- Email: [email protected]
Pre-endoscopy screening for helicobacter
showed pronounced bilateral lesions in the thalamus, the cerebral peduncles, and the left caudate nucleus without
(figure). During the next few weeks neurological signs slowly improved. A follow-up MRI 17 days after admission revealed a slight regression of the aforementioned lesions. At the time of discharge from hospital, 21 days after admission, the patient was able to communicate, but had a 4/5 grade paresis of the left arm, and slight facial palsy on the left side. During the next weeks contrast enhancement
her condition further improved, but she died from a pulmonary embolism 10 weeks after transfer to her local
hospital. The localisation of the MRI abnormalities corresponded well with neuropathological reports of severe lesions in the thalamus and basal ganglia in TBE.2 In addition, clinical reports of an extrapyramidal tremor in 75-5% of 679 patients with TBE suggested that basal ganglial involvement is a common
phenomenon in TBE.’
S Lorenzl, H W Pfister, C Padovan, T
Yousry
Department of Neurology and Radiology, Klinikum Großhadern, Ludwig-Maximlians-University of Munich, D-81377 Munich, Germany
1 Kaiser R. Tick-borne encephalitis in southern Germany. Lancet 1995; 345: 463. 2 Jellinger K. The histopathology of tick-borne encephalitis. In: Kunz TH, ed. Tick-borne encephalitis. Vienna: Facultas Verlag, 1981: 59-75. 3 Duniewicz M. Clinical picture of central European tick-borne encephalitis. Münch Med Wschr 1976; 118: 1609-12.
origin of the patients’ two families respectively. However, no common ancestor was discovered until the ninth (patient 1) and llth (patient 2) previous Figure:
Area of
generations. Since this roughly coincides with the period of the 30-years war, the genetic information causing 21hydroxylase deficiency has been preserved in these two individuals for more than 300 years, resulting in an unexpected family reunion in an endocrine outpatient department. Supported in part by grant P 10110-Med from the Austrian Fonds Forderung der Wissenschaftlichen Forschung.
zur
*H Vierhapper, M S Vierhapper, K Kapelari, Sabina Baumgartner-Parzer, R Kofler *Division of Endocrinology and Metabolism, Department of Internal Medicine, of Vienna, 1090 Vienna, Austria; and Department of Molecular Biology, of Innsbruck
University University
Consanguinity in two seemingly unrelated patients with congenital adrenal hyperplasia SiR-Two female patients, born in 1976 (patient 1) and 1980 (patient 2), with an identical family name, were referred to our outpatient department for evaluation of possible congenital adrenal hyperplasia. Both patients were called Alexandra, a name given to 5-4% of female Austrian babies when these patients were born. The two patients did not know of each other’s existence, patient 1 having been bom in Vienna and patient 2 in a small village about 150 km northwest of Vienna. Their parents were also unaware of the other family. Clinical examination, plasma concentrations of 17-OHand testosterone (measured progesterone by and 16-3-855 nmol/L, patients 1 radioimmunoassay) (1381 and 2, respectively), urinary steroid excretion rates (capillary gas-chromatography’); and the pregnantriol/tetrahydro-cortisone ratio’ 31-0 and 1-0-39-0, respectively) confirmed the presence of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in both patients. HLA typing showed one identical allele (A26,B47,Cw6; DR7,DRB4,DQ2) in both patients. Molecular biological analysis2 from blood samples obtained from the patients and their parents showed the following defects: patient 1, V281L mutation of the CYP21B gene and deletion of the CYP21B gene on both maternal and paternal chromosome, respectively; patient 2, complete deletion of the CYP21B gene on both paternal and maternal chromosomes. There was no apparent difference in the genetic defects inherited by the patients from their fathers. These results suggest with a very high probability that the two girls are related to each other. No other member of either family was or is known to have 21-hydroxylase deficiency. The patients’ families were retraced to a possible common area of origin in northwestern Czechia (formerly Austrian Silesia; figure), from where they had migrated to their present home towns around 1850 and 1890,
1
Vierhapper H, Nowotny P, Waldhäusl W, Frisch H. Capillary gas chromatography as a tool for characterization of urinary steroid excretion in patients with congenital adrenal hyperplasia. J Steroid Biochem
2
1985; 3: 363-69. Helmberg A, Tabarelli M, Fuchs MA, et al. Identification of molecular defects causing congenital adrenal hyperplasia by cloning and differential
hybridization of polymerase chain reaction-amplified 21-hydroxylase (CYP21) genes. DNA Cell Biol 1992; 11: 359-68.
Pre-endoscopy screening for helicobacter prospective study by Patel and 18, (Nov 1315)1 colleagues p looking at helicobacter as a serology pre-endoscopy screening test. However, the 36% saving on endoscopies is, we feel, a generous suggested estimate on two accounts. First, patients who were screened negative, were not endoscoped, and did not return their questionnaire, were classified as endoscopies saved. Although this grouping may be correct, it could equally be true that this group were endoscoped elsewhere. On the assumption that all these patients were endoscoped, the number of investigations saved in this study falls from 67 to 54, or 29-5% of patients under 45. Second, we recognise, as SiR-We welcome the first
do Patel and co-workers, that 6 months is insufficient time establish whether an endoscopy has actually been saved
to
or
merely postponed.
With respect to the service as a whole, it is relevant to emphasise that Patel et al do not specify what proportion of the population who undergo endoscopy with biopsy are under 45 years. In a district general hospital setting in midEssex, this proportion is 28% (212/750) at most. Overall savings in endoscopies in this district at best will be between 29-5 and 36-0% on this figure-ie, 8-10%, which more accurately represents the best one might expect to achieve by the use of serological testing to screen in this way, although it does not detract from our support for this approach. Nationally, savings on endoscopies would be 699
considerable. Screening would actually pay for itself if only 2% of endoscopies were saved. However, one could argue that the endoscopies are not actually saved by screening but rather reallocated to a more worthy population. The actual saving is related to the improved early diagnosis of neoplasms in older patients and of management of helicobacter-related pathology in others, indices that are difficult to quantify or cost. Benefits of a screening programme are thus not quickly realised. In the absence of more tangible savings, funding for serological testing will be difficult. For effective screening, results must be accurate. Existing studies evaluating commercial helicobacter serology kits have shown that sensitivities and specificities against gold standard (culture and histology) vary but at best are around 90-95%.2 Between 1 in 10 and 1 in 20 patients will be misclassified on serological screening as negative when they actually harbour the organism. With our own figures and a scenario of 10% patients being misclassified, 13% of these, or 1-3% of peptic ulcer patients, would be missed and would not receive the best treatment initially. The rarity of neoplasms in this age group, especially in the absence of sinister symptoms, means that the clinical implications of false-negative serological tests, though undesirable, are not serious. Carriage of the organism in non-ulcer dyspeptics is common, and evidence for the benefits of eradicating helicobacter in patients without ulcers remains very poor. Last, serology will not detect the very small number of patients who have ulcer disease in the absence of NSAID use and are genuinely Helicobacter pylori
expense of
specificity, which was lowered to 75%.2 With second-generation tests it should prove possible to improve the performance substantially. The proportion of endoscopies saved will also depend on the prevalence of H pylori in the population being screened. Our population is an inner city population with a high proportion of ethnic minorities and a high rate of infection. Populations in more affluent areas could be expected to have a lower rate of infection. Our seropositivity rate was 90/183 (49%), which is similar to that found in Leeds (77/161 [51%]).’ In Northern Ireland where the proportion of individuals with H pylori infection is much higher, serological tests may not be as useful. On the other hand, rates of transmission of H pylori could be decreasing by 25% per decademeaning that the gain from screening can be expected to be greater in coming years. M A Asante, P Patel, R
Lloyd, M A Mendall
Division of Biochemical Medicine, St George’s University of London, London SW17 0RE, UK
1
2
Hospital Medical School,
Sobala GM, Crabtree JE, Pentith JA, et al. Screening dyspepsia by serology to Helicobacter pylori. Lancet 1991; 338: 94-96. Mendall MA, Goggin PM, Levy J, et al. Role of Helicobacter pylori serology in screening prior to endoscopy. Eur J Gastroenterol Hepatol
1992; 4: 713-17. 3
4
negative.
Murray L, Bamford K, O’Reilly D, McCrumm E, Evans A. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease and social class. Br Heart J 1995; 74: 497-501. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis 1993; 168: 219-21.
C Goodbourn, E L Teare, S Saverymuttu, C Khin Public Health
Laboratory, Chelmsford CM2 0YX, UK
bleeding disorder characterised by isolated deficiency of platelet microvesicle generation
A 1
Patel P, Khulusi S, Mendall MA, et al. Prospective screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995; 346: 1315-18.
2
Kost L, Haddad A, Zinsmeister AR. Comparison of commercial serological tests for the detection of Helicobacter pylori antibodies. J Clin Microbiol 1992; 30: 3146-50.
Talley NJ,
A uthors’
reply
SiR-Goodbourn and colleagues make two valuable points. We acknowledge that longer follow-up would be useful. We have checked the computerised records of the Norman Tanner endoscopy unit where all upper gastrointestinal endoscopies are done at St George’s Hospital in the seronegative patients who were screened by serological testing. There was a median follow-up of 29 months (range 20-37) (158-7 patient-years in total). In this period, seven of 70 patients underwent endoscopy at 3, 5, 5, 11, 11, 11, 20, and 21 months. Hence most endoscopies were done in the first year, and the savings after some 2-5 years were 63/183 (34%). Some of the patients could have had endoscopy elsewhere, but we doubt whether many did. All the endoscopies were in those who returned their questionnaires, which suggests that people in the original study who were lost to follow-up may have moved out of the area. Savings in endoscopies will depend on several factors. They will depend on the age distribution of the population being screened if an age cut-off is to be applied to screening. In our population 330/822 (40%) of patients referred for endoscopy are under age 45. This is a lower proportion than in a series from Leeds (151/293=52%).’ The proportion of young people may vary with the ease of access to endoscopy. We and the Leeds team run direct access systems for general
practitioners. With respect to the sensitivity and specificity of the serological test, we used a first-generation test, and the cutoff point was lowered to increase sensitivity to 98% at the 700
injured vessel wall with subsequent aggregation, platelets contribute to fibrin formation by providing intrinsic platelet coagulant proteins (eg, factor V) and a catalytic surface for assembly of prothrombinase complex.’ This activity, referred to as platelet procoagulant activity (PPA), is largely dependent on components of platelet membrane, such as phospholipids.’ Impaired PPA has been reported in patients with congenital and acquired platelet disorders.2,3 An isolated deficiency of PPA was described by Weiss et al4 in a young woman with a lifelong bleeding history and normal laboratory values, apart from prothrombin consumption test (PCT) and platelet factor 3 availability (PF3a), which reflects PPA. In this disorder, referred to as Scott syndrome, platelets have marked deficiency in their ability to support both tenase and prothrombinase complex and impaired capacity to generate microvesicles (MV) upon activation.3 We have observed four patients from three unrelated families with lifelong bleeding disorders in whom all the examinations for coagulation abnormalities were normal, apart from PCT, suggesting an isolated deficiency of PPA. At variance with Scott syndrome, these patients showed consistently slight prolongation of bleeding time (BT) (8 to 15 min ; normal <7-5 min) and no evidence of other platelet function abnormality. The bleeding diathesis was characterised by mucocutaneous haemorrhage and prolonged bleeding after surgery, often requiring blood transfusions. In one patient, severe bleeding after herniorraphy was controlled by giving platelet concentrates. PCT was repeatedly abnormal in all the patients tested over 6 to 9 years (>30%; normal 2-15%) and the abnormality pesisted even after prolonged incubation. By mixing studies, only platelets obtained for PNP test, normal serum and, to a lesser extent, commercial phospholipids SiR-In addition
to
adhesion
to
(figure). During the next few weeks neurological signs slowly improved. A follow-up MRI 17 days after admission revealed a slight regression of the aforementioned lesions. At the time of discharge from hospital, 21 days after admission, the patient was able to communicate, but had a 4/5 grade paresis of the left arm, and slight facial palsy on the left side. During the next weeks contrast enhancement
her condition further improved, but she died from a pulmonary embolism 10 weeks after transfer to her local
hospital. The localisation of the MRI abnormalities corresponded well with neuropathological reports of severe lesions in the thalamus and basal ganglia in TBE.2 In addition, clinical reports of an extrapyramidal tremor in 75-5% of 679 patients with TBE suggested that basal ganglial involvement is a common
phenomenon in TBE.’
S Lorenzl, H W Pfister, C Padovan, T
Yousry
Department of Neurology and Radiology, Klinikum Großhadern, Ludwig-Maximlians-University of Munich, D-81377 Munich, Germany
1 Kaiser R. Tick-borne encephalitis in southern Germany. Lancet 1995; 345: 463. 2 Jellinger K. The histopathology of tick-borne encephalitis. In: Kunz TH, ed. Tick-borne encephalitis. Vienna: Facultas Verlag, 1981: 59-75. 3 Duniewicz M. Clinical picture of central European tick-borne encephalitis. Münch Med Wschr 1976; 118: 1609-12.
origin of the patients’ two families respectively. However, no common ancestor was discovered until the ninth (patient 1) and llth (patient 2) previous Figure:
Area of
generations. Since this roughly coincides with the period of the 30-years war, the genetic information causing 21hydroxylase deficiency has been preserved in these two individuals for more than 300 years, resulting in an unexpected family reunion in an endocrine outpatient department. Supported in part by grant P 10110-Med from the Austrian Fonds Forderung der Wissenschaftlichen Forschung.
zur
*H Vierhapper, M S Vierhapper, K Kapelari, Sabina Baumgartner-Parzer, R Kofler *Division of Endocrinology and Metabolism, Department of Internal Medicine, of Vienna, 1090 Vienna, Austria; and Department of Molecular Biology, of Innsbruck
University University
Consanguinity in two seemingly unrelated patients with congenital adrenal hyperplasia SiR-Two female patients, born in 1976 (patient 1) and 1980 (patient 2), with an identical family name, were referred to our outpatient department for evaluation of possible congenital adrenal hyperplasia. Both patients were called Alexandra, a name given to 5-4% of female Austrian babies when these patients were born. The two patients did not know of each other’s existence, patient 1 having been bom in Vienna and patient 2 in a small village about 150 km northwest of Vienna. Their parents were also unaware of the other family. Clinical examination, plasma concentrations of 17-OHand testosterone (measured progesterone by and 16-3-855 nmol/L, patients 1 radioimmunoassay) (1381 and 2, respectively), urinary steroid excretion rates (capillary gas-chromatography’); and the pregnantriol/tetrahydro-cortisone ratio’ 31-0 and 1-0-39-0, respectively) confirmed the presence of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in both patients. HLA typing showed one identical allele (A26,B47,Cw6; DR7,DRB4,DQ2) in both patients. Molecular biological analysis2 from blood samples obtained from the patients and their parents showed the following defects: patient 1, V281L mutation of the CYP21B gene and deletion of the CYP21B gene on both maternal and paternal chromosome, respectively; patient 2, complete deletion of the CYP21B gene on both paternal and maternal chromosomes. There was no apparent difference in the genetic defects inherited by the patients from their fathers. These results suggest with a very high probability that the two girls are related to each other. No other member of either family was or is known to have 21-hydroxylase deficiency. The patients’ families were retraced to a possible common area of origin in northwestern Czechia (formerly Austrian Silesia; figure), from where they had migrated to their present home towns around 1850 and 1890,
1
Vierhapper H, Nowotny P, Waldhäusl W, Frisch H. Capillary gas chromatography as a tool for characterization of urinary steroid excretion in patients with congenital adrenal hyperplasia. J Steroid Biochem
2
1985; 3: 363-69. Helmberg A, Tabarelli M, Fuchs MA, et al. Identification of molecular defects causing congenital adrenal hyperplasia by cloning and differential
hybridization of polymerase chain reaction-amplified 21-hydroxylase (CYP21) genes. DNA Cell Biol 1992; 11: 359-68.
Pre-endoscopy screening for helicobacter prospective study by Patel and 18, (Nov 1315)1 colleagues p looking at helicobacter as a serology pre-endoscopy screening test. However, the 36% saving on endoscopies is, we feel, a generous suggested estimate on two accounts. First, patients who were screened negative, were not endoscoped, and did not return their questionnaire, were classified as endoscopies saved. Although this grouping may be correct, it could equally be true that this group were endoscoped elsewhere. On the assumption that all these patients were endoscoped, the number of investigations saved in this study falls from 67 to 54, or 29-5% of patients under 45. Second, we recognise, as SiR-We welcome the first
do Patel and co-workers, that 6 months is insufficient time establish whether an endoscopy has actually been saved
to
or
merely postponed.
With respect to the service as a whole, it is relevant to emphasise that Patel et al do not specify what proportion of the population who undergo endoscopy with biopsy are under 45 years. In a district general hospital setting in midEssex, this proportion is 28% (212/750) at most. Overall savings in endoscopies in this district at best will be between 29-5 and 36-0% on this figure-ie, 8-10%, which more accurately represents the best one might expect to achieve by the use of serological testing to screen in this way, although it does not detract from our support for this approach. Nationally, savings on endoscopies would be 699
considerable. Screening would actually pay for itself if only 2% of endoscopies were saved. However, one could argue that the endoscopies are not actually saved by screening but rather reallocated to a more worthy population. The actual saving is related to the improved early diagnosis of neoplasms in older patients and of management of helicobacter-related pathology in others, indices that are difficult to quantify or cost. Benefits of a screening programme are thus not quickly realised. In the absence of more tangible savings, funding for serological testing will be difficult. For effective screening, results must be accurate. Existing studies evaluating commercial helicobacter serology kits have shown that sensitivities and specificities against gold standard (culture and histology) vary but at best are around 90-95%.2 Between 1 in 10 and 1 in 20 patients will be misclassified on serological screening as negative when they actually harbour the organism. With our own figures and a scenario of 10% patients being misclassified, 13% of these, or 1-3% of peptic ulcer patients, would be missed and would not receive the best treatment initially. The rarity of neoplasms in this age group, especially in the absence of sinister symptoms, means that the clinical implications of false-negative serological tests, though undesirable, are not serious. Carriage of the organism in non-ulcer dyspeptics is common, and evidence for the benefits of eradicating helicobacter in patients without ulcers remains very poor. Last, serology will not detect the very small number of patients who have ulcer disease in the absence of NSAID use and are genuinely Helicobacter pylori
expense of
specificity, which was lowered to 75%.2 With second-generation tests it should prove possible to improve the performance substantially. The proportion of endoscopies saved will also depend on the prevalence of H pylori in the population being screened. Our population is an inner city population with a high proportion of ethnic minorities and a high rate of infection. Populations in more affluent areas could be expected to have a lower rate of infection. Our seropositivity rate was 90/183 (49%), which is similar to that found in Leeds (77/161 [51%]).’ In Northern Ireland where the proportion of individuals with H pylori infection is much higher, serological tests may not be as useful. On the other hand, rates of transmission of H pylori could be decreasing by 25% per decademeaning that the gain from screening can be expected to be greater in coming years. M A Asante, P Patel, R
Lloyd, M A Mendall
Division of Biochemical Medicine, St George’s University of London, London SW17 0RE, UK
1
2
Hospital Medical School,
Sobala GM, Crabtree JE, Pentith JA, et al. Screening dyspepsia by serology to Helicobacter pylori. Lancet 1991; 338: 94-96. Mendall MA, Goggin PM, Levy J, et al. Role of Helicobacter pylori serology in screening prior to endoscopy. Eur J Gastroenterol Hepatol
1992; 4: 713-17. 3
4
negative.
Murray L, Bamford K, O’Reilly D, McCrumm E, Evans A. Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease and social class. Br Heart J 1995; 74: 497-501. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis 1993; 168: 219-21.
C Goodbourn, E L Teare, S Saverymuttu, C Khin Public Health
Laboratory, Chelmsford CM2 0YX, UK
bleeding disorder characterised by isolated deficiency of platelet microvesicle generation
A 1
Patel P, Khulusi S, Mendall MA, et al. Prospective screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995; 346: 1315-18.
2
Kost L, Haddad A, Zinsmeister AR. Comparison of commercial serological tests for the detection of Helicobacter pylori antibodies. J Clin Microbiol 1992; 30: 3146-50.
Talley NJ,
A uthors’
reply
SiR-Goodbourn and colleagues make two valuable points. We acknowledge that longer follow-up would be useful. We have checked the computerised records of the Norman Tanner endoscopy unit where all upper gastrointestinal endoscopies are done at St George’s Hospital in the seronegative patients who were screened by serological testing. There was a median follow-up of 29 months (range 20-37) (158-7 patient-years in total). In this period, seven of 70 patients underwent endoscopy at 3, 5, 5, 11, 11, 11, 20, and 21 months. Hence most endoscopies were done in the first year, and the savings after some 2-5 years were 63/183 (34%). Some of the patients could have had endoscopy elsewhere, but we doubt whether many did. All the endoscopies were in those who returned their questionnaires, which suggests that people in the original study who were lost to follow-up may have moved out of the area. Savings in endoscopies will depend on several factors. They will depend on the age distribution of the population being screened if an age cut-off is to be applied to screening. In our population 330/822 (40%) of patients referred for endoscopy are under age 45. This is a lower proportion than in a series from Leeds (151/293=52%).’ The proportion of young people may vary with the ease of access to endoscopy. We and the Leeds team run direct access systems for general
practitioners. With respect to the sensitivity and specificity of the serological test, we used a first-generation test, and the cutoff point was lowered to increase sensitivity to 98% at the 700
injured vessel wall with subsequent aggregation, platelets contribute to fibrin formation by providing intrinsic platelet coagulant proteins (eg, factor V) and a catalytic surface for assembly of prothrombinase complex.’ This activity, referred to as platelet procoagulant activity (PPA), is largely dependent on components of platelet membrane, such as phospholipids.’ Impaired PPA has been reported in patients with congenital and acquired platelet disorders.2,3 An isolated deficiency of PPA was described by Weiss et al4 in a young woman with a lifelong bleeding history and normal laboratory values, apart from prothrombin consumption test (PCT) and platelet factor 3 availability (PF3a), which reflects PPA. In this disorder, referred to as Scott syndrome, platelets have marked deficiency in their ability to support both tenase and prothrombinase complex and impaired capacity to generate microvesicles (MV) upon activation.3 We have observed four patients from three unrelated families with lifelong bleeding disorders in whom all the examinations for coagulation abnormalities were normal, apart from PCT, suggesting an isolated deficiency of PPA. At variance with Scott syndrome, these patients showed consistently slight prolongation of bleeding time (BT) (8 to 15 min ; normal <7-5 min) and no evidence of other platelet function abnormality. The bleeding diathesis was characterised by mucocutaneous haemorrhage and prolonged bleeding after surgery, often requiring blood transfusions. In one patient, severe bleeding after herniorraphy was controlled by giving platelet concentrates. PCT was repeatedly abnormal in all the patients tested over 6 to 9 years (>30%; normal 2-15%) and the abnormality pesisted even after prolonged incubation. By mixing studies, only platelets obtained for PNP test, normal serum and, to a lesser extent, commercial phospholipids SiR-In addition
to
adhesion
to