563 MODIFICATION OF ERYTHROCYTE
ABNORMALITIES IN HODGKIN’S DISEASE AFTER CHEMOTHERAPY
SIR,-Target cells in the peripheral blood smear may be in a wide variety of blood disorders, such as haemoglobin C disease, thalassaemia, sickle-cell thalassaemia, sickle-cell disease, and certain haemolytic anaemias.’ The target cells seen in seen
hsmoglobinopathies are permanent, whereas those seen in liver disease and haemolytic anaemias may vary with the disease. The following case demonstrates the modification of tar-
courses of chemotherapy, the liver-function almost normal and the liver had returned to normal size. The number of target cells fell dramatically and the osmotic fragility curve returned to the normal range (fig. 2). The correction of the erythrocyte abnormalities after chemotherapy indicates that these changes were directly related to the Hodgkin’s involvement of the liver. Therefore, this case demonstrates that the red-cell abnormalities secondary to malignant disease involving the liver can be altered by a chemotherapeutic effect on the underlying liver abnormality.
bicin. After three tests were
K. A. RAO
Georgetown University Medical Center, Washington, C. C. 20007, U.S.A.
S.A. STASS
M. L. SMITH D. E. UDDIN H. R. SCHUMACHER
National Naval Medical Center, Bethesda, Maryland 20014
CONTROL OF HYPERTENSION WITH ACUTE RENAL FAILURE IN SCLERODERMA WITHOUT NEPHRECTOMY
Fig. I-Target cells in peripheral blood (x200).
SIR,-Scleroderma (progressive systemic sclerosis) is characterised by vascular lesions in many organs and widespread alteration of connective tissue. Renal involvement, in the form of proteinuria, hypertension, and azota:mia, occurs in 45% of cases.’ Malignant hypertension with acute renal failure is less common and carries a bad prognosis: in this syndrome very high blood-pressure does not respond to drugs and renal failure progresses rapidly. Haemodialysis, while lowering the blood-urea, often does not control blood-pressure satisfactorily, and because plasma-renin activity (P.R.A.) is very high, bilateral nephrectomy is usually done. Of sixteen patients who survived renal failure (ten on hoemodialysis and six with renal transplant) all but one underwent bilateral nephrectomy. I-" Oliver and Cannon9 treated eleven patients with renal failure in scleroderma:
two
who underwent bilateral
nephrectomy sur-
vived while the remainder died within a month of the start of renal failure. We have maintained a patient with scleroderma, malignant hypertension, and progressive renal failure on hasmodialysis without resorting to bilateral nephrectomy. A 57-year-old man was seen at the V.A. Hospital in July, 1976, with symptoms of Raynaud’s phenomenon, sclerodactyly, polyarthritis, and morning stiffness of several weeks’ duration. Blood-pressure was 140/80 mm Hg. Periarticular soft-tissue was present in the hands, wrists, and ankles, and the skin over the fingers was tight and shiny. Haematocrit 40%, sedimentation-rate 20 mm in the first hour, and the white blood-count was 6600/pd with normal differential. Urinalysis, rheumatoid factor, and antinuclear antibodies negative. Serum-creatinine 0.9 mg/dl. Oesophageal motility normal, as assessed by radiology. Scleroderma was diagnosed. On aspirin and ibuprofen the patient had some relief over the next few months. In September, 1977, he was admitted with hypertension, headaches, epistaxis, and ankle oedema. Blood-pressure 200/90 mm Hg; 3 weeks earlier it had been only 146/88 mm Hg. Urinalysis showed few hyaline casts and 1+ protein. Serumcreatinine 2.7 mg/dl. Hypertension persisted in the range of -
swelling
Fig. 2-Osmotic fragility curves before and after chemotherapy. get cells and osmotic fragility curves by chemotherapy in a patient with Hodgkin’s disease and liver involvement (biopsy
proven). A 25-year-old White male with IVB nodular sclerosing Hodgkin’s disease was admitted to the National Naval Medical Center in August, 1977, with an exacerbation. He had a fever, liver enlarged 2 cm below the right costal margin, and very abnormal liver-function tests. A repeat bone-marrow demonstrated Hodgkin’s disease which had not previously been present. A peripheral smear contained more than 70% target cells (fig. 1). Haemoglobin electrophoresis showed 97% HbA and 2.1% HbA2. The osmotic fragility curve (fig. 2) revealed a marked shift to the left, indicating increased resistance of the red blood-cells to lysis. Since the clinical and laboratory findings confirmed relapse of the disease he was put on a regimen of bleomycin dacarbazine, vincristine, prednisone, and doxoru1.Miale, J.
B.
Laboratory
Medicine:
Hematology; p. 554.
Saint Louis, 1977.
1.
Cannon, P. J., Hassar, M., Case, D. B., Casarella, W. J., Sommers, S. C., LeRoy, E. C. Medicine, 1974, 53, 1. 2. Richardson, J. A. Arthritis Rheum. 1973, 16, 265. 3. Keane, W. F., Davidson, B., Raij, L. Ann. intern. Med. 1976, 85, 199. 4. Shapiro, C. Clin. Nephrol. 1977, 8, 321. 5. Ehrenfeld, M., Licht, A., Stessman, J., Yanko, L., Rosenmann, E. Nephron, 1977, 18, 175. 6. Gavras, H., Gavras, I., Cannon, P. J., Brunner, H. R., Laragh, J. H. Archs intern. Med. 1977, 137, 1554. 7. Woodhall, P. B., McCoy, R. C., Gunnells, J. C., Seigler, H. F. J. Am. med. Ass. 1976, 236, 1032. 8. Merino, G. E., Sutherland, D. E. R., Kjellstrand, C. M., Simmons, R. L., Najarian, J. S. Am. J. Surg. 1977, 133, 745. 9. Oliver, J. A., Cannon, P. J. Nephron, 1977, 18, 141.
564 145-230 mm Hg systolic and 85-120 mm Hg diastolic despite propranolol 320 mg/day, hydrallazine 320 mg/day, methyldopa 2 g/day, and frusemide 200 mg/day. Ocular fundoscopy revealed arterial spasm, flame haemorrhages, and mild blurring of disc margins. P.R.A. 43 ng angiotensin n/ml/h (normal 2-7). Renal function rapidly declined, and serum-creatinine rose to 11 mg/dl in one week. A 300 mg bolus of diazoxide was given twice intravenously and lowered the patient’s blood-pressure to 80-90 mm Hg diastolic. His hypertension was subsequently controlled with oral medication. Renal failure, however, was permanent, and intermittent haemodialysis was started. The patient’s clinical status is now stable and he is on home haemodialysis. He requires small doses of propranolol and hydrallazine (40 mg/day of each) to control his blood-pressure. The P.R.A. is still high (37 ng angiotensin ii/ml/h before dialysis). Apart from some headaches, he has no significant com-
plaints. and rapidly progressive renal failin scleroderma is caused by vascular lesions in the kidney. Renal cortical ischasmia has been demonstrated, and a raised P.R.A. is said to indicate a poor prognosis.6 However, our patient with a very high P.R.A. has remained normotensive on haemodialysis and on small drug doses. Bilateral nephrectomy in this clinical setting is risky. Moreover, residual renal parenchyma is desired for erythropoietin production and vitamin D metabolism. Renal transplantation does not seem satisfactory: of six patients who had kidney transplants three lost function in the allograft with recurring scleroderma, two having had rapidly progressive deterioration of kidney function within 3 months of transplantation.8 We suggest that haemodialysis and antihypertensive medications be given a proper trial for control of hypertension in patients with acute renal failure and scleroderma. A raised P.R.A. is not necessarily associated with refractory hypertension. Bilateral nephrectomy may not be necessary in all patients with scleroderma and acute renal failure.
Malignant hypertension
ure
This work was supported Veterans Administration.
by the
Department of Medicine, Wm. S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin 53705, U.S.A.
Medical Research Service of the
(cup or bowl-shaped red blood-cells) in the blood-film is also a useful pointer to excess alcohol consumption. Department of Therapeutics and Clinical Pharmacology and Hæmatology Unit, Department of Pathology, J. HOW University of Aberdeen, R. J. DAVIDSON Aberdeen AB9 2ZD HIGH RISK OF DOWN’S SYNDROME AT ADVANCED MATERNAL AGE
SIR,-Prenatal chromosome studies’ indicate that Down’s syndrome is more prevalent than surveys of live births2.3 suggest. We have found a very high frequency of aneuploidy in fetuses carried by women aged 40 or more. TableI shows the chromosome findings in fetuses from 76 women aged 40 or more, from a group referred on the grounds of maternal age alone with no history of an abnormal child. 2 abnormalities (47,XX,+18; 47,XY,+21) were found amongst 179 fetuses in the 35-39 age-group. Table n shows how the incidence of Down’s syndrome at birth is lower than that found in fetal studies. TABLE I-CHROMOSOME FINDINGS AT MATERNAL AGE
TABLE II-RISK OF
DOWN’S
40
PLUS
SYNDROME AT ADVANCED MATERNAL AGE
A. VISHNU MOORTHY MING J. WU GREGORY J. BEIRNE WALTER S. SUNDSTROM
ALCOHOLISM AND BLOOD PICTURE
SIR,-Some aspects of the peripheral-blood/alcoholism
question’-4
have not yet received adequate coverage. Davidson and Hamilton, in a study of 200 consecutive adult patients with a raised Coulter mean corpuscular volume (M.c.v.) (3.9% of over 6000 routine blood-samples from inpatients and outpatients) found a history of alcoholism in 30 (24 males, 6 females).’ Almost half of these patients had normal tests of liver function. Our data show the high frequency of alcoholism in patients with macrocytosis, and confirm that a Coulter measurement of M.c.v. is a sensitive screening procedure for alcohol abuse.2
Although it has been stated that tolate dehciency does not play a major role in the macrocytosis of alcoholism, we found a low serum-folate in 2 of 19 patients in whom it was measured, and the serum-vitamin-B,2 was low in 1 patient who, apart from being an alcoholic, also had gastro-colic fistula, malabsorption, and early megaloblastic hasmopoiesis. It is thus clinically unwise to disregard the possibility of folate or even vitamin B 1zdeficiency in patients with drinking problems. In
our
experiencethe
transient presence of stomatocytes
1. Lancet, 1977, ii, 806. 2. Wright, G. H., Ree, S. G. ibid. Jan. 7, 1978, p.49. 3. Khaund, R. R. ibid. Feb. 11, 1978, p.327. 4. Foster, A. R. ibid. 5. Davidson, R. J. L., Hamilton, P. J.J. clin. Path. (in the press). 6. Unger, K. W., Johnson, D. Am. J. med. Sci. 1974, 267, 281. 7. Davidson, R. J. L., How, J., Lessels, S. Scand. J. Hœmat. 1977,
*1 in 45 for maternal age 45+.
In our series the risk of both Down’s syndrome and sexchromosome abnormality was very high at advanced maternal age-1 in 9.5for Down’s and 1 in 25 for 47,XXX and 47,XXY combined. These figures from the London area are higher but not significantly higher than those recorded in the West of Scotland.’ Our series might have contained a chance cluster of abnormalities, and this point is being investigated by further studies. Any discrepancy between the incidence of Down’s syndrome detected by amniocentesis and by studies of live births is unlikely to be due to fetal loss at late gestation. A few severely malformed cases may be stillborn and not diagnosed, but the discrepancy must largely be due to underdiagnosis. A true incidence of Down’s syndrome at birth can no longer be estimated because as amniocentesis becomes more generally available more affected pregnancies will be terminated. 1.
Ferguson-Smith, M. A., Ferguson-Smith, M. E. J. clin. suppl. 10, 165. 2. Collman, R. D., Stoller, A. Am. J. publ. Hlth. 1962, 52, 813 19, 47.
3. Hook, E. B. Lancet, 1976, ii, 33.
Path.
1976, 29,
ABNORMALITIES IN HODGKIN’S DISEASE AFTER CHEMOTHERAPY
SIR,-Target cells in the peripheral blood smear may be in a wide variety of blood disorders, such as haemoglobin C disease, thalassaemia, sickle-cell thalassaemia, sickle-cell disease, and certain haemolytic anaemias.’ The target cells seen in seen
hsmoglobinopathies are permanent, whereas those seen in liver disease and haemolytic anaemias may vary with the disease. The following case demonstrates the modification of tar-
courses of chemotherapy, the liver-function almost normal and the liver had returned to normal size. The number of target cells fell dramatically and the osmotic fragility curve returned to the normal range (fig. 2). The correction of the erythrocyte abnormalities after chemotherapy indicates that these changes were directly related to the Hodgkin’s involvement of the liver. Therefore, this case demonstrates that the red-cell abnormalities secondary to malignant disease involving the liver can be altered by a chemotherapeutic effect on the underlying liver abnormality.
bicin. After three tests were
K. A. RAO
Georgetown University Medical Center, Washington, C. C. 20007, U.S.A.
S.A. STASS
M. L. SMITH D. E. UDDIN H. R. SCHUMACHER
National Naval Medical Center, Bethesda, Maryland 20014
CONTROL OF HYPERTENSION WITH ACUTE RENAL FAILURE IN SCLERODERMA WITHOUT NEPHRECTOMY
Fig. I-Target cells in peripheral blood (x200).
SIR,-Scleroderma (progressive systemic sclerosis) is characterised by vascular lesions in many organs and widespread alteration of connective tissue. Renal involvement, in the form of proteinuria, hypertension, and azota:mia, occurs in 45% of cases.’ Malignant hypertension with acute renal failure is less common and carries a bad prognosis: in this syndrome very high blood-pressure does not respond to drugs and renal failure progresses rapidly. Haemodialysis, while lowering the blood-urea, often does not control blood-pressure satisfactorily, and because plasma-renin activity (P.R.A.) is very high, bilateral nephrectomy is usually done. Of sixteen patients who survived renal failure (ten on hoemodialysis and six with renal transplant) all but one underwent bilateral nephrectomy. I-" Oliver and Cannon9 treated eleven patients with renal failure in scleroderma:
two
who underwent bilateral
nephrectomy sur-
vived while the remainder died within a month of the start of renal failure. We have maintained a patient with scleroderma, malignant hypertension, and progressive renal failure on hasmodialysis without resorting to bilateral nephrectomy. A 57-year-old man was seen at the V.A. Hospital in July, 1976, with symptoms of Raynaud’s phenomenon, sclerodactyly, polyarthritis, and morning stiffness of several weeks’ duration. Blood-pressure was 140/80 mm Hg. Periarticular soft-tissue was present in the hands, wrists, and ankles, and the skin over the fingers was tight and shiny. Haematocrit 40%, sedimentation-rate 20 mm in the first hour, and the white blood-count was 6600/pd with normal differential. Urinalysis, rheumatoid factor, and antinuclear antibodies negative. Serum-creatinine 0.9 mg/dl. Oesophageal motility normal, as assessed by radiology. Scleroderma was diagnosed. On aspirin and ibuprofen the patient had some relief over the next few months. In September, 1977, he was admitted with hypertension, headaches, epistaxis, and ankle oedema. Blood-pressure 200/90 mm Hg; 3 weeks earlier it had been only 146/88 mm Hg. Urinalysis showed few hyaline casts and 1+ protein. Serumcreatinine 2.7 mg/dl. Hypertension persisted in the range of -
swelling
Fig. 2-Osmotic fragility curves before and after chemotherapy. get cells and osmotic fragility curves by chemotherapy in a patient with Hodgkin’s disease and liver involvement (biopsy
proven). A 25-year-old White male with IVB nodular sclerosing Hodgkin’s disease was admitted to the National Naval Medical Center in August, 1977, with an exacerbation. He had a fever, liver enlarged 2 cm below the right costal margin, and very abnormal liver-function tests. A repeat bone-marrow demonstrated Hodgkin’s disease which had not previously been present. A peripheral smear contained more than 70% target cells (fig. 1). Haemoglobin electrophoresis showed 97% HbA and 2.1% HbA2. The osmotic fragility curve (fig. 2) revealed a marked shift to the left, indicating increased resistance of the red blood-cells to lysis. Since the clinical and laboratory findings confirmed relapse of the disease he was put on a regimen of bleomycin dacarbazine, vincristine, prednisone, and doxoru1.Miale, J.
B.
Laboratory
Medicine:
Hematology; p. 554.
Saint Louis, 1977.
1.
Cannon, P. J., Hassar, M., Case, D. B., Casarella, W. J., Sommers, S. C., LeRoy, E. C. Medicine, 1974, 53, 1. 2. Richardson, J. A. Arthritis Rheum. 1973, 16, 265. 3. Keane, W. F., Davidson, B., Raij, L. Ann. intern. Med. 1976, 85, 199. 4. Shapiro, C. Clin. Nephrol. 1977, 8, 321. 5. Ehrenfeld, M., Licht, A., Stessman, J., Yanko, L., Rosenmann, E. Nephron, 1977, 18, 175. 6. Gavras, H., Gavras, I., Cannon, P. J., Brunner, H. R., Laragh, J. H. Archs intern. Med. 1977, 137, 1554. 7. Woodhall, P. B., McCoy, R. C., Gunnells, J. C., Seigler, H. F. J. Am. med. Ass. 1976, 236, 1032. 8. Merino, G. E., Sutherland, D. E. R., Kjellstrand, C. M., Simmons, R. L., Najarian, J. S. Am. J. Surg. 1977, 133, 745. 9. Oliver, J. A., Cannon, P. J. Nephron, 1977, 18, 141.
564 145-230 mm Hg systolic and 85-120 mm Hg diastolic despite propranolol 320 mg/day, hydrallazine 320 mg/day, methyldopa 2 g/day, and frusemide 200 mg/day. Ocular fundoscopy revealed arterial spasm, flame haemorrhages, and mild blurring of disc margins. P.R.A. 43 ng angiotensin n/ml/h (normal 2-7). Renal function rapidly declined, and serum-creatinine rose to 11 mg/dl in one week. A 300 mg bolus of diazoxide was given twice intravenously and lowered the patient’s blood-pressure to 80-90 mm Hg diastolic. His hypertension was subsequently controlled with oral medication. Renal failure, however, was permanent, and intermittent haemodialysis was started. The patient’s clinical status is now stable and he is on home haemodialysis. He requires small doses of propranolol and hydrallazine (40 mg/day of each) to control his blood-pressure. The P.R.A. is still high (37 ng angiotensin ii/ml/h before dialysis). Apart from some headaches, he has no significant com-
plaints. and rapidly progressive renal failin scleroderma is caused by vascular lesions in the kidney. Renal cortical ischasmia has been demonstrated, and a raised P.R.A. is said to indicate a poor prognosis.6 However, our patient with a very high P.R.A. has remained normotensive on haemodialysis and on small drug doses. Bilateral nephrectomy in this clinical setting is risky. Moreover, residual renal parenchyma is desired for erythropoietin production and vitamin D metabolism. Renal transplantation does not seem satisfactory: of six patients who had kidney transplants three lost function in the allograft with recurring scleroderma, two having had rapidly progressive deterioration of kidney function within 3 months of transplantation.8 We suggest that haemodialysis and antihypertensive medications be given a proper trial for control of hypertension in patients with acute renal failure and scleroderma. A raised P.R.A. is not necessarily associated with refractory hypertension. Bilateral nephrectomy may not be necessary in all patients with scleroderma and acute renal failure.
Malignant hypertension
ure
This work was supported Veterans Administration.
by the
Department of Medicine, Wm. S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin 53705, U.S.A.
Medical Research Service of the
(cup or bowl-shaped red blood-cells) in the blood-film is also a useful pointer to excess alcohol consumption. Department of Therapeutics and Clinical Pharmacology and Hæmatology Unit, Department of Pathology, J. HOW University of Aberdeen, R. J. DAVIDSON Aberdeen AB9 2ZD HIGH RISK OF DOWN’S SYNDROME AT ADVANCED MATERNAL AGE
SIR,-Prenatal chromosome studies’ indicate that Down’s syndrome is more prevalent than surveys of live births2.3 suggest. We have found a very high frequency of aneuploidy in fetuses carried by women aged 40 or more. TableI shows the chromosome findings in fetuses from 76 women aged 40 or more, from a group referred on the grounds of maternal age alone with no history of an abnormal child. 2 abnormalities (47,XX,+18; 47,XY,+21) were found amongst 179 fetuses in the 35-39 age-group. Table n shows how the incidence of Down’s syndrome at birth is lower than that found in fetal studies. TABLE I-CHROMOSOME FINDINGS AT MATERNAL AGE
TABLE II-RISK OF
DOWN’S
40
PLUS
SYNDROME AT ADVANCED MATERNAL AGE
A. VISHNU MOORTHY MING J. WU GREGORY J. BEIRNE WALTER S. SUNDSTROM
ALCOHOLISM AND BLOOD PICTURE
SIR,-Some aspects of the peripheral-blood/alcoholism
question’-4
have not yet received adequate coverage. Davidson and Hamilton, in a study of 200 consecutive adult patients with a raised Coulter mean corpuscular volume (M.c.v.) (3.9% of over 6000 routine blood-samples from inpatients and outpatients) found a history of alcoholism in 30 (24 males, 6 females).’ Almost half of these patients had normal tests of liver function. Our data show the high frequency of alcoholism in patients with macrocytosis, and confirm that a Coulter measurement of M.c.v. is a sensitive screening procedure for alcohol abuse.2
Although it has been stated that tolate dehciency does not play a major role in the macrocytosis of alcoholism, we found a low serum-folate in 2 of 19 patients in whom it was measured, and the serum-vitamin-B,2 was low in 1 patient who, apart from being an alcoholic, also had gastro-colic fistula, malabsorption, and early megaloblastic hasmopoiesis. It is thus clinically unwise to disregard the possibility of folate or even vitamin B 1zdeficiency in patients with drinking problems. In
our
experiencethe
transient presence of stomatocytes
1. Lancet, 1977, ii, 806. 2. Wright, G. H., Ree, S. G. ibid. Jan. 7, 1978, p.49. 3. Khaund, R. R. ibid. Feb. 11, 1978, p.327. 4. Foster, A. R. ibid. 5. Davidson, R. J. L., Hamilton, P. J.J. clin. Path. (in the press). 6. Unger, K. W., Johnson, D. Am. J. med. Sci. 1974, 267, 281. 7. Davidson, R. J. L., How, J., Lessels, S. Scand. J. Hœmat. 1977,
*1 in 45 for maternal age 45+.
In our series the risk of both Down’s syndrome and sexchromosome abnormality was very high at advanced maternal age-1 in 9.5for Down’s and 1 in 25 for 47,XXX and 47,XXY combined. These figures from the London area are higher but not significantly higher than those recorded in the West of Scotland.’ Our series might have contained a chance cluster of abnormalities, and this point is being investigated by further studies. Any discrepancy between the incidence of Down’s syndrome detected by amniocentesis and by studies of live births is unlikely to be due to fetal loss at late gestation. A few severely malformed cases may be stillborn and not diagnosed, but the discrepancy must largely be due to underdiagnosis. A true incidence of Down’s syndrome at birth can no longer be estimated because as amniocentesis becomes more generally available more affected pregnancies will be terminated. 1.
Ferguson-Smith, M. A., Ferguson-Smith, M. E. J. clin. suppl. 10, 165. 2. Collman, R. D., Stoller, A. Am. J. publ. Hlth. 1962, 52, 813 19, 47.
3. Hook, E. B. Lancet, 1976, ii, 33.
Path.
1976, 29,
