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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Background : Recently, biliary sludge has been strongly correlated with ‘idiopathic pancreatitis’. It is often diagnosed by trans-abdominal ultrasonography, despite the low sensitivity of this investigation. New scanners, using second harmonic imaging, may improve the quality of the echographic picture.

Aim : To verify the impact of this methodology on the detection of biliary sludge in patients with ‘idiopathic’ pancreatitis.

Methods : Fifty patients with ‘idiopathic’ pancreatitis observed over a 18-month period entered the study. Exclusion criteria were gall-bladder stones, polyps, clinical conditions related to biliary sludge development and haemolytic disorders. Patients were assessed blind by two operators using either conventional ultrasonography or second harmonic imaging. The parameters of diagnostic quality of both examinations were evaluated using, as the gold standard, microscopic examination of the gall-bladder content collected at endoscopy after cholecystokinin infusion.

Results : An improvement in sensitivity, specificity, efficiency and negative predictive value was obtained by second harmonic imaging compared with conventional ultrasonography.

Conclusions : Second harmonic imaging, in our experience, is a reliable non-invasive tool for the diagnosis and follow-up of biliary sludge in the course of ‘idiopathic’ pancreatitis.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Biliary sludge represents a clinical entity first described in 1979 by Conrad et al.1 It is defined as a mixture of particulate matter and bile due to solute precipitation.2 The chemical composition is variable, although it is most commonly composed of cholesterol monohydrate crystals, calcium bilirubinate granules, other calcium salts and gall-bladder mucus.3 Clinically, its course may be characterized by spontaneous resolution, long-term persistence or progression to gallstones.4–7 The persistence of biliary sludge may be asymptomatic, or responsible for biliary colic in about 10% of patients and acalculous cholecystitis or acute pancreatitis in a smaller percentage.8–10

Recent evidence has shown that ‘idiopathic’ pancreatitis, a clinical condition characterized by recurrent episodes of acute pancreatic inflammation without an evident known cause, is associated with biliary sludge in 75–90% of patients when detected by microscopy of bile sediment and/or endoscopic ultrasonography.11–14

The diagnosis of biliary sludge is most often performed by trans-abdominal ultrasonography. However, this investigation has a low sensitivity, and only microscopic examination of the gall-bladder content can lead to a definite diagnosis.15 Nevertheless, the quality of the echographic picture and the consequent diagnosis may be improved by new ultrasound scanners.16 In particular, innovative technological systems which use second harmonic imaging have been successfully employed for some pathological conditions, such as hepatic neoplasms17–19 and cardiovascular disorders.20–22

In this paper, we report the results of a multicentre study performed to verify the impact of second harmonic imaging ultrasonography on the diagnosis of biliary sludge in patients with ‘idiopathic’ pancreatitis.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Fifty patients (14 males and 36 females; mean age, 51.3 ± 8.7 years; range, 46–60 years), affected by ‘idiopathic’ pancreatitis as defined according to well-established criteria,14 were enrolled. All were referred between January 2000 and June 2001 to four Gastroenterology Units located in southern Italy. The study was performed during a phase of clinical and biochemical remission of the disease. In detail, clinical remission was defined as absent or minimal symptoms, and biochemical remission as a serological lipase value no higher than double the normal level.

Patients with gall-bladder stones or polyps and those affected by clinical conditions specifically related to biliary sludge development (i.e. pregnancy, rapid weight loss, critical illness, prolonged fasting, administration of total parenteral nutrition, ceftriaxone or octreotide, recipients of bone marrow or solid organ transplantation) were excluded, as were those with haemolytic disorders.

Diagnosis of biliary sludge

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

The diagnosis of biliary sludge was performed in all subjects by microscopic examination of the gall-bladder content, i.e. the bile collected at oesophago-gastro-duodenoscopy after cholecystokinin infusion, according to the protocol described by Ko et al.15 In detail, patients underwent endoscopy and aspiration of the duodenal content 10 and 20 min after infusion of cholecystokinin at a dose of 0.1 mg/kg body weight intravenously over a period of 10 min. Endoscopy was performed by a single investigator in all patients (VDF). Aspirate samples were centrifuged at 3000 g for 15 min and the sediment was frozen to avoid false positive results due to solute precipitation. Freezing was necessary as bile examination was performed for all patients exclusively in one of the four units involved in the study (Bari). In detail, the sediment was transferred to a glass slide with a drop of distilled water and examined blind under light microscopy by two investigators (EI and MM).

Therapeutic indications

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Patients with positive bile sediment examination received the following therapeutic indications: (i) cholecystectomy when biliary sludge was composed of cholesterol monohydrate and calcium bilirubinate; (ii) ursodeoxycholic acid administration when only cholesterol monohydrate crystals were present.

Ultrasonography

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Enrolled subjects were investigated by trans-abdominal ultrasonography using conventional methods and, successively, by second harmonic imaging (Esaote Hitachi 512 Hse). The investigation was performed exclusively in one centre (Foggia). The acquisition of images was achieved once the optimal scanning plane had been set for each sequence for both ultrasonographic procedures. Two investigators (NM and MN) analysed blind the images recorded by the two methods and then compared their diagnostic judgements. Both used the same examination technique, including turnover manoeuvres of the patients and ‘shaking’ of the gall-bladder to detect echoes otherwise hidden.

Biliary sludge was diagnosed according to well-defined criteria, based on the characteristics of the ultrasound devices,1 only when agreement was reached between the two operators.

Diagnostic quality evaluation

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

The sensitivity, specificity, efficiency and positive and negative predictive values were evaluated for both echographic techniques according to conventional formulae, using microscopic examination of bile sediment as the diagnostic gold standard.

Ethical considerations

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the a priori approval by our institutions' ethical committees.

Before inclusion in the study, written informed consent was obtained from each patient.

Clinical aspects

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

In the 50 patients studied, the clinical aspects in the last 12 months were as follows: (i) one episode of ‘idiopathic’ acute pancreatitis (29 patients); (ii) two episodes of ‘idiopathic’ acute pancreatitis (20 patients); (iii) more than two episodes of ‘idiopathic’ acute pancreatitis (one patient).

Microscopy

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Cholesterol monohydrate crystals were identified in 41 of the 50 patients (80%); calcium bilirubinate granules were found in association in 39 of the 50 patients (78%) and were never found isolated. The typical aspect of the microscopic picture of biliary sludge is illustrated in Figure 1. Cholecystectomy was performed in only 12 of the 39 patients with calcium bilirubinate granules. Both the presence and composition of biliary sludge observed at duodenal aspirate microscopy were confirmed in surgical samples.

image

Figure 1. Microscopic examination of bile sediment. Cholesterol monohydrate crystals (open arrow) appear as polygonal plates. Granules of calcium bilirubinate (filled arrow) appear as reddish-brown clumps (× 400).

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Ultrasonography

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

Conventional ultrasonography allowed the detection of biliary sludge in 29 of the 41 patients who were positive at microscopic examination of bile sediment. In one patient, a false positive finding was observed.

Second harmonic imaging demonstrated a positive finding in 34 of the 41 patients, and no false positive was seen. Second harmonic imaging allowed a clear picture of biliary sludge to be obtained in six patients who were given as negative (four patients) (Figure 2) or doubtful (two patients) at conventional ultrasonography.

image

Figure 2. A false negative picture observed at conventional ultrasonography (right); presence of biliary sludge with second harmonic imaging (left).

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The sensitivity, specificity, efficiency and positive and negative predictive values are reported in Table 1. Increases in sensitivity (8.1%), specificity (10%) and efficiency (8.4%) were obtained by second harmonic imaging. The positive predictive value was very high for both investigations. Moreover, there was an increase in the negative predictive value (42.6%) with second harmonic imaging.

Table 1.  Parameters of diagnostic quality for conventional ultrasonography and second harmonic imaging in patients with biliary sludge
 Conventional ultrasonographySecond harmonic imaging
Sensitivity (%)77.385.4
Specificity (%)90100
Efficiency (%)79.387.7
Positive predictive  value (%)97.6100
Negative predictive  value (%)42.885.4

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References

In this study, we compared two different types of trans-abdominal ultrasonographic technique for the diagnosis of biliary sludge in patients affected by ‘idiopathic’ pancreatitis. This patient selection was based on recent evidence suggesting that this disorder is strongly related to biliary sludge,11–14 and therefore represents an ‘ideal’ model for the detection of this condition. Moreover, the well-known conflicting aspects of echographic diagnosis of biliary sludge stimulated our study. Indeed, although trans-abdominal ultrasonography represents the most common investigation used in clinical practice to reveal biliary sludge, it shows a low sensitivity.11 Second harmonic imaging is an innovative technological system based on the acquisition and processing of ultrasound through its return with a double frequency.23 This technique produces detailed images and, with the improvement of the signal/noise ratio, adulterations and background noise are easily eliminated.24, 25 Second harmonic imaging has shown an improvement of diagnostic accuracy in certain conditions, such as the characterization of hepatic masses (haemangioma, hepatocellular carcinoma, metastases) and the visualization of the endocardial/myocardial morphological details or detection of cardiac thrombi.26, 27

Our study showed a sensitivity of 77.3% for conventional ultrasonography; this is higher than the values obtained in other series, which report a mean of 55%,15 ranging between 35.7% and 65%.28 The difference between the results of our study and those of other series may be due to the inclusion criteria used. The specificity of conventional ultrasonography did not reach 100% due to a false positive finding. In comparison with the conventional method, second harmonic imaging led to an improvement in both the sensitivity and specificity of the ultrasonographic diagnosis of biliary sludge, reaching values of 90% and 100%, respectively, with a total gain in efficiency of about 10%. Even though the value of sensitivity obtained by second harmonic imaging (85.4%) is lower than that (96%) reported for endoscopic ultrasonography,29, 30 our result has the advantage that it was obtained by a non-invasive investigation.

As expected, the positive predictive value was close to 100% for both ultrasonographic investigations. Moreover, the negative predictive value was significantly higher with second harmonic imaging than with the conventional method; indeed, this parameter was unsatisfactory only for conventional ultrasound scan (42.8%).

In conclusion, second harmonic imaging, in our experience, improves the diagnosis of biliary sludge. The technical explanation for this result is probably the increase in the signal/noise ratio in second harmonic imaging, such that adulterations of the echographic picture are eliminated.24, 25 Therefore, it may be proposed as the most reliable non-invasive diagnostic tool, although microscopic examination of bile sediment remains the definitive investigation as it allows the chemical composition to be determined from the precipitate structure.31 However, this investigation is often difficult to perform in clinical practice, and the availability of a non-invasive test which shows a satisfactory sensitivity and specificity may be helpful. Consequently, our data suggest that second harmonic imaging could be useful, in the future, in patients with biliary sludge for both diagnosis and follow-up. This second aspect may be even more relevant, as accurate follow-up is necessary in some subjects in order to evaluate the progression towards gallstones,32 and to determine the effect of medical treatments on biliary sludge and the prevention of its more dramatic clinical expressions.8 Nevertheless, before firm conclusions can be drawn, studies on larger series of patients are necessary to clearly assess the role of second harmonic imaging in biliary sludge detection. Moreover, the use of this technique in clinical practice needs to be based on an accurate evaluation of its diagnostic accuracy and economic advantages.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Diagnosis of biliary sludge
  7. Therapeutic indications
  8. Ultrasonography
  9. Diagnostic quality evaluation
  10. Ethical considerations
  11. Results
  12. Clinical aspects
  13. Microscopy
  14. Ultrasonography
  15. Discussion
  16. Acknowledgement
  17. References
  • 1
    Conrad MR, Janes JO, Dietchy J. Significance of the low level echoes within the gallbladder. Am J Roentgenol 1979; 132: 96772.
  • 2
    Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology 1986; 90: 67786.
  • 3
    Allen B, Bernhoft R, Blanckaert N, et al. Sludge is calcium bilirubinate associated with bile stasis. Am J Surg 1981; 141: 516.
  • 4
    Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. Gastroenterology 1988; 94: 1706.
  • 5
    Janowitz P, Kratzer W, Zemmler T, Tudyka J, Wechsler JG. Gallbladder spontaneous course and incidence of complications in patients with stones. Hepatology 1994; 20: 2914.
  • 6
    Ohara N, Schaefer J. Clinical significance of biliary sludge. J Clin Gastroenterol 1990; 12: 2914.
  • 7
    Moschowitz M, Min TC, Gavaler JS. The microscopic examination of bile in patients with biliary pain and negative imaging tests. Am J Gastroenterol 1986; 84: 10129.
  • 8
    Ros E, Navarro S, Bru C, Garcia-Puges A, Valderrama R. Occult microlithiasis in idiopathic acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 1991; 101: 17019.
  • 9
    Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med 1992; 326: 58993.
  • 10
    Grier JF, Cohen SW, Grafton WD, Gholson CF. Acute suppurative cholangitis associated with choledocal sludge. Am J Gastroenterol 1994; 89: 6179.
  • 11
    Chebli JM, Ferrari Junior AP, Silva MR, Borges DR, Atallah AN, Das Neves MM. Biliary microcrystals in idiopathic acute pancreatitis: clue for occult underlying biliary etiology. Arq Gastroenterol 2000; 37: 93101.
  • 12
    Frossard JL, Sosa Valencia L, Amouyal G, Marty O, Hadengue A, Amouyal P. Usefulness of endoscopic ultrasonography in patients with ‘idiopathic’ acute pancreatitis. Am J Gastroenterol 2000; 109: 196200.
  • 13
    Perez-Martin G, Gomez-Cerezo J, Codoceo R, et al. Bilirubinate granules: main pathologic bile component in patients with idiopathic acute pancreatitis. Am J Gastroenterol 1998; 93: 3602.
  • 14
    Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med 1992; 326: 6357.
  • 15
    Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Intern Med 1999; 130: 30111.
  • 16
    Seitz K, Merz M. Incidental ultrasound findings of the gallbladder. Schweiz Rundsch Med Prax 1998; 87: 15714.
  • 17
    Wilson SR, Burns PN, Muradali D, Wilson JA, Lai X. Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of haemangioma, hepatocellular carcinoma and metastasis. Radiology 2000; 215: 15361.
  • 18
    Ding H, Kudo M, Maekawa K, Suetomi Y, Minami Y, Onda H. Detection of tumor parenchymal blood flow in hepatic tumors: value of second harmonic imaging with galactose based contrast agent. Hepatol Res 2001; 21: 24251.
  • 19
    Cioni D, Lencioni R, Rossi S, et al. Radiofrequency thermal ablation of hepatocellular carcinoma using contrast enhanced harmonic power Doppler sonography to assess treatment outcome. Am J Roentgenol 2001; 177: 7838.
  • 20
    Kuijer JP, Jansen E, Marcus JT, Van Rossum AC, Hoethaar RM. Improved harmonic phase myocardial strain maps. Magn Res Med 2001; 46: 9939.
  • 21
    Sozzi FB, Poldermans D, Bax JJ, et al. Improved identification of viable myocardium using second harmonic imaging during dobutamine stress echocardiography. Heart 2001; 86: 6728.
  • 22
    Sozzi FB, Poldermans D, Boersma E, et al. Does second harmonic imaging improve left ventricular endocardial border identification at higher heart rates during dobutamine stress echography? J Am Soc Echocardiogr 2000; 13: 101924.
  • 23
    Tranquart F, Grenier N, Eder V, Poucerlot L. Clinical use of ultrasound tissue harmonic imaging. Ultrasound Med Biol 1999; 25: 88993.
  • 24
    Basude R, Wheatley MA. Generation of ultrasoundharmonics in surfactant based ultrasound contrast agents: use and advantages. Ultrasonics 2001; 39: 43744.
  • 25
    Campagnola PI, Millard AC, Terasaki M, Hoppe PE, Malone CJ, Mohler WA. Three dimensional high resolution second harmonic generation imaging of endogenous structural proteins in biological tissues. Biophys J 2002; 82: 493508.
  • 26
    Ono M, Asanuma T, Tanabe K, et al. Improved definition of left atrial thrombus by tissue second harmonic imaging. J Ultrasound Med 1999; 18: 2535.
  • 27
    Swinburn J, Lahiri A, Senior R. Tissue harmonic imaging: a new method for predicting left ventricular thrombus. J Am Soc Echocardiogr 2000; 13: 6801.
  • 28
    Wilkinson LS, Levine TS, Smith D, Chadwick SJ. Biliary sludge: can ultrasound reliably detect the presence of crystals in bile? Eur J Gastroenterol Hepatol 1996; 8: 9991001.
  • 29
    Dahan P, Andant C, Levy P, et al. Prospective evaluation of endoscopic ultrasonography and microscopic examination of duodenal bile in the diagnosis of cholecystolithiasis in 45 patients with normal conventional ultrasonography. Gut 1996; 38: 27781.
  • 30
    Dill JE, Hill S, Berkhouse L, Evans P, Martin D, Palmer ST. Combined endoscopic ultrasound and stimulated biliary drainage in microlithiasis — diagnoses and outcomes. Endoscopy 1995; 27: 4247.
  • 31
    Lee SP, Hayashi A, Kim YS. Biliary sludge: curiosity or culprit? Hepatology 1994; 20: 5235.
  • 32
    Janowitz P, Krayzer W, Zemmler T, Tudyka J, Wechsler JG. Gallbladder sludge: spontaneous course and incidence of complications in patients without stones. Hepatology 1994; 20: 2914.