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UNUSUAL LIMB-REDUCTION DEFECT IN INFANT BORN TO MOTHER TAKING PERICONCEPTIONAL MULTIVITAMIN SUPPLEMENT
507 256 days before delivery (-256 days). Isotretinoin (’Accutane’) 40 mg daily had been started at - 256 days before the
about
birth at a time when a copper 7 intrauterine contraceptive device was in place. Because of irregular menstrual periods, spotting, and cramping, the device was removed and oral contraception (norethindrone 1 mg and ethinyloestradiol 35 J.lg; ’Ortho-Novum 1/35’) was started at -242 days. Because of a missed menstrual period with nausea, vomiting, and bloating, isotretinoin was discontinued at - 191 days. A urine pregnancy test was positive at 188 days. Fetal ultrasound measurements at -174 days suggested 81-82 days’ gestation. The patient was treated for chest congestion (’Triaminicol’) at some time during the period of isotretinoin -
therapy.
Ultrasonography art - 116 days demonstrated cerebral ventricular dilatation. The pregnancy was complicated by false labour requiring hospital admission 2 weeks before delivery. On vaginal delivery polyhydramnios was noted and the baby did not breathe spontaneously. Malformations of the external ears, abnormal facies, and a single umbilical artery were noted. Laboratory tests included karyotyping of peripheral blood lymphocytes which revealed a 46XY karyotype, with enlargement of a single short arm of chromosome 22. Severe metabolic acidosis developed and persisted until death at 15 hours of age. Post-mortem examination revealed a dysmorphic syndrome, with malformations of the ears, heart, and brain, of which the following were the main features: External ears rudimentary and low set. Right pinna replaced by two skin tags. Left pinna represented by a 4 mm rim of skin surrounding a 1 x 1 mm blindended sinus tract. X-rays revealed apparently intact inner and middle ears, but with the auditory tubes directed inferiorly. Nasal bndge depressed. Redundant skin folds present on neck with hair sparse on scalp but extending over forehead and temples. Bilateral asymmetric accessory parietal sutures were present. The brain (cerebrum, cerebellum, brainstem) weighed 330 g after fixation. Moderate cerebral oedema was present. A collapsed leptomeningeal cyst overlay the posterior cerebellum in the midline. Cerebellar vermis absent; cerebellum small with, within both hemispheres, heterotopic masses of nerve cells. Extensive heterotopic neural tissue in the leptomeninges about the brainstem. In the pons, the corticospinal tract was displaced dorsally and the inferior olive was also malformed. Sections confirmed diffuse, symmetrical dilatation of the ventricles. Hippocampal gyri small and malformed. Brainstem showed ventral displacement. The cerebellar leptomeningeal cyst formed its roof caudally. In the heart there was complete transposition of the great vessels with a ventricular septal defect. R subclavian artery arose distal to the L and followed a retro-oesphageal course. The superior vena cava was congested and R atrium and R ventricle were moderately dilated.
This is the first case of human isotretinoin teratogenicity to be described in detail. This and additional cases formed the basis for a recent warning of major fetal anomalies related to isotretinoin administration to pregnant women.’ In rabbits, isotretinoin is less teratogenic than vitamin A, tretinoin, and etretinate.2 A dose of 10 mg/kg daily was embryotoxic, teratogenic, and abortifacient. Teratogenicity in rats at a dose of 150 mg/kg daily included microcephaly, exencephaly, spina bifida, cleft palate, and abnormalities of the external ear.3 These abnormalities and those seen in our patient are similar to the malformations seen with administration of vitamin A and its analogues. Because of the similarity of malformations reported in human and experimental vitamin A administration and in experimental isotretinoin administration to those in the case reported here we attribute the anomalies present to maternal isotretinoin therapy. We thank Ms Candace Booker and Mr Michael assistance and Ms Cathy Day for typing.
Pathology Department, Minneapolis Children’s Medical Center, Minneapolis, Minnesota 55404, USA; Neuropathology Department, University of Minnesota; and Department of Family Practice, University of Minnesota
Wengler for technical
JOHN T. BRAUN RALPH A. FRANCIOSI ANGELINE R. MASTRI ROBERT M. DRAKE BERNARD L. O’NEIL
1. Rosa FW.Teratogenicity of isotretinoin. Lancet 1983; ii: 513. 2. Kammn JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982;6:(no4,partII, suppl):652-59. 3. ’Accutane’ package insert. Hoffman-LaRoche Inc (August, 1983).
UNUSUAL LIMB-REDUCTION DEFECT IN INFANT BORN TO MOTHER TAKING PERICONCEPTIONAL MULTIVITAMIN SUPPLEMENT
SIR,—I describe here an unusual and severe combination of birth a child born to a woman taking the multivitamin
defects in
preparation ’Pregnavite Forte F’ (Bencard) in the periconceptional period. A mother, then aged 36, entered a UK multicentre vitamin supplementation study1 at the end of 1977. Earlier in that year her second child, a girl, had been born with spina bifida and hydrocephalus. In the ensuing pregnancy she took one tablet of pregnavite forte F three times a day from 3 months before to 12 weeks after the pregnancy had been discovered, and a healthy boy ’
was
born in
December, 1978, and included in the results of the first
cohort. Identical multivitamin supplementation was repeated before and during the next pregnancy (second cohort). No other drugs were given in pregnancy, which was uncomplicated. A boy was born by normal delivery at 40 weeks’ gestation in July, 1981, birthweight 2-53 kg. The neonatal period was complicated by neonatal hepatitis, with a low serum al-antitrypsin concentration (0 -6g/l; normal 1.8—5 -0). Examination at the age of 2 years 4 months shows
a most
unusual reduction defect of the left upper
limb, affecting both pre-axial and post-axial structures. There is dislocation of the elbow, hypoplasia of the ulna with failure of development of the olecranon notch and process, absence of the thumb, hypoplasia of the index and little finger, partial fusion of the fourth and fifth metacarpals, and a single ossification centre in the carpus (hamate rather than capitate). He also has marked plagiocephaly, and a thoracolumbar scoliosis, convex to the left, which was recorded at birth. The scoliosis has since worsened; its apex is at T10 with an angle of 36°. There is no family history of scoliosis, limb defects or any other congenital malformation, apart from the sibling with spina bifida, and there is no evidence of in-utero compression. The possibility that this child’s unusual defects were caused by pregnavite forte F led me to report the case to the Committee on Safety of Medicines (CSM). The CSM received reports of sixty-one adverse reactions to pregnavite forte F and fourteen related iron and iron-vitamin compound preparations, between January, 1964, and February, 1983. Eight reports were of congenital malformations. The manufacturers confirm that no formal systematic study has ever been done to test the safety of pregnavite forte F in the first trimester. Neither the CSM nor Bencard know of any reports of any untoward reactions from pregnant women that have been attributed to pregnavite forte F. Children from the first cohort were examined for the presence not only of spina bifida but also of any other malformation. However, not all the second cohort children have yet been examined, and the organisers of the trial were unaware of this patient’s malformations despite the fact that they were evident at birth and affected the spine. The plan is to examine all children from the second cohort, and these data will be useful in view of the increasing use of periconceptional vitamins. Three-quarters of obstetricians in the North West region are already recommending periconceptional vitamin supplementation to women at risk. Furthermore, concern about reports of self-administration of high dose vitamin A supplements by pregnant women has recently led the Department of Health to propose that these preparations should be available
only on prescription. In view of the theoretical possibility that vitamin supplementation, whether or not preventing neural tube defects, might harm the embryo/fetus, it is important to establish safety. Preliminary published evidence2does not suggest an increased rate
of malformations in supplemented pregnancies. However, the two cohorts of the UK multicentre trial the women studied are small in number and selected. 1. Smithells
RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981; 56:
911-18. 2. Smithells RW, Nevin NC, Seller. MJ, et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983; i: 1027-31.
.
508 All associations between drug use and side-effects are underreported, and this may be especially true for supposedly innocuous vitamins. All malformations after periconceptional vitamin supplementation, whether in a trial or not, should be reported to the CSM in case any pattern of defects emerges. I would be grateful to
receive details
of any
cases
of limb
defect
after vitamin
supplementation, particularly in view of a report of the interaction of a vitamin D metabolites and genes
differentiation.3
intimately involved with cell
University Department of Child Health, Booth Hall Children’s Hospital,
T. J. DAVID
Manchester M9 2AA
AVAILABILITY OF FOLIC ACID
SIR,—Dr Blank and his colleagues (Feb 4, p 291) state that "Pregnavite forte F and all other preparations containing folic acid at the dosage under discussion can be obtained only on prescription". This is true of preparations marketed for medicinal purposes and sold by pharmacists. However, vitamin products marketed as health foods are available over the counter and by mail order. The quantity of folic acid in the recommended daily dose ranges from less than 1 µg to more than 1 mg, but 5 mg tablets are obtainable. Possibly of more concern, in view of the evidence of teratogenicity in man of high doses of vitamin A analogues, some of the "health" products contain as much as 25 000 IU vitamin A per
ULTRASONIC DEMONSTRATION OF SMALL THYROID NODULES
SIR,-We were perplexed to read Dr Woestyn and Dr Afschrift’s (Nov 26, p 1252) describing "small solid nodules in the thyroid gland which are not palpable and are not detected on letter
radionuclide examination" but without defining precisely what they mean by "small solid nodules". Impalpable thyroid nodules are small and intraparenchymal; those undetectable by scintillation camera in an accurate examination are very small (3-5 mm or less) or fairly small and with normal function; those reliably detectable by ultrasonography must be larger than the resolving power of the ultrasonograph (2-3 mm). In any case with echogenic areas sized about 3 mm it is very difficult, with either scintigraphy or ultrasonography, to be certain that they are really "small solid nodules". If the echogenic areas are large enough for the ultrasonographer to consider them as "small solid nodules" and if they are neither palpable nor detected on scintigraphy, they are probably intraparenchymal normally functioning adenomas which are clinically present with euthyroidism. We have occasionally found echogenic areas in the thyroid gland which were neither palpable nor seen by scintigraphy, but the presence of such areas in 18% of males and 20% of females, among 300 symptom-free patients, as reported by Woestyn and Afschrift, is puzzling. Departments of Infectious Diseases, and Radiology and Nuclear Medicine, USL 31, Ferrara, Italy
MICHELE CASELLI LUCIANO M. FEGGI
tablet. University Department of Paediatrics and Child Health, General Infirmary at Leeds, Leeds LS2 9NS
DRUGS THAT CAN CAUSE CANCER R. W. SMITHELLS
ANTINUCLEAR ANTIBODIES IN PRIMARY BILIARY CIRRHOSIS
SIR,—Antibodies to nuclear antigens (ANA) detectable in dividing rather than resting cells are surprisingly common in primary biliary cirrhosis (PBC). The immunofluorescence pattern on HEp-2 cells described by Dr Powell and colleagues as "atypical discrete speckled nuclear" staining (Feb 4, p 288) has also been termed "multiple nuclear dots". 4,5 NSpI3 and "small bright speckles" (M. Reichlin, F. Arnett, Jr, unpublished).6 We observed this ANA pattern chiefly in PBC (18/135 cases, 13%) and associated it with the presence of Sjogren’s syndrome. 1,2 By contrast, the antibody was found in only 1 case out of 60 with systemic lupus, in only 1 case of primary sicca syndrome (out of 55), and in none of 200 cases of systemic sclerosis or 80 cases of chronic active hepatitis (50 HBsAg-, 30 HBsAg+ )4,5 (and unpublished); the frequency in myositis is about 3% (Reichlin and Arnett). The antigen appears to be a protein,5 and the dots may correspond7 with one of the nuclear bodies recognised by electron microscopy. Besides the new patterns of antinuclear antibody staining seen on HEp-2 cell monolayers, we have found three types of precipitating antibody that seem to be specific for liver disease. Designated XH, XR, and XR2, these precipitin systems are detected by counterimmunoelectrophoresis against tissue extracts. While absent from SLE and other connective tissue diseases, they are found in about 10% of PBC sera and 25% of HBsAg negative .
chronic active
hepatitis.5
Royal Postgraduate Medical School, London W12 0HS
ROBERT M. BERNSTEIN
SIR,—Your Feb 4 editorial is a timely reminder of possible hazards from chemotherapy. Patients with benign lesions must be especially vulnerable. The induction of cancer involves several stages. An early stage of initiation is caused by agents which are mutagenic and produce latent tumour cells which may remain dormant. If these cells are exposed to promoting agents they are converted into tumours which are often benign. A later stage is progression, which involves the transformation of benign lesions into malignant neoplasia. Many experiments in chemical carcinogenesis have shown that progression involving malignant transformation is caused by mutagenic carcinogens, not by promoters. Recent work2 has shown that progression can be caused by mutagens. Nitrogen mustard, chlorambucil, melphalan, and doxorubicin and other therapeutic agents which are mutagenic would cause the progression of benign lesions into malignant tumours. The treatment of benign adenomas or papillomas with agents which are mutagenic would therefore seem to be a dangerous procedure. In the early stages of carcinogenesis a promoting agent is necessary. Most promoting agents increase cell division. Such stimulation of cell division may not be needed with an existing tumour. The urine of smokers contains mutagens,3 so smoking would convert papillomas into carcinomas. The effect the cessation of smoking has in reducing the incidence of cancer4could be due to the removal of the mutagens, reducing the incidence of malignant transformation. Patients with benign tumours such as adenomas and papillomas should not smoke and should not be treated with drugs which have mutagenic activity. TUC Centenary Institute of Occupational Health, London School of Hygiene and
Tropical Medicine, PH, Rothberg PG, Astrin SM, et al. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature 1983; 306: 492-94. Bernstein RM, Callender ME, Neuberger JM, Bunn CC, Williams R, Hughes GRV. Antinuclear antibodies in primary biliary cirrhosis. Ann Rheum Dis 1981; 40: 624
3. Reitsma 4.
(abstr). RM, Neuberger JM, Bunn CC, Callender ME, Hughes GRV, Williams R. Diversity of autoantibodies in primary biliary cirrhosis and chronic active hepatitis. Clin Exp Immunol 1984; 55: 553-60. Fritzler MJ, Valencia DW, McCarty GA. Speckled pattern antinuclear antibodies
5. Bernstein
6.
resembling anticentromere antibodies. Arthritis Rheum 1984; 27: 92-96 7. Bouteille M, Laval M, Dupuy-Coin AM. Localization of nuclear functions as revealed by ultrastructural autoradiography and cytochemistry. In: Busch H, ed Cell nucleus; Vol I. New York: Academic Press, 1974: 3-71.
London WC 1E 7HT
E. BOYLAND
1. Shubik P. Studies on the promoting phase in the stages of carcinogenesis in mice, rats, rabbits and guinea pigs. Cancer Res 1950; 10: 13-17. 2. Henning H, Shores R, Wenk ML, Spangler EF, Tarone R, Yuspa SH. Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters. Nature 1983; 304: 67-69. 3. Yamasaki E, Ames BN. Concentration of mutagens from urine by adsorption with the nonpolar resi XAD2: Cigarette smokers have mutagenic urine. Proc Natl Sci (USA) 1977, 74: 3555-59. 4. Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J 1976; ii: 1525-36.
about
birth at a time when a copper 7 intrauterine contraceptive device was in place. Because of irregular menstrual periods, spotting, and cramping, the device was removed and oral contraception (norethindrone 1 mg and ethinyloestradiol 35 J.lg; ’Ortho-Novum 1/35’) was started at -242 days. Because of a missed menstrual period with nausea, vomiting, and bloating, isotretinoin was discontinued at - 191 days. A urine pregnancy test was positive at 188 days. Fetal ultrasound measurements at -174 days suggested 81-82 days’ gestation. The patient was treated for chest congestion (’Triaminicol’) at some time during the period of isotretinoin -
therapy.
Ultrasonography art - 116 days demonstrated cerebral ventricular dilatation. The pregnancy was complicated by false labour requiring hospital admission 2 weeks before delivery. On vaginal delivery polyhydramnios was noted and the baby did not breathe spontaneously. Malformations of the external ears, abnormal facies, and a single umbilical artery were noted. Laboratory tests included karyotyping of peripheral blood lymphocytes which revealed a 46XY karyotype, with enlargement of a single short arm of chromosome 22. Severe metabolic acidosis developed and persisted until death at 15 hours of age. Post-mortem examination revealed a dysmorphic syndrome, with malformations of the ears, heart, and brain, of which the following were the main features: External ears rudimentary and low set. Right pinna replaced by two skin tags. Left pinna represented by a 4 mm rim of skin surrounding a 1 x 1 mm blindended sinus tract. X-rays revealed apparently intact inner and middle ears, but with the auditory tubes directed inferiorly. Nasal bndge depressed. Redundant skin folds present on neck with hair sparse on scalp but extending over forehead and temples. Bilateral asymmetric accessory parietal sutures were present. The brain (cerebrum, cerebellum, brainstem) weighed 330 g after fixation. Moderate cerebral oedema was present. A collapsed leptomeningeal cyst overlay the posterior cerebellum in the midline. Cerebellar vermis absent; cerebellum small with, within both hemispheres, heterotopic masses of nerve cells. Extensive heterotopic neural tissue in the leptomeninges about the brainstem. In the pons, the corticospinal tract was displaced dorsally and the inferior olive was also malformed. Sections confirmed diffuse, symmetrical dilatation of the ventricles. Hippocampal gyri small and malformed. Brainstem showed ventral displacement. The cerebellar leptomeningeal cyst formed its roof caudally. In the heart there was complete transposition of the great vessels with a ventricular septal defect. R subclavian artery arose distal to the L and followed a retro-oesphageal course. The superior vena cava was congested and R atrium and R ventricle were moderately dilated.
This is the first case of human isotretinoin teratogenicity to be described in detail. This and additional cases formed the basis for a recent warning of major fetal anomalies related to isotretinoin administration to pregnant women.’ In rabbits, isotretinoin is less teratogenic than vitamin A, tretinoin, and etretinate.2 A dose of 10 mg/kg daily was embryotoxic, teratogenic, and abortifacient. Teratogenicity in rats at a dose of 150 mg/kg daily included microcephaly, exencephaly, spina bifida, cleft palate, and abnormalities of the external ear.3 These abnormalities and those seen in our patient are similar to the malformations seen with administration of vitamin A and its analogues. Because of the similarity of malformations reported in human and experimental vitamin A administration and in experimental isotretinoin administration to those in the case reported here we attribute the anomalies present to maternal isotretinoin therapy. We thank Ms Candace Booker and Mr Michael assistance and Ms Cathy Day for typing.
Pathology Department, Minneapolis Children’s Medical Center, Minneapolis, Minnesota 55404, USA; Neuropathology Department, University of Minnesota; and Department of Family Practice, University of Minnesota
Wengler for technical
JOHN T. BRAUN RALPH A. FRANCIOSI ANGELINE R. MASTRI ROBERT M. DRAKE BERNARD L. O’NEIL
1. Rosa FW.Teratogenicity of isotretinoin. Lancet 1983; ii: 513. 2. Kammn JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982;6:(no4,partII, suppl):652-59. 3. ’Accutane’ package insert. Hoffman-LaRoche Inc (August, 1983).
UNUSUAL LIMB-REDUCTION DEFECT IN INFANT BORN TO MOTHER TAKING PERICONCEPTIONAL MULTIVITAMIN SUPPLEMENT
SIR,—I describe here an unusual and severe combination of birth a child born to a woman taking the multivitamin
defects in
preparation ’Pregnavite Forte F’ (Bencard) in the periconceptional period. A mother, then aged 36, entered a UK multicentre vitamin supplementation study1 at the end of 1977. Earlier in that year her second child, a girl, had been born with spina bifida and hydrocephalus. In the ensuing pregnancy she took one tablet of pregnavite forte F three times a day from 3 months before to 12 weeks after the pregnancy had been discovered, and a healthy boy ’
was
born in
December, 1978, and included in the results of the first
cohort. Identical multivitamin supplementation was repeated before and during the next pregnancy (second cohort). No other drugs were given in pregnancy, which was uncomplicated. A boy was born by normal delivery at 40 weeks’ gestation in July, 1981, birthweight 2-53 kg. The neonatal period was complicated by neonatal hepatitis, with a low serum al-antitrypsin concentration (0 -6g/l; normal 1.8—5 -0). Examination at the age of 2 years 4 months shows
a most
unusual reduction defect of the left upper
limb, affecting both pre-axial and post-axial structures. There is dislocation of the elbow, hypoplasia of the ulna with failure of development of the olecranon notch and process, absence of the thumb, hypoplasia of the index and little finger, partial fusion of the fourth and fifth metacarpals, and a single ossification centre in the carpus (hamate rather than capitate). He also has marked plagiocephaly, and a thoracolumbar scoliosis, convex to the left, which was recorded at birth. The scoliosis has since worsened; its apex is at T10 with an angle of 36°. There is no family history of scoliosis, limb defects or any other congenital malformation, apart from the sibling with spina bifida, and there is no evidence of in-utero compression. The possibility that this child’s unusual defects were caused by pregnavite forte F led me to report the case to the Committee on Safety of Medicines (CSM). The CSM received reports of sixty-one adverse reactions to pregnavite forte F and fourteen related iron and iron-vitamin compound preparations, between January, 1964, and February, 1983. Eight reports were of congenital malformations. The manufacturers confirm that no formal systematic study has ever been done to test the safety of pregnavite forte F in the first trimester. Neither the CSM nor Bencard know of any reports of any untoward reactions from pregnant women that have been attributed to pregnavite forte F. Children from the first cohort were examined for the presence not only of spina bifida but also of any other malformation. However, not all the second cohort children have yet been examined, and the organisers of the trial were unaware of this patient’s malformations despite the fact that they were evident at birth and affected the spine. The plan is to examine all children from the second cohort, and these data will be useful in view of the increasing use of periconceptional vitamins. Three-quarters of obstetricians in the North West region are already recommending periconceptional vitamin supplementation to women at risk. Furthermore, concern about reports of self-administration of high dose vitamin A supplements by pregnant women has recently led the Department of Health to propose that these preparations should be available
only on prescription. In view of the theoretical possibility that vitamin supplementation, whether or not preventing neural tube defects, might harm the embryo/fetus, it is important to establish safety. Preliminary published evidence2does not suggest an increased rate
of malformations in supplemented pregnancies. However, the two cohorts of the UK multicentre trial the women studied are small in number and selected. 1. Smithells
RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981; 56:
911-18. 2. Smithells RW, Nevin NC, Seller. MJ, et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983; i: 1027-31.
.
508 All associations between drug use and side-effects are underreported, and this may be especially true for supposedly innocuous vitamins. All malformations after periconceptional vitamin supplementation, whether in a trial or not, should be reported to the CSM in case any pattern of defects emerges. I would be grateful to
receive details
of any
cases
of limb
defect
after vitamin
supplementation, particularly in view of a report of the interaction of a vitamin D metabolites and genes
differentiation.3
intimately involved with cell
University Department of Child Health, Booth Hall Children’s Hospital,
T. J. DAVID
Manchester M9 2AA
AVAILABILITY OF FOLIC ACID
SIR,—Dr Blank and his colleagues (Feb 4, p 291) state that "Pregnavite forte F and all other preparations containing folic acid at the dosage under discussion can be obtained only on prescription". This is true of preparations marketed for medicinal purposes and sold by pharmacists. However, vitamin products marketed as health foods are available over the counter and by mail order. The quantity of folic acid in the recommended daily dose ranges from less than 1 µg to more than 1 mg, but 5 mg tablets are obtainable. Possibly of more concern, in view of the evidence of teratogenicity in man of high doses of vitamin A analogues, some of the "health" products contain as much as 25 000 IU vitamin A per
ULTRASONIC DEMONSTRATION OF SMALL THYROID NODULES
SIR,-We were perplexed to read Dr Woestyn and Dr Afschrift’s (Nov 26, p 1252) describing "small solid nodules in the thyroid gland which are not palpable and are not detected on letter
radionuclide examination" but without defining precisely what they mean by "small solid nodules". Impalpable thyroid nodules are small and intraparenchymal; those undetectable by scintillation camera in an accurate examination are very small (3-5 mm or less) or fairly small and with normal function; those reliably detectable by ultrasonography must be larger than the resolving power of the ultrasonograph (2-3 mm). In any case with echogenic areas sized about 3 mm it is very difficult, with either scintigraphy or ultrasonography, to be certain that they are really "small solid nodules". If the echogenic areas are large enough for the ultrasonographer to consider them as "small solid nodules" and if they are neither palpable nor detected on scintigraphy, they are probably intraparenchymal normally functioning adenomas which are clinically present with euthyroidism. We have occasionally found echogenic areas in the thyroid gland which were neither palpable nor seen by scintigraphy, but the presence of such areas in 18% of males and 20% of females, among 300 symptom-free patients, as reported by Woestyn and Afschrift, is puzzling. Departments of Infectious Diseases, and Radiology and Nuclear Medicine, USL 31, Ferrara, Italy
MICHELE CASELLI LUCIANO M. FEGGI
tablet. University Department of Paediatrics and Child Health, General Infirmary at Leeds, Leeds LS2 9NS
DRUGS THAT CAN CAUSE CANCER R. W. SMITHELLS
ANTINUCLEAR ANTIBODIES IN PRIMARY BILIARY CIRRHOSIS
SIR,—Antibodies to nuclear antigens (ANA) detectable in dividing rather than resting cells are surprisingly common in primary biliary cirrhosis (PBC). The immunofluorescence pattern on HEp-2 cells described by Dr Powell and colleagues as "atypical discrete speckled nuclear" staining (Feb 4, p 288) has also been termed "multiple nuclear dots". 4,5 NSpI3 and "small bright speckles" (M. Reichlin, F. Arnett, Jr, unpublished).6 We observed this ANA pattern chiefly in PBC (18/135 cases, 13%) and associated it with the presence of Sjogren’s syndrome. 1,2 By contrast, the antibody was found in only 1 case out of 60 with systemic lupus, in only 1 case of primary sicca syndrome (out of 55), and in none of 200 cases of systemic sclerosis or 80 cases of chronic active hepatitis (50 HBsAg-, 30 HBsAg+ )4,5 (and unpublished); the frequency in myositis is about 3% (Reichlin and Arnett). The antigen appears to be a protein,5 and the dots may correspond7 with one of the nuclear bodies recognised by electron microscopy. Besides the new patterns of antinuclear antibody staining seen on HEp-2 cell monolayers, we have found three types of precipitating antibody that seem to be specific for liver disease. Designated XH, XR, and XR2, these precipitin systems are detected by counterimmunoelectrophoresis against tissue extracts. While absent from SLE and other connective tissue diseases, they are found in about 10% of PBC sera and 25% of HBsAg negative .
chronic active
hepatitis.5
Royal Postgraduate Medical School, London W12 0HS
ROBERT M. BERNSTEIN
SIR,—Your Feb 4 editorial is a timely reminder of possible hazards from chemotherapy. Patients with benign lesions must be especially vulnerable. The induction of cancer involves several stages. An early stage of initiation is caused by agents which are mutagenic and produce latent tumour cells which may remain dormant. If these cells are exposed to promoting agents they are converted into tumours which are often benign. A later stage is progression, which involves the transformation of benign lesions into malignant neoplasia. Many experiments in chemical carcinogenesis have shown that progression involving malignant transformation is caused by mutagenic carcinogens, not by promoters. Recent work2 has shown that progression can be caused by mutagens. Nitrogen mustard, chlorambucil, melphalan, and doxorubicin and other therapeutic agents which are mutagenic would cause the progression of benign lesions into malignant tumours. The treatment of benign adenomas or papillomas with agents which are mutagenic would therefore seem to be a dangerous procedure. In the early stages of carcinogenesis a promoting agent is necessary. Most promoting agents increase cell division. Such stimulation of cell division may not be needed with an existing tumour. The urine of smokers contains mutagens,3 so smoking would convert papillomas into carcinomas. The effect the cessation of smoking has in reducing the incidence of cancer4could be due to the removal of the mutagens, reducing the incidence of malignant transformation. Patients with benign tumours such as adenomas and papillomas should not smoke and should not be treated with drugs which have mutagenic activity. TUC Centenary Institute of Occupational Health, London School of Hygiene and
Tropical Medicine, PH, Rothberg PG, Astrin SM, et al. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature 1983; 306: 492-94. Bernstein RM, Callender ME, Neuberger JM, Bunn CC, Williams R, Hughes GRV. Antinuclear antibodies in primary biliary cirrhosis. Ann Rheum Dis 1981; 40: 624
3. Reitsma 4.
(abstr). RM, Neuberger JM, Bunn CC, Callender ME, Hughes GRV, Williams R. Diversity of autoantibodies in primary biliary cirrhosis and chronic active hepatitis. Clin Exp Immunol 1984; 55: 553-60. Fritzler MJ, Valencia DW, McCarty GA. Speckled pattern antinuclear antibodies
5. Bernstein
6.
resembling anticentromere antibodies. Arthritis Rheum 1984; 27: 92-96 7. Bouteille M, Laval M, Dupuy-Coin AM. Localization of nuclear functions as revealed by ultrastructural autoradiography and cytochemistry. In: Busch H, ed Cell nucleus; Vol I. New York: Academic Press, 1974: 3-71.
London WC 1E 7HT
E. BOYLAND
1. Shubik P. Studies on the promoting phase in the stages of carcinogenesis in mice, rats, rabbits and guinea pigs. Cancer Res 1950; 10: 13-17. 2. Henning H, Shores R, Wenk ML, Spangler EF, Tarone R, Yuspa SH. Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters. Nature 1983; 304: 67-69. 3. Yamasaki E, Ames BN. Concentration of mutagens from urine by adsorption with the nonpolar resi XAD2: Cigarette smokers have mutagenic urine. Proc Natl Sci (USA) 1977, 74: 3555-59. 4. Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J 1976; ii: 1525-36.