Volume 171 Issue 9

Research Reliability of sentinel node status in predicting axillary lymph node involvement in breast cancer James Kollias, P Grantley Gill, Barry E Chatterton, Vivian E Hall, Melissa A Bochner, Brendon J Coventry and Gelareh Farshid MJA 1999; 171: 461-465 For editorial comment, see Ung & Wetzig Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Oncology Abstract Objectives: To assess the reliability of determining sentinel node status in staging regional lymph nodes in breast cancer. Design and setting: Prospective validation study in a major public teaching hospital, comparing histological sentinel node status with that of remaining axillary nodes. Patients: 117 women who underwent sentinel node biopsy and axillary dissection for primary breast cancer between 1995 and 1998. Main outcome measures: Intraoperative success rate in sentinel node identification; false negative rate; predictive value of negative sentinel node status; overall accuracy of sentinel node status. Results: The sentinel node was identified at operation in 95 patients (81.2%). Tumour involvement of the sentinel node was demonstrated in 29 of 31 women (93.5%; 95% CI, 79%-99%). Sixty-four of the 66 women in whom the sentinel node was negative for tumour showed no further involvement of remaining axillary nodes (standard haematoxylin-eosin histological assessment), giving a predictive value of negative sentinel node status of 97% (95% CI, 89%-100%). The overall accuracy in 95 women in whom sentinel node status was compared with axillary node status was 97.9%. Conclusions: Histopathological examination of the sentinel node is an accurate method of assessing axillary lymph node status in primary breast cancer and is likely to be incorporated into future surgical management of women with primary breast cancer. Introduction Axillary lymph node status is the most important prognostic indicator in early breast cancer, and the detection of nodal metastases is a key factor in recommending adjuvant systemic therapy after surgery.1,2 Surgical removal and histopathological assessment of these nodes remains the only accurate way of determining their involvement with tumour. Axillary dissection also reduces the risk of regional recurrence of breast cancer in the axilla,3 as the risk is inversely related to the number of axillary nodes removed.4However, axillary lymph node dissection is not without morbidity: seroma formation, wound infection, damage to nerves, and reduced shoulder mobility. Of particular importance is lymphoedema, which occurs in 15% and 30% of women.5-8 As a consequence, other, less invasive methods of assessing axillary node status have been investigated (eg, mammography, ultrasound and colour doppler imaging, magnetic resonance imaging [MRI] and positron emission tomography [PET] scanning), but have yet to achieve the accuracy of surgical staging. Axillary node sampling -- removal of a small number of Level 1 nodes (those below the lower border of the pectoralis minor muscle) -- is associated with fewer complications, and has been proposed as an alternative to complete axillary dissection for staging of the axilla.9,10 However, its efficacy has been questioned.11 With the advent of population-based mammographic screening programs, there has been a dramatic decrease in tumour size and lymph node involvement in women diagnosed with early breast cancer.12,13 Thus, an increasing proportion of women will undergo axillary dissection only to find that their lymph glands are free of disease. Ideally, there should be a method of providing accurate assessment of axillary lymph node status without the need for axillary dissection. The sentinel lymph node (the first draining node within a lymph node basin) is the first to receive lymphatic drainage from a tumour site. Selective biopsy of this node allows the detection of metastases in clinically normal nodes with a low false negative rate, and has been used in patients with operable breast cancer by several groups.14-19 Their findings indicate that the status of the sentinel node(s) can accurately predict that of the fully dissected axilla. We report our experience of lymphoscintigraphy, intraoperative sentinel node mapping and sentinel node biopsy in 117 women with primary operable breast cancer. Our aims were: To assess the success rate of lymphoscintigraphy and intraoperative lymph node mapping in identifying the sentinel node; and To assess the accuracy of sentinel node biopsy in staging the axillary nodes. Methods Patients A consecutive series of 117 women treated for primary breast cancer at the Royal Adelaide Hospital Breast Unit between June 1995 and August 1998 entered a prospective evaluation of the technique of sentinel lymph node biopsy in breast cancer. Ethical approval for the study was provided by the Human Ethics Committee of the Royal Adelaide Hospital. All women gave written informed consent to participate in the study. Eligibility criteria were: Operable primary breast cancer (tumour, < 5 cm in diameter), detected clinically and by imaging, and confirmed by cytology, core biopsy or open biopsy; Clinically impalpable axillary lymph nodes; and The usual surgical indications for axillary dissection (ie, invasive, operable cancer). Patients were excluded if their condition did not fulfil these criteria; if they were pregnant or currently breastfeeding; if there was a high clinical suspicion or preoperative verification of axillary nodal involvement; or if they had metastatic breast carcinoma or a preoperative diagnosis of ductal carcinoma-in-situ. The women's ages ranged from 31 to 82 years (median, 60 years). Their clinical characteristics are summarised in Table 1. During the period of study, no eligible women refused entry to the study. Isotope injection technique The radiopharmaceutical used was 99mTc-labelled antimony sulfide colloid ("Lymph-Flo", Royal Adelaide Hospital Radiopharmacy). The colloid underwent filtration through a 0.2-µ sterile filter, ensuring more than 80% of the filtered particles were smaller than 20 nm. A 32-mm, 25-gauge needle was used to inject 40 MBq of tracer to four sites surrounding the palpable margin of the breast lesion. If the lesion was not palpable, ultrasound localisation was performed, and the injection was given in a similar manner under ultrasound guidance. In the initial stages of the study, 0.5 mL of tracer was injected in each of 82 patients. For the remaining 35 women, the injected volume was increased to 4 mL in four divided doses. In these latter women, the injection site was lightly massaged, and they were instructed to move their arms to encourage lymphatic movement. All radioisotope injections were given on the morning of the day of surgery. Lymphoscintigraphy and lymph node mapping After injection, serial anterior and appropriate lateral images were obtained with a large-field-of-view gamma camera (GE XRT, General Electric) at about 15-minute intervals until the initial draining node (or nodes) was visualised (Figure 1). The surface projection of the sentinel node was then marked on the skin with a radioactive marker. Orthogonal projections were made by the established technique of "triangulation"; the marks were joined by a straight line to indicate the base of a right-angled triangle with the node at the apex. Body outline was marked with a radioactive marker, or a transmission image was performed by holding a "flood" source behind the patient. The intraoperative probe (RMD CTC 4 with audible guidance system, Gammasonics, Melbourne) was calibrated in the Nuclear Medicine Department to the counts detected at the skin surface. Surgical technique After completion of lymphoscintigraphy and sentinel node mapping, the patient and hand-held gamma probe were transferred to the operating theatre. In 66 patients, 1-2 mL of 2.5% Patent Blue V dye (Guerbet Laboratories, France; distributed by Fauldings Australia, Adelaide) was injected into the breast parenchyma or subdermal fat overlying the tumour to facilitate intraoperative identification of the sentinel node. Blue dye alone was used in 19 patients before a gamma probe was available. At operation, a 2-cm transverse axillary incision was made in accordance with the planned axillary lymph node dissection, but taking into account the preoperative skin markings indicating the location of the sentinel node at lymphoscintigraphy. An attempt was made to identify the node in vivo before commencement of axillary dissection. The node was identified by its blue colour (if dye was used) and/or by the hand-held gamma probe (in a sterile sheath). The probe enabled detection of individual nodes with radioactivity levels significantly greater than those of the axillary fat (Figure 2). Sometimes more than one sentinel node was identified. If both dye and radioisotope were used for lymphatic mapping, the blue node corresponded to the most radioactive node. Once the sentinel node was removed, its activity was reassessed ex vivo and it was sent for histological examination separately from the main axillary nodal specimen. The axillary fat was then examined with the gamma probe in vivo to exclude any residual activity suggesting further sentinel nodes. The axillary skin incision was then lengthened and a level I and II axillary lymph node dissection was performed. The resected axillary tissue was examined ex vivo using the probe to identify any further radioactive or blue lymph nodes not identified during in-vivo examination. Histopathological examination All specimens were examined by duty histopathologists at the Institute of Medical and Veterinary Science. The histological tumour features were classified according to tumour size and grade,20 and presence or absence of vascular invasion.21 Generally, sentinel nodes were submitted in their entirety for histological evaluation. Those larger than 1.5 cm were sliced before paraffin embedding. Each node was placed in an individual cassette. At least one section of each node was stained with haematoxylin-eosin (H&E) and examined with light microscopy. Immunohistochemical analysis (antikeratin antibody CAM 5.2, Becton Dickinson) was performed in H&E-stained sections suspected of having metastatic tumour deposits. The axillary fat was fixed in formalin and the nodes were later isolated from the fat after clearance in Carnoy's solution. Each node was placed in an individual cassette and larger nodes were sliced before being embedded in paraffin. At least one H&E-stained section of each node was examined. Statistical analysis A false negative sentinel node was defined as an excised sentinel lymph node which contained no microscopically detectable tumour, but which was associated with at least one tumour-positive node in the remaining resected axillary tissue. The false negative rate and the predictive value of negative sentinel node status were calculated together with 95% confidence intervals. The kappa (κ) statistic for paired data was used to assess the level of agreement between sentinel node status and axillary node status.22 A score of -1 indicates perfect disagreement and + 1 indicates perfect agreement. The corresponding z and P values were calculated. Univariate analysis was used to assess clinical and histological factors that predicted intraoperative sentinel node localisation. Fisher's exact and χ2 tests were used for other analyses between groups. Results Lymphoscintigraphy The sentinel node was identified on preoperative lymphoscintigraphy in 74 of 117 women (63.2%). One sentinel node was identified in 52 women, two were identified in 20 women, and in two further women three and four sentinel nodes were identified, respectively. The sentinel node was identified outside the lower axilla in nine patients (Table 2). A significant increase in sentinel node identification at lymphoscintigraphy was noted after the injection of larger isotope volumes into the breast (77% v 57%; χ2 = 4.15; P = 0.04), while rates of intraoperative detection of the sentinel node also increased (91% v 76%; χ2 = 3.4; P = 0.06). Intraoperative sentinel node identification The sentinel node was identified in 95 patients (81.2%) at operation. In 66 women, one sentinel node was identified, two were identified in 20 women, three in eight women, and in one four sentinel nodes were identified. The sentinel node was identified in 35 of the 51 women in whom radioisotope alone was used (68.6%), compared with 18 of 19 women in whom blue dye alone was used (94.7%) and 42 of 47 women in whom both isotope and blue dye were used (89.4%) (χ2 = 9.6; P = 0.008). Of the clinical and histological factors assessed for predicting intraoperative sentinel node identification, only a positive preoperative lymphoscintigram was significant (χ2 = 28.7; P < 0.001) (Table 3). Predictive value of sentinel node(s) In 95 patients in whom the sentinel node was identified, 31 had metastatic tumour involvement of axillary nodes (32.6%). Tumour involvement of the sentinel node was demonstrated in 29 of these 31 women (93.5%; 95% CI, 79%-99%), giving a false negative rate of 6.5%. The sentinel node was the only positive node in 13 of 31 women (41.9%). Of 66 women with a negative sentinel node, 64 had no tumour involvement in the remainder of the axillary nodes (by standard H&E histological assessment), giving a predictive value of negative sentinel node status of 97% (95% CI, 89%-100%). The overall accuracy in 95 patients in whom sentinel node status was compared with axillary node status was 97.9% (κ, 0.95; z = 9.3; P < 0.001) (Table 4). Of the 22 women in whom the sentinel node was not identified at operation, six had nodal metastases on histological examination of the dissected axillary nodes. Discussion The concept of the sentinel lymph node is based on the premise that the first lymph node to receive lymphatic drainage from a tumour site should be the first site of lymphatic spread; that "skip metastases" do not occur; and that the absence of tumour metastases in the sentinel node implies the absence of lymph node metastases in the entire lymphatic basin. This concept was first described in penile carcinoma in 197723 and was later studied in patients with cutaneous melanoma.24 Previous detailed pathological studies of axillary nodes in women with breast cancer have demonstrated a skip metastasis rate of less than 5%.25,26Our results confirm that the status of the sentinel lymph node(s) predicts the overall axillary lymph node status with a high degree of accuracy, and can thus be used to limit the morbidity associated with axillary surgery. More importantly, the predictive value of a tumour-free sentinel node was 97%. As such, women identified with a sentinel node free of metastatic tumour can be reassured that further axillary lymph node involvement is highly unlikely. Other studies of sentinel node biopsy in breast cancer (using blue dye and radioactive isotope techniques) have shown sentinel node status to accurately determine axillary lymph node status in more than 95% of women.14-19 We still need to deal with the problem that 3% of patients exhibited tumour-positive axillary nodes when the biopsied sentinel node was negative. The optimal method of pathological assessment of the sentinel node remains unresolved and was not addressed in our study. This issue was discussed at the Adelaide Workshop on Sentinel Node Biopsy in Breast Cancer27 and is the subject of further studies by one of us (G F). Giuliano et al28 have found that immunohistochemical studies of sentinel nodes showed micrometastases in an additional 11% of women whose sentinel node was tumour negative on light microscopy. However, similar assessment of two women with false negative results in our study did not reveal metastases. The implications of micrometastases detected by sensitive immunohistochemical and polymerase chain reaction (PCR) techniques for multidisciplinary care are unknown. They are currently being investigated in trials in the United States (Merrick Ross, Associate Professor of Surgical Oncology, M D Anderson Hospital, Texas, USA, personal communication). Until the answers to this question are available, a large UK trial (ALMANAC) is assessing sentinel node status by conventional microscopy (R Mansell, Professor of Surgery, Cardiff University, UK, personal communication), as this is the current method on which treatment planning is based. These uncertainties emphasise the need for Australian studies to incorporate detailed protocols for pathology assessment of the sentinel node. The prognostic implications of a false negative sentinel node are uncertain, but should be compared with the considerable physical morbidity associated with axillary dissection in lymph node negative women. There is a definite error rate in routine pathological assessment of axillary dissection specimens which may underestimate metastatic disease by 11%-30%,27,29 while unselective sampling of the axilla fails to remove involved nodes in many women.11 The false negative rate must ultimately be minimised by maximal detection of the sentinel node by scintigraphy, careful operative technique and optimal pathological assessment, which requires an experienced multidisciplinary team. The concomitant intraoperative use of both blue dye and radionuclide methods for lymphatic mapping was particularly useful for sentinel node biopsy. Preoperative lymphoscintigraphy permits identification of the sentinel node and subsequent planning of the site of skin incision. Several radiolabelled colloids are currently in use around the world, but the recent workshop in Adelaide27 identified antimony colloids as having excellent properties for lymphoscintigraphy. This is the only agent available for this purpose in Australia and is able to visualise sentinel nodes in the internal mammary chain as well as in the axillary node group. The blue dye technique facilitated visualisation of the sentinel node at the time of surgery and was supplemented by the use of an intraoperative gamma probe. In all patients in whom both blue dye and radionuclide were used, the blue node corresponded to the "hot" node previously identified on lymphoscintigraphy and identified intraoperatively with the hand-held gamma probe. Furthermore, the identification of a sentinel node at preoperative lymphoscintigraphy was the only factor significantly associated with the intraoperative identification of the sentinel node. Lymphoscintigraphy also demonstrates the number and location of potential sentinel nodes requiring biopsy. The initial rate of preoperative identification of the sentinel node by lymphoscintigraphy in our series was lower than that in published reports. However, this was overcome by increasing the volume of the isotope injection and presumably increasing tissue oncotic pressure, lymphatic uptake and drainage. The importance of isotope volume in achieving successful scintigraphic identification of the sentinel node has also been suggested by others.30 Sentinel lymph node mapping and biopsy are likely to be incorporated into clinical practice, provided they can be successfully performed in most patients, and it can be shown that women with negative sentinel nodes who undergo no further treatment to the axilla are not adversely compromised in terms of disease-free and overall survival. This will be best established by randomised controlled studies comparing sentinel node biopsy with standard axillary surgical management. In addition, these studies should address the implied assumption of lower short and long term morbidity associated with this procedure, the optimal methods of pathological assessment, and allow analysis and comparison with clinicopathological variables in predicting sentinel node status. Studies are currently being undertaken in Europe, the United Kingdom and the United States and it is hoped that Australian women can soon participate in similar trials in Australia. References Carter CL, Allen C, Henson DE. Relation of tumour size, lymph nodes status and survival in 24,740 breast cancer cases. Cancer 1989; 63: 181-187. Fisher ER, Anderson S, Redmond C, Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project Protocol B-06: 10 year pathological and clinical prognostic discriminants. Cancer 1993; 71: 2507-2514. Fisher D, Woolmark N, Bauer M, et al. The accuracy of clinical nodes staging and of limited axillary dissection as a determinant of histological nodal status in carcinoma of the breast. Surg Gynecol Obstet 1991; 152: 765-772. Axellsson CK, Mouridsen HT, Zedeler K. Axillary dissection of Level I and II lymph nodes is important in breast cancer classification: The Danish Breast Cancer Cooperative Group (DBCG). Eur J Cancer 1992; 28: 1415-1418. Kissin MW, Querci-Della-Rovere G, Easton D, Westbury G. Risk of lymphoedema following the treatment of breast cancer. Br J Surg 1986; 73: 580-584. Aitken RJ, Gayes MN, Rodger A, et al. Arm morbidity within a trial of mastectomy and either node sample with selective radiotherapy or axillary clearance. Br J Surg 1989; 76: 568-571. Larson D, Weinstein M, Goldburg I, et al. Oedema of the arm as a function of the extent of axillary surgery in patients with Stage 1-2 carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 1986; 12: 1575-1582. Liljegren G, Holmburg L. Arm morbidity after sector resection and axillary dissection with or without postoperative radiotherapy in breast cancer. Stage 1: Results from a randomised trial. Uppsala Orebro Breast Cancer Study Group. Eur J Cancer 1997; 33: 193-199. Steel RJC, Forrest APM, Gibson T, et al. The efficacy of lower axillary sampling in obtaining lymph node status in breast cancer: a controlled randomised trial. Br J Surg 1985; 72: 368-369. Dixon JM, Dillon P, Anderson TJ, Chetty U. Axillary node sampling in breast cancer: an assessment of its efficacy. Breast 1998; 7: 206-208. Kissin MW, Thompson PH, Price AB, et al. The inadequacy of axillary sampling in breast cancer. Lancet 1982; 1: 1210-1212. Tabar L, Fagerberg G, Duffy SW, et al. Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 1992; 30: 187-210. Cady B, Stone MD, Schuler JG, et al. The new era in breast cancer: invasion, size and lymph node involvement dramatically decreased as a result of mammographic screening. Arch Surg 1996; 131: 301-308. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy in breast cancer. Ann Surg 1994; 220: 391-401. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818-1822. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 1997; 349: 1864-1867. Borgstein PJ, Pijpers R, Comans EF, et al. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 1998; 186: 275-283. Cox CE, Pendas S, Cox JM, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998; 227: 645-653. O'Hea BJ, Hill ADK, El-Shirbiny AM, et al. Sentinel lymph node biopsy in breast cancer: initial experience at Memorial Sloan-Kettering Cancer Center. J Am Coll Surg 1998; 186: 423-427. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403-410. Pinder SE, Ellis IO, Galea M, et al. Pathological prognostic factors in breast cancer. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology 1994; 24: 41-47. Fliess JL. Statistical methods for rates and proportions. 2nd edition. New York, NY: John Wiley and Sons, 1981. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456-466. Morton DL, Wen D-R, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392-399. Berg JW. The significance of axillary node levels in the study of breast cancer. Cancer 1955; 8: 776-778. Veronesi U, Rilke F, Luimi A, et al. Distribution of axillary node metastases by level of invasion: an analysis of 539 cases. Cancer 1987; 59: 682-687. Kollias J, Gill PG, Chatterton B, et al. Sentinel node biopsy in breast cancer: recommendations for surgeons, pathologists, nuclear physicians and radiologists in Australia and New Zealand. Aust N Z J Surg 1999. In press. Giuliano AE, Dale PS, Turner RR, et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995; 222: 387-399. Hainsworth PJ, Tjandra JJ, Stillwell RG, et al. Detection and significance of occult metastases in node negative breast cancer. Br J Surg 1993; 80: 459-463. Krag DN, Ashikaga T, Harlow SH, Weaver DL. Development of sentinel node targeting technique in breast cancer patients. Breast J 1998; 4: 67-74. (Received 22 Apr, accepted 9 Sep, 1999) Authors' details Royal Adelaide Hospital and Women's Health Centre, Adelaide, SA. James Kollias, MB BS, FRACS, Staff Surgeon, Breast-Endocrine and Surgical Oncology Unit. P Grantley Gill, FRACS, MD, Head, Breast-Endocrine and Surgical Oncology Unit; and Associate Professor, University of Adelaide. Barry E Chatterton, MB BS, FRACP, Director, Department of Nuclear Medicine. Vivian E Hall, MB BS, FRACR, Radiologist, Department of Radiology. Melissa A Bochner, MB BS, FRACS, Senior Registrar, Breast-Endocrine and Surgical Oncology Unit. Brendon J Coventry, FRACS, PhD, Senior Surgeon, Breast-Endocrine and Surgical Oncology Unit; and Senior Lecturer, University of Adelaide. Department of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, SA. Gelareh Farshid, MB BS, FRCPA, Senior Lecturer, University of Adelaide. Reprints will not be available from the authors. Correspondence: Associate Professor P G Gill, Breast-Endocrine Surgical Oncology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000. cbatesbrownswordATmedicine.adelaide.edu.au Back to textBack to textBack to textBack to text 3: Clinical and histological features predicting success in sentinel node identification at operationVariableNo. of womenSentinel node identified (%)χ2 (P)Age (years)< 503330 (91%)2.84> 508465 (77%)(0.09)Tumour site (quadrant)Upper/outer86 69 (80%)0.2Lower/inner31 26 (84%)(0.66)Tumour detectionScreening56 42 (75%)2.7Symptomatic61 53 (87%)(0.1)Previous core biopsyYes1210 (83%)0.04No10585 (79%)(0.84)Previous open biopsyYes11089 (81%)0.1No76 (86%)(0.75)Scintiscan resultPositive74 71 (96%)28.7Negative43 24 (56%)(< 0.001)OperationMastectomy31 24 (77%)1.23Wide local excision5547 (85%)(0.54)Localised wide local excision3124 (77%)Tumour size*< 2cm79 64 (81%)0.03≥ 2cm36 29 (81%)(0.95)Tumour grade*12721 (78%)2.425346 (87%)(0.31)33526 (74%)Lymphatic/vascular invasionNegative101 83 (82%)0.44Positive16 12 (75%)(0.5)Lymph node statusNegative80 64 (80%)0.2Positive37 31 (84%)(0.6) * Excludes two cases of ductal carcinoma-in-situ, diagnosed after excision. 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James Kollias · Barry E Chatterton · Vivian E Hall · Melissa A Bochner · Brendon J Coventry · Gelareh Farshid

Research Iodine deficiency in ambulatory participants at a Sydney teaching hospital: is Australia truly iodine replete? Jenny E Gunton, Graham Hams, Marcelle Fiegert and Aidan McElduff MJA 1999; 171: 467-470 For editorial comment, see Eastman Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Endocrinology Abstract Objective: To assess iodine status in four separate groups -- pregnant women, postpartum women, patients with diabetes mellitus and volunteers. Design and setting: Prospective cross-sectional study at a tertiary referral hospital in Sydney. Participants: 81 pregnant women attending a "high risk" obstetric clinic; 26 of these same women who attended three months postpartum; 135 consecutive patients with diabetes mellitus attending the diabetes clinic for an annual complications screen; and 19 volunteers. There were no exclusion criteria. Methods: Spot urine samples were obtained, and urinary iodine was measured by inductively coupled plasma mass spectrometer. Outcome measures: Iodine status based on urinary iodine concentration categorised as normal (> 100 µg/L), mild deficiency (51-100 µg/L) and moderate to severe deficiency (< 50 µg/L). Results: Moderate to severe iodine deficiency was found in 16 pregnant women (19.8%), five postpartum women (19.2%), 46 patients with diabetes (34.1%) and five volunteers (26.3%). Mild iodine deficiency was found in an additional 24 pregnant women (29.6%), nine postpartum women (34.6%), 51 patients with diabetes (37.8%) and 9 normal volunteers (47.4%). Median urinary iodine concentration was 104 µg/L in pregnant women, 79 µg/L in postpartum women, 65 µg/L in patients with diabetes mellitus and 64 µg/L in volunteers. Conclusions: The high frequency of iodine deficiency found in our participants suggests that dietary sources of iodine in this country may no longer be sufficient. Further population studies are required. Introduction It is currently believed that iodine deficiency does not exist in Australia.1,2 However, iodine status is seldom, if ever, measured in routine clinical care, and iodine deficiency may have significant adverse consequences, particularly during pregnancy (Box 1). Box 2 shows some of the reasons why iodine intake in Australia may be inadequate. The recommended daily intake (RDI) of iodine is 100 µg daily for the general population and 150-200 µg daily for women who are pregnant or breastfeeding6-8,10 (iodine demand increases during pregnancy because of increased renal clearance and fetal iodine transfer). Approximately 90% of iodine is excreted in the urine,1,11 and iodine status is usually assessed by measuring urinary iodine concentration. The accepted minimum adequate level of urinary iodine is 100 µg/L, and levels above this are considered normal.1,6-9,12 Urinary iodine concentrations below 25 µg/L are classified as severe deficiency, and are associated with an increased risk of cretinism; 26-50 µg/L is classified as moderate deficiency, and 51-100 µg/L is regarded as mild iodine deficiency.1,6-9,12 The World Health Organization (WHO) recommends that the median urinary iodine concentration for populations as a whole should be more than 100 µg/L, that less than 20% of the population should have a urinary iodine concentration below 50 µg/L, and that no cretinism occurs.12 Having previously found low levels of free thyroxine in pregnant women,13 and in light of the adverse consequences of iodine deficiency during pregnancy, we initially set out to test the iodine status of a group of pregnant women. We subsequently included other groups to widen our investigation of iodine status. Methods Study participants Our study was conducted at a tertiary referral hospital in Sydney. Participants in the study included women who attended a specialist "high risk" obstetric clinic, patients of both sexes with diabetes who attended the hospital's diabetes clinic, and healthy, non-pregnant volunteers recruited after a presentation about iodine. Participants thus comprised 81 consecutive pregnant women who attended the obstetric clinic between 1 August 1998 and 1 April 1999, 26 of these same women who were reassessed at three months postpartum, 135 consecutive patients who attended the diabetes clinic for an annual complications screen between 1 November 1998 and 1 February 1999, and 19 volunteers recruited between 1 February and 1 July 1999. All participants provided a routine urine sample. There were no exclusion criteria. One of the 81 pregnant women had thyrotoxicosis as a result of Graves' disease -- she particpated before commencing therapy. Twenty-two of the patients attending the diabetes clinic (16.1%) had type 1 diabetes, 103 (76.3%) had type 2 diabetes and 10 (7.5%) had impaired glucose tolerance. One of the patients with diabetes had recently received iodine-containing intravenous contrast medium during a coronary angiogram, and one was taking amiodarone. No other participant was known to have received contrast medium, or to be taking amiodarone or iodine supplements. Urinary iodine measurement Urinary iodine concentrations were determined by means of a Varian UltraMass inductively coupled plasma mass spectrometer with SPS-5 autosampler (Varian Inc., Palo Alto, California, USA). The measurement was calibrated over a range of 0-1000 µg iodine per litre. The lower limit of detection for the assay was 2 µg/L. The reproducibility of the assay as represented by the 100 µg/L calibrator assessed over three months was ± 6 µg/L (± 2 SD). Comparison with the colorimetric/Sandell-Koltkoff reaction method showed a highly significant correlation (P < 0.001; see Box 3). Other authors have also compared the methods and found high correlation.14 In particular, no systematic biases were found at low iodine concentrations. Some investigators use the urinary iodine/creatinine ratio to determine iodine status.1,14 We thus measured urinary creatinine by the Creatinine Jaffa method (Boehringer Mannheim Systems, Mannheim, Germany) and calculated iodine/creatinine ratios (µg iodine/g creatinine) for each participant. The correlation between urinary iodine and iodine/creatinine ratio was high for non-pregnant participants (r = 0.969; P < 0.001) and lower for the pregnant group (r = 0.419; P < 0.001). Twenty-four-hour urinary iodine measurement may be used to assess iodine status,6 but this method can be unreliable because of incorrect or incomplete collection,15 and is less practical than spot samples for population surveys.9,12 To compare this method with our spot sampling, we selected six pregnant women (on the basis of their spot urine concentrations to cover a range of values) who collected 24-hour urine samples for iodine content measurement. The correlation was highly significant (r2 = 0.82), thus confirming that spot urine samples were a reliable way of measuring iodine status. As part of routine care, 70 of the 81 pregnant women and 121 of the 135 patients with diabetes had thyroid function tests. Free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were measured by means of an automated chemiluminescence system (Chiron Diagnostics, Scoresby, Vic.). We did not seek ethical approval for this study as it involved no deviation from usual care, except in the case of the 19 volunteers who agreed to provide a urine sample. Statistical analysis We used SPSS for statistical analysis.16 Means are expressed with ± 2 standard deviations, and medians with 95% confidence intervals (CI) are shown where data were not normally distributed. The results of non-parametric variables (including iodine results) were compared by means of the Mann-Whitney Wilcoxon rank sum test. Results Box 4 shows the mean and median ages and the results of spot urinary iodine concentration for the four groups. The three non-pregnant groups had similar urinary iodine concentration results, with a slightly higher median in the postpartum group compared with the group with diabetes. As expected,17-19 the pregnant women had higher urinary iodine concentrations than the other groups as a whole (P = 0.004). The iodine/creatinine ratios also show a high proportion of abnormal results (Box 4). The median iodine concentration in the 26 postpartum women (79 µg/L) who provided repeat urine samples for iodine measurement three months after delivery was considerably lower than that in the 81 pregnant women (104 µg/L). However, this difference was not statistically significant (P = 0.249). The patient with diabetes who had received iodine-containing intravenous contrast medium during a coronary angiogram in the month before the urinary spot test had a urinary iodine concentration of 2170 µg/L. Box 5 shows TSH levels and FT4 levels versus iodine status in pregnant and non-pregnant participants. There was no significant relationship between iodine status and FT4 or TSH levels in either the pregnant group or non-pregnant group. Separate analysis of patients with diabetes and postpartum women did not significantly alter these results. However, there was a weak correlation between FT4 and urinary iodine levels when examined as a continuous variable (Pearson correlation coefficient, 0.26; P = 0.016). Discussion By WHO criteria,12 the median iodine levels in our pregnant participants were only just adequate, while those in postpartum women, patients with diabetes and normal volunteers were inadequate. The slightly higher median iodine level in the postpartum group compared with that in the group with diabetes may have been the result of this concentration not having returned to baseline after pregnancy, although further study is required to document the rate of change post partum. We believe the low values in patients with diabetes was not a problem specific to diabetes, but merely a reflection of low urinary iodine levels in the general population. The similarity between the patients with diabetes and our small group of volunteers supports this view. Our data are consistent with generally low iodine intake. Our findings mirror recent reports from other countries.9,11,20 A United States study showed that the median urinary iodine concentration in 1988-1994 had decreased by more than 50% from that in 1971-1974.9,11 The 1988-1994 results showed 11.7% of the US population to be iodine deficient (a 4.5-fold increase since 1971-1974). The mean urinary iodine concentration in that population was 265 µg/L, and people from higher socioeconomic groups were more likely to be iodine deficient. Our data may also reflect this effect, as, although our patients were attending a public clinic, the hospital catchment area is a relatively high socioeconomic group. Our data suggest that Australia may be experiencing a similar trend to that seen in the US. Iodine deficiency during pregnancy can affect the thyroid glands of both the mother and baby,10,17-19 and may have many adverse health consequences (Box 1). Some, but not all, researchers have found an increase in urinary iodine levels during pregnancy.10,17-19 Smyth et al studied urinary iodine concentration in a group of pregnant women in an area of Ireland with known borderline iodine deficiency.10 In the third trimester, they found a mean urinary iodine concentration of 132 µg/L (standard error of the mean, 6.8), and found that urinary iodine concentration increased during pregnancy. In a more iodine-deficient area, Glinoer et al found that urinary iodine concentration did not increase during pregnancy (median iodine concentration 45 µg/L after 20 weeks' gestation, no mean given).19 So, it is not clear whether the apparently higher levels in our pregnant women were pregnancy related or, in fact, masked iodine deficiency in pregnancy. We found that a considerable percentage of pregnant women (4.9%) were severely iodine deficient, with spot urine results of < 25 µg/L. While this is the threshold below which cretinism may occur, other factors, such as selenium deficiency and the presence of dietary goitrogens, also play a part in determining cretinism,21 and these two factors are not usually seen in Sydney. Therefore, we would not expect to see an increased incidence of cretinism in Sydney on the basis of these results alone. However, more subtle adverse fetal outcomes may occur. Our findings suggest that we should no longer automatically consider Australia an iodine-replete country. We found that iodine deficiency was common among 235 people attending a Sydney teaching hospital and speculate that these data are applicable to the general population, although this will require independent confirmation. The frequency of iodine deficiency in our pregnant population (18.8%) approaches the maximum acceptable level recommended by WHO (20%); this recommendation was exceeded in our group with diabetes (34.1%) and the normal volunteers (26.3%). The postpartum women had a median iodine concentration of 79 µg/L, which is lower than the WHO recommendation of 100 µg/L. This has important public health implications. The weaknesses of this study include the small group of normal volunteers, and perhaps the use of a sample from a teaching hospital rather than the community. The normal volunteers had results which are equivalent to those seen in postpartum women and non-pregnant patients with diabetes. Our subjects were all ambulatory, not inpatients at the time of testing, and generally well. Although 24-hour urinary iodine excretion studies may be the ideal method of assessing iodine status, these are not generally performed in large numbers for a variety of technical and practical reasons. A weak correlation between urinary iodine and free thyroxine was observed for all non-pregnant participants in total, and for the participants with diabetes mellitus. Because of the large number of other factors which influence thyroid function (including pregnancy),13 the relatively loose correlations are an expected finding. Further studies are needed, and these include (i) population surveys in Sydney and elsewhere in Australia; (ii) assessment of thyroid size (eg, by ultrasound) in relation to iodine status; and (iii) detailed assessment of neonates, including thyroid size, neonatal TSH levels, and detailed neurological outcomes. References Hetzel BS. Iodine deficiency disorders. In: Garrow JS, James WPT, editors. Human nutrition and dietetics. Edinburgh: Churchill Livingstone, 1993: 534-555. Mortimer RH. Thyroid disease and pregnancy. Aust N Z J Med 1998; 28: 647-653. Tasmanian Thyroid Advisory Committee. Study in disease surveillance. 1950-1979. Med J Aust 1981; 2: 234-238. Clements FW. Goitre studies. 1. The incidence of endemic goitre in three areas in Australia. Med J Aust 1948; 21: 637-639. Hales I. Studies in diseases of the thyroid gland [MD thesis] Sydney: University of Sydney, 1971. Boyages S. Iodine deficiency disorders. J Clin Endocrinol Metab 1993; 77: 587-591. Clugston GA, Hetzel BS. Iodine. In: Shils ME, Olson JA, Shike M, editors. Modern nutrition in health and disease. 8th ed. Vol. 1. Philadelphia: Lea and Febiger, 1994; 252-263. Delange F. The disorders induced by iodine deficiency. Thyroid 1994; 4: 107-128. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from the National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998; 83: 3401-3408. Smyth PPA, Hetherton AMT, Smith DF, et al. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab 1997; 82: 2840-2843. Dunn JT. What's happening to our iodine? [editorial]. J Clin Endocrinol Metab 1998; 83: 3398-3400. World Health Organization Nutrition Unit. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Document No. WHO/NUT 94.6. Geneva: WHO, 1994: 36. McElduff A. Measurement of free thyroxine levels (fT4) in pregnancy. Aust N Z J Obstet Gynaecol 1999; 39: 158-161. May SL, May WA, Bourdoux PP, et al. Validation of a simple, manual urinary iodine method for estimating the prevalence of iodine-deficiency disorders, and interlaboratory comparison with other methods. Am J Clin Nutr 1997; 65: 1441-1445. McElduff A, Shuter B, Cooper R, et al. Measuring renal function in patients with diabetes mellitus. J Diabetes Complications 1997; 11: 225-229. SPSS [computer program], version 6.0. Chicago, Ill: SPSS Inc, 1996. Silva JE, Silva S. Interrelationships among serum thyroxine, triiodothyronine, reverse triiodothyronine, and thyroid-stimulating hormone in iodine-deficient pregnant women and their offspring: effects of iodine supplementation. J Clin Endocrinol Metab 1981; 52: 671-677. Glinoer D, De Nayer P, Bourdoux et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71: 276-287. Glinoer D, Delange F, Laboureur I, et al. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab 1992; 75: 800-805. Valiex P, Zarabska M, Preziosi P, et al. Iodine deficiency in France [letter]. Lancet 1999; 353: 1766-1767. Moreno-Reyes R, Suetens C, Mathieu F, et al. Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 1998; 339: 1112-1120. Received 13 Apr, accepted 21 Aug, 1999 Authors' details Royal North Shore Hospital, St Leonards, NSW. Jenny E Gunton, MB BS, Endocrine Fellow, Department of Endocrinology. Graham Hams, MAppSc, Senior Staff Scientist, Pacific Laboratory Medicine Services. Marcelle Fiegert, BEd, MNutri Diet, Dietitian, Department of Nutrition. Aidan McElduff, FRACP, PhD, Senior Staff Specialist in Endocrinology, Department of Endocrinology. Reprints: Dr J E Gunton, C/- Clinic 1, Royal North Shore Hospital, St Leonards, NSW 2065. jennyegAThotmail.com. 1: Iodine deficiency disorders Maternal Goitre Hypothyroidism Decreased fertility Miscarriage Fetal Stillbirth Neonatal Cretinism Increased mortality Goitre Hypothyroidism Back to text 2: The iodine situation in AustraliaIn the past, an increased incidence of goitre and iodine deficiency was documented in certain parts of Australia.3-5 Prevention of iodine deficiency in industrialised countries most commonly relies on iodised salt, iodine in milk, or iodine-supplemented bread.1,6-8 The upper limit of the recommended daily intake of salt (NaCl) is 100 mmol, or 6 g (a heaped teaspoon); 100 mmol of iodised salt per day would provide 175-240 µg of iodine. However, most salt is incorporated into foods before purchase, and the three major Australian manufacturers of processed food we contacted all reported using non-iodised salt only. Non-iodised table salt is readily available, and may be used more frequently than in the past as campaigns to use iodised salt are forgotten. (We reviewed supermarket shelves in our local area, and found that the space allocated for display suggests that more non-iodised than iodised salt is purchased.) In the United States, only 50%-60% of salt currently consumed is iodised.9 Milk products, which used to contain significant concentrations of iodine (up to 300 µg/100 mL) by virtue of iodine-containing solutions used to clean the milk vats, now contain low levels of iodine because volatile cleaning solutions are used (Dairy Farmers Association, Nutrition Panel for Milks, personal communication). While the incidence of iodine deficiency and goitre was decreased by legislation requiring iodine supplementation of bread in 1966,3 this is no longer a requirement (because of concerns about an increased incidence of thyrotoxicosis). Marine fish, shellfish, seaweed and kelp contain high amounts of iodine,1,7 and such ocean seafood, as well as added iodised salt, provide most of the iodine in the Australian diet. However, many people may consume these products rarely, if at all. Back to text Back to text 4: Iodine status resultsGroupPregnant womenPostpartum womenPatients with diabetesVolunteersNumber of participants8126135 19Age (years)Mean (± 2 SD)32.9 ± 9.835.3 ± 11.350.1 ± 35.3*49.5 ± 17.4*Median (95% CI)34 (24-42)35 (25-42)50 (25.7-83.0)49 (45.3-53.8)Spot iodine concentration (µg/L)Median10479‡65† 64(95% CI)(89-129)(44-229)(58-89)(54-75)No. of participants (%) withSevere to moderate deficiency < 50 µg/L16 (19.8%)5 (19.2%)46 (34.1%)5 (26.3%)Mild deficiency 51-100 µg/L24 (29.6%)9 (34.6%)51 (37.8%)9 (47.4%)Normal iodine status > 100 µg/L41 (50.6%)12 (46.1%)38 (28.1%)5 (26.3%)Iodine/creatinine ratio (µg iodine/g creatinine)Median159131114 108(95% CI)(169-232)(106-218)(93-505)(84-209)No. of participants (%) withSevere to moderate deficiency< 50 µg iodine/g creatinine6 (7.4%)2 (7.7%)7 (5.2%)1 (5.3%)Mild deficiency 51-100 µg iodine/g creatinine 22 (27.2%)9 (34.6%) 50 (37.0%)5 (26.3%)Normal iodine status > 100 µg iodine/g creatinine53 (65.4%)15 (57.7%)78 (57.8%)13 (68.4%)* P < 0.001 for comparison with pregnant women. †P < 0.01 for comparison with pregnant women. ‡P < 0.05 for comparison with patients with diabetes. Back to text 5: Levels of thyroid-stimulating hormone and free thyroxine compared with iodine status in pregnant women and patients with diabetesThyroid-stimulating hormone (µIU/mL)Free thyroxine (pmol/L)GroupNo. Mean (± 2 SD)Mean (± 2 SD)Pregnant women70Normal iodine status*411.56 ± 0.8012.9 ± 3.70Mild deficiency†231.67 ± 0.9012.5 ± 3.00Severe to moderate deficiency‡16 1.56 ± 0.7712.1 ± 2.25Patients with diabetes121Normal iodine status*342.1 ± 3.1015.0 ± 2.60Mild deficiency†451.9 ± 1.2015.0 ± 2.60Severe to moderate deficiency‡42 2.6 ± 2.4014.5 ± 2.90 * > 100µg/L. † 51-100 µg/L. ‡ < 50 µg/L. Back to text

Jenny E Gunton · Graham Hams · Marcelle Fiegert · Aidan McElduff

Healthcare Accidental paracetamol overdosing and fulminant hepatic failure in children Fiona K Miles, Ramananda Kamath, Stuart F A Dorney, Kevin J Gaskin and Edward V O'Loughlin MJA 1999; 171: 472-475 See also Hynson Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Pathology Abstract Objective: To delineate clinical characteristics useful for identifying children with liver failure due to accidental paracetamol overdose. Design: Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. Setting: Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. Main outcome measures: Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. Results: 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. Conclusion: Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy. Introduction Paracetamol is a commonly used antipyretic and analgesic medication; in 1996, it was the second most common drug used in Australia, with 4.75 million units dispensed.1 There is a large range in the preparations of doses available, and the potential for accidental overdose due to confusion over concentration and frequency of dosing is high.2Intentional paracetamol overdose is a well-recognised cause of fulminant liver failure.2 However, there are few reports of accidental overdose due to recurrent ingestion of high therapeutic doses in children.3-6 Alonso et al reported seven children with fulminant liver failure without obvious cause.5 All patients had ingested paracetamol, but serum paracetamol levels were not in the toxic range. The authors postulated that, although paracetamol may have contributed to the liver injury, it was not causative. Two other reports describe accidental multiple dosing causing liver failure in children, with many patients receiving doses in the recommended therapeutic range.3,6 Prodromal illness associated with prolonged fasting was also recognised as potentially important in the development of liver injury.4,5 Since 1985, the Royal Alexandra Hospital for Children has been a tertiary referral centre for paediatric liver transplantation. Over this period, 19 patients have presented with acute liver failure. Our aims were to review all cases of acute liver failure, to identify patients with accidental (overdose with therapeutic intent) paracetamol-induced liver failure, and to define clinical features which may be useful in identifying such cases. Methods All patients at the Royal Alexandra Hospital with fulminant hepatic failure -- severe acute liver injury with no pre-existing liver disease resulting in encephalopathy within eight weeks of onset -- are managed by members of the liver transplant service. We reviewed case records of such patients for a history of liver disease, presenting symptoms, pre-existing history of paracetamol ingestion, clinical status at presentation, laboratory investigations and outcome. Paracetamol hepatotoxicity was considered likely if patients with liver failure had: a history of paracetamol ingestion over several days, confirmed by the finding of paracetamol in the blood; and exclusion (by routine laboratory testing) of other known causes of acute liver failure, such as viral hepatitis (A, B, C, Epstein-Barr virus, cyto-megalovirus, HSV-6, varicella or adenovirus), drug- or toxin-induced hepatotoxicity, inborn errors of metabolism (Wilson's disease, α1-antitrypsin deficiency, and fatty acid oxidation abnormalities). Approval for our study was obtained from the hospital's institutional ethics committee. Results Ninteen patients were identified, aged 6-165 months. One adolescent developed liver failure from suicidal overdose (30 g), and made a complete recovery with conservative treatment; this patient was excluded from the study. Paracetamol hepatotoxicity Eleven of the remaining 18 patients had presumed paracetamol hepatotoxicity. The patient data shown in the Table represent peak levels of study parameters or stage of encephalopathy. All patients had coagulopathy, elevated transaminase levels, and abnormal total serum bilirubin. Eight patients (numbers 1-8, Table) were identified as having paracetamol overdose as the only risk factor for liver failure. All eight patients had a history of a prodromal illness for which they received paracetamol for 4-21 days prior to the identification of liver disease. Reported paracetamol intakes ranged from 20 to 200 mg/kg per day. Paracetamol was detected in the blood of all eight patients, and all were encephalopathic (stage I-III) at presentation. Patients 1, 2, 3, 5 and 7 were hypoglycaemic (blood glucose levels < 3 mmol/L) at admission. Liver failure resolved with supportive treatment in six of these patients; Patients 2 and 6 died while awaiting liver transplants. Patient 5 survived, but had severe neurological sequelae as a result of protracted hypoglycaemia and stage IV encephalopathy. Patient 4 was admitted to the intensive care unit, but was not initially recognised as having liver failure. Patients 9, 10 and 11 had probable paracetamol hepatotoxicity, but also had other risk factors for liver injury. Patient 9 had Ewing's sarcoma and had been receiving chemotherapy. Multiple doses of paracetamol had been administered in hospital before the onset of liver failure. At postmortem, hepatic centrilobular necrosis consistent with paracetamol hepatotoxicity was found. Patient 10 also had a history of paracetamol ingestion, although the quantity could not be determined from the history. However, a high level of paracetamol was detected in the blood. The patient had had one previous admission with mumps encephalitis, which resulted in epilepsy and mental retardation. He had also been taking sodium valproate for seizures for several years, with no evidence of liver abnormalities. The patient died of end-stage liver failure and post-mortem revealed severe centrilobular necrosis consistent with paracetamol- rather than valproate-induced liver injury. Patient 11 had a mild prodromal illness due to Epstein-Barr virus infection, but ingested large quantities of paracetamol and presented with the clinical picture as described for Patients 1-8. Coagulopathy precluded liver biopsy in this group of patients. Metabolic studies: Urinary metabolic studies failed to reveal abnormal metabolites indicative of fatty acid oxidation defects in Patients 1, 2, 5, 6, 7 and 8, and skin fibroblast assays for fatty acid oxidation defects were normal in Patients 3, 6, 7 and 8. For Patient 4, no metabolic studies were performed. Other causes of liver failure Seven patients presented with fulminating liver failure from other causes, including Wilson's disease (1), cytomegalovirus infection (1), hepatitis B virus infection (1), presumed viral hepatitis (3), and an adverse reaction to dapsone (1). All patients presented with evidence of severe synthetic failure (coagulopathy and hypoalbuminaemia) and hepatic encephalopathy. Distinguishing paracetamol hepatotoxicity The Figure compares the serum bilirubin levels plotted against alanine transaminase levels in both groups of patients. In contrast to patients with other causes of acute liver failure, patients with presumed paracetamol hepatotoxicity all had serum bilirubin levels less than 200 µmol/L, and most had alanine transaminase levels greater than 4000 IU/L. Hypoglycaemia was not detected in any of the patients with liver failure from causes other than paracetamol, and all patients in this group either died or received transplants. Discussion Clinical features Accidental paracetamol overdose was the likely cause of acute liver failure in most children in this series presenting to a single paediatric institution. Eight of the 18 patients had likely paracetamol-induced liver failure due to accidental overdose, and in a further three paracetamol was a major risk factor. A distinct clinical pattern emerges when the patients with definite or presumed paracetamol toxicity are compared with patients with other causes of fulminant hepatic failure. Patients with paracetamol toxicity presented with a non-specific prodromal illness, often with fasting and/or vomiting. At the time of hospitalisation they had evidence of severe synthetic failure, often with associated hypoglycaemia, coagulopathy and mild encephalopathy, but with disproportionately low bilirubin levels. Moreover, most patients recovered with supportive therapy. A history of paracetamol ingestion over several days is important in establishing the diagnosis of paracetamol toxicity. In our study, reported ingestion of as little as 20 mg/kg per day over a protracted period was associated with liver failure. Similar toxic dosage ranges have been reported in other studies of children,3,5 raising the question of whether some susceptible children could suffer acute liver failure as a result of therapeutic doses of paracetamol ingested over several days. However, it is important to emphasise that the paracetamol intake data reported in this study, as in previous published reports, rely on history alone. The dosages reported by parents could not be verified by other means. Whether therapeutic doses of paracetamol could result in liver failure in susceptible children remains unresolved owing to the poor quality of the existing paediatric data. Serum paracetamol levels Paracetamol was detected in the serum of patients with presumed paracetamol hepatotoxicity. Although other investigators have used a level of 0.04 mmol/L3,4 as indicative of toxicity, it is not clear that this is a meaningful level in an individual with repeated ingestions over several days. A level of 40 µmol/L or greater at 24 hours after the ingested dose is thought to predict the likely development of liver failure, as portrayed in the nomogram adapted by Rumack and Matthews.7 However, this nomogram was derived from adult patients presenting with liver failure from a single suicidal overdose. No studies have addressed the question of serum levels likely to predict hepatic failure after repeated doses. We observed that the possible role of paracetamol was, on occasion, discounted because paracetamol levels were lower than those predictive of the development of liver failure from the nomogram. Poor correlation between paracetamol levels and liver toxicity with accidental overdose has been observed in a large series of adult patients in whom less than 50% had peak serum levels greater than 10 µg/mL (40 µmol/L).4 Similarly, low levels were reported in a small series of children.5 Nevertheless, serum paracetamol levels should be measured routinely in the investigation of children presenting with acute liver failure as soon as possible after assessment, but should be interpreted with caution. A recent study of paracetamol toxicity in adults by Schiodt et al identified a distinct group of patients who developed liver dysfunction after accidental poisoning with therapeutic intent.4 This group of 21 patients had ingested frequent doses of paracetamol for pain relief. Toxicity may have been compounded by prior starvation.2 Mortality in that study (4/21) was similar to ours, but was substantially higher than in a group of adult patients with non-accidental overdose. Some doubts about the role of paracetamol in causing fulminant hepatic failure in the study by Schiodt et al have been raised, as a high proportion of patients had a history of concurrent alcohol abuse and dosage levels were considered by some to be too low to cause toxicity.8-11 In contrast to that study of adults, studies in children raise considerable concern that accidental paracetamol overdose causes liver failure in this age group.3,5 However, it is important to note that all the reported series in children (including our own) are anecdotal reports. No studies have included a control group or undertaken a case-control study design, although liver biopsies were performed in six of seven patients in one series.5 While one could argue that the association between accidental overdose and liver failure in children is speculative, several arguments support the likely association with paracetamol: Suicidal overdose in adults produces acute liver failure with a clinical and biochemical picture very similar to that reported in our study of overdose due to repeated ingestion. The presence of severe liver synthetic failure and encephalopathy with the pattern of liver function tests we describe (see Figure) is a very atypical presentation for most diseases which produce liver failure in children. In our study, four children had centrilobular necrosis on postmortem examination, a finding consistent with paracetamol hepatotoxicity. While some of the clinical characterisics, such as prodromal illness, hypoglycaemia, high transaminase levels and coagulopathy, would be consistent with Reye's syndrome,12 it is not likely that this diagnosis would explain the abnormalities which we attribute to paracetamol toxicity. Recent in-vitro and animal studies indicate that paracetamol or its metabolites impair mitochondrial metabolism, and this effect occurs before hepatocyte necrosis.13-15 In this regard, paracetamol hepatotoxicity demonstrates some remarkable clinical and biochemical similarities to some inborn errors of fatty acid oxidation which can present with fulminant liver failure.16 Despite several attempts to define a safe therapeutic regimen, there is still no consensus as to the appropriate dose, or even efficacy, in children. One report recommended single doses of 10-15 mg/kg four-hourly as a "safe maximum".17 However, Nahata et al demonstrated that paracetamol may accumulate substantially, with raised concentrations after therapeutic doses for two to three days, even with doses of 13 mg/kg 24-hourly.18 One study which did review the potential for chronic overdose in children was done by Penna et al,19 in which 190 of 299 paediatric inpatients received paracetamol for indications of fever and postoperative pain. Most were prescribed four-hourly doses, with potential for greater than 90 mg/kg per day. Nearly a quarter of the high doses were for children under 12 months of age. Although it can be argued that paracetamol "is commonly administered to children . . . for most febrile illnesses",5 and thus can be a frequent coincidental association, there is evidence that accidental overdose while ingesting high therapeutic doses of paracetamol for pain and fever relief may cause fulminating liver failure in children. Clinicians should be alerted to the possibility of paracetamol toxicity in an infant or child presenting with a prodromal illness associated with fasting and the regular ingestion of paracetamol over several days. Hypoglycaemia, severe synthetic failure and encephalopathy with very high transaminase levels (above 4000 IU/L) and a serum bilirubin level less than 200 µmol/L would support the diagnosis. It is important to distinguish this group of patients, as the prognosis for recovery is good with conservative therapy. If N-acetylcysteine is instituted early, liver transplantation may be avoided. References Commonwealth Department of Health and Family Services. Top 10 drugs. Australian Prescriber 1997; 20: 92. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346: 547-552. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Walker AM. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543. Avorn J. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543-544. Rao RB, Hoffman RS. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Makin AJ, Williams R, Bernal W. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Diagnosis and treatment of Reye's syndrome. JAMA 1981; 246: 2441-2444. Burcham PC, Harman AW. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 1991; 266: 5059-5054. Vendemiale G, Grattagliano I, Altomare E, et al. Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochem Pharmacol 1996; 52: 1147-1154. Nazareth WM, Sethi JK, McLean AE. Effect of paracetamol on mitochondrial membrane function in rat liver slices. Biochem Pharmacol 1991; 42: 931-936. Tyni T, Palotie A, Viinikka L, et al. Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients. J Pediatr 1997; 130: 67-76. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol 1983; 3: 321-327. Nahata MC, Powell DA, Durrell DE, Miller MA. Acetaminophen accumulation in pediatric patients after repeated therapeutic doses. Eur J Clin Pharmacol 1984; 27: 57-59. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106. (Received 25 Jun, accepted 2 Sep, 1999) Authors' details The Royal Alexandra Hospital for Children, Sydney, NSW. Fiona K Miles, MB ChB, Fellow in Intensive Care; Ramananda Kamath, MD, FRACP, Associate Professor and Staff Specialist, Department of Gastroenterology; Stuart F A Dorney, MB BS, FRACP, Staff Specialist, Department of Gastroenterology; Kevin J Gaskin, MD, FRACP, Professor and Staff Specialist, Department of Gastroenterology; Edward V O'Loughlin, MD, FRACP, Staff Specialist, Department of Gastroenterology. Reprints: Dr E V O'Loughlin, Department of Gastroenterology, The Royal Alexandra Hospital for Children, PO Box 3515, Parramatta, NSW 2124. tedoATnch.edu.au Clinical characteristics of 11 patients with liver failure due to paracetamolPatient: 1Age (months): 21Paracetamol dosage (mg/kg per day): 20 (21 days) & 171 (last day)Serum:Paracetamol level (µmol/L): 10 (D2)*Bilirubin level (µmol/L): 123Alanine transaminase level (IU/L): 9618PT INR: 3.3Hepatic coma stage: IIOutcome: ResolvedPatient: 2Age (months): 63Paracetamol dosage (mg/kg per day): 100 (6 days)Serum:Paracetamol level (µmol/L): 560 (D1)*Bilirubin level (µmol/L): 87Alanine transaminase level (IU/L): > 10 000PT INR: 9.7Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 3Age (months): 36Paracetamol dosage (mg/kg per day): Very frequent oral and rectal dosesSerum:Paracetamol level (µmol/L): 30 (D2)*Bilirubin level (µmol/L): 70Alanine transaminase level (IU/L): > 10 000PT INR: 4Hepatic coma stage: IIOutcome: ResolvedPatient: 4Age (months): 77Paracetamol dosage (mg/kg per day): 200 (11 days)Serum:Paracetamol level (µmol/L): 30 (D6)*Bilirubin level (µmol/L): 19Alanine transaminase level (IU/L): 1216PT INR: 1.4†Hepatic coma stage: IIIOutcome: ResolvedPatient: 5Age (months): 31Paracetamol dosage (mg/kg per day): 71 (4 days)Serum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 143Alanine transaminase level (IU/L): > 10 000PT INR: > 20Hepatic coma stage: IVOutcome: Resolved, severe brain damagePatient: 6Age (months): 129Paracetamol dosage (mg/kg per day): 20 (7 days)Serum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 82Alanine transaminase level (IU/L): > 10 000PT INR: 5Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 7Age (months): 6Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 94Alanine transaminase level (IU/L): 9 170PT INR: 6.9Hepatic coma stage: IIIOutcome: ResolvedPatient: 8Age (months): 54Paracetamol dosage (mg/kg per day): 74mg/kg/day (5 days) & 150mg/kg/day (final day)Serum:Paracetamol level (µmol/L): 900 (D1)*Bilirubin level (µmol/L): 57Alanine transaminase level (IU/L): 8 300PT INR: 5.4Hepatic coma stage: IIOutcome: ResolvedPatient: 9Age (months): 79Paracetamol dosage (mg/kg per day): Unknown (frequent dosing over several days)Serum:Paracetamol level (µmol/L): 70 (D1)*Bilirubin level (µmol/L): 185Alanine transaminase level (IU/L): 4 300PT INR: 3.1Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 10Age (months): 132Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 195Alanine transaminase level (IU/L): 3 620PT INR: 4.2Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 11Age (months): 106Paracetamol dosage (mg/kg per day): 175 (7 days)Serum:Paracetamol level (µmol/L): 80 (D3)*Bilirubin level (µmol/L): 102Alanine transaminase level (IU/L): 6 700PT INR: 2.4Hepatic coma stage: IIIOutcome: Resolved* Days post admission to hospital. †Alanine transaminase level and INR measured on admission to hospital but not subsequently, despite deterioration of coma stage. PM = postmortem. OD = overdose. PT-INR = international normalised ratio (of prothrombin time). Normal ranges: serum bilirubin, 1-15 µmol/L; alanine transaminase, 10-50 IU/L; INR, 1-1.2. Back to textBack to text

Fiona K Miles · Ramananda Kamath · Kevin J Gaskin · Edward V O'Loughlin

Review Breast cancer screening and management A Patrick M Forrest and Elaine D C Anderson MJA 1999; 171: 479-484 Synopsis - Introduction - Why screen for breast cancer? - Evidence for screening - Screening programs - Breast self-examination - Familial breast cancer - Management of screen-detected breast cancer - The future -- specialised, multidisciplinary services - Acknowledgements - References - Authors' details - - More articles on Oncology Synopsis Mammographic screening to detect preclinical cancer was introduced when it was realised that once breast cancer became symptomatic it could not be cured regularly by local surgery, as early systemic dissemination had almost invariably occurred. Meta-analysis of randomised controlled trials of screened versus unscreened women has demonstrated a mortality benefit approaching 30% in screened women (> 50 years of age) seven to nine years from the start of the trials. The UK and Australian breast screening programs are compared. Differences in the design are largely a result of differences in the healthcare systems in the two countries. Breast self-examination, although still recommended by many Australian practitioners, is not an appropriate screening method, as it does not affect breast cancer death rates. About 5% of women have familial breast cancer (associated with mutations of BRCA1 or BRCA2). Women at high risk are screened at an earlier age and at more frequent intervals. Current best practice management of screen-detected breast cancer, including surgery, radiotherapy, assessment of the axilla, and systemic therapy, is summarised. Women with symptomatic breast disease ideally should be treated by a specialised multidisciplinary service, which can provide sophisticated diagnosis and treatment as well as supportive care. Introduction In 1987, the UK government initiated screening for breast cancer by a single medial-lateral oblique view of each breast every three years for all women aged 50-64 years.1 The breast screening program in Australia -- BreastScreen -- began in 1991 and provides two-view mammographic screening at two-year intervals, mainly for women aged 50-69 years.2 Why screen for breast cancer? Screening was introduced when long term follow-up studies showed that most women with symptomatic breast cancer could not be cured by local surgery.3,4 Breast cancer was not a slowly progressive, locoregional disease; early systemic dissemination with the formation of distant micrometastases was the rule. Proof of this has now come from unequivocal evidence that systemic treatment, either by anti-oestrogens or chemotherapy, significantly prolongs survival in women with symptomatic disease.5-7Mammographic screening can detect cancer of the breast in its preclinical phase (ie, before it is palpable). The success of screening depends in part on the size of the tumour and whether the cancer has spread to the axillary lymph nodes, but the tumour's biological aggressiveness also needs to be taken into account. The excision of small tumours which are markedly undifferentiated may save lives in the short term, but it is the detection of small tumours while still of favourable grade which is likely to confer the greatest long term benefit. Evidence for screening Evidence that mammographic screening reduces mortality comes from randomised trials comparing mortality from breast cancer of women invited to be screened with women without any intervention. Recent meta-analyses have demonstrated a mortality benefit approaching 30% in women over 50 years of age seven to nine years from the start of the trials.8,9 In the 70% of women who accepted the invitation, mortality reduction is obviously larger. The 14-year follow-up of one of these six randomised trials,10 initiated in Edinburgh in 1978 and including over 22 000 women, indicated a reduction in breast cancer deaths of 21% (relative risk [RR], 0.79; 95% CI, 0.60-1.02), which bordered on significance. As patients diagnosed with breast cancer after the conclusion of the trial (when both study and control groups were eligible for screening) could not have influenced the mortality rate, a further analysis was performed with patients censored 10 years after entry. The 29% mortality reduction was significant (RR, 0.71; 95% CI, 0.53-0.95), and this mortality advantage was no less in women 45-50 years of age than in older women.10 Screening programs In the NHS Breast Screening Programme in the United Kingdom, the need for quality at every stage of the screening process has been emphasised, and national coordinators and regional advisory committees publish annual reports which include regularly revised targets against which performance can be measured (Boxes 1 and 2).11Australia's program, BreastScreen, which began in 1991, has a different design and less standardisation than in the UK program, largely because Australian general practitioners and surgeons work as independent providers. Women aged 50-69 years are eligible for two-yearly screening, but younger women, 40-50 years, and those over 70 years are screened on request. Women in the target group are invited to take part by direct mailouts based on the electoral roll, and 1996-1997 compliance rates were 52.2%.2 Two-view mammography is used, and double reading of mammograms is mandatory. However, the experience of radiologists reading mammograms, the protocols for assessment of screen-detected lesions, and arrangements for surgical biopsies and their pathological interpretation vary greatly between clinics and between States and Territories. National evaluation is only now under way. Breast self-examination Breast self-examination (BSE) can detect symptomatic breast cancer at an earlier stage, but it does not appear to influence mortality. A recent American Cancer Society study compared 177 602 women who practised BSE during the preceding 13 years with 272 554 women who did not, and found similar breast cancer death rates in the two groups.12 The UK Trial of Early Detection of Breast Cancer (TEDBC)13 involved 300 000 women in eight health districts, two with mammographic screening centres, two where BSE was taught by trained nurses, and four where neither form of intervention was available. At 16 years the relative risk of death from breast cancer in women attending the two screening clinics was reduced by 27% (RR, 0.73; 95% CI, 0.63-0.84), but there was no risk reduction in the two BSE centres (RR, 0.99; 95% CI, 0.87-1.12). Three randomised trials to evaluate the effect of BSE on breast cancer mortality are under way in St Petersburg and Moscow,14 and Shanghai.15 Preliminary results of the Shanghai study, which included over 250 000 women, found a similar incidence and an identical number of breast cancer deaths among BSE subjects and controls.15 BSE has greatly increased biopsy rates, with the number of benign lesions detected in the BSE group being twice those of the controls.15 These findings indicate that women should be aware of their breasts as part of general body awareness and seek medical help when their breasts look or feel abnormal, but the promotion of regular BSE is not justified. Familial breast cancer Some 20% of women with breast cancer report a "family history", but only about 5% are truly familial cancers, with the proportion being greater in women under 45 years at diagnosis (Box 3). Management of screen-detected breast cancer A recent audit of 500 screen-detected invasive cancers treated in Scottish hospitals found that 75% were under 1 cm in size and 70% node negative.30 Mastectomy is not necessarily the best treatment for such cancers; some surgeons believe that local excision alone is appropriate. However, the results of five randomised trials show a high local relapse rate if radiotherapy is not also given (Box 4).31-35 After nine years of follow-up in the US National Surgical Adjuvant Breast Project B-06 (NSABP B-06) trial, the relapse rate reached 43%.36 As these trials included tumours of 2.5-4 cm in size, the need for radiotherapy in small (< 1 cm) tumours of low grade and special histological type is unknown. Some surgeons believe that if tamoxifen is given after local excision radiotherapy can be avoided. The Scottish Conservation Trial, in which all 585 patients were prescribed adjuvant systemic therapy (tamoxifen or CMF [cyclophosphamide-methotrexate-5-fluorouracil]) appropriate to the oestrogen-receptor status of the tumour, indicated that this was not so.35 After six years of follow-up, locoregional relapse rates in the non-irradiated group were 24.5%, compared with 5.8% in those irradiated. This does not mean that no patients can safely be treated by local excision alone, but that more precise methods of selection are required before this can be recommended. A number of factors affect relapse rates after local excision and radiotherapy. These include tumour size, the extent of an in-situ component and histological grade. However, the need for complete excision with "clear margins" overrides other considerations, and it is essential that surgeons ensure accurate margin assessment. Biopsy of the excision cavity (cavity shavings) is reported to increase the accuracy of margin assessment.37 The axilla Some surgeons still perform complete dissection of the axilla for all invasive breast cancers; others advise routine radical radiotherapy. Neither approach is logical; an uninvolved axilla needs no treatment. Trials in Edinburgh have shown that sampling fewer axillary nodes (four nodes) provides adequate information on axillary node status, but, as this requires exposure of the axilla under general anaesthesia, it is appropriate only if radiotherapy is the preferred treatment for the involved axilla.38-40For staging the axilla, sentinel node biopsy is under intensive study. The sentinel node or nodes, the first node to which lymph drains from the tumour, can be marked by injecting blue dye or a radioactive marker around the breast tumour.41,42 With the former, visualisation of the axillary contents is necessary, but a radioactive marker allows precise identification of the sentinel node in the operating room with a hand-held gamma probe. The node can be removed with minimal disturbance to other tissues. Some surgeons advocate immediate examination by frozen section, and, if the sentinel node is shown to be involved, a full axillary dissection can proceed. However, frozen section examination is less accurate for node assessment,43 and histopathological examination of the suspected node is preferred practice. If the node can be identified by radionuclear scanning, it can be removed under local anaesthesia before final treatment is planned. Cytokeratin immunostaining improves the accuracy of detection of metastases, but is not appropriate for peroperative assessment. Many surgeons are already practising sentinel node biopsy, but, as recently stressed, the definition of a best method and its evaluation under controlled conditions is required before sentinel node biopsy can be regarded as an acceptable alternative to axillary sampling or clearance.44,45 Systemic therapy Despite evidence that ovarian ablation, tamoxifen and chemotherapy appropriate to the oestrogen-receptor status of the tumour increases this benefit, most surgeons do not advise adjuvant systemic therapy in small node-negative tumours.5-7 Yet, a small proportion of these are still aggressive and cause rapid death. There is a need for tumour markers which can predict likely outcomes for these small tumours; in the meantime, histological grade (as used in the Nottingham Prognostic Index), oestrogen-receptor status and possibly expression of C-erb B2 (HER-2) are the only markers routinely available.46The Nottingham Prognostic Index,47 which combines the size and histological grade of the tumour with the status of the axillary lymph nodes, has been validated in several studies as a reliable prognostic indicator in symptomatic breast cancer.48This Index has also been applied to predict mortality differences in the UK randomised trial of frequency of screening,49 but in a recent study of its application to the Edinburgh randomised trial of screening we have found that the inclusion of more detailed discrimination of size and also of histological type improves prediction in screen-detected cancers (Dr T J Anderson, Pathologist, Department of Pathology, University of Edinburgh, personal communication). Ductal carcinoma in situ (DCIS) Mammographic screening detects an increased number of cases of DCIS,11 but the natural history of the disease is not well understood. In an extensive review of 11 760 excisional breast biopsies performed for accepted benign conditions, 28 DCIS were identified for which a 24-year follow-up was available.50 Invasive breast cancer developed in nine of the 28 patients (32%). However, all were of favourable (non-comedo) type and had been excised, although the completeness of the excision was unknown. These figures may underestimate the true risk in those with more aggressive comedo-type of disease, but it is clear that there is a need for effective treatment. Some surgeons still advocate mastectomy as the only means of guaranteeing cure, but this can no longer be regarded as best practice for other than extensive disease. In Europe, local excision with radical radiotherapy is the preferred option. Features influencing relapse include size, architecture, the presence or absence of necrosis, and cytological nuclear grade.51 However, the factor of overriding importance is the completeness of surgical excision as indicated by free margins.52 Management options have recently been reviewed,53 and three randomised trials are in progress. The results of two trials (NSABP B-17 and B-24, and EORTC 10853) have been reported, the EORTC trial in abstract only.54,55 In B-17 local excision alone (403 patients) and local excision plus radiotherapy (411 patients) are compared. At a median follow-up time of eight years, local relapse was reported in 104 (25.8%) of the non-irradiated group (53 invasive) versus 47 (11.4%) of the irradiated patients (17 invasive). The EORTC trial, which included 1011 patients, had a similar design. At a median follow-up time of 51 months, the cumulative incidence of ipsilateral local recurrence was reduced in the radiotherapy arm (9% v 16%), this including both non-invasive and invasive cancers.56 Only limited information on the completeness of excision is available.57 In the B-24 trial, of 1804 women with DCIS treated by local excision and radiation, half were randomly allocated to receive tamoxifen 20 mg daily for 5 years and half to receive placebo. At a median follow-up of 74 months in women treated by tamoxifen, the cumulative incidence of recurrent breast cancer in either breast was 8.0%, compared with 12.7% in the placebo group; 3.9% and 6.5%, respectively, were invasive.55 It is essential that, as with small invasive tumours, eligible patients with DCIS are entered into randomised trials so that best management can be determined on scientific grounds. A recent survey of practice by 110 surgeons in the south of England showed that, although all four options of local excision, radiotherapy and tamoxifen were being used electively, only 27% of patients were included in the UK trial which compares them, a lamentable disregard of the need for evidence-based practice.58 The future -- specialised, multidisciplinary services Mammographic screening has increased the complexity of breast cancer management. Women with breast cancer must be aware of these complexities, understand the reliability of diagnostic methods, the safety of breast conservation, reasons for not advising systemic therapy and policies of after-care and support. Only then can they participate in decision making. Their questions can no longer be answered with authority by an individual surgeon, but require multidisciplinary input by radiologists, clinical and medical oncologists and pathologists supported by a breast-care nurse or counsellor. The experience of multidisciplinary assessment within the screening service led to the development of a specialised service in Edinburgh for women with symptomatic breast disease. Initially sited in a small hospital equipped with mammographic and operative facilities, this unit has now been transferred to the large Regional Cancer Centre as the Edinburgh Breast Unit, which, although still having independent diagnostic and inpatient facilities, has ready access to sophisticated diagnostic and treatment methods, including computed tomography and magetic resonance imaging, radiotherapy, chemotherapy and all aspects of supportive care. In the UK, women are coming to expect comprehensive care by breast specialists. In Australia, with its emphasis on provision of healthcare by individual practitioners, as well as problems of distance between the major population centres, such a similar pattern may be more difficult to achieve but is likely to be demanded. Acknowledgements We are grateful to Ms Gil Morton for providing facilities in Melbourne for the initial preparation of this paper; to Mrs Ruby Wood for assistance, and to Professor James Garden and the Hunter Research Fund for support. References Breast cancer screening. Report to Health Ministers of England, Wales, Scotland and Northern Ireland by Working Group chaired by Sir Patrick Forrest, 1987. London: HMSO, 1987. Australian Institute of Health and Welfare. Breast and cervical cancer screening. Canberra: AIHW, 3-27. Brinkley B, Haybittle JL. The curability of cancer. Lancet 1975; 2: 951. Kerr GR, Kunkler IH, Langlands AO, Rodger A. (In)curability of breast cancer: a 30 year report of a series of 3933 cases. Breast 1998; 7: 90-94. Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189-1196. Early Breast Cancer Trialists' Collaborative Group. 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A prognostic index in primary breast cancer. Br J Cancer 1982; 45: 361-366. Balslev I, Axelsson CK, Zedeler K, et al. The Nottingham Prognostic Index applied to 9149 patients from the studies of the Danish Breast Cancer Cooperative Group. Breast Cancer Res Treat 1994; 32: 281-290. Blamey RW, Day N, Young R, et al. The UKCCCR trial of frequency of breast screening. Breast 1999; 8: 215. Page DL, Dupont WD, Rogers LW, et al. Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade carcinoma in situ treated by biopsy only. Cancer 1995; 76: 1197-1200. Delaney G, Ung O, Bilous M, et al. Ductal carcinoma in situ. Part I: Definition and diagnosis. Aust N Z J Surg 1997; 67: 81-93. Silverstein MJ, Poller DN, Waisman JR, et al. Prognostic classification of breast ductal carcinoma in situ. Lancet 1995; 345: 1154-1157. Delaney G, Ung O, Cahill S, et al. Ductal carcinoma in situ. Part II: Treatment. Aust N Z J Surg 1997; 67: 157-165. Fisher B, Dignam J, Wolmark N, et al. 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Authors' details Department of Clinical and Surgical Sciences, University of Edinburgh, and Edinburgh Breast Unit, Western General Hospital, University of Edinburgh, Edinburgh, Scotland. A Patrick M Forrest, Kt, MD, FRCS, FRACS(Hon), Professor Emeritus. Elaine D C Anderson, MD, FRSCEd, Consultant Surgeon and Honorary Senior Lecturer. Reprints will not be available from the authors. Correspondence: Sir Patrick Forrest, 19 St Thomas Road, Edinburgh, EH9 2LR, Scotland, UK. patrick.forrestATed.ac.uk Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> We appreciate your comments. 1: NHS Breast Screening Programme11Program instituted1987Age of women screened50-64 years (younger age under trial) Method of invitationBy personal letterCompliance ratesStrictly monitored (1995-96, 75.8%)Frequency of scanningEvery three years (optimum frequency under trial)Reading of mammogramsBy experienced radiologists only (read minimum of 5000 mammograms per year). Double reading variableQuality assurance/evaluationFor each specialty, regional and national quality assurance groups (including one for monitoring and evaluation) were set up. National coordinators and advisory committees publish annual reports. Strict auditing of clinical and pathological characteristics (size, node status, grade) of screen-detected cancers (Box 2)Data collectionNational Screening Evaluation Unit maintains a database for the whole UK programResearch organisationNational Breast Screening Reseach Committee of the UK Committee for Co-ordination of Cancer Research Back to text 2: Consistency of screening activity in women over 50 years in the UK NHS Screening ProgrammeVariable1995-961994-95Women invited1 517 0331 507 605Acceptance rate75.876.7Total screened1 222 3891 207 316Recalled for assessment62 682 (5.1%)63 925 (5.3%)Breast biopsy6496 (5.3/1000)6334 (5.2/1000)Benign biopsy2472 (2.0/1000)2000 (1.6/1000)Cancers detected6664 (5.4/1000) 6500 (5.4/1000)In situ (% of cancers)19.9%20.0%Invasive < 15 mm (% of cancers)42.1% 40.9% Back to text 3: Woman with a family history of breast cancer16-20 Genetic mutations: True familial breast cancer may be associated with mutations of BRCA1, causing breast and ovarian cancers and (in men) an increased incidence of cancer of the prostate; BRCA2, predominantly associated with cancer of the breast but also with other epithelial tumours; or p53, causing the rare Li-Fraumeni syndrome. Determining risk: Pedigree analysis is the important first step. In women with more than four family members with a dominant history of breast and ovarian cancer, a mutation of BRCA1 is associated with an 87% risk of either disease. In those with fewer affected family members, penetrance of a mutated gene may be lower, and the risk of breast or ovarian cancer is in the region of 20%-30%. Although breast cancer is more likely to be familial in young women, only a minority have mutations of either gene. In a study of 73 women with breast cancer diagnosed before age 32 years, common mutations of BRCA1 and BRCA2 were detected in only 12% and 2%, respectively.21 Genetic clinics: In the United Kingdom, as in Australia, genetic clinics have been established. In the UK, criteria for referral are based on national guidelines.22 Australian guidelines for genetic clinics, published by the National Breast Cancer Centre, are exemplary and should be stringently followed.23 The genetic service of the screening clinic in Edinburgh offers screening to women whose risk is three times that of the age-specific population risk (a lifetime risk greater than 24%). Screening starts at age 35 years or five years younger than the first index case and includes an annual physical examination and biennial mammographic examination to the age of 40 years; then annual mammography to the age of 50. In families at very high risk, the screening interval is reduced to 18 months in women over 50 years. Genetic testing of blood is currently used only for research. In those with a dominant family history, germline mutations of BRCA1 and BRCA2 are sought from the index case. Prophylactic mastectomy: In a large Mayo Clinic series of 639 women with a family history of breast cancer (214 high risk and 425 moderate risk), prophylactic mastectomy was associated with a reduction in the incidence of breast cancer of at least 90%.24 Modelling of life-years gained suggests that benefit from prophylactic mastectomy depends on age and penetrance of the gene, and women must be made aware of the likely benefits, risks and costs, while recognising that regular mammographic screening is a viable alternative to mastectomy.25 The uncritical use of genetic testing has inherent hazards, such as loss of insurance or employment, psychological distress, risk of prophylactic surgery and disruption of family relationships. Chemoprevention: In the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial, 13 388 women considered to be at increased risk of breast cancer were randomly allocated to receive tamoxifen or placebo. Over a mean follow-up period of four years, 89 women who received tamoxifen developed invasive cancer compared with 175 cases in the placebo group, a reduction of 49%.26 Tamoxifen increased the risk of endometrial cancer, pulmonary embolism and deep vein thrombosis. Unfortunately, the NSABP trial was stopped and women in the control group were given tamoxifen before mortality data were available, but two other trials in Milan and London (which to date have shown no reduction in risk) will provide this.27,28 A large international trial (IBIS) is under way. Raloxifene (a selective oestrogen-receptor modulator), recently reported to decrease the risk of newly diagnosed breast cancer in postmenopausal women with no prior history of breast cancer,29 may also be suitable for chemoprevention in patients at high risk of breast cancer. Back to text 4: Trials of conservative therapy for early breast cancerTrialNumber of patientsFollow-up (years)Tumour size (cm)MarginsNSABP B-06*3118435≤ 4.0ClearToronto328377.6< 4.0ClearMilan335673.25< 2.5WideOrebro Uppsala343815≤ 2.0ClearScottish355856≤ 4.01 cmRelapse in ipsilateral breastTrialNode positiveSystemic therapyRadiotherapyNo radiotherapyNSABP B-06*3135.4%Node positive7.7%27.9%Toronto32NoneNone11.3% 35.2%Milan3330.5%Node positive0.3%10.2%Orebro-Uppsala34NoneNone2.3%18.4%Scottish3522.9%All5.8%24.5% *National Surgical Adjuvant Breast Project (B-06). Back to text

Lessons from Practice Childhood hepatotoxicity with paracetamol doses less than 150 mg/kg per day MJA 1999; 171: 497 Paracetamol is widely used as an antipyretic and analgesic. Adverse effects are regarded as unlikely at doses below 150 mg/kg per day.1 However, lower doses have resulted in hepatotoxicity,2 and there is growing evidence of the potential for hepatotoxicity in children given multiple therapeutic or supratherapeutic doses of paracetamol.3-6The nomogram devised by Rumack and Matthews7 was based on data obtained from previously well adult patients who had taken a single large dose of paracetamol. The relevance of this to children given multiple doses in the context of a febrile illness is unknown, particularly as the metabolism in this population appears to be quite different.8 It has been suggested that the therapeutic index for paracetamol may be as low as 1.7,9 and that sick children under the age of two years given in excess of 90 mg/kg per day for more than one day should be regarded as being at higher risk.6 The product information recommends a maximum daily dose of 60 mg/kg, but it is not uncommon for children to receive doses in excess of 90 mg/kg per day in the hospital setting.10 Although the number of reported cases of hepatotoxicity induced by therapeutic doses of paracetamol is small, it is possible that cases have gone unrecognised. It is important to administer the drug with caution and according to current dosage guidelines. Case reports Case 1: Six days before transfer to our hospital, a previously well four-year-old, 20 kg girl had commenced a course of cefaclor for otitis media, and over 72 hours she received about 2400 mg of paracetamol in divided doses. She was admitted to her local hospital with fever (39ºC), abdominal pain, vomiting and diarrhoea. Her aspartate transaminase (AST) level was 2050 U/L (normal range, < 45 U/L). She was tachypnoeic and hypoxic, and over the next 17 hours received 2800 mg (140 mg/kg) paracetamol. Her condition deteriorated. Results of liver function tests were: AST, 4580 U/L (Figure A); alanine transaminase, 2785 U/L (normal range, < 55 U/L); and serum bilirubin, 27 µmol/L (normal range, < 15 µmol/L). The international normalised ratio of prothrombin time was 4.2, and activated partial thromboplastin time, 47 s (control, < 42 s). Left lower lobe pneumonia was diagnosed, and treatment commenced with fresh frozen plasma, vitamin K, and antibiotics. The AST level rose to 11 475 U/L. The paracetamol level 22 hours after the last documented dose of the drug was 55 µmol/L. N-acetylcysteine (150 mg/kg) was administered intravenously. After the child was transferred to our hospital, intravenous N-acetylcysteine was continued (10 mg/kg/h for 32 h). Abdominal ultrasound revealed a large homogeneous liver and a small amount of ascites. Serology for hepatitis A and B, Epstein-Barr virus, cytomegalovirus and Mycoplasma pneumoniae was negative. Respiratory syncytial virus was detected in a nasopharyngeal aspirate. Blood cultures were negative. Stool examination revealed no viral agent. The patient was discharged after seven days, with an AST level of 171 U/L. Three months later she was completely well, with normal liver function tests. Case 2: A 12-year-old, 43 kg boy with Duchenne's muscular dystrophy was admitted for posterior spinal fusion and tendon-release surgery. He was anaesthetised using propofol and nitrous oxide, and during the operation required transfusion for a one-litre blood loss. He returned to the ward on a morphine infusion (20 µg/kg/h) and cephazolin (1 g eight-hourly). Over the next 24 hours he received a total dose of 3000 mg (70 mg/kg) paracetamol rectally. Similar total doses were given over the next five days, with a maximum of 4650 mg (108 mg/kg) in any 24-hour period. Liver function tests taken the day after surgery revealed an AST level of 193 U/L (Figure B) and a gamma-glutamyl transpeptidase (GGT) level of 43 U/L (normal range, < 40 U/L). He developed paralytic ileus 48 hours after surgery; this resolved with intravenous hydration. On day seven, he became irritable and disoriented and was pale, icteric and lethargic. Results of investigations were: serum bilirubin, 120 µmol/L; GGT, 68 U/L; AST, 7377 U/L; and ammonia, 88 µmol/L (normal range, < 50 µmol/L). His serum paracetamol level was 528 µmol/L. The haemoglobin level was 68 g/L and he received two units of packed cells. Serology for hepatitis B and C was negative. The paracetamol level was 206 µmol/L 34 hours after the last dose, but, as the liver enzyme levels were falling and the child's conscious state improving, N-acetylcysteine was not administered. He was discharged 22 days after surgery with an AST level of 113 U/L. Back to text Jenny L Hynson,* Mike South** * Consultant Paediatrician ** Associate Professor, and Director Department of General Paediatrics, Royal Children's Hospital Flemington Road, Parkville, VIC 3052 Rumack BH. Acetaminophen overdose in young children. Am J Dis Child 1984; 138: 428-433. Schoidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with therapeutic intent [editorial]. J Pediatr 1998; 132: 5-8. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol 1991; 32: 143-149. Heubi JE, Bien JP. Acetaminophen use in children: more is not better [editorial]. J Pediatr 1997; 130: 175-177. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106.