Treatment of iron overload in adults with continuous parenteral desferrioxamine

Treatment of Iron Overload in Adults with Continuous

Parenteral Desferrioxamine

BARRY COOPER, M.D.

H. FRANKLIN BUNN, MD.

RICHARD D. PROPPER, M.D.

DAVID G. NATHAN, M.D.

DAVID S. ROSENTHAL, M.D.

WILLIAM C. MOLONEY, M.D.

Boston, Massachusetts

From the Division of Hematology, Peter Bent Brigham Hospital, and Division of Hematology and Oncology, Children’s Hospital Medical Center, and the Departments of Medicine and Pediatrics, Harvard Medical School, Boston, Massachusetts. This work was supported by N.I.H. Grant No. RR00888 to the Clinical Center, Peter Bent Brig- ham Hospital. Requests for reprints should be addressed to Dr. H. Franklin Bunn, Hematology Research Laboratory, Peter Bent Brigham Hos- pital, 721 Huntington Avenue, Boston, Massa- chusetts 02115. Manuscript accepted March 30, 1977.

Adult patients with transfusional hemosiderosis were given ascorbic acid and treated with the iron chelator, desferrioxamine B. The drug was administered by continuous subcutaneous or intravenous infusions using a light weight portable constant infusion device. On this regimen, four of the five patients studied were able to excrete significant amounts of iron (>35 mg/day) when receiving a daily desferrioxamine dose of 1.5 to 2.2 g. Continuous subcutaneous infusion was well tolerated and about 80 per cent as effective as intravenous therapy in chelating iron. The number of prior transfusions, the hepatic iron content and the serum ferritin levels appear to be useful in predicting which patients will respond to iron chelation therapy, especially if there is little bone marrow erythropoietic activity. One patient with ineffective erythropoiesis did not have significantly increased hepatic iron stores but responded to the administration of desferrioxamine. Continuous subcutaneously administered desferrioxamine may prove to be adaptable for long-term outpatient therapy, allowing patients with ongoing transfusion re- quirements to go into negative iron balance. Long-term studies will be needed to demonstrate reversal of endocrine, hepatic and cardiac dysfunction secondary to iron deposition in these patients.

Iron overload becomes a clinical problem in patients with severe anemia who survive long enough to accumulate toxic quantities of iron from transfused blood (transfusional hemosiderosis). In patients with pure red cell aplasia, aplastic anemia, myeloid metaplasia, various chronic refractory anemias and thalassemia from 40 to 50 g iron may be accumulated from transfusions, resulting in a variety of clinical problems. Endocrine abnormalities include diabetes mellitus, hyperpigmentation, adrenal insufficiency, hypopituitarism, hypogonadism with testicular atrophy and hypoparathyroidism [l-3]. Hepatic dysfunction arises from iron deposition in reticuloendothelial and parenchymal cells resulting in hepatomegaly and cirrhosis [4,5]. Perhaps the greatest cause of morbidity from iron overload is congestive heart failure and arrhythmias secondary to myocardial deposits. This problem may account for a significant amount of the mortality thought to be associated with high output failure seen in patients with chronic anemias. The prototype siderotic state for this pathology occurs in children with homozygous beta thalassemia who are maintained on hypertransfusion programs. These patients generally die of heart failure in their second decade [6,7].

958 December 1877 The American Journal of Medicine Volume 63

IRON OVERLOAD

Although patients with idiopathic hemochromatosis can be treated by phlebotomy [8,9], chelation therapy remains the only available approach for the removal of iron in anemic patients given transfusions. The most widely studied iron chelator is the hydroxamic acid compound, desferrioxamine 6, which was first intro- duced in 1960 [lo]. This drug has a very high affinity for trivalent iron (KAss = 103’) forming the soluble compound ferrioxamine. The majority of chelated iron is excreted in the urine, but a significant amount has also been found in the stool [ 1 l]. Early studies with intermittent intramuscular administration of desferrioxamine in patients appeared promising [ 121 but, in general, investigators have been unable to demonstrate the excretion of enough iron to achieve negative iron balance [ 13- 151. Ascorbic acid loading increased about twofold the amount of iron excreted during therapy with desferrioxamine [ 13,161, probably because this reducing agent increases the dissociable pool of ferrous ions on the surface of ferritin [ 17,181. This pool can then be reoxidized and made available for chelation. However, even patients treated with ascorbic acid have not had uniformly good responses to desferrioxamine when administered intramuscularly. Part of the poor response is undoubtedly related to the rapid urinary excretion of desferrioxamine.

Propper et al. [19] have shown, in children with thalassemia major, that good iron mobilization requires sustained exposure of the labile iron pool to the drug. In this paper we describe the use of continuous subcutaneous and/or intravenous desferrioxamine therapy in a group of adult patients with transfusional hemosiderosis. We found that significant quantities of iron can be excreted in the urine in adults with this approach and that continuous subcutaneous administration was almost as effective as the intravenous route. In addition, we present laboratory and clinical information that is helpful in predicting which patients will respond to the drug.

MATERIALS AND METHODS

Five patients with transfusional iron overload were selected to receive continuous subcutaneous and/or intravenous administration of desferrioxamine at doses varying from 0.75 to 2.25 g/day. All patients gave informed consent and were admitted to The Clinical Center at the Peter Bent Brigham Hospital for these studies. Patients received ascorbic acid (500 mg orally daily) for at least one week prior to hospitali- zation, except for preliminary studies on one patient (Case 4). Estimation of iron overload was made from transfusion history, serum iron determinations, liver biopsies with quantitative iron analysis, bone marrow stains for iron, and serum ferritin levels. In addition, liver function studies, an oral glucose tolerance test, chest roentgenogram, electrocardiogram, noninvasive left ventricular function studies,’ indium bone scans and ferrokinetic studies were carried out rou-

ASSOCIATED WITH DESFERRIOXAMINE THERAPY-GOOPER ET AL.

tinely. Liver biopsies were performed by Dr. Thomas Lamont. Iron stores of the bone marrow were qualitatively estimated by the Prussion blue reaction. Serum ferritin levels were kindly determined by Dr. David Drum by radioimmunoassay [20]. Iron analysis of urine, stool and liver biopsy specimens was performed with a Perkin-Elmer atomic absorption pho- tometer. Ferrokinetic studies were performed by Mr. Larry Button of the Children’s Hospital Medical Center.

Continuous subcutaneous and intravenous infusion of desferrioxamine was accomplished with a light weight portable constant infusion pump (Auto-Syringe, Inc., Farm- ingdale, N.Y.) connected to a 25 gauge butterfly infusion set (Abbott). Patients conveniently wore the infusion pump on a belt, and a needle was inserted subcutaneously into abdominal tissue or intravenously through an arm vein. With this pump, no more than 5 ml of volume was needed over a 24 hour period to administer doses up to 2.2 g.

CASE REPORTS

Case 1. A 42 year old businessman was diagnosed as having pure red cell aplasia in June 1972. He had no known exposure to industrial solvents or toxins, and his only exposure to drugs was a brief course of sulfonamide therapy for prostatitis three months prior to the onset of his illness. To- mograms of the mediastinum did not reveal a thymoma. Evaluation of his serum for antierythroblast antibodies (Dr. Sanford Krantz, Nashville, Tennessee) gave equivocal results on two occasions. Ferrokinetic studies at the Massachusetts General Hospital indicated decreased plasma iron clearance with a half life (T l/2) of 10 hours (normal ‘T l/2 = 60 to 90 minutes). The patient was given trials of immunosuppressive therapy with cyclophosphamide, azathioprine and prednisone without a response. He showed no improvement with an- drogen therapy or following a splenectomy in May 1973. He was maintained on a transfusion program of approximately 4 U a month for four years (>210 U) which was generally well tolerated. In 1975, symptomatic diabetes mellitus developed for which he required insulin therapy. He has been receiving methyltestosterone since May 1975 for impotence and testicular atrophy.

He was admitted to The Clinical Center of the Peter Bent Brigham Hospital on August 4, 1976, for a trial of desferrioxamine after three weeks of ascorbate loading. Physical examination at that time revealed skin hyperpigmentation and pallor. Mild gynecomastia was present. Abdominal examination revealed an enlarged liver palpable 3 cm below the right costal margin. Testes were descended and soft. Labo- ratory data included a hematocrit value of 22 per cent, reticulocyte count of 0.6 per cent, white blood cell count of 8,400/mm3 with a normal differential, platelet count of 480,000/mm3, alkaline phosphatase of 120 IU. serum glutamic oxaloacetic transaminase (SGOT) of 106 IU, serum glutamic pyruvate transaminase (SGPT) of 225 IU, bilirubin of 0.6 mg/dl and a fully saturated serum iron of 250 pg/lOO

* Cardiac studies included echocardiographic left ventricular volume measurements, estimation of cardiac output (index:, ejection fraction and systolic time intervals. Diastolic function was evaluated by echocardiographic mitral valve motion and by apex cardiogra-

phy.

December 1977 The American Journal of Medicine Volume 63 959

IRON OVERLOAD ASSOCIATED WITH DESFERRIOXAMINE THERAPY-COOPER ET AL.

Figure 1. Case 1. Liver biopsy specimen showing prominent iron deposition in Kupffer cells, ( =j ) hepatocytes, ( + ), and bile duct epithelium. A cirrhotic pattern was not evident although some portal fibrosis was noted. Prussian blue stain, magnification X 400, reduced by 50 per cent.

ml. A chest roentgenogram showed a slightly prominent left ventricle, and an electrocardiogram met borderline criteria for left ventricular hypertrophy. Studies of left ventricular function disclosed a slightly decreased ejection fraction. On bone marrow examination there was normal myeloid matu- ration and megakaryocytes but almost absent erythroid percursors. Marrow iron stores were markedly increased. lndium bone marrow scan demonstrated essentially no radioactivity within the axial skeleton and extremities com- patible with absent marrow erythroid activity [2 1,221. Liver biopsy (Figure 1) revealed prominent iron deposition in Kupffer and parenchymal cells without cirrhosis. Quantitative iron analysis was 25.6 mg iron/g weight liver (normal = 1.88 f 0.15 mg iron/g liver). The patient was given increasing doses of desferrioxamine either by continuous subcutaneous or intravenous infusion as noted in Figure 2. Urinary iron excretion increased linearly, approaching a plateau at a daily desferrioxamine dose of 1.5 g. Urinary iron output during continuous subcutaneous therapy was about 80 per cent of the iron excretion noted with continuous intravenous administration. The average urinary creatinine excretion was 1.6 g/day, resulting in an average daily urinary iron output of 34 mg. Analysis of iron content in stool indicated an increase of 20 to 25 mg/day during administration of the drug. Thus, total excretion of chelated iron was 55 to 60 mg/day.

Case 2. A 61 year old woman of Mediterranean descent had a life-long history of anemia for which she required many transfusions (>200 U); she was diagnosed as having beta thalassemia intermedia at the Peter Bent Brigham Hospital in 1952. A splenectomy in 1960 failed to lessen her anemia. She noted bronzing of her skin after the age of 50 years. She began to have symptomatic congestive heart failure in 1974 for which she required therapy with digitalis and diuretics. She had multiple admissions at a local hospital in 1975 because of pulmonary edema with persistent chronic exertional dyspnea and 3-pillow orthopnea during medical therapy. She was admitted to The Clinical Center at the Peter Bent Brigham

Hospital in April 1976. Physical examination revealed a thin, deeply pigmented woman with a blood pressure of 110780 mm Hg and a respiratory rate of 18/min. Cardiac examination revealed a prominent left ventricular impulse in the sixth in- tercostal space at the anterior axillary line. Ventricular (Ss) and atrial (S4) gallops were present with a grade 316 holo- systolic murmur radiating to the apex. Her liver was firm and palpable 6 cm below the right costal margin. There was no peripheral edema. Laboratory data on admission included a hematocrit value of 29 per cent, a mean corpuscular volume of 76 p3, a reticulocyte count of 4.8 per cent and a white blood cell count of 10,400/mm3 with a normal differential. There were 75 nucleated red blood cells/100 white blood cells with many Howell Jolly bodies and strippled red cells on her blood smear. Alkaline phosphatase was 237 IU, SGPT 100 IU, SGOT 112 IU, creatinine 0.9 mg/dl, uric acid 6.4 mg/dl and serum iron 243 pg/ 100 ml with a total iron-binding capacity of 230 pg/lOO ml. The oral glucose tolerance test result was abnormal and indicated chemical diabetes mellitus. A chest roentgenogram demonstrated cardiomegaly, and an electrocardiogram indicated intermittent atrial fibrillation with many multifocal premature ventricular contractions. Hemo-

o---c Intravenous r---- -- -0 / .

.

.

I I

0.75 1.5

Desferrioxamine [g 124 hr)

J 2.25

1

____ jgure 2.

_ Case 1. Dose response curve for urinary rroJn

excretion during administration of continuous intravenous (0 - - - - 0) or subcutaneous (0 - 0) desferrioxamine. Urinary iron excretion was initially linear and approaches a plateau at 1.5 g/day desferrioxamine.


globin electrophoresis showed decreased hemoglobin A (85 per cent) with increased hemoglobin A2 (5.1 per cent) and fetal hemoglobin (5.6 per cent). This pattern was affected by the presence of transfused red cells. Impaired incorporation of tritiated (3H)-leucine into beta chains confirmed the diagnosis of beta thalassemia. Bone marrow aspiration revealed marked iron deposition and erythroid hyperplasia. Liver biopsy (Figure 3) disclosed marked hemosiderosis with cirrhosis, moderate portal inflammation and bile duct proliferation. Quantitative iron analysis indicated a 20-fold increase in hepatic iron content (35.7 mg iron/g wet weight liver). Be- cause of refractory heart failure with arrhythmias and evidence of considerable iron overload, the patient was given ascorbic acid, and desferrioxamine therapy was started. These data are summarized in Table I. Following a single intramuscular injection of 750 mg of desferrioxamine for eight days, she excreted 21.7 f 3.3 mg/day of iron in her urine. When this same dose was given by continuous subcutaneous infusion, she excreted 29.4 mg and 37.1 mg/day of iron in her urine on two separate occasions. With 1.5 g/day of desferrioxamine, her urinary iron excretion increased from


TABLE I Effect of Desferrioxamine on Urinary Iron Excretion in 61 Year Old Patient with Thalassemia Intermedia ---.-__-

Daily Desterrioxamine

Dose Urinary Iron Excretion

(9) Route 01 Administration (mg124 hour) -__~--

0.75 Intramuscular 21.7 zt 3.3’ 1.50 Intramuscular+ 44 0.75 Subcutaneously by 331

continuous infusion 1.50 Intravenously by 64%

continuous infusion

* Standard error of the mean for n = 8 days. + Two daily doses of 0.75 g. f Average excretion for two days.

44 mg/day when given intramuscularly on a twice daily

schedule to 64 mglday when the drug was given by continuous infusion. No analysis of iron in the stool could be reliably obtained. She was maintained with 1.5 g desferrioxamine daily by continuous infusion for two months without complications and with good urinary iron excretion (>65 mg/day), but she died of refractory heart failure on August 31, 1976.

Figure 3. Case 2. A, liver biopsy specimen showing cirrhosis with mild periporfal inflammation and marked bile ductular proliferation. Hematoxylin and eosin stain, magnification x 40, reduced by 50 per cent. 6, liver biopsy specimen showing marked diffuse hemosiderosis. ffematoxylin and eosin stain, magnification x 400, reduced by 50 per cent.

Case 3. In this 60 year old civil engineer from Columbia, S.A., exertional dyspnea developed and a 12 pound weight loss occurred in January 1973. Blood studies revealed pan- cytopenia with a hemoglobin level of 8.4 gldl, a white blood cell count of 2,500/mm3 with 37 per cent polymorphonuclear cells, 4 per cent band forms, 41 per cent lymphocytes, 11 per cent monocytes and a platelet count of 54,000/mm.3 Bone marrow biopsy disclosed hypocellularity, and he was treated with androgens for aplastic anemia with little response. A repeat bone marrow biopsy in April 1974 revealed marked fibrosis. He received 110 U of blood between June 1973 and August 1976; increased skin pigmentation was noted but no endocrine or cardiac symptoms. He was admitted to The Clinical Center of the Peter Bent Brigham Hospital on August 30, 1976. Physical examination revealed skin hyperpigmentation and moderate pallor. There was a grade 216 systolic ejection murmur at the cardiac apex. Neither adenopathy nor palpable hepatosplenomegaly was present. Laboratory studies included a hematocrit value of 26 per cent, a hemoglobin level of 8.4 gldl, a reticulocyte count of 0.4 per cent, a platelet count of 21,000/mm3 and a white blood cell count of 2,500/mm3 (50 per cent polymorphonuclear cells, 8 per cent eosinophils, 32 per cent lymphocytes, 8 per cent monocytes and 1 per cent basophils). Blood smear demonstrated tear drops, schistocytes and marked poikilocytosis of red cells. Bone marrow biopsy disclosed fibrosis and some areas of increased cellularity containing atypical megakaryocytes and immature myeloid forms consistent with a myeloproliferative disorder. Etythroid elements were decreased, and iron was abundant. Liver function studies included an alkaline phosphatase of 72 IU, SGOT of 35 IU, SGPT of 58 IU and a bilirubin of 0.4 mg/dl. An oral glucose tolerance test result was normal. A chest



1

LIVER

I- SPLEEN

Li!ig!g MIZJTES ONi

TIME

igure 4. Case 3. Organ scanning after administration t ‘Fe, showing marked hepatic uptake of label with little sacral

activity.

roentgenogram showed a slightly enlarged cardiac silhouette, and studies of left ventricular function were within normal limits. Serum iron was 241 pug/100 ml with a total iron-binding capacity of 258 pg/lOO ml. Ferrokinetic studies demonstrated a prolonged plasma iron clearance of 167 minutes (normal = 60 to 90 minutes) with a slight increase in plasma iron turnover of 0.78 mg/kg/day (normal = 0.42 mg/kg/day). Figure 4 shows the pattern of organ scanning after the administration of radioactive iron (5gFe). Almost all of the isotope was rapidly taken up by the liver with considerably less splenic and bone marrow uptake. lndium bone marrow scan showed minimal radioactivity in the central axial skeleton. Urinary iron excretion with continuous desferrioxamine therapy is shown in Figure 5. Iron excretion approached a plateau at a dose of 1.5 g/day of desferrioxamine, and there was little difference between continuous intravenous and subcutaneous administration. His average 24 hour urinary creatinine was 1.5 g with a total urinary iron excretion of 42 mg/day with maximal doses of desferrioxamine. His stool iron output was increased approximately 10 mg/day for a total excretion of 50 to 55 mg iron/day.

Case 4. A 67 year old lawyer was well until 1969 when a physician noted anemia and splenomegaly. In July 1973, a bone marrow biopsy specimen revealed myelofibrosis, and he was given a trial of androgens without response. Because of recurrent angina and exertional dyspnea he was given an intermittent transfusion regimen, receiving 62 units of blood

prior to May 1976. At that time he was admitted to The Clin- ical Center of the Peter Bent Brigham Hospital. On physical examination he had a blood pressure of 140170 mm Hg and a regular pulse rate of 80/min. There was moderate pallor without hyperpigmentation. Upon examination of his heart, a grade 3/6 systolic ejection murmur was heard throughout the precordium with radiation to the base. Carotid pulses were full and without a delayed upstroke. There was no adenopathy. Liver was firm and palpable 5 cm below the right costal margin. Spleen tip was palpable 7 cm below the left costal margin. There was no peripheral edema. Laboratory data included a hemoglobin level of 6.2 g/dl, a hematocrit value of 19.3 per cent, a white blood cell count of 6,900/mm3 with 54 per cent polymorphonuclear cells, 2 per cent band forms, 2 per cent eosinophils, 25 per cent lymphocytes, 7 per cent monocytes, 1 per cent meylocytes and 9 per cent blast forms. Reticulocyte count was 3.8 per cent, platelet count 355,000/mm3, serum alkaline phosphatase 129 IU, SGOT 25 IU, bilirubin 0.7 mg/dl and serum iron 252 pg/lOO ml with a total iron-binding capacity of 243 kg/ 100 ml. Chest roentgenogram showed cardiomegaly, and the electrocardiogram met criteria for left ventricular hypertrophy with anterolateral T-wave inversions suggestive of ischemia. A cardiology consultant was of the opinion that the patient had coronary artery disease exacerbated by anemia without evidence of

3 .P 30 -

z

d

8

a? N

0.75 1.5 2.25

Desferrioxamine (g/24 hr)

fgure 5. Case 3. Dose response curve for urinary iron excretion during administration of continuous intravenous (0 - - - - 0) or subcutaneous (0 - 0) desferrioxamine. Urinary iron excretion was initially linear and approaches a plateau at 1.5 g/day desferrioxamine.


aortic stenosis. Bone marrow biopsy revealed extensive marrow fibrosis with few hematopoietic elements, including dysplastic megakaryocytes, and myeloid and erythroid forms at varying stages of maturity. Iron stores were increased. Bone marrow scan revealed increased activity over peripheral joints and pelvis. Ferrokinetics disclosed a delayed plasma iron clearance of 142 minutes; plasma iron turnover was slightly increased at 0.99 mg/kg/day and red cell utilization of iron was only 33 per cent at 8 days (normal = 90 per cent). Organ scanning after the administration of 5gFe revealed primarily isotope uptake in the liver and spleen with very little activity over the sacrum. Corrected red cell survival using chromium labelled red cells was 39 days (normal = 110 to 125 days). Labelled red cells were markedly sequestered in the spleen suggesting that splenectomy would probably diminish anemia by prolonging red ceil survival. The patient was given a trial of desferrioxamine at a dose of 750 mg/day by continuous intravenous infusion without ascorbate loading

TABLE II Effect of Desferrioxamine on Urinary Iron Excretion in 67 Year Old Patient with Mveloid Metaolasia

Urinary Iron Excretion When Studied (mg04 hour) _ I__-

Presplenectomy 5.1 6.4

Postsplenectomy 1.8 3.6

NOTE: Desferrioxamine dose was 0.75 g administered by continuous intravenous infusion without prior ascorbate loading


Figure 7. Case 5. Electron micrograph of marrow nor- moblast showing accumulation of iron in mitochondria with a perinuclear distribution characteristic of sideroblastic anemia. Magnification x 10,000, reduced by 28 per cent.

r

- Subcutaneous

intravenous

(Table II). Total urinary output averaged only 5.8 mg iron/day. After splenectomy the same dose of desferrioxamine resulted in an average urinary iron excretion of only 2.7 mg/day, a decrease of over 50 per cent. A liver biopsy specimen obtained during splenectomy revealed mild portal fibrosis with extramedullary hematopoiesis and marked hemosiderin deposition. Quantitative iron analysis of the specimen was not obtained. Following splenectomy the patient’s anemia lessened considerably, maintaining a hematocrit value of 25 per cent without transfusions. He was readmitted to The Clinical Center of the Peter Bent Brigham Hospital on October 5, 1976, for an additional trial of desferrioxamine after ascorbic acid loading for one month. As noted in Figure 6 he failed to excrete clinically significant amounts of iron during continuous chelation therapy, his maximal daily excretion of iron being only 8 mg (6 mg iron/g creatinine).

Desferrioxamine (gI24hr) I

Figure 6. Case 4. Dose response curve for urinary iron excretion during administration of continuous intravenous (0 - - - - 0) or subcutaneous (0 - 0) desferrioxamine. Patient failed to excrete significant amounts of iron in the urine during chelation therapy.

Case 5. A 58 year old salesman noted easy fatiguability in July 1974 and was found to be pancytopenic with a hematocrit value of 26 per cent, a white blood cell count of 3,800/mm3, a platelet count of 127,000/mm3 and a reticulocyte count of 0.8 per cent. He was referred to the Hema- tology Division of the Peter Bent Brigham Hospital where bone marrow aspiration revealed erythroid hyperplasia with megaloblastoid features. Ringed sideroblasts were noted on iron stains and electron micrographs (Figure 7). Serum folate was normal and a vitamin 812 level was > 1,000 pg/ml (normal = 150 to 700 pg/ml). The patient was given a trial



TABLE III Effect of Desferrioxamine on Urinary Iron

Excretion in 58 Year Old Patient with

Refractory Sideroblastic Anemia

Daily Desferrioxamine

Dose Urinary Iron Excretion

(9) Route of Administration (mg/24 hour)

0.75 Intramuscular 1.5 1.50 Intramuscular’ 2.3 0.75 Intravenously by 13.6

continuous infusion 1.50 Intravenously by 39.2

continuous infusion

l Two daily doses of 0.75 g.

of pyridoxine for three months without a response. Because

of symptomatic anemia he received approximately 20 units

of blood prior to his admission to the Peter Bent Brigham Hospital on June 5, 1976. Physical examination was essentially within normal limits without adenopathy or hepatosplenomegaly. Laboratory data included a hematocrit value of 29 per cent, a white blood cell count of 4,400/mm3 (50 per cent polymorphonuclear cells, 2 per cent bands, 1 per cent basophils, 29 per cent lymphocytes, 16 per cent monocytes and 2 per cent blast forms) and a platelet count of 140,000/mm3. Alkaline phosphate, SGOT, SGPT and bilirubin were all within normal limits. Serum iron was 231 pg/lOO ml with a total iron-binding capacity of 227 pg/lOO ml. The oral glucose tolerance test was abnormal and indicated chemical diabetes mellitus. An electrocardiogram and chest roentgenogram were within normal limits. Repeat bone marrow aspiration again showed increased marrow cellularity with abundant iron and many ringed sideroblasts. Immature myeloid elements were also increased but fully differentiated cells were present. On liver biopsy there was moderate periportal iron deposition with no evidence of necrosis, inflammation or fibrosis. Quantitative iron analysis of liver was 3.96 mg/g wet weight of liver. Ferrokinetics showed a rapid plasma iron clearance with a T l/2 of 49 minutes (normal T l/2 = 60 to 90 minutes). Red cell utilization of labelled iron was decreased (38 per cent by eight days), indicating ineffective erythropoiesis. The patient received a trial of des-

ferrioxamine therapy after ascorbate loading for one month; results are indicated in Table Ill. With 750 mg desferrioxamine given intramuscularly he excreted only 1.5 mg iron in his urine. However, when the same dose of desferrioxamine was given by continuous intravenous infusion he excreted 13.6 mg iron. When 1.5 g desferrioxamine was given by continuous infusion, he excreted 39 mg of iron in his urine compared to only 2.3 mg iron excreted when the same dose was given intramuscularly. Predictive Factors for Response to Iron Chelation Therapy. Table IV summarizes the pertinent clinical

and laboratory data in the five patients studied. Evalu-

ation of these data suggests certain factors that help predict which adult patients with iron overload will respond to continuous chelation therapy. Serum iron was maximally saturated in all patients studied and was not included in this table. The patient with thalassemia (Case 2) had the greatest response to desferrioxamine, excreting greater than 65 mg iron/day in her urine. Al- though ferrokinetic studies were not made, she had marked ineffective erythropoiesis as documented by decreased beta globin chain synthesis, an increased reticulocyte count and many nucleated red cells on her blood smear. This patient received many transfusions (>200); in addition, in patients with thalassemia iron absorption is increased [23]. This patient with thalassemia had both ineffective erythropoiesis and a 20-fold increase in hepatic iron. The patient with ineffective erythropoiesis due to refractory sideroblastic anemia (Case 5) excreted nearly as much iron when receiving continuous intravenous desferrioxamine even though hepatic iron stores were only slightly increased (2.2- fold). These results suggest that the rapid iron turnover in the marrow provides an important pool for chelatable iron.

However, ineffective erythropoiesis does not provide the sole or necessarily primary source of chelatable iron. The patient with pure red cell aplasia (Case 1) excreted significant amounts of iron despite absent marrow erythropoietic activity, as shown by absent bone marrow uptake of labelled indium and markedly

TABLE IV Summary of Clinical and Laboratory Data In Patlents with Transfusional Hemosiderosis

Number of Serum Hepatic Iron Results of Urinary Iron Case Age Transfusions Ferritln Content Marrow Scan Excretion* No. Diagnosis (yr) (U) (ng/mf) (mg/g wet weight) and/or Ferroklnetics (mg/day)

(10-350) (1.880 f 0.150) (<I m9) 1 Pure red cell aplasia 42 210 2,000 25.6 No active erythropoiesis 34 2 P-thalassemia intermedia 61 200 2,200 35.7 --- 65 3 Myeloid metaplasia 60 110 2,800 _-_ Marked hepatic uptake of iron 42 4 Myeloid metaplasia 67 62 540 ___ Primarily hepatic uptake of iron a 5 Refractory sideroblastic 58 20 176 3.96 Ineffective erythropoiesis 39

anemia

NOTE: Normal data in parentheses. l Urinary iron excretion with maximally effective dose of continuous desferrioxamine (1.5 to 2.2 g/day).

664 December 1977 The Amertcan Journal of Medicine Volume 63

prolonged plasma iron clearance. His increased stores of hepatic iron (15fold) suggest that hepatic parenchymal or reticuloendothelial iron is readily chelatable.

The two patients with myelofibrosis (Cases 3 and 4) had similar ferrokinetic measurements showing marked hepatic uptake of iron and poor red cell utilization. One (Case 3) excreted significant quantities of iron in the urine (42 mg/day) whereas the other (Case 4) did not (<8 mg/day). In view of the differences in serum ferritin levels and in transfusion history, it is likely that the good responder (Case 3) had significantly higher iron stores than the poor responder (Case 4). Unfortunately, spe- cific iron analysis of the liver was not obtained in either patient.

The three patients who received the most transfusions (Cases 1, 2 and 3) had the highest serum ferritin levels (>2,000 ng/ml). One patient (Case 4) with myeloid metaplasia had received only 62 units of blood, had only a slightly elevated ferritin level of 540 ng/ml and did not respond to iron chelation therapy. This ob- servation suggests that the ferritin level may turn out to be a predictor of chelatable hepatic iron stores. The only normal ferritin level was in the patient with refractory sideroblastic anemia (Case 5) who had only slightly increased hepatic iron stores.

COMMENTS

These studies indicate that continuous parenteral administration of desferrioxamine can remove significant quantities of iron from adult patients with transfusional hemosiderosis and put them in negative iron balance. In addition, the administration of desferrioxamine subcutaneously with a light weight portable constant infusion pump was 80 per cent as effective as continuous intravenous therapy. Subcutaneous therapy was well tolerated by most patients without local reactions (transient cellulitis in one patient) and seems feasible for outpatient management programs. The patient with pure red cell aplasia (Case 2) has been undergoing continuous outpatient therapy for four months while working full-time and has increased his urinary iron excretion to 45 mg/day with a daily dose of 2.2 g given subcutaneously over 16 hours.

Prior experimental studies with desferrioxamine have indicated that hepatic parenchymal iron probably rep- resents the primary source of chelatable iron [ 24-261. However, Karabus and Fielding [27] found that iron chelation in patients with ineffective erythropoiesis (i.e., megaloblastic anemias) decreased following therapy, which suggests that iron turnover in the marrow is also a potential source of chelatable iron. In contrast, Brown et al. [28] could not correlate the amount of iron chelated by intramuscular desferrioxamine (without ascorbate loading) to plasma iron clearance or to inef-

fective erythropoiesis in the group of patients they studied.

Our data on patients given continuous desferrioxamine administration after ascorbate loading suggests that hepatic iron stores and the degree of ineffective erythropoiesis are the most important variables in predicting a good response to iron chelation therapy. Although a liver biopsy with quantitative analysis is impractical in many patients, the transfusion history is a fairly accurate predictor of total body iron stores. Serum ferritin has been found to be increased in patients with transfusional hemosiderosis [29-311, ap- pears to reflect total body iron stores in most cases [29] and, perhaps more specifically, hepatic iron stores 1321. However, certain patients with acute and chronic leukemias and Hodgkin’s disease have been found to have increased ferritin levels without evidence of iron overload [33], and normal serum ferritin concentrations have been reported in patients with precirrhotic hemochromatosis [34]. In our patients serum ferritin levels seemed to be a good predictor of chelatable iron in those patients with little marrow activity. Still, a patient (Case 5) may have ineffective erythropoiesis with only moderately increased tissue iron stores and still respond to the drug. Obviously, studies of many other patients with transfusional hemosiderosis will be needed to confirm these observations.

Since patients with significant transfusional iron overload may have over 50 g of excess iron, many month’s of therapy will be required to achieve a significant decrease in total body iron stores. However, these patients may at least begin reducing their iron stores while still continuing to receive blood replacement. In addition, parenchymal iron in the liver, pancreas and other tissues may be the most readily chelatable source of iron, resulting in significant clinical improvement after a short interval of treatment. Reversal of hepatic, endocrine and cardiac disease in patients with idiopathic hemochromatosis has been well documented after removal of iron by phlebotomy [35]. Only long-term following-up of adult patients receiving continuous subcutaneous therapy with desferrioxamine will de- termine the degree of clinical improvement and whether long-term iron chelation can be maintained safely and effectively.

ACKNOWLEDGMENT

We wish to thank Dr. Thomas Lament for performing liver biopsies, Dr. Laurence Sloss for performing left ventricular function studies, Dr. David Drum for assaying serum ferritin and Mr. Larry Button for performing ferrokinetic studies. We thank Drs. Leonard Ellman and Marjorie Boyd for referring two of the patients studied. The excellent technical assistance of Susan Marino and Geoffrey Schmidt are gratefully acknowledged.




REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Bannerman RM, Keusch G, Kreimer-Birnbaum M, et al.: Thal- assemia intermedia with iron overload, cardiac failure, diabetes mellitus, hypopituitarism and porphyrinuria. Am J Med 42: 476, 1967.

Sherman LA, Pfefferbaum A, Brown EB, Jr: Hypoparathy- roidism in a patient with long-standing iron storage disease. Ann Intern Med 73: 259, 1970.

Gabriele OF: Hypoparathyroidism associated with thalassemia. So Med J 64: 115, 1971.

Sinniah R: Transfusional siderosis and liver cirrhosis. J Clin Pathol 22: 567, 1969.

Grace ND, Powell LW: Iron storage disorders of the liver. Gastroenterology 64: 1257, 1974.

Engle MA: Cardiac involvement in Cooley’s anemia, Ann NY Acad Sci 119: 694, 1964.

Engle MA, Erlandson M, Smith CH: Late cardiac complications of chronic severe refractory anemia with hemochromatosis. Circulation 30: 698, 1964.

Davis WD Jr, Arrowsmith WR: The treatment of hemochromatosis by massive venesection. Ann Intern Med 39: 723, 1953.

Weintraub LR, Conrad ME, Crosby WH: The treatment of hemochromatosis by phlebotomy. Med Clin North Am 50: 1579, 1966.

Bickel H, Gaumarin E, Keller-Schierlein W, et al.: Uber eis- enhattige Wachstrusfaktoren der eisenhattigen Antibiotika Sideromycine. Experientia 16: 129, 1960.

Cumming LC, Millar JA, Smith JA, et al.: Clinical and laboratory studies on the action of desferrioxamine. Br J Haematol 17: 257, 1969.

Wohler F: The treatment of haemochromatosis with desferrioxamine. Acta Haematol 30: 65, 1963.

Model1 CB, Beck J: Long-term desferrioxamine therapy in thalassemia. Ann NY Acad Sci 232: 201, 1974.

Seshadri R, Colebatch JG, Gordon P, et al.: Long-term administration of desferrioxamine in thallasemia major. Arch Dis Child 49: 621, 1974.

Waxman HS, Brown EB: Clinical Usefulness of iron chelating agents. Prog Hematol 6: 338, 1969.

O’Brien RT: Ascorbic acid enhancement of desferrioxamine-induced urinary iron excretion in thalassemia major. Ann NY Acad Sci 232: 221, 1974.

Mazur A, Baer S, Shorr E: The mechanism of iron release for ferritin as related to biological properties. J Biol Chem 213: 147, 1955.

Miller JPG, Perkins DJ: Model experiment for study of iron transfer from transferrin to ferritin. Eur J Biochem 10: 146, 1969.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

Propper RD, Shurin SB, Nathan DG: Reassessment of the use of desferrioxamine B in iron overload. N Engl J Med 294: 1421, 1976.

Miles LEM, Lipschitz DA, Bieber CP, et al.: Measurement of serum ferritin by a 2-site immunoradiometric assay. Ann Biochem 61: 209. 1974.

McNeil BJ, Holman BL, Button LN, et al.: Use of indium chloride scintigraphy in patients with myelofibrosis. J Nuclear Med 16: 66. 1974.

Bunn HF. McNeil BJ, Rosenthal DS, et al.: Bone marrow imaging in pure red blood cell aplasia. Arch Intern Mad 136: 1169, 1976.

Risdon RA, Barry M, Flynn DM: Transfusional iron overload: the relationship between tissue iron concentration and hepatic fibrosis in thalassemia. J Pathol 116: 83, 1975.

Harker LA. Funk DD. Finch CA: Evaluation of storage iron by chelates. Am J Med 45: 105. 1968.

Lipschitz DA, Dugard J, Simon MO, et al.: The site of action of desferrioxamine. Br J Haematol 20: 395, 1971.

Hershko C, Cook JD, Finch CA: Storage iron kinetics. Ill. Study of desferrioxamine action by selective radioiron labels of RE and parenchymal cells. J Lab Clin Med 81: 876, 1973.

Karabus CD, Fielding J: Desferrioxamine chelatable iron in haemolytic, megaloblastic and sideroblastic anaemias. Br J Haematol 13: 924, 1967.

Brown, EG, Hwang YF, Allgood JW: Studies of the site of action of desferrioxamine. J Lab Clin Med 69: 382. 1967.

Jacobs A, Miller F, Worwood M: Fenitin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J 4: 206, 1972.

Simes MA, Addiego JE, Dallman PR: Ferritin in serum: diagnosis of iron deficiency and iron overload in infants and children. Blood 43: 581, 1974.

Lipschitz DA, Cook JD, Finch CA: A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med 290: 1213, 1974.

Letsky EA, Flynn DM, Barry M: The effect of treatment with long-term chelation agents in iron overload in thalassemia (abstract). Br J Haematol 20: 395, 1973.

Jones PAE, et al.: Ferritenemia in leukemia and Hodgkins disease. Br J Cancer 27: 212, 1973.

Wands JR, Rowe JA. Mazey SE, et al.: Normal serum ferritin concentrations in precirrhotic hemochromatosis. N Engl J Med 294: 302. 1976.

Weintraub LR, Conrad ME, Crosby WH: The treatment of hemochromatosis by phlebotomy. Med Clin North Am 50: 1579. 1966.


Treatment of iron overload in adults with continuous parenteral desferrioxamine

Documents

Transcript of Treatment of iron overload in adults with continuous parenteral desferrioxamine