t.c. i. 30 cm + r.c.
t.i. + t.c. t.i. ++ t.c. t.i. + r.c. j.
j
++
0 -
5 = ileum; r.c. = right half of colon; 1.c. = left half of colon; t.c. = total colon; ti. = terminal ileum; j =jejunum; s = sigmoid; r = rectum. tSASP = salicylazosulphapyridine; P = prednisone; Im = Imurel@ (azathioprine).
5YFeCI,to the overnight fasting patient, who was allowed to eat 2 h later. Only 0.5 mg Fe (as FeSO,) was used as carrier (9, 15). Net counting rate of the whole-body counter 1 h after the administration was set as the ‘100% value’. The average of the whole-body counting rate 1 1 and 14 days later was, after correction for physical decay of 5yFe,used as a measure of iron absorption (the counting rate as percentage of the 100% value). Red cell incorporation, as an indirect measure of absorption, was determined from the amount of 5yFe present in the red cell mass 14 days after 5YFe administration, which was expressed as percentage of 5yFegiven. Red cell mass was calculated indirectly from plasma volume determined with Evans blue ( 17) and a body haemotocrit taken as venous haematocrit multiplied by 0.9 1 (1 3 ) .
Bone marrow iron. The amount of stainable iron in aspirated sternal marrow was determined semiquantitatively ( 19) after staining with Prussian blue. All marrow smears were examined blindly by the same observer (U.B.). Serum ferritin. The serum ferritin values were measured by a two-site immunoradiometric assay, using antibody-coupled paper discs as a solid phase. The method is based on principles described by Ceska & Lundkvist (4),and the present modification for serum ferritin determination is described in detail elsewhere (1 8). The normal value for men is
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
Bartels, U., Strandberg Pedersen, N. & Jarnum, S. Iron absorption and serum ferritin in chronic inflammatory bowel disease. Scand. J. Gasfroent. 1978, 13, 649-656. Iron absorptionand serum ferritin concentrationwere studied in 44 patients with chronic intlammatory bowel disease (CIBD) (31 with Crohn’s disease (CD) and 13 with ulcerative colitis (UC)), in 11 control subjects and in 3 patients with simple irondeficiencyanaemia. lion absorption was determined from both whole body counting and red cell ’9Fe incorporation following oral administration of 59FeCI, with a small carrier dose (0.5 mg Fe). Serum fenitin was measured by a two-site immunoradiometric assay. Iron stores were estimated from the amount of stainable iron in sternal marrow. Normal range of iron absorption was 7-86%. In patients with CD and UC no correlation was present between iron absorption and disease activity, site of lesion, intestinal resection (no patient with severe short-bowel syndrome was studied), serum iron, transfenin, albumin or haemoglobin. In contrast, a significant and inverse correlation was found between iron absorption and serum ferritin, and a significantly positive correlation was found between serum ferritin and the iron content of sternal marrow. Following intravenous supply of 1 g iron (as iron-dextran) in 8 patients with CIBD, iron absorption decreased and serum ferritin increased,both on a statistically significant level. It is concluded that : (1) The ability to absorb iron is well preserved in CIBD, even in severe cases. (2) A decreased serum iron concentration does not imply an iron-deficiency state in CIBD. (3) Serum ferritin determination is a sensitiveand little invasive way to assess whether a patient with CIBD is iron-deficient or not. (4)Parenteral supply of iron is in practice superior to oral iron medication in iron-deficientpatients with CIBD. Keywords: Chronic inflammatory disease; Crohn’s disease; ferritin; iron absorption;
ulcerative colitis Stig Jarnum, M.D., Medical Dept. P, Division of Gastroenterology, Rigshospitalef, Blegdamsvej 9, DK-2100 Copenhagen 0,Denmark
In simple iron-deficiency anaemia the iron stores of the body are depleted, and serum ferritin, which reflects the amount of iron stores (12, 16, 21), is low. In chronic inflammatory bowel disease (CIBD) a low serum iron concentration is a common finding. It may simply be due to iron deficiency caused by chronic intestinal bleeding, but quite often a decreased serum iron is associated with normal haemoglobin, low normal or decreased serum transferrin, and a normal ‘saturation index’ of transferrin. The latter type of decreased serum iron is similar to that found in other non-bleeding, chronic, inflammatory conditions like rheumatoid arthritis (2, 3), where no depletion of iron stores occurs.
In the present study we compared serum iron with serum transferrin, serum ferritin, iron stores as estimated from the iron content of bone marrow, and intestinal iron absorption in CIBD. Patients with simple iron-deficiency anaemia due to non-inflammatory gastrointestinal lesions with bleeding and normal subjects served as controls. Furthermore, we studied the effect of parenteral iron therapy on serum ferritin and iron absorption.
CASE MATERIAL Fifty-eight subjects were studied. Informed consent was obtained in every case.
U.Bartels, N . Strandberg Pedersen & S. Jarnum
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
650
Crohns’s disease (CD): 3 1 cases. The diagnosis was established by clinical, laboratory and radiographic findings. In 16 cases the diagnosis was confirmed by the pathoanatomical lesions of resected intestinal specimens at the time of the study, and in 5 patients the diagnosis was later confirmed at operation (Case Nos. 17, 23, 2 5 , 26, 29). Subgrouping was made according to site of lesion in unoperated patients and kind of operation in operated patients and according to disease activity (mild, moderate, severe) (Table I) (1 1). Ulcerative colitis (UC): 13 cases. All fulfilled widely accepted diagnostic criteria ( 1 1). A smallintestinal X-ray series was normal in everyone. The extent of the lesion and the disease activity are listed in Table 11. The type of medical treatment given to patients with CIBD is recorded in Tables I and 11. Seventeen
patients (1 1 with C D , 6 with U C ) received prednisone, and 5 (4 with C D , 1 with UC) received salicylazosulphapyridine. Iron medication was stopped at least 14 days before the study. Simple iron-deficiency anaemia. Three patients with chronic bleeding were studied: one with a bleeding peptic ulcer, one with haemangioma of the small intestine, and one with severe menorrhagia. Control subjecfs. Eleven subjects with normal haemoglobin, serum iron and transferrin, and no gastrointestinal bleeding served as controls.
METHODS Iron absorption. Iron absorption was determined by whole-body counting and by red cell incorporation of 5yFefollowing oral administration of 10 pCi
Table 1. Clinical data in patients with Crohn’s disease (CD)with disease activity of grade I (mild), I1 (moderate)and HI (severe) (1 1) Case No.
Sex/Age
Disease activity
Resection*
Site of lesion *
Treatment?
Serum Ferritin ng/ml
Iron content of sternal
marrow
~
-
2 3
F/5 8 F/45 F/28
C D gr. 1 C D gr. 1 C D gr. 1
None None None
1.c. 1.c. t.i.+ r.c.
SASP P 10mg
8.2 28 140
0 0
4
F/28
C D gr. 1
I.
P 5 mg
5
+
5
MI37
C D gr. 1
t.i.
-
120
+
6
F/25
CDgr. 1
-
P 7.5 mg
220
++
7
€7125
C D gr. 1
-
-
5
0
8
Fl5 9
CDgr. 1
-
-
100
+
9
FI3 6
C D gr. 1
-
SASP
32
+
10
F/34
C D gr. 1
-
-
14
+
11
MI5 5
C D gr. 1
I.C.
-
160
++
12 13
Mi23 F/52
C D gr. 1 C D gr. 1
P 10 mg + Im -
300 26
+++ ++
14 15
MI55 F/22
C D gr. 2 C D gr. 2
i. 10 cm +r.c. i. 15 cm +r.c. i. 20 cm +r.c. i. 40 cm +r.c. i. 5 0 cm +r.c. i. 50 cm +t.c. i. 140 cm +r.c. i. 200 cm + rc. j. i. 50 cm + r.c. None None
-
150
+++
300
+++
1
i.
+ t.c. -
t.c. t.c. + t.i.
0
651
Scand J Gastroenterol Downloaded from informahealthcare.com by Freie Universitaet Berlin on 10/16/14 For personal use only.
Iron Absorption and Serum Ferritin in CIBD Disease activity
Resection *
Case No.
Sex/Age
16
MI26
C D gr. 2
None
17
Fl55
CD gr. 2
None
18
MI30
C D gr. 2
19
Fl33
C D gr. 2
20
MI2 1
C D gr. 2
21 22 23 24 25
MI50 MI3 3 Fl23 F/28 Fl30
C D gr. 2 C D gr. 3 C D gr. 3 C D gr. 3 C D gr. 3
26
MI35
CD gr. 3
Site of lesion *
Treatment7
t.C. + ti. t.c. + t.i.
P 15 mg
75
-
P 15mg
10
+
P 7.5 mg + SASP -
10
0
11
0
I.C. i. 10 cm. + r.c. r. i. 35 cm + r.c. Duodenum t.c. + 10 cm duodenum j. 160cm j. r.c. None t.c. None t.c. None t.i. + None t.C. t.i. ++ None
Serum Ferritin nglml
Iron content of sternal marrow
-
3600
-
-
19 280 150 10 104
0
-
10
0
-
180
-
5
0
P 10mg + SASP P 80 mg -
92
-
5 -
-
P 6 0 mg P 15mg -
++ +++
-
t.C.
27
MI28
C D gr. 3
None
28
MI40
CD gr. 3
None
29
MI18
C D gr. 3
None
30 31
MI3 1 Fl30
CD gr. 3 CD gr. 3
t.c. i. 30 cm + r.c.
t.i. + t.c. t.i. ++ t.c. t.i. + r.c. j.
j
++
0 -
5 = ileum; r.c. = right half of colon; 1.c. = left half of colon; t.c. = total colon; ti. = terminal ileum; j =jejunum; s = sigmoid; r = rectum. tSASP = salicylazosulphapyridine; P = prednisone; Im = Imurel@ (azathioprine).
5YFeCI,to the overnight fasting patient, who was allowed to eat 2 h later. Only 0.5 mg Fe (as FeSO,) was used as carrier (9, 15). Net counting rate of the whole-body counter 1 h after the administration was set as the ‘100% value’. The average of the whole-body counting rate 1 1 and 14 days later was, after correction for physical decay of 5yFe,used as a measure of iron absorption (the counting rate as percentage of the 100% value). Red cell incorporation, as an indirect measure of absorption, was determined from the amount of 5yFe present in the red cell mass 14 days after 5YFe administration, which was expressed as percentage of 5yFegiven. Red cell mass was calculated indirectly from plasma volume determined with Evans blue ( 17) and a body haemotocrit taken as venous haematocrit multiplied by 0.9 1 (1 3 ) .
Bone marrow iron. The amount of stainable iron in aspirated sternal marrow was determined semiquantitatively ( 19) after staining with Prussian blue. All marrow smears were examined blindly by the same observer (U.B.). Serum ferritin. The serum ferritin values were measured by a two-site immunoradiometric assay, using antibody-coupled paper discs as a solid phase. The method is based on principles described by Ceska & Lundkvist (4),and the present modification for serum ferritin determination is described in detail elsewhere (1 8). The normal value for men is
