Adrian Lim

Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C

Background and aims: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. Materials and methods: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F ⩽2/6, NI ⩽3/18), moderate/severe hepatitis (3 ⩽F <6 or NI ⩾4), and cirrhosis (F = 6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. Results: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. Conclusion: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Quantitative contrast-enhanced ultrasound imaging: a review of sources of variability

Ultrasound provides a valuable tool for medical diagnosis offering real-time imaging with excellent spatial resolution and low cost. The advent of microbubble contrast agents has provided the additional ability to obtain essential quantitative information relating to tissue vascularity, tissue perfusion and even endothelial wall function. This technique has shown great promise for diagnosis and monitoring in a wide range of clinical conditions such as cardiovascular diseases and cancer, with considerable potential benefits in terms of patient care. A key challenge of this technique, however, is the existence of significant variations in the imaging results, and the lack of understanding regarding their origin. The aim of this paper is to review the potential sources of variability in the quantification of tissue perfusion based on microbubble contrast-enhanced ultrasound images. These are divided into the following three categories: (i) factors relating to the scanner setting, which include transmission power, transmission focal depth, dynamic range, signal gain and transmission frequency, (ii) factors relating to the patient, which include body physical differences, physiological interaction of body with bubbles, propagation and attenuation through tissue, and tissue motion, and (iii) factors relating to the microbubbles, which include the type of bubbles and their stability, preparation and injection and dosage. It has been shown that the factors in all the three categories can significantly affect the imaging results and contribute to the variations observed. How these factors influence quantitative imaging is explained and possible methods for reducing such variations are discussed.

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

BACKGROUND Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. AIM The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. METHODS We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. RESULTS On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. CONCLUSION Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study.

Background: A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. Aim: To see if this index can also grade diffuse liver disease. Patients: Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child’s A, seven Child’s B, and eight Child’s C). Methods: Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase >10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. Results: Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child’s A 21 (1) s, Child’s B 16 (3) s, and Child’s C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child’s A 8 (1) s, Child’s B 4 (4) s, and Child’s C 3 (3) s. These differences were highly significant (p<0.001, ANOVA comparison). A HVTT <24 s and a CDT <10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values <10 s and 3/9 had HVTT <24 s. Conclusion: This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.

Assessing the Validity of an Abdominal CT Scoring System in the Diagnosis of Encapsulating Peritoneal Sclerosis

BACKGROUND AND OBJECTIVES Encapsulating peritoneal sclerosis (EPS) is a severe peritoneal fibrotic reaction in patients on long-term peritoneal dialysis (PD). The early clinical features may be nonspecific. The purpose of the study is to assess the reliability and diagnostic utility of abdominal CT scanning in the diagnosis of EPS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Abdominopelvic CT scans of 27 patients diagnosed with EPS on clinical and radiologic grounds in our unit from 1997 to 2006 were retrospectively analyzed. In addition, 35 control CT scans were scored: 15 from hemodialysis patients (HD controls) and 20 from patients on PD (PD controls). Scans were anonymized and scored independently by three radiologists. RESULTS Inter-rater agreement was moderate to very good (kappa = 0.40 to 0.75) for peritoneal calcification, bowel distribution, bowel wall thickening, and bowel dilation but poorer for loculation of ascites and peritoneal thickening. There was a strongly significant difference between the total CT scan scores at EPS diagnosis and controls (P < 0.00001). Each individual parameter also showed significant differences between EPS and controls (P < 0.006). Bowel tethering and peritoneal calcification were the most specific parameters, and. loculation was the least discriminatory parameter. Interestingly, prediagnostic scans a median of 1.5 yr before EPS diagnosis were normal or near-normal in 9 of 13 EPS patients. CONCLUSIONS CT scanning is a valid and reliable adjunct to the diagnosis of EPS but may not be useful as a screening tool, as the prediagnostic scans did not show abnormalities in many patients who subsequently developed EPS.

Twice‐Weekly Administration of Kisspeptin‐54 for 8 Weeks Stimulates Release of Reproductive Hormones in Women With Hypothalamic Amenorrhea

Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin‐54 (KP‐54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), a commonly occurring condition characterized by absence of menstruation; however, twice‐daily administration of KP‐54 results in tachyphylaxis. We determined the time course of desensitization to twice‐daily KP‐54 injections, compared the effects of twice‐daily and twice‐weekly administration regimens of KP‐54, and studied the effects of long‐term twice‐weekly administration of KP‐54 on the release of reproductive hormones in women with HA. When KP‐54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle‐stimulating hormone (FSH) was nearly abolished by day 2. Twice‐weekly KP‐54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice‐daily administration. Women with HA who were treated with twice‐weekly KP‐54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP‐54 on the release of reproductive hormones in women with HA.

Incidental findings in healthy control research subjects using whole-body MRI

AIM Magnetic resonance imaging (MRI) is a powerful clinical tool used increasingly in the research setting. We aimed to assess the prevalence of incidental findings in a sequential cohort of healthy volunteers undergoing whole-body MRI as part of a normal control database for imaging research studies. MATERIALS AND METHODS 148 healthy volunteers (median age 36 years, range 21-69 years; 63.5% males, 36.5% females) were enrolled into a prospective observational study at a single hospital-based MRI research unit in London, UK. Individuals with a clinical illness, treated or under investigation were excluded from the study. RESULTS 43 (29.1%) scans were abnormal with a total of 49 abnormalities detected. Of these, 20 abnormalities in 19 patients (12.8%) were of clinical significance. The prevalence of incidental findings increased significantly with both increasing age and body mass index (BMI). Obese subjects had a fivefold greater risk of having an incidental abnormality on MRI (OR 5.4, CI 2.1-14.0). CONCLUSIONS This study showed that more than one quarter of healthy volunteers have MR-demonstrable abnormalities. There was an increased risk of such findings in obese patients. This has ethical and financial implications for future imaging research, particularly with respect to informed consent and follow-up of those with abnormalities detected during the course of imaging studies.

A comparison of the diagnostic accuracy of MARS MRI and ultrasound of the painful metal-on-metal hip arthroplasty.

Background and purpose — Metal artifact reduction sequence (MARS) MRI and ultrasound scanning (USS) can both be used to detect pseudotumors, abductor muscle atrophy, and tendinous pathology in patients with painful metal-on-metal (MOM) hip arthroplasty. We wanted to determine the diagnostic test characteristics of USS using MARS MRI as a reference for detection of pseudotumors and muscle atrophy. Patients and methods — We performed a prospective cohort study to compare MARS MRI and USS findings in 19 consecutive patients with unilateral MOM hips. Protocolized USS was performed by consultant musculoskeletal radiologists who were blinded regarding clinical details. Reports were independently compared with MARS MRI, the imaging gold standard, to calculate predictive values. Results — The prevalence of pseudotumors on MARS MRI was 68% (95% CI: 43–87) and on USS it was 53% (CI: 29–76). The sensitivity of USS in detecting pseudotumors was 69% (CI 39–91) and the specificity was 83% (CI: 36–97). The sensitivity of detection of abductor muscle atrophy was 47% (CI: 24–71). In addition, joint effusion was detected in 10 cases by USS and none were seen by MARS MRI. Interpretation — We found a poor agreement between USS and MARS MRI. USS was inferior to MARS MRI for detection of pseudotumors and muscle atrophy, but it was superior for detection of joint effusion and tendinous pathologies. MARS MRI is more advantageous than USS for practical reasons, including preoperative planning and longitudinal comparison.

The Efficacy of Axillary Ultrasound in the Detection of Nodal Metastasis in Breast Cancer

OBJECTIVE Recent reports indicate a lack of survival benefit for axillary lymph node dissection (ALND) versus sentinel lymph node biopsy in early breast cancer. To study this issue further, we assessed the accuracy and effectiveness of ultrasound examination in detecting axillary nodal involvement in breast cancer patients with the aim of refining our current clinical pathways. MATERIALS AND METHODS Ultrasound data were collected from breast cancer cases over 3 years. Images were reviewed by experienced radiologists and the following characteristics were assessed: size, morphology, hyperechoic hilum, and cortical thickness of the ipsilateral axillary nodes. The findings were correlated with histologic outcomes after ALND. RESULTS Two hundred twenty-four cases were included in the analysis, 113 (50.4%) of which had evidence of metastatic nodal involvement at final histology. Of these 113 cases, ultrasound findings for 59 (52.2%) were positive. The overall positive predictive value of ultrasound for detecting metastatic nodal involvement measured 0.81. The negative predictive value was 0.60. The sensitivity was 53.7%; specificity, 85.1%; and accuracy, 67.9%. The ultrasound morphologic lymph node features with the greatest correlation with malignancy were the absence of a hyperechoic hilum (p = 0.003) and increased cortical thickness (p = 0.03). Patients with a metastatic nodal burden density of at least 20% were more likely to have abnormal findings on axillary ultrasound examination (p = 0.009). CONCLUSION Axillary ultrasound has a low negative predictive value and negative ultrasound results do not exclude axillary node metastases with sufficient sensitivity to justify its routine clinical use. Clinical pathways need to consider an evidence-based approach, focusing on the criteria by which we select breast cancer patients for ALND.

CT Angiography of Inferior Epigastric and Gluteal Perforating Arteries before Free Flap Breast Reconstruction

Muscle-sparing perforator free flap breast reconstruction with the use of an inferior epigastric or gluteal perforating artery to create a vascular pedicle is increasingly popular because it obviates breast implants and results in lower donor site morbidity than breast reconstruction with myocutaneous flaps. The tissue harvesting procedure for a perforator free flap involves dissecting the subcutaneous fat of the anterior abdominal wall or the buttock to locate and visually evaluate the perforating arteries so as to decide which one is most suitable for the vascular pedicle. The vessel selected depends on multiple anatomic and surgical considerations, and the decision-making process can be exceptionally time-consuming, in part because of the wide variation that occurs in vascular anatomy. Preoperative imaging can greatly improve the efficiency of the selection process. Doppler ultrasonography (US) is the most frequently used modality for vascular mapping, but the results are mixed because most perforating arteries have a diameter of less than 15 mm, the threshold for reliable visualization with US. A computed tomographic (CT) angiographic evaluation performed with the use of specific postprocessing and display techniques may be more accurate for identifying the most suitable vessel. CT angiography provides valuable information that can help optimize surgical planning, decrease time spent in the operating room, and improve the outcome of breast reconstruction surgery.