syndrome. The bileduct damage and immunostains on this biopsy specimen were not consistent with the previously described fibrosing cholestatic hepatitis due to hepatitis B. Serum HBV DNA was 27-4 pg/mL. She was treated with high-dose hepatitis B immunoglobulin. 8 months after transplantation, HBV DNA was 0-4 pg/mL. Immunostains for HBsAg and HBcAg showed that the recipient’s native liver was negative for HBV. Biopsy specimens from the transplanted liver were negative for HBsAg and HBcAg until 7 months after transplantation. The donor was seronegative for HBsAg with serum HBV DNA under 0-4 pg/mL (table). Most adults who acquire HBV infection recover, with loss of HBsAg in the serum and acquisition of anti-HBs and anti-HBc. In some cases of chronic HBV infection, non-neutralising anti-HBs is present with HBsAg in the serum. HBV has been reported after transfusion with blood that was positive for anti-HBe.3 HBV has also been identified by PCR in the serum of some patients with anti-HBc who are HBsAg-negative.4 However, these have increases in serum patients typically aminotransferases.5 Transmission of hepatitis B infection from HBsAg-positive donors to kidney-transplant recipients has been well documented. In addition, HBV has been found in the liver in the absence of HBsAg in the Omata et all demonstrated immunohistochemical evidence of HBcAg in liver biopsy specimens in 7 of 7 patients who were positive for anti-HBc and negative for anti-HBs. Immunohistochemical evidence of HBcAg in liver biopy specimens was also detected in 2 of 5 patients who had both anti-HBc and anti-HBs. Our case illustrates that HBV can reside in the liver (presumably in small amounts) of a patient who appears to have recovered from HBV. If this "recovered" liver is used as a donation, viral replication can be reactivated in the presence of immunosuppression. Others have reported similar findings The 5’ promoter region of HBV has a steroid-responsive element leading to increased viral replication.8 Although our patient manifested HBV infection, clinically she has had mild disease. She was unable to eradicte infection because of her immunosuppressed state.9 Ongoing high-dose immunosuppresion led to the development of rapid viral replication in the liver with HBsAg and HBeAg in the serum, and subsequent acute hepatitis B infection. The donor for our patient did not have active viral replication at organ procurement (HBV DNA was undetectable in serum). The usefulness of this one test in the assessment of the infectivity of potential organs is limited. PCR techniques have also been criticised for being overly sensitive.1O Also, because PCR technology is not readily available, it would not be possible to wait for an HBV DNA test of serum (or a liver biopsy specimen) to judge whether to use a donor who is seropositive for anti-HBc and anti-HBs. Based on our experience, we recommend against transplantation of livers from patients who are seropositive for anti-HBc and anti-HBs. serum.
Omata M, Afroudakis A, Liew C-T, Ashcavai M, Peters RL. Comparison of serum hepatitis B surface antigen (HBsAg) and serum anticore with tissue HBsAg and hepatitis B core antigen (HBcAg). Gastroenterology 1978; 75: 1003-09. 2 Marcellin P, Giostra E, Martinot-Peifnoux M, et al. Redevelopment of
antigen after renal transplantation. Gastroenterology
1991; 100: 1432-34. Seeff LB, Buskell B, et al. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen. N Engl J Med 1978; 298: 1379-83. 4 Thiers V, Kremsdorf D, Nakajima E, et al. Transmission of hepatitis B from hepatitis-B-seronegative subjects. Lancet 1988; ii: 1273-76. 5 Scully LJ, Sung H, Pennie R, Gill P. Detection of hepatitis B virus DNA in the serum of Canadian hepatitis B surface antigen negative, anti-HBc positive individuals, using the polymerase chain reaction. J Med Virol 1994; 44: 293-97. 6 Radomski JS, Moritz MJ, Armenti VT, Munoz S, Smolinski S. Risk of hepatitis B transmission from organ donors who are hepatitis B surface antigen (-) and hepatitis core antibody (+). Hepatology 1994; 20: 129A. 7 Donovan JP, Schafer DF, Goonewardene T, et al. Development of hepatitis B infection after liver transplantation with donor livers from patients with HBcAb and HBsAb. Hepatology 1994; 20: 129A. 8 Tur-Kaspa R, Laub O. Corticosteroids stimulate hepatitis B virus DNA, mRNA and protein production in a stable expression system. J Hepatol 1990; 11: 34-36. 9 Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982; 96: 447-79. 10 Brainard JA, Greenson JK, Vesy CJ, et al. Detection of cytomegalovirus in liver transplant biopsies: a comparison of light microscopy, immunohistochemistry, duplex PCR, and nested PCR. Transplantation
1994; 57: 1753-57.
Departments of Surgery (J A Lowell MD, T K Howard MD, S Shenoy MD), Medicine (H M White MD, D C Brennan MD, M G Peters MD), and Pathology (P C Huettner MD), Washington University School of Medicine, St Louis, MO 63110, USA Correspondence to: Dr Jeffrey A Lowell
Sleep apnoea and nocturnal angina
Hypoxaemia occurs with sleep apnoea and might induce nocturnal angina. Sleep apnoea was found in 9 of 10 patients with nocturnal angina pectoris. Nocturnal angina diminished during treatment of sleep apnoea by continuous positive airway-pressure, and the number of nocturnal myocardial ischaemic events measured by computerised vector-cardiography was reduced. Lancet 1995; 345: 1085-87
Hypoxaemia and increased blood
pressure and heart rate of obstructive consequences sleep apnoea and these factors may induce nocturnal angina.’-3 Our objective was to investigate whether nocturnal angina was related to sleep apnoea and to evaluate the effect of continuous positive airway-pressure on nocturnal angina. are
We studied ten consecutive men with severely disabling angina and nocturnal angina on at least 2 nights per week for at least 1 month who were referred for coronary arteriography. No drugs were withdrawn before or during study. Overnight recordings of nasal and oral airflow, abdominal and chest saturation, body position, movements, oxygen
electrocardiogram (V5), electro-oculograms, electroencephalograms, and submental electromyogram were registered on a Nihon Koden 17-channel ink-jet recorder. Apnoea was defined as cessation of airflow for at least 10 s, and hypopnoea as a 50% decrease in the thermistor tracing compared with baseline and an arousal, a pulse alteration, or an oxygen desaturation. 1085
Computerised vector-cardiogram (MIDA 1000, Ortivus Medical) was continuously recorded during the study night with the ST deviation measured at 20 ms after the J-point. The complexes were averaged for 20 s. A reversible increase for at least 40 s of the ST-change vector-magnitude (STC-VM) by over .4 0-05 mV was defined as myocardial ischaemia A repeat sleep study with nasal continuous positive airwaypressure or bilevel positive airway-pressure (Respironics) was done on average 11 (SD 9) days after the initial study if sleep apnoea with more than five apnoea or hypopnoea episodes per hour of sleep was foundNo changes in medication were made and no patient underwent any coronary intervention between the two occasions. Vector-cardiographic data from periods when the patient was disconnected from continuous positive airwaypressure were excluded from analysis. Mean age was 63 (SD 7) years and body-mass index 30 (4) kg/m2. All patients had coronary artery disease with over 50% stenosis in at least one vessel on coronary arteriograms, and eight had three-vessel disease. All patients snored except one with central apnoea. Six patients stated they were always or almost always tired
during the daytime. One patient remained awake during the study night. All the remaining nine patients were found to have sleep apnoea with 40 (19, range 19-71) apnoea/hypopnoea episodes per hour of sleep. Such episodes decreased during continuous positive airway-pressure to 11 (14, 0-46) (p<0-01, Wilcoxon’s signed-rank test). Four patients were awakened by nocturnal angina (chest pain associated with increased STC-VM) during the initial sleep study; none were awakened during the night of continuous positive airways-pressure (table, figure). Four of the five nocturnal angina attacks were preceded by apnoea and one with heart-rate increase during rapid-eye-movement (REM) sleep. Thirty-two episodes of increased STC-VM occurred during the initial recordings in six patients. The number of STC-VM increases
were reduced to nine in five examination with continuous or follow-up patients bilevel positive airway-pressure (table). Five episodes were excluded because of disconnection in two patients for a total of 85 min. Apnoea or hypopnoea occurred within 90 s before the increase in STC-VM in 18 of 32 episodes in five patients during the initial study. This was reduced to 1 of 9 episodes during treatment (p<0-01). An increase in heart rate of over 10/min preceded 5 of 32 increases in STCVM during the initial recordings and 1 of 9 at follow-up. The increases in STC-VM were equally distributed between REM and non-REM sleep in all but one patient (number 6). Increased STC-VM during REM sleep was
Figure: Sleep stage, oxygen saturation (Sa02) and STC-VM in patient 2 Patient was awakened by attack of angina by apnoea and hypoxaemia.
in this patient during the initial recording but not during the night of continuous positive airway-pressure. The nocturnal angina disappeared after onset of home continuous positive airway-pressure in all but one patient. Three patients were improved from functional class III (New York Heart Association) to class II immediately after onset of home treatment. Our results show a relation between nocturnal angina pectoris and sleep apnoea. All patients examined with disabling coronary artery disease and nocturnal angina had sleep apnoea. Apnoea was the most common preceding factor of nocturnal ischaemia and ischaemic episodes decreased during treatment of nocturnal angina with continuous positive airway-pressure. Apnoea was more common than expected. Over 5 episodes of apnoea and hypopnoea per hour of sleep occur in 31%, and over 15 in 9% of men aged 50-60.6 Signs of increased oxygen demand, such as increased heart rate before ischaemia, were seldom seen, by contrast with the results of Quyyumi et al. Both hypoxaemia and increased vasomotor tone may trigger nocturnal ischaemia. Less than 90 s elapsed between apnoea and signs of ischaemia according to vector-cardiography. Increased blood pressure or contractility without heartrate increase appears unlikely to increase myocardial oxygen requirement within such a short period. A reduction in coronary blood-flow and a consequent reduction in oxygen supply by a swift increase in seen
*Did not fall asleep.
†p<0.01, ‡p<0.05 (Wilcoxon’s signed-rank test). OA=obstructlve apnoea, CA=central apnoea. Table: Clinical details with and without night-time continuous positive airway-pressure
at 0446 h that was
is a more probable because this may induce ischaemic STmechanism, changes within 40 s.’ A study that includes more patients is needed to establish whether sleep apnoea triggers
vasomotor tone or coronary spasm
The study was supported by grants from the Swedish Heart and Lung Foundation and the Swedish Association for Heart and Lung Patients.
Jensen SM, Johansson G, Osterman G, Reiz S, Näslund U. On-line computerized vectorcardiography monitoring of myocardial ischaemia during coronary angioplasty: comparison with 12-lead electrocardiography. Coron Artery Dis 1994; 5: 507-14. 5 Sullivan CE, Issa FQ, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; i: 862-65. 6 Young T, Palta M, Dempsey J, Skatrod J, Weber S, Badr S. The
References 1 Guilleminault C, Connolly S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome. Lancet 1984; 1: 126-31. 2 Bålfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Resp Crit Care Med 1994; 150: 1587-91.
Quyyumi AA, Mockus LJ, Wright CA, Fox KM. Mechanisms of nocturnal angina pectoris: importance of increased myocardial oxygen demand in patients with severe coronary artery disease. Lancet 1984; i:
Circulation 1980; 61: 759-68.
Departments of Pulmonary Medicine and Allergology (K A Franklin MD, C Sahlin RTA), and of Internal Medicine (J B Nilsson MD, U Näslund MD PhD), University Hospital of Northern Sweden, S-90185 Umeå, Sweden Correspondence to:
occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: 1230-35. Chierchia S, Brunelli C, Simonetti I, Lazzari M, Maseri A. Sequence of events in angina at rest: primary reduction in coronary flow.
The geographic association between ovarian cancer and tall stature suggests a link with rapid growth in early childhood. Among 5585 women born in Hertfordshire, UK, 41 who died from ovarian cancer had had a high rate of weight gain in infancy. Whereas their mean birthweight was the same as that of the other women, their mean weight at 1 year was higher (22·3 pounds [10·1 kg] vs 21·4 pounds [9·7 kg], p=0·01). These observations are consistent with the hypothesis that ovarian cancer is linked to altered patterns of gonadotropin release established in utero when the fetal hypothalamus is
imprinted. Lancet 1995; 345 : 1087-88
Although ovarian cancer has been linked to high fatconsumption, mumps virus, and use of talcum powder,’ the evidence that it is caused by external agents of this kind is inconclusive. Rather, associations with early age at menarche and nulliparity suggest that ovarian cancer is linked to the regulation of reproductive hormones. 1,2 The geographic distribution of ovarian cancer in the counties of England and Wales is inversely related to that of coronary heart disease.3 Counties with high death rates from ovarian cancer, which are mostly in the south and east, have low death rates from coronary heart disease. Counties with high rates of ovarian cancer also tend to have tall populations, whereas the populations of counties with high rates of coronary heart disease tend to be short. Adult height is predicted by height and weight in early childhood, and the association between short stature and coronary heart disease, which has been found consistently in epidemiological studies, reflects in part an association between the disease and low weight gain in infancy.4 In Hertfordshire, England, men who had low weights at 1 year of age had a threefold increase in risk of death from coronary heart disease.4
Dr Karl A Franklin
Could the geographic relation between ovarian cancer and tall stature reflect an association with high rates of infant growth? Such an association would be consistent with the high rates of ovarian cancer in affluent, western countries. We have examined this association in women who were born in a southern county of England. Their birthweights and weights at 1 year were recorded, and their death rates from different causes are known. All births in Hertfordshire from 1911 onwards were notified by the attending midwife.4 Health visitors saw the babies periodically throughout infancy and recorded the method of feeding. At 1 year of age the babies were weighed. We traced 5585 (60%) of the 9323 girls born during 1923-30. The average birthweight and weight at 1 year of those who were traced were the same as those for girls who were not traced. Their death rates from coronary heart disease have been describedWe compared the numbers of deaths from ovarian cancer at ages 20-74, during 1951-93, with the national rates for women of a corresponding age and year of birth. Death rates were expressed as standardised mortality ratios with the national average as 100. We used the same groups of birthweight and weight at 1 year as in our previous analyses. Tests for trend were based on the corresponding log-linear model, and for differences between means we used a two-sample t test. 41 of the women had died from ovarian cancer. Their average age at death was 55 years (range 32-68). The
SMR=standardised mortality ratio. Table: Standardised mortality ratios for ovarian according to birthweight and weight at 1 year