Minilaparoscopy for Early Diagnosis of Cirrhosis: Is the Endoscopist’s Eye Better than the Histopathologist’s?

In this issue of Endoscopy, Helmreich-Becker and colleagues present a study analyzing the sensitivity of minilaparoscopy for diagnosing the early stages of liver cirrhosis. Minilaparoscopy examinations were conducted prospectively in 226 consecutive patients with chronic liver disease [1]. Cirrhosis was assessed macroscopically on the basis of nodularity in nontumorous liver. At the same time, liver biopsy material was obtained, and staging was carried out by an experienced pathologist using the Ishak-Knodell scoring system [2]. The biopsy material was inadequate in 22 of the 226 patients. In 16 of these 22 patients, the diagnosis of cirrhosis was made by the endoscopist. In 44 % (94 of the remaining 204 patients), the diagnosis of cirrhosis was established macroscopically based on the visual impression observed by the endoscopist. However, stage 5 or 6 fibrosis (incomplete or complete cirrhosis) was only found in 68 of the 204 liver biopsies (33 %). By contrast, a histological diagnosis of cirrhosis was reached in the absence of macroscopically evident cirrhosis in only four of the 204 patients (2 %).

The authors conclude that in comparison with percutaneous liver biopsies alone, macroscopic evaluation of liver disease using minilaparoscopy increases the sensitivity for the detection of liver cirrhosis, particularly in the early Child A stage of liver disease. The difference in sensitivity is reported to be 30 %. In view of the minimal invasiveness of minilaparoscopy and the higher sensitivity for diagnosing Child A cirrhosis, this method thus appears to be superior for the staging of chronic liver disease.

This group of investigators was the originator of the technique of minilaparoscopy, and have published what is, so far as we are aware, the largest series to date. The use of laparoscopy to diagnose liver disease has established itself mainly in continental Europe, while laparoscopy is rarely used for the diagnosis of liver disease in other areas of the world, including North America, Australia, and the United Kingdom. The hypothesis underlying the approach is that more sensitive diagnosis of the earliest stages of liver cirrhosis may have a clinical impact on the management of patients, particularly those with chronic hepatitis C. In patients with hepatitis C, it has been shown that cirrhotic patients have a reduced sustained virological response in comparison to those without cirrhosis [3] [4] [5] [6].

There are several aspects that require closer attention. It is certainly a significant advantage that new laparoscopic equipment has become available that reduces the risks associated with laparoscopy. The main differences are that the penetrating trocar has been reduced to a diameter of 2 mm, compared to the previous 10 mm, and that the same abdominal wall incision is used to create the pneumoperitoneum and insert the laparoscope. While macroscopic evaluation of the liver surface through the 2-mm laparoscope is apparently as good as observation using the earlier 10-mm laparoscope, the reduced invasiveness does not seem to be associated with a reduction in the diagnostic yield. Less invasiveness also means that less gas insufflation is needed and that there are fewer cardiopulmonary complications. In addition, using a smaller trocar to introduce the laparoscope means fewer complications due to injury to abdominal vessels and organs. However, the results of liver biopsy and histopathology depend on the biopsy size and thus on the size of the biopsy needle. The Silverman biopsy needle is no different from the biopsy needle used in conventional laparoscopy. A significant percentage of the complications occurring with conventional laparoscopy are due to the liver biopsy itself.

Some additional issues also arise:

The superiority of minilaparoscopy in terms of invasiveness, complication rates, and diagnostic yield has not yet been evaluated prospectively and compared with conventional laparoscopy, which represents the gold standard. The historical controls are from studies undertaken several decades ago, and the reported complication rates were already very low 7 8. However, subjective quality-of-life assessments were not included in these early studies. In both the present and previous studies, modern ultrasound technology was not used in the diagnostic work-up of chronic liver disease. The percentage of liver cirrhosis in this series, which reached 46 % in 204 patients, is very high. It is unusual for 50 % of consecutive liver biopsies to result in the diagnosis of cirrhosis, and a selection bias must be assumed here. It is possible that a high percentage of the laparoscopies were carried out as follow-up investigations, rather than for an initial liver biopsy in the first-line diagnosis and classification of chronic liver disease. The macroscopic diagnosis of liver disease due to laparoscopy is not standardized. In this study, it was carried out by two experienced endoscopists. There is a high level of interobserver variation in the histological staging of liver diseases 5. The grading and staging of chronic liver disease using histopathology is much better defined and also internationally accepted 2 9 10 11. The major concern here is the clinical usefulness of a higher sensitivity for the diagnosis of Child A liver cirrhosis. Patients with chronic hepatitis, particularly hepatitis C patients, are treated in the early stages of cirrhosis, despite the lower response rates. This finding does not therefore help in the decision-making process regarding whether or not to treat, or how to treat, the individual patient. This decision is based on clinical, biochemical, virological, and histological grounds. Liver biopsy is no longer generally accepted as a prerequisite for treatment in patients with chronic liver disease. However, the authors of this editorial do not share this opinion.

One of the most experienced liver histopathologists, who has served as the central pathologist for many of the important and pivotal registration trials on the treatment of chronic hepatitis C [3] [4] [5], considers that the scoring systems [9] used for staging and grading of liver disease have been developed to evaluate the efficacy of new treatments in multicenter trials, rather than for analyzing individual biopsies from individual patients in order to make individual treatment decisions (Goodman, personal communication). In one of the large recent trials on the treatment of chronic hepatitis C with the combination of pegylated interferon and ribavirin, stratification was carried out on the basis of hepatitis C genotype and a diagnosis of liver cirrhosis by the local histopathologist at each of the 62 participating centers [5]. Overall, the local histopathologists at the individual centers diagnosed cirrhosis in 10 % of the 1530 patients entering the study. At the end of the study, the central pathologist (Z.G.) analyzed the blinded pretreatment and posttreatment biopsies. Interestingly, he diagnosed liver cirrhosis in 20 % of all patient biopsies obtained before treatment. If the grading and staging of liver disease using standardized histopathology criteria [2] [9] differ by 100 % between local histopathologists and a central pathologist, one can only guess what the interobserver variation may be when early liver cirrhosis is assessed using the endoscopist’s eye at minilaparoscopy. When minilaparoscopy has become a widely used procedure, standardization of the diagnostic images produced using minilaparoscopy will become essential. One problem frequently debated in connection with liver biopsies in patients with liver cirrhosis is that of sampling error, as a “blind” liver biopsy may capture tissue from regenerative nodules that shown noncirrhotic liver histopathology. If this is to be avoided, the biopsy needle needs to be guided by the endoscopist’s eye to target representative areas of the liver. The authors do not mention whether the location of the biopsy was standardized, or whether it was targeted in accordance with the endoscopist’s subjective judgment of the appearance of the liver surface.

We are convinced that minilaparoscopy ought to replace conventional “macrolaparoscopy,” even though it has not yet been scientifically confirmed that minilaparoscopy is associated with fewer complications, or that it is a more acceptable procedure for the patient. Perhaps such confirmation will not be necessary. However, the higher sensitivity for diagnosing Child A cirrhosis has no implications for the management of chronic viral hepatitis patients, since all patients are treated once liver biopsy has confirmed significant activity and/or fibrosis. It might be asked what is the point of achieving a higher sensitivity with minilaparoscopy for diagnosing the early stages of liver cirrhosis. It can be presumed that the value of the method will lie more in the area of diagnosing or excluding liver tumors, other abdominal tumors, and peritoneal carcinosis. Examples of situations in which the technique could prove useful might be: patients with known liver cirrhosis and increasing α₁-fetoprotein levels; patients with primary sclerosing cholangitis who develop cholangiocellular carcinoma; and assessing patients for liver transplantation or the planning of nonsurgical treatment.

References

• 1 Helmreich-Becker I, Schirmacher P, Denzer U. et al . Minilaparoscopy in the diagnosis of cirrhosis: superiority in patients with Child-Pugh A and macronodular disease.  Endoscopy. 2003;  35 55-60
• 2 Ishak K, Baptista A, Bianchi L. et al . Histological grading and staging of chronic hepatitis.  J Hepatol. 1995;  22 696-699
• 3 Poynard T, Marcellin P, Lee S S. et al . Randomised trial of interferon alfa-1b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.  Lancet. 1998;  352 1426-1432
• 4 McHutchison J G, Gordon S C, Schiff E R. et al . Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.  N Engl J Med. 1998;  339 1485-1492
• 5 Manns M, McHutchison J G, Gordon S C. et al . Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 958-965
• 6 Heathcote E J, Shiffman M L, Cooksley W G. et al . Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.  N Engl J Med. 2000;  343 1673-1680
• 7 Vido I, Wildhirt E. Korrelation des laparoskopischen und histologischen Befundes bei chronischer Hepatitis und Leberzirrhose.  Dtsch Med Wochenschr. 1969;  94 1633-1637
• 8 Henning H, Look D. Komplikationen. In: Henning H, Look D, editors. Laparoskopie. Atlas und Lehrbuch. Stuttgart; Thieme 1985: 32-46
• 9 Godmann Z D, Ishak K G. Histopathology of hepatitis C virus infection.  Semin Liv Dis. 1995;  15 70-81
• 10 Desmet V J, Gerber M, Hoofnagle J H. et al . Classification of chronic hepatitis: diagnosis, grading and staging.  Hepatology. 1994;  19 1513-1520
• 11 Knodell R G, Ishak K G, Black W C. et al . Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.  Hepatology. 1981;  1 431-435